About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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June 18, 2015

Aging As a Disease

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Posted by Derek

I've mentioned numerous times around here that therapies directed against aging in general have a rough regulatory outlook. The FDA, in general, has not considered aging a disease by itself, but rather the baseline against which disease (increasingly) appears. This has meant that companies with ideas for anti-aging therapies have had to work them into other frameworks - diabetes, osteoporosis, what have you - in order to get clinical data that the agency will be able to work with.

Now, according to Nature News, the group that's testing metformin for a variety of effects in elderly patients is going to meet with the FDA to address just this issue:

Barzilai and other researchers plan to test that notion in a clinical trial called Targeting Aging with Metformin, or TAME. They will give the drug metformin to thousands of people who already have one or two of three conditions — cancer, heart disease or cognitive impairment — or are at risk of them. People with type 2 diabetes cannot be enrolled because metformin is already used to treat that disease. The participants will then be monitored to see whether the medication forestalls the illnesses they do not already have, as well as diabetes and death.

On 24 June, researchers will try to convince FDA officials that if the trial succeeds, they will have proved that a drug can delay ageing. That would set a precedent that ageing is a disorder that can be treated with medicines, and perhaps spur progress and funding for ageing research.

During a meeting on 27 May at the US National Institute on Aging (NIA) in Bethesda, Maryland, Robert Temple, deputy director for clinical science at the FDA’s Center for Drug Evaluation and Research, indicated that the agency is open to the idea.

Metformin and rapamycin are two of the compounds that would fit this way of thinking, and there will surely be more. Let's face it - any other syndrome that caused the sorts of effects that age does on our bodies would be considered a plague. To quote Martin Amis's lead character in Money, who's thinking about an actress he's casting in a movie who "time had been kind to", he goes on to note that "Over the passing years, time had been cruel to nearly everybody else. Time had been wanton, virulent and spiteful. Time had put the boot in." It sure does.

But we're used to it, and it happens to everyone, and it happens slowly. Does it have to be that way? The history of medicine is a refusal to play the cards that we've been dealt, and there's no reason to stop now.

Comments (43) + TrackBacks (0) | Category: Aging and Lifespan | Regulatory Affairs

June 16, 2015

Are Things Really Picking Up?

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Posted by Derek

Is the recent upturn in drug approvals the real thing? Years of overall decline would have to be overcome, but it would be good news if the industry has, in fact, picked back up again. A new article in Nature Reviews Drug Discovery"the ratio of the first 7 years of revenue for all innovative launches in a given year to the corresponding portion of R&D investment over the previous 7 years". So that clears out the fourth-in-a-category stuff, and also uses a reasonable time horizon (which is the big problem with declaring a trend based on only one or two years' worth of drug launch data).

This measure shows that innovative drug approvals reached a peak in the mid-to-late 1990s, followed by a pretty steady decline, bottoming out around 2009-2011. And yes, they do see a slight rise since then, which is good to know. But there are a few factors to keep in mind: (1) this rise still only takes things back to levels that would have been considered awful before 2003 - if this trend is real, it's still got a ways to go. And (2), a good part of the rise in their chart is based on revenue forecasts. If you regard these as over-optimistic and tone them down, there's still a small rise, but only back to, say, 2006 levels.

It's also worth noting the authors' beliefs about where this increased productivity is coming from:

We estimate that ~45% of the productivity improvement comes from slowing growth of, and increasing rationalization in, pharmaceutical R&D spending, and that the remaining ~55% comes from the higher total revenue that is expected from new launches. However, we believe that the more significant driver is the slower growth in spending, as 70–90% of the revenue impact on productivity can be attributed to forecast exuberance, and only 10–30% to the actual increase in the number and quality of launches.

There's the problem with relying on forecast revenues - that 45/55 split is if things go perfectly on the 55 (revenue) side. To be fair, the cost-cutting they're talking about is not all just ax-the-R&D-department stuff. It can also include lower expenses from any increase in clinical success rates (the jury is still out on those). And the authors also make the point that individual therapeutic areas often drive overall figures like these - for example, some of the recent rise is due to the huge successes in anti-infectives, which largely means HCV.

So overall, "cautious optimism" is probably warranted. If the recent clinical successes in oncology translate as they should, the industry may well see the sort of turnaround that can't be explained away.

Comments (11) + TrackBacks (0) | Category: Business and Markets | Drug Industry History | Regulatory Affairs

June 15, 2015

The Incomplete Response Letter

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Posted by Derek

When a drug company's New Drug Application runs into some sort of major issue, the FDA sends what's called a CRL, a Complete Response Letter. This details why the application was rejected and what can be done to fix the problem. And all this is, naturally of great interest to the company's investors.

But they can go mow their lawns. Most of the time, that's going to provide as much information as the company will divulge on its own. That's what I took away from this study in the BMJ (here's a summary at FierceBiotech). The authors (who are with the FDA) looked at the full text of dozens of CRLs (from 2008 to 2013) and compared what's in them to the press releases at the time. What results is a sort of regulatory Rashomon.

18% of the time, the companies issued no press release at all, although you would have to characterize a CRL as a "material event", wouldn't you? Another 21% of the time, though, press releases "did not match any statements from the letters", so that's the next best thing to not issuing anything at all. 32 of the CRLs from this period called for new clinical trials to be conducted, but 40% of the press releases never got around to mentioning that. And of the 7 CRLs that brought up a higher mortality in the drug treatment group, only one of the corresponding press releases noted that fact. In none of the 61 cases did the company involved release the complete text of the CRL.

So, to quote that noted philosopher Bullwinkle, if you're waiting for the companies to finish the story, you're going to have a long wait. There have been calls over the years to make CRLs public, and this study shows why that's not a bad idea. Since the authors themselves are from the FDA, and note that this proposal was recommended by the agency's own transparency task force in 2009.

At the very least, a summary of the CRL could be released by the agency in its own words - something that wouldn't disclose any proprietary details, but would at least tell everyone what's going on. Does the FDA need anyone else's permission to do this? The authors say that releasing the full texts "would likely require a change in FDA’s regulations". (Does that make it a matter for Congress to take up?) Someone needs to, because the current system is just not right.

Comments (30) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

June 10, 2015

PCSK9 at the FDA

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Posted by Derek

So an FDA advisory committee met yesterday to consider the PCSK9 antibody from Regeneron and Sanofi, and today it's the turn of Amgen's candidate. These, as anyone with even a passing interest in cardiovascular medicine will know, are potential gigantic blockbusters and advances in the field, promising to lower LDL across a huge swath of the patient population. The question, though, is clinical outcomes - the big question is always clinical outcomes. Does lowering LDL via this mechanism lead to lower CV mortality, fewer heart attacks, etc.? By now, we have such data for statin therapy, and it does indeed seem to provide those benefits. Those numbers take years to generate, though, and although these studies are underway, the various PCSK9 developers would much rather not wait another two or three years for them to report, in much the same way that you or I would rather not spend that time dangling by our feet. So everyone is looking for a way to get these drugs onto the market.

Sanofi and Regeneron are looking to target patients who have a genetic predisposition to high LDL levels, and a larger group who are intolerant to statin therapy. The FDA committee was fine with the first plan, but not wildly enthusiastic about the second one. One worry they seemed to have was sending a "ditch your statins" message, which they don't want to do.

A whole generation of well-known statins, now cheap and easily available, has emerged with proven cardiovascular benefits for patients. Other LDL drugs, though, turned out to be controversial failures on CV outcomes. The FDA is fretting that an approval based on the LDL surrogate leaves it with no authority to demand a cardiovascular study. And regulators are alarmed over the impact these new drugs could have on statins, even though there are no proven CV advantages.

That's from this FierceBiotech piece, written before the committee meeting. Here's their take afterwards. Matthew Herper has an analyst who thinks that many statin-intolerant patients will go onto the new therapies, no matter what the label might way. We'll see. No PCSK9 antibody is going to reach its full market potential until the outcomes data arrive - that much has been clear for a long time. But now the companies (and their investors) are wondering about what they'll be able to realize before that happens.

Comments (23) + TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs

May 8, 2015

Freedom of Off-Label Speech

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Posted by Derek

Three years ago, a Federal appeals court ruled that restraints on off-label promotion of drugs by pharma companies is a violation of the freedom-of-speech provisions of the Constitution. At the time, there was a lot of talk about where this might lead (with some betting on another court challenge to try to settle the issue).

Here's an update from Ed Silverman. The court case is here:

The FDA did not challenge the decision. And since then, the pharmaceutical industry has been lobbying the agency to revise its guidelines, because the ruling only applied to three states. The FDA has not indicated when it will take action, but plans to hold a meeting this summer to review the contentious topic.

Now, one drug maker is trying to force the issue. Amarin yesterday filed a lawsuit hoping to convince a federal court that the FDA prohibition on off-label promotion violates the company’s First Amendment rights, and that its reps should be able to convey truthful and “non-misleading” information to doctors.

Won't this be interesting to watch? I'm no constitutional lawyer, but the FDA seems to have lost a few decisions in this area already, and I'm betting that they'll lose this one, too. If they do, then we'll have a pretty lively time of it, sorting out what can and can't be said, but the "can" side will be on top.

Comments (48) + TrackBacks (0) | Category: Regulatory Affairs

May 6, 2015

A New Old Antibiotic

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Posted by Derek

Via FierceBiotech, here's an odd story about a small company you've probably never hears of, Symbiomix. They were launched just a couple of years ago, and are now heading into Phase III with an antibiotic. How, you ask, is that remotely possible?

Well, it's an antibiotic (secnidazole, a nitroimidazole) that's been sold in other countries for so many years that it's gone generic, but was never taken to the FDA over here. So that does speed things up. The company says that the compound has a real advantage in treating bacterial vaginosis (single-dose versus longer course of treatment), and plans to market it accordingly. What insurance companies will think about this as an advantage worth paying for it yet to be seen.

This looks like a one-shot regulatory arbitrage play. For some reason, this compound was never marketed here, so even though it's an older generic drug overseas, it gets to be turned into a New Drug here, with New Pricing. It's safe to say that no one is going to be holding their breath waiting to see if Symbiomix's Phase III trial goes as expected - of course it's going to go as expected. Everyone else has already done all that work. Symbiomix just gets to put together as much of a package as they need for the FDA, and then they can go try to make money with it.

It'll be worth watching to see if they do. I dislike regulatory arbitrage, as many posts around here have made clear. That's partly because, as someone who's spent all his time in new drug research, it feels to me like cheating, like pulling a fast one. Hah-hah, someone forgot to cross their fingers and stand on their right leg back in 1991, which means that I get to price my drug today as if I'd done the work of discovering it myself! Suckers! But this isn't quite as airtight a case as the odious ones of companies who pick some obscure one-supplier drug and ratchet the price up on it. There are alternatives to secnidazole out there - specifically metronidazole, one less methyl group at the cost of faster clearance and a few more pills. Symbiomix will be devoting as much time to figuring out their price point as they will to their clinical trial.

Comments (19) + TrackBacks (0) | Category: Business and Markets | Infectious Diseases | Regulatory Affairs

April 23, 2015

Genervon and ALS: What's Going On Here?

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Posted by Derek

Ever hear of Genervon, and their ALS therapy, GM604? There's not too much to hear about, unless of course you're a desperate patient or relative, looking for something, anything that might help. Genervon is certainly trying to reach those people, with press releases that include phrases such as "dramatic" and "very robust". And they've been giving everyone the impression that this dramatic, robust therapy was already being evaluated by the FDA. But not so fast. As Pharmalot reports, the company is now acting as if it's never said anything of the kind:

. . .Genervon said in an email that it is “at the point of communicating with FDA about whether [the agency] would accept our formal application” for accelerated approval. In other words, the company has not yet submitted a New Drug Application, a step needed to officially set the FDA approval process in motion.

The company's acknowledgement that it has not filed an NDA appears to contradict earlier press releases and statements made by the firm's owners, Winston and Dorothy Ko -- or at least to have sown confusion about the actual status of GM604. In one February press release, for example, the company said that in a meeting with the FDA, "three times during the one-hour meeting we requested that the FDA grant GM604 accelerated approval."

The drug's effects had better have been dramatic: the trial that's causing all this controversy was twelve patients for twelve weeks. That's not a very long time to evaluate a disease like ALS, and you have to wonder just how impressive these numbers are with such a small sample size, and what the FDA is going to think about them. (There's a lot of room to wonder). Genervon isn't doing itself any favors, either, by its response to questions about all this, saying that "Some are crating [sic] an issue out of nothing hoping to discredit Genervon and causing delay to make treatment available to ALS sufferers".

Big red flag there. When you start accusing people of plotting against your company and trying to harm patients, you sound like a crank. Or a fraud. Or a fool, or maybe some of each of those - they're not mutually exclusive. I certainly hope that Genervon's owners are none of the above, and that GM604 will prove to be a useful therapy. But they should realize that they're not making a good case for that so far.

This sort of situation is the beginning of what I fear could develop from "right to try" laws, if they're not carefully written. I certainly understand people wanting access to experimental therapies, especially for a terrible condition like ALS, where there's basically nothing that anyone can do. But figuring out whether a new drug works is really a lot harder than it looks. For the most part, it takes more than twelve people, and it takes more than twelve weeks. We may decide that patients have the right to waste their money and to waste their time chasing such things, but letting them do that without also hurting the chances of finding something real, that's the hard part. A rare disease may wind up with not enough patients around to participate in controlled trials. A small company might end up spending too much of its resources providing its unproven therapy to people who want it now, proof or not. And worst of all, you might end up enabling unscrupulous operators to keep providing "drugs" at "cost" for as long as people are willing to pony up, and the heck with clinical trials.

These aren't the issues with Genervon. But this story shows, I think, how such things could happen. What the issues are with Genervon, though, are hard to say. The FDA has called on the company to release all its data, and the company says it's already sent everything they have (although for the purposes of applying for accelerated approval, not for an NDA package). Someone's confused. Or confusing. Or both - those aren't mutually exclusive, either.

Comments (38) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System

March 4, 2015

The SEC Tells Companies to Speak Up

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Posted by Derek

The SEC is specifically warning drug companies to be more forthcoming about their dealings with the FDA. He's definitely got a point. Too many companies try to act as if important, material information from the agency is under some sort of confidential shield, when it really should be disclosed as soon as possible. I should clarify that: we're talking about important, material bad news from the agency. Good news gets trumpeted out within milliseconds. As is only proper.

If the SEC is serious about this - and I'm hoping that they are - then we should look for some well-publicized actions by the agency to signal that this isn't just talk. It'll be worth keeping an eye on the regulatory landscape over the next few months to see if this really happens. . .

Comments (4) + TrackBacks (0) | Category: Regulatory Affairs

February 4, 2015

Breakthroughs Aren't Forever

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Posted by Derek

This appears to be a first: the FDA has revoked a "breakthrough" designation for a drug heading into the approval process. Merck's latest entry into the hepatitis C field, the MK-5172/MK-8742 combo, had this status, but the recent approvals from Gilead and from Abbott AbbVie have made it, well. . .less of a breakthrough. Merck disclosed this in its earnings release, and the news isn't helping its stock today.

I think this is an excellent move by the FDA. Things change, and the agency has to keep up with the changes, and to be seen to be keeping up with them. Ignoring this would be one way to start making the entire "breakthrough" category meaningless.

Comments (13) + TrackBacks (0) | Category: Infectious Diseases | Regulatory Affairs

January 29, 2015

Flex Pharmaceuticals Is Testing What?

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Posted by Derek

Flex Pharmaceuticals went public the other day, another in the string of IPOs in the biopharma world. This is also another Christopher Westphal company - he was a founder of Sirtris, about which much ink and many pixels (here and elsewhere) have been shed, and more recently founded Verastem (who also went public with alacrity). Before that he was working with GSK's venture capital operation, an association which ended rather suddenly in 2011.

So what does Flex have going for it? They have a therapy being tested for noctural leg cramps and other neuromuscular spasms. Fine. What is this therapy? It is a mixture of capsicum, ginger extract, and cinnamon extract, and that makes me think that if you added some fish sauce and some rice that you could probably serve it in a Thai restaurant. These are all regulated as food ingredients, and the company hopes to skip the normal IND requirements by treating the mixture as a dietary supplement.

This should be interesting to watch. It's certainly possible that these extracts could have medicinal effects - they're certainly all full of tasty natural products. And I appreciate that the the company is actually going to run clinical trials and prove efficacy, rather than go the usual dietary supplement route and just sell the stuff anyway. (Or sell some other stuff entirely and never mind the label!) No, this is how plant-extract-based medicine should be done, and while the temptation is to make fun of it (with a few more Thai restaurant jokes), I wish the Flex folks luck. It is possible to wish them well, though, and still wonder about a market in which they are able to raise $86 million dollars with apparent ease.

Comments (30) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

January 26, 2015

India's GVK Accused of Systematic Fraud

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Posted by Derek

This does not look good at all. The European Medicines Agency (EMA) has accused the large Indian generic company (and outsourcing contractor) GVK of widespread systematic fraud. According to this press release, the agency investigated about 1000 generic formulations of various drugs from GVK, and found that 300 of them had enough data (from other sources) to support them. But the other 700 (representing 10 to 15 separate drug substances) don't:

The inspection of GVK that led to the CHMP's recommendation was carried out by the French medicines agency (ANSM). The inspection revealed data manipulations of electrocardiograms (ECGs) during the conduct of some studies of generic medicines. These manipulations appeared to have taken place over a period of at least five years. Their systematic nature, the extended period of time during which they took place and the number of members of staff involved cast doubt on the integrity of the way trials were performed at the site generally and on the reliability of data generated at that site.

And there you see Falsus in unum in action. How can the rest of the studies be trusted, when you know that at least one important one has been faked? And faked with care and attention? European countries are in the process of pulling marketing authorizations for many GVK drugs. For its part, the FDA says that it conducted its own inspection after the French one, and found no irregularities, but one might assume that GVK made sure that things didn't go quite so catastrophically that second time. We'll see if they have something more to add.

Comments (21) + TrackBacks (0) | Category: Regulatory Affairs | The Dark Side

January 23, 2015

Elizabeth Warren's "Pharma Swear Jar" Idea

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Posted by Derek

Elizabeth Warren has come out with a proposal for what she's calling a "pharmaceutical swear jar". Once a drug company had been fined, this bill would earmark a percentage of their profits over a multiyear period for use in NIH funding. Like many of Warren's ideas, this one has a lot of populist appeal - but does it make any sense?

It actually reminds me of that "Take back the grant money in case of fraud" idea that I vacillated about earlier this week. That one, though, at least has the benefit of having a pretty direct connection between the people causing harm and some of the ones getting harmed. In this idea, the tie is pretty indirect - unless, of course, Warren is one of those people who believe that the drug industry mostly makes its money by ripping off NIH-funded discoveries. And she seems to be: she says that such companies are "generating enormous profits as a result of federal research investments". So she probably sees this as a perfectly logical quid pro quo. This idea makes it seem as if drug companies have harmed the NIH when they're fined for over-promotion of a drug or for manufacturing problems, but that connection doesn't exist.

Note: Elizabeth Warren is not alone in her belief. There are a number of people who passionately believe that the bulk of drug research is done with NIH money, and that drug companies exist just to skim off the cream. I never knew this before I started this blog, I have to tell you, and if you try this idea out on anyone who actually works in biopharma they stare at you as if you've lost your mind, but there it is. The topic has come up at length around here several times: try here, here, here, here, and here. And this is a nice perspective from a former director of the NIH.

In the same way that I was wondering about incentives (appropriate ones and perverse ones) in that grant money idea, it's worth looking at the incentives here. One good thing is that it wouldn't be the NIH, the interested party, bringing the accusations against pharma. In such situations, the potential for abuse, the moral hazard, is too high. You end up with problems like the ones seen with police department seizures of assets, or (in a less dramatic, but still pernicious way) with stoplight cameras. What's supposed to be a public service ends up as a revenue source.

But what this does remind me of are the various states that use lottery income to fund education. The trouble with that is that the education budget itself doesn't necessarily stay the same when such a system goes into effect. The lottery money gets sent in that direction, while some (or damn near all) of the money that was earmarked for education gets moved over to other worthy vote-getting projects. In the end, the education budget doesn't really go up. So one problem with this idea is that it might not end up providing much extra money to the NIH, in the end.

So where does the money go when a drug company is fined under the current system? Into the general fund, as far as I can tell. I don't think it goes right to the Department of Justice, the FDA, or the FTC (that would set up that moral hazard problem mentioned above). No, it seems to go right back into the big pile, to be divided up by the House during budget negotiations. Some of that money (although not a very large per cent) finds its way to the NIH as it is; the rest gets spread out to service on the debt, "entitlement" programs, defense, and so on. (Actually, those three categories alone are a pretty good proxy for the entire federal budget - the NIH, by contrast, gets less than one per cent of the total).

Warren's plan would earmark money, then, for one agency. My sense is that in general lawmakers are not keen on doing that. They'd rather fund the various parts of the government by dividing up a general fund, rather than by a maze of bespoke conduits from Source A to Recipient B. (As the lottery example shows, even when something like this is set up, money gets dragged back into that general fund anyway). And as distasteful as the budgetary process is, I have to agree with the current system. I think the potential for flexibility is worth more than the sense of fitness that one might get from knowing that some (more or less) appropriate source is funding some particular program. To pick a large example, it's not like Social Security or Medicare taxes all go off to some special place where they get spent only on Social Security or Medicare (much less, as some people apparently believe, that "their money" is going into "their account").

The current NIH budget is about $30 billion. Warren's proposal, by her own reckoning, would have increased the agency's budget by $6 billion a year over the last five years, but the last five years have also seen the biggest fines ever. Historically, that isn't the kind of cash that comes in all the time (although if Elizabeth Warren were in charge of the process, no doubt things would pick up). The agency's funding has been flat, and flat at a lower level than its peak during George W. Bush's first term, so I'm sure that they'd be glad of the money.

But if Congress wants to give more money to the NIH - and they could do worse, and often do - then they should give more money to the NIH the old-fashioned way: by voting on a budgetary resolution that does this. That way, the agency itself knows what's coming, and when it's showing up, and can figure out what best to do with the money. The "Pharma Swear Jar" idea seems to me to be a stunt, designed to make people feel better and to give Elizabeth Warren a chance to campaign on having helped to stick it to the big drug companies.

Comments (56) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

December 17, 2014

Actavis and Namenda

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Posted by Derek

John LaMattina has a column at Forbes about the situation with Actavis and their Alzheimer's drug, Namenda (memantine). That situation is not a pretty one: the company has an extended-release form of the drug coming on, which they believe will be more convenient to dose. And that's fine - except that part of their strategy is to discontinue the original dosage form.

This is a larger-scale version of the sort of thing that I banged on Retrophin about earlier this year. Dropping useful drugs just so that your new formulation can rule the world seems to be a particularly nasty form of portfolio management, and LaMattina is absolutely right when he says that:

Discontinuation of Namenda in order to boost sales of the XR version reinforces all of the bad views that people have of the pharmaceutical industry and provides great fodder for its critics. Actavis has joined the “Big Pharma” club. It would be nice if it became part of the solution to Big Pharma’s image woes, rather than adding to the problem.

Right now, the whole issue is in court, thanks to an injunction that prevents the company from following through on this strategy. Actavis has appealed, and a hearing took place earlier this week (more on this at Pharmalot). I would not mind seeing this tactic vanish from the earth, and if it takes the law to make it happen, then that's what we get. We'll get worse if this sort of thing continues.

Comments (51) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

December 3, 2014

Puma and Neratinib Take Longer Than Expected

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Posted by Derek

When I last wrote about Puma Biotechnology and their irreversible kinase inhibitor neratinib, things were going great. The company had reported good Phase III data, taking investors by surprise, and the stock had shot up. An FDA filing was planned for just after the first of the year, and the future was bright.

The story has become complicated since then, as a lot of stories in our line of work have a tendency to do. Neratinib recently failed to beat Herceptin in a head-to-head trial (one Puma had downplayed, at least for that primary endpoint). And now comes more bad news: the company has been talking about changing its target patient population, and a recent meeting with the FDA looks to delay their regulatory filing for at least a year. (They need to address some preclinical carcinogenicity data).

So this is not exactly a home run just yet. Neratinib may well make it through fine after the delay. But if you bought the stock when it jumped back in the summer, you're flat now, and probably wondering if you're ready to be a long-term investor or not. . .

Comments (5) + TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs

November 19, 2014

AstraZeneca: How Many Approvals, Again?

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Posted by Derek

So AstraZeneca says that they're expecting "8 to 10 " approvals in 2015-2016. Has anyone ever done that? Even close? I take it that this whole press release is there to pump up investors and keep Pfizer from coming back and making another bid for them, but although the company does have a lot of stuff going on, this just seems wildly optimistic. What's the modern record for most drug approvals in one year? Two years?

Comments (17) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

October 2, 2014

Catalyst Pharmaceuticals and Their Disgusting Business Strategy

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Posted by Derek

OK, this seems to be a new business model, damn it all. I wrote here recently about the huge price increase of Thiola (tiopronin) by a small company called Retrophin.

Now, as I wrote about here last year, another small company called Catalyst Pharmaceuticals is preparing to jack up the price of Firdapse (3,4-diaminopyridine) for the rare disorder Lambert-Eaton Myasthenic Syndrome (LEMS).

This disease is so rare, and the drug is so easily available, that it is currently being given away for free. But Catalyst is going to make sure that it won't stay free for long. Not at all:

There was never any doubt about Firdapse's ability to treat LEMS symptoms effectively because it's the same active drug as 3,4-Dap. With that perspective, Catalyst's triumphant press release Monday is all the more galling. The company took no risks with Firdapse. The company did no development work, made no effort to improve the drug's efficacy, safety or convenience for patients. The only thing Catalyst did was write a check to Biomarin and take over supervision of a Firdapse clinical trial already well underway.

For the zero work done by Catalyst, LEMS patients and their insurance companies will be paying as much as $80,000 for the exact same drug they use now for a fraction of the cost, if not gratis.

To just add a rancid cherry on top, that piece by Adam Feuerstein also details the way the company is apparently intimidating LEMS patients by telling them that they'll need to be deposed in a shareholder lawsuit. Now this is what regulatory failure looks like. I can think of no possible reason, no public good that comes from taking a drug that was easily available and working exactly as it should and have someone suddenly be able to charge $80,000 a year for it. This is not a reward for innovation or risk-taking - this is exploitation of a regulatory loophole, a blatant shakedown, or so it seems to me.

Why does the FDA let this happen? It brings the agency into disrepute, and the whole drug industry as well, and for no benefit at all. Well, unless you're the sort of person who executes one of these business plans, in which case you should get out of my sight. Too many people already think that all drug companies do is grab someone else's inexpensive compound and then raise the price as high as they possibly can. Watching people like Catalyst and Retrophin actually live the stereotype is infuriating.

Update: The previous licensee for this drug, Biomarin (in Europe) was harshly criticized for just this sort of business plan. Here is an open letter from 2010 from a group of British physicians to Prime Minister David Cameron, and its opening paragraph succinctly describes the problem here:

". . .The original purpose of this (orphan drug) legislation, passed in 1999, was to encourage drug companies to conduct research into rare diseases and develop novel treatments. However, as the rules are currently enacted, many drug companies merely address their efforts to licensing drugs that are already available rather than developing new treatments. Once a company has obtained a licence, the legislation then gives the company sole rights to supply the drug. This in turn allows the company to set an exorbitant price for this supply and effectively to bar previous suppliers of the unlicensed preparation from further production and distribution.

Similar regulatory loopholes have been used to raise the price of colchicine and hydroxyprogesterone, among others, and we can expect this to be done over and over, with every single drug that it can be done to, because the supply of people who think that this is a good idea is apparently endless. And the public backlash and the regulatory (and legislative) scrutiny that this brings down will then be distributed not just to the rent-seeking generic companies involved, but to every drug company of any type, because whatever hits the fan is never evenly spread. Do we really want this?

Postscript: In an interesting sequel to the Retrophin story, the company's board this week replaced CEO Martin Shkreli, whose sudden appearance on Reddit in response to this issue probably didn't help his position).

Comments (48) + TrackBacks (0) | Category: Drug Prices | Regulatory Affairs | The Dark Side

August 28, 2014

The Early FDA

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Posted by Derek

Here's a short video history of the FDA, courtesy of BioCentury TV. The early days, especially Harvey Wiley and the "Poison Squad", are truly wild and alarming by today's standards. But then, the products that were on the market back then were pretty alarming, too. . .

Comments (2) + TrackBacks (0) | Category: Drug Industry History | Regulatory Affairs

Drug Repurposing

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Posted by Derek

A reader has sent along the question: "Have any repurposed drugs actually been approved for their new indication?" And initially, I thought, confidently but rather blankly, "Well, certainly, there's. . . and. . .hmm", but then the biggest example hit me: thalidomide. It was, infamously, a sedative and remedy for morning sickness in its original tragic incarnation, but came back into use first for leprosy and then for multiple myeloma. The discovery of its efficacy in leprosy, specifically erythema nodosum laprosum, was a complete and total accident, it should be noted - the story is told in the book Dark Remedy. A physician gave a suffering leprosy patient the only sedative in the hospital's pharmacy that hadn't been tried, and it had a dramatic and unexpected effect on their condition.

That's an example of a total repurposing - a drug that had actually been approved and abandoned (and how) coming back to treat something else. At the other end of the spectrum, you have the normal sort of market expansion that many drugs undergo: kinase inhibitor Insolunib is approved for Cancer X, then later on for Cancer Y, then for Cancer Z. (As a side note, I would almost feel like working for free for a company that would actually propose "insolunib" as a generic name. My mortgage banker might not see things the same way, though). At any rate, that sort of thing doesn't really count as repurposing, in my book - you're using the same effect that the compound was developed for and finding closely related uses for it. When most people think of repurposing, they're thinking about cases where the drug's mechanism is the same, but turns out to be useful for something that no one realized, or those times where the drug has another mechanism that no one appreciated during its first approval.

Eflornithine, an ornithine decarboxylase inhibitor, is a good example - it was originally developed as a possible anticancer agent, but never came close to being submitted for approval. It turned out to be very effective for trypanosomiasis (sleeping sickness). Later, it was approved for slowing the growth of unwanted facial hair. This led, by the way, to an unfortunate and embarrassing period where the compound was available as a cream to improve appearance in several first-world countries, but not as a tablet to save lives in Africa. Aventis, as they were at the time, partnered with the WHO to produce the compound again and donated it to the agency and to Doctors Without Borders. (I should note that with a molecular weight of 182, that eflornithine just barely missed my no-larger-than-aspirin cutoff for the smallest drugs on the market).

Drugs that affect the immune system (cyclosporine, the interferons, anti-TNF antibodies etc.) are in their own category for repurposing, I'd say, They've had particularly broad therapeutic profiles, since that's such a nexus for infectious disease, cancer, inflammation and wound healing, and (naturally) autoimmune diseases of all sorts. Orencia (abatacept) is an example of this. It's approved for rheumatoid arthritis, but has been studied in several other conditions, and there's a report that it's extremely effective against a common kidney condition, focal segmental glomerulosclerosis. Drugs that affect the central or peripheral nervous system also have Swiss-army-knife aspects, since that's another powerful fuse box in a living system. The number of indications that a beta-blocker like propanolol has seen is enough evidence on its own!

C&E News did a drug repurposing story a couple of years ago, and included a table of examples. Some others can be found in this Nature Reviews Drug Discovery paper from 2004. I'm not aware of any new repurposing/repositioning approvals since then, but there's an awful lot of preclinical and clinical activity going on.

Comments (35) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History | Regulatory Affairs

August 15, 2014

Incomprehensible Drug Prices? Think Again.

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Posted by Derek

There's a post by Peter Bach, of the Center for Health Policy and Outcomes, that's been getting a lot of attention the last few days. It's called "Unpronounceable Drugs, Incomprehensible Prices", and you know what it says.

No, really, you do, even if you haven't seen it. Too high, unconscionable, market can't support, what they can get away with, every year, too high. Before I get to the uncomfortable parts of my own take on this, let me stipulate a couple of things up front: (1) I do think that the industry is inviting trouble for itself by the way it it raising prices. It is in drug companies' short term interest to do so, but long term I worry that it's going to bring on some sort of price-control regimen. (2) Some drug prices probably are too high (but see below for what that means). Big breakthroughs can, at least in theory, command high prices, but not everything deserves to be priced at the level it is.

I was about to say "see below" again, but this paragraph is below, so here goes. Let me quote a bit from Bach's article:

Cancer drug prices keep rising. The industry says this reflects the rising costs of drug development and the business risks they must take when testing new drugs. I think they charge what they think they can get away with, which goes up every year. . .Regardless of the estimate, the pricing of new drugs for cancer and now other common diseases has come unglued from the rationale the industry has long espoused. Instead, pricing is explained by a phenomenon of increasing boldness by the industry against a backdrop of regulators and insurers who have no legal authority to dictate or even propose alternative pricing models.

Bach's first assertion is correct: drug companies are charging what they think they can get away with. In that, they are joined by pretty much every other business in the entire country. I did a post once where I imagined car sales transplanted into the world of drug sales- you couldn't just walk in and buy a car, for example. No, you had to go to a car consultant first, licensed by the state, who would examine your situation and determine the sort of car you needed. Once they'd given you a car prescription, you could then go to a dealer.

Well, we don't have that, but what car companies do charge is, well, what they can get away with. The same as steel companies, soft drink companies, cardboard box companies, grocery stores, and people who are selling their houses. You charge what you think the market will bear. Even people selling basic necessities of life like food and shelter charge what they think the market will bear. It's true that health care does feel different from any of those (a point that I went into in that post linked in the last paragraph), and there's the root of many a problem.

And, some will say, a big difference is that none of these other sellers have patents on their side, the legal right to put the screws on. But remember the flip side of the patent system: the legal certainty that you will lose that pricing power on a set date. The pricing of new drugs is completely driven by their expected patent lifetimes, because almost all the money that the developing company is ever going to make off the drug is going to have to be made during that period.

And sometimes that period isn't very long. The patent clock starts ticking a long time before a drug ever gets on the market; there are often only five to ten years left when it's finally approved for sale. There are other factors, too. Everyone is talking about the price of Sovaldi for hepatitis C, but no as many people have thought about the fact that the drug is, in fact, so effective that it has blown two other recently approved Hep C treatments right out of the market, well before their patent lifetimes had even expired. There really is competition in the drug business, and that sector shows it in action.

Now, what there isn't so much of is competition on price, true. And that's what you do see in the other businesses I named above. There are grocery stores that occupy the "Wonderful Prestigious High Quality" part of the market, and others that occupy the "Low Low Prices Every Day" part. (And interestingly, if you Venn-diagram out what's on the shelves of those two, there's still some overlap, allowing you to watch people paying wildly different prices for blueberries that came off the same truck, not to mention even less perishable stuff like aluminum foil). You don't see this in the drug industry, partly because for patented drugs we're never selling the same blueberries. the same gasoline, or the same khaki trousers. Even the biggest "me-too" drugs still differ from each other to some degree.

And that brings up another point. Bach uses (as his example of pricing in the cancer field) two Alk compounds, Xalkori (crizotinib) from Pfizer and Zykadia (ceritinib) from Novartis. Xalkori was first, and Bach makes a lot of the fact that Zykadia is priced higher, even though he says that Pfizer ran bigger clinical trials, had to work out the associated diagnostic test with the FDA, and launch the new mechanism into the oncology market. Novartis, he says, got to piggy-back on all that, and yet their drug is priced higher. There can be no other reason for that pricing decision, Bach says, other than that they can.

Let's go into some details that Bach's article leaves out. Zykadia is indeed second to market. But the time gap between the two drugs means that Novartis was working on it before they knew that Xalkori worked in the clinic. Bach makes an error here made by many others who have not actually done drug discovery work: the time course of these things is longer than it looks. A screen had to be run against Alk, compounds had to be confirmed, a medicinal chemistry team had to optimize them and make lots of new structures, all of which except one fell by the side of the road. The compound had to go through animal tests for efficacy and safety, and it had to be scaled up and formulated. And so on, and so on. Novartis did not sit back, watch Xalkori succeed, and then decide "Hey, we should get us some of that action, too".

Now Zykadia is, as Bach says, a second-line therapy. But it's approved for patients who do not respond to, or have become intolerant to Xalkori. So this "me-too" drug is, in fact, different enough to work on patients for whom Xalkori has failed. In fact, most patients will start to show relapse inside of a year on Xalkori, so it would appear that most non-small-cell lung cancer patients with multiyear survival are probably going to end up taking both compounds. Cancers mutate quickly, and we need all the options we can get - and guess what, some of those options are going to be second to market, because they can't all be first.

Another point to note is that while Zykadia was indeed approved on the basis of a smaller clinical trial set, that's because it received "breakthrough" designation from the FDA for accelerated review and approval. Startlingly, it actually got approved after Phase I trials alone. (Not bad for what Bach characterizes as a simple copycat drug, by the way). Novartis has run the compound in more clinical trials than that, and they continue to do so. It's not like they slipped in with a mere 163 patients and then trotted off to the FDA while brushing the dust off their hands. To find this out, by the way, you'll want to use "LDK378", the internal Novartis designation for the drug, and I'm passing this information on to Bach for free. shows 13 trials in the US when you do that, and there are others outside the country as well.

Bach's article, as mentioned, plays down any differences between these two drugs, saying that "they have not been directly compared". But that's not accurate. Let me quote from that link in the paragraph just above:

As described by Shaw and colleagues in the New England Journal of Medicine, ceritinib has striking activity in ALK-rearranged NSCLC, both in treatment-naïve patients and in those who experienced tumor progression on crizotinib. . .The drug has clear pharmacological advantages over crizotinib. Its surprising level of activity in crizotinib-resistant tumors may be explained by its greater potency and its particular ability to inhibit ALK with gatekeeper mutations that confer resistance to crizotinib.

The two drugs have had a very important comparison: people who are going to die on Xalkori are going to survive longer if they switch to Zykadia. "Me-too" drug, my ass.

But rather than end on that note, tempting as that is, let me circle back to pricing once again. The price for these cancer drugs is not borne by individual patients emptying their piggy banks. It is borne by insurance, both private and government. And drug companies do indeed price their drugs at what the think the insurance plans will pay for them. This is not a secret, and should not be a surprise, and I continue to be baffled by people who react to this with horror and disbelief. Prices appear when you find out what the payers will pay. If Pfizer, Novartis, or Gilead priced their drugs at fifty million dollars a dose, no insurance company would reimburse. But the insurance companies are paying the current prices, and if they believe that they will be put out of business by doing so, they need to stop doing that. And they could.

They will, too, if we in the industry keep pushing them towards doing it. That's our big problem in drug development: our productivity has been too low, and we're making up for it by charging more money. But that can't go on forever. There are walls closing in on us from both sides, and we're going to have to scramble out from between them at some point. Pricing power can only take you so far.

Comments (43) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Prices | Regulatory Affairs | Why Everyone Loves Us

July 21, 2014

Allergan Twists and Turns

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Posted by Derek

It's getting nasty over at Allergan. They're still trying to fight off a takeover attempt by Valeant, making the case that the company's R&D efforts are not a waste of money (which, only slightly simplified, is the Valeant position regarding every company they're taking over).

But Allergan's had a lot of trouble getting one of their drugs (Semprana) through the FDA. Semprana is an inhaled version of the classic dihydroergotamine therapy for migraine, and had been rejected last year when it was still known as Levadex. The recent further delay isn't helping Allergan make its case, and Valeant is using this news to peel off some more shareholders.

This morning comes word that Allergan is cutting back staff. That Fierce Biotech report says that it looks like a lot of the cuts will be hitting discovery R&D, which makes you wonder if Allergan will manage to escape Valeant's grip only by becoming what Valeant wanted to make them.

Comments (7) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

June 23, 2014

The Virtual Clinical Trial: Not Quite Around the Corner

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Posted by Derek

Here's one of those "Drug Discovery of. . .the. . .Future-ure-ure-ure" articles in the popular press. (I need a reverb chamber to make that work property). At The Atlantic, they're talking with "medical futurists" and coming up with this:

The idea is to combine big data and computer simulations—the kind an engineer might use to make a virtual prototype of a new kind of airplane—to figure out not just what's wrong with you but to predict which course of treatment is best for you. That's the focus of Dassault Systèmes, a French software company that's using broad datasets to create cell-level simulations for all different kinds of patients. In other words, by modeling what has happened to patients like you in previous cases, doctors can better understand what might happen if they try certain treatments for you—taking into consideration your age, your weight, your gender, your blood type, your race, your symptom, any number of other biomarkers. And we're talking about a level of precision that goes way beyond text books and case studies.

I'm very much of two minds about this sort of thing. On the one hand, the people at Dassault are not fools. They see an opportunity here, and they think that they might have a realistic chance at selling something useful. And it's absolutely true that this is, broadly, the direction in which medicine is heading. As we learn more about biomarkers and individual biochemistry, we will indeed be trying to zero in on single-patient variations.

But on that ever-present other hand, I don't think that you want to make anyone think that this is just around the corner, because it's not. It's wildly difficult to do this sort of thing, as many have discovered at great expense, and our level of ignorance about human biochemistry is a constant problem. And while tailoring individual patient's therapies with known drugs is hard enough, it gets really tricky when you talk about evaluating new drugs in the first place:

Charlès and his colleagues believe that a shift to virtual clinical trials—that is, testing new medicines and devices using computer models before or instead of trials in human patients—could make new treatments available more quickly and cheaply. "A new drug, a succesful drug, takes 10 to 12 years to develop and over $1 billion in expenses," said Max Carnecchia, president of the software company Accelrys, which Dassault Systèmes recently acquired. "But when it is approved by FDA or other government bodies, typically less than 50 percent of patients respond to that therapy or drug." No treatment is one-size-fits-all, so why spend all that money on a single approach?

Carnecchia calls the shift toward algorithmic clinical trials a "revolution in drug discovery" that will allow for many quick and low-cost simulations based on an endless number of individual cellular models. "Those models start to inform and direct and focus the kinds of clinical trials that have historically been the basis for drug discovery," Carnecchia told me. "There's the benefit to drug companies from reduction of cost, but more importantly being able to get these therapies out into the market—whether that's saving lives or just improving human health—in such a way where you start to know ahead of time whether that patient will actually respond to that therapy."

Speed the day. The cost of clinical trials, coupled with their low success rate, is eating us alive in this business (and it's getting worse every year). This is just the sort of thing that could rescue us from the walls that are closing in more tightly all the time. But this talk of shifts and revolutions makes it sound as if this sort of thing is happening right now, which it isn't. No such simulated clinical trial, one that could serve as the basis for a drug approval, is anywhere near even being proposed. How long before one is, then? If things go really swimmingly, I'd say 20 to 25 years from now, personally, but I'd be glad to hear other estimates.

To be fiar, the article does go on to mentions something like this, but it just says that "it may be a while" before said revolution happens. And you get the impression that what's most needed is some sort of "cultural shift in medicine toward openness and resource sharing". I don't know. . .I find that when people call for big cultural shifts, they're sometimes diverting attention (even their own attention) from the harder parts of the problem under discussion. Gosh, we'd have this going in no time if people would just open up and change their old-fashioned ways! But in this case, I still don't see that as the rate-limiting step at all. Pouring on the openness and sharing probably wouldn't hurt a bit in the quest for understanding human drug responses and individual toxicology, but it's not going to suddenly open up any blocked-up floodgates, either. We don't know enough. Pooling our current ignorance can only take us so far.

Remember there are hundreds of billions of dollars waiting to be picked up off the ground by anyone who can do these things. It's not like there are no incentives to find ways to make clinical trials faster and cheaper. Anything that gives the impression that there's this one factor (lack of cooperation, too much regulation, Evil Pharma Executives, what have you) holding us back from the new era, well. . .that just might be an oversimplified view of the situation.

Comments (15) + TrackBacks (0) | Category: Clinical Trials | In Silico | Regulatory Affairs | Toxicology

June 20, 2014

Stem Cells: The Center of "Right to Try"

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Posted by Derek

I wanted to point out an excellent editorial on the whole "Right to Try" issue at Nature. The authors note correctly that stem cells are the therapeutic area where these battles are being fought most often, since their regulatory status (particularly with any sort of autologous cell treatment) is sometimes unclear, the number of possible treatments (well-intentioned and otherwise) is huge, and the medical need is even bigger.

Many countries have made such experimental stem cell treatments more widely available without proof of efficacy. We're not just talking about the usual "medical tourism" list, although those countries are certainly on this one, but places like Japan and Australia. That cuts both ways. Proponents of the idea say that these countries are making more progress than the US for this reason, but a look at what's happened since these regulations were loosened isn't always encouraging. It's very, very, hard to open up such trials without opening them up to the sort of people who will gladly exploit patients for as long as possible without caring if any efficacy is ever proven or not.

Even the idea of putting products up for sale and into consumers' bodies on the basis of phase I data is disturbing. Early-stage clinical trials reveal only whether a product is safe enough for continued testing, not for widespread use. Some 80% of products that make it through phase I clinical trials fail in later studies — about half of those proving to be insufficiently effective and one-fifth insufficiently safe.

When test subjects are paying for the product under investigation, establishing efficacy is hard: controls, randomization, masking and other hallmarks of clinical research break down. Many stem-cell clinics offer their procedures for disparate conditions, further complicating post-market studies.

Under the guise of 'patient-funded clinical trials', clinics in the United States and Mexico persuade people who are seriously ill to pay tens of thousands of dollars for procedures. Because such patients have been told that a product is experimental, they have little recourse when hoped-for cures fail to materialize. Companies can thus profit from selling hope. With their products already on the market, they have little reason to conduct rigorous, conclusive research.

Stem cells, as has been said many times on this side, are surely one of the most overhyped areas in all of medical research. This has been true for at least ten years now, and the hype does not die down. Some may remember that this was an issue during the 2004 presidential election. I'll bet if you took a poll back then and asked where the field would be by 2014, that the general public would have bet on it being much more advanced than it is now. The usual reason applies: it's because this area of research is extremely, inhumanly complicated and difficult, but people get tired of hearing that and think that it's an excuse for some other factor.

There are libertarian and free-market groups behind several of the legal initiatives in the US, who honestly believe that the current FDA structure is an impediment to medical progress, and that this sort of deregulation will end up helping more people more quickly. I believe that their motives are sincere - not everyone pushing these ideas is looking for a quick buck. But the people who aren't need to look around and realize how many quick-buck artists are surrounding them. Every libertarian reform needs to have someone thinking "OK, less regulation and more freedom of choice, check. But what are the ways that this could be abused by unscrupulous SOBs? Can those abuses mount up to where they cancel out the good that's done on the other end?"

In this case, I think that danger is very real, and very likely. As opposed to the caricatures that you hear from people on the left end of the political spectrum, many free-market types, in my experience, have good hearts. Perhaps too good, in some cases. It would never occur to them personally to immediately turn around and use this newly loosened regulatory environment to start looting desperately ill people of their money. But it sure would occur to some others. Homo homini lupus: man is a wolf to man.

Comments (37) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | Snake Oil

June 10, 2014

Right To Try: Here We Go

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Posted by Derek

At what point should an experimental drug be made available for anyone to try it? The usual answer is "Unless you're enrolled in a clinical trial, then not until it's no longer an experimental drug". There's always compassionate use, but that's a hard topic to deal with, and one that has a different answer for every drug. Otherwise, the regulatory position is that volunteers take unproven drugs, and paying patients take the ones that have been through testing and review.

Colorado would like to try something different. They've passed a "Right To Try" law, which allow a therapy to be prescribed after it's passed Phase I and is under active investigation in Phase II. (Arizona, Louisiana, and Missouri are heading in the same direction). Insurance companies are not required to pay for these, it should be noted, nor are drug companies required to offer access. But if there are willing patients and a willing company, they can work together. The patient has to be suffering from a terminal illness, and has to have exhausted all approved therapies (if any).

As my fellow science-blogger David Kroll notes, though, this doesn't seem to add much past what was already allowed by the FDA:

I submit that this seemingly well-meaning but meaningless Colorado act does nothing but create a sense of false hope for similar families. The act does nothing more than assuage the concerns of lawmakers that they haven’t done enough to help their constituents. Instead, they’ve done a disservice.

At Science-Based Medicine there are similar thoughts from oncologist David Gorski. He goes into the details of the law that's under consideration in Arizona, and worries that it has such broad definitions that it opens the door to unscrupulous operators. I've worried about that as well. The Arizona law also allows the companies (at their discretion) to charge for providing the drugs (Colorado's allows for at-cost charging). The fear is that some unscrupulous operators could run the lightest, breeziest "Phase I" trial they possibly could, and then settle down into a long, lucrative spell of milking desperate patients while their "Phase II' trials creep along bit by bit. I realize that that's not a very nice thing to assume about people, but as a character in The War of the Worlds says about a similar predatory proposal, there are those who would do it cheerful. In fact, we already have evidence of people working in just this fashion.

These arguments have come up around here before, when Andy Grove (ex-Intel) proposed changing the structure of clinical trials (more here), and when Andy Eschenbach (ex-FDA) proposed something similar himself. Balancing these things is very hard indeed, and anyone who says it isn't either hasn't thought about the situation enough or is eager to sell you something. We've come to Chesterton's Gate again:

There exists in such a case a certain institution or law; let us say, for the sake of simplicity, a fence or gate erected across a road. The more modern type of reformer goes gaily up to it and says, “I don’t see the use of this; let us clear it away.” To which the more intelligent type of reformer will do well to answer: “If you don’t see the use of it, I certainly won’t let you clear it away. Go away and think. Then, when you can come back and tell me that you do see the use of it, I may allow you to destroy it.

Gorski (in that Science-Based Medicine link above) has many other good points, but there's one more that I'd like to emphasize. Some of these laws seem to be based on the idea that there are all sorts of wonderful cures out there that for some reason are tied up in sloth and red tape. It isn't so. Clearing out bureaucratic obstacles, while no picnic, is still a lot easier than discovering drugs. And allowing patients access after a Phase I does not offer very good odds, considering that almost all clinical failures take place later than that. Plenty of tox gets discovered later than that, too - only the fast and nasty stuff gets picked up in Phase I.

So overall, I think that these laws offer, for the most part, chances for people to feel good about themselves for voting for them, and chances for patients to get their hopes up, likely for no reason. Even with that, I don't see them doing much harm compared to the existing regulatory regime, except for the provisions that offer companies the chance to charge money. Those give the added bonus of opening the door to unscrupulous quacks, some of whom might have very creative ideas of what "at cost" might mean.

According to Biocentury, a Colorado company is already planning to offer access through this program:

Neuralstem Inc. (NYSE-M:CUR) plans to take advantage of Colorado's right-to-try law to offer patients access to an experimental, unapproved human neural stem cell (hNSC) therapy (NSI-566) to treat amyotrophic lateral sclerosis. President and CEO Richard Garr told BioCentury the company will not apply for an IND or other permission from FDA, noting that "the Colorado right-to-try law allows a company to prescribe for a fatal disease a therapy that has passed a Phase I safety trial and is being actively pursued in a Phase II trial." Garr said Neuralstem's hNSC ALS therapy meets these criteria, and the company plans to start a Phase III trial next year.
Neuralstem is in the process of training surgeons and identifying a hospital and neurologists in Colorado to administer the hNSC therapy. The therapy will be administered with the identical procedure, cells and training as a clinical trial, but without FDA oversight and without "the artificial limitations built around a trial," said Garr. "The whole point of right-to-try is it sits parallel to the clinical trial process, it is not instead of clinical trials." Neuralstem has not determined whether it will charge Colorado patients.

I know nothing about Neuralstem or their therapy, so I'll defer comment until I learn more. Looks like we're going to see how this works, whether we're ready for it or not.

Comments (25) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Regulatory Affairs

March 13, 2014

The Reasons for Failure at the FDA

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Posted by Derek

Here's a good retrospective in JAMA, from the FDA, about what's happened when the agency has rejected a new molecule entity (NME). The authors look over the data set from 2000-2012 to see what the most common reasons for trouble were, and what happened after that in each case.

Overall, 302 new molecules were submitted during those years. Half of them were rejected the first time through - a figure that does not jibe with most investors' ideas of the prospects for any given drug, for sure. But Tolstoy was right - approved drugs are all alike, but every rejected one is rejected in its own way. Looking over those, it appears that a bit under half of the rejects eventually did get approved (meaning that, ultimately, about 73% of all NMEs do eventually make it). But the median delay to approval, after that first rejection, was well over a year.

And that has to do with the reasons for rejection. They vary, and none of them are easily fixed:

Of the unsuccessful first-time applications, 24 (15.9%) included uncertainties related to dose selection, 20 (13.2%) choice of study end points that failed to adequately reflect a clinically meaningful effect, 20 (13.2%) inconsistent results when different end points were tested, 17 (11.3%) inconsistent results when different trials or study sites were compared, and 20 (13.2%) poor efficacy when compared with the standard of care.

But you'll note that while some of these are just nasty results in the clinic (like insufficient efficacy), some of them could also have presumably been mitigated a bit. You can see how crucial good trial design is when you note how many problems there are around endpoint selection and dosing. Now, it's also true that well-designed well-powered trials are invariably more expensive than most of the alternatives, and smaller companies are often running on fumes by the time they get to the end, but compare the pain of spending the time and money up front to the pain of a Complete Response Letter.

Taking a look at the ones that never did get approved shows a definite bias towards efficacy problems. Overall, safety concerns were similar between that group and delayed-approval group, but lack of efficacy was a problem with 76% of the never-approved drugs, almost double the rate of the delayed approvals. So the take-home is that you may be able to rescue a drug with safety concerns, given time and money, but there is likely to be no cure for poor efficacy.

And that's just what I think the effect of the FDA regulatory process should be. Once in a while, you hear calls for the agency to just let everything through as long as it's shown safety, to let the medical community and the marketplace sort it out. And although I'm a laissez-faire kind of guy, I think that would be a recipe for disaster. You'd have people selling repackaged barbecue sauce in gel caps as a cure for cancer. I'd rather have the agency focus on efficacy, and even let some drugs through that have some safety concerns, as long as they're known (as much as practical) up front and monitored thereafter. Just as long as they work against a disease.

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January 27, 2014

The 2013 Crop of New Drugs

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Posted by Derek

Here's Lisa Jarvis's roundup of the 2013 drug approvals (PDF version). There's also a list of notable late-stage clinical failures, and unfortunately, these tended to be potentially bigger drugs than the ones that got through last year.

I have to wonder if the structures included along with the chart were chosen especially to highlight the occasional "non-druglike" features (acrylamides, aminals, and so on). It's well worth taking a look at new-approval lists and things like the Top 200 Drugs posters to remind yourself that structures you might have crossed off the screening list are out there making hundreds of millions of dollars.

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January 24, 2014

PTC's Latest Ataluren Woes

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Posted by Derek

I wrote here about PTC Therapeutics and their drug candidate for Duchenne muscular dystrophy (ataluren, PTC124). Opinion has been divided, to put it mildly, about how it works and whether it works at all.

Well, the saga continues. The company is having a rough time with that program these days, though. PTC applied to the European Medicines Agency for conditional approval of ataluren, but that request has just been firmly rejected.

Ataluren failed both a Phase IIb study for DMD as well as a Phase III study for cystic fibrosis, yet the biotech went on to wrap one of 2013's hottest IPOs in the resurgent biotech field, grabbing $125 million from investors. And over the last month its stock price jumped 37%.

Peltz has argued for years now that even though ataluren hasn't produced statistically significant results in later stage studies, the improvements in walking distance warranted an approval. But the EMA has now formally said no, leaving the drug's fate to be decided by a late-stage study the biotech describes as "confirmatory."

Hey, they might be right in that description - the Phase III might confirm the Phase II results and show that the drug truly does not work. And it looks like the regulatory agencies are thinking the same way. . .

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January 16, 2014

Merck Pulls One Out

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Posted by Derek

Merck's vorapaxar, a thrombin antagonist that many had thought might never make it, has received a positive FDA advisory committee vote. I'm glad to see it - peripherally, I go way back with this compound (well, its ancestors), and I really had doubts that Merck could get things to fly. Anticoagulants are a very tricky business - we'll see (if and when it does get approved) what sort of market it can carve out. They're up for treating patient who have already had one cardiac event, which is still a good-sized market.

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January 6, 2014

The 2013 Drug Approvals: Not So Great?

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Posted by Derek

So we finished the year with 27 new drugs approved. Compared to the 39 approvals the year before, is that a reversion to the mean, a sudden downturn, a meaningless fluctuation, or what?

John Carroll seems to be in the "something to worry about" camp at FierceBiotech:

The wave of new drug approvals that had been building at the FDA has broken. According to the official tally of new drug and biologics approvals at the agency, the biopharma industry registered only 27 OKs for new entities in 2013--a sharp plunge from 2012's high of 39 that once again raises big questions about the productivity and sustainability of the world's multibillion-dollar R&D business.

After 2012 some experts boasted that the industry had turned a corner, with the agency boasting that it was outstripping the Europeans in the speed and number of new drug approvals. But for 2013 the numbers look a lot closer to the bleak average of 24 new approvals per year seen in the first decade of the millennium than the 35 per year projected by McKinsey through 2016.

And here's Bernard Munos at Forbes on the same topic. He thinks that looking at the industry as a monolith might be obscuring something:

Overall, 2013 was good or great for half of big pharma, and forgettable for the rest. Is this the beginning of a split in the group that has long dominated the industry? Some companies may counter that approval statistics is a lagging indicator that reflects past performance and not the promise of their pipelines. If one looks at FDA’s Breakthrough Designations, however, which is a leading indicator of pipeline quality, they tend to show the same picture, and cluster around the companies that have been most successful. . .Success seems to beget success, which suggests that today’s winners may also be tomorrow’s winners.

One thing remains worrisome: 11 new drugs per year — the average big pharma output for the last 5 years — is not enough to support these companies’ $370 billion of current sales, especially since only 3 or 4 will become blockbusters. The giddy promises to deliver 2 drugs per year consistently have not materialized, and there is no indication that they will. . .

(You can tell he's never gotten over Lilly's promise some years ago to deliver approvals on that schedule, and who could blame him)? As for me, I wish that I had some sort of crystal-ball insight to deliver, but I don't. Drug discovery (and thus NDA filings and approvals) seems to be such a statistically noisy process that it's hard to draw conclusions from a year or two of data. Let's watch what happens this year and see both what the numbers are and how the FDA and the companies involve try to interpret them. One thing to note already is how some people were ready to use the 2012 approvals as clear evidence that the industry was getting more productive - are the 2013 numbers such clear evidence in the other direction, or not?

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December 23, 2013

Merry Christmas From the FDA

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Posted by Derek

I see that the FDA is in the holiday spirit - they've told Ariad that they can bring Iclusig back to the market in the US, subject to restrictions, and Amarin, who have been trying, quite unsuccessfully, to get approval for wide use of a fish-oil-pill, have at least gotten a stay of execution for now. And in what is a real surprise, United Therapeutics got approval for an oral version of treprostinil, a synthetic prostaglandin analog, for PAH. Since they'd been turned down twice before on that one, I don't think anyone anticipated that one, since it hadn't looked too impressive in the clinic.

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November 27, 2013

23 And Me And the FDA

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Posted by Derek

As everyone will have heard the personal-genomics company 23 and Me was told by the FDA to immediately stop selling their product, a direct-to-consumer DNA sequence readout. Reaction to this has been all over the map. I'll pick a couple of the viewpoints to give you the idea.

From one direction, here's Matthew Herper's article, with the excellent title "23 And Stupid". Here's his intro, which makes his case well:

I’d like to be able to start here by railing against our medical system, which prevents patients from getting data about our own bodies because of a paternalistic idea that people can’t look at blood test results, no less genetic information, without a doctor being involved or the government approving the exact language of the test. I’d like to be able to argue that the Food and Drug Administration is wantonly standing in the way of entrepreneurism and innovation by cracking down on 23andMe, a company that is just trying to give patients the ability to know about their own DNA, to understand their own health risks, and to participate in science.

I wish that was the story I’m about to write, but it’s not, and it all really comes down to one fact in the FDA’s brutally scathing warning letter to 23andMe, the Google-backed personal genetics startup. It’s this quote from the letter by Ileana Elder, in the agency’s diagnostics division: “ FDA has not received any communication from 23andMe since May.”

So we can call that one the practical view: "It doesn't matter what you think about 23 and Me's product, and it doesn't matter what you think about the FDA. They're supposed to be working with the FDA, they knew it, but they haven't done squat about it, so what did you expect the agency to do, anyway?". From that, let's go to the idealistic view, from economist Alex Tabarrok at Marginal Revolution, who writes just the sort of article that Herper deliberately passes up the chance to:

Let me be clear, I am not offended by all regulation of genetic tests. Indeed, genetic tests are already regulated. To be precise, the labs that perform genetic tests are regulated by the Clinical Laboratory Improvement Amendments (CLIA) as overseen by the CMS (here is an excellent primer). The CLIA requires all labs, including the labs used by 23andMe, to be inspected for quality control, record keeping and the qualifications of their personnel. The goal is to ensure that the tests are accurate, reliable, timely, confidential and not risky to patients. I am not offended when the goal of regulation is to help consumers buy the product that they have contracted to buy.
What the FDA wants to do is categorically different. The FDA wants to regulate genetic tests as a high-risk medical device that cannot be sold until and unless the FDA permits it be sold.

Moreover, the FDA wants to judge not the analytic validity of the tests, whether the tests accurately read the genetic code as the firms promise (already regulated under the CLIA) but the clinical validity, whether particular identified alleles are causal for conditions or disease. The latter requirement is the death-knell for the products because of the expense and time it takes to prove specific genes are causal for diseases. Moreover, it means that firms like 23andMe will not be able to tell consumers about their own DNA but instead will only be allowed to offer a peek at the sections of code that the FDA has deemed it ok for consumers to see.

The thing is, I can see merits in both these views. And you know, they're not mutually exclusive, either, not as much as it looks like at first glance. I don't even think that the FDA itself thinks that they're so mutually exclusive, if you read their letter (emphasis added):

The Office of In Vitro Diagnostics and Radiological Health (OIR) has a long history of working with companies to help them come into compliance with the FD&C Act. Since July of 2009, we have been diligently working to help you comply with regulatory requirements regarding safety and effectiveness and obtain marketing authorization for your PGS device. FDA has spent significant time evaluating the intended uses of the PGS to determine whether certain uses might be appropriately classified into class II, thus requiring only 510(k) clearance or de novo classification and not PMA approval, and we have proposed modifications to the device’s labeling that could mitigate risks and render certain intended uses appropriate for de novo classification. Further, we provided ample detailed feedback to 23andMe regarding the types of data it needs to submit for the intended uses of the PGS. As part of our interactions with you, including more than 14 face-to-face and teleconference meetings, hundreds of email exchanges, and dozens of written communications, we provided you with specific feedback on study protocols and clinical and analytical validation requirements, discussed potential classifications and regulatory pathways (including reasonable submission timelines), provided statistical advice, and discussed potential risk mitigation strategies. As discussed above, FDA is concerned about the public health consequences of inaccurate results from the PGS device; the main purpose of compliance with FDA’s regulatory requirements is to ensure that the tests work.

As much as I might agree with Alex Tabarrok in principle, I think he's missing a key point here. The FDA is not telling everyone that they don't own their own DNA information, and that they can't see it unless the agency lets them. The agency is saying that 23 and Me can certainly make a business out of selling people their own DNA sequence information, but if they do so by explicitly claiming medical benefits or diagnostic uses, then their business will fall under the FDA's jurisdiction. From their letter, it appears that they have been telling the company this over and over for several years now, during which 23 and Me has, apparently, been dragging their feet and trying to have it both ways. As the FDA letter notes:

For example, your company’s website at (most recently viewed on November 6, 2013) markets the PGS for providing “health reports on 254 diseases and conditions,” including categories such as “carrier status,” “health risks,” and “drug response,” and specifically as a “first step in prevention” that enables users to “take steps toward mitigating serious diseases” such as diabetes, coronary heart disease, and breast cancer.

I'll add a bitter, cynical note: if only 23 and Me had been able to come up with some way to market their DNA test as a nutritional supplement, they'd be in the clear. Maybe some sort of sugar pill that you took before you spit in the little sample container? Then they could say "Not intended to treat, cure, or modify any disease" at the bottom of the page, in six-point microtype, and everything would have been fine, as if by magic. No one would have paid any attention to it, of course, because no one ever pays any attention to that language when they go out and buy all kinds of "supplements", and the FDA would have staggered backwards at the sight of Orrin Hatch's law, like Christopher Lee in a Hammer vampire film being hosed down with a face full of holy water.

Well, that might not have worked perfectly, but it would have worked better than what 23 and Me actually tried. They wouldn't have sold nearly as many DNA tests without talking about preventing disease and making medical decisions in their advertising, true, but those are the breaks. I think that if they'd stuck to some neutral language, rather than presenting Immediate Actionable Medical Decisions, they might well have stayed out of trouble.

Update: via Matt Herper's Twitter feed, here's an interesting take on the whole situation. 23 and Me has been hoping to get some real (and really profitable) insights into population genomics by accumulating such a large sample size. Have they? The way they're acting makes one think that nothing good has popped up yet. . .

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November 13, 2013

Sarepta's Approval Woes

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Posted by Derek

I briefly mentioned Sarepta and etiplirsen, their proposed therapy for Duchenne muscular dystrophy (DMD) in September. In that post, I made reference to the "delirious fun of investing in biotech". Well, the company recently got some regulatory news that illustrates that point even more clearly. The FDA told Sarepta that it would not get accelerated approval for the drug, and that sent the stock into a mineshaft (and infuriated the DMD community, as you might well think).

Matthew Herper at Forbes has some good background on the story here Etiplirsen is one of these drugs aimed at a small market (one particular DMD mutation). And the clinical data were pretty thin:

It can be hard to imagine saying no to a plea like that – but sometimes that is the FDA’s job. As one muscular dystrophy expert told me when I wrote about Sarepta’s results earlier this year, it was always possible that it might be “too much to hope for” to think that eteplirsen could be approved based on the data so far. Eteplirsen was studied in only twelve boys, half of whom received the medicine immediately, the other half of whom initially got placebo but then switched to taking the drug. Those who started on the medicine earlier have higher levels of dystrophin, at least according to muscle biopsies, and appeared to be able to walk a greater distance in six minutes, a sign that their muscles are deteriorating less quickly.

Unfortunately, great results from small trials have a history of not bearing out in larger studies. Even for rare disease drugs, this study was tiny. Worse, the Sarepta results only look good when two of the 12 patients are excluded – two boys were too sick to be helped by the drug. The FDA usually insists that clinical trials be presented in what is known as an “intent-to-treat” analysis, which means that if you even thought about treating a patient they need to be included when you do the math on the study’s results. This is intended to keep scientists from lying to themselves, convincing themselves that a drug works when it doesn’t. One biotech executive with a great deal of experience in rare diseases told me recently that this issue meant the data “would never fly” with the FDA. The recent failure of a similar, but less effective, drug from Prosensa and GlaxoSmithKline GSK -1.64% made the odds dimmer.

And Adam Feuerstein of, who thought that the company would get the accelerated designation, has a look at the decision here. He spoke with a bearish investor who made this case:

The FDA's issues with trial design are so wide-ranging that it seems like wishful thinking that Sarepta will be able to agree on a study design and start enrolling by the second quarter 2014.

Major questions with dystrophin quantitative assay. Questions with results of anything less than two years. Need for a larger study to power the six-minute walk test (6MWT) data. Possible need to expand study population both high and low and go beyond 6MWT as primary endpoint. The FDA is very deeply skeptical and Sarepta will have a difficult time coming to a study design that the company thinks they can do and that the FDA will be satisfied with.

And any trial seems likely to last 2 years. Seems to me that even if all goes well, approval would get pushed out much more than two years. They're going to spend 9 months arguing over study design and probably won't start enrolling until early 2015. Two-year trial plus filing and approval. Sounds like early 2018 approval at best.

I have to say, this is consistent with worries resulting from the Prosensa trial that the market ignored. But it's actually even more negative that I expected. I thought the FDA would just say, do a larger trial along the same lines. What they're saying is much more confused than that. What is a valid marker and what do you need to get the data to support it?

It makes you wonder whether the FDA really changed their minds lately or if Sarepta misrepresented (through wishful thinking or worse) what the FDA had been telling them all along.

The agency really did made things much trickier than most people had been expecting. They're talking about completely new endpoints, rather than just shoring up the data collected so far (which was already more than the company's boosters were willing to think about, in some cases). I don't envy the folks at the FDA, but then, I never do. They get to look like heartless bureaucrats, bleating about numbers while children are suffering. The flip side, though, is trying to keep people from raising their hopes for something that does no good. If we approve things that just look as if they might work, all sorts of charlatans will rush in, human nature being what it is.

But we're not talking about approval here, just an accelerated protocol for it. Surely they could have at least agreed to fast-track this one? I think, though, that the FDA saw itself being put into an untenable position. They did not think that there was enough solid evidence to approve the drug as it stood, and accelerated approval would ensure that no more was going to be forthcoming. All that would do would be to get everyone's hopes up even more, for what still would looked very much like a rejection based on insufficient data. And in that case, why not tell the company now and get it over with?

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November 8, 2013

The Other Shoe Drops at Ariad

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Posted by Derek

Ever since Iclusig (ponatinib) (note: fixed that name as an update) ran into trouble with blood-cloting side effects, Ariad has had a huge uncertain cloud blocking out its sunlight. Now that the FDA has told them to take the drug off the market completely, it was clear what was going to happen. Happen it has: the company is laying off a large part of its workforce.

It's very much in doubt whether Iclusig will ever come back. Update: in Europe, the EMA has now said that Iclusig can remain on the market "with increased caution").And if it doesn't, it's very much in doubt whether Ariad will, or how long that might take. There's a large, mostly-completed building around the corner from me covered in blue-green glass that was going to be the home of a larger, more solvent Ariad, and no one knows what's going to happen to that, either. It's a rough business.

Update: turns out the blue-green glass one was going to be Aveo, which cratered earlier this year. Who's going to occupy that, one wonders? Ariad's is the less-complete large framework going up across from the (incongruous) Mormon church. That's a pretty large building, or will be, and you wonder who will end up in there. There are so many biopharma construction sites in this town that you need a guidebook.

Comments (23) + TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs

October 30, 2013

The FDA: Too Loose, Or Appropriately Brave?

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Posted by Derek

The topic of the various "accelerated review" options at the FDA has come up here before. Last month JAMA ran an opinion piece suggesting that the agency has gone too far. (Here's the Pharmalot take on the article). This, of course, is the bind the agency is always in. Similar to the narrow window with an anticoagulant drug (preventing clots versus encouraging hemorrhages), the FDA is constantly getting complaints that they're stifling innovation by setting regulatory barriers too high, and that they're killing patients by letting too many things through. It's an unwinnable situation - under what conditions could neither camp feel wronged?

The FDA defended its review procedures at the time, but now (according to BioCentury Extra, a more emphatic statement has been made:

FDA's Richard Pazdur, director of CDER's Office of Hematology & Oncology Products (OHOP), made it clear at an FDA briefing on personalized medicine on Monday that the agency is willing to take risks to get drugs for serious and life-threatening diseases to patients quickly. Pazdur said, "If we are taking appropriate risks in accelerated approval, some drugs will come off market, some will have restricted labeling." If that doesn't ever happen, "we probably aren't taking the appropriate risks," he said.

It reminds me of the advice that if your manuscripts are all getting accepted, then you aren't sending them to good enough journals. I agree with Pazdur on this one, and I wish that this attitude was more widely circulated and understood. Every new drug is an experimental medication. No clinical trial is ever going to tell us as much as we want to know about how a drug will perform in the real world, because there is no substitute and no model for the real world. (Anyone remember the old Steven Wright joke about how he'd just bought a map of the US - actual size? Down in the corner, it says "One mile equals one mile".)

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October 21, 2013

Catalyst Pharmaceuticals And Their Business Plan

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Posted by Derek

The orphan-drug model is a popular one in the biopharma business these days. But like every other style of business, it has something-for-nothing artists waiting around it. Take a look at this article by Adam Feuerstein on Catalyst Pharmaceuticals, and see what category you think they belong in.

They're developing a compound called Firdapse for Lambert-Eaton Myasthenic Syndrome (LEMS), a rare neuromuscular disorder. It's caused by an autoimmune response to one set of voltage-gated calcium channels in the peripheral nervous system. Right now, the treatments for the condition that seem to provide much benefit are intravenous immunoglobin and 3,4-diaminopyridine (DAP). That latter compound is a potassium channel blocker that allows calcium to accumulate intracellularly in neurons and thus counteracts some of the loss of function in the system.

DAP is not an FDA-approved treatment, but it's officially under study at a number of medical centers, and the FDA is allowing it to be given to patients under a compassionate-use protocol. It's supplied, free of charge, by a small company in New Jersey, Jacobus Pharmaceuticals, who got into the area through a request from the Muscular Dystrophy Association. So how well does Firdapse work compared to this existing drug? Pretty much the same, because it's the same damn compound.

Yep, this is another one of those unexpected-regulatory-effects stories, such as happened with colchicine and with hydroxyprogesterone. The FDA has wanted to get as many therapies as possible through the actual regulatory process, and has provided a marked-exclusivity incentive for companies willing to do the trials needed. But if you're going to offer incentives, you need to think carefully about what you're giving people an incentive to do. In this case, the door is open for a company to step in, pick up an existing drug that is being given away to patients for free, a compound that it has spent no money discovering and no money developing, run the fastest trial possible with it, and then jack the price up to whatever the insurance companies might be able to pay. Now, pricing drugs at what the market will pay for them is fine by me. But that's supposed to be a reward for taking on the risk of discovering them and getting them through the approval process. This Catalyst case is another short-circuit in the system, a perverse incentive that some people seem to have no shame about taking advantage of. A similar situation has taken place in the EU with DAP and Biomarin Pharmaceuticals.

The LEMS patient community is not a large one, and they seem to be getting the word out for people to not sign up for Catalyst's clinical trials. Jacobus themselves have realized what's going on, and are running a trial of their own, hoping to file before Catalyst does and pick up the market exclusivity for themselves, so they can continue to supply the compound at the current price: nothing.

It's worth taking a minute to contrast this situation with Biogen's Tecfidera. That's another very small molecule (dimethyl fumarate) being given to patients with a neurological disease. It's also expensive. But in this case, MS patients had not been taking dimethyl fumarate for years (to the best of my knowledge). It was not already in the medical literature as an effective treatment (the way DAP is already there for LEMS). Biogen bought the company with the rights (Fumapharm) and took on the expense of the clinical trials, taking the risk that things might not work out at all. A lot of stuff doesn't. And they're pricing their drug according to what the market will pay, because they also have to fund the many other projects they're working on, most of which can be expected to wipe out at some point.

So how does a situation like Catalyst and DAP affect the drug companies who actually do research? Not too much, you might think, and they apparently think so, too, because I don't recall any statements about any of these cases so far from that end of the industry. They may not want to take any stands that call into question the ability of a company to set the price of its drugs according to what it thinks the market will bear. But since we are not, last I saw, living in some sort of radical libertarian free-for-all, it would be worth remembering that the ability to set such prices is not some sort of inalienable right. It can be restricted or even abrogated entirely by governments all around the world. And one way to get that to happen is for these governments and (in the democratic states, their constituents) to feel as if they're being taken advantage of by a bunch of cynical manipulators.

Comments (19) + TrackBacks (0) | Category: Drug Prices | Regulatory Affairs | The Central Nervous System

October 18, 2013

Ariad (And Its Drug) In Trouble

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Posted by Derek

Ariad's Inclusig (ponatimib) is in even more trouble than it looked like, and that was already a lot. The company announced earlier this morning that its Phase III trial comparing the drug to Gleevec (imatinib) is not just on hold - it's been stopped, and patients are being taken off the drug. That can't be good news for the drug's current approved status, either:

Iclusig is commercially available in the U.S. and EU for patients with resistant or intolerant CML and Philadelphia-chromosome positive acute lymphoblastic leukemia. ARIAD continues to work with health authorities to make appropriate changes to the Iclusig product labeling to reflect the recently announced safety findings from the pivotal PACE trial that was the basis of its marketing approvals.

If the approval trial has now shown such unfavorable safety, is approval still warranted at all? That's what investors are wondering, and I would imagine that the oncologists who would be prescribing Inclusig are wondering the same thing. This is bad news for everyone. There are patients who very much need a drug like this for resistant CML, and Ariad (needless to say) needs to be selling it. I believe that the company is putting up a new building, not far from where I work, and you have to wonder if there are some clauses in the contract that are going to need to be invoked. Do sudden adverse events with your main commercial product count as force majeure?

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October 9, 2013

Ariad's Ponatinib Runs Into Big Trouble

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Posted by Derek

Just a note, in case any investors didn't realize it: no, drugs (and a drug companies) are not out of the woods after a compound has been approved and is on the market. Take a look at what's happening to Ariad and their BCR-ABL compound Iclusig (ponatinib). This is used to treat patients that have become resistant to Gleevec, and it's a very big deal for both those patients and for Ariad as a company.

But the percentage of patients on the drug showing serious complications from blood clots has been rising, and that's prompted a number of moves: enrollment in further clinical trials is on hold, dosages are being lowered for current patients, and the product's label is being changed to add warnings of cardiovascular effects. If you're wondering how this affects Ariad as a whole, well, the stock is down 66% in premarket trading as I write. . .

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September 25, 2013

Sugammadex's Problems: Is the Merck/Schering-Plough Deal the Worst?

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Posted by Derek

That didn't take long. Just a few days after Roger Perlmutter at Merck had praised the team that developed Bridon (sugammadex), the FDA turned it down for the second time. The FDA seems to be worried about hypersensitivity reactions to the drug - that was the grounds on which they rejected it in 2008. Merck ran another study to address this, but the agency apparently is now concerned about how that trial was run. What we know, according to FiercePharma, is that they "needed to assess an inspection of a clinical trial site conducting the hypersensitivity study". Frustratingly for Merck, their application was approved in the EU back in that 2008 submission period.
It's an odd compound, and it had a nomination in the "Ugliest Drug Candidate" competition I had here a while back. That's because it works by a very unusual mechanism. It's there to reverse the effects of rocuronium, a neuromuscular blockade agent used in anaesthesia. Sugammadex is a cyclodextrin derivative, a big cyclic polysaccharide of the sort that have been used to encapsulate many compounds in their central cavities. It's the mechanism behind the odor-controlling Febreze spray - interestingly, I've read that when that product was introduced, its original formulation failed in the market because it had no scent of its own, and consumers weren't ready for something with no smell that nonetheless decreased other odors). The illustration is from the Wikipedia article on sugammadex, and it shows very well how it's designed to bind rocuronium tightly in a way that it can no longer at at the acetylcholine receptor. Hats off to the Organon folks in Scotland who thought of this - pity that all of them must be long gone, isn't it?

You see, this is one of the drugs from Schering-Plough that Merck took up when they bought the company, but it was one of the compounds from Organon that Schering-Plough took up when they bought them. (How much patent life can this thing have left by now?) By the way, does anyone still remember the ridiculous setup by which Schering-Plough was supposed to be taking over Merck? Did all that maneuvering accomplish anything at all in the end? At any rate, Merck really doesn't seem to have gotten a lot out of the deal, and this latest rejection doesn't make it look any better. Not all of those problems were (or could have been) evident at the time, but enough of them were to make a person wonder. I'm willing to nominate it as "Most Pointless Big Pharma Merger", and would be glad to hear the case for other contenders.

Comments (29) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Pharmacokinetics | Regulatory Affairs | Toxicology

September 13, 2013

Value For the Money

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Posted by Derek

BioCentury always does a big issue for the fall, entitled "Back to School". They often use this as a state-of-biopharma platform, going into depth on what they see as the biggest issues that need to be addressed. This year, the September 2 issue, they're telling people (and not for the first time!) to get braced for higher standards for what health insurance is going to pay for:

Drug companies must start creating the case for value differentiation in discovery and then steadily build a body of evidence throughout the product development process.

Some drug developers have figured this out and have reshaped both their pipelines and development practices accordingly. But the number of me-too and purportedly me-better products still in the pipeline — coupled with the fact that drugs are still getting to Phase III and beyond without comparisons to relevant SOC (standard of care) or data on quality of life and other metrics that patients value — shows efforts in this department are still wanting.

For example, BioCentury’s BCIQ online database shows 54 compounds in active development that target VEGF or its receptors, not counting line extensions of approved VEGF and VEGF receptor inhibitors.

Even accounting for different variants of the receptor and its ligand and differences in delivery, formulation and dosing, it is highly unlikely that so many compounds could be differentiated sufficiently that physicians and patients would strongly prefer them to marketed alternatives — or that payers would be willing to reimburse them without restrictions.

. . .Back to School argues bio-industry must abandon efforts to block third-party assessments of value, and instead ramp up nascent efforts to be at the table where technology assessment takes place in the U.S., Europe and the rest of the world. Comparative effectiveness and cost effectiveness assessments will not be stopped. Industry can either contribute its expertise to improve the quality of the results, or stand by while others who may know less about both the drugs and the best ways to study them do the work based on their own priorities. Right now that priority is finding ways to avoid paying for new drugs.

Well put. But doing so is not going to be easy, or cheap. Differentiating new drug candidates in the clinic has often been left for later on in Phase III, and smaller companies often don't do much of it at all, figuring that'll be a job for their bigger partners when the time comes. The FDA "Breakthrough" designations can help here, because they explicitly encourage companies to show, as early as possible, why their compound stands out from the others. But as the Biocentury piece goes on to say, even then companies are going to have to be get ready to collect even more data on real-world outcomes, after the drug is approved, if they want to be able to persuade the various payers out there.

There's another issue here, too. Incremental innovation is just as much a part of the business (and the science) as are sudden leaps forward. There's room to wonder if the frequency of those sudden leaps (and the distance they cover) will go down if we don't get to take as many steps in the run-up to them. This is one of those issues that moves slowly enough to be effectively unprovable on any sort of reasonable financial or political time scale, but there are a lot of very real things out there that don't fit themselves to our calendars.

BioCentury recommends that (1) companies should work with regulatory agencies, insurance (both public and private), and patient groups to define just what constitutes real value for a given disease area, (2) they should immediately get to work with those payers who are already mandated to show improvements in their quality of care, (3) as mentioned above, whenever some government or international agency starts rating health care and medical technology advances, the industry had better be there, and (4) the drug industry had better change some of its traditional attitudes, and fast, because its pricing power is clearly diminishing.

As a drug-discovery guy, I don't spend as much time thinking about these issues as I do scientific ones. But if I'm discovering new things that no one wants, because no one needs them, that no one will then feel like paying for, all my work (and that of my colleagues) will be in vain. None of us can afford to keep our heads down these days.

Comments (20) + TrackBacks (0) | Category: Business and Markets | Drug Prices | Regulatory Affairs

August 19, 2013

Is The FDA the Problem?

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Posted by Derek

A reader sends along this account of some speakers at last year's investment symposium from Agora Financial. One of the speakers was Juan Enriquez, and I thought that readers here might be interested in his perspective.

First, the facts. According to Enriquez:

Today, it costs 100,000 times less than it once did to create a three-dimensional map of a disease-causing protein

There are about 300 times more of these disease proteins in databases now than in times past

The number of drug-like chemicals per researcher has increased 800 times

The cost to test a drug versus a protein has decreased ten-fold

The technology to conduct these tests has gotten much quicker
Now here’s Enriquez’s simple question:

"Given all these advances, why haven’t we cured cancer yet? Why haven’t we cured Alzheimer’s? Why haven’t we cured Parkinson’s?"

The answer likely lies in the bloated process and downright hostile-to-innovation climate for FDA drug approvals in this day and age...

According to Enriquez, this climate has gotten so bad that major pharmaceuticals companies have begun shifting their primary focus from R&D of new drugs to increased marketing of existing drugs — and mergers and acquisitions.

I have a problem with this point of view, assuming that it's been reported correctly. I'll interpret this as makes-a-good-speech exaggeration, but Enriquez himself has most certainly been around enough to realize that the advances that he speaks of are not, by themselves, enough to lead to a shower of new therapies. That's a theme that has come up on this site several times, as well it might. I continue to think that if you could climb in a time machine and go back to, say, 1980 with these kinds of numbers (genomes sequenced, genes annotated, proteins with solved structures, biochemical pathways identified, etc.), that everyone would assume that we'd be further along, medically, than we really are by now. Surely that sort of detailed knowledge would have solved some of the major problems? More specifically, I become more sure every year that drug discovery groups of that era might be especially taken aback at how the new era of target-based molecular-biology-driven drug research has ended up working out: as a much harder proposition than many might have thought.

So it's a little disturbing to see the line taken above. In effect, it's saying that yes, all these advances have been enough to release a flood of new therapies, which means that there must be something holding them back (in this case, apparently, the FDA). The thing is, the FDA probably has slowed things down - in fact, I'd say it almost certainly has. That's part of their job, insofar as the slowdowns are in the cause of safety.

And now we enter the arguing zone. On the one side, you have the reducio ad absurdum argument that yes, we'd have a lot more things figured out if we could just go directly into humans with our drug candidates instead of into mice, so why don't we just? (That's certainly true, as far as it goes. We would surely kill off a fair number of people doing things that way, as the price of progress, but (more) progress there would almost certainly be. But no one - no one outside of North Korea, anyway - is seriously proposing this style of drug discovery. Someone who agrees with Enriquez's position would regard it as a ridiculous misperception of what they're calling for, designed to make them look stupid and heartless.

But I think that Enriquez's speech, as reported, is the ad absurdum in the other direction. The idea that the FDA is the whole problem is also an oversimplification. In most of these areas, the explosion of knowledge laid out above has not yet let to an explosion of understanding. You'd get the idea that there was this big region of unexplored stuff, and now we've pretty much explored it, so we should really be ready to get things done. But the reality, as I see it, as that there was this big region of unexplored stuff, and we set into to explore it, and found out that it was far bigger than we'd even dreamed. It's easy to get your scale of measurement wrong. It's quite similar to the way that humanity didn't realize just how large the Earth was, then how small it was compared to the solar system (and how off-center), and how non-special our sun was in the immensity of the galaxy, not to mention how many other galaxies there are and how far away they lie. Biology and biochemistry aren't quite on that scale of immensity, but they're plenty big enough.

Now, when I mentioned that we'd surely have killed off more people by doing drug research by the more direct routes, the reply is that we've been killing people off by moving too slowly as well. That's a valid argument. But under the current system, we choose to have people die passively, through mechanisms of disease that are already operating, while under the full-speed-ahead approaches, we might lower that number by instead killing off some others in a more active manner. It's typically human of us to choose the former strategy. The big questions are how many people would die in each category as we moved up and down the range between the two extremes, and what level of each casualty count we'd find "acceptable".

So while it's not crazy to say that we should be less risk-averse, I think it is silly to say that the FDA is the only (or even main) thing holding us back. I think that this has a tendency to bring on both unnecessary anger directed at the agency, and raise unfulfillable hopes in regards to what the industry can do in the near term. Neither of those seem useful to me.

Full disclosure - I've met Enriquez, three years ago at SciFoo. I'd be glad to give him a spot to amplify and extend his remarks if he'd like one.

Comments (40) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Regulatory Affairs

July 17, 2013

More on the NIH and Its Indian Clinical Trials

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Posted by Derek

Steve Usdin of BioCentury sends along word that they've managed to get a tiny bit more out of the NIH on the Indian clinical trials business. As opposed to the happy-talk that they gave FiercePharma the day before, the agency was now willing to confirm that enrollment has been stopped in some Indian trials, while others have been postponed. No numbers, though. They said that they hoped that "future changes will enable studies to resume", which is a bit of a telling statement in itself, suggesting that the current situation will not allow that at all.

The most detailed account of the situation remains the report in the Live Mint newspaper, an Indian source affiliated with the Wall Street Journal. That article mentions the "unstable regulatory environment" as the big factor, but according to BioCentury, this might be the biggest problem:

The new regulations require clinical trial sponsors to provide compensation to patients who suffer injury or death during or as a result of the trial, including as a result of the "failure of investigational product to provide intended therapeutic effect"

Oh, boy. If companies find themselves having to compensate everyone - in unspecified amounts - that joins a Phase II trial where the compound turns out not to work, that'll mount up fast. We have high failure rates around here, as everyone knows, and everyone involved (investors, patients, clinical trial participants) should be aware of that going in and act accordingly. I believe that both companies and granting agencies feel as if they're paying quite enough money already for the way that many drugs don't work in the clinic.

Comments (3) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs

July 10, 2013

On the Priority Breakthrough Accelerated Fast Track

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Posted by Derek

So the FDA has the good ol' drug approval process. And then there's Priority Review, and Fast Track, and Accelerated Approval, and now the Breakthrough designation. What, exactly, do all these things mean, and how are they different?

Matthew Herper has a good overview here at Forbes. In short, Priority Review is supposed to take a few months off the usual review period. Fast Track is for drugs that target some unmet medical need, and speeds up their review as well. Accelerated Approval is the process for approving important unmet-need drugs based on preliminary data, with a review once larger studies are completed. (That, for example, is what Avastin went through for its onetime breast cancer indication). Note that these categories aren't mutually exclusive; a drug can have more than one at a time.

And the new "Breakthrough" category is similar to Fast Track and Accelerated Approval, in that it's supposed to be for drugs whose early clinical evidence shows that they might be a real advance over existing treatments. According to Herper's interview with Richard Pazdur, of the FDA's Office of Oncology and Hematology Products, the big difference in this latest category is early and broad cooperation with the agency.

. . .(the designation) catalyzes communication between a company and the FDA. Traditionally, drug reviews take place through a series of scheduled meetings. A breakthrough designation means there are more times a company can expect to be able to pick up the phone and get an answer. The designation can lead to cleared calendars, and it also means that the senior management of the FDA division becomes involved, not just the reviewers who serve on the FDA’ s front lines.

“The true measure of success is going to be how active we are in working with the companies,” Pazdur says. “If someone gets a breakthrough therapy and it’s business as usual, than the breakthrough therapy is meaningless.”

And these communication isn't just about trial design, although that's one of the biggest issues. Manufacturing, naming, and all the other regulatory issues are treated as well. Pazdur says that the biggest reason that some companies haven't achieved breakthrough status for their new compounds, though, is that they come in when it's still too early to make a decision. It sounds like this is something companies have to time pretty well: too early, and you'll be told to come back later. But if you wait too long, the designation might not be as much help as it could be.

Here's an overview from the FDA, and here's ta more detailed guidance document. The FDA says that just over half the drugs approved in 2012 took advantage of one or more of these categories, and it looks like the trend will continue. If the majority of things get Special Expedited Priority Shipping, what does that say about the Regular Shipping option? An outside observer (or investor) should keep this in mind - you probably shouldn't celebrate when a drug gets a designation like this, as worry about when it doesn't.

Comments (6) + TrackBacks (0) | Category: Regulatory Affairs

June 19, 2013

The Drug Industry and the Obama Administration

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Posted by Derek

Over at Forbes, John Osborne adds some details to what has been apparent for some time now: the drug industry seems to have no particular friends inside the Obama administration:

Earlier this year I listened as a recently departed Obama administration official held forth on the industry and its rather desultory reputation. . .the substance of the remarks, and the apparent candor with which they were delivered, remain fresh in my mind, not least because of the important policy implications that the comments reflect.

. . .In part, there’s a lingering misimpression as to how new medicines are developed. While the NIH and its university research grantees make extraordinary discoveries, it is left to for-profit pharmaceutical and biotechnology companies to conduct the necessary large scale clinical studies and obtain regulatory approval prior to commercialization. Compare the respective annual spending totals: the NIH budget is around $30 billion, and the industry spends nearly double that amount. While the administration has great affection for universities, non-profit patient groups and government researchers (and it was admirably critical of the sequester’s meat cleaver impact on government sponsored research programs), it does not credit the essential role of industry in bringing discoveries from the bench to the bedside.

Terrific. I have to keep reminding myself how puzzled I was when I first came across the "NIH and universities discover all the drugs" mindset, but repeated exposures to it over the last few years have bred antibodies. If anyone from the administration would like to hear what someone who is not a lobbyist, not a CEO, not running for office, and has actually done this sort of work has to say about the topic, well, there are plenty of posts on this blog to refer to (and the comments sections to them are quite lively, too). In fact, I think I'll go ahead and link to a whole lineup of them - that way, when the topic comes up again, and it will, I can just send everyone here:

August 2012: A Quick Tour Through Drug Development Reality
May 2011: Maybe It Really Is That Hard?
March 2011: The NIH Goes For the Gusto
Feb 2011: The NIH's New Drug Discovery Center: Heading Into the Swamp?
Nov 2010: Where Drugs Come From: The Numbers
August 2009: Just Give It to NIH
August 2009: Wasted Money, Wasted Time?
July 2009: Where Drugs Come From, and How. Once More, With A Roll of the Eyes
May 2009: The NIH Takes the Plunge
Sep 2007: Drugs From Where?
November 2005: University of Drug Discovery?
October 2005: The Great Divide
September 2004: The NIH in the Clinic
September 2004: One More On Basic Research and the Clinic
September 2004: A Real-World Can O' Worms
September 2004: How Much Basic Research?
September 2004: How It Really Works

There we go - hours of reading, and all in the service of adding some reality to what is often a discussion full of unicorn burgers. Back to Osborne's piece, though - he goes on to make the point that one of the other sources of trouble with the administration is that the drug industry has continued to be profitable during the economic downturn, which apparently has engendered some suspicion.

And now for some 100-proof politics. The last of Osborne's contentions is that the administration (and many legislators as well) see the Medicare Part D prescription drug benefit as a huge windfall for the industry, and one that should be rolled back via a rebate program, setting prices back to what gets paid out under the Medicaid program instead. Ah, but opinions differ on this:

It’s useful to recall that former Louisiana Congressman and then PhRMA head Billy Tauzin negotiated with the White House in 2009 on behalf of the industry over this very question. Under the resulting deal, the industry agreed to support passage of the ACA and to make certain payments in the form of rebates and fees that amounted to approximately $80 billion over ten years; in exchange the administration agreed to resist those in Congress who pressed for more concessions from the drug companies or wanted to impose government price setting. . .

Tauzin's role, and the deal that he helped cut, have not been without controversy. I've always been worried about deals like this being subject to re-negotiations whenever it seems convenient, and those worries are not irrational, either:

. . .The White House believes that the industry would willingly (graciously? enthusiastically?) accept a new Part D outpatient drug rebate. Wow. The former official noted that the Simpson-Bowles deficit reduction panel recommended it, and its report was favorably endorsed by no less than House Speaker Boehner. Apparently, it is inconceivable to the White House that Boehner’s endorsement of the Simpson-Bowles platform would have occurred without the industry’s approval. Wow, again. That may be a perfectly logical assumption, but the other industry representatives within earshot never imagined that they had endorsed any such thing. No, it’s clear they have been under the (naïve) impression that the aforementioned $80 billion “contribution” was a very substantial sum in support of patients and the government treasury – and offered in a spirit of cooperation in recognition of the prospective benefits to industry of the expanded coverage that lies at the heart of Obamacare. With that said, the realization that this may be just the first of several installment payments left my colleagues in stunned silence; some mouths were visibly agape.

This topic came up late last year around here as well. And it'll come up again.

Comments (37) + TrackBacks (0) | Category: Academia (vs. Industry) | Current Events | Drug Development | Regulatory Affairs

June 17, 2013

Pay-to-Delay: Not Necessarily Illegal, But Not Long For The World

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Posted by Derek

The Supreme Court has another ruling that affects the drug industry: FTC v. Actavis took up the question of "pay to delay", the practice of paying generic companies to go away and not challenge a branded drug. Actavis was in the process of bringing a version of Solvay's AndroGel to market, claiming that the Solvay patent was invalid. They won that case, and the FDA approved their generic version, but Solvay turned around and paid them (and Paddock, another generic firm) to not bring any such drug to the market.

The Federal Trade Commission (FTC) filed suit, alleging that re- spondents violated §5 of the Federal Trade Commission Act by unlawfully agreeing to abandon their patent challenges, to refrain from launching their low-cost generic drugs, and to share in Solvay’s monopoly profits. The District Court dismissed the complaint. The Eleventh Circuit concluded that as long as the anticompetitive effects of a settlement fall within the scope of the patent’s exclusionary potential, the settlement is immune from antitrust attack. Noting that the FTC had not alleged that the challenged agreements excluded competition to a greater extent than would the patent, if valid, it affirmed the complaint’s dismissal. It further recognized that if parties to this sort of case do not settle, a court might declare a patent invalid. But since public policy favors the settlement of disputes, it held that courts could not require parties to continue to litigate in order to avoid antitrust liability.

And now the Supreme Court reverses the Eleventh Circuit. The FTC, they hold, should have been given a chance to make its antitrust case. The Court makes a point out of declining to hold such agreements "presumptively unlawful", but gives a guide to breaking them down. There are both patent validity questions and anticompetitive questions involved, they point out, and these are separate issues (and because of that, they might not take forever to litigate, as the Eleventh Circuit decision worried about). Besides, as the justices note, a sudden large payment in such a case could be a reasonable indication of the underlying patent's validity (and chances of holding up to a determined challenge). The Hatch-Waxman Act has a generally pro-competitive bent to it, and that should operate in this situation as well.

I think this is the decision that most people expected (it's certainly the one I did). Pay-to-delay has always had an antitrust-violation smell to it. The Supreme Court has now gone on record as saying that this scent may well be no illusion, and at the very least, the FTC should be able to make a case if it can. I suspect that we're going to see fewer of these deals now - perhaps none at all - because I doubt many of them would hold up.

Comments (3) + TrackBacks (0) | Category: Patents and IP | Regulatory Affairs

June 6, 2013

Today's Avandia Hearing at the FDA

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Posted by Derek

If you want to follow the blow-by-blow of today's FDA hearing on the marketing restrictions on Avandia (rosiglitazone), I can send you to Matthew Herper's Twitter feed. He has the goods.

Comments (3) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

May 2, 2013

Aveo Gets Bad News on Tivozanib

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Posted by Derek

The kinase inhibitor tivozanib (for renal cell carcinoma) was shot down this morning at an FDA committee hearing. There are going to be a lot of arguments about this decision, because feelings have been running high on both sides of the issue.

And this has been an issue for over a year now. As that FierceBiotech story puts it:

Tivozanib hit its primary endpoint, demonstrating a slim but statistically significant improvement in progression-free-survival of patients with advanced renal cell carcinoma when compared to Nexavar (sorafenib). But the sorafenib arm experienced a slightly better overall survival rate, and Aveo has been trying to explain it away ever since.

The developer had to start in the spring of 2012 at a pre-NDA meeting. According to the review document, "the FDA expressed concern about the adverse trend in overall survival in the single Phase III trial and recommended that the sponsor conduct a second adequately powered randomized trial in a population comparable to that in the US."

The Phase III in question was performed in Eastern Europe, and one of the outcomes of today's decision may be a reluctance to rely on that part of the world for pivotal trials. I'm honestly not sure how much of tivozanib's problems were due to that (if the data had been stronger, no one would be wondering). But if the patient population in the trial was far enough off the intended US market to concern the FDA, then there was trouble coming from a long way away.

Aveo, though, may not have had many options by this time. This is one of those situations where a smaller company has enough resources to barely get something through Phase III, so they try to do it as inexpensively as they can (thus Eastern Europe). By the time things looked dicey, there wasn't enough cash to do anything over, so they took what they had to the FDA and hoped for the best. The agency's suggestion to do a US trial must have induced some despair, since (1) they apparently didn't have the money to do it, and (2) this meant that the chances of approval on the existing data were lower than they'd hoped.

One of the other big issues that this decision highlights is in trial design. This was a "crossover" trial, where patients started out on one medication and then could be switched to another as their condition progressed. So many crossed over to the comparison drug (Nexavar, sorafenib) that it seems to have impaired the statistics of the trial. Were the overall survival numbers slightly better in the eventual Nexavar group because they'd been switched to that drug, or because they'd gotten tivozanib first? That's something you'd hope that a more expensive/well-run Phase III would have addressed, but in the same way that this result casts some doubt on the Eastern European clinical data, it casts some doubt on crossover trial design in this area.

Update: a big problem here was that there were many more patients who crossed over to tivozanib from Nexavar than the other way around. That's a design problem for you. . .

What a mess - and what a mess for Aveo, and their investors. I'm not sure if they've got anything else; it looks like they'd pretty much bet the company on this. Which must have been like coming to the showdown at the poker table with a low three-of-a-kind, knowing that someone else probably has it beat. . .

Comments (27) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs

March 27, 2013

The NIH, Pfizer, and Senator Wyden

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Posted by Derek

Senator Ron Wyden (D-Oregon) seems to be the latest champion of the "NIH discovers drugs and Pharma rips them off" viewpoint. Here's a post from John LaMattina on Wyden's recent letter to Francis Collins. The proximate cause of all this seems to be the Pfizer JAK3 inhibitor:

Tofacitinib (Xeljanz), approved last November by the U.S. Food and Drug Administration, is nearing the market as the first oral medication for the treatment of rheumatoid arthritis. Given that the research base provided by the National Institutes of Health (NIH) culminated in the approval of Xeljanz, citizens have the right to be concerned about the determination of its price and what return on investment they can expect. While it is correct that the expenses of drug discovery and preclinical and clinical development were fully undertaken by Pfizer, taxpayer-funded research was foundational to the development of Xeljanz.

I think that this is likely another case where people don't quite realize the steepness of the climb between "X looks like a great disease target" and "We now have an FDA-approved drug targeting X". Here's more from Wyden's letter:

Developing drugs in America remains a challenging business, and NIH plays a critically important role by doing research that might not otherwise get done by the private sector. My bottom line: When taxpayer-funded research is commercialized, the public deserves a real return on its investment. With the price of Xeljanz estimated at about $25,000 a year and annual sales projected by some industry experts as high as $2.5 billion, it is important to consider whether the public investment has assured accessibility and affordability.

This is going to come across as nastier than I intend it to, but my first response is that the taxpayer's return on this was that they got a new drug where there wasn't one before. And via the NIH-funded discoveries, the taxpayers stimulated Pfizer (and many other companies) to spend huge amounts of money and effort to turn the original discoveries in the JAK field into real therapies. I value knowledge greatly, but no human suffering whatsoever was relieved by the knowledge alone that JAK3 appeared to play a role in inflammation. What was there was the potential to affect the lives of patients, and that potential was realized by Pfizer spending its own money.

And not just Pfizer. Let's not forget that the NIH entered into research agreements with many other companies, and that the list of JAK3-related drug discovery projects is a long one. And keep in mind that not all of them, by any means, have ever earned a nickel for the companies involved, and that many of them never will. As for Pfizer, Xeljanz has been on the market for less than six months, so it's too early to say how the drug will do. But it's not a license to print money, and is in a large, extremely competitive market. And should it run into trouble (which I certainly hope doesn't happen), I doubt if Senator Wyden will be writing letters seeking to share some of the expenses.

Comments (35) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | Drug Prices | Regulatory Affairs

March 25, 2013

The FDA's New Alzheimer's Guidance: Wonder or Blunder?

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Posted by Derek

You can get either answer, depending on whom you ask. Last month, the agency unveiled new guidelines for developing Alzheimer's therapies. They're trying to deal with the difficulty of showing actual cognitive improvement in more advanced patients, while at the same time figuring out how to evaluate therapies in early-stage patients who really aren't cognitively impaired yet. It's a worthy problem, for sure, and a good thing to be thinking about. Two of the agency's scientists laid out the thinking in a NEJM editorial:

The current landscape of research and drug development in Alzheimer's disease offers a study in contrasts. On the positive side, numerous discoveries over the past decade have begun to unmask complex pathophysiological processes that underlie disease progression. Such advances have, in part, resulted from large, well-organized observational studies, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), that have elucidated various disease biomarkers that reflect, or even predict, the progression of disease. On the negative side, drug discovery has been disappointing. Despite all best efforts to translate mechanistic insights concerning Alzheimer's disease into new drug products, several candidate agents have failed to demonstrate efficacy in large, well-designed, phase 3 clinical trials of late-stage disease.

That they have, and how. Avoiding these, or at least finding out ways to fail more cheaply, is very much on the minds of everyone working in the field. The New York Times, though, had a rather unexpected fit about the whole idea, culminating in this editorial:

. . .The goal is commendable — to find ways to prevent or slow the progression of this terrible disease before it can rob people of their mental capacities. But the proposal raises troubling questions as to whether the agency would end up approving drugs that provide little or no clinical benefit yet cause harmful side effects in people who take the medications for extended periods. . .

. . .F.D.A. officials say they would never approve drugs based on cognitive effects alone unless absolutely convinced that patients with very early-stage Alzheimer’s that is likely to progress to full-blown dementia could be reliably identified. It will be up to the drug companies or other sponsors of clinical trials to do the convincing.

The F.D.A.’s proposal is open for comment for 60 days. Independent analysts need to look hard at whether the F.D.A. should lower the bar for these drugs — or should demand a very high level of proof of safety and effectiveness before exposing still-healthy people to possible harm. Even if drugs are eventually approved under this new approach, it will be imperative to force manufacturers to conduct follow-up studies, as required by law, to see if patients benefit in the long run. . .

That's not a crazy point of view at all, though - I've worried about something similar myself. But I think that the Times is a bit too worked up over the current FDA guidance. On the other hand, as BioCentury has it in their latest issue (March 25), there are people in the biotech industry who have been talking up the new guidelines as some sort of regulatory breakthrough. "Not So Fast", is the response:

. . .The only reasonable conclusion to be drawn from a careful reading of both the guidance and the commentary is that while FDA would be willing to accelerate approval of AD drugs, the science isn’t there to allow it to do so. . .

The guidance states FDA would grant accelerated approval to a treatment for AD “based on the use of a biomarker as a single primary surrogate efficacy measure” — if a biomarker that reliably predicted clinical benefit existed.

As the guidance notes — and as anyone who follows the field knows — “no reliable evidence exists at the present time that any observed treatment effect on such a measure is reasonably likely to predict ultimate clinical benefit (the standard for accelerated approval), despite a great deal of research interest in understanding the role of biomarkers in AD.”

. . .The process of reaching scientific consensus on an appropriate assessment tool will take years. And no one knows how much longer it will take for regulators to generate sufficient confidence in the tool to use it as the sole basis for approving an AD drug.

I think that's the key part of all this. It's fine that the FDA is open to the idea of biomarkers for Alzheimer's; we're probably going to have to do it that way. But no one knows how to do that yet, and it's not like the agency is just going to pick one of the current measures and tell everyone that that's fine. What I would expect this latest initiative to do, actually, is to end up pushing more money into the hunt for such biomarkers, with perhaps less going to direct shots-on-goal. That's disappointing, from one perspective, but the shots on goal will bankrupt us all at the current rate.

Comments (8) + TrackBacks (0) | Category: Alzheimer's Disease | Regulatory Affairs

March 11, 2013

Suing A Generic Drug Maker: When And How?

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Posted by Derek

The great majority of prescriptions in this country are for generic drugs. And generic drugs are cheaper in the US than they are in Europe or many other areas - they're a large and important part of health care. And as time goes on, and more and more medicines move into that category, that importance, you'd think, can only increase.

So a case that's coming before the Supreme Court later this month could have some major effects. It concerns a woman in New Hampshire, Karen Bartlett, who was prescribed sulindac, one of the non-steroidal anti-inflammatory drugs that have been around for decades. All the NSAIDs (and other drugs besides) carry a small risk of Stevens-Johnson Syndrome, which is an immune system complication that ranges from mild (erythema multiforme) to very severe (toxic epidermal necrolysis, and I'm not linking anyone to pictures of that). Most unfortunately, Mrs. Bartlett came down with severe TEN, which has left her permanently injured. She spent months in burn units and under intensive medical care.

But now we come to the question that always comes up in modern life: whose fault is this? She sued that generic drug company (Mutual Pharmaceutical), and won a $21 million dollar judgment, which was upheld on appeal. But the Supreme Court has agreed to hear the next level of appeal, and a lot of people are going to be watching this one very closely. Mutual's defense is that the original manufacturer of the drug (Merck) and the FDA are responsible for these sorts of things (if anyone is), and that they are merely making (under regulatory permission) a drug that others discovered and that others have regulated over the decades.

A case with some similarities came before the court in 2010, Pliva v. Mensing. That one, though, turned on the labeling language, and how much control a generic company had over the label warnings. "Not much", said the court, which limited patients' ability to sue on those grounds. That seems proper, but, as that New York Times article shows, it also has the perverse effect of giving people more potential recourse if they take a drug as made by the original manufacturer as opposed to the exact same substance as made by a generic company, which doesn't make much sense.

This latest case does not argue label warnings; it argues that the drug itself is defective. Now, it does not seem fair that a generic company should have to pay for the bad effects of a drug it did not discover, did not take through the clinic, and did not reap the benefits of during its patent lifetime (when any bad effects in the real world should have become clear). On the other hand, there are problems with going the other way and sending all lawsuits back to the original developers of the drug. After all, sulindac has been on the market since the early 1980s, under the regulatory authority of the FDA, which could have pulled it from the market at any time and has not. The agency has also authorized several generic manufacturers to produce it since that time. From a regulatory standpoint, how defective can it be? Allowing the originating company to be sued for all the generic versions, after such a long interval, would seem to open up a "find the deep pockets" strategy for everyone who comes along. (And as that older post argues, if this is made the law of the land, it will add to the costs of current drugs, whose prices will surely then be adjusted to deal with decades of future liability concerns).

And if I had to guess, I would think that the Supreme Court is going to find a way out of coming down firmly on one side of the issue or the other. A 2008 decision, Riegel v. Medtronic, said that medical device makers were, in some cases, shielded from state-level tort claims because of regulatory pre-emption. (But note that this isn't always the case; nothing is always the case in law, which is so close to a perpetual motion machine that you start to wonder about the laws of thermodynamics). But an earlier attempt to use these arguments in a pharmaceutical case (Wyeth v. Levine) got no traction at all in the court. But to avoid having either of those outcomes in the paragraph above, I still think that the justices are going to find some way to make this more of a federal regulatory pre-emption case, and to distinguish it from Wyeth v. Levine.

And if that happens, it will mean what for Karen Bartlett? Well, it would mean that she has no recourse. Something terrible has happened to her, but terrible things happen sometimes. That's a rather cold way of looking at it, and I would probably not be disposed to look at it that way were it me, or a member of my family. But that might end up being the right call. We'll see.

Update: as detailed over at Pharmalot, the Obama administration has reversed course on this issue, and is now directing the Solicitor General to argue in favor of federal pre-emption in this case. But two former FDA commissioners (David Kessler and Donald Kennedy) have filed briefs in support of Bartlett, arguing that to assume pre-emption would be to assume too much ability of the FDA to police all these issues on its own (without the threat of lawsuits to keep manufacturers on their toes). So there's a lot of arguing to be done here. . .

Comments (30) + TrackBacks (0) | Category: Regulatory Affairs | Toxicology

March 4, 2013

von Eschenbach Takes Another Whack at Phase III Trials

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Posted by Derek

Here's a new editorial on clinical trials and drug development by Tomas Philipson and Andy von Eschenbach (former head of the FDA). It continues his earlier theme of scaling back Phase III trials (which I commented on here).

These Phase 3 clinical trials served us well in the past. Today, in an era of precision or personalized-drug development, when medicines increasingly work for very specific patient groups, the system may be causing more harm than good for several reasons.

First, because of their restrictive design and the way the FDA interprets their results, Phase 3 trials often fail to recognize the unique benefits that medicines can offer to smaller groups of patients than those required in trials.

Second, information technologies have created improvements in our ability to monitor and improve product performance and safety after medicines are approved for sale. Post-market surveillance can and should reduce dependence on pre-market drug screening in Phase 3 trials.

Third, reducing reliance on Phase 3 trials is unlikely to introduce an offsetting harm induced by more dangerous drugs, since evidence supporting safety is produced in earlier phases. Manufacturers also have powerful incentives to maintain drug safety, since they take enormous financial hits -- well beyond the loss of sales -- when drugs are withdrawn after approval.

I'm still of two minds about this proposal. The idea of moving to less preclinical study and more post-marketing surveillance is not a ridiculous one, but our current system (and the expectations it generates) do make a good fit with it. The nasty details I noticed being glossed over earlier are still with us: how will health insurance companies deal with this change? How do we keep unscrupulous gaming of the system, with companies rushing things to market and spinning out the postmarketing studies as thinly and cheaply as possible? What would keep the real bottom-of-the-barrel types from pumping out high-priced placebos for demanding diseases like Alzheimer's, which compounds would fly through safety studies and reap big profits until they (slowly) were proved ineffective? What would be the legal aspect of all this - that is, when would a patient have the right to sue if something goes badly wrong, and when would they have to just realize that they're taking an investigational drug and that they're part of a research study?

These are real problems, but you wouldn't imagine that they even exist when you read these editorial pieces. I'm a fairly libertarian guy, but these are the sorts of things that occur to me within the first few minutes of thinking about such proposals, which means that there must be many other wrinkles I haven't thought of yet. I agree that increasing the research productivity of the drug industry would be an excellent thing, but I'm really not sure that this is the way to do it.

Comments (9) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs

February 11, 2013

2012's New Drugs

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Posted by Derek

Thanks to Lisa Jarvis at C&E News, here's a chart (PDF) of the 39 drugs approved last year by the FDA. Last year was a good year, by almost any measure. The question as we go on will be whether this was a one-time spike, or the start of a long-awaited turnaround. If the latter, I think it will be as much of a regulatory phenomenon as a scientific one (faster reviews, etc.)

Comments (3) + TrackBacks (0) | Category: Regulatory Affairs

PhRMA And Why People Dislike the Drug Industry

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Posted by Derek

John LaMattina takes off after PhRMA's effectiveness here at Forbes. His two points are release of clinical trial data and openness about consultant payments to physicians. And I agree with him on both of those - as I've said here many times, we're not going to regain anyone's trust until we stop giving people reasons to think that we're trying to hide things from them.

The problem, though, as LaMattina shows, is PhRMA (the biggest industry association) doesn't seem especially interested in taken on these issues. Are they stupid, or short-sighted? Possibly. But when I see something like this going on, my assumption is to assume that the people involved are rational actors, who have made an informed decision. And that means that I'm somehow not looking at things the same way that they are.

My guess is that PhRMA's sees the public perception of the drug industry as a comparatively minor problem. The thing is, even if everyone liked the drug industry just fine, sales of prescription drugs would be about the same. They're not purchased because people have good feelings about the companies; they're not all that discretionary. People take medicines grudgingly, for the most part, because they're trying to correct something that's gone wrong.

So what's PhRMA's major concern? Regulatory and legislative affairs. Our industry is absolutely, crucially dependent on government's attitude towards it. We are regulated heavily at every point once we start to close in on an actual drug. So if you're trying to spend your time and effort in the most cost-effective way, you will go to Congress, to the regulatory agencies, to anyone at any level in government who can make and modify the rules that you have to live under. And you will spend your time and money making sure that the rules you like stay in force, that ones that you like even better are on the table, and that ones you don't like get slowed or watered down.

It's true that doing this would be somewhat easier if everyone had a better opinion of us. That's especially true for avoiding the regulations and laws that you don't like; that would be helped if you could go to the people involved with a big groundswell of public support behind you. But trying to influence the public to the point where that would reliably affect legislation is a very large undertaking. The same amount of effort (and money) will have far more impact if applied directly to the legislators and regulators themselves, rather than trying to use public opinion as a lever on them. It's just not cost-effective. This is especially true if you've already worked yourself into a situation where your industry is unpopular; trying to reverse that becomes a bigger and bigger proposition, which makes the alternatives look even more effective. And this is, after all, the way that every other interest group (well, every effective one) works in a highly regulated environment. What else would one expect?

That's my answer, then, to the question of why PhRMA doesn't do more to improve the industry's image. It's not a priority. Thoughts?

Notes: LaMattina's post is also partly a reponse to Ben Goldacre's book "Bad Pharma". I have been meaning to take that one on, but it's also a large undertaking. Book-length arguments are often best addressed at book length, unfortunately. But I do plan to do a big roundup on the subject.

Comments (8) + TrackBacks (0) | Category: Regulatory Affairs | Why Everyone Loves Us

February 7, 2013

DUCTS: Down with Useless Clinical Trial acronymS

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Posted by Derek

I'm not the first person to complain about these things, of course. Even by 2003, there were sixteen different clinical trials in the literature with the acronym HEART. It appears that the cardiovascular field picked up the acronym bug early, probably due to the size and length of their clinical programs. It also may been the first field to think up the jazzy clinical trial name first, and find something half-sensible to match it afterwards. But who can doubt that this is what goes on most of the time now? For those who still want to run the algorithm the other way, there's the Acronym Generator, which, wouldn't you know it, is run out of a cardiac hospital unit in Liverpool.

I wonder if the FDA would ever consider requiring drug companies and other research organizations to tone all this down, in the interest of sanity. If you're studying a drug called, say, kevorkirol (a generic name I invented a few years back, and hereby give freely to the scientific community), couldn't the clinical studies just be named "Kevorkirol Efficacy Trial #1", and "Kevorkirol Expanded Efficacy Trial #2" and so on? That would actually help people to keep them straight, instead of having to make a chart of bizarre trial names and their actual purpose. Anyone up for this idea?

Comments (25) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs

December 11, 2012

Free To Promote Off-Label? Not So Fast. . .

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Posted by Derek

Steve Usdin at BioCentury has a very interesting article (free access) following up on that surprise decision that the FDA's restrictions on off-label promotion are a violation of the First Amendment:

But companies and individuals who take the decision as a signal that the rules of the road have changed and they are now free to promote off-label indications put themselves in great legal and economic peril, attorneys who helped persuade the court to overturn Caronia's conviction told BioCentury.

At the same time, the decision by one of the country's most influential and respected courts to overturn a criminal conviction on First Amendment grounds is persuasive evidence that, in the long term, FDA will have to change some of the assumptions underpinning its regulation of medical products.

FDA, which now has lost a string of First Amendment cases, cannot forever hold on to the notion that it is empowered to prohibit drug companies and their employees from saying things that anyone else is free to say. Sooner or later, according to legal experts, the agency will have to reconcile itself with the idea that industry has the right to truthful, non-misleading speech.

Some of the people the article quotes are expecting the same thing I am - a further appeal to the Supreme Court - but no matter what, it's going to be quite a while before all the debris stops landing. Any company that tries to be the first to take advantage of what might be a new-found freedom could find itself right back in court, becoming a test case for what this ruling really means. Anyone feel like being a pioneer?

Comments (2) + TrackBacks (0) | Category: Regulatory Affairs

December 5, 2012

Off-Label Promotion Is Legal, You Say?

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Posted by Derek

You'll have seen the headlines about off-label promotion of drugs by pharma companies. No, not the ones that decry it as a shady marketing technique, punishable by huge fines. I mean the ones about how a federal court has ruled that it's completely legal.

This came as a surprise, at least to me. The U. S. Court of Appeals, in United States v. Caronia ruled explicitly that "government cannot prosecute pharmaceutical manufacturers and their representatives under the (Food, Drug and Cosmetic Act) for speech promoting the lawful, off-label use of an FDA-approved drug." That does go up against the previous belief that if it's off-label, it isn't lawful. So how did the court get here, and what happens next?

The case concerns Alfred Caronia, a sales rep for Orphan Medical, who was prosecuted for off-label promotion of Xyrem (the sodium salt of gamma-hydroxybutyrate, GHB) in 2005. (The company has since been acquired by Jazz Pharmaceuticals of Dublin). He appealed his conviction on First Amendment grounds, and this argument seems to have rung the bell with the appeals court. Here's a writeup at the FDA Law Blog:

The Court explained that FDA’s construction of the FDCA legalizes the outcome of off-label use by doctors, but “prohibits the free flow of information that would inform that outcome.” The Second Circuit concluded that “the government’s prohibition of off-label promotion by pharmaceutical manufacturers ‘provides only ineffective or remote support for the government’s purpose.’”

There's some case law that backs up this decision, namely Sorrell v. IMS Health Inc.. The Supreme Court decision, for those of you who are truly hard-core about this stuff, is here. In that one, the court found that a Vermont law that restricted physicians from selling information on their prescription history violated the First Amendment as well. From this earlier post at the FDA Law Blog, it appears that a lot of the maneuvering during this latest case was about whether Sorrell applied here or not. That post also makes it clear that the FDA's own statements on the legality of off-label promotion are, to put it gently, unclear.

Well, this ruling certainly clears it up. For now. Here's the 82-page decision itself, with a vigorous dissent from the third judge on the appellate panel. But I can tell you that I'm not reading it yet. That's because I expect the FDA to try to take this to the Supreme Court, and it looks (to my non-lawyer eyes) like just the sort of thing they'd grant certiorari to. So I don't think this story is done - but for now, off-label promotion cannot be prosecuted.

And that's a big change indeed. This whole issue has been a black eye for the industry over the years, because (for one thing) the FDA made it clear, over and over, that it believed the practice was illegal, and that companies (and individuals) could be prosecuted for it. In that atmosphere, a company that went ahead was doing so in knowing violation of the rules as they were understood. No drug company, as far as I know, ever tried to make a First Amendment court case out of an FDA fine for off-label promotion (if anyone knows of any examples, send 'em along). Instead, they argued about whether it had happened or not, how much of it there really was, then paid the whacking fines, and then (likely as not) went out and did it some more. And they did it not because they were free-speech activists, but because that's where a lot of big money was to be found. Not the sort of thing that covers you with glory, for sure.

So it's not like this latest ruling is going to rehabilitate many reputations in the marketing departments. It's more like "Great! Turns out to be legal after all! Who knew?"

Comments (28) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | Why Everyone Loves Us

November 14, 2012

Budgets and Revenues

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Posted by Derek

Note: politics ahead. This will not be a regular feature around here, but when events warrant, it'll rear its scaly head.

BioCentury has an interesting piece this week on the growing budget impasse and its implications for both academic and industrial biomedical research. It's already widely known that the so-called "Fiscal Cliff", the budget sequestration process that will trigger if no better deal is reached, will perforce come after funding for both the NIH and the FDA. It's always tricky to figure out the impact of such spending cuts, due to the well-known "Washington Monument" tactic. (That refers to the way that if you try to cut the budget for, say, the Park Service, the first thing they'll do is close the Washington Monument. After all, you are having to save money, right? And if you can do it in a way that causes the most outrage and inconvenience, thus increasing the chance that your budget will be restored, well, why wouldn't you?)

So that means that I don't necessarily believe all the predictions for what sequestration would do to any given agency's budget. But there's no doubt that it would have a powerful effect. At the very least, current plans for increased services or expanded programs would immediately go into the freezer, and there would be layoffs and program cancellations on top of that. New NIH grants would surely be hit, and the approval process at the FDA would slow down. Budget sequestration would not mean The End of Science in America, but we'd feel it, all right.

The flip side of budget-cutting is raising revenue. And for that, we can (among many other places) turn back to the deals made with PhRMA when the Affordable Care Act (aka "Obamacare") was passed. Says BioCentury:

Many of the deficit reduction playbooks Congress and the White House will consult include recommendations to suck money out of the pharmaceutical industry. These include a number of proposals that were taken off the table in the PhRMA deal to support the Affordable Care Act.

Near the top of the list: Imposing rebates on drugs purchased under Medicare Part D by so-called “dual-eligibles,” individuals who are eligible for both Medicare and Medicaid.

The Obama administration’s proposed fiscal 2013 budget projected $135 billion in revenues over a decade from dual-eligibles rebates. The idea, which is anathema to PhRMA, was also endorsed by the National Commission on Fiscal Responsibility and Reform chaired by Alan Simpson, a former Republican senator from Wyoming, and Erskine Bowles, President Clinton’s chief of staff.

The White House is also likely to continue to press for reducing the exclusivity period for biologics to seven years from the 12 years established when Congress created a biosimilars pathway in the Affordable Care Act.

Some readers may recall that I predicted something like this. There's a quote from the head of a health-care consulting firm, who says that "Everything that was taken off the table is back", and I can't say that I'm surprised. The twelve-year exclusivity idea had already been on the block to be chopped; I assume that one way or another, it's a goner.

Here's another provision of the Affordable Care Act that could affect the pharma industry. Starting in 2014, health insurance plans will have a defined "minimum level of coverage", which will be determined state-by-state. Late last year, the Department of Health and Human Services said that it plans to require that "essential" will mean one drug in each therapeutic class, with that one drug to be determined by some process I can only imagine. That idea hasn't been popular, with either drug companies or patients, and one might expect to see it altered. But not without a huge amount of wrangling, that's for sure.

Comments (12) + TrackBacks (0) | Category: Business and Markets | Current Events | Regulatory Affairs

October 31, 2012

The Coming Battle Over Alzheimer's Disease

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Posted by Derek

Solanezumab is a story that won't go away. Eli Lilly's antibody therapy for Alzheimer's is the subject of a lot of arguing among investors: some people (and I'm one of them) think that there is no strong evidence for its efficacy, not yet, and that the amount of time and effort devoted to finding that out means that there likely isn't any meaningful efficacy to be found. Others are more optimistic, which is why Lilly's stock has risen in recent months.

The latest point of contention is an independent analysis of biomarker data which came out this week at a conference in Monaco. This suggests that there was a meaningful change in the amount of circulating beta-amyloid after treatment, which could mean that the antibody was working as planned to increase clearance of soluble amyloid, thus altering the amyloid balance in the CNS. It should be noted that this line of attack depends on several factors - first among them, that amyloid is a causative factor in Alzheimer's, and secondly, that clearing it from the periphery can affect its concentration and distribution inside the brain. There's evidence for both of these, and there's evidence against both of them. Such questions can only be answered in the clinic, and I'm glad that Lilly, Roche/Genentech, and others are trying to answer them.

What I want to focus on today, though, is an issue that comes up in passing in the Fierce Biotech link above:

Biomarkers and pooled data may help support further studies of the drug, as well as other programs that rest on the beta amyloid hypothesis, but they don't prove that solanezumab works as hoped. Nevertheless, the first sign of success in this field has fueled tremendous enthusiasm that something in the pipeline could eventually work--perhaps even pushing regulators to approve new therapies with something less than clear efficacy data. And any newly approved drug would find a massive market of millions of desperate patients.

That's a big "perhaps", one that's worth tens of billions of dollars. What I worry about is pressure building for the FDA to approve an Alzheimer's therapy (solanezumab or something else) based on these hints of mechanistic efficacy. The problem is, solanezumab hasn't shown much promise of improving the lives of actual Alzheimer's patients. Lilly's own trials showed a possible improvement in a measure of cognitive decline, but this did not show up again in a second patient group, even when they specifically modified the endpoints of the trial to look for it. And neither group showed any functional effects at all, which I think are what most Alzheimer's patients (and their family members) would really want to see.

But there really is such a huge demand for something, anything, with any hint of hope. People would line up to buy anything that got FDA approval, no matter how tenuous the evidence was. And that puts the agency in a very tough position, similar to the one it was in with the Avastin breast cancer issue. Update: there was, to be sure, more of a safety question with Avastin at the same time. You can argue that one of the main purposes of the agency is to make sure that medicines that people can be prescribed in this country will actually do some good, rather than raise hopes for nothing. You could also argue that responsible adults - and their physicians, and their insurance companies - should be able to make such choices for themselves, and should be able to spend their time and money in the ways that they best see fit. You could argue that companies with marginally effective (or ineffective) therapies face a huge moral hazard, in that their incentives are to get such treatments onto the market whether they do anyone else any good or not. None of these are foolish positions, but they are also, in places, mutually incompatible. Alzheimer's disease might well turn into the next place in which we thrash them out.

Comments (17) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Prices | Regulatory Affairs

October 26, 2012

"Basically, They're A Bunch of Lemmings"

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Posted by Derek

True, but that's unfair to lemmings. This is Raghuram Selveraju of Aegis Capital, talking about deal-making executives in the big pharma companies and the string of costly blowups so far this year. That link has the list, and it's quite an impressive string of fireballs.

“What all of these deals had in common was the desperation of big pharma, because its R&D productivity has been dropping and we’ve known that for a long time,” he said.

That desperation leads to the repetition of familiar mistakes which derive from the predictable thinking of too many business development executives at big pharma, Selveraju opined. First, when looking for licensing opportunities, pharmas very often seek out their comfort zone – a potential product for which they can deploy an existing sales force or promote to doctors they already know and communicate with. Also, to be confident in an experimental drug’s preclinical and clinical data, pharmas often want to go into areas where their competitors also have a compound as well as into validated targets.

“Basically, they’re a bunch of lemmings,” Selveraju said. “As soon as a target becomes hot, they all have to have a molecule in that space, hitting that target."

But who could blame them? Going out into areas that haven't been explored, or haven't worked out for others, can get you slaughtered, too (ask Eli Lilly about Alzheimer's). And when that happens, you have nowhere to hide. If everyone else was rushing into a given therapeutic area and it turns out to be a disaster, well, you yourself might be able to get by, because that's just one of those things, and it happened to everyone at the same time. It reminds me of something I saw years ago about investment managers. If you go out and buy a bunch of (say) IBM for your clients and it drops, people might say "Man, what's wrong with IBM?" But if you go out and buy a bunch of WhoZat, Inc., and it drops, people will ask what's wrong with you.

My own biases make me think that if the chances for failure are high both ways, then maybe you should go ahead and strike out for the unknown territory, because the payoff is larger if you succeed. Selveraju himself has a much more cautious (and perhaps outright dispiriting) recommendation:

What then is Selveraju’s prescription for better business development practices? It might disappoint those who want pharma to be in the vanguard of innovation. He recommends incremental innovation – using FDA’s 505b2 pathway to develop products with already defined efficacy and safety – as well as biosimilars and re-purposing. Pharma also should focus on niche and specialty indications, and largely eliminate primary care products and the large commercial operations that come with them.

That's cranking up the dial even more on the Bernard Munos strategy. Munos also recommends getting out of the big, expensive areas and going more for niche and specialty ones, but mainly because of the cost of the clinical trials (and the validation step inherent in them). Alzheimer's, for example, scores big on innovation, but very, very poorly on the risk/cost ratio, since it's going to take you years and years in huge clinical trials to see if you've got something.

But that "develop products with already defined efficacy and safety" line is Selveraju’s own, and doesn't that sound like loads of fun? Coming up with new formulations and dosing schedules of existing drugs is what a 505(b)(2) strategy amounts to, and it brings up thoughts of alternative careers - going off to trucking school and learning to drive the big rigs, for example. Actually, as a drug-discovery chemist, that's probably what I'd end up doing if everyone switched to that plan, since you certainly don't need people like me if you're five-oh-five-bee-twoing.

Comments (21) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Regulatory Affairs

October 18, 2012

The Generic Wellbutrin Problem: Whose Fault Is It?

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Posted by Derek

One of the questions I get asked most often, by people outside of the drug industry, is whether generic medications really are the same as the original branded ones. My answer has always been the same: that yes, they are. And that's still my answer, but I'll have to modify it a bit, because we're seeing an exception right now. Update: more exceptions are showing up in the comments section.

Unfortunately, "right now" turns out, in this case, to mean "over the last five years". The problem here is bupropion (brand name Wellbutrin), the well-known antidepressant. A generic version of it came on the market in 2006, and it went through the usual FDA review. For generic drugs, the big question is bioequivalence: do they deliver the same ingredient in the same way as the originally approved drug and formulation? The agency requires generic drug applications to show proof of this for their own version.

For bupropion/Wellbutrin, the case is complicated by the two approved doses, 150mg and 300mg. The higher dose is associated with a risk of seizures, which made the FDA grant a waiver for its testing - they extrapolated from the 150mg data instead. And right about here is where the red flags began to go up. The agency began to receive reports, almost immediately, of trouble with the 300mg generic dose. In many cases, these problems (lack of efficacy and/or increased side effects) resolved when patients switched back to the original branded formulation. That link also shows the pharamacokinetic data comparing the two 150mg dosages (branded and generic), which turned out to have some differences, mostly in the time it took to reach the maximum concentration (the generic came on a bit faster).

At the time, though, as that link shows, the FDA decided that because of the complicated clinical course of depression (and antidepressant therapy) that they couldn't blame the reported problems on a difference between the two 300mg products. A large number of patients were taking each one, and the number of problems reported could have been explained by the usual variations:

The FDA considers the generic form of bupropion XL 300 mg (Teva Pharmaceuticals) bioequivalent and therapeutically equivalent to (interchangeable with) Wellbutrin XL 300 mg. Although there are small differences in the pharmacokinetic profiles of these two formulations, they are not outside the established boundaries for equivalence nor are they different from other bupropion products known to be effective. The recurrent nature of (major depression) offers a scientifically reasonable explanation for the reports of lack of efficacy following a switch to a generic product. The adverse effects (e.g., headache, GI disorder, fatigue and anxiety) reported following a switch were relatively few in number and typical of adverse drug events reported in drug and placebo groups in most clinical trials. . .

But they seem to have changed their minds about this. It appears that reports continued to come in, and were associated most frequently with the generic version marketed by Teva (and produced by Impax Pharmaceuticals). That FDA page I've quoted above is not dated, but appears to come from late 2007 or so. As it turns out, the agency was at that time asking Teva to conduct that missing bioequivalence study with their 300mg product. See Q12 on this page:

FDA continued to review postmarketing reports throughout 2007. In November 2007, taking into consideration reports of lack of efficacy, FDA requested that Impax/Teva conduct a bioequivalence study directly comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg. The study protocol stipulated the enrollment of patients who reported problems after switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg. Impax/Teva began the study, but terminated it in late 2011, reporting that despite efforts to enroll patients, Impax/Teva was unable to recruit a significant number of affected patients.

The agency apparently was continuing to receive reports of problems, because they ended up deciding to run their own study, which is an uncommon move. This got underway before Teva officially gave up on their study, which gives one the impression that the FDA did not expect anything useful from them by that point:

In 2010, because of the public health interest in obtaining bioequivalence data, FDA decided to sponsor a bioequivalence study comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg. The FDA-sponsored study enrolled 24 healthy adult volunteers and examined the rate and extent of absorption of the two drug products under fasting conditions. In that study, the results of which became available in August 2012, Budeprion XL 300 mg failed to demonstrate bioequivalence to Wellbutrin XL 300 mg.

That FDA-sponsored study is what led to the recent decision to pull the Imapax/Teva 300mg product from the market. Their 150mg dosage is still approved, and doesn't seem to have been associated with any increased reports of trouble (despite the small-but-real PK differences noted above). And it's also worth noting that there are four other generic 300mg bupropion/Wellbutrin products out there, which do not seem to have caused problems.

How big a difference are we talking about here? There are several measurements that are used for measuring blood levels of a drug. You have Cmax, the maximum concentration that is seen at a given dosage, and there's also Tmax, the time at which that maximum concentration occurs. And if you plot blood levels versus time, you also get AUC (area under the curve), which is a measure of the total exposure that a given dose provides. There are a lot of ways these measurements can play out: a very quickly absorbed drug will have an early Tmax and a large Cmax, for example, but that concentration might come back down quickly, too, which could lead to a lower AUC than a formulation of the same drug (at the same nominal dose) that came on more slowly and spread out over a longer time period. To add to the fun, some drugs have efficacy that's more driven by how high their Cmax values can get, while others are more driven by how large the AUCs are. And in the case of bupropion/Wellbutrin, there's an additional complication: some of the drug's efficacy is due to a metabolite, a further compound produced in the liver after dosing, and such metabolites have their own PK profiles, too.

So in this case, it turns out that the AUC just missed on the low side. The FDA wants the statistical 90% confidence interval to fall between 80 and 125% compared to the original drug, and in this case the 90% CI was 77-96%. The Cmax was definitely lower, too - 90% CI was 65-87% of the branded product. And while the agency doesn't provide numbers for the metabolite, they also state that it missed meeting the standards as well. There are drugs, it should be said, that would still be effective at these levels, but Wellbutrin clearly isn't one of them.

My own take is that the FDA was willing to consider the adverse reports as just the usual noisy clinical situation with an antidepressant until the other generics were approved, at which point it became clear that the problems were clustering around the Impax/Teva product. Here's how the FDA addresses the "Why didn't we find out about this earlier?" question:

Q17. In retrospect, were FDA’s decisions regarding the approval and ongoing monitoring of Budeprion XL 300 mg appropriate?

A17. A less cautious approach in studying the bioequivalence of Budeprion XL 300 mg could have brought the data to light earlier. The FDA-sponsored study was completed only weeks ago, which is a very short time for data from a clinical experiment to be announced to the public.

Bupropion is associated with a risk for seizures, which was the basis of the Agency's cautious approach with regard to the early Budeprion XL bioequivalence studies, in which data were extrapolated from Budeprion XL 150 mg in patients to the projected consequences of exposure to Budeprion 300 mg. In retrospect, it is clear that this extrapolation did not provide the right conclusion regarding bioequivalence of Budeprion XL 300 mg. FDA also has much more knowledge today of the seizure-associated risk of bupropion-containing drugs. The trial design of the sponsor-initiated study of 2007 could have been successful, had it been replaced by the trial design employed in the recent FDA-sponsored study.

Of course, the trial design in the sponsor-initiated study of 2007 was that requested by the FDA. But Teva, for their part, does not appear to have been a ball of fire in getting that study recruited and completed, either. It's quite possible, though, that they couldn't round up enough patients who'd had trouble with the generic switch and were also willing to go back and experience that again in the cause of science. Overall, I think that the FDA is more on the hook here for letting things go on as long as they did, but there's plenty of blame to go around.

Still, I find this post at Forbes to be full of unnecessary hyperventilation. You wouldn't know, from reading it, that the FDA initially waived the requirement for 300mg testing in this case because of the risk of seizures. There's a line in there about how the agency is making patients their guinea pigs by not testing at the higher dose, but you could have scored the same debating points after a 300mg study that harmed its patients, which is what it looked at the time would happen. You also wouldn't know that the other generic 300mg formulations don't seem to have been associated with increased adverse-event reports, either.

And that post makes much of the way that these bioequivalence tests are left up the manufacturers. That they are: but if you want to change that, you're going to have to (1) fund the FDA at a much higher level, and (2) wait longer for generic switches to occur. The generic manufacturers will run these tests at the absolute first possible moment, since they want to get onto the market. The FDA will run them when they get around to it; they don't have the same incentives at all. Their incentives, in fact, oscillate between "Don't approve - there might be trouble" and "Definitely approve - we might be missing out on benefit". The winds of fortune blow the line between those two around all the time.

In this case, I think the FDA should have exercised its court-of-last-resort function earlier and more forcefully. But that's easy for me to say, sitting where I am. I don't have to see the mass of noisy adverse event reports coming in over the transom day after day. If the agency acted immediately and forcefully on every one, we'd have no drugs on the market at all. There's a middle ground, but boy, is it hard to find.

Comments (44) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System

September 6, 2012

Accelerated Approval And Its Discontents

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Posted by Derek

This may sound a little odd coming from someone in the drug industry, but I have a lot of sympathy for the FDA. I'm not saying that I always agree with them, or that I think that they're doing exactly what we need them to do all the time. But I would hate to be the person that would have to decide how they should do things differently. And I think that no matter what, the agency is going to have a lot of people with reasons to complain.

These thoughts are prompted by this article in JAMA on whether or not drug safety is being compromised by the growing number of "Priority Review" drug approvals. There are three examples set out in detail: Caprelsa (vandetanib) for thyroid cancer, Gilenya (fingolimod) for multiple sclerosis, and the anticoagulant Pradaxa (dabigatran). In each of these accelerated cases, safety has turned out to be more of a concern than some people expected, and the authors of this paper are asking if the benefits have been worth the risks.

Pharmalot has a good summary of the paper, along with a reply from the FDA. Their position is that various forms of accelerated approval have been around for quite a few years now, and that the agency is committed to post-approval monitoring in these cases. What they don't say - but it is, I think, true - is that there is no way to have accelerated approvals without occasional compromises in drug safety. Can't be done. You have to try to balance these things on a drug-by-drug basis: how much the new medication might benefit people without other good options, versus how many people it might hurt instead. And those are very hard calls, which are made with less data than you would have under non-accelerated conditions. If these three examples are indeed problematic drugs that made it through the system, no one should be surprised at all. Given the number of accelerated reviews over the years, there have to be some like this. In fact, this goes to show you that the accelerated review process is not, in fact, a sham. If everything that passed through it turned out to be just as clean as things that went through the normal approval process, that would be convincing evidence that the whole thing was just window dressing.

If that's true - and as I said, I certainly believe it is - then the question is "Should there be such a thing as accelerated approval at all?" If you decide that the answer to that is "Yes", then the follow-up is "Is the risk-reward slider set to the right place, or are we letting a few too many things through?" This is the point the authors are making, I'd say, that the answer to that question is "Yes", and we need to move the settings back a bit. But here comes an even trickier question: if you do that, how far back do you go before the whole accelerated approval process is not worth the effort any more? (If you try to make it so that nothing problematic makes it through at all, you've certainly crossed into that territory, to my way of thinking). So if three recent examples like these represent an unacceptable number (and it may be), what is acceptable? Two? One? Those numbers, but over a longer period of time?

And if so, how are you going to do that without tugging on the other end of the process, helping patients who are waiting for new medications? No, these are very, very hard questions, and no matter how you answer them, someone will be angry with you. I have, as I say, a lot of sympathy for the FDA.

Comments (7) + TrackBacks (0) | Category: Drug Development | Regulatory Affairs | Toxicology

August 14, 2012

Is Ampyra Any Good?

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Posted by Derek

I wrote here about Ampyra, the multiple sclerosis drug from Acorda Therapeutics, one that came close to the record for "simplest chemical matter in a marketed drug". (As it happens, Biogen Idec is making sure that it doesn't even have the title of "simplest drug for multiple sclerosis", and the shadow of valproic acid looms over this entire competition).

That post mentioned some doubts that had been expressed about how effective Ampyra is for its target: improving gait in MS patients. And now those doubts are increasing, because the company has been asked to conduct a trial of a lower 5 mg dose of the drug along with the approved 10 mg one (which was associated with seizures in some patients). And neither one of them met the primary endpoint. As that link shows, the company has several explanations - different endpoint than used before, higher placebo response than usual, wider variety of patients - but those are all ex post facto. Acorda wouldn't have set up the trial like this in the first place if they didn't think that the approved dose would work, and it didn't.

For a drug with a rather narrow symptomatic indication, that's not good news. And it comes as Acorda is still trying to get the compound approved in Europe. The cost/benefit ratio usually can't stand a big hit to the "benefit" term.

Comments (11) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System

July 30, 2012

Bert Vogelstein on Cancer Drugs and Cancer Screening

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Posted by Derek

Here's an interesting profile of Bert Vogelstein, who has had a major impact on oncology over the years, especially in the area of cancer-associated genetic mutations. Some of his recent work bears on the question of how useful some of the newer drugs are:

Vogelstein seems to enjoy pricking balloons. Recently, he has focused on a new target: exuberance over targeted cancer drugs. He says he got interested after seeing a paper last year on melanoma therapy. It included photos of the torso of a man with melanoma who had received a new drug aimed at a mutated gene called BRAF. Before treatment, the patient's skin was riddled with metastatic tumors; soon after treatment, the tumors vanished, and the man looked perfectly healthy. Five months later, the tumors reappeared in exactly the same locations. The photos “blew my mind,” Vogelstein says. “Why do the tumors all return at roughly the same time? It's almost as miraculous as when they disappear.”

Targeted drugs for other cancers usually stop working after about the same number of months, presumably because rare resistant cells in the tumors continue to grow and ultimately proliferate. To investigate, Luis Diaz and others in the Vogelstein-Kinzler lab drew on a sensitive technique they had developed for detecting mutations in the very small amount of tumor DNA present in a cancer patient's blood. They collected a series of these “liquid biopsy” measurements from patients with advanced colorectal cancer whose tumors had become resistant to a targeted cancer drug. With Harvard University computational biologist Martin Nowak, they devised a model showing that even before the patient begins treatment, some tumor cells always carry genes with random mutations that can support resistance to targeted drugs. This form of resistance, they wrote last month in Nature, is therefore “a fait accompli.”

But the modeling study also suggested that this resistance can be delayed by combining two drugs that target different pathways. Indeed, Vogelstein and colleagues suggest that once a targeted drug has passed initial safety trials, it's so clear that single-drug therapy will fail that they consider it unethical to give patients just one such drug. “Why shouldn't you design a large, very expensive trial to incorporate more than one agent?” Vogelstein asks.

There are a lot of labs working on this "liquid biopsy" idea, and it's the sort of thing that you could only imagine doing with modern DNA sequencing technology (and modern DNA sequencing costs). A big worry, as with any screening technology, is the false positive rate. As you make finer and finer distinctions among different tumor types, the incidence of any given one in the population gets lower and lower, and thus your test has to be more and more reliable in order to avoid overdiagnosing hordes of panicked patients.

Interestingly, when I talk to people outside of the medical research field, they seem less worried about overdiagnosis than underdiagnosis (false positives versus false negatives). Psychologically, I can see how that happens - they don't want to the test to miss anyone. But being told that you do have cancer, when you really don't, is not a good outcome, considering what the therapy will put you through. And this is what makes things like the PSA test recommendation (and mammograms in younger patients) so controversial. In the push to make sure that you find every patient, you can end up harming more people than you help. "But if you just save one life. . ." goes the phrase, at least goes the phrase from people who don't realize that they might be ending the sentence with ". . .it's worth killing off a few more".

I hope that the blood test idea works out; it would be a great advance. But a less-than-optimal one could be worse than having none at all. Look for plenty of arguments about this in the coming years - I'll fill in some of the talking points in advance: "The FDA is holding back medical progress by not approving this new test". "The FDA has given in to commercial pressures by approving this faulty new test". "This test will end up hurting more people than it helps". "How can you be against cancer screening? Isn't it always worth looking?". "This is all just a disguised cost-cutting effort; they're approving this test because it's cheaper than doing better screening". "This is all just a disguised cost-cutting effort; they're not approving this test because they're afraid that too many people will be diagnosed with cancer". And so on.

Comments (11) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

July 25, 2012

A Diazirine That Will Knock You Out

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Posted by Derek

Now here's one of those structures that you don't see very often in a drug molecule. It wasn't intended to be a drug, though - it's a photolabel tool compound based on the general anesthetic mephobarbital, which is what that trifluoromethyldiazirine group is doing in there. (When those are exposed to light, nitrogen gas takes off, leaving behind a reactive carbene that generally attacks something nearby as quickly as possible).

But when the two enantiomers were tested, it turns out that one of them is about as potent as the best compounds in its class, while the other (the R enantiomer) is ten-fold better. And when used for its intended purpose, as a photolabeling agent, it does show up stuck to specific sites on human GABA receptors, as hoped. So this should provide some interesting information about barbituate binding, although I sort of doubt if anyone's going to try to develop it into a general anesthetic all on its own.

In a related topic, note that the model for this series, mephobarbital itself, is disappearing from the market. It's one of those ancient compounds that never really went through the modern regulatory process, but the FDA has stated that it's not going to let it be grandfathered in. Its manufacturer, Lundbeck, said earlier this year (PDF) that it saw no path forward other than a completely new NDA filing, which didn't seem feasible, so it was abandoning the product. Existing stocks have expired by now, so mephobarbital is no more, at least in the US.

Comments (8) + TrackBacks (0) | Category: Chemical News | Regulatory Affairs

July 23, 2012

A Total Mess At the FDA

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Posted by Derek

As expected, there's a lot more to the story about the FDA and its monitoring of whistleblowing employees. Steve Usdin at BioCentury has details (PDF, free access), and good grief, what a mess. Read the whole thing; you'll be amazed.

It looks like the agency's Center for Devices and Radiologic Health has devolved into a cross between "Dilbert" and some ministry in Pyongyang. The employees that the agency has been monitoring have been accusing their superiors of approving screening devices based on flawed (even fraudulent) data, while the agency seems to think that they're out of line and off on their own crusade. At issue is whether the reviewers or their bosses really have the expertise to make regulatory decisions, and there seems to be a real, uh, divided opinion on that question. To put it lightly.

As it turns out, any time an employee at the FDA logs on to a computer, the following warning pops up: "You have no reasonable expectation of privacy regarding any communica- tions or data transiting or stored on this information system. At any time, and for any lawful government purpose, the government may monitor, intercept, and search and seize any communication or data transiting or stored on this information system." This case shows that they're not kidding about any of that, since the employees in question found everything they did being keylogged, screen-captured, etc., without (of course) their knowledge.

The CDRH higher-ups were treating this primarily as a criminal case by this point. But legitimate whistleblowing is a tricky grey area in this regard - with varying values of "legitimate" often decided years later - and the Office of Special Counsel is now investigating the FDA's own steps for their legality. No one is going to come out of this looking good, is my guess.

There's even more reason to think that, because (as it turns out), several of the CDRH employees were simultaneously filing suit (!) against the manufacturers of the devices that they were arguing about inside the agency:

While FDA reviewers were publicly working to persuade the agency to with- draw approval of computer-aided detection (CAD) mammography and CT colonoscopy devices, they also were secretly pursuing a lawsuit against the products’ manufactur- ers. The suit included a request that a substantial share of any financial awards go directly to the plaintiffs. . .

The suit was filed “under seal,” so the defendants were not aware that the FDA staff reviewing their products were also asking a court to levy potentially billions of dollars in civil penalties against them.

Under the False Claims Act, private individuals can file a suit under seal and invite the U.S. Department of Justice to join the case. If the federal government joins the case, it takes responsibility and foots the bill for prosecution, and the individual plain- tiffs can be awarded a portion of the civil penalties.

The FDA employees requested in the suit that they be awarded “at least 15% but not more than 25% of the proceeds of any award or settlement” if the government joined the suit, and more if the government did not join.

No, this whole business is a stink bomb. I really don't see how the CDRH can be operating effectively at all with all this sort of stuff going on. Is the rest of the FDA this hosed up, or is this just a particularly dysfunctional branch? Who knows?

Comments (19) + TrackBacks (0) | Category: Regulatory Affairs

July 17, 2012

Vivus and Qsymia: The Oddest Drug Approval

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Posted by Derek

More and Vivus and the peculiar timing of the approval of their new obesity therapy, now named Qsymia. OK, in addition to the article mentioned in the previous post, a video went up this evening at ABC news about the compound's availability, also before any word from the FDA. Not long afterwards, the agency released its official decision.

I heard about both of these leaks via Adam Feuerstein on Twitter, and he's rightly getting credit for getting the word out. All this makes it seem that (1) Vivus had heard earlier from the FDA that the drug was going to be approved, but was told to embargo the news, and (2) the company talked to at least one press outlet (USA Today) before the announcement, and told them to hold the story as well.

But I still have a whole list of questions: for starters, how often is it that companies get the advanced word like this from the FDA? I've never been in the position of being one of the first to hear these things, but I've certainly had the impression that this isn't the usual policy. (The potential for leaks, as we've seen today, is just too high). So why did Vivus get the tip-off this time? And how often does a company in this position go to the news media with quotes and photos ready, telling them to sit on the story until the FDA speaks up? Doesn't that increase the potential for leaks even more?

And what about Regulation FD? Isn't material information like this supposed to made available to all investors at the same time? I realize that there are press embargoes in situations like the ASCO meeting, but those clampdowns have been turning into more of a fiasco every year as well. It seems funny for the FDA to be getting into the information embargo business just as others are realizing how hard it is to make it work.

Comments (7) + TrackBacks (0) | Category: Regulatory Affairs

Qnexa Approved? Someone Seems To Know. . .

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Posted by Derek

People are waiting to hear the fate of Qsymia (or Qnexa?), the obesity combo therapy being developed by Vivus (fixed the typoed names)!. In a weird development, an article went up on USA Today about the drug's approval by the FDA - before any such decision had been announced. (As of this writing, it still hasn't, but there's still time later in the afternoon). The article, which I didn't see before it disappeared, apparently included quotes from the company's CEO about the approval. (Note the URL of that ghostly link).

Basically, it looks like the company knows that the drug is going to be approved, as do some news outlets, but that news is under an embargo, which someone at USA Today inadvertently violated. This has made trading in the company's stock rather interesting, and has confused everyone mightily. So, how often do companies get this sort of tip-off? Your guess is as good as mine. . .

Update: more at Retraction Watch.

Comments (12) + TrackBacks (0) | Category: Regulatory Affairs

Employee Surveillance at the FDA

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Posted by Derek

What on earth has been going on at the FDA? The agency has engaged in a large and long-running surveillance of its own staff. This story was broken earlier this year by the Washington Post, but a mistake by a contractor gave the New York Times (and others) access to many more intercepted files. And things seem to have gotten out of hand pretty quickly:

What began as a narrow investigation into the possible leaking of confidential agency information by five scientists quickly grew in mid-2010 into a much broader campaign to counter outside critics of the agency’s medical review process, according to the cache of more than 80,000 pages of computer documents generated by the surveillance effort.

Moving to quell what one memorandum called the “collaboration” of the F.D.A.’s opponents, the surveillance operation identified 21 agency employees, Congressional officials, outside medical researchers and journalists thought to be working together to put out negative and “defamatory” information about the agency.

A good old-fashioned enemies list! The agency used key-logger and screenshot capture software on the government laptops of several employees, and the whole thing started over an internal dispute:

The extraordinary surveillance effort grew out of a bitter dispute lasting years between the scientists and their bosses at the F.D.A. over the scientists’ claims that faulty review procedures at the agency had led to the approval of medical imaging devices for mammograms and colonoscopies that exposed patients to dangerous levels of radiation.
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A confidential government review in May by the Office of Special Counsel, which deals with the grievances of government workers, found that the scientists’ medical claims were valid enough to warrant a full investigation into what it termed “a substantial and specific danger to public safety.”

The FDA is insisting that these actions had nothing to do with rooting out whistleblowers or tracking down critics of its regulatory decisions. Not at all - they were just making sure that no one was leaking proprietary documents. The rooting out of whistleblowers and identification of critics, those were just side effects. Not everyone is buying that explanation:

Representative Chris Van Hollen, a Maryland Democrat, sent a letter on Monday to Kathleen Sebelius, the secretary of health and human services, calling on her to conduct a full investigation into whether the surveillance program violated federal employee protections and whistle-blower laws.

“The tactics reportedly used by the F.D.A. send a terrible message to those who are prepared to expose waste, abuse or wrongdoing in government agencies,” wrote Mr. Van Hollen, whose staff communications were monitored by the F.D.A.

He's got a point. If a company does something like this to its own disgruntled employees, it exposes itself to a great deal of legal jeopardy. I'm not a lawyer, so I don't know what applies to the FDA itself, but I hope that there's a thorough investigation indeed. The agency takes a lot of flack, from every direction: groups on the left of the political spectrum, among others, blast them for having sold out to industry and not protecting the consumer, drug companies complain about arbitrary decisions and regulatory delays, and the more libertarian types would like big chunks of the whole apparatus to just disappear somehow.

But when I say "the agency", I'm talking about its people, its employees, many of whom are doing very difficult work for not all that much money. The people who authorize this kind of thing, well. . .they're in another category. Now, I understand that people inside the FDA (and other regulatory agencies) need some oversight. They're the referees in this business, and quis custodiet ipsos custodes? is always an appropriate question to ask. The recent insider trading scandal at the agency is just one example of what can happen when someone in a rule-making department goes astray.

But that doesn't mean that you can't go astray while chasing such things. You start reading people's mail and keylogging their passwords, and all sorts of ideas can come to your mind about what you're doing and why. So, who had these ideas at the FDA this time, and just what were they thinking?

Comments (9) + TrackBacks (0) | Category: Regulatory Affairs

July 3, 2012

The GlaxoSmithKline Settlement

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Posted by Derek

You'll have heard that GlaxoSmithKline has paid out three billion dollars in a settlement on illegal marketing practices, misreporting of safety data, and other violations. Needless to say, GSK does not have a spare three billion lying around that's not being used for anything; they'd be a lot better off if they hadn't put themselves in this position.

What's hard to figure, though, is how much money the company made through these actions. There's a lot of talk, understandably, about how drug companies (and their executives) could be warned off such behavior, but if GSK realized, say, an extra $4 billion in the process of incurring their $3 billion dollar fine, it's going to be hard to make the case to some of those people. The settlement actually appears to be a bit less than some investors were expecting, and there may, in the end, be no way to have the magnitude of the potential fines do all the work of a deterrent.

Matthew Herper at Forbes notes that the company's current CEO, Andrew Witty, has issued an unusually forthright statement (by CEO standards) on the whole matter:

All of the actions predated the tenure of current GlaxoSmithKline chief executive Andrew Witty, who has been trying to improve the company’s reputation. He has pushed forward with efforts to develop medicines for poor nations, including a malaria vaccine that Glaxo is developing with the Bill & Melinda Gates Foundation. He has also taken steps to remove incentives that made pharma salespeople so overzealous, no longer tying compensation to how much of a drug they can sell. In a statement, he said that employees have been removed from positions as a result of the changes and that new provisions will allow the company to take back compensation from executives if they don’t adhere to the company’s standards.

Glaxo has done something else right, too: Witty actually managed, in the press release disclosing this settlement, something close to a full-throated apology. He said:

“Whilst these originate in a different era for the company, they cannot and will not be ignored. On behalf of GSK, I want to express our regret and reiterate that we have learnt from the mistakes that were made.”

That may not sound like much, but in the context of an industry that has almost never seen fit to apologize for anything it is a step in the right direction.

But I also wanted to mention by name two of the people who set this entire thing in motion. One of them is Blair Hamrick, and another is Greg Thorpe. These were GSK sales reps who grew concerned about illegal activity over ten years ago:

“Regardless of what company policy may be, my letters to human resources and my previous complaints of misconduct have been quashed. My 23-plus year career with this company has been trashed, and it is obvious I can no longer work with my district manager and friends/counterparts just because I have come forward with the truth, which could save the reputation of GSK and millions of dollars in fines,” wrote Thorpe, one of the whistleblowers on whose claims the feds based their allegations, in a January 2002 note to Glaxo officials. . .instead, though, Glaxo officials issued their own warnings to Thorpe about his willingness to be a team player and refused to address various violations of the False Claims Act, which he referred to specifically and repeatedly in numerous communications.

"Team player" is one of those phrases that should put a person on their guard. It can be used completely innocuously, but it can also be used to justify pretty much any behavior that the rest of a group is doing, and on no more basis than, well, the rest of the group is doing it. I reserve my admiration for those who need more justification than that for their actions.

There are some effects that I hope this GSK news will have: making someone think twice about getting caught when they're planning something that goes over the line, or (on the other side) shoring up the resolve of a person who's deciding not to go along with something that they've realized is wrong. The world tends to run short of both of those.

Comments (32) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | The Dark Side

June 28, 2012

Effects of the Health Care Law on Pharma

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Posted by Derek

Over at Forbes, Matthew Herper has some thoughts now that the major parts of the Affordable Care Act have been upheld. Among them is this on its effect on the pharma business:

Will the law actually benefit some drug companies? Many in the drug business have expressed regret about the decision to back the Affordable Care Act, even blaming former Pfizer chief Jeffrey Kindler, a Democrat, for having pushed a deal through. I think that some of this opposition is based on outdated thinking that says that even though the government already pays for a lion’s share of health care spending through Medicare and Medicaid, giving it even more control will eventually create price controls like in Europe.

This made sense when the industry made all of its money selling mass market pills such as Lipitor and Plavix, both now off-patent. But the model for many new cancer drugs (the biggest category in drug company pipelines) and for drugs for rare diseases is that the companies charge a price no individual can pay, and then try to get insurers and governments to pay for them. This is the basic strategy taken by companies like Alexion, Biomarin, and the Genzyme division of Sanofi, all of which charge hundreds of thousands of dollars per patient per year for there medicines. Getting more people insured is good for these companies. Right now Alexion and Biomarin are down, which makes little sense. Fundamentally, the success of the drug industry depends on inventing new medicines; at most, the law is neutral. . .

We'll see. I think that the high-price/low-patient-population strategy that Herper refers to will be up for revision at some point, and perhaps sooner than we expect. One of the selling points of the ACA/Obamacare was that it would (somehow) contain costs, and I still have a lot of trouble believing that it will do anything of the kind. If (when?) we find that we're still spending piles of money on health care, one of the more politically popular ways to cut costs (or at least look as if you're cutting costs) will be to go after therapies that cost six figures a year.

And this could get tricky, because any cancer drugs that are actually effective are likely to be so only for small populations (the people who have tumors that are driven by one treatable mutation, as opposed to a swarm of genomically unstable cells that can mutate their way out of attempts to shut them down). The more we learn about which drugs to give to which patients, the smaller the treatable population gets for any individual drug, and the higher the price. These lines have been heading for an intersection for some time now, and I don't see how the health care law will keep things from getting messy.

Comments (27) + TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs

June 27, 2012

Shire's Replagal Problems: An Inside Look?

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Posted by Derek

If you've been following Shire Pharmaceuticals and their Replagal saga, you've had quite a few twists and turns to keep you occupied. Replagal (agalsidase) is Shire's alternative to Fabrazyme, the Fabry's disease therapy from Genzyme, and during Genzyme's protracted manufacturing troubles, Shire was only to glad to step up in the market in the US. (Replagal hadn't been approved here, but had been on the market in Europe for some years).

So back in March, it was quite a surprise when the FDA turned down Shire's application. And details of why this happened have been scarce - until now? BioCentury is out with a very interesting story, based on what they say is "an unsolicited package of documents that are labeled as FDA briefing materials" from an anonymous source.

If these are on the level, the FDA seems to have had concerns that Replagal's physical characteristics have changed over the years, due to changes in manufacturing (most specifically, the switch to a bioreactor from roller bottles and the use of a different purification method). The content of sialic acid and mannose-6-phosphate, among other factors, seems to be an issue, and cellular uptake of the final product may have drifted downwards. The FDA seems to have decided that the only way to answer such questions was in the clinic, and that's when Shire seems to have balked.

No one at Shire or the FDA would comment on the authenticity of the documents, as Biocentury says, no one has taken the opportunity to dispute them, either. You wonder just how they walked out of the FDA. . .

Comments (3) + TrackBacks (0) | Category: Regulatory Affairs

May 1, 2012

Regulatory Hurdles

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Posted by Derek

John LaMattina has a good piece up on the FDA, where they might be trying to have it both ways. About a recent speech by Janet Woodcock, he has this:

But Dr. Woodcock begins to stray into areas where I think she is off base. For one thing, she asserts that “many late stage [clinical] failures are due to efficacy problems.” That’s not exactly true. It is only when companies take compounds into late stage development with little or poor proof-of-concept data where this happens. The majority of phase 3 clinical trial failures are due to unforeseen, unpredicted side-effects or else due to finding that, in direct comparison to existing therapy, the new drug doesn’t show the superiority necessary to be successful commercially. Dr. Woodcock goes on to advocate for the generation of “evaluative tools,” new methodologies that can better predict the performance of a compound in late stage studies.

Of course, those tools are a good idea, and would be worth a lot (which is why everyone's been spending time and money trying to find them). But the FDA will not approve drugs based on them. They probably shouldn't - as LaMattina says, there have been quite a few drugs in recent years that looked like they would work based on one secondary endpoint or another, only to come up short in the real world. Woodcock is right to call for such approaches, but they won't necessarily shorten the time until approval. The hope is that they'll save time and money another way, in letting us kill projects earlier, with some hope of being right. Anything that spares us an unnecessary Phase II, or especially an unnecessary Phase III, is a good thing. But the eventual drug is going to have to jump through all the hoops, same as before.

Comments (9) + TrackBacks (0) | Category: Regulatory Affairs

March 15, 2012

Side Effects - Lots of Side Effects

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Posted by Derek

Here's a study that suggests that there are a lot more drug-drug interactions than we've ever recognized. (If you don't have access to Science Translational Medicine, here's a summary from Nature News).

Postmarketing surveillance yields huge piles of data that could potentially be mined for such, but it's a messy and heterogeneous pile. This study tries to correct for some of the confounding variables, by attempting to match each patient with a non-treated control patient with as many similarities as possible. They do look to have fished some useful correlations out that no one had ever observed before. For example, selective serotonin reuptake inhibitors (SSRIs) given with thiazide diuretics seem to be associated with a notably greater risk of the cardiac side effect of QT prolongation, which is a new one.

And while that's good news, you can't help but bury your head in your hands for a least a bit. It turns out that the average number of side effects listed on a full drug label is 69. That might seem to be quite enough, thanks, but this study suggests that about 329 different adverse effects per drug might be more accurate.

Comments (15) + TrackBacks (0) | Category: Regulatory Affairs | Toxicology

Not Quite So Accelerated, Says PhRMA

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Posted by Derek

We've spent a lot of time here talking about provisional approval of drugs, most specifically Avastin (when its approval for metastatic breast cancer was pulled). But the idea isn't to put drugs on the market that have to be taken back; it's to get them out more quickly in case they actually work.

There's legislation (the TREAT Act) that is attempting to extend the range of provisional approvals. But according to this column by Avik Roy, an earlier version of the bill went much further: it would have authorized new approval pathways for the first drugs to treat specific subpopulations of an existing disease, nonresponders to existing therapies, compounds with demonstrable improvements in safety or efficacy, or (in general) compounds that "otherwise satisfy an unmet medical need". As with the existing accelerated approval process, drugs under these categories could (after negotiation with the FDA) be provisionally marketed after Phase II results, if those were convincing enough, with possible revocation after Phase III results came in.

Unlike the various proposals to put compounds on the market after Phase I (which I fear would be an invitation to game the system), this one strikes me as aggressive but sensible. It would, ideally, encourage companies to run more robust Phase II trials in the hopes of going straight to the market, and it would allow really outstanding drugs a chance to start earning back their R&D costs much earlier. As long as everyone understood that Phase III trials are no slam dunk any more (if they ever were), and that some of these drugs would turn out not to be as good as they looked, I think that on balance, everyone would come out ahead.

According to Roy, this version of the bill had (as you'd expect) attracted strong backers and strong opponents. On the "pro" side was BIO, the biotech industry group, which is no surprise. On the "anti" side, the FDA itself wasn't ready for this big a change, which isn't much of a shock, either. (To be fair to them, this would increase their workload substantially - you'd really want to couple a reform like this with more people on their end). And there were advocacy groups that worried that this new regulatory regime would water down drug safety requirements too much. The article doesn't name any groups, but anyone who's observed the industry can fill in some likely names.

But there was another big group opposing the change: PhRMA. Yes, the trade organization for the large drug companies. Opinions vary as to the reason. The official explanations are that they, too, were concerned for patient safety, and they wanted the PDUFA legislation renewed as is, without these extra provisions (a "bird in the hand" argument). But Roy's piece advances a less charitable thesis:

Sen. Hagan’s proposal would have been devastating to the big pharma R&D oligopoly. If small biotech companies could get their drugs tentatively approved after inexpensive phase II studies, they would have far less need to partner those drugs with big pharma. They could keep the upside themselves and attract far more interest from investors. Big pharma, on the other hand, would be without its largest source for innovative new medicines: the small biotech farm team.

I'd like to be able to doubt this reasoning more than I do. . .

Comments (19) + TrackBacks (0) | Category: Drug Development | Regulatory Affairs

March 13, 2012

Nexavar Licensed by Force in India

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Posted by Derek

India has decided to invoke compulsory licensing, and is approving a local generic company's application to make and sell Bayer's Nexavar (sorafenib).

I'm assuming that there's a political dimension to this that I'm not quite following. There must be something else going on between Bayer and the Indian authorities. Nexavar is indeed expensive, but (meaning no offense to the people who discovered it, whom I know), it's not the most necessary part of the oncology drug world, either. Anyone have more details?

The most recent time this issue has come up here is 2007.

Comments (26) + TrackBacks (0) | Category: Drug Prices | Regulatory Affairs

March 7, 2012

Eight Billion Dollars Apparently Isn't Enough

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Posted by Derek

You'd think that 8 billion dollars would be enough to get some attention. But that's how much drugmakers have paid in fines in recent years, and the regulatory agencies are wondering if anything's changing. This USA Today article has the details.

The fines, as many readers here will know, are for a range of offenses - Medicare reimbursements, off-label marketing, kickbacks from the sales force, and so on. And as things stand now, the government has really only two options when it comes time to lower the boom: fines, and the threat to remove the company from eligibility to sell via Medicare. But that second one is really sort of an empty threat, since most large companies are (for now!) selling drugs that are quite valuable to the Medicare patient population. So new techniques are being sought:

To try to change that trend, the government announced in 2010 that, rather than exclude an entire company, investigators would go after individuals within a company. [Gregory Demske at HHS] said his organization, the Justice Department and the Food and Drug Administration have come up with some ideas to use within the scope of the rules — such as taking away a company's patent rights as a condition of a settlement. That could begin with cases being investigated now, he said.

Now, that might get some attention, for sure. We'll see if it happens, because you can expect the industry to fight this as hard as possible. To that end, the article notes that $200 million was spent on lobbying last year by the drug and medical device industries. One first thought might be "Two hundred million! That's a lot of money!", but mine was "Two hundred million! Why, that's nothing compared to the issues involved. . ." Marginal Revolution has had some posts about lobbying and money in politics, mostly wondering why there isn't more of it than there is. With that kind of bang-for-the-buck, I wonder the same thing.

Comments (16) + TrackBacks (0) | Category: Regulatory Affairs | The Dark Side

March 2, 2012

Stem Cells in Texas: Quite the Business

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Posted by Derek

I (and many of the readers here) have long thought that stem cells are perhaps the most overhyped medical technology out there - at least for now. I definitely agree that the possibilities for their use are staggering, and I very much hope that some of these pan out, but the gap between those possibilities and the current reality is just as huge. And it's a gap that really shows how hard medical progress is compared to how hard it is in the public imagination.

Nature has an article that bears on this, and on some other important topics. They've found that stem cell treatments are being sold to patients in Texas.

(The investigation) suggests that (Celltex Therapeutics) has supplied adult stem cells to Texas doctors who offer unproven treatments to patients, and that the company is involved in these treatments. One doctor claims that the treatments are part of a clinical study run by Celltex and that the company pays him US$500 a time to inject the cells into patients, who are charged up to $25,000 for a course. The US Food and Drug Administration (FDA) considers it to be a crime to inject unapproved adult stem cells into patients. David Eller, chief executive of Celltex, denies that the company is involved in treatment procedures, but would not comment on Nature's findings about how its cells are used or answer questions about them.

This makes me wonder about what is going on down there in Texas (and I can tell you, as an Arkansan, I'm willing to believe just about anything in that department). This latest business reminds me of the Burzynski cancer treatment stuff, in the way that definitions of "clinical trial" are stretched like rubber bands. Personally, I think that clinical trials are supposed to follow something very much like Yog's Law in publishing ("Money flows towards the writer"). If you're being asked to put up all kinds of money to get your book edited and published, you're very likely being scammed. And if you're being asked to pay thousands of dollars to be in a "clinical trial", well. . .you're being sold something. Real clinical trials reimburse their patients for time and effort, with money and/or medical care. They do not bill them for 25 long ones at the end of the dosing schedule

I should mention here that Slate also had an article up on Celltex, but there have been some problems. They've taken the piece down, citing editorial problems, but (as you'd figure), the cherchez le lawsuit rule applies here. Nature, though, doesn't seem to be getting sued for what they've written.

Now, back to the stem cell treatments. Among other things, Nature mentions a blog by a woman in Texas, who's written about her experiences being treated with adult stem cells from Celltex. It appears that she's receiving these treatments for multiple sclerosis, and was told that "This method has been successful with auto immune diseases such as Parkinson’s, arthritis, Multiple Sclerosis as well as others." She had apparently had a similar procedure done earlier in Mexico, but then:

". . .a friend told Larry about a doctor in Houston who went to South Korea two years ago for a stem cell transplant to treat the debilitating effects of psoriatic arthritis. He is now able to continue his medical practice, perform surgeries, and live without pain. Because our friends had noticed progress from my first stem cell transplant, they wanted us to know that Dr. Jones was now licensed to perform the procedure in Houston. To say the least, we were both excited about the possibilities and timing."

As that extract illustrates, at no point (that I have found) does this patient mention the phrase "clinical trial". One gets the strong impression, actually, that she believes that she is paying to undergo a new medical procedure, the latest thing, rather than participating in any kind of investigational study for a therapy that has not yet been reviewed by the FDA. The Nature writer, David Cyranoski, was able to speak with the physician involved, who says he's treated a number of people with cells from Celltex:

Lotfi says that most of his patients claim to get better after the treatment, but he admits that there is no scientific evidence that the cells are effective. “The scientific mind is not convinced by anecdotal evidence,” he acknowledges. “You need a controlled, double-blind study. But for many treatments, that's not possible. It would take years, and some patients don't have years.”

“The worst-case scenario is that it won't work,” he adds. “But it could be a panacea, from cosmetics to cancer.” He says that Celltex is conducting a trial in which patients “will be their own control”. “If you can compare before and after and show improvement, there's no need for a placebo,” he explains. “How can you charge people, and then give them a placebo?”

Indeed! Maybe you could try not charging them, and not making them spend their own money to find out whether your treatment is any good. Maybe you could get a large, statistically significant number of people together, who've been given thorough diagnostic workups, and give half of them the best standard of care for multiple sclerosis and half of them the stem cell treatment - at your expense - and see if they get better. How about that? (Oh, and just a little note - the worst case is not that nothing happens at all. It might be good for the people involved to think about that a bit).

This gets back to the discussions we've had around here about rethinking clinical trials. One of the things I'll say for the FDA is that they do force people to be rigorous, and to put new medical ideas to well-controlled tests. My worry about the "sell, then test" ideas was summed up in the first link in this paragraph: "I fear that there are any number of entrepreneurial types who would gladly stretch things out, as long as someone else is paying, in the hopes of finally seeing something useful. No one will - or should - pay for extending fishing expeditions." Read that Celltex article and see if that sounds familiar.

Comments (16) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System | The Dark Side

February 29, 2012

Statin Safety

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Posted by Derek

You'll have seen the news about the FDA safety warning on statins. The agency is warning that instances of hyperglycemia have occurred with statin use, as well as memory loss and confusion.

I'm really not sure what to make of this. On the one hand, these drugs have been through many, many large clinical trials under controlled conditions, and they've been taken by a huge numbers of patients out in the real world. So you might think that if these effects were robust, that they might have been noticed before now. But there are side effects that are below the threshold of even the largest clinical trials, and a patient population the size of the one taking these drugs is just where you might be able to see such things.

I lean towards the latter, and if that's true, then the agency's statement is appropriate. If these could be real effects in some patients, then it's worth keeping an eye out for them. One problem, though, is that hyperglycemia is rather more sturdy. You can measure it, and people don't really feel it when they have it. Memory loss and confusion are fuzzier, but they're immediately felt, so they're subject to more post hoc ergo propter hoc judgments. It's possible that more people will stop taking statins because of that part of the warning to cancel out the public health good that it might do otherwise.

Comments (12) + TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs | Toxicology

February 9, 2012

Guidance on Biosimilars

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Posted by Derek

If you're interested, here's the FDA's draft of their guidance on biosimilars, up on their site today. This is a slow-moving story that's going to end up having a big effect on the industry. Look at the number of top-selling drugs that are biologics, look at how long they're lasting on the market (patent protection or not), and you wonder how much competition will emerge, how successful it'll be, and how tricky it will be to approve things. If I were a real-time journalist, I'd mark this "Developing", but while that's true, in this case it means "Developing. . .over the next ten years".

Comments (5) + TrackBacks (0) | Category: Regulatory Affairs

January 30, 2012

(Un)stoppable Pixantrone

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Posted by Derek

This one mixes two categories on the blog: "Regulatory Affairs" with "How Not to Do It". A small company called Cell Therapeutics (catchy name) has been developing pixantrone for last-ditch non-Hodgkin's lymphoma. You'll note from that Wikipedia article that this compound has been knocking around for a long time, and it's had a very hard road towards any sort of approval.

In 2010, an FDA advisory committee voted it down 12-0, and from the sound of things, it wasn't even that close. But the company appealed and resubmitted, since hope springs eternal and all. They were heading towards an FDA decision next week, and the company's CEO was apparently been going around to investors telling them how confident he was of approval. You see, one of the drug's major critics at the FDA, he claimed, had been disciplined for his totally unfair review of the drug back in 2010. So how could they lose?

Like this. The company has announced that they're withdrawing their application, citing communication difficulties with the FDA. I'm sure they have some. The agency keeps trying to tell the company that the drug isn't approvable, and the company keeps on not hearing it.

Comments (18) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

January 5, 2012

Reaction to Andy Grove's Clinical Trial Proposals

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Posted by Derek

I should mention that Science is publishing some letters that it received in response to Andy Grove's proposal to rework the clinical trial system for drug development.

Sidney Wolfe and Michael Carome of Public Citizen aren't too happy with the idea, as you might expect. Their take, as I would reword it, could be summarized as "Hey, the existing system allows the drug industry to spew unsafe crap all over the market, and this would make it even worse". Actually, the language in their letter isn't far off:

A. Grove proposes returning to the era before the enactment of the 1938 Federal Food, Drug, and Cosmetic Act, when new drugs were marketed in the United States without evidence that they were safe or effective. His irrational and dangerous proposal, which would limit the Food and Drug Administration's (FDA) premarket review of new drugs to phase 1 clinical trials, is premised on the fundamental misunderstanding that such trials can provide proof of a drug's safety and on the misguided belief that it is not necessary to establish proof of efficacy. . .

Grove's proposal would subject patients on a massive scale to haphazard, uncontrolled, poorly regulated experimentation involving drugs with unknown safety and effectiveness. Such a flawed proposal does not deserve serious consideration.

Norman Marcus of the Virginia Cartilage Institute is more even-tempered, and his view is closer to my own blog post:

. . .Grove's proposed system needs some fine-tuning.

Grove correctly leaves the safety issues to the FDA, but he does not address dosage issues, which should also be determined before distribution. He does not explore how virtual clinical research organizations of the future would monitor issues of compliance and establish fair methods of measuring response. Replacing the heralded phase 3 trial with a self-administered trial would indeed save money and introduce the product much sooner to at least part of the potential market, but pharmaceutical companies would need some shielding of liability to protect them from the increased risks inherent in this plan. Because patients and third-party payers would undoubtedly see the new drugs as experimental, the pharmaceutical companies should be required to offer them at nominal cost.

That said, experimenting (carefully) is exactly what we should be doing. . .

Finally, David Borhani and J. Adam Butts (of DE Shaw Research) go right to what I've named the Andy Grove Fallacy:

. . .Compared to the semiconductor industry's gains over the past 50 years, the pharmaceutical industry's productivity must seem disappointing. There exists, however, an important distinction between engineering integrated circuits and discovering drugs. The semiconductor industry's realization of Moore's Law has always benefited from a fundamental understanding of solid-state physics. Conversely, we still don't know how living organisms work; new “components,” as well as interactions between well-known components, are discovered daily. . .This ignorance is the real reason why 90% of drug candidates fail in clinical trials: They simply don't work. The trial process is doing just what we ask of it.

None of these are unexpected reactions, and I'm sure that Grove himself has heard them before (and anticipated these). So where does this leave us? Status quo ante, with everyone having stated their positions?

Comments (12) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs

December 7, 2011

Plan B and the FDA: Unprecedented

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Posted by Derek

I haven't been blogging about the Plan B contraceptive issue, and I'm certainly staying out of the politics of the whole thing. But today's news that the FDA was planning to make it available over-the-counter, but was overruled by Health and Human Services. . .well, that brings up a question.

Can anyone else recall a case like this, where the FDA was not, in fact, the final word on drug regulation? Having HHS overrule appears to be completely legal under the provisions of the Food, Drug, and Cosmetic Act, but when's the last time it happened? And if this is the first time, how much of a precedent does it set for extra-FDA lobbying and politicking?

Comments (35) + TrackBacks (0) | Category: Regulatory Affairs

December 2, 2011

Not Just FDA-Bashing?

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Posted by Derek

There have been a lot of complaints about the FDA over the years, from all sorts of people. Many of these complaints are, well, incompatible: there are those who feel that the agency is letting too many bad compounds through, and not keeping a close enough eye on drug companies and their marketing departments. Then there's another vocal contingent that think that the agency is stifling innovation with overbearing regulations. Those can't both be right.

I'm at neither end of this spectrum. I think that we need an FDA, and that its purview should be roughly what it is now. That is, I think that the agency should require proof of safety and efficacy for marketed drugs, and that this proof should include rigorous clinical trials. I think that it should, in fact, make sure that drug companies don't go too far in their efforts to market their compounds, with "too far" to be determined (as it is now) by continuous wrangling. But I don't mean to suggest that the agency is doing all of its jobs optimally, or that it couldn't think of new ways to fulfill its mission.

Here's an example, a column in Bio-IT World that (at first glance) comes across as just more FDA-hammering. But there are some interesting ideas, once you get past the boilerplate. Such as:

While wholesale FDA reform is needed, doing it right would entail a monumental effort that could take years. But there are modest steps we can take in the meantime. How about carving out one or more FDA-free Enterprise Zones where doctors, scientists, and volunteer patients can make their own decisions unfettered by the heavy hand of regulators? Imagine an experimental terminal-illness wing of the Cleveland Clinic where informed consent was the only law. How hard would it be to draft enabling legislation?

Defenders of the FDA’s prerogatives would fight such proposals tooth and nail. But what kind of nanny state arguments can be made against conducting such a policy experiment when anyone who objects doesn’t have to be treated? Breakthroughs that emerge would still have to pass through the FDA gantlet before they would be generally available. The difference is that researchers could continue making improvements while treating volunteers during this long process.

Now, it's fair to ask how heavy the hand of regulation is in the case of terminal illnesses. We already have an awful lot of unusual therapies being tried in such situations. But could we accomplish more under these proposed conditions? Should we? I invite debate in the comments.

Comments (23) + TrackBacks (0) | Category: Regulatory Affairs

November 29, 2011

Podcast on Avastin

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Posted by Derek

As if hearing my voice on the page isn't enough, here's a podcast I did last week with Paul Howard of the Manhattan Institute on the FDA's Avastin decision. You might think that they'd be all worked up about this (a la the Wall Street Journal's editorial page), but you might be surprised. . .

Comments (4) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

November 22, 2011

Regeneron Finally Makes It to the Market

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Posted by Derek

I've been doing drug research since 1989 myself, which means that I'm fairly experienced. But Regeneron started in this business a year or two before I did, and they're just now getting their first major drug, Eylea (aflibercept) onto the market. To be fair, they did get approval for Araclyst (rilonacept) in 2008, but that one pays the electric bill and not much more - although that might be changing (see below).

As Andrew Pollack at the New York Times points out, the company has run through over two billion dollars over the years. I remember when they were working on nerve growth factors for ALS and other diseases, back in the early 1990s (I worked in the area briefly myself, to no good effect whatsoever). There are not a lot of nerve growth factor drugs on the market, although it seemed like a perfectly plausible mechanism for one back then.

That work shaded into another indication, ciliary neurotrophic factor for obesity. Regeneron spent a lot of time and money developing a modified form of that protein called Axokine, but in 2003 that project ran into the rocks. Some patients did lose weight on the drug (with daily injections), but too many of them developed antibodies to it, which raised the possibility of cross-reactivity with their own CNF, which would surely not have been a good thing. So much for Axokine.

But Eylea, a VEGF-based therapy for macular degeneration (entering the same space as Lucentis and Avastin), has now made it. And the company has another use for Arcalyst in preventative gout therapy coming along, and some interesting cholesterol work targeting PCSK9 in collaboration with Sanofi. So welcome, Regeneron, to the ranks of profitable biotech companies (well, pretty soon) who've developed their own products. It's taken a lot of time, a lot of patience - yours and your investors' - and a lot of cash. But you're still here, and how many other bioctech startups from the late 1980s can say that?

Comments (6) + TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Drug Industry History | Regulatory Affairs | The Central Nervous System

November 21, 2011

Avastin Coverage, Amended

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Posted by Derek

In response to the press coverage on the FDA's Avastin decision on Friday, a reader forwarded a revised and extended version of the New York TImes article that appeared soon afterwards. Here are some excerpts, which I think get across the thinking of many medicinal chemists and drug researchers. His contributions are bolded for emphasis, although it's not all that hard to see where the original ends and his revisions start.

"The commissioner of the Food and Drug Administration on Friday revoked the approval of the drug Avastin as a treatment for breast cancer, ruling in an emotional issue that pitted the hopes of some desperate patients against the statistics of clinical trials, two things that should never be compared, because that would be stupid.

The commissioner, Dr. Margaret A. Hamburg, said that the drug was not helping breast cancer patients to live longer or control their tumors, but did expose them to potentially serious side effects such as severe high blood pressure and hemorrhaging, making her decision very easy.

. . .The F.D.A. “recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use.” Also, they shouldn’t take drugs that don’t work, so we thought that is was important that they stop eating 88 thousand dollar magic beans, and instead use drugs and medical procedures that work.

. . .Avastin will remain on the market as a treatment for other types of cancers, including forms of cancer that it actually treats, so doctors can use it off-label for breast cancer if they hate science. But some insurers might no longer pay for the drug, which would put it out of reach of many women because it costs about $88,000 a year.

Yet pressure came from the other direction as well the outcome was certain once the statistical analysis was done, so this could have been a much shorter article. The administration had pledged to make scientific decisions on the basis of science, which seems like a pretty good idea as well. That made it difficult for Dr. Hamburg to go against the pharmaceutical lobby, and easy to accept the conclusions of the F.D.A.’s own staff and the strong recommendations of the outside experts on its advisory committee.

. . .An initial clinical trial showed that Avastin, when combined with the drug (paclitaxel), delayed appeared to delay the progression of disease by about five and
a half months, compared to use of paclitaxel alone. However, the women who received
Avastin in the study did not live significantly longer and they suffered more side effects. As an example, high doses of sodium cyanide completely stops the progression of disease almost immediately and permanently, though women who receive this treatment don’t live as long and suffer more serious side effects from the control group.

. . .Many breast cancer specialists say that Avastin does appear to work very well for some patients, but that the effect gets drowned in a clinical trial that looks at overall results. Some doctors and patient advocates argued the drug should remain available for that reason. Representatives from large sugar companies also noted that their drug, placebo, works very well for some patients, but that effect is usually gets drowned in a clinical trial that looks at overall results. The FDA has yet to approve placebo for the treatment of breast cancer."

Comments (23) + TrackBacks (0) | Category: Cancer | Press Coverage | Regulatory Affairs

November 18, 2011

Avastin's Metastatic Breast Cancer Approval Revoked

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Posted by Derek

Here's the FDA's decision (70 page PDF). As I've said here many times, I think that this is the right decision. A key section:

. . .As noted, FDA may withdraw an accelerated approval when confirmatory trials fail to confirm clinical benefit, or when the evidence does not show that the drug is safe and effective. However, the agency also carefully considers the effect on current and future patients of such a decision, and there may be circumstances, in particular cases, that would lead the agency to conclude that it would be appropriate to exercise discretion and leave an approval in place pending further study. This is not such a case.

Accelerated approval was based on the results of E2100, which showed an effect on (progression-free survival) that would be large enough to constitute clinical benefit, despite the known risks of Avastin, which are serious. However, we now have five trials, and they have substantially changed our view of this drug. The current evidence no longer supports a determination that it has a strong effect in metastatic breast cancer, and it appears likely that its effects are very weak, while the risks associated with this drug remain serious and potentially life-threatening.

There's going to be a lot of commentary, not all of it very informed, to the effect that this decision is a price-driven attempt to bring down health care costs, an assault on medical progress, the opening salvo of Obamacare, and so on. Wrong.

Avastin doesn't work as well as we thought it did for this indication. If you're going to believe in medical progress at all, you have to believe in what multiple well-controlled clinical trials are telling you - trials carried out, keep in mind, by the drug company that has every interest in having them come out favorably. But they didn't. On medical grounds, on scientific grounds, this was the right decision.

Comments (12) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

November 10, 2011

Makena's Market. Or Lack of One.

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Posted by Derek

I put up a note here yesterday about KV Pharmaceuticals and their complaint to the FDA about compounding pharmacies selling a version of their Makena progesterone ester drug. The conclusion was that the combination of Makena's high price and the FDA's we-won't-enforce attitude towards the compounders was hurting sales.

And that it is. The people at BioCentury have more. Basically, the estimate is that about 140,000 women per year fall into the potential treatment class of high-risk pregnancies. How much Makena has been sold since its launch last March? The company says that about 2,400 patients have started treatment or are enrolled to start. Now, we don't have figures on how many patients have filled prescriptions from compounding pharmacies, and I don't know how many people took this therapy before KV got involved.

But still. . .that's what, a 2 or 3% market penetration? I'll bet KV's sales projections weren't at that level.

Comments (4) + TrackBacks (0) | Category: Drug Prices | Regulatory Affairs

November 9, 2011

KV Pharmaceutical's Latest Makena Move

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Posted by Derek

Remember the Makena story from earlier this year? That's the progesterone ester whose price was raised (and how) after FDA approval by its manufacturer, KV Pharmaceuticals. (Here's the whole history). When last heard from, the FDA had sent out a letter to compounding pharmacies who were providing the drug at lower cost, saying that they were not intending to take action against them (an unusual move, to be sure).

Now KV has made their next move. According to this FDA statement, the company has provided the agency with data on a number of samples of the drug, claiming variable purity and potency in the compounded products. The FDA is looking over KV's data, and is conducting their own investigation into this as well. For now, they're reminding people that "greater assurance of safety and effectiveness is generally provided by the approved product than by a compounded product". But they're not taking any more action, for now. We'll probably be hearing more about this. . .

Comments (14) + TrackBacks (0) | Category: Regulatory Affairs

November 1, 2011

President Obama Orders the FDA to. . .Do What, Exactly?

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Posted by Derek

Headlines of the "Obama Orders FDA to Take Action on Drug Shortages" were all over the news yesterday. But anyone who actually knows the industry could be forgiven for wondering what was going on.

That's because the drug shortage problem is not something that can be solved by fiat. There are a number of factors that got us all into this fix: two big ones are changes in Medicare billing for generic cancer drugs, and manufacturing problems with overseas suppliers. (A low-margin business gives you even more incentive to source the bargain-basement options). None of these things can be fixed overnight.

And when you look at the executive order itself, you find that there's not much there. It directs FDA to expedite reviews of new suppliers and new manufacturing sites, but aren't they doing that already? And it also tells the agency to send out letters to all the companies, reminding them to remind the FDA about potential shortages, which is clearly the kind of decisive step this crisis has been waiting for. Oh, and it also calls for determining whether any of the shortages have led to "price gouging". Can't have the price of something going up just because there's a shortage - that's just basic economics, right?

So call me cynical, or call me someone who just hasn't been that impressed with Obama. (Note: the Republicans have not been covering themselves in glory, either, as far as I can see). But this whole announcement seems to be just a public relations game, made to provide a line for a speech. "Congress wouldn't take action, so I issued an Executive Order for the FDA to. . ." But during the campaign, that sentence won't end the way it should: ". . .for the FDA to do what it's already doing! Yes! And send out some letters, too!"

Comments (33) + TrackBacks (0) | Category: Regulatory Affairs

October 14, 2011

Avastin: False Hope for Metastatic Breast Cancer

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Posted by Derek

There should be a decision soon on the controversial Avastin-for-metastatic-breast-cancer indication. I've written about that several times here, and my position is unchanged: the preliminary clinical data made it worth a provisional approval, but the follow-up data didn't back it up. This happens. The provisional approval should, I think, be withdrawn, because based on the best evidence we have (which is a lot more than we had when the approval was granted), Avastin is not effective for metastatic breast cancer, and carries notable risks all its own.

Now, via NPR's Scott Hensley, I see that one of the members of the FDA's committee on this issue has published a letter in the New England Journal of Medicine explaining his vote. Says Mikkael Sekeres of the Cleveland Clinic:

"The responsibility of ODAC is to carefully consider the scientific data presented as part of an FDA application for a cancer drug and weigh the benefits that the drug may provide to patients with cancer against the risks posed by the drug's side effects. We try to be dispassionate, but we always think about the person we face in clinic sitting a foot or two away from us in our cramped examination rooms, waiting to hear what treatment we can offer to get rid of her cancer. What kind of conversation would I have with such a patient if I were trying to convince her to take a treatment like this?

“Well, I can offer you a drug that will not make you live longer, won't make you feel better, and may have life-threatening side effects, but it will keep your cancer from worsening by an average of 1 to 2 months.”

Hope? Or false hope?"

Survival is the first thing you have to consider with a cancer therapy. And right next to it comes quality of life, because extending someone's life for a brief period at the cost of horrible side effects is no bargain, either. Should women with metastatic breast cancer take Avastin? It does not, as far as anyone can tell, extend their lives. And it does not improve their quality of life - if anything, it makes it worse. Avastin can be a good drug against other forms of cancer, but it's not for this one. I very much hope the FDA follows the recommendation of the advisory panel.

Comments (22) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

September 28, 2011

Andy Grove's Idea For Opening Up Clinical Trials

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Posted by Derek

The last time I talked here at length about Andy Grove, ex-Intel CEO, I was rather hard on him, not that I imagine that I ruined his afternoon much. And in the same vein, I recently gave his name to the fallacy that runs like this: other high-tech R&D sector X is doing better than the pharmaceutical business is. Therefore the drug industry should do what those other businesses do, and things will be better. In Grove's original case, X was naturally "chip designers like Intel", and those two links above will tell you what I think of that analogy. (Hint: not too much).

But Grove has an editorial in Science with a concrete suggestion about how things could be done differently in clinical research. Specifically, he's looking at the ways that large outfits like Amazon manage their customer databases, and wonders about applying that to clinical trial management. Here's the key section:

Drug safety would continue to be ensured by the U.S. Food and Drug Administration. While safety-focused Phase I trials would continue under their jurisdiction, establishing efficacy would no longer be under their purview. Once safety is proven, patients could access the medicine in question through qualified physicians. Patients' responses to a drug would be stored in a database, along with their medical histories. Patient identity would be protected by biometric identifiers, and the database would be open to qualified medical researchers as a “commons.” The response of any patient or group of patients to a drug or treatment would be tracked and compared to those of others in the database who were treated in a different manner or not at all. These comparisons would provide insights into the factors that determine real-life efficacy: how individuals or subgroups respond to the drug. This would liberate drugs from the tyranny of the averages that characterize trial information today.

Now, that is not a crazy idea, but I think it still needs some work. The first issue that comes to mind is heterogeneity of the resulting data. One of the tricky parts of Phase II (and especially Phase III) trials is trying to make sure that all the patients, scattered as they often are across various trial sites, are really being treated and evaluated in exactly the same way. Grove's plan sort of swerves around that issue, in not-a-bug-but-a-feature style. I worry, though, that rather than getting away from his "tyranny of averages", that this might end up swamping things that could be meaningful clinical signals, losing them in a noisy pile of averaged-out errors. The easier the dosing protocols, and the more straighforward the clinical workup, the better it'll go for this method.

That leads right in to the second question: who decides which patients get tested? That's another major issue for any clinical program (and is, in fact, one of the biggest differences between Phase II and Phase III, as you open up the patient population). There are all sorts of errors to make here. On one end of the scale, you can be too restrictive, which will lead the regulatory agencies to wonder if your drug will have any benefit out in the real world (or to just approve you for the same narrow slice you tested in). If you make that error in Phase II, then you'll go on to waste your money in Phase III when your drug has to come out of the climate-controlled clinical greenhouse. But on the other end, you can ruin your chances for statistical significance by going too broad too soon. Monitoring and enforcing such things in a wide-open plan like Grove's proposal could be tough. (But that may not be what he has in mind. From the sound of it, wide-open is the key part of the whole thing, and as long as a complete medical history and record is kept of each patient, then let a thousand flowers bloom).

A few other questions: what, under these conditions, constitutes an endpoint for a trial? That is, when do you say "Great! Enough good data!" and go to the FDA for approval? On the other side, when do you decide that you've seen enough because things aren't working - how would a drug drop out of this process? And how would drugs be made available for the whole process, anyway? Wouldn't this favor the big companies even more, since they'd be able to distribute their clinical candidates to a wider population? (And wouldn't there be even more opportunities for unethical behavior, in trying to crowd out competitor compounds in some manner?)

Even after all those objections, I can still see some merit in this idea. But the details of it, which slide by very quickly in Grove's article, are the real problems. Aren't they always?

Comments (46) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs

July 29, 2011

2011 Drug Approvals Are Up: We Rule, Right?

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Posted by Derek

I've been meaning to comment on this article from the Wall Street Journal - the authors take a look at the drug approval numbers so far this year, and speculate that the industry is turning around.

Well, put me in the "not so fast" category. And I have plenty of company there. Neither Bruce Booth (from the venture capital end), John LaMattina (ex-Pfizer R&D head) nor Matthew Herper at Forbes are buying it either.

One of the biggest problems with the WSJ thesis is that most of these drugs have been in development for longer than the authors seem to think. Bruce Booth's post goes over this in detail, and he's surely correct that these drugs were basically all born in the 1990s. Nothing that's changed in the research labs in the last 5 to 10 years is likely to have significantly affected their course; we're going to have to wait several more years to see any effects. (And even then it's unlikely that we're going to get any unambiguous signals; there are too many variables in play). That, as many people have pointed out over the years, is one of the trickiest parts about drug R&D: the timelines are so long and complex that it's very hard to assign cause and effect to any big changes that you make. If your car only responds to the brake pedal and steering wheel a half hour after you touch them, how can you tell if that fancy new GPS you bought is doing you any good?

Comments (8) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Press Coverage | Regulatory Affairs

July 28, 2011

Massive Piles of Faked Data - But Right On Time

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Posted by Derek

Here's every outsourcing manager's nightmare: you contract out for research, and your CRO turns around the studies you want right on schedule. They send back the complete data package, and everything's in place. But they faked it.

Gives you the shivers, doesn't it? Well, unfortunately, it seems to be the case with an outfit called Cetero Research out of Houston. The FDA has been investigating them, and has found enough warning signs to believe that none of the data generated there can be relied on. The companies that used their services now have to decide if they need to re-run these studies themselves, which I'm sure excites them no end.

FDA is taking this action as a result of two inspections of Cetero's bioanalytical facility in Houston, Texas conducted in 2010, as well as the company's own investigation and third party audit. The inspections and audit identified significant instances of misconduct and violations of federal regulations, including falsification of documents and manipulation of samples.

The pattern of misconduct was serious enough to raise concerns about the integrity of the data Cetero generated during the five-year time frame. FDA concurs with the assessment of Cetero's independent auditor who stated, "This misconduct appears to be significant enough to cast doubt on the data generated...If the foundation of the laboratory is corrupt, then the data generated will be also."

The investigation appears to have started with an internal whistleblower, according to this letter from the FDA. The company conducted its own investigation, but the agency is slamming them both for the violations and for the inadequacy of that internal review:

According to your internal investigation, electronic records of key card building entry times demonstrated approximately 1900 instances of blood/plasma samples allegedly extracted on weekends and holidays between April 15, 2005, and June 30, 2009, where the arrival times of laboratory chemists were greater than one hour after the documented start time of the sample extraction. In addition, there were approximately 875 instances where the laboratory chemists were not present in the facility at the documented sample extraction date.

The company's original theory was that its scientists were falsifying the weekend hours in order to get paid more, but that the numbers themselves were OK. But as the FDA notes, they didn't go on to see if times were being faked during the working week (where there was no overtime incentive), and it turns out that they were. Falsus in uno, falsus in omnibus, as the lawyers say, and that appears to be the case here. A third-party investigation found many other irregularities - faked standard concentration curves and back-filling of internal standards, for example. One of the worst was the use of not-yet-analyzed samples as preliminary runs, apparently as a quick look to see if the numbers were going to come out looking good or not. That's not quite how you want to be conducting your research, and most especially if you're going to follow that up by "fixing" the numbers that you don't like. The whistleblower alleged just that. The FDA letter says that the company's conduct makes that a real possibility, and that the documention that's available sure isn't sufficient to rule it out.

You hear a lot of talk (in the comments on this blog and in other venues) about the alleged unreliability of offshore CRO work. But you don't have to go to China to get shaky data. Houston is far enough.

Update: Here's Cetero's response to the FDA.

Comments (35) + TrackBacks (0) | Category: Regulatory Affairs | The Dark Side

July 8, 2011

The Duke Cancer Scandal and Personalized Medicine

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Posted by Derek

Here's a good overview from the New York Times of the Duke scandal. Basically, a team there spent several years publishing high-profile papers, and getting high-profile funding, and treating cancer patients based on their own tumor-profiling biomarker work. Which was shoddy, as it turns out, and useless, and wasted everyone's time, money, and (in some cases) the last weeks or months of people's lives. I think that about sums it up. It was Keith Baggerly at M. D. Anderson who really helped catch what was going on, and Retraction Watch has a good link to his presentation on the whole subject.

The lead investigator in this sordid business, Anil Potti, ended up retracting four papers on the work and left Duke last fall (although he's since resurfaced at a cancer treatment center in South Carolina). That's an interesting hiring decision. Looking over the case (and such details of it as Potti lying about having a Rhodes Scholarship), I don't think I'd consider hiring him to mow my yard. Perhaps that statement will be something for his online reputation management outfit to deal with.

But enough about Dr. Potti himself; I hope I never hear about him again. What this case illustrates are several very important problems with the whole field of personalized medicine, and with its public perception. First off, for some years now, everyone has been hearing about the stuff: the coming age of individual cancer treatment, biomarkers, zeroing in on the right drugs for the right patient, and so on. You'd almost get the impression that this age is already here. But it isn't, not yet. It's just barely, barely begun. By one estimate, no major new cancer biomarker has been approved for clinical use in 25 years. Update: changed the language here to reflect differences of opinion!)

Why is that? What's holding things up? We can read off DNA so quickly these days - what's to stop us from just ripping through every cancer sample there is, matching those up with who responded to which treatment regime and which cancer targets are (over)expressed, and there you have it. That's what all these computers are for, right?

Well, that sort of protocol has, in fact, occurred to many researchers. And it's been tried, over and over, without a whole lot of success. Now, there are some good correlations, here and there - but the best ones tend to be in relatively rare tumor types. There's nowhere near as much overlap as we'd like between the cancers that present the most serious public health problems and the ones that we have good biomarker-driven treatment data for. Breast cancer may be one of the fields where things have moved along the most - treatment really is affected by checking for things like Her-2. But it's not enough, nowhere near enough.

So why, then, is that the case? Several reasons - for one, tumor biology is clearly a lot more complex than we'd like it to be. Many common forms of cancer present as a host of mutated cells, each with a host of mutations (see this breast cancer work for an example). And they're genetically unstable, constantly changing. That's why so many cancers relapse after initially successful treatment - you kill off the tumor cells that can be killed off, but that may just give the ones that are left a free field.

Given this state of affairs, and the huge need (and demand) for something that works, the field is primed for just the sort of trouble that occurred at Duke. Someone unscrupulous would have no problem convincing people that a hot new biomarker was worthwhile - any patients that survived would praise it to the skies, while the ones that didn't would not be around to add their perspective. And even without criminal behavior, it's all too easy for researchers to honestly believe that they're on to something, even what that isn't true. The statistical workup needed to go through data sets like these is not trivial; you really have to know what you're doing. Adding to the problem, a number of judgment calls can be made along the way about what to allow, what to emphasize, and what to ignore.

The other problem is that cancer is such an emotional issue. It's very easy for anyone with a drum to beat to join in at full volume. Do you think that the FDA is letting all sorts of toxic junk through? Or do you think that the FDA is killing people by being stupidly cautious? Are drug companies ignoring dying patients, or ruthlessly profiteering off them? Are there too few good ideas for people to work on, or too many? Come to oncology; you can find plenty of support for whatever position you like. They can't all be right, but when did that ever slow anyone down? Besides, that means that there will invariably be Wrong-Thinking Evil People on the other side of any topic, and that's always stimulating, too.

It is, in fact, a mess. Nor are we out of it. But our only hope to is to keep hacking away. Wish us luck!

Comments (22) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs | The Dark Side

July 1, 2011

Avastin and Medicare

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Posted by Derek

So, the FDA's advisors voted unanimously to remove Avastin's indication for metastatic breast cancer. Fine. But Medicare is saying that they'll continue to cover it? Really?

Now, as opposed to the other day, we're starting to talk about cost. Avastin is (famously) not cheap, and insurance companies often don't want to reimburse for off-label use of drugs. But if Medicare, well, doesn't care, then what? A number of insurance companies take their policies into account for their own coverage recommendations.

So this makes a person wonder what all the arguing over this issue has accomplished. Perhaps fewer oncologists will be willing to write off-label prescriptions after the FDA makes its call - there is that. But (on the one hand) this isn't looking quite like the consigning-people-to-death outcome that patient advocates were warning about. It also gives you an insight into health care costs, doesn't it? The FDA says "We don't recommend you use this. The clinical trial data don't support it." And Medicare says "Well, yeah, sure, but we'll pay for it, so what the hey". What, indeed, the hey?

Comments (13) + TrackBacks (0) | Category: Cancer | Drug Prices | Regulatory Affairs

June 29, 2011

Avastin At the FDA Today: Passion Should Lose

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Posted by Derek

Today is Day Two of the FDA's hearings on Avastin for metastatic breast cancer. Note: if you want to follow things in near real time, I'd suggest a Twitter search for #Avastin. I can particularly recommend Len Lichtenfeld's feed. This has been a very contentious issue - as most of you know, Avastin was provisionally approved for these patients, then pulled when more trial data came in showing no benefit. Roche/Genentech's team is now appealing that decision, and the questions are:

1. Should Avastin be approved for metastatic breast cancer patients? The answer to this one is "depends on the evidence for it". So. . .

2. Is there enough evidence to decide one way or another? Both the FDA and Roche seem to think that there is. The problem's that they come to opposite conclusions. So. . .

3. What's the risk/benefit ratio for Avastin in these patients? Now the serious arguing starts. Avastin is not without its serious side effects - but metastatic breast cancer is a terrible disease. The initial reports were promising - but none of the larger follow-up trials have really confirmed those results. Genentech is proposing still another confirmatory trial, with the drug to stay approved during that period, but the FDA seems to be arguing that leaving the drug approved for this indication will hurt more people than it helps. There you have it.

And all of this is being done against a backdrop of emotional cancer patient testimony. The problem with that is summed up by one of the most fervent advocates, Patricia Howard, who told the FDA "I’m not just a statistic; it is in your hands to ensure that I don’t become one."

She is wrong. It pains me to say this, but she's wrong. If we're ever going to get anywhere with cancer (or any other disease), we're going to need all the statistics we can get our hands on, and no amount of passionate testimony should be allowed to move one number in them. I've had family members with cancer; I've seen good friends and plenty of good people die from cancer. But cancer cells do not care about how strong your feelings are. The growth factor receptors, the checkpoint kinases, the apoptosis regulators, the metabolic enzymes and cell adhesion proteins: they don't give a damn. They have no damn to give. We have to fight them on those terms, on that battlefield, because that's the only one that matters and the only one where they can be defeated.

As it stands, I agree with the FDA's position: I don't think that Avastin has been shown to offer enough benefit. The 2008 provisional approval was already arguable - the agency went against its own advisory committee just to do that much - and the subsequent data have made it even less tenable. If we're going to have provisional approvals, then they have to be able to be taken back. And if we're going to evaluate drugs by their risks versus their benefits, then Avastin - for this indication, in these patients - doesn't (to my eyes) seem to make the cut.

If, on the other hand, you disagree with the provisional approval process, fine. Propose something more useful. If you disagree with the risk/benefit analysis in this case, then you should bring some new numbers or some new arguments (which is what Genentech is trying to do right now, as I write this, and I hope that they don't slip over the line while doing it). If you disagree with the whole idea of risk/benefit analysis, then. . .well, you'd better have something more useful to offer. And you'd better be sure that it doesn't end with the decisions going to whoever is the most passionate and tearful in making their case. That won't end well.

One more side issue: you'll note that I've done this whole blog post without talking about the price of Avastin at all. That's because I don't think that the price is the issue at all here. This is not a health-care-rationing issue, no matter how much some people would like for it to be. Roche gets to charge what they think Avastin can bring - they and Genentech have put the time, effort, and money into the drug. But for metastatic breast cancer, as I said here, Avastin doesn't seem like a good idea even if it were free.

Comments (63) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

June 24, 2011

Generic Drug Warning Labels: The Supreme Court Speaks

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Posted by Derek

There are plenty of headlines about the recent Supreme Court decision (PDF) on suing generic drug manufacturers. But this is not so much about generic drugs, or suing people, as it is about the boundaries between state and federal law. That, actually, is why the case made this far - that's just the sort of issue the Supreme Court is supposed to untangle. Readers may decide for themselves whether such distentangling has actually occurred.

Reglan (metoclopramide) is the drug involved here. It's been generic for many years, and for many years it's also been known to be associated with a severe CNS side effect, tardive dyskinesia. This is the same involuntary-movement condition brought on by many earlier antipsychotic medications, and it's bad news indeed. The labeling for the product has been revised several times by the FDA over the years.

In this case, the plaintiffs were prescribed metoclopramide in 2001 and 2002, and their claim was that the generic manufacturers are at fault under state tort law (in these cases, Minnesota and Louisiana). It should be noted at this point that the package insert for the drug warned at the time that tardive dyskinesia could develop, and that treatment for more than 12 weeks had not been evaluated. In 2004 and 2009, the labe was strengthened to warn that treatment beyond twelve weeks should only be undertaken in rare cases. The plaintiffs both took metoclopramide for years, although this was not at issue in this case as it was brought.

What's at issue is the drug label and how it's regulated. The plaintiffs claimed that state law required a stronger safety warning than did federal law at the time, and that they thus have standing to sue. On the other hand, you have the whole process of generic drug approval. A generic company has to show that its product is equivalent to the original drug, and it then uses the exact same label information. Under federal law, the generic companies claim, they have no authority to independently change the labeling of their products.

The plaintiffs (and their lawyers) countered this argument by claiming that there were still mechanisms ( the CBE (changes-being-effected) process and "Dear Doctor" letters) by which the manufacturers could have changed the safety warnings on their own. The FDA, however, disputes that, and the Supreme Court deferred to the agency, saying that this is not an obviously mistaken position and there is no reason to doubt that it represents the FDA's best judgment in the matter.

That disposed of, the question comes back to federal law versus state. And in direct conflicts of that sort, state law has to yield, according to Justice Thomas for the majority:

The Court finds impossibility here. If the Manufacturers had independently changed their labels to satisfy their state-law duty to attach a safer label to their generic metoclopramide, they would have violated the federal requirement that generic drug labels be the same as the corresponding brand-name drug labels. Thus, it was impossible for them to comply with both state and federal law. And even if they had fulfilled their federal duty to ask for FDA help in strengthening the corresponding brand-name label, assuming such a duty exists, they would not have satisfied their state tort-law duty. State law demanded a safer label; it did not require communication with the FDA about the possibility of a safer label.

And that last sentence is where Justice Sotomayor's dissent breaks in. The minority holds that the generic manufacturers only showed that they might have been unable to comply with both federal and state requirements, and that this isn't enough for an impossibility defense. Sotomayor's dissent agrees, though, that the FDA does not allow the generic companies to unilaterally change their labels. But she says that this does not mean that they just have to sit there. Instead of just making sure that their labels match the brand-name labeling, she says, they likely have a responsibility to ask the FDA to consider label changes when necessary, and this wasn't done in this case. And even if you take the position that they don't have to do so, they still can do so, making the impossibility defense invalid.

This is explicitly addressed in the majority opinion - saying, in so many words, that this is a fair argument, but that they reject it. On what grounds? That it would actually

". . .render conflict pre-emption largely meaningless because it would make most conflicts between state and federal law illusory. We can often imagine that a third party or the Federal Government might do something that makes it lawful for a private party to accomplish under federal law what state law requires of it. In these cases, it is certainly possible that, had the Manufacturers asked the FDA for help, they might have eventually been able to strengthen their warn­ing label. Of course, it is also possible that the Manufac­turers could have convinced the FDA to reinterpret its regulations in a manner that would have opened the CBE process to them. Following Mensing and Demahy’s argu­ment to its logical conclusion, it is also possible that, by asking, the Manufacturers could have persuaded the FDA to rewrite its generic drug regulations entirely or talked Congress into amending the Hatch-Waxman Amendments."

The "supremacy clause" in the Constitution, the majority says, clearly treats pre-emption conflicts as real problems, and therefore any line of argument that just makes them go away is therefore invalid. At about this point in the majority opinion, Justice Kennedy bails out, though. Thomas and the remaining three justices have a point to make about non obstante provisions that he does not join in - and since this is not exactly a legal blog, nor am I a lawyer (although that's easier for me to forget on morning like this one), I'm going to bypass this part of the dispute).

For those of you who are still with me, there's one more feature of interest in this case. Metoclopramide has already been the subject of an important lawsuit - in this case, going back to Wyeth, the original brand manufacturer. That's Conte v. Wyeth, which I wrote about here. The dispute in that case was not about labeling, it was over who was liable for the tardive dyskinesia in the first place. A court in California held that the originator of the drug was on the hook for that, no matter how long the compound had been generic, and the California Supreme Court refused to hear an appeal. That issue is not yet laid to rest, though, and we'll be hearing about it again.

Given these cases, though, let's say that someone takes metoclopramide and is affected by tardive dyskinesia. Who can they sue? Well, the way the labeling is now, if you take it for more than a few weeks, you're doing so at your own risk, and in the face of explicit warnings not to do so. If your physician told you to do so, you could presumably sue for malpractice.

And what about the whole labeling dispute? Well, the language of the majority decision, it seems to me, is basically a message to the FDA and the legislative branch. If you don't like this decision, it says, if it doesn't seem to make any sense, well, you have the power to do something about it. We've shown you what the law says now, and you know where to start working on it if you want it to say something else.

One more point: on the train in to work this morning, I heard the argument advanced that because of these cases, once a drug goes generic, that brand-name manufacturers will probably want to consider just exiting the market in the case of drugs that have significant warnings in their labels. That will put the whole pharmacovigilence burden on the generic companies - which they won't like, but someone's going to have to soak it up. We'll see if that happens. . .

Comments (14) + TrackBacks (0) | Category: Regulatory Affairs | Toxicology

June 23, 2011

Cladribine Is Gone

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Posted by Derek

Multiple sclerosis therapy has been changing a lot in recent years, and one of the biggest events was the introduction of Gilenya (fingolimod). That's the first non-injectable for MS, and it's quite a story (as well as being quite a weird compound from a chemistry perspective).

Novartis has been racing ahead in selling that one, because they knew the Merck KgGa (Merck-Darmstadt) had another oral compound in the works, cladribine. That's a nucleoside analog with a different mechanism (targeting some lymphoctye subtypes and thus changing immune response), and it was already used in treatment of some forms of leukemia. It did show promising results in the clinic for relapsing MS, and there were high hopes.

Not now. Word has come that the company that they're withdrawing their application in Europe and the US, and taking the drug off the market in the only two countries (Russia and Australia) where it had been approved. The FDA had already said that it would not approve cladribine without more safety information, and Merck KgGa has decided that (1) the ongoing trials won't do the job, and (2) it's not worth it (risk/reward) to try new ones.

So that leaves the field open for Novartis, and German Merck (who have had several disappointments in recent years) in some trouble. . .

Comments (16) + TrackBacks (0) | Category: Regulatory Affairs | The Central Nervous System

June 14, 2011

A Shortage of Cancer Drugs?

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Posted by Derek

There have been several headlines about a shortage of classic chemotherapy drugs recently. How do these things happen? This post at Marginal Revolution is the best short overall look at the problem that I've seen so far:

Currently there are about 246 drugs that are in short supply, a record high. These shortages are not just a result of accident, error or unusual circumstance, the number of drugs in short supply has risen steadily since 2006. The shortages arise from a combination of systematic factors, among them the policies of the FDA. The FDA has inadvertently caused drugs long-used in the United States to be withdrawn from the market and its “Good Manufacturing Practice” rules have gummed up the drug production process and raised costs.

As Alex Tabarrok says there, one pebble, or a few, won't dam up a stream. But if you keep throwing them in, something's going to happen, and I think that we've reached that point here. . .

Comments (19) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

June 13, 2011

Block That Review

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Posted by Derek

Now here's a biotech investing strategy that I haven't come across before. Adam Feuerstein reports on a hedge fund manager, Martin Shkreli of MSMB Capiral, who's very much short the the stock of a small company called NeoProbe. They're developing a contrast agent for lymph nodes called Lymphoseek, and Shkreli doesn't think very much of their data - thus the short trade.

Not leaving anything to chance, though, he's filed a "citizen petition" with the FDA, maintaining that there are severe problems with the regulatory filings for Lymphoseek and asking the agency to deny a review to the product. At issue is the concept of "standard of care". There's a blue dye that's FDA-approved for this lymph-mapping purpose, but it seems that in actual practice, almost everyone uses it along with a radiosulfur tracer (even though the sulfur colloid isn't specifically approved for that purpose). Lymphoseek's Phase III trials are controlled against the dye alone, which has some people wondering just how meaningful its data will be.

Shkreli discloses his investment position in his FDA position - there's really nothing underhanded about what he's doing. And as Feuerstein notes, "Citizen petitions are rarely if ever filed for altruistic reasons." But although companies have used them to throw elbows during the regulatory process, this is the first time I've ever heard of a short-seller trying this move.

Comments (17) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

June 3, 2011

More Insider Trading at the FDA?

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Posted by Derek

Today's Wall Street Journal has the news that the Liang insider-trading case may not be the end of the story at the FDA. The SEC has amended their complaint against Liang, adding another company's stock and another relief defendant (Liang's 87-year-old father in Shanghai, who also had his name on a brokerage account). Here's a chart of his trading, for those who are interested - make note that he did manage to lose money twice, on Pozen and Mannkind, but otherwise he hit 'em over the fence, time after time, in a most unnatural manner. (The chart also backs up my earlier speculation that Liang's trading in Vanda was what rang the alarm bells - it's far and away the biggest on the whole list).

But the Journal says that "people familiar with the case" think that Liang may have involved several other federal employees. The word is also that the insider trading may have begun well before 2006, and run to a lot more money than has been totaled so far. This might account for the delay in hearing the case - it could well be that the SEC is trying to get Liang to implicate more people as part of a plea-bargain deal. Another scientist at the FDA is apparently involved, according to the paper's sources, but that's all anyone is saying.

Rather weirdly, Liang appears to have refinanced his house ten times in the last few years - four times in as many months at one point - and taken out $350,000 in equity lines against the property. I'm not sure if he was rounding up more capital for his trading business or what. . .

Comments (18) + TrackBacks (0) | Category: Regulatory Affairs | The Dark Side

May 18, 2011

Fenofibrate: Good For Much?

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Posted by Derek

Abbott has some difficult times ahead with their fenofibrate franchise. That's TriCor, and its newer formulation, TriLipix. Fenofibrate, as I've mentioned here before, is an oddity among drugs. It was discovered way before anyone had a mechanism of action, and even now, while it's supposed to be a PPAR-alpha ligand, no one's completely happy with that explanation. (For one thing, it's not very potent at that nuclear receptor, while other PPAR-alpha compounds have crashed in clinical trials for various reasons). But it can lower triglycerides and raise HDL, which should both (in theory) be beneficial effects, and it's been a big seller over the years.

But how much good does it do? That's always the big, important, slow question in the cardiovascular field. The data for fenofibrate have always been somewhat messy (although probably positive overall), but a new study has muddied things up. As the FDA puts it, in the documents for an advisory committee meeting tomorrow (PDF):

Over the last 40 years laboratory and clinical data have suggested the potential of fibrates to reduce cardiovascular risk. However, data from large clinical outcomes trials have produced mixed results. The inconsistent outcomes may be a result of differences in pharmacodynamic properties among individual fibrates or study populations or both.

The new data, from a trial called ACCORD-Lipid, is another one looking at fenofibrate plus a statin, which is the usual combination (that way, at least in theory, you go after triglycerides, low HDL, and high LDL simultaneously). But this trial, in a large population of diabetic patients, showed that overall, the rate of major adverse cardiovascular events (MACE) was statistically identical between the statin/fenofibrate and statin/placebo groups. No advantage! It gets trickier with a bit of subgroup analysis: women showed some evidence of worse outcomes with fenofibrate as opposed to statin alone. The group that seemed to benefit, on the other hand, were the patients who started out with the highest triglycerides and the lowest HDL. (See that FDA file above for all the numbers and more).

That's disconcerting. Is fenofibrate only helping the worst-off patients, and doing nothing (or worse) for the others? That a question worth wrestling with for a drug that sold well over a billion dollars last year. And beyond that is the same sort of question that came up when all the ezetimibe data hit: how much do we really know about blood markers versus real cardiovascular outcomes? Can you hit the various numbers by different routes, some of which are beneficial and some of which aren't? What is it that we're not understanding?

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Regulatory Affairs

May 5, 2011

When Lipitor Goes Generic

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Posted by Derek

So, when Lipitor goes generic later this year, it's Ranbaxy that's going to step in and make the big bucks for a few months, right? Well. . .there's room to wonder. Ranbaxy has had some severe regulatory problems, and other companies are trying to see if they can use those to their advantage. Fortune magazine has more:

You'd think that in this era of generic-drug dominance, making the transition to a nonbranded version of Pfizer's vaunted cholesterol-fighting statin would be smooth, or at least controlled. And indeed, that's precisely how it seemed -- until just a few months ago. Now the process appears to have unraveled, leaving serious questions about who will make the cheaper form of Lipitor, whether the price will really drop, and most disturbing of all, whether patients will be able to trust that the medication is safe. . .

Comments (14) + TrackBacks (0) | Category: Regulatory Affairs

May 3, 2011

Let the Healing Begin

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Posted by Derek

This piece is too short to excerpt, so just Read The Whole Thing, as they say. The headline is "Pfizer Breaks Psychological Need To Always Seek FDA's Approval". And yes, it's The Onion.

Comments (4) + TrackBacks (0) | Category: Regulatory Affairs

March 30, 2011

KV Pharmaceuticals and Makena: The FDA's Move

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Posted by Derek

Most interesting - here's the FDA's latest statement on Makena, in response to KV Pharmaceuticals sending letters to compounding pharmacies telling them to stop providing the drug, now that they have regulatory approval and market exclusivity:

. . .Because Makena is a sterile injectable, where there is a risk of contamination, greater assurance of safety is provided by an approved product. However, under certain conditions, a licensed pharmacist may compound a drug product using ingredients that are components of FDA approved drugs if the compounding is for an identified individual patient based on a valid prescription for a compounded product that is necessary for that patient. FDA prioritizes enforcement actions related to compounded drugs using a risk-based approach, giving the highest enforcement priority to pharmacies that compound products that are causing harm or that amount to health fraud.

FDA understands that the manufacturer of Makena, KV Pharmaceuticals, has sent letters to pharmacists indicating that FDA will no longer exercise enforcement discretion with regard to compounded versions of Makena. This is not correct.

In order to support access to this important drug, at this time and under this unique situation, FDA does not intend to take enforcement action against pharmacies that compound hydroxyprogesterone caproate based on a valid prescription for an individually identified patient unless the compounded products are unsafe, of substandard quality, or are not being compounded in accordance with appropriate standards for compounding sterile products. As always, FDA may at any time revisit a decision to exercise enforcement discretion.

The agency does not quite make clear that the "unique situation" might be, although they do mention the amount of work done by NIH-funded researchers that was part of the approval package. The FDA has, of course, no authority on pricing - but they do have other means at their disposal, and this is one of them. KV must be wondering at this point what, exactly, the phrase "market exclusivity" might mean. (The answer, for better or worse, is that it, and other statuatory language, means whatever the regulatory authorities want it to mean, at least until something goes to the courts. Then it means whatever the courts want it to mean).

Overall, I think that this is a good thing, since (as I've said before) I think that the law in this case is providing a bit too much incentive, considering the relatively small risks involved in bringing progesterone caproate into the modern regulatory world. It worries me, though, that the FDA is making it so explicit that they plan to pick and choose which laws to enforce and how strictly they're going to enforce them. But honestly, it's always been this way, and a no-exceptions letter-of-the-law approach leads to craziness of its own. In this case, I think that clarifying the hazards of pushing things as hard as they can possibly be pushed will help make future business plans in this area a bit more realistic.

Comments (28) + TrackBacks (0) | Category: Drug Prices | Regulatory Affairs

Insider Trading at the FDA

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Posted by Derek

Ah, insider trading. It's the province of Wall Street types in really expensive shirts, right? Like in the movies? Well, read on.

Even the most clueless know that you're not supposed to trade on material nonpublic information, and the only really fuzzy part is what constitutes material information. A lawyer once told me that if you're an employee of a company, material information is "anything that makes you think about trading the stock". That's a pretty intelligent rule, and one that the recent Matrixx Supreme Court decision would seem to have reaffirmed. If someone could think it's nonpublic material information, odds are that it is.

In the drug business, the hottest potatoes in this category are the results of clinical trials and FDA decisions. People (a very short, well-defined, and well-paperworked list of people) inside a given company know the first news before anyone else, and people inside the FDA get to hear about the second. And there is no way that you can act on such information legally before it's released. Those tempted to try realize that, of course, and act accordingly.

They do, in fact, what Cheng Li Yiang (a chemist, regrettably) and his son Andrew Liang were accused yesterday of doing since 2006: they used the accounts of at least least seven other people to trade on knowledge of FDA approval decisions, pulling in over three million dollars in the process. The single biggest winner (over $1 million) appears to have been front-running the surprise approval of Vanda Pharmaceutical's Fanapt in 2009. It wouldn't surprise me if this was the one that blew up the whole business. That was such an unexpected move by the FDA (after which the stock went up by a factor of six) that the SEC must have gone back and carefully checked to see if anyone had been building up a position beforehand.

Liang got in on most of the big percentage moves of the last few years: Mannkind, Momenta, Pharmacyclics and many others, all small companies whose stocks saw some major action in both directions. If you want more details, here's the SEC complaint (PDF). It's a blueprint for getting caught, I should add. The various friend-and-family brokerage accounts mostly listed Liang's phone numbers as contact information, and almost always transferred money to an account held by Liang and his wife. The trading was done (one account right after the other) from IP addresses associated with his home account or voice lines billed to his name - this for accounts like the one ostensibly held by his 84-year-old mother back in China. Honestly, ten minutes after the SEC got suspicious about this guy and started checking him out, they must have known that they had him by the valuable body parts. It was really just a matter of time - well, time and greed.

Interestingly, Liang worked for the FDA for ten years before he seems to have decided to cash in. It would be interesting to know what went on, but my guess is that it's a familiar story. I think that he watched these decisions being made, watched the stocks jump around, thought about the profits to be made, and didn't act on those desires. Until one day he finally did - and nothing happened. So he probably told himself that he got away with it that time, and really shouldn't do that again for fear of getting caught - until he did it again, and didn't get caught. By this time, from the accounts you read of people in such situations, the hook is well and truly set. There may be a few people who are philosophical enough to take a set amount of money and walk away, but I'll bet that they're mighty scarce compared to the number of people who can't keep themselves from riding the train until, to their surprise, it suddenly pulls into a station.

Comments (25) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | The Dark Side

March 25, 2011

The Supreme Court Slams Big Pharma? Not Exactly.

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Posted by Derek

The Supreme Court came down with a decision the other day (Matrixx Initiatives v. Siracusano) that the headlines say will have an impact on the drug industry. Looking at it, though, I don't see how anything's changed.

The silly-named Matrixx is the company that made Zicam, the zinc-based over-the-counter cold remedy that was such a big seller a few years back. You may or may not remember what brought it down - reports that some people suffered irreversible loss of their sense of smell after using the product. That's a steep price to pay for what may or may not have been any benefit at all (I never found the zinc-for-colds data very convincing, not that there were a lot of hard numbers to begin with).

This case grew out of a shareholder lawsuit, which alleged (as shareholder lawsuits do) that the company knew that there was trouble coming and had insufficiently informed its investors in time to keep them from losing buckets of their money. To get a little more specific about it, the suit claimed that Matrixx had received at least a dozen reports of anosmia between 1999 and 2003, but had said nothing about them - and more to the point, had continued to make positive statements about Zicam the whole way. The suit alleges that these statements were, therefore, false and misleading.

And that's what sent this case up the legal ladder, eventually to the big leagues of the Supreme Court. At what point does a company have an obligation to report such adverse events to the public and to its shareholders? Matrixx contended that the bar was statistical significance, and that anything short of that was not a "material event" that had to be addressed, but the Court explicitly shut that down in their decision:

"Matrixx’s premise that statistical significance is the only reliable indication of causation is flawed. Both medical experts and the Food and Drug Administration rely on evidence other than statistically significant data to establish an inference of causation. It thus stands to reason that reasonable investors would act on such evidence. Because adverse reports can take many forms, assessing their materiality is a fact-specific inquiry, requiring consideration of their source, content, and context. . .

Assuming the complaint’s allegations to be true, Matrixx received reports from medical experts and researchers that plausibly indicated a reliable causal link between Zicam and anosmia. Consumers likely would have viewed Zicam’s risk as substantially outweighing its benefit. Viewing the complaint’s allegations as a whole, the complaint alleges facts suggesting a significant risk to the commercial viability of Matrixx’s leading product. It is substantially likely that a reasonable investor would have viewed this information “ ‘as having significantly altered the “total mix” of information made available.’ "

I think that's a completely reasonable way of looking at the situation. (Note: that "total mix" language is from an earlier decision, Basic, Inc. v. Levinson, that also dealt with disclosure of material information). The other issue in this case is what the law calls scienter, broadly defined as "intent to deceive". As the decision explains, this can be assumed to hold when a reasonable person would find it as good an explanation of a defendant's actions as any other that could be drawn. And in this case, since Zicam was Matrixx's entire reason to exist, and since a link with permanent damage to a customer's sense of smell would surely damage sales immensely (which is exactly what happened), a reasonable person would indeed find that the company had a willingness to keep such information quiet.

But here's the puzzling part - not the Court's decision, which is short, clear, and unanimous, but the press coverage. This is being headlined as a defeat for Big Pharma, but I don't see it. We'll leave aside the fact that Matrixx is not exactly Big Pharma, although I'm sure that they were, for a while, making the Big Money selling Zicam. No, the thing is, this decision leaves things exactly as they were before. (Nature's "Great Beyond" blog has it exactly right).

It's not like statistical significance was the cutoff for press-releasing adverse events before, and now the Supreme Court has yanked that away. No, Matrixx was trying to raise the bar up to that point, and the Court wasn't having it. "The materiality of adverse event reports cannot be reduced to a bright-line rule", the decision says, and there was no such rule before. The Court, in fact, had explicitly refused another attempt to make such a rule in that Basic case mentioned above. No, Matrixx really had a very slim chance of prevailing in this one; current practice and legal precedent were both against them. As far as I can tell, the Court granted certiorari in this case just to nail that down one more time, which should (one hopes) keep this line of argument from popping up again any time soon.

By the way, if you've never looked at a Supreme Court decision, let me recommend them as interesting material for your idle hours. They can make very good reading, and are often (though not invariably!) well-written and enjoyable, even for non-lawyers. I don't exactly have them on my RSS feed (do they have one?), but when there's an interesting topic being decided, I've never regretted going to the actual text of the decision rather than only letting someone else tell me what it means.

Comments (20) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | Toxicology

March 24, 2011

More on KV and Makena's Pricing

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Posted by Derek

I wanted to do some follow-up on the Makena story - the longtime progesterone ester drug that has now been newly FDA-approved and newly made two order of magnitude more expensive. (That earlier post has the details, for those who might not have been following).

Steve Usdin at BioCentury has, in the newsletter's March 21st issue, gone into some more detail about the whole process where KV Pharmaceuticals stepped in under the Orphan Drug Act to pick up exclusive marketing rights to the drug. The company, he says, "arguably has played a marginal role" in getting the drug back onto the market.

Here's the timeline, from that article and some digging around of my own: in 1956, Squibb got FDA approval for the exact compound (progesterone caproate) for the exact indication (preventing preterm labor), under the brand name Delalutin. But at that time, the FDA didn't require proof of efficacy, just safety. There were several small, inconclusive academic studies during the 1960s. In 1971, the FDA noted that the drug was effective for abnormal uterine bleeding and other indications, and was "probably effective" for preventing preterm delivery. In 1973, though, based on further data from the company, the agency went back on that statement, and said that there was now evidence of birth defects from the use of Delalutin in pregnant women, and removed any of these as approved uses. In the late 1970s, warning language was further added. In 1989, the agency said that its earlier concerns (heart and limb defects) were unfounded, but warned of others. By 1999, the FDA had concluded that progesterone drugs were too varied in their effects to be covered under a single set of warnings, and took the warning labels off.

In 1998, the National Institute of Child Health and Human Development launched a larger, controlled study, but this was an example of bad coordination all the way. By this time, Bristol-Myers Squibb had requested that Delalutin's NDAs be revoked, saying that they hadn't even sold the compound for several years. This seems to have also been a move, though, in response to FDA complaints about earlier violations of manufacturing guidelines and a request to recall the outstanding stocks of the drug. So the NICHD study was terminated after a year, with no results, and the drug's NDA was revoked as of September, 2000.

The NICHD had started another study by then, however, although I'm not sure how they solved their supply problems. This is the one that reported data in 2003, and showed a real statistical benefit for preterm labor. More physicians began to prescribe the drug, and in 2008, the American College of Obstetricians and Gynecologists recommended its use.

So much for the medical efficacy side of the story. Now we get back to the regulatory and marketing end of things. In March of 2006, a company called CUSTOpharm asked the FDA to determine if the drug had been withdrawn for reasons of safety or efficacy - basically, was it something that could be resubmitted as an ANDA? The agency determined that the compound was so eligible.

Meanwhile, another company called Adeza Biomedical was moving in the same direction (as far as I can tell, they and CUSTOpharm had nothing to do with each other, but I don't have all the details). Adeza submitted an NDA in July 2006, under the FDA's provision for using data that that applicant had not generated - in fact, they used the NICHD study results. They called the compound Gestiva, and asked for accelerated approval, since preterm delivery was accepted as a surrogate for infant mortality. An advisory committee recommended this in August of 2006, by a 12 to 9 vote. (Scroll down to the bottom of this page for the details).

The agency sent Adeza an "approvable" letter in October 2006 which asked for more animal studies. The next year, Adeza was bought by Cytec, who were bought by Hologic, who sold the Gestiva rights to KV Pharmaceuticals in January 2008. So that's how KV enters the story: they bought the drug program from someone who bought it from someone who just used a government agency's clinical data.

The NDA was approved by the FDA in February 2011, along with a name change to Makena. By this time, KV and Hologic had modified their agreement - KV had already paid up nearly $80 million, with another $12.5 million due with the approval, and has further payments to make to Hologic which would take the total purchase price up to nearly $200 million. That's been their main expense for the drug, by far. The FDA has asked them to continue two ongoing studies of Makena - one placebo-controlled trial to look at neonatal mortality and morbidity, and one observational study to see if there are any later developmental effects. Those studies will report in late 2016, and KV has said that their costs will be in the "tens of millions". So they paid more for the rights to Makena than it's costing them to get it studied in the clinic.

That only makes sense if they can charge a lot more than the generic price for the drug had been, of course, and that's what takes us up to today, with the uproar over the company's proposed price tag of $1500 per treatment. But the St. Louis Post-Dispatch (thanks to FiercePharma for the link) says that the company has now filed its latest 10-Q with the SEC, and is notifying investors that its pricing plans are in doubt:

The success of the Company’s commercialization of Makena™ is dependent upon a number of factors, including: (i) the Company’s ability to maintain certain net pricing levels for Makena™; (ii) successfully obtaining agreements for coverage and reimbursement rates on behalf of patients and medical practitioners prescribing Makena™ with third-party payors, including government authorities, private health insurers and other organizations, such as HMOs, insurance companies, and Medicaid programs and administrators, and (iii) the extent to which pharmaceutical compounders continue to produce non-FDA approved purported substitute product. The Company has been criticized regarding the list pricing of Makena™ in a number of news articles and internet postings. In addition, the Company has received, and expects to continue to receive, letters criticizing the Company’s list pricing of Makena™ from several medical practitioners and several advocacy groups, including the March of Dimes, American College of Obstetricians and Gynecologists, American Academy of Pediatrics and the Society for Maternal Fetal Medicine. Further, the Company has received one letter from a United States Senator and expect to receive another letter from a number of members of the United States Congress asking the Company to reduce its indicated pricing of Makena™, and the same Senator, together with a second Senator, has sent a letter to the Federal Trade Commission asking the agency to initiate an investigation of our pricing of Makena™.

The Company is responding to these criticisms and events in a number of respects. . .The success of the Company is largely dependent upon these efforts and appropriately responding to both the media and governmental concerns regarding the pricing of Makena™.

Personally, I'm torn a bit by the whole situation. I think that people and companies have the right to charge what the market will bear for their goods and services. But at the same time, I find myself also very irritated by KV in this case, because I truly think that they are taking advantage of the regulatory framework. As I said in the last post, it's not like they took on much risk here - they didn't discover this drug, didn't do the key clinical work on it, and don't even manufacture it themselves. Their business plan involves sitting back and collecting the rent, but that's what the law allows them to do.

In the end, if political pressure forces them to back down on their pricing, this will come down to a poor business decision. Companies should, in fact, charge what the market will bear - but KV may have neglected some other factors when they calculated what that price should be. Before setting a price, you should ask "Will the insurance companies pay?" and "Will Medicare pay?" and "Will people pay out of their own pocket?", but you should also ask "Will this price bring down so much controversy that we won't be able to make it stick?"

Comments (17) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Prices | Regulatory Affairs | Why Everyone Loves Us

March 11, 2011

Makena's Price: What to Do?

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Posted by Derek

The situation with KV Pharmaceuticals and the premature birth therapy Makena has been all over the news in the last couple of days. Briefly, Makena is an injectable progesterone formulation, given to women at risk of delivering prematurely. It went off the market in the early 1990s, because of side effect concerns and worries about overall efficacy, but since 2003 it's made an off-label comeback, thanks largely to a study at Wake Forest. This seemed to tip the risk/benefit ratio over to the favorable side.

Comes now the FDA and the provisions for orphan drugs. There is an official program offering market exclusivity to companies that are willing to take up such non-approved therapies and give them the full clinical and regulatory treatment. The idea, which is well-intentioned, as so many ideas are, was to bring these things in from the cold and give them more medical, scientific, and legal standing as things that had been through the whole review process. And that's what KV did. But this system says nothing about what the price of the drug will be during the years of exclusivity, in the same way that the approval process for new drugs says nothing about what their price will be when they come to market.

KV has decided that the price will now be about $1500 per patient, as opposed to about $15 before under the off-label regime. The reaction has been exactly what one would expect, and why not? Here, then are some thoughts:

Unfortunately, this should not have come as a surprise. It seems to have, though. The news stories are full of quotes from patients, doctors, and insurance companies saying that they never saw this coming. Look, though, at what happened recently with colchicine. Same situation. Same price jump. Same outrage, understandably. As long as these same incentives exist, any no-name generic company that comes along to adopt an old therapy and bring it into the modern regulatory regime can be assumed to be planning to run the price up to what they think the market will bear. That's why they're going to the trouble.

KV seems to have guessed correctly about the price. You wouldn't think so, with a hundred-fold increase. And the news stories, as I say, are full of (understandably) angry quotes from people at the insurance companies who will now be asked to pay. But (as that NPR link in the first paragraph says), Aetna, outraged or not, is going to pony up. It's going to cost them $20 to $30 million per year, most of which is going to go directly to KV's bottom line, but they're going to pay. And the other big health insurance providers seem to be doing the same. Meanwhile, the company has announced a program to provide low-cost treatment to people without insurance. From what I can see, it looks like basically everyone who had access to the drug before will have it now, the main difference being that the payers with deeper pockets will now be getting hammered on by KV. This is not a nice way to run a business, and it's not something I would sleep well on after having done myself. But there it is.

How much is regulatory approval worth, anyway? That seems to be what we're really arguing about. After all, patients are getting the same drug, in the same formulation, dosed the same way as before. But now it's **FDA Approved**. For new substances, I think regulatory approval is worth quite a bit. There are all kinds of things that can go wrong. But how about drugs that have been dosed in humans for years? And already run through the equivalent of Phase II trials by other people? The main thing that's being added is some confirmation that yes, the dose that everyone's been using is about right, and yes, the effects that are being seen are, in fact, real. And that's not worthless, not at all - but how much is it worth, really? The agency itself seems to place a pretty high value on it - seven years of market exclusivity, to be exact, and we can see by example just what that goes for on the market.

This does the drug industry no good, either. We have a bad enough reputation as it is, wouldn't you think? What's irritating, to someone like me who works at a "find a new drug" type of company, is that these no-name generic outfits (KV in this case, URL Pharma for colchicine) are doing pretty much what critics of the industry think that we all do, all the time. That is, walk up to situations where other people have done a lot of the work, a good amount of it with public/NIH money, and step right in and profit. Now it's true that these companies have to basically run Phase II/Phase III trials to take the data to the FDA, and that's a significant amount of money. But their risks in doing so have been watered down immensely by the history of these drugs in the medical community. When a research company closes its eyes, holds its breath, and jumps into the clinic with a new molecule, that's one thing. And that's where those 90% failure rates come from. But the failure rate of drugs that have been used for years in human patients already, and already studied under clinical conditions, is not anything like 90%. Is it zero per cent? Has anyone failed yet, taking one of these old medications back to the FDA? Even once?

The company picked its target carefully. I will say this, that KV's trials have presumably clarified the question of whether progesterone therapy actually does help. You'd think that the 2003 study would have answered that, and as it turned out, it had. A review of the field in 2006 concluded that it was a worthwhile therapy, from a cost/benefit standpoint, as did another review in 2007. (Mind you, that wasn't at any $1500 a throw, was it?) But a Cochrane review from last year concluded that there still wasn't enough evidence to recommend the whole idea. And progesterone therapy doesn't seem to help with twin or tripletpregnancies or with some other gestational problems. No, the 2003 study seemed fairly strong, and has the greatest relevance to public health, so that's what the company went for. From one viewing angle, the system worked.

My take, though, is that as long as the regulatory environment is set to value FDA's stamp of approval for old drugs this highly, that people will continue to take advantage of it. You subsidize something; you're going to get it. Personally, I don't think that the balance is right, but I'm open to suggestion about what to do about it. A shorter period of market exclusivity would just mean, I think, that the prices go up even higher once a drug gets re-approved. Just throwing up our hands and letting all that old stuff stand is a possibility, but there may well still be some of these things that aren't as effective as we think, or aren't being dosed right, and we have to decide what the cost is of letting those situations stand.

Update: see also Alex Tabarrok's thoughts on the effects of the Orphan Drug Act in general.

Comments (57) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Prices | Regulatory Affairs | Why Everyone Loves Us

February 22, 2011

Oncology Follow-Up Trials

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Posted by Derek

During the most recent Avastin controversy (with its conditional approval for metastatic breast cancer being pulled by the FDA), the role of follow-up studies in oncology became a big point of discussion.

Now there are reports that some companies aren't exactly following up in the way that they're supposed to. This isn't good. Conditional approvals are granted under the banner of "better to help people now than wait for more data", but eventually the numbers have to show up. After all, not all of these treatments are going to confirm when they're looked at more closely.

Not all of this can be put down to foot-dragging on the part of the companies. In some cases, it's proven hard to round up enough patients for further trials, and in others, the trial protocols themselves have become outdated. But there needs to be some way to review these things more regularly (as seems to be the case in the EU) to keep the process from getting tangled up.

You'll note from the article that opinions are all over the place on how lenient the FDA's approval process really is. You have people who say that the agency is dragging its feet on life-saving treatments, and people (looking at the same data set) who say that they're letting too much stuff through on the flimsiest grounds. We're not going to resolve that argument any time soon. But can we at least agree that we're going to require evidence at some point?

Comments (11) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs

February 17, 2011

Health Care Reform and the Drug Industry: How Goes It?

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Posted by Derek

We haven't had enough controversy and arguing around here this week, have we? Let's talk politics for the morning, then. Here's a piece from a former VP for public affairs at Pfizer, arguing that PhRMA got thoroughly snookered during the health care reform bill. He's looking over the current budget proposal:

For biotech and pharmaceutical companies, the president’s budget repudiates one of the most important benefits of their “deal” with the White House: the ability to market biotech drugs without generic competition for twelve years. The president would reduce that period to seven years, precisely the position of the generics industry and a position that the pharmaceutical industry had fought aggressively before it decided to make a deal with the president.

I worried about this sort of thing at the time, in the last post in which I had the nerve to bring up this issue. (In fact, if you go back and read some of the dissenting comments to that post, the twelve-year exclusivity provision was listed as one of the main reasons the bill was a good idea for the industry). Even I didn't think my last paragraph would start coming true quite this quickly, though. (I'll note in passing that my worries about the "doc fix" were justified, too). And yes, it's true that the President's budget proposal is a political football, put onto this earth to be kicked around by all parties, and that nothing in it will necessarily turn into reality. But still - isn't that a rather short time to be about-facing on this provision? Less than a year?

There's an alternate explanation: that the twelve-year provision was never really in there at all. We just thought it was! No, that wasn't marketing exclusivity at all, but data exclusivity. Or not - was it a mix of the two? What sort of mix? All sorts of people are writing to the FDA these days, telling them what they think the law actually means. Not that the agency is legally bound to listen to a word of it.

Even without any backtracking on exclusivity, the article maintains that health care reform was a loser for the drug industry. The author goes on on to detail the various other costs of the bill as it was passed, and then gets to the biggest structural problem:

While the healthy part of the pharmaceutical market will be pounded, the government-run segment of the market, Medicaid, will be expanded by 16 million patients. Medicaid has the worst pricing structure and the worst track record in paying for innovations of any sector in the United States market. Like government health-care systems around the world, Medicaid must be dragged to pay for medical advances. Unlike employers and seniors in Part D, Medicaid patients cannot vote with their feet if their health plan does not provide the new medicines they want. The incentives in Medicaid all run against paying for pharmaceutical innovations.

So, Obamacare significantly expands the worst sectors of the pharmaceutical market while degrading the best.

Well, fine, you may say, this are quotes from an opinion piece at National Review, and what else would you expect but that they're opposed to the bill over there? But these issues would be worth thinking about even if they were squawked out by flocks of crows. I really do worry that the drug industry made a serious mistake by agreeing to the health care reform bill - not only agreeing to it, mind you, but committing large amounts of money to beating the drum for it and seeing that it got passed. And that means that PhRMA made a serious mistake by putting Billy Tauzin in charge of that effort. Perhaps a backslapping deal-maker wasn't what was needed?

Okay, that gets politics out of my system for a bit. The whole health care reform bill is going to end up in the Supreme Court anyway, on commerce-clause grounds, so arguing about specific language may turn out to be a waste of time. But while I'm in the mood, though, I'll close with (what else?) a quote from Barry Goldwater. A government that's big enough to give you everything you want, he used to say, is big enough to take it all away. . .

Comments (63) + TrackBacks (0) | Category: Current Events | Regulatory Affairs

January 24, 2011

Not Enough Progress Against Cancer?

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Posted by Derek

Here's a topic that's come up here before: for a new cancer drug, how much benefit is worthwhile? As it stands, we approve things when they show a statistically meaningful difference versus standard of care (with consideration of toxicology and side effects). But should our standards be higher?

That's what this paper in the Journal of the National Cancer Institute is proposing. The authors look at a number of recent Phase III trials for metastatic solid tumors. It's a tricky business:

When designing a randomized phase III clinical trial, the investigators must specify in the protocol the difference (δ) in the primary endpoint between experimental and control groups that they aim to detect or exclude (24). The number of patients to be recruited and the duration of the study will depend on the value of δ; increasing the sample size will allow the detection or exclusion of smaller values of δ. Ideally, trials should be designed such that δ represents the minimum clinically important difference, taking into account the tolerability and toxicity of the new treatment, that would persuade oncologists to adopt the new treatment in place of the standard treatment. Of course, the opinions of oncologists as to what constitutes a minimal important value of δ will vary, but a reasonable consensus can be reached by seeking the opinions of oncologists who manage a given type of cancer. For example, an increase in median survival by less than 1 month for patients with advanced-stage cancer would not be regarded by most as clinically important, unless the new agent had less toxicity than standard treatment, whereas an improvement of median survival by greater than 3 months for a drug that was reasonably well tolerated would usually be accepted as clinically important.

And the problem is, given the costs of some of these drugs versus their benefits, you run the risk of, finally, paying too much for too little. I know that people say that you can't put a cost on a human life, but that's probably not true, when you're talking about an entire economy. As the article points out, the rough estimate is that the developed world can support expenditures of up to roughly US $100,000 per year of life gained, but past that, we're into arguable territory. (If someone wants to spend more out of their own pocket, that's another matter, naturally, but at these levels, we're usually talking public and private insurance).

The benefits can indeed be marginal, and you have to look at the statistics carefully so as not to be misled:

. . .several trials showed a statistically significant difference in a major outcome measure between the experimental and control groups, but the difference in outcome was of lower magnitude (eg, hazard ratio was closer to one) than that specified in the protocol. For example, the clinical trial that led to approval of erlotinib for treatment of pancreatic cancer was designed to detect a relative risk reduction of 25% (HR ≤ 0.75), but the best estimate of hazard ratio from the trial showed a relative risk reduction of 18% (HR = 0.82, 95% confidence interval = 0.69 to 0.99). The difference was statistically significant (P = .038), but the median survival differed by only 10 days.

What happens is that the trials are (understandably enough) designed to detect the minimum difference that regulatory authorities are likely to find convincing enough for approval of the drug. And the FDA has generally set the bar at "anything that's statistically significant for overall survival". These authors (and others) would like to see that raised. They're calling for trials not to go for a statistically significant P value, so much as to show some sort of meaningful clinical benefit - because it's become clear that you can have the first without really achieving the second.

I think that might be a good idea, whether or not you buy into that cost-per-year-of-life figure or not. At this point, I think it's fair to say that we can come up with drugs that provide some statistical measure of efficacy, given enough effort in the clinic, for many kinds of cancer (although certainly not all of them). But how many add-a-month-maybe therapies do we need? Not everyone's convinced, though:

Wyndham Wilson, a lymphoma researcher at the National Cancer Institute in Bethesda, Maryland, argues that the proposed clinical endpoints are somewhat arbitrary. “What constitutes a clinically meaningful difference? Six months is obvious, but where do you cut the line?” What's more, he adds, simply focusing on median responses often ignores important outlier effects that could merit approval for an experimental drug. “The difference in overall survival may not be great, but it may be driven by a great benefit to a small group,” he says.

Problem is, it's often quite difficult to figure out who that small group might be, and just treat them, instead of treating everyone and hoping for the best. And there's always the argument that these therapies are stepping stones to more significant improvements, but I wonder about that. My impression of oncology research has always been more like "OK, this looks reasonable. Lots of these tumors have UVW upregulated; let's make an UVW inhibitor. (Years later): Hmm, that's disappointing. Our UVW inhibitor doesn't seem to do as much as you'd think it should. But now it's been found that XYZ looks like it's necessary for tumor growth; let's see if we can inhibit it. (Years later): Hmm, that's not as big an effect as you would have thought, either, is it? Seems to help a few people, but it's hard to say who they'll be up front. How's the JKL antagonist coming along? No one's tried that yet; looks like a good cell-division target. . ."

It's just sort of one thing after another - that one didn't work so well, neither did that one, this other one and these three together seem to be a bit better, but not always, and so on. Would we learn as much, or nearly so, just from the earlier clinical work on such compounds as opposed to taking them to market? And although you can't deny that there's been incremental progress, I'm not sure what form it's taking. It's very likely that the answer isn't to keep turning over mechanistic ideas until we find The One That Really Truly Works - cancer is a tough enough (and varied enough) disease that there probably isn't going to be one of those.

My guess is that meaningful cancer success will come from combinations of therapies that we mostly don't even have yet. I think that we'll need to hit several different mechanisms at the same time, but that some of what we'll need to hit hasn't even been discovered. And on top of that, each patient presents a slightly different problem, and ideally would receive a more customized blend of therapies (not that we know how to do that, either, in most cases).

What I'm saying is that we'll probably need combinations of things that already work better than most of what we have already, and that these will stand out enough in clinical trials that we'll know that they're worth developing. As it stands, though, companies see hints here and there in the clinic, enough to run a Phase III trial, and if it's large enough and tightly controlled enough, they see enough efficacy to get things through the FDA and onto the market. Would we be better off to not proceed with the marginal stuff, and put the significant amounts of money into things that stand out more? Or would that choke off the market too much, since we mostly end up making marginal things anyway (damn it all), leaving no one able to keep going long enough to find the good stuff? It's a hard business.

Comments (32) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs

January 17, 2011

Reboxetine Doesn't Work. But That's Not the Real Problem.

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Posted by Derek

Some time ago, I took nominations for Least Useful Animal Models. There were a number of good candidates, many of them from the CNS field. A recent report makes me think that these are even stronger contenders than I thought.

The antidepressant reboxetine (not approved in the US, but sold in a number of other countries by Pfizer) was recently characterized by a German meta-analysis of the clinical data as "ineffective and potentially harmful". Its benefits versus placebo (and SSRI drugs) have been overestimated, and its potential for harm underestimated. It was approved in Europe in 1997, and provisionally by the FDA in 1999, although that was later rolled back when more studies came in that showed lack of efficacy.

Much has been made of the fact that Pfizer had not published many of the studies they conducted on the drug. These do seem, however, to have been available to regulatory authorities, and were the basis for the FDA's decision not to grant full approval. As that BMJ link discusses, though, there's often not a clear pathway, especially in the EU, for a regulatory agency to go back and re-examine a previous decision based on efficacy (as opposed to safety).

So the European regulatory agencies can be faulted for not revisiting their decision on this drug in a better (and quicker) fashion, and Pfizer can certainly be faulted for letting things stand (in the face of evidence that the drug was not effective). All this is worrisome, but these are problems that are being dealt with. Since 2007, for example, trials for the FDA have been required to be posted at, although the nontranparency of older data can make it hard to compare newer and older treatments in the same area.

What's not being dealt with as well is an underlying scientific problem. As this piece over at Scientific American makes plain, reboxetine, although clinically ineffective, works just fine in all the animal models:

And this is a rough moment for scientists studying depression. Why? Because reboxetine works beautifully in our animal models. It’s practically a poster-child antidepressant. It produces acute effects in tests such as forced-swim tests and tail-suspension tests (which use changes in struggle as a measure of antidepressant efficacy). It produces neurogenesis in the hippocampus, which is thought to be correlated with antidepressant effects. When behavioral pharmacologists are doing comparisons between older antidepressants and newer ones, reboxetine is often used as a positive control, a drug known to have an effect in the behavioral test of choice.

But it doesn’t work in patients. And patients are what matters. Now, scientists are stuck with a difficult question: What went wrong?

A very good question, and one without any very good answers. And this certainly isn't the first CNS drug to show animal model efficacy but do little good in people. So, how much is the state of the art advancing? Are we getting anywhere, or just doing the same old thing?

Comments (54) + TrackBacks (0) | Category: Animal Testing | Clinical Trials | Regulatory Affairs | The Central Nervous System | The Dark Side

January 10, 2011

Ahem: "Sell Gobs of Dope"?

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Posted by Derek

Thanks to Jim Edwards at Bnet, we have an example of some of the worst pharma sales techniques imaginable. A lawsuit alleging that Gilead Pharmaceuticals had been illegally pushing off-label indications for their angina medication Ranexa (ranolizine) was dropped recently, which brought a lot of court papers into view. According to the whistle-blower who filed the suit, a director of sales force training at the company said that their mission to, and nothing will do except a direct quote, "sell gobs of dope" and "get those pills into people's mouths any way you can."

The drug's supposed to be used only for refractory angina, but the suit alleges that Gilead's sales people were targeting the larger cardiovascular market. "I do not care what you do to sell the drug," a sales manager is quoted as saying. "I don't see anything and I don't hear anything. Just get those scripts."

Now, I realize that these are papers from only one side of this case. And as it turns out the Department of Justice actually did not get involved in the suit, which is probably why it's been dropped (for now). Furthermore, even if these allegations are true, they may well reflect the culture of CV Therapeutics, the company selling Renexa when Gilead bought them in 2009.

But this should really be an alarm bell for the management at Gilead. If they have people in their sales organization with this worldview, then it's only a matter of time before some of them do enough, say enough, present enough, and write down enough evidence to allow a successful whistle-blower case. And if that's what's going on, then such a suit would be richly deserved. This sort of stuff is idiotic, and it's wrong, and it's a big reason why the public opinion of our industry has been relentlessly sliding down over the years.

Comments (15) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | Why Everyone Loves Us

January 3, 2011

Drug Approvals 2010

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Posted by Derek

2010 wasn't, though, a particularly good year for getting new drugs on the market. But it wasn't an outstandingly bad one, either. The 21 approvals last year are lower than the previous two years (25 and 24), but still better than 2007's 18. It's actually right in the recent range, with the weirdo exception of 2004, which broke into the low 30s for no particular reason that I can see.

Of course, this level of drug development (and the sorts of drugs that we're able to get through) doesn't seem to be enough, considering all the cost-cutting and job-shedding that's been going on. So staying in the range of the past ten years, while it certainly could be worse, is still nothing to celebrate. . .

Comments (7) + TrackBacks (0) | Category: Regulatory Affairs

December 17, 2010

The Avastin Decision: A Reality Check

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Posted by Derek

So the FDA did indeed rescind their conditional approval for Avastin in metastatic breast cancer. I think that this was the right thing to do, given that the weight of the evidence now says that it doesn't do any good in that situation. Problem is, there are a lot of people trying to make political points off this decision, saying "See? We told that Obama's health care plan would lead to this. Life-saving medical breakthroughs, pulled because some bureaucrat says that they're too expensive".

Wrong. And I say this as someone who still thinks that the health care plan is a bad idea, poorly implemented. It would be good if other people opposed to it could resist the any-weapon-to-hand temptation in this case, but that's politics for you. (I'd hoped back in August that we could avoid this stuff, but that was always a long shot). The FDA is not in the business of considering costs, just safety and efficacy. And the balance between those two, in the case of hard-to-treat metastatic breast cancer, is not in Avastin's favor. If we're going to speed things up with conditional approvals, we're going to have to be able to take them back when they don't work out. This one didn't.

Here's some good background from WebMD on this decision, and more from Science-Based Medicine on the clinical evidence. That's the evidence we have, and that's why I think this was the right decision.

Comments (9) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

October 29, 2010

A Whistleblowing Record

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Posted by Derek

The former GSK employee who went to the FDA about quality control problems in their manufacturing has been awarded $96 million dollars for her work (it's calculated as a share of the fine against the company). This breaks all previous records - and you know, I think that's a good thing.

I've written about this sort of thing before, and I continue to think that this is a good law. It takes a tremendous amount of nerve to put your own livelihood at stake to report something that's going wrong (and isn't being fixed). The incentives need to be there. If we were a perfectly altruistic species, any of us would have no problem sacrificing ourselves immediately for the good of the whole. But the very fact that there's such bad conduct to take the risk of reporting on tells you that we're not that sort of species at all.

The case centred on a factory in Cidra, Puerto Rico, where GSK made a range of products including an antibiotic ointment for babies, and drugs to treat nausea, depression and diabetes. In August 2002, Eckard, a global quality assurance manager, led a team sent to the plant to investigate manufacturing violations that had been identified by the US Federal Drugs Administration (FDA). Eckard lost her job nine months later after warning that the problems ran deeper than the FDA realised.

Eckard's lawyers, Getnick & Getnick, said she was made redundant against her will in May 2003 after repeatedly complaining to GSK's management that some drugs made at Cidra were being produced in a non-sterile environment, that the factory's water system was contaminated with micro-organisms, and that other medicines were being made in the wrong doses. . .

. . .Eckard tried to alert GSK's management to the situation in Cidra even after she left the company. According to the lawsuit brought by Eckard, she tried to call GSK's chief executive JP Garnier in July 2003, but he declined to speak to her. She took her concerns to the FDA in August 2003 after concluding that GSK's compliance department lacked the authority to address her concerns.

I'm not enough of a libertarian to think that the market will take care of all such behavior without an extra possibility of punishment backing it up. I think that we really do need regulatory authorities (although we can argue the details after that statement!), in the same way that we really do need police forces. Both of those groups can (and do) abuse their authority at times, but both of them also provide a much-needed function, human nature being what it is.

And the nature of big organizations being what it is, too. "Never explain by malice what can be explained by stupidity" is a pretty good rule, and in a large company, you can add inertia, backside-covering, careerism, and deciding that a given mess is someone else's problem. The bigger a company, the more chances there are for these things to happen. Perhaps the possibility of a $750 million dollar fine will help to concentrate attention in such cases - and if not, well, how about a billion? Try for two?

Comments (32) + TrackBacks (0) | Category: Regulatory Affairs

October 25, 2010

Lorcaserin's Complete Response

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Posted by Derek

Arena released their complete response from the FDA over the weekend, regarding the non-approval of their weight loss drug Lorcaserin. And the arguing has already started about just how bad the news is. There are several levels that this process could be tracking on, and we just don't know which one it's on yet.

And the varied regulatory paths that result give you answers to "When will the drug be approved" ranging from "Maybe in six months" through "Maybe in a year" on out to "Maybe in a few years", which at that point shades into "Never". One of the main sticking points is the carcinogenicity data from the animal studies - the FDA is worried, and they want Arena to round up some outside experts to go over the data to address their concerns. Problem is, we don't quite know what that means. It could be anything from "Have some people assure that FDA that everything's actually fine" (the Arena bull position) to "Go run a bunch more long clinical trials" (which is one of the bear positions). I think it's unlikely that the FDA will let the company go through without at least running more rodent studies; I just can't see an outside review of the data doing enough to calm them down. The agency, I believe, is in more of a "Get some people to help you design some good studies" mode.

Matthew Herper's take seems reasonable to me. As he points out, even when companies have gotten a drug through after one of these Complete Response Letters, it's taken at least seven months when the issues didn't involve the clinic. He seems to be taking flak from Arena investors who have loarcaserin penciled in for somewhere around Valentine's Day. But I don't see how that's going to happen, either. Try April Fool's - of some other year.

Comments (4) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

September 24, 2010

Avandia Goes Down: A Research Rant

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Posted by Derek

So now Avandia (rosiglitazone) looks to be withdrawn from the market in Europe, and heavily restricted here in the US. This isn't much of a surprise, given all the cardiovascular worries about it in recent years, but hindsight. Oh, hindsight: all that time and effort put into PPAR ligands, back when rosi- and pioglitazone were still in development or in their first few years on the market. Everyone who worked on metabolic diseases took a swing at this area, it seems - I spent a few years on it myself.

And to what end? Only a few drugs in this class have ever made it to market, and all of them were developed before we even knew they they hit the PPAR receptors at all. The only two that are left are Actos (pioglitazone) and fenofibrate, which is a PPAR-alpha compound for lack of any other place to put it. Everything else: a sunk cost.

Allow me to rant for a bit, because I saw yet another argument the other day that the big drug companies don't do any research, no, it's all done at universities with public funds, at which point Big Pharma just swoops in and makes off with the swag. You know the stuff. Well, I would absolutely love to have the people who hold that view explain the PPAR story to me. I really would. The drug industry poured a huge amount of time and money into both basic and applied research in that area, and they did it for years. No one has to take my word for it - ask any of the academic leaders in the field if GSK or Merck, to name just two companies, managed to make any contributions.

We did it, naturally, because we expected to make a profit out of it in the end. The whole PPAR story looked like a great way to affect metabolic disorders and plenty of other diseases as well: cancer, inflammation, cardiovascular. That is, if we could just manage to understand what was going on. But we didn't. Once we all figured out that nuclear receptors were involved and got busy on drug discovery on that basis, we didn't help anyone with any diseases, and we didn't make any profits. Big piles of money actually disappeared during the process, never to be seen again. You could ask Merck about that, or GSK (post-rosiglitazone), or Lilly, or BMS, or Bayer, and plenty of other players large and small.

No one hears about these things. We're understandably reluctant to go on about our failures in this industry, but the side effect is that people who aren't paying attention end up thinking that we don't have any. Nothing could be more mistaken. And they aren't failures to come up with a catchy slogan or to find a good color scheme for the packaging - they're failures back at the actual science, where reality meets our ideas about it, and likely as not beats them down to the floor.

Honestly, I don't understand where these they-don't-do-any-research folks get off. Look at the patent filings. Look at the open literature. Where on earth do you think all those molecules come from, all those research programs to fill up all those servers? There are whole scientific journals that wouldn't exist if it weren't for a steady stream of failed research projects. Where's it all coming from?

Note: previous posts about PPAR drug discovery can be found here, here, and here. Previous posts (and rants) about research in the drug industry (and academia, and the price of it all) can be found here, here, here, here, here, here, here, here, and here.

Comments (49) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Industry History | Regulatory Affairs | Why Everyone Loves Us

September 16, 2010

Live-Blogging Arena's FDA Committee Hearing

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Posted by Derek

San Diego newspaper blogger Keith Darce is doing it here. The meeting should start up again about 1 PM Eastern. So far, the company and the FDA staff have been presenting reviews of the Lorcaserin data. The committee member questions don't look particularly encouraging. . .

Update: the committee votes "No", 9-5. We'll see what the agency itself does. I expect the same outcome.

Comments (7) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

September 14, 2010

Lorcaserin in Trouble

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Posted by Derek

The FDA committee that will be looking over Arena's lorcaserin for weight loss has released its briefing information, and there were some nasty surprises therein. A memo states that the drug did not satisfy the mean efficacy requirements that the FDA has laid down for obesity therapies, and satisfied the categorical efficacy one "by a slim margin".

Well, that was known. I said as much back in May of last year, and didn't the Arena fans ever give me an earful about it. What wasn't apparent was the two-year rodent tox. The briefing document raises questions about the number of malignancies that showed up in these rats, and that's not good. The safety profile of any drug in this area has to be very clean, especially if the efficacy is borderline.

As for the big worry about any serotinergic compound in this area, 5-HT2b heart valve trouble, the briefing document isn't too reassuring there, either. The FDA staffers note that the company didn't run a positive control in the animal models, and didn't look at proliferative markers during the human clinical trials. They conclude that "the FDA has not definitively concluded that lorcaserin is devoid of valvulopathy-related cardiac effects in animals".

Frankly, I think that the tox/efficacy combination is likely to sink the drug's approval chances. There are other problems, but this is the big one. The market seems to be agreeing - Arena's stock is getting hammered today. I look forward to hearing from the various people who were after my hide about this.

Comments (39) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

A New Way to Approve Drugs

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Posted by Derek

Who are our customers in this drug business? Well, sick patients, naturally. But their physicians, too, since they're the ones who will be writing the prescriptions. And the insurance companies, of course, since in most cases they're the ones who will be paying at least some of the bill. But the customer before we get to all that is the FDA.

Not many other industries have a gatekeeper that absolute. Every product has to be submitted and given an explicit, detailed review, with a thumbs-up or thumbs-down at the end of it. Imagine a car maker putting together a New Model Authorization package for each new model of light truck for Approval To Sell in the fall, or waiting for the Committee On SUVs to define the review criteria for Truck-Like Four-Door Crossovers before any of them can be sent to the dealers. A fast food chain wants to offer a new Double Taco Burger? Fine - submit the paperwork, and the agency will get right on it. The review committee on Fake Mexican Entrees meets in March.

The reasons for all this are no mystery. Anything that can directly affect a person's health, in either direction, is going to have a lot more oversight than the new Double Taco Burger, which will probably not kill you, although you may wonder about that forty minutes later. But given that we're going to have a large, complicated regulatory regime for new drugs, do we have the right large, complicated regulatory regime?

Steve Usdin and the team at BioCentury have a good article out that asks just this question. Since we were talking around here about the conditional approval for Avastin in metastatic breast cancer, that's a good example of how this new system might work: instead of binary decisions, the whole thing is adaptive.
The idea is to set things up so that decision-making data can be generated more quickly, and so that these decisions can be modified based on later findings. The big push in the early phases of the clinic would involve biomarkers - and yes, I know that everyone's been trying to do that, with rather mixed success. But the plan here is not to add on biomarker work, but to make it an integral part of every clinical program, with stored samples (and incentives to share them), and a clear regulatory framework for what the FDA wants to see in each case.

But since biomarkers aren't easy to come by, the next part of the plan is wider use of conditional approval and adaptive clinical trials. Another way to speed things up with adaptive designs would be to run several new therapies in a given space simultaneously, re-assigning patients as the more effective candidates show themselves. If the trials are going on continuously, the barriers to getting in on them would be lower than they are under the current system, where everyone has to start their own work from the ground up. Again, the idea is to be able to make some sort of decision as early as feasible, with the option of going back if later data don't pan out. (That's the key mental adjustment in the whole thing, actually - the willingness to act on the belief that, if done well, enough of these early decisions will turn out to be the right ones to outweigh the ones that aren't).

Conditional approval would have to be coupled with restrictions on marketing until more data came in - you couldn't just go crazy as soon as possible. But it would work both ways - a company would get wider authorization as the numbers got better, or would have to narrow things down or even pull a compound altogether. This would be a big adjustment for the public to make, frankly - I can already see the editorials going on about making the entire American public a group of test subjects, and so on. But you know, they already are: every compound that makes it to market is still an investigational drug, no matter what anyone might think.

There's more at that BioCentury link, and I encourage anyone who's interested to read it all. I think that there's a lot of merit in these ideas myself, although getting them implemented in the real world won't be easy. There's also the worry that half-implementing them would leave us with a system that's no better (or subtly worse) than the one we have now. Thoughts?

Comments (13) + TrackBacks (0) | Category: Regulatory Affairs

August 30, 2010

Avastin For Metastatic Breast Cancer: The Whole Story

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Posted by Derek

Here's an excellent roundup of the Avastin story, referenced in an earlier post here.

I have to say, I've been disappointed in some of the commentary on this issue (which that article goes into as well). Too many people have jumped right to the conclusion that yep, here's what the new health care plan is going to do to us, yank life-saving medicines out of our hands because they cost too much. Well, I think that the health care bill was a disastrous idea, myself, and at the same time I still think that Avastin doesn't deserve approval for metastatic breast cancer.

The best evidence we have is that Avastin doesn't help these patients and may well even hurt them. That would be true even if it were free. And remember, off-label use is still perfectly legal. Anyone who wishes to spend their own money on something that does not appear to work - and that Wall Street Journal editorial aside, Avastin really doesn't, here - is free to do so. Getting everyone else to pay for it is quite another thing, and you'd think that conservatives and libertarians would find that argument more appealing than they seem to.

The FDA meets to discuss this issue on September 17. I wish everyone who's gearing up to write editorials about the decision would get up to speed on the facts before then.

Comments (8) + TrackBacks (0) | Category: Cancer | Drug Prices | Regulatory Affairs

August 27, 2010

Not Your Usual FDA Hearing

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Posted by Derek

You always had to wonder how the move of appointing Sidney Wolfe to the Drugs Safety and Risks Management Committee at the FDA was going to work out. The signs of friction are appearing. I'm with the InVivo Blog: this is the first time I've heard of an FDA committee cutting off the microphone on one of its own members. And you'd think that everyone involved would be able to manage things so that didn't happen - wouldn't you?

Comments (7) + TrackBacks (0) | Category: Regulatory Affairs

August 20, 2010

Going Hollywood

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Posted by Derek

A reader at one of the big pharma companies sends along this note:

. . .Over my 10 years or so of experience, I have seen a severe decline in risk tolerance at my company, and other large companies as well. When we put a project forward, we are told that either: (a) There are too many unknowns, the target is not well established, and therefore the risk in putting forward the large sums of money required for development are too high; or (b) There are too many other players in the market already and we would never be able to capture enough market share to justify the investment required to go forward. The band considered acceptable in the risk/benefit spectrum has become so narrow that it is like threading a needle with your feet.

I believe that this risk aversion is due to the escalating cost of developing new drugs. Big Pharma has invested such a tremendous amount of money into the infrastructure they deemed necessary to increase project turnaround time that any drug that hoes forward has to be seen as a guaranteed blockbuster or it is considered a failure.

Film buff that I am, I use a Big Studio Production vs. Independent Film analogy when I discuss this with people outside the profession. For example, the film Avatar cost about 300 million to make. That means that if it brings in a mere 50 million in ticket sales, it is a catastrophic failure for the studio. Paranormal Activity on the other hand cost a few tens of thousands of dollars to make. Bringing in 50 million dollars in ticket sales would exceed the filmmakers wildest dreams of avarice.

The end result is that the Big Studio has to KNOW that Avatar will bring in greater than 300 million dollars in ticket sales or it cannot take the risk. Therefore only tried and true box office magic directors like James Cameron are given the opportunity to work at that level. On the other end of the spectrum, an independent film distribution company is willing to take on a high risk project like Paranormal Activity because even a failure will not destroy the comany, and the rewards of success (even if moderate by Big Studio standards) is very high.

So, has Big Pharma doomed itself by massively inflating its drug discovery infrastructure in a misguided attempt to stregnthed its pipeline (which was clearly a failure)? Or is it the regulatory agencies that require such vast and expensive trials that are the cause of this risk aversion? Is there a solution?

Well, the Hollywood analogy has been made before, but that's because it's a pretty good one. There are a few places where it breaks down, though. Some of these are unfavorable to the drug business:

1. Copyright. It lasts a lot longer than patent rights. I think that copyright has been extended to ridiculous levels in the US, but it's always been significantly longer than patent terms. So a studio has a much longer time to makes its money back.

2. Regulatory affairs. There's no FDA approval process for a new film. You think it up, you get it shot and produced, you release it, and good luck to you. The drug industry hasn't worked that way since the 1930s.

3. Cycle time. It takes a lot longer to get a drug project through than it takes to get a movie done. And since time is most definitely money, this hurts.

4. Toxicity and liability. While it's true that a bad film might make you feel sick, it's not going to lead to anything actionable in court. Bad news on a new drug's side effects or performance most definitely will, though. And how.

5. Costs and benefits. A movie, from the consumer's standpoint, is a momentary purchase, made with a small amount of discretionary income. If it delivers, great - if not, no harm done, other than some wasted time and a bit of cash. Drugs, of course, are a much more high-stakes business, both in their pricing and in their utility. And they affect a person's health, which is about as fundamental a thing as you can mess with, and moves any transaction up into a whole new spotlight.

On the other hand, there are some problems that the studios face that we don't:

1. Limits of copyright. While copyright goes on next to forever, it's still easy to move a new film or book right up next to an existing work. Movies get ripped off much more quickly than drugs can be, and often more blatantly. That shorter cycle time cuts both ways.

2. Easier copying. You can find pirated versions of first-run movies pretty quickly - they're not always great, but there's a market. Lots of free stuff gets tossed around in digital formats, too. Drugs are much harder to truly copy, and an inferior version is much, much less attractive.

3. Fashion. An antihypertensive drug from thirty years ago doesn't wear funny-looking retro clothes or pick up a mobile phone the size of a loaf of bread. It lowers your blood pressure, same as always. There may be better ones around now, but it'll still work exactly as it did when it came on the market.

All that said, I think that the key point here is that there's no equivalent in the drug industry to indie filmmaking, which is too bad. Our fixed costs are much, much, higher due to the field we operate in - human health and the regulations around it. My question is - is there any way to bring these down? Of course, that's what everyone in the business has been asking for some time now.

Because if we can't, we're going to see even more of the behavior that my correspondent noted. Risk aversion, I might add, can be fatal to research-driven companies. Our whole business is founded on taking risks, and if the costs are pushing us to deny that, we have a huge conflict right at the center of the whole enterprise. . .

And yeah, I realize that this doesn't help too much with the "less depressing" promise I made for this week!

Comments (36) + TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History | Drug Prices | Regulatory Affairs

July 26, 2010

Biosimilars: Not Easy, But Not Impossible, Either

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Posted by Derek

So we actually had two converging stories on Friday afternoon - the news that Sanofi-Aventis is going after Genzyme, and the news that tiny Momenta Pharmaceuticals finally got FDA approval for a biogeneric of Lovenox (enoxaparin). . .a big seller for Sanofi-Aventis.

I knew something was going on with those folks - I'm close enough in Cambridge that I could hear them whooping and popping champagne corks. They've got backing from Novartis, who will actually be making the stuff using Momenta's techniques, but this was make-or-break news for them, and they've been waiting for quite a while to hear it. Meanwhile, Sanofi-Aventis has been hoping just as long that this day wouldn't come.

And they're not alone. A lot of companies have built their business model around the fact that it's very hard to produce biosimilars, so anything that chips away at that is a potential attack on their profits. Genzyme is very much one of those companies, and Shire is one of the companies hoping to move them into the new world.

Every biologic product is different, though, and some of them are going to be harder to break than others. But the financial incentives for doing so are there, and Friday's approval makes them more definite than ever. As a small-molecule guy, I'm not all that sad about this, although that may be an unworthy emotion. I think that some sort of exclusivity (which we now grant mostly through the patent system) is necessary for research companies to turn a profit. But that exclusivity shouldn't be perpetual, either. Everyone should have an incentive to look for the next new thing - hoofbeats, coming up from behind, should be the constant background sound.

Comments (12) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

July 23, 2010

Vivus, Qnexa, Arena, Lorcaserin and the FDA

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Posted by Derek

One big story from the last week was the FDA advisory panel's "No" decision on Qnexa, the drug-combo obesity therapy developed by Vivus. This is the one that's a combination of phentermine and topiramate, both of which have been around for a long time. And clinical trials showed that patients could indeed lose weight on the drug (with the required diet and exercise) - but also raised a lot of questions about safety.

And it's safety that's going to always be a worry with any obesity drug, even once you get past the (rather large) hurdle of showing efficacy. That's what took the Fen-Phen combination off the market, and what torpedoed Acomplia (rimonabant) and the other CB-1 compounds before they'd even been property launched. The FDA panel basically agreed that Qnexa helps with weight loss, but couldn't decide how bad the side effects might be in a wider patient population, and whether they'd be worth it:

But the drug has side effects, both known and theoretical. It may cause birth defects, it may increase suicide risk, it can cause a condition called metabolic acidosis that speeds bone loss, it increases risk of kidney stones, and may have other serious effects.

"It is difficult if not impossible to weigh these issues as the clinical trials went on only for a year, and patients will use this drug for lifetime," (panel chair Kenneth) Burman said. "It is impossible to extrapolate the trial data to the wider population."

That's a problem, all right, and it's not just Vivus that has to worry about it. When the potential number of patients is so large, well, any nasty side effects that are out there will show up eventually. How do you balance all these factors? Is it possible at all? As that WebMD article correctly points out, a new obesity drug will come on the market with all kinds of labeling about how it's only for people over some nasty BMI number, the morbidly obese, people with other life-threatening complications, and so on. But that's not how it's going to be prescribed. Not after a little while. Not with all the pent-up demand for an obesity drug.

Although that's probably the worst situation, this problem isn't confined to obesity therapies - any other drug that requires long-term dosing has this hanging over it (think diabetes, for one prominent example). That brings up the question that anyone looking over clinical trial data inevitably has to face: how much are the trials telling us about the real world? After all, the only way to be sure about how a drug will perform in millions of people for ten years is to dose millions of people for ten years. No one's going to want to pay for any drugs that have been through that sort of testing, I can tell you, so that puts us right where we are today, making judgment calls based on the best numbers we can get.

The FDA itself still has that call to make on Qnexa, and they could still approve it with all kinds of restrictive labeling and follow-up requirements. What about the other obesity compound coming along, then? A lot of people are watching Arena's lorcaserin (which I wrote about negatively here and followed up on here). Arena's stock seems to have climbed on the bad news for Vivus, but I have to say that I think that's fairly stupid. Lorcaserin may well show a friendlier side-effect profile than Qnexa, but if the FDA is going to play this tight, they could just let no one through at all - or send everyone back to the clinic for bankrupting.

As the first 5-HT2C compound to make it through, lorcaserin still worries me. A lot of people have tried that area out and failed, for one thing. And being first-to-market with a new CNS mechanism, in an area where huge masses of people are waiting to try out your drug. . .well, I don't see how you can not be nervous. I said the same thing about rimonabant, for the same reasons, and I haven't changed my opinion.

Since I got a lot of mail the last time I wrote about Arena, I should mention again that I have no position in the stock - or in any of the other companies in this space. But I could change my mind about that. If Arena runs up in advance of their FDA advisory panel in the absence of any new information, I'd consider going short (with money I could afford to lose). If I do that, I'll say so immediately.

Comments (24) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Regulatory Affairs | The Central Nervous System | Toxicology

June 22, 2010

Mylotarg and the FDA

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Posted by Derek

Someone completely outside the industry asked me the other day what I thought about the FDA. I replied that I had a lot of sympathy for them, actually. There's almost no way that they can avoid being yelled at by one group or another. You know - they're a bunch of foot-dragging nitpickers who are keeping effective medicines (things used in other industrialized countries, yet!) off the market here. Oh, hold it, it's Tuesday already - they're actually a bunch of incompetent industry shills who let all kinds of useless, toxic stuff through because they can't be bothered to do their jobs.

That's the sort of thing. If you want a good example of this, take a look at Mylotarg. Wyeth developed this oncology agent years ago for some forms of leukemia. It's a monoclonal antibody to CD33 (a cell-surface receptor found on leukocytes), conjugated to ozogamicin, a fairly aggressive chemotherapy agent. It was approved back in 2000 under "accelerated approval" rules, which are supposed to bring drugs for life-threatening conditions to market more quickly. The requirement is that companies continue to study such drugs after they're marketed, though.

Well, the studies have been completed on Mylotarg. It's not a very widely used drug, since it's only indicated for people 60 and older with particular forms of leukemia who aren't candidates for the more common therapies. But the numbers are in. . .and it turns out that people die more quickly while taking it than while taking the standard of care. Oh, dear. The drug has now been pulled from the market.

And there you have the FDA's dilemma: if they had sat on Mylotarg longer and required more studies, this probably wouldn't have happened. On the other hand, Wyeth might have decided to abandon it at that point - and not everything that gets accelerated approval is a Mylotarg. Some compounds that could actually help people could get lost that way. It's a real tightrope, and the rope is set up completely differently for every new drug. There's no way to get all these decisions right, but for life-threatening diseases, letting through more iffy compounds is still probably the right way to do it, I think.

Update: fixed all sorts of formatting and spelling issues, after taking a break from my real job to have a look (!)

Comments (10) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

June 21, 2010

Flibanserin: Not a "Female Viagra" At All

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Posted by Derek

I haven't commented on the controversy over Boehringer Ingleheim's drug for female libido, flibanserin. An FDA advisory panel voted it down on Friday, and it wasn't close: 10-1 against whether the drug showed efficacy, and unanimously against its side effect profile. I really don't see how the drug is going to make it back from that kind of reception.

The press coverage of this compound has not been good. Far too many headlines have called it "Female Viagra", which is ridiculously off-base. Viagra, for its part, does absolutely nothing for the libido; it's plumbing, a pure cardiovascular effect. The assumption (a reasonable one, for many men) is that the desire is already there. Meanwhile, flibanserin is a central nervous system agent, affecting the mental state of sexual satisfaction, not any cardiovascular sequelae. The drugs are completely different.

And the FDA panel's problem (one of their problems) with the drug was that it doesn't seem to do much for desire, either. We can argue all day about whether low desire is a disease or not, but even if someone does want to do something about it, flibanserin doesn't seem to be the answer.

Boehringer is taking a lot of criticism for bringing the drug this far, actually. It was originally developed as an antidepressant, but during the trials reports came in of the sexual effects in female patients, so they repurposed it - taking the drug out of a crowded field and into completely new territory. You can admire that as showing flexibility, or you can worry that the company found a possible drug and then went shopping for a disease, with a willingness to invent one if it didn't quite exist.

I don't know where I stand on that latter point; I've no idea what the statistics are on low sexual desire as a problem (and I'm willing to bet that what numbers might exist have whopping error bars on them). But I think that we're not going to be revisiting this topic any time soon. The FDA panel officially encouraged Boehringer to continue research, but the vote tallies are not the sort of thing that would encourage anyone.

Comments (25) + TrackBacks (0) | Category: Drug Development | Regulatory Affairs | The Central Nervous System

June 10, 2010

Nativis: In Which the Distant Footfalls of Lawyers Can Be Heard

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Posted by Derek

I've received a letter from John Kingma, the Chief Financial Officer of Nativis. I reproduce it below word-for-word (Here's the PDF of the original, in case anyone would like to check):

Dear Dr. Lowe,

The scientific nature of your blog seems to have taken a turn for the worse with the negative personal attacks on John and Lisa Butters and othe rmatters related to Nativis. The comments have gone far beyond reasoned scientific debate, skepticism and criticism. In fact, the overall tone seems to have degenerated into something resembling the Internet bulletin boards of old, with personal attacks, sexual comments and statements that may well amount to libel and defamation of character.

It appears to us that that the same person, using multiple names, is responsible for many of the negative personal comments (indications are that this is a person who bears a personal grudge against John Butters, and who now seems intent on ruining his reputation and that of Nativis). It seems clear to us that you have permitted unprofessional, bizarre, and even potentially activity prohibited by law to be conducted by this commenter and others on your blog site, activity that clearly overrides the scientific debate.

No one in the Nativis family has experienced anything so outrageous and unprofessional as the content of your blog site. I don't know if the current non-scientific banter is what you intended for your blog - essentially now a forum for personal attacks. Not only have you allowed theses attacks to be posted, you have also been selective in posting (screening out) information that would be more favorable to Nativis, such as the positive pre-clinical research data that John Butters provided you, showing how drug signal therapy reduced tumors in mouse models.

Moreover, apart from personal attack comments, your blog also contains comments from a person who announced his attempts to gain access to Nativis's facility. In fact, he visited Nativis's site, posing as a representative of your blog, The Pathfinder. When he was turned away by security, he reportedly took photographs or videos through office windows. His actions were reported and encouraged on your site. His actions may well have been illegal.

We have asked counsel to take a look at what is happening on your blog and the activities by commenters promoted there, and to recommend a course of action. But everyone at Nativis would rather get past this unfortunate situation and spend 100 percent of our time advancing our technology.

In that regard, may we suggest that in the best interest of all parties that you moderate your blog, focus on the scientific debate, delete all personal attacks and prevent personal attacks from occurring in the future? That would seem fair and reasonable, while also keeping the scientific debate going.

Thank you, in advance, for the consideration. I look forward to your response.


John E. Kingma
Chief Financial Officer

Well. I suppose that the rest of this post should begin with "Dear Mr. Kingma:"

I am, as you see, in receipt of your letter of June 9. Allow me to comment on it, so that we may understand each other.

Your first objection is that the tone of some of the comments to my two posts on Nativis have "gone far beyond reasoned scientific debate". A less charitable observer might say that the claims that Nativis makes for its technology have long since occupied that territory. But I've actually tried to be charitable. Until your letter arrived, most of the criticism I'd received from readers and colleagues in the industry was that I'd been far too tolerant in my discussion of your company.

Your CEO, in addition to sending me papers on such disparate subjects as the Mossbauer effect (and offering generously to send along a large book on quantum electrodynamics), did indeed provide a graph of what is said to be the effect of your most advanced. . .well, let's call it a "therapeutic agent" in a mouse model. This does not help me as much as you seem to believe it does. Imagine some other company claiming that they can show effects in a mouse xenograft model though the intervention of invisible pink unicorns - and providing a dose-response curve as proof. Extraordinary claims, which yours surely are, require extraordinary evidence, and I don't see how you can possibly provide enough in a blog forum to convince your critics. Besides, this would be a waste of your time. You will surely be generating a tremendous amount of data in preparation for your company's IND application, and I certainly can't ask you to share all of it. Convince the FDA, and you'll have gone a long way to convincing everyone else.

Now, to your observations about my blog's comment section: I do not actively moderate it, except to occasionally remove duplicate posts. No real moderation has been needed: the tone of discussion around here is unusually civil, for the most part. It's especially so compared to the rest of the blog world and the Internet as a whole - not just "of old", but every day of the week. If no one in the "Nativis family" has ever experienced anything so outrageous as the contents of this blog, permit me to observe that you appear to have led sheltered lives.

Believe me, you will hear worse from other people as you go on developing your company's approach to drug therapy. I mean this in the best possible way, but the material that Nativis uses to explain and promote its technology does not inspire confidence in trained observers. I assume that you're well aware of this; if you're not, you should be. And that's fine - huge breakthroughs in the sciences often have that effect on people. But the problem is, nonsense has the same effect. If I may quote the late Carl Sagan on this very problem, "They laughed at Galileo. They laughed at Einstein. But they also laughed at Bozo the Clown."

Your company's claims are so startling, and so far beyond what most scientists would assume to be possible, that you truly have no alternative but to fall into one of those two categories. A red nose, a fuzzy wig, and floppy shoes are waiting for anyone who makes such claims. Your job is avoid being fitted for them. To that end, you do not have to convince me, or any random bunch of people on the internet. You have to convince the patent offices, the journal editors, and the regulatory authorities. My advice is to devote your time and effort to that task, and to stop worrying about what people say about you on blogs.

Worse things have been said on this site about other (far larger) companies; worse things are said all over the internet a thousand times a second. I certainly do not endorse the making of defamatory comments about people, but I fear that some of the very comments you might object to might not be seen that way by every observer. If I start taking down every comment that offends anyone who writes to me, there will be no end to it.

If you read my posts, you will see that I have not encouraged anyone to engage in illegal conduct. That goes for the entire 8-year archives of the blog, for that matter. I did not encourage anyone to visit your site in any way, and did not comment when someone reported that they did so. I live and work on the other side of the country from you, and my readers are responsible for their own actions. By the way, if the person you speak of did identify themselves as a representative of "The Pathfinder", as you state, then their connection to a blog called "In the Pipeline" is unclear.

As to whether some individual is engaging in a campaign of defamation against your company and your CEO, I can see no evidence of that in my blog's records. The uncomplimentary comments seem, from what I can tell, to have come in from a wide variety of separate sources - you truly have brought people together. On the other hand, some of the glowing endorsements and defenses of your company have come in under different names from the exact same IP addresses. Make of that what you will.

Mr. Kingma, you (and John Butters, and all the other officers and employees at Nativis) should be out there working to revolutionize the entire drug industry. If you can do what you say you can, that's exactly what will happen. Any scientist on the trail of something this wonderful, this huge - and potentially this profitable - would not allow anything to deter them from claiming their place in history. Go do that. I'll be overjoyed if you manage to pull it off. But having heard, after only two blog posts, from both the CEO and the CFO of your company makes me wonder about how you choose to use your time.


Derek Lowe

Comments (139) + TrackBacks (0) | Category: Blog Housekeeping | Regulatory Affairs | Snake Oil

June 3, 2010

Eribulin Gets Reviewed, Finally

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Posted by Derek

So it looks like the FDA is giving reviewing Eisai's oncology drug Eribulin (E7389) a priority review. The company had hoped to get it reviewed three years ago, but the FDA told them to get back into the clinic and collect more data.
The compound is being reviewed for advanced breast cancer, and the earlier clinical data looked pretty good. (Head and neck tumors, on the other hand, didn't show much of a response). It binds to yet another site on tubulin (a popular site for various oncology agents), but in a rather complicated fashion that differs from the other agents in this category.

The compound is remarkable mainly for its brutal structural complexity, and for the fact that it's being made synthetically. It looks like a natural product, for sure, but it's actually a modified version of the right-hand side of halichondrin B, whose structure is still more horrific. Kishi's group at Harvard synthesized that beast back in 1992, and that work was the foundation of the synthesis of Eribulin. I don't think this is necessarily going to spark a renaissance of Big Natural Product Analog Synthesis inside the pharma labs, but it's quite a story. Here's hoping it has a good ending - we should know in September.

Comments (23) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

May 11, 2010

Regulatory Approvals in the US versus Europe

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Posted by Derek

I was looking at the list the other day of the 2009 drug approvals from the FDA. Here's a breakdown from Nature Reviews Drug Discovery - 25 total, 16 small molecules and 9 biologics. And here, from the same journal, is a look at approvals in Europe. There were 29 - but the weird thing is that only five entries overlap on the two lists. The authors of this latest article suggest that this raises questions about global strategy.

Does it? Let's break that down. Here are the small molecules approved by the FDA in 2009 that were not approved in the EU:

Milnacipran: was already on the market in Europe for depression, approved in the US for fibromyalgia.
Febuxostat: approved by the EU in late 2008, by the FDA in early 2009.
Artemether–lumefantrine: approved by the EU back in 2001.
Benzyl alcohol (Ulesfia), of all things, for head lice: not yet approved in the EU.
Iloperidone: approved (most unexpectedly) in the US, not even submitted yet in Europe, as far as I know. May never be.
Besifloxacin (opthalmic): not approved in the EU yet.
Prasugrel: apparently didn't make the list because the CHMP in Europe approved it in December 2008.
Pitavastatin: expected to be approved in the EU this year, and has been in Japan since 2003.
Asenapine: still under review in the EU.
Vigabatrin: approved for infantile spasms in the US, but has been approved as an antiepileptic in Europe since 1989 and in the US since 1997.
Bepotastine: not approved in the EU yet, although I think that's underway.
Telavancin: has had a complicated past in the EU - basically, they have approval against hospital-acquired pneumonia as part of the EU application, while in the US it's part of a separate add-on.
Pralatrexate: approved for lymphoma in the US, and under review in the EU.
Pazopanib: under review in the EU.
Romidepsin: under review in the EU as well.

So overall, it's not as much of a split as it looks. Several compounds are just missing showing up in the same calendar year, and if you did this analysis using a two-year window, I think the overlap would be much greater. Admittedly, for some drug launches every day counts, so ideally you'd want approval for both the US and EU to come soon and simultaneously, but mostly, things are reasonably close. The next thing to do will be to look at the compounds on the EU approval list and see how they stand in the US - no time for me to do that today, but shortly.

Comments (12) + TrackBacks (0) | Category: Regulatory Affairs

May 7, 2010

Environmental Cancer?

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Posted by Derek

I find the President's Cancer Panel report -at least, the general tone of it - hard to believe. Most of the headlines yesterday focused on the "grievous harm", "bombarding", and "grossly underestimated" statements, and suggested that there was an epidemic of environmentally-caused cancer. Since most age-adjusted cancer incidence rates have, in fact, been dropping, I find this a bit hard to believe.

Here's the whole report (whopping PDF). Update: that link may be bad - try here. It actually does mention that cancer rate data, but (as far as I can see) just sort of blows right past it. And while I take the point that endocrine disruptors and the like need to be watched (and that we really do need to study these things more), I don't see why the alarm bells need to be rung quite this loudly.

I see that the American Cancer Society seems to agree. My own views are closer to those of Bruce Ames (PDF) than to the President's panel. We should always be alert to possible environmental causes of cancer, but we should also realize that (as far as we can tell) they seem to be relatively minor.

Comments (35) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

May 5, 2010

Intermune: Right Back Down Again

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Posted by Derek

Back in March, Intermune's stock saw a sudden jump on news that an FDA advisory committee treated their drug pirfenidone more positively than expected. But the agency is in no way committed to following these recommendations, and yesterday they turned down the drug, sending Intermune stock right back down into the basement again.

Pirfenidone was, even after the advisory committee, an iffy proposition. It made it through one Phase III trial, but missed its endpoints on another. And even though there's no current treatment for idiopathic pulmonary fibrosis, there's no use in telling people that there is one (and asking their insurance companies to pay for it) if there really isn't. The company isn't saying much, but all indications are the the FDA is concerned about efficacy: they aren't convinced that the drug really works, and will want fresh clinical trial data before reconsidering approval.

Whether Intermune can raise the cash to do that is in doubt. If they can't convince the FDA that they have something worthwhile, they'll likely have trouble persuading investors.

Comments (3) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

April 29, 2010

Treatment INDs - For Any Generex Fans Out There

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Posted by Derek

Adam Feuerstein schools the Generex folks on what a "Treatment IND" really means, quoting chapter and verse from the FDA. The company's fans have made much of that designation for its flagship buccal insulin product. As has the company's CEO - but that link shows her making statements at investor conferences which are, on the face of them, in flat contradiction to the FDA's own understanding of such matters.

The article's worth reading even if you don't give two hoots about Generex, since it'll give you an understanding of what it means (and doesn't mean) when a company has a product designated for "compassionate use". It can also give you an understanding of what it means when a company misrepresents that status, but I think a lot of people here already know what that must mean. . .

Comments (3) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Regulatory Affairs

April 13, 2010

Novartis, Roche Threaten To Leave the UK

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Posted by Derek

Now, here's some hardball negotiating: Roche and Novartis, fighting with the UK government over drug pricing and regulations on clinical trials, are threatening to pull their R&D out of the country.

The Swiss drug companies made their threats known in personal meetings with a government minister, according to Whitehall documents seen by the Guardian.

The documents also make clear that cabinet ministers have been conducting a vigorous charm offensive to prevent multinational drug companies leaving Britain. Novartis employs 3,500 people in Britain at nine sites while Roche has 1,500 workers in this country.

The ministers, including business secretary Lord Mandelson, have in recent months visited executives at their headquarters in Japan, the US and Europe in what officials call a "programme of ministerial visits".

The visits have been organised to patch up a relationship strained by ministers' efforts to force the firms to cut the prices of the drugs they sell to the NHS, according to the documents.

In any of these "according to documents obtained by. . ." cases, you have to ask cui bono? Roche and Novartis have not made these threats publicly, so this could be a leak from them to apply more pressure to the government. Or it could be a leak from inside the NHS, in order to make the companies look bad. I would be inclined to not pay attention to any of the public statements on this issue from either side - the real story will take place out of the headlines, unless someone spills some more meeting minutes.

Either way, I think it's unlikely that this would be followed through - but neither is it completely impossible, either, which is what makes it a reasonably effective move.

Comments (22) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

March 12, 2010

Garage Biotech

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Posted by Derek

Freeman Dyson has written about his belief that molecular biology is becoming a field where even basement tinkerers can accomplish things. Whether we're ready for it or not, biohacking is on its way. The number of tools available (and the amount of surplus equipment that can be bought) have him imagining a "garage biotech" future, with all the potential, for good and for harm, that that entails.

Well, have a look at this garage, which is said to be somewhere in Silicon Valley. I don't have any reason to believe the photos are faked; you could certainly put your hands on this kind of equipment very easily in the Bay area. The rocky state of the biotech industry just makes things that much more available. From what I can see, that's a reasonably well-equipped lab. If they're doing cell culture, there needs to be some sort of incubator around, and presumably a -80 degree freezer, but we don't see the whole garage, do we? I have some questions about how they do their air handling and climate control (although that part's a bit easier in a California garage than it would be in a Boston one). There's also the issue of labware and disposables. An operation like this does tend to run through a goodly amount of plates, bottles, pipet tips and so on, but I suppose those are piled up on the surplus market as well.

But what are these folks doing? The blog author who visited the site says that they're "screening for anti-cancer compounds". And yes, it looks as if they could be doing that, but the limiting reagent here would be the compounds. Cells reproduce themselves - especially tumor lines - but finding compounds to screen, that must be hard when you're working where the Honda used to be parked. And the next question is, why? As anyone who's worked in oncology research knows, activity in a cultured cell line really doesn't mean all that much. It's a necessary first step, but only that. (And how many different cell lines could these people be running?)

The next question is, what do they do with an active compound when they find one? The next logical move is activity in an animal model, usually a xenograft. That's another necessary-but-nowhere-near-sufficient step, but I'm pretty sure that these folks don't have an animal facility in the basement, certainly not one capable of handling immunocompromised rodents. So put me down as impressed, but puzzled. The cancer-screening story doesn't make sense to me, but is it then a cover for something else? What?

If this post finds its way to the people involved, and they feel like expanding on what they're trying to accomplish, I'll do a follow-up. Until then, it's a mystery, and probably not the only one of its kind out there. For now, I'll let Dyson ask the questions that need to be asked, from that NYRB article linked above:

If domestication of biotechnology is the wave of the future, five important questions need to be answered. First, can it be stopped? Second, ought it to be stopped? Third, if stopping it is either impossible or undesirable, what are the appropriate limits that our society must impose on it? Fourth, how should the limits be decided? Fifth, how should the limits be enforced, nationally and internationally? I do not attempt to answer these questions here. I leave it to our children and grandchildren to supply the answers.

Comments (42) + TrackBacks (0) | Category: Biological News | Drug Assays | General Scientific News | Regulatory Affairs | Who Discovers and Why

March 11, 2010

Intermune's Rise

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Posted by Derek

If you want to know why people continue to speculate in biotech stocks, just take a look at the stairsteppy last few days of trading in Intermune (ITMN). Last Thursday it was at $15; now it's at $38. And all you have to do to cash in on these moves is read the FDA's mind!

That's not a money-making proposition, in case anyone thinks I'm advocating it. There are just too many surprises. But Intermune's good fortune started last week, when the FDA briefing documents came out on the application on the company's pirfenidone for idiopathic pulmonary fibrosis and were characterized as "not as bad as they could have been". (The company's history of overzealous PR wasn't helping it at this point). And if you still don't think that the moves in the stock have been surprising, consider that two ITMN executives sold shares on after the first jump, missing out on the second one completely when the FDA advisory panel gave the drug a favorable recommendation.

Pirfenidone, by the way, is another structure entry in the so-simple-I-can't-believe-it drug sweepstakes. If approved, it would be the first specific therapy for IPF, which can be a nasty disease. I certainly hope it helps out the patients involved (a few hundred thousand in the US), but that small patient population means that the drug isn't going to be cheap. Intermune's investors certainly don't think so.

But as has been clear for some time, we're in a rather tricky environment for expensive health care options. If pirfenidone makes it, I'd guess that it will be picked up widely, but cautiously, by health insurance. No one knows how it'll perform in the real world, and if little benefit is seen, it'll be hard to justify reimbursing for it. (It made one Phase III trial's endpoint, but missed another one, so there's room to wonder). The more cost-conscious European regulatory agencies will be a good place to watch this argument play out. One correspondent of mine refers to the drug as the next Iressa. That's not a compliment.

Comments (5) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Regulatory Affairs

March 10, 2010

Vaccines in the Court

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Posted by Derek

The Supreme Court has agreed to hear a vaccine-liability case, in an attempt to untangle conflicting lower court rulings. This all turns on the 1986 act that shields manufacturers from liability suits and a followup law that establishes a separate compensation system for injuries. A Georgia Supreme Court ruling has recently held that such suits can go on in state court, which seems to contradict other court decisions (and the intent of the 1986 law as well, you'd think).

I agree with Jim Edwards of BNET that although this particular case involves the DPT vaccine, the vaccines-cause-autism crowd will be watching this one very closely. Lawsuits will no doubt be ready to fly later this year in case the Supreme Court breaks that way - which seems to me unlikely, but I'm no judge. . .

Comments (17) + TrackBacks (0) | Category: Autism | Regulatory Affairs | Toxicology

March 2, 2010

The Plasmid Committee Will See You Now

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Posted by Derek

From Nature comes word of a brainlessly restrictive new law that's about to pass in Turkey. The country started out trying to get in line with EU regulations on genetically-modified crops, and ended up with a bill that forbids anyone to modify the DNA of any organism at all - well, unless you submit the proper paperwork, that is:

. . .Every individual procedure would have to be approved by an inter-ministerial committee headed by the agriculture ministry, which is allowed 90 days to consider each application with the help of experts.

The committee would be responsible for approving applications to import tonnes of GM soya beans for food — but also for every experiment involving even the use of a standard plasmid to transfer genes into cells. Work with universally used model organisms, from mice and zebrafish to fruitflies and bacteria, would be rendered impossible. Even if scientists could afford to wait three months for approval of the simplest experiment, the committee would be overwhelmed by the number of applications. One Turkish scientist who has examined the law estimates that his lab alone would need to submit 50 or so separate applications in a year.

It's no doubt coming as a surprise to them that biologists modify the DNA of bacteria and cultured mammalian cells every single day of the week. Actually, it might come as a surprise to many members of the public, too - we'll see if this becomes a widespread political issue or not. . .

Comments (9) + TrackBacks (0) | Category: Biological News | Regulatory Affairs

February 26, 2010

HER2 Confusion

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Posted by Derek

For years now, drug companies and journalists have been touted the new era of personalized medicine. This is one of those things that always seems to be arriving, but is taking its time getting here. The industry has sunk a huge pile of money into biomarker research, and it's safe to say that it hasn't paid off yet - although, at the same time, one still has to think that it should, eventually.

Nature Biotechnology has a good article that shows how tricky the whole business can be. HER2 is one of the more validated cancer biomarkers, and there's a drug (Herceptin) that's targeted specifically for breast cancer patients that express it. So how's that going? Not so well:

A recent study from the University of California, San Francisco, reveals that one in five HER2 tests gives the wrong answer1. Furthermore, the article, which reviews the medical literature, reports that as many as two-thirds of breast cancer patients who should be tested for HER2 are not, and consequently a significant fraction of women treated with Genentech's Herceptin (trastuzumab) have never been tested for HER2 overexpression.

The health benefit provider Wellpoint, of Indianapolis, might dispute that finding. According to Genentech staff scientist Mark Sliwkowski, the insurer has data showing that 98% of its breast cancer patients are tested. However, doctors differ in their views on testing before prescribing Herceptin. “Some doctors don't know how to interpret test results, they prefer just to prescribe it and assess the patient's progress,” says Michael Liebman of the patient stratification company Strategic Medicine of Kennett Square, Pennsylvania.

More than a decade after the drug received US Food and Drug Administration (FDA) approval, the personalized medicine paradigm clearly has holes. . .

That it does. As the article goes on to explain, there are doubts about how good many of the existing HER2 tests are, worries about how they don't always agree, questions about whether some HER2-negative patients might be benefiting from Herceptin anyway, and more questions about those results due to uncertainties about the tests. That's the state of the art right there, folks, and it's clear that we have a long way to go. I don't see any reason why biomarkers (of various kinds, not just genetic) won't help us figure out which patients should be getting which drugs, but don't let anyone tell you that we're there yet.

Comments (15) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs

February 22, 2010

Avandia: Off the Market or Not?

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Posted by Derek

The Senate report that leaked on Avandia (rosiglitazone) over the weekend has made plenty of headlines. It quotes an internal FDA report that recommends flatly that the drug be removed from the market, since its beneficial effects can be achieved by use of the competing PPAR drug Actos (pioglitazone), which doesn't seem to have the same cardiovascular risks. The two drugs have been compared (retrospectively) head to head, and Avandia definitely seems to have come out as inferior due to safety concerns.

There had been worries for several years about side effects, but the red flag went up for good in 2007, and the arguing has not ceased since then. According to another FDA document in the Senate report, there are "multiple conflicting opinions" inside the agency about what to do. The agency ordered GSK to set up a prospective head-to-head trial of Avandia and Actos, but other staffers insist that the whole idea is unethical. If the cardiovascular risks are real, they argue, then you can't expose people to Avandia just to find out how much worse it is. The trial is enrolling patients, but will take years to generate data, and Avandia will be generic by the time it reports, anyway. (Presumably, the only reason GSK is running it is because the drug would be taken off the market for sure if they didn't).

The FDA's internal debate is one issue here (as is the follow-up question about whether the agency should be restructured to handle these questions differently). But another one is GlaxoSmithKline's response to all the safety problems. Says that New York Times article:

In 1999, for instance, Dr. John Buse, a professor of medicine at the University of North Carolina, gave presentations at scientific meetings suggesting that Avandia had heart risks. GlaxoSmithKline executives complained to his supervisor and hinted of legal action against him, according to the Senate inquiry. Dr. Buse eventually signed a document provided by GlaxoSmithKline agreeing not to discuss his worries about Avandia publicly. The report cites a separate episode of intimidation of investigators at the University of Pennsylvania.

GlaxoSmithKline said that it “does not condone any effort to silence” scientific debate, and that it disagrees with allegations that it tried to silence Dr. Buse. Still, it said the situation “could have been handled differently.”

Well, yeah, I should think so. I don't know what the state of the evidence was as early as 1999, but subsequent events appear to have vindicated Buse and his concerns. And while you can't just sit back and let everyone take shots at your new drug, you also have to be alert to the possibility that some of the nay-sayers might be right. We honestly don't know enough about human toxicology to predict what's going to happen in a large patient population very well, and companies need to be honest with the public (and themselves) about that.

Comments (16) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs | Toxicology

February 16, 2010

Pharma and the Health Care Bill: Value For the Money?

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Posted by Derek

I hesitate to open up the whole topic of health care reform again. (For the record, I think that the bills, in their current forms, are dead). But one thing that struck me was how early the pharma industry trade group PhRMA got involved in the negotiations, and the sort of deal that they struck.

I note that Billy Tauzin, head of the organization at the time, seems to have been instrumental in those negotiations, and that he has now left his position. You can read this account of the whole affair, courtesy of the Sunlight Foundation, and decide to what extent those two statements are related. I also note that, if that article is accurate, at least $100 million dollars was spent by the trade group in the process.

I get emails from people at PhRMA once in a while. I'm expecting the next one by this afternoon. . .

Comments (9) + TrackBacks (0) | Category: Current Events | Regulatory Affairs

November 19, 2009

Plavix vs. Effient

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Posted by Derek

The InVivo Blog has a good article on a controversy in the blood-thinning market. Plavix (clopidogrel) has a very strong share of that, of course, but since Effient (prasugrel) was finally approved, Lilly and Dai-Ichii are looking to take as much of that market as they can. And one opening might be that not everyone responds similarly to Plavix.

In some cases, that's because there are some drug-drug interactions, a problem the FDA has recently addressed. The proton pump inhibitors, especially, are metabolized through the CYP2C19 pathway. That's a problem, since that enzyme is needed to convert clopidogrel into its active form (Plavix, as it comes out of the pill, is a prodrug - its thiophene ring needs to get torn open). This sort of thing has been seen many times before - it's one of the many headaches that you can endure in drug development as you profile the metabolizing pathways for your drug candidate and compare them to the other compounds your patient population might be taking. There are some combinations that just will not work (several involving CYP3A4, which is often the first one you test for), and it looks like we can add Plavix/2C19 to the list.

But the population genetics of the 2C19 enzyme are rather heterogeneous. About a third of the patients taking Plavix have a less-active form of the enzyme to start with, and they might not respond as robustly to the drug. The FDA has emphasized this effect in its latest public health warning. That's an opportunity for Effient, since it doesn't go through that metabolic route.

The In Vivo people point out, though, that this story isn't being driven by the usual players. It's not the FDA that's pushed to find this out, and it's not even Eli Lilly. It's Medco and Aetna. They studied their insurance claims data to see if the numbers supported the proton pump inhibitor/Plavix interaction, found that they did, and publicized their findings - and that led to an actual observational trial from BMS and Sanofi, which confirmed the problem. Now Medco is going further, and is actually running its own observational study comparing Plavix and Effient. Their theory is that the efficacy that Lilly showed compared to Plavix was driven by the (deliberate, one assumes) inclusion of a high number of poor metabolizers.

Medco is getting ready for generic Plavix, and trying to keep its costs down by making the case that the drug will do the job just fine for most patients. They could, on the other hand, end up making the case for Effient in that poor-metabolizing third of the patients, which would also be interesting. Lilly would presumably settle for that, although they'd like even more of the market if they can get it, naturally.

And I have to say: I like this sort of thing. I like it a lot. This, to me, is how the system should work. Companies are pursuing their own competing interests, but in the end, we get a higher standard of care by finding out which drug really works for which patients. The motivation to do all this? Money, of course, earning it and saving it. This may sound crass, but I think that's a reliable, proven method to motivate people and companies, one that works even better than depending on their best impulses. You could even build an economic system around such effects, with some attention to channeling these impulses in ways that benefit the greatest number of people. Worth a try.

Comments (22) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Regulatory Affairs

November 2, 2009

In Which You Get to Hear the Phrase "Hatch-Waxman" Again

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Posted by Derek

There's a constant running battle in the drug industry between the two kinds of pharmaceutical companies: the ones who discover the drugs first, and the ones who sell the drugs cheaply after the patents have expired. It surprises me still how many people I run into (outside my work) who don't make that distinction, or who don't even realize that there is one.

But the generic industry is a very different place. Their research budgets are far smaller than the ones at the discovery companies, since they're only dealing with drugs that everyone knows to already work. Their own research is directed toward satisfying the regulatory requirements that they're making the equivalent substance, and to finding ways to make it as cheaply as possible. And some of them are very good at it - some ingenious syntheses of marketed drugs have come out of the better generic shops. Of course, some real head-shaking hack work has, too, but that you can find everywhere.

The tension between the two types of company is particularly acute when a big-selling drug is nearing its patent expiration. It's very much in the interest of the generic companies to hurry that process along, so often they challenge the existing patents on whatever grounds they can come up with, figuring that the chances of success jutify the legal expenses. Since the 1984 Hatch-Waxman act, there's been an even greater incentive, the so-called "Paragraph IV" challenge. A recent piece in Science now makes the case that this process has gotten out of control.

After four years of a drug's patent life, a generic company can file an Abbreviated New Drug Application (ANDA) and challenge existing patents on the grounds that they're either invalid or that the ANDA doesn't infringe them. (This, for example, is what happened when Teva broke into Merck's Fosamax patent, taking the drug generic about four years early). If the challenge is successful, which can take two or three years to be resolved, the generic company gets an extra bonus of 180 days of exclusivity. The authors of the Science piece say that this process is tipped too far toward the generic side, and it's cutting too deeply into the research-based companies. (As noted here, that's rather ironic, considering the current debate about such provisions for biologic drugs, where some parties have been citing the Hatch-Waxman regime as a wonderful success story in small molecules).

This all took a while to get rolling, but the big successes (such as the Fosamax example) have bred plenty of new activity. There are now five times as many Paragraph IV challenges as there were at the beginning of the decade. Teva, for example, which is one of the big hitters in the generic world, had 160 pending ANDAs in 2007, of which 92 were running under Paragraph IV. Here's a look at some recent litigation in the area, which has certainly enriched various attorneys, no matter what else it's done.

Under Hatch-Waxman, a new drug starts off with five years of "data exclusivity" during which a generic version can't be marketed. The Science authors argue that the losses from Paragraph IV now well outweigh the gains from this provision, and that the term should be extended (which would put it closer to those found in Europe, Canada, and Japan. They also bring up the possibility of selectively extending data exclusivity case-by-case or for certain therapeutic areas, but I have to say, this makes me nervous. There are too many opportunities for gamesmanship in that sort of system, and I think that one goal of a regulatory regime should be to make it resistant to that sort of thing.

But I do support the article's main point, which is that the whole generic industry depends on someone doing to the work to discover new drugs in the first place, and we want to make sure that this engine continues to run. Politically, though, anything like this will be a very hard sell, since it'll be easy to paint it as a Cynical Giveaway to the Rapacious and Hugely Profitable Drug Companies. But speaking as someone working for the RHPDCs, I can tell you that we are indeed having a tougher time coming up with the new products with which to exploit the helpless masses. . .

Comments (23) + TrackBacks (0) | Category: Business and Markets | Drug Industry History | Drug Prices | Patents and IP | Regulatory Affairs

September 25, 2009

The Details of the Baucus Bill

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Posted by Derek

Since we were discussing the Baucus health care proposal here the other day, I thought that people would appreciate a chance to read through the provisions of the bill before forming an opinion of it.

Sorry! You can't. It's not online, and it won't even be online by the time the Finance Committee is through with it. Senator Baucus, though, would like you know know that it's because it's just too darn difficult to put it up.

So we'll just have to trust them. I suppose. We may get a chance to look things over before the House votes on anything. Unless some good reason comes up not to do that, of course. It has before.

Comments (23) + TrackBacks (0) | Category: Current Events | Regulatory Affairs

September 23, 2009

Pay Them Now, Or Pay For It Later

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Posted by Derek

Time for a brief comment on health care reform, now that Sen. Baucus has presented a bill to the Finance Committee (which, to be sure, I believe has already attracted over 500 proposed amendments). As is well known, the largest drug industry trade group, PhRMA, signed on to the whole idea of a large reform effort early, in exchange for a seat at the table (and a chance to make things go favorably). How's that working out so far?

As Steve Usdin at Biocentury writes, the answer is "fairly blatantly":

The parochial value of PhRMA’s controversial decision to cut a deal with the Senate Finance Committee and the White House became clear last week as details of the committee’s healthcare reform bill emerged that favor big pharma companies over their biotech siblings. The bill also pounds the medical device industry and slams laboratory service providers, sectors that didn’t agree on “voluntary” contributions to healthcare expansion. . .

. . .A 233-page summary of the America’s Healthy Future Act released by Finance Committee Chairman Max Baucus (D-Mont.) includes most of PhRMA’s healthcare reform wish list and has only one major provision pharma companies hope to kill: a commission with powers to constrain Medicare spending.

The tax put on medical devices by this bill has already been noted widely in the press, and I see that Sen. Kerry is already objecting to that provision - naturally enough, since Massachusetts has some big players in that area. The Senators from Guidant and Medtronics (also known as Indiana and Minnesota) are speaking up as well. The trade association for that industry (AdvaMed) apparently couldn't come to terms with Washington, so this tax is their reward - which, in a nutshell, is the sort of thing that keeps gradually turning me into a libertarian.

There are more examples. Biocentury goes on to detail an excise tax provision in the bill that's based on sales figures and market share. But this isn't calculated on total US sales, which is the method various biotech companies were pushing for. No, it's calculated by market share of sales to the US government, which (because of Medicare) tends to emphasize drugs for an older population. In general, if your drug is provided substantially through any government-supported program, (HIV medications come to mind), you're going to see a higher fee. Orphan drugs are exempt from the tax, which must gladden the hearts of several companies, though.

It's still way too early to get worked up over any specific provisions of any one bill, and there's plenty of room to wonder if anything substantial at all will get passed. But it is worth paying some attention to how the process works. When the same tactics are used in the private sector, the unfortunate phrase "protection racket" comes to mind. But government, well, that's different. Clearly.

Comments (28) + TrackBacks (0) | Category: Current Events | Regulatory Affairs

September 22, 2009

Statin Safety?

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Posted by Derek

Senator Charles Grassley of Iowa has sent the FDA a letter asking if the agency has sufficiently considered adverse events from statin drugs. I've been unable to find the text of the letter, but here's a summary at Business Week. (Grassley's own list of press releases, like most other senators and representatives, is a long, long list of all the swag and booty that he's been able to cart back to his constituents.

His main questions seem to be: has the agency seen any patterns in adverse event reports? Is there reason to believe that such events are being under-reported? Is there information from other countries where the drugs are prescribed that might tell us things that we're missing here?

Business Week's reporter John Carey has been on this are-statins-worse-than-they-appear beat for some time now, and it wouldn't surprise me if someone from Grassley's office sent him a copy of the Senator's letter on that basis. Those considerations aside, are statins really worse than they appear, or not?

The muscle side effects of the drugs (rhabdomyolysis) have been known for some time, and it's clear that some patients are more sensitive to this than others. But there are other possible side effects kicking around, such as cognitive impairment. The evidence for that doesn't seem very strong to me, at first glance, and could (as far as I can see) come out the other way just as easily. In the same way, I haven't seen any compelling evidence for increased risk of cancer, although it's quite possible that they may have effects (good and bad) when combined with existing therapies.

The one thing that you can say is that the epidemiological data we have for statin treatment is probably about as good as we're going to get for anything. These drugs are so widely prescribed, and have now been on the market for so many years, that the amount of data collected on them is huge. If that data set is inadequate, then so are all the others. I'm not sure what Sen. Grassley is up to with his letter, but that's something he should probably keep in mind. . .

Comments (20) + TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs | Toxicology

September 17, 2009

The Drug Business: A Turbulent Future?

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Posted by Derek

One of this blog's regular correspondents has just been attending a chemistry outsourcing conference (program here), and heard a very interesting talk from Stefan Loren of a Baltimore investment advisory firm, Westwicke Partners. Loren's a product of the Sharpless lab, who went on to Abbott, then Wall Street (Legg Mason and into the hedge fund business), and had some very provocative things to say about our industry:

His talk, "The Pharma Titanic: It's Time to Root for the Iceberg" presented a sobering view of the challenges that big pharma will have to deal with if it wants to survive.

Loren opened with an overview of the US national health care debate. Regardless of the ultimate form that a national system takes, he believes we'll see mandatory insurance; this will be good for big pharma. He also believes that there will be strong pressure for mandatory comparative effectiveness testing...probably not good for big pharma. Who will pay for this and what resources this would require is another matter. Wearing his investment advisor glasses, he sees global pharma sales declining, led by North America, with future growth coming in Asia and Latin America. He also sees evidence of healthcare avoidance in the US: unfilled prescriptions, unfinished courses of prescriptions, and people just not visiting medical and dental practitioners - not a good trend.

The coming wave of patent expirations of the top 10 drugs will hit big pharma hard. Generics will grow: In 5 to 10 years, he predicts that 80 percent of ALL prescriptions will be generic. When coupled with the meager investments in bow wave research over the past 15+ years, as measured by IPOs, there's trouble ahead. Global biotech IPOs are in the toilet and the US is no longer viewed by the investment community as the global leader in biotech. There have been an unprecedented number of bankruptcies in biotech. There is going to be a huge oversupply of production capacity for small molecule manufacturing. ROIs for pharma and biotech are largely gets worse. He calls this the "death spiral."

Pharma pipelines are seen as very poorly run and wasteful. Poor projects linger far longer than they should. Too much emphasis is placed on me-too and line extensions. Too much emphasis is placed on acquisitions and licensing rather than innovation. Here it comes: he says "I have NEVER seen a merger that worked" We were then entertained by a chart showing Pfizer's stock market performance over the period of time from pre-WLA, through Pharmacia-Upjohn, and now would not be a happy camper if you had put your retirement account in Pfizer management's hands and their merger mania. Wall Street has a saying "Two dogs don't make a kennel." Of course, what we hear is "this time it's different" along with the usual happy talk about synergies. Loren does believe that mergers can work and can be synergistic if the two companies merging are small...large mergers just don't work and large companies get paralyzed by bureaucratic inertia.

His solution? Break up large pharma into therapeutic areas and build shared networks between distinct entities. Small organizations can operate far more efficiently in decision making about research directions - use the network to maintain manufacturing efficiencies. Small focused companies will revitalize the industry and offer opportunities for scientists coming out of academia. In response to a question from the audience regarding Merck's ambitions to adopt this networked architecture, he doesn't believe they can make it work.

He does see light at the end of the tunnel with respect to supply chain assurance driving a return to sanity. The heparin, glycerin, and melamine disasters have awakened people and the cost of securing global supply chains is going to make US industry much more competitive. It also will focus serious scrutiny on big pharma. The "next heparin" case will have serious personal consequences for big pharma managers. . ."

Well, a good amount of this I agree with, but some of it I'm not sure about. Taking things in order, I don't know about a decline in US sales, but Asia is most definitely where a lot of companies are expecting growth. (And for "Asia", you could substitute "China" and be within margin of error). And his generic prescription figures may not be right on target, but the trend surely is. We've discovered a lot of useful drugs over the years, and anything new we find has to compete against them. The only way to break out of that situation is to find drugs in new categories entirely, and we all know how easy that is.

But as for the US not being the global leader in biotech - well, if we aren't, then who is? You could possibly make a case for "no clear leader at all, for now", but I think that's as far as I can go. And that coming oversupply of manufacturing for small molecule drugs, which may well be real, will be bad news for the companies that have already invested in that area, of course, but good news for up-and-comers, who will be able to pick up capacity more cheaply.

But Loren's comments about mergers I can endorse without reservation. I've been saying nasty things about big pharma mergers since this blog began, and nothing in the last seven years has changed my mind. And I certainly hope that his idea of smaller companies coming along to revitalize the industry is on target, because it's sure not going to be revitalized by (for example) Pfizer buying more people. I've made that Pfizer stock-chart point of his here, as well - like the rest of the industry, PFE stock had a wonderful time of it in the 1990s, but this entire decade it's been an awful place to have your money.

I expect these comments to bring in a lot of comments of their own - so, how much of this future are you buying?

Comments (23) + TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History | Regulatory Affairs

September 3, 2009

A 2.3 Billion Dollar Attention-Getter

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Posted by Derek

No sooner do I write another post about pharma marketing than Pfizer finds itself paying 3.2 2.3 billion dollars in fines for doing it improperly. 1.2 billion of that is a criminal penalty, and needless to say, they've set the current record.

The issues were off-label promotion of Bexxtra, Geodon, Zyvox, and Lyrica, with the largest penalties coming from the first two. Pfizer's had three other settlements of this kind in the last few years, and that record was definitely a factor this time, as the Justice Department looked for a figure that might get the company's attention. Also supposed to get the company's attention is a five-year "integrity agreement" with the Department of Health and Human Services, but it's worth noting that the company was already supposedly operating under an earlier such agreement when it was promoting Bexxtra. I think the money has a better chance of being noticed, myself.

I think that these kinds of penalties should be levied, in case anyone's wondering. Our current system almost makes sure that it will happen over and over, but that's because we're splitting the difference between two competing principles. The first one is that physicians should have the freedom to practice medicine as they best see fit, which means that they can write prescriptions for drug uses that have not (yet) been approved by the FDA. The second principle, though, is that drug companies should not be free to promote such uses. And I agree with both of those, but sticking to both of them simultaneously leaves open a constant temptation to break the law.

But there are a lot of industries that operate under such conditions, and in each case, they're supposed to control themselves (and get hammered on when they don't). Perhaps this latest fine will be enough of an example to keep the marketing people thinking ahead a bit. If that won't do it, then the way this whole case came up might - it's another example of whistleblower laws at work. John Kopchinski, a sales rep who left Pfizer in 2003, looks to get around $50 million of the settlement for bringing key information to the government's attention, and others are involved as well. I think that's a good thing, too, a useful counterbalance to the financial incentives on the other side.

But for now, we're left with another huge black mark on the industry's reputation. Thank you, Pfizer.

Comments (16) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | The Dark Side

August 28, 2009

REACH for the Sky!

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Posted by Derek

I wrote years ago on this blog about REACH, the European program to (as the acronym has it) Register, Evaluate, Authorize and Restrict Chemical substances. (I'm not sure where that second R got off to in there). This is a massive effort to do a sort of catch-up for chemicals that were introduced before modern regulatory regimes, and it involves fresh toxicological investigations and an absolute blizzard of paperwork. This program was launched in 2006, after years of wrangling, and the last few years have been spent in yet more wrangling about its implementation.

The worried voices are getting louder. Thomas Hartung (a toxicologist at Johns Hopkins and the University of Konstanz) and his co-author, Italian chemist Costanza Rovida, now say that the program is heading off the cliff. (Their full report is here as a PDF). In Nature, the authors have a commentary that summarizes their findings. They estimate that around 68,000 chemical substances will fall under the program, and when they run the numbers on how those will need to be tested, well. . .

"Our results suggest that generating data to comply with REACH will require 54 million vertebrate animals and cost 9.5 billion Euros over the next 10 years. This is 20 times more animals and 6 times the costs of the official estimates. By comparison, some 90,000 animals are currently used every year for testing new chemicals in Europe, costing the industry some 60 million Euros per year. Without a major investment into high-throughput methodologies, the feasibility of the programme is under threat — especially given that our calculations represent a best-case scenario. In 15 months' time, industry has to submit existing toxicity data and animal-testing plans for the first of three groups of old chemicals."

These are staggering numbers. There are not enough labs, not enough toxicologists, and not enough rats (well, usable rats) in Europe to even come close to realizing such an effort. It turns out that the biggest expense, on both the animal and money counts, is reproductive toxicity testing, which is apparently being mandated into the second generation of rodents. That works out to an average of 3,200 rats sacrificed per chemical evaluated, so you can see how things get out of hand. The authors are calling for an immediate re-evaluation of the reproductive toxicity testing protocols, arguing that the cost/benefit ratio is wildly out of whack, and that the rate of false positives (especially involving second-generation studies) is high enough to end up scaring a lot of people for no sound reason at all.

I'm absolutely with them on this. The program seems like one of these "No cost is too high for absolute safety" ideas that make politicians and regulators happy, but don't do nearly as much good for society as you'd think. (It's worth noting that Hartung and Rovida actually support the idea of REACH, but think that its implementation has gone off the rails). One beneficial side effect, as the authors mention, is that the whole mess will probably end up advancing the state of the art in toxicology a good deal, partly in ways to figure out how to avoid the coming debacle.

Not suprisingly, the European Chemicals Agency is disputing the study, saying that they don't anticipate the numbers of chemicals registered (or the costs associated with studying them) to differ much from their estimates. If I can suggest it, though, I would like to mention that the history of large regulatory programs in general does not provide much support for that optimistic forecast. At all. To put it in the mildest possible terms. We'll see who's right, though, won't we?

Comments (19) + TrackBacks (0) | Category: Regulatory Affairs | Toxicology

August 21, 2009

Obesity Shows Up in the Death Rate? Right?

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Posted by Derek

Here's an interesting post at Chemiotics (a new addition to the blogroll): Something is Wrong With the Model

. . . The Center for Disease Control released new data for 2007 (based on 90% of all USA death certificiates) showing that mortality rates dropped again (by over 2%) to 760/100,000 population. It’s been dropping for the past 8 years, and viewed longer term is half of what it was 60 years ago. Interestingly death rates from heart disease dropped a staggering 5% and even cancer dropped 2%.

But the populace is fat and getting fatter. . .

The heart disease death rate is particularly interesting. One explanation, which we can't rule out, is that these improvements are due to other factors (which the post goes on to elaborate), and that the improvement would be even more impressive if everyone weren't packing on the pounds. Another possibility is that excess weight, up to a point, may not have as big an effect on mortality and morbidity as we've been thinking it does.

That's a real possibility, and it's been looked at in the context of these sorts of public heath figures. The current use of BMI, at the very least, doesn't seem to be that useful in that regard. Only the high end of the BMI envelope (>30) seems to show much of a meaningful health effect. Of course, there are other costs to being obese, but (up to a point) bad health may not be one of the major ones. As for what this means to the current health care proposals, you can go here for the arguing.

Comments (24) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

August 19, 2009

The PhRMA Deal

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Posted by Derek

I'm not always a fan of John Boehner, but I think he's on the right track with his letter to Billy Tauzin (PDF here from NPR's health care site). I understand that line about how in Washington, if you're not at the table you're on the menu. And I understand how the industry wants to get into the middle of the whole process to try to protect its interests. I just don't think that cutting this kind of deal is, in the end, doing that. And apparently Boehner agrees:

The Obama Administration tacitly acknowledged last week that the President will not be bound by the $80 billion limit PhRMA and its board of directors were led to believe had been secured in exchange for your organization's support of the Administration's health care takeover, and key Democrats in Congress, including Speaker Nancy Pelosi (D-CA) and Energy & Commerce Committee Chairman Henry Waxman (D-CA) have said explicitly they will not honor the agreement. In other words, now that the deal is publicly known and would be messy for your to reverse, Big Government is now changing the terms. . .because it can.

Boehner goes on to say that Tauzin will surely "object to this letter and quarrel with its premise", which I think is a pretty sure bet. But stripped of the boilerplate that's found in the rest of it, I find that I agree with its key point very much, as stated above. I don't think that it's possible to do a PhRMA-style deal with an entity like the federal government. Because, you know, they can always change their minds, and what possible recourse do you have then?

Update: Yes, of course Boehner is a political opponent of President Obama, and has interests beyond purely philosophical ones in scuppering some of his grander plans. Both Boehner and Obama make me grit my teeth when I hear them talk about this issue, to tell you the truth, and boy howdy, there are plenty of other people in that category with them. And I realize that when I start talking politics, that many readers start to grit their own teeth in response.

Fear not, this is not going to turn into a political blog. But it's always been concerned with the drug industry, how it does what it does, and what its future might be. The current efforts at health care reform could well have an impact on these things, to put it delicately, so the topic has to come up. My free-market biases are pretty well known, though, so some readers may be able to save time by just skipping over what I write about it on the grounds that they probably have a good idea of what I'll have to say. I wouldn't blame anyone for doing that; vita brevis est. And I promise to not have the issue take over the site - I don't want to be a political blogger, either, really. . .

Comments (17) + TrackBacks (0) | Category: Current Events | Drug Prices | Regulatory Affairs

August 17, 2009

PhRMA's Negotiating Game

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Posted by Derek

Now for a bit on the pharma industry and the current fight over health care legislation. Does the industry want a new system to come into force, or not?

Depends on what that new system is, of course. But the industry is naturally trying to make sure that it has a hand in whatever passes. And here we come to a meeting of political interests. The administration would also prefer not to have the drug industry actively working against it, since drug companies have a lot of money to use for such purposes. Therefore, as anyone who knows politics could have predicted, a deal has been struck.

Or has it? As everyone has heard by now, Billy Tauzin, head of the industry's largest association (PhRMA), said that an understanding had been reached with Max Baucus of the Senate Finance Committee, with the approval of the White House. The industry would agree to come up with 80 billion dollars of savings, and the administration would then consider them to have done their part. More specifically, there would be no more talk of price negotiations for Medicare-approved drugs, of drug reimportation, or rebates for drugs prescribed to joint Medicare/Medicaid patients. The industry would also agree to support the new health plan by running ads (and, no doubt, by lobbying behind the scenes). Come, let us reason together.

It doesn't surprise me at all that such a quid pro quo would be worked out in advance - that's exactly how politics gets done. But what amazed me was that Tauzin would go around telling people. Predictably, many of the other players are now complaining, and PhRMA is reduced to saying that it's "counterproductive" to keep on talking about it.

Tauzin and PhRMA are also taking flak from their right - the Wall Street Journal blasted the whole idea of a deal the other day, calling it short-sighted. Congress could, after all, change the terms any time they can round up the votes, which would be any time it's convenient to blame the drug companies for something. I find myself more in this camp. I understand that PhRMA can't afford to stay out of this process (in which case the carving knives would come out sooner rather than later), but I think it's a sad business all the same, trading the threat of price controls now for the threat of price controls a little later on. Here's more complaining from National Review.

But that brings us back to Tauzin. I will work under the assumption that he's not an idiot, although I'm willing to listen to evidence for either side on that one. But if he isn't, why did he go around boasting of this wonderful backroom deal? All it seems to have done is endanger whatever agreement was reached. If my not-an-idiot stipulation is justified, though, the only reason I can see for doing this is as a tactic to get something even better. Did PhRMA look at the polls and decide the time was right to help torpedo everything? (And yes, I know the Rasmussen polls lean right, but I think they're picking up something real). Is that the game here?

Well, I get e-mails from people at PhRMA once in a while, and I'll probably get another one after I put this post up. Something tells me that I'm not going to get to hear what's really going on, but that doesn't stop a person from wondering.

Comments (50) + TrackBacks (0) | Category: Current Events | Drug Prices | Regulatory Affairs

August 3, 2009

Savient Feels The Pains of Gout

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Posted by Derek

Well, here's a nasty surprise for you: your new drug gets a 14 to 1 "Yes" vote from an FDA advisory committee, but the agency turns you down, anyway. That's what's just happened to Savient and their new biologic product for gout, Krystexxa (pegloticase).

The FDA isn't required to say why they do such things, at least not to anyone else other than the company that submitted the drug. And they're aren't talking this time, either, but it looks like there's a manufacturing issue involved. The process for making Krystexxa seems to have changed a bit since the clinical trial batches, and the agency apparently wants to make sure that this hasn't altered anything. If all goes well, then, you'd expect the company to get things straightened out sometime next year, but for Savient, that's an awful long time to wait.

People who follow the company (and the gout market) have been arguing for the last few years about its prospects. Krystexxa is a pegylated form form of an enzyme called uricase (urate oxidase) that clears out uric acid (crystals of which are the proximate source of trouble in gout). Interestingly, this is one of those enzymes that's found all over the various phyla, and in mammals up to primates - but it stops there. We have the gene for the enzyme, but it appears to have been mutated to an inactive form at some point (rather like our gene for the last step in endogenous Vitamin C synthesis - I always wonder what the Intelligent Design people have to say about such things, although I'm pretty sure that it's some variant of "Because it was Designed that way for some good reason that's not immediately clear to us right now").

Bringing in this enzyme, then, isn't a case of replacing something that we already have. This is adding a function that we lost back in the early primate days, so we're talking "foreign protein" here. The pegylation is partly there to help with that, and partly just to give the protein a chance to survive the usual metabolic processes. For those who don't know the term, "Peg" is short for "polyethylene glycol", so a pegylated protein has long polymer chains of this hanging off it at various points. The total effect is rather like spraying the thing down with a coat of clear varnish - it changes the solubility, slows down metabolism and clearance, and changes the immune response to the protein. Pegylation is useful indeed, but something of a black art, since it's difficult to predict just what'll happen each time you try it.

Well, I wish Savient luck in getting things straightened out. And I wish their shareholders luck today. The company's stock has not been a place for the easily alarmed over the last year or two, and I'll bet that a lot of people thought that the fear had been cleared by that 14-1 advisory committee meeting. But that's the thing about this whole industry: you can never quite breath easy. . .

Comments (13) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

July 30, 2009

Health Care Reform - Really?

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Posted by Derek

I haven't written about the various health care reform packages that are being hammered out and hammered through the various parts of Congress. That's partly because I began to think fairly early on in the process that we weren't actually going to see something happen as quickly as the administration wanted, which meant that there were still plenty of twists and turns left. I still think that's true - in fact, I have no idea when a final bill will ever get Frankensteined together for a vote, and no one else seems to have a good idea, either.

And since the main focus of this blog is pharmaceutical research, the first question I have to deal with is what effect such a bill will have on what I (and many of the readers here) do for a living. Absent a good idea of what the legislation will really look like, that's impossible to do in detail. But I can paint some broad strokes at this point, and they're probably not going to come as much of a surprise: I don't like what I see.

On the macro level, I don't like the administration's rhetoric on this issue. I do not believe that health care costs are crippling our economy, and the implication that they're tied to our current economic downturn seems specious. (And yes, that argument has been made, and more than once). Such an any-weapon-to-hand approach seems a bit different from what many people may have thought that they were voting for in the last election.

But I didn't vote for Obama, although I certainly wasn't crazy about the McCain-Palin ticket, either. My fears (expressed here) that he might turn out to be a zealous world-changing reformer have been amply confirmed. What do I have against zealous world-changing reformers, you ask? Why, I fear that the world is trickier than they are, for one thing. And too many of these people seem to come across as "If you people would just have enough sense to see that I'm doing this for your own good" types. At the rate we're going, that'll be the key phrase in a presidential speech right after Labor Day. (Mickey Kaus has been pointing out for some time now that this eat-your-peas-for-the-common-good approach is not doing the administration any favors).

The only big changes I'm in the mood for, generally speaking, are ones that give people more control over their own destiny, and if that's what we're seeing here, I've missed it. (I'm not alone). I guess that I just don't believe that systems this large and this complex are subject to wholesale intervention by the Wise and the Good. I worry that the Wise and Good will, in fact, decide that if they're truly going to control costs that they're going to ration health care in ways that people aren't necessarily expecting. Part of that rationing may well have to be either de facto (or flat-out de jure) price controls on pharmaceuticals and other parts of the system - and if applied thoroughly enough, these will be an excellent way of creating shortages of just the things that are being controlled, in the same way that price controls have always functioned. Some of those shortages will be silent ones: the things we don't discover.

Alternatively, we could end up with a Great Big Plan that doesn't really attempt to cut costs, or defers those cost savings into the glorious future. It's worth considering that, as far as I can see, every single attempt to run a large state-sponsored heath plan has ended up costing far, far more than even the most pessimistic initial estimates. And this time will be different. . . how, exactly?

And that leads us to the sort of bill that I think we're most likely to get: one that doesn't satisfy the biggest advocates of sweeping health care reform, since it's had to abandon the big proposals for the sake of political reality, but one that at the same time spends lots and lots more money, with no clear plan of how to raise these funds, all of that again for the sake of political reality. One, in short, that gives all the politicians involved a chance to pin "I Passed Health Care Reform!" buttons on their jackets while pissing off everyone who bothers to look at the thing closely, and one that commits us to spending oceans of money to accomplish not very much.

Perhaps I'm just in a bad mood. But that looks like what we're heading for.

Comments (72) + TrackBacks (0) | Category: Current Events | Drug Prices | Regulatory Affairs

July 1, 2009

Vanda Comes Back From the Dead

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Posted by Derek

I wrote last summer about Vanda Pharmaceuticals and their difficulty getting a new antipsychotic Fanapt (iloperidone) through the FDA. At the time, they'd received one of those wonderful requests for more information from the agency, of the kind that spread cheer whenever they appear. I couldn't see how the company could clear this up without (probably) having to spend a lot of money that it didn't have, and I was very pessimistic about their survival.

And I was wrong. Big-time. Vanda received approval for iloperidone, in what is a major surprise not just for me, but for the company's hardy shareholders and for the few analysts left covering them. After congratulating the company, I feel like asking them "So, how did you do that, anyway?" To the best of my knowledge, the company didn't go back into the clinic - and it's hard to see how they even could have. Less than a year just isn't feasible from a standing start in an antipsychotic trial just on logistic grounds, let alone the fact that Vanda doesn't seem to have had the funds to even try.

So was this all just a regrettable misunderstanding? And if so, on whose part? Did the FDA misinterpret something, only to be argued back by the company? Or did Vanda mess something up in the original regulatory package? We may never know.

The question now that the dog has caught the mail truck is what to do with it. No deal has been announced yet to market the compound, and Vanda still doesn't seem to have the funds to sell it by itself. (Moreover, they don't seem to be recruiting a sales force). Some observers think that the company may have had time selling itself off, and that the run in the stock was overdone just for that reason.

In the meantime, though, the company should enjoy its good fortune (as should anyone who was holding its stock when the news hit). And readers of this blog should make a note that, in case there was any doubt, I can be completely, totally wrong about the field I work in. . .

Comments (8) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | The Central Nervous System

June 26, 2009

Snort Yourself Some Zinc. Or Maybe Not.

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Posted by Derek

I missed commenting on this earlier, but many readers may have noticed the recent scandal caused by Zicam. This is a cold remedy which was sold as a homeopathic medicine, but its makers committed the unforgivable sin of actually having something in its formula besides well-shaken distilled water.

A lot of people are convinced that zinc is good for colds - I'm agnostic, having not seen much convincing evidence - so if that's the case, why not snort zinc up your nose? That, at any rate, seems to be the condensed version of the Zicam pitch, although I don't believe that they used that exact wording in their ads. (A gift for advertising copy might not be one of my more robust talents. . .) At any rate, snorting zinc salts has actually been known, for some time now, to injure the sense of smell in some people. So it's proved with Zicam, with several hundred victims.

The moral? If you're going to sell homeopathic medicine - and boy, is it a lucrative business - make sure that you don't put anything in there except sterile water. That'll cut down on your expenses, too, since most ingredients cost more than water, anyway. Stick with that strategy, and you can be absolutely sure that nothing bad will happen to your customers. Nothing good will happen to them either, but they won't know that. When their cold/headache/whatever goes away of its own accord, they'll ascribe it to your miracle product. Sit back and profit! Be sure to thank Senator Hatch while you count your money, though - it's only proper.

Comments (138) + TrackBacks (0) | Category: Regulatory Affairs | Snake Oil

June 12, 2009

Selling Zyprexa

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Posted by Derek

Well, this doesn't look good for Lilly. A huge pile of court documents has been unsealed in the ongoing lawsuits about Zyprexa's off-label promotion. The company has already paid some serious fines, and is now fighting it out with insurance companies and other plaintiffs who are seeking to recover their costs. Several states are suing them as well; those cases are still on their way.

Bloomberg News was given a lengthy list of internal company statements that will surely be difficult to explain in court. These were provided by one of the plaintiff's attorneys, Hagens Berman Sobol Shapiro LLP, so it's hardly a neutral selection (as Lilly is saying in response). But it's going to be interesting to see what sorts of explanations the company has for these. On the one hand, you have this:

In 1998, Lilly went back to the FDA seeking approval to market Zyprexa to those battling Alzheimer’s, the most common form of dementia, the company said in its 2003 request for a meeting on a proposed label change. Lilly withdrew its bid to promote Zyprexa for Alzheimer’s cases in 1999, according to the document.

In a November 2000 memo to Lilly salespeople, company executives said the dementia marketing initiative was abandoned because the FDA questioned Zyprexa’s effectiveness in treating the ailment.

“It was withdrawn due to vagueness on the FDA’s part regarding a definition of efficacy,” Lilly officials said in the document.

In a 2003 memo to FDA regulators citing the clinical studies, Lilly researchers acknowledged the death rates among older dementia patients on Zyprexa in the reviews were two times higher than their counterparts taking placebos.

Deaths among the patients taking Zyprexa in the studies were “significantly greater than placebo-treated patients (3.5 percent v. 1.5 percent, respectively),” Lilly officials said, according to the unsealed documents.

The studies didn’t find Zyprexa was effective in treating dementia, the company acknowledged in this document.

Lilly recognized this earlier, according to a 2002 document entitled “Zyprexa in serious mental illness (65 plus years) -- A Strategy Review.”

“The treatment of serious mental illness for people over the age of 65 has been identified as a growing opportunity for Zyprexa,” the authors wrote. “Unfortunately, attempts to gain the data to support an application for an indication in the treatment of dementia have to date been unsuccessful.”

But on the other hand, we have:

Lilly’s long-term care unit also saw Zyprexa sales rise 2.9 percent in the second quarter of 2002 as sales of Risperdal, Johnson & Johnson’s rival antipsychotic, fell, according to the 2002 marketing plan.

At that time, long-term care sales made up about 20 percent of Zyprexa prescriptions, according to the summary. Of that number, 65 percent were written for nursing-home patients.

Overall, prescriptions for older patients were the “2nd biggest money-producing segment” for Zyprexa in the U.S., according to a Feb. 15, 2002, e-mail from Lilly researcher Peter Feldman to Denice Torres, the company’s global marketing director.

In that e-mail, Feldman said company officials were saying in internal memos that they were going to stop studying Zyprexa’s potential health benefits for elderly consumers.

That would risk “killing the goose that lays the golden eggs to save on poultry feed costs,” Feldman said in the unsealed messages.

Torres assured him older consumers would continue to be a prime target for Zyprexa sales, according to the e-mail.

“Elderly remains an important aspect of target PT and affiliate focus,” she said in the message.

Increased Zyprexa sales to elderly patients also won Lilly’s long-term care unit praise in a 2003 newsletter unsealed as part of the documents.

“For two consecutive years, you have been on top and have turned in above-plan performance,” Grady Grant, Lilly’s national sales director, wrote in the newsletter. “I look forward to working with you as we set our sights on overtaking Risperdal as the number one antipsychotic in the marketplace!”

Lilly says these are cherry-picked quotes taken out of context. I'll await seeing what context they can be put in that will make them look less like. . .what they look like now.

Comments (19) + TrackBacks (0) | Category: Regulatory Affairs | The Central Nervous System | The Dark Side

May 22, 2009

Arena, Lorcaserin, and the FDA

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Posted by Derek

I’ve been getting a lot of objections to my opinion on Arena’s obesity candidate lorcaserin. Specifically, the first level of the dispute seems to be whether or not the recent clinical trial results met the FDA’s criteria for efficacy or not. So, let’s look at the details. Here’s how Arena press-released the results of the trial:

The hierarchically ordered endpoints were the proportion of patients achieving 5% or greater weight loss after 12 months, the difference in mean weight loss compared to placebo after 12 months, and the proportion of patients achieving 10% or greater weight loss after 12 months. Compared to placebo, using an intent-to-treat last observation carried forward (ITT-LOCF) analysis, treatment with lorcaserin was associated with highly statistically significant (p<0.0001) categorical and average weight loss from baseline after 12 months:

-- 47.5% of lorcaserin patients lost greater than or equal to 5% of their
body weight from baseline compared to 20.3% in the placebo group. This
result satisfies the efficacy benchmark in the most recent FDA draft
-- Average weight loss of 5.8% of body weight, or 12.7 pounds, was achieved
in the lorcaserin group, compared to 2.2% of body weight, or 4.7 pounds,
in the placebo group. Statistical separation from placebo was observed
by Week 2, the first post-baseline measurement.
-- 22.6% of lorcaserin patients lost greater than or equal to 10% of their
body weight from baseline, compared to 7.7% in the placebo group.

Lorcaserin patients who completed 52 weeks of treatment according to the protocol lost an average of 8.2% of body weight, or 17.9 pounds, compared to 3.4%, or 7.3 pounds, in the placebo group (p<0.0001).

Now let’s go to the FDA’s 2007 draft guidance for weight management therapies. Regarding the primary efficacy endpoint in a Phase III trial of such a new agent, the agency says:

The efficacy of a weight-management product should be assessed by analyses of both mean and categorical changes in body weight.

• Mean: The difference in mean percent loss of baseline body weight in the active-product versus placebo-treated group.

• Categorical: The proportion of subjects who lose at least 5 percent of baseline body weight in the active-product versus placebo-treated group.

And here’s the part that people keep wanting me to highlight:

In general, a product can be considered effective for weight management if after 1 year of treatment either of the following occurs:

• The difference in mean weight loss between the active-product and placebo-treated groups is at least 5 percent and the difference is statistically significant

• The proportion of subjects who lose greater than or equal to 5 percent of baseline body weight in the active-product group is at least 35 percent, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant

So lorcaserin showed 47.5% of patients losing at least 5% of their body weight, versus 20.3 for placebo. And yes, that does appear to meet what the FDA's looking for in terms of categorical efficacy, which is why the company highlighted that result in their press release. And yes (here it comes, Arena fans), the FDA does say ("in general") that an agent can be considered efficacious if a compound meets either the mean or the categorical standards.

But (and you knew that this paragraph was going to start with that word). . .but the FDA does not say "efficacious enough for approval". In general, to use their phrase, the agency does approve things that are efficacious and show safety. But they do that on their own terms, and they are (for better or worse) completely within their rights to turn around and ask for more details - for example, how well a compound like this performs as a combination therapy (which is how many physicians would likely wish to prescribe it).

Then we have the issue of "efficacious to interest a partner". Arena is surely looking to do that, since (as noted the other day) it does not appear that they have the resources to push the product through on their own. Given the potential size of the market for an effective obesity drug, we can be sure that a number of potential partners have been approached, and have taken a meaningful look at the data. So far, no one has taken them up on it. And whatever one thinks about the press coverage that lorcaserin has received (or the reaction from analysts who follow the stock, which has also not been good), it's for sure that these opinions don't count for much when it comes time for two companies to do a deal. Put more directly, if Arena sits down with Merck or Pfizer, what I say on this blog means nothing at all once the door closes. Heck, what they say at JP Morgan means nothing at all, either, because we're all outsiders. Potential partners are getting a chance to look over Arena's prospects, and if the numbers look convincing, someone will bite. If no one bites, we can assume that no one was convinced.

Or perhaps they're waiting for Arena to get even more cash-strapped and desperate. That isn't a very nice way to do business, but isn't unheard of, either, and I can tell you that these aren't very nice times in the drug business. At any rate, for those Arena fans who have been waiting for me to say something about all this, well, here you are. This is as good as you'll get from me - but really, you're wasting your time. You need to be hoping to persuade the people who can initiate nine-figure wire transfers.

Comments (9) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Diabetes and Obesity | Regulatory Affairs

May 12, 2009

Book Review Department

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Posted by Derek

For those who are interested, I have a review up at Nature Biotechnology of Reasonable Rx: Solving the Drug Price Crisis, a book that proposes an. . .interesting solution for reworking the drug industry.

And as Fate would have it, I also have a review in the latest issue of Nature Chemistry of Drug Truths: Dispelling the Myths About Pharma R & D, from Pfizer's John LaMattina. The only reason these are showing up at the same time is that I took an unconscionably long time to come to grips with Reasonable Rx - it wasn't something that I could just dismiss, but it has (I think) a lot of things wrong with it.

Comments (11) + TrackBacks (0) | Category: Drug Industry History | Drug Prices | Regulatory Affairs

April 14, 2009

Dendreon's Revenge?

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Posted by Derek

Post updated below - DBL Dendreon is a company that's really been through it, as have their investors. Many will remember the upheaval back in 2007, when the company showed what they felt were impressive results for their autologous prostate cancer immunotherapy Provenge, got a favorable reception from the FDA's advisory panel, but were then hit with an "approvable" letter asking for more data. (Here are three posts on that: before, during, and after).

Well, the company is back with more data, in 512 patients. And initial reports are that the numbers look good. They're doing a conference call as I write, so we'll know more shortly, and I'll update this post as things become more clear.

Update: Hmmm. On the conference call, the company has declined to present any numbers, saying that it's bound by a blackout requirement for its presentation at the American Urological Association on April 28th. Their main statement seems to have been that the drug met its primary endpoint, reducing the risk of death compared to a placebo. There are a lot of other questions about Provenge - whether it slows the progression of prostate cancer or not, for example - but survival is presumably the bottom line. That was the main focus of the whole trial (as opposed to the cancer-progression endpoint of their smaller, earlier one).

So we'll see at the end of the month how impressive the statistics look. The market's reacting well to the news, although you could argue that the stock has pulled back a bit. It closed yesterday at 7 and change, traded over 21 during the morning, and is around 17 now. (Of course, some of that pullback could be from people giddily selling their shares on the news, just as some of the spike could well have been some people rather less giddily covering their short positions).

Comments (17) + TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs

March 31, 2009

A DPP-IV Compound Makes It Through

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After talking the other week about the problems that Takeda has had with their DPP-IV inhibitor for diabetes, it now appears that AstraZeneca and Bristol-Myers Squibb have made it through the same narrows with their own drug. Saxagliptin has met the FDA's latest guidelines for cardiovascular safety, which (you'd think) will remove the biggest potential barrier to approval. The advisory committee is meeting today, so we'll see how their vote goes.

Comments (10) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

March 23, 2009

And While We're Talking About Industry-Sponsored Studies. . .

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Posted by Derek

Last week's discussions around here about the merits (and demerits) of pharma-industry research seem to be coming at what's either a really good or a really bad time. Take a look at this Washington Post article on the handling of clinical data at AstraZeneca.

These details have come up during a large array of lawsuits over Seroquel (quetiapine). And if they're as represented in this article, it doesn't make AZ's marketing folks look very good, and (by extension) the rest of the industry's. We shouldn't be doing this sort of thing, on general principle. But if that's not enough, and it probably isn't, here's a more practical concern: does it take much imagination or vision to think that, with all kinds of health care reform ideas in the air, this sort of behavior might just make Congress want to reform our industry really good and hard?

Comments (6) + TrackBacks (0) | Category: Clinical Trials | Press Coverage | Regulatory Affairs | The Central Nervous System | Why Everyone Loves Us

March 17, 2009

Takeda Gets A Surprise

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Posted by Derek

DPP-IV is short for “dipeptidylpeptidase IV”, understandably, and we need a good abbreviation for it. It’s an important enzyme target for diabetes therapy, since under normal conditions it breaks down glucagon-like-peptide 1. Longer-circulating GLP-1 would actually do a lot of diabetics good, and people have actually made such proteins as separate drugs, so inhibiting an enzyme that clears it out looks like a good bet. Of such reasoning are drug targets made.

A lot of companies have bought into this reasoning, for sure. For quite a while, Novartis looked like the leader in the area, with the most advanced clinical candidate and a lot of publications in the literature from their development work. But Merck turned out to be running a big effort of their own, and actually got to market first with Januvia (sitagliptin). Novartis’s drug (Galvus, vildagliptin) looks as if it will never make it at all here in the US.

They had to slow down development due to some troubling side effects, giving Merck the edge. There are several DPP subtypes, and you need to be pretty selective, as it turns out – at least some of the problems stem from that consideration. This wasn’t fully appreciated in the first wave of development in this area – the pioneers had to figure it out the hard and expensive way. But a number of companies have come up behind, trying to get a piece of the market, and they now have a clearer idea of what they need to accomplish.

Or do they? Takeda recently heard from the FDA that their DPP-IV inhibitor alogliptin has been turned down for now. What’s more, the agency wants more cardiovascular safety data from them and from anyone else who comes in with a drug in that category. Cardiovascular problems have always been the weak point for Type II diabetes drugs, to be sure. The patient population tends to be older and overweight, often with elevated blood pressure, so you really don’t have much room to work in when it comes to side effects. That’s led to a lot of attempts to come up with therapies that address the CV side of things at the same time as glucose levels (such as the ill-fated disaster of the PPAR alpha-gamma compounds, all of when went most expensively down in flames). DPP-IV inhibitors wouldn’t be expected to have any direct CV benefits, but they do have to avoid making things any worse.

So Merck looks to have the market to itself for a while longer, but as the only DPP-IV drug on the market, they’re going to be under a good deal of scrutiny. The company has already had its share of post-launch cardiovascular nightmares; you’d think that they’re going to work hard to avoid any more. And now all we have to do is assure ourselves that the actions of the DPP-IV inhibitors are all through making GLP-1 last longer. Because even if you're selective for that one enzyme, it has a lot of other substrates. So the story may well swing back to the biochemical mechanism again before we're through.

Comments (19) + TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Regulatory Affairs

March 5, 2009

More on Wyeth v. Levine and Preemption

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Posted by Derek

For those who want it, I have more thoughts on the Wyeth v. Levine pre-emption decision over at The Atlantic's business site. Reading the decision, it looks less like a loss for the drug companies than a loss for the FDA, but see what you think.

Comments (9) + TrackBacks (0) | Category: Regulatory Affairs

March 4, 2009

Wyeth v. Levine: Pre-emption Goes Away

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Posted by Derek

The idea of preemption in drug liability cases has been coming up a lot in recent years. If the FDA approves a drug, does that Federal-level approval stop liability suits at the state level, or not?

The Supreme Court has ruled today in the Wyeth v. Levine case, which directly addresses this issue. And pre-emption now appears to be a dead issue, at least in my first reading:

". . .State tort suits uncover unknown drug hazards and pro-vide incentives for drug manufacturers to disclose safety risks promptly. They also serve a distinct compensatory function that may motivate injured persons to come for-ward with information. . .

. . .Wyeth has not persuaded us that failure-to-warn claims like Levine’s obstruct the federal regulation of drug labeling. Congress has repeatedly declined to pre-empt state law, and the FDA’s recently adopted position that state tort suits interfere with its statutory mandate is entitled to no weight. Although we recognize that some state-law claims might well frustrate the achievement of congressional objectives, this is not such a case.

We conclude that it is not impossible for Wyeth to comply with its state and federal law obligations and that Levine’s common-law claims do not stand as an obstacle to the accomplishment of Congress’ purposes in the FDCA. Accordingly, the judgment of the Vermont Supreme Court is affirmed."

And that, I would say, is that.

Comments (12) + TrackBacks (0) | Category: Current Events | Regulatory Affairs

February 9, 2009

We Won't Stay Off The Radar Screen For Long, Y'Know

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Posted by Derek

And here’s an even more Macro topic: when do you think the new administration is going to turn its attention to the drug industry? That’ll be after this stimulus-bill business is settled, one way or another – and the only thing I’ll say about that, this not being the soapbox for my political opinions, is that (as far as I know) the only way for the government to come up with money to spend like this is to tax it out of its citizens, borrow it from third parties, or print it from thin air.

But once we’ve decided which of those will bring us prosperity, health care will surely make its way up the list, even if Tom Daschle won’t be around to lead the effort. So I’m throwing this question out to the readership: what are we in the industry likely to see, and to what effect? Negotiation of Medicare drug prices? Reimportation or other attempts to arbitrage the difference between US prescription prices and those in many other countries? And how about the FDA – without a new commissioner, it’s hard to say what the administration’s up to, but who do you think we’ll see? (Here are the current front runners).

Speculate away in the comments; later we’ll see whose crystal ball has been properly shimmed up.

Comments (21) + TrackBacks (0) | Category: Regulatory Affairs

January 15, 2009

Lilly Pays the Price

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Posted by Derek

Eli Lilly has been in trouble for some time now regarding off-label promotion of their antipsychotic Zyprexa – specifically, their sales reps seem to have gone around saying that it was useful in treating the dementia of Alzheimer’s patients, although there was no FDA approval for that indication. (Whether it actually is any good for that, or whether much of anything is, I don’t know).

Word is this morning that the company will pay a total of about 1.4 billion dollars to settle the regulatory and civil complaints. That appears to be the new record. The idea is to send a strong message to other companies about aggressive off-label promotion, and a billion dollars should certainly get attention. Lilly will also be operating under a special monitor for five years, which is no joke, either.

But still. . .this is going to happen again, at some point. As we run things in the US, physicians are free to prescribe medications as they see fit (and I have to say, I agree with that principle). Insurance companies can pay for these or not as they wish, but the doctors can write for what they like. Drug companies, on the other hand, can only market for the indications that they’ve been approved for, and in this gap you can lose 1.4 billion dollars.

Despite these problems, I think the lines need to stay about where they are, although this is always going to cause problems. There’s a temptation to try to broaden your market when you have only preliminary data – worse, there’s a temptation to broaden it when you have no data at all. That’s got to be kept in check somehow. If you want to mark the limits of my libertarian leanings, there’s one of them. I worry that if every company were free to market every drug for everything, the resulting free-for-all would drag us all back down to the level of the late-night infomercial hucksters. The potential profits are just too great; they’re a moral hazard, and they’re not commensurate with the benefits for society at large.

The only middle ground I can think of at the moment would be a category of “Some evidence exists for. . .”, which would be in between an approved and unapproved indication. Perhaps then the sales reps could mention it? Maybe not, though, because where would you draw the line for how much promotion you could do? How would we keep this from turning into a battle zone? And there are too many ways that it could be abused: running a few sloppy studies to try to get some arrows pointing the right way, for example, and then turning the marketing department loose. (You know, the sort of thing that critics of the industry figure that we do already). No, again, I think that the temptation would be too great.

So here’s a general principle: we need enough regulation in the industry to keep ourselves from turning into what our worst critics think we are already. Not the most stirring call to arms, but there it is.

Comments (14) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | The Dark Side

November 17, 2008

Liable For Generics? You Are Now!

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Posted by Derek

There was a legal ruling last week in California that we’re going to hear a lot more of in this business. Conte v. Wyeth. This case involved metaclopramide, which was sold by Wyeth as Reglan before going off-patent in 1982. The plaintiff had been prescribed the generic version of the drug, was affected by a rare and serious neurological side effect (tardive dyskinesia, familiar to people who’ve worked with CNS drugs) and sued.

But as you can see from the name of the case, this wasn’t a suit against her physician, or against the generic manufacturer. It was a suit against Wyeth, the original producer of the drug, and that’s where things have gotten innovative. As Beck and Herrmann put it at the Drug and Device Law Blog:

The prescribing doctor denied reading any of the generic manufacturer's warnings but was wishy-washy about whether he might have read the pioneer manufacturer's labeling at some point in the more distant past.

Well, since the dawn of product liability, we thought we knew the answer to that question. You can only sue the manufacturer of the product that injured you. Only the manufacturer made a profit from selling the product, and only the manufacturer controls the safety of the product it makes, so only the manufacturer can be liable.

Not any more, it seems. The First District Court of Appeals in San Francisco ruled that Wyeth (and other drug companies) are also liable for harm caused by the generic versions of their drugs. At first glance, you might think “Well, sure – it’s the same drug, and if it causes harm, it causes harm, and the people who put it on the market should bear responsibility”. But these are generic drugs we’re talking about here – they’ve already been on the market for years. Their behavior, their benefits, and their risks are pretty well worked out by the time the patents expire, so we’re not talking about something new or unexpected popping up. (And in this case, we're talking about a drug that has been generic for twenty-six years).

The prescribing information and labeling has been settled for a long time, too, you’d think. At any rate, that’s worked out between the generic manufacturers and the FDA. How Wyeth can be held liable for the use of a product that it did not manufacture, did not label, and did not sell is a mystery to me.

Over at Law and More, a parallel is drawn between this ruling and the history of public nuisance law during the controversy over lead paint; the implication is that this ruling will stand up and be with us for a good long while. But at Cal Biz Lit, the betting is that “this all goes away at the California Supreme Court”. We’ll see, because that’s exactly where it’s headed and maybe beyond that, eventually.

And if this holds up? Well, Beck and Herrmann lay it out in their extensive follow-up post on the issue, which I recommend to those with a legal interest:

Conte-style liability can only drive up the cost of new drugs – all of them. Generic drugs are cheaper precisely because their manufacturers did not incur the cost of drug development – costs which run into the hundreds of millions of dollars for each successful FDA approval. Because they are cheap, generics typically drive the pioneer manufacturer’s drug off the market (or into a very small market share) within a few years, if not sooner. Generic drugs will stay cheap under Conte. But imposing liability in perpetuity upon pioneer manufacturers for products they no longer sell or get any profit from means that the pioneer manufacturers (being for-profit entities) have to recoup that liability expense somewhere. There’s only one place it can come from. That’s as an add-on to the costs of new drugs that still enjoy patent protection.

Exactly right. This decision establishes a fishing license for people to go after the deepest-pocketed defendents. Let’s hope it’s reversed.

Comments (31) + TrackBacks (0) | Category: Regulatory Affairs | The Central Nervous System | Toxicology

September 26, 2008

Prasugrel Today?

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Posted by Derek

I wrote back in the summer about the FDA's delayed decision on Lilly's potential anticoagulant blockbuster Effient (prasugrel). Well, those three months have zipped right by, and the agency is supposed to rule today.

Prediction, for what it's worth: I think the drug will be approved, but with label restrictions for the group(s) that seemed to respond best to it in trials - who may have been. at least partly, the groups that could put up with the associated bleeding the best, too. So no elderly patients, no low-weight ones, and no one with a history of stroke or TIA. That'll cut down the market for the drug, definitely, but not as much as if it doesn't get approved at all, right? I think the FDA will require Lilly to keep a careful eye on how Prasugrel performs in the real world while they wait on the results of the next trial to come in, with a possible label-language change to come at that point.

I'll give that option about a 70% chance. The 30% chance is that they delay things yet again, since the agency has been in a delaying risk-averse mood these days. We'll know soon. This new policy of not issuing those irritating "approvable" letters has made this sort of thing rather more tense, hasn't it?

Comments (6) + TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs

July 31, 2008

Rember for Alzheimer's: Methylene Blue's Comeback

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Posted by Derek

Today we take up the extremely interesting story of Rember, hailed in this week’s press as a potential wonder drug for Alzheimer’s. There are a lot of unusual features to this one.

To take the most obvious first, the Phase II data seem to have been impressive. It’s hard to show decent efficacy in an Alzheimer’s trial – you can ask Wyeth and Elan about that, although it’s a sore subject with them. But Rember, according to reports (this is the best I've seen), was significantly more effective than the current standard of care (Aricept/donezepil, a cholinesterase inhibitor). In light of some of the more breathless news stories, though, it’s worth keeping in mind that this was efficacy in slowing the rate of decline – not stopping it, and certainly not reversing it. Especially in the later stages of the disease, it’s extremely hard to imagine reversing the sort of damage that Alzheimer’s does to the brain (and yes, I know about the TNF-alpha reports – that subject is coming in a post next week). If Rember is twice as effective as Aricept, that's great - except Aricept's efficacy has never been all that impressive.

But that's still something, considering how the drug is supposed to work. Its target is different than the usual Alzheimer’s therapy. Accumulation of amyloid protein has long been suspected as the cause of the disease, but there have always been partisans for another pathology, the neurofibrillary tangles associated with tau protein. Arguments have been going on for years – decades – about which of these has more to do with the underlying cause(s) of Alzheimer’s. Rember is the first clinical shot (that I’m aware of) at targeting tau. If the first attempt manages to show such interesting results, it’s a strong argument that tau must be important. (Other people are working in this area, too, of course, but my impression is that it's nowhere near as many as work on amyloid).

That’s food for thought, considering the amount of time and effort that’s been expending on amyloid. It may be that both pathologies are worth targeting, or it may even be that these results with Rember are a fluke. But it’s also possible that tau is really the place to be, in which case the amyloid hypothesis will take its place in the medical histories as a gigantic dead end. I’m not quite ready to bet that way myself, but it’s definitely not something that can be ruled out. I wouldn’t put all my money on amyloid either, at this point. (Boy, am I glad I'm not still working in Alzheimer's: this sort of stuff is wonderful to watch from the outside, but from the inside it's hard to deal with).

Now, what about the drug itself? It’s coming from a small company called TauRx, whose unimpressive web site just went up recently. The underlying science (and the clinical data) all come from Dr. Claude Wischik of the University of Aberdeen, who has so far not published anything on the drug. The presentation this week has, by far, been the most that anyone’s seen of it (papers are said to be in the works).

And Rember itself is. . .well, it’s methylene blue. Now there’s an interesting development. Methylene blue has been around forever, used for urinary tract infections, malaria, and all sorts of things, up to treating protozoal infections in fish tanks. (For that matter, it’s turned up over the years as a surreptitious additive to blueberry pies and the like, turning the unsuspecting consumer’s urine greenish/blue, generally to their great alarm: a storied med school prank from the old days). What on earth is it doing for tau protein?

According to TauRx, the problem is that the aggregation of tau protein is autocatalytic: once it gets going, it's a cascade. They believe that methylene blue disrupts the aggregation, and even helps to dissociate existing aggregates. Once they're out in their monomeric forms, the helical tau fragments are degraded normally again, and the whole tau backup starts to clear out.

Now for another issue: there's been some commentary to the effect that Rember can't possibly make anyone any money, because it's a known compound. Au contraire. While we evil pharmaceutical folks would much rather have proprietary chemical matter, there are plenty of other inventive steps worth a patent. For one thing, I suspect that formulation will be a challenge here (and that Medpage story seems to bear this out). I doubt if methylene blue crosses the blood-brain barrier so wonderfully, and I also believe that it's cleared pretty well (thus that green urine). So TauRx had to dose three times a day, and their highest dose didn't seem to work, probably because of absorption issues. (That's also going to lead to gastrointestinal trouble). So formulating this ancient stuff so it'll actually work well could be a real challenge: t.i.d with diarrhea is not the ideal dosing profile for an Alzheimer's therapy, to put it mildly.

And for another, there's always mechanism of action. I deeply dislike patent claims that try to grab hold of an entire area, but there's so much prior art in tau that no one could try it. But use of a specific compound (or group of compounds) for a specific therapy: oh, yes indeed. It's a complicated area, and the law varies between Europe and the US, but it definitely can be done. The people who say that this can't be patented should check out the issued patents US7335505 or US6953794. Or patent applications US20070191352, WO2007110627, WO2007110629, and WO2007110630. There you go; that wasn't hard. Mind you, there might be some prior art for using such compounds as cognition-improving agents: I'd start here if I were in the business of looking into that sort of thing.

Finally, is methylene blue (or some derivative thereof) actually going to be a reasonable drug? There's that dosing problem, for one thing, but the long history in humans is encouraging (and is a key part of TauRx's hopes not to spend so much money on toxicity testing in the clinic - talks with the FDA should be starting soon). There have been contradictory reports (plus, minus) on the effects of the compound on the brain in general, though, so they may have to do more work than they're planning on. All in all, a fascinating story.

Comments (117) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Patents and IP | Regulatory Affairs

July 8, 2008

Glaxo Asks the Eurocrats

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Posted by Derek

There was a story yesterday about GlaxoSmithKline taking what’s being called an unusual step to prioritize their clinical candidates. According to the Wall Street Journal, they invited officials from the national health care plans of several European countries to a presentation on the company’s pipeline and asked them which ones they’d be more likely to pay for (and what they’d need to see in the clinic to convince them to do that).

Actually, I think the unusual thing here is that they made a formal meeting out of the whole process. I believe that this sort of thing goes on already – after all, drug companies spend a lot of time trying to figure out the size of potential markets and what the eventual purchasers will be willing to pay. In Europe, those are the national health care systems, and if they’re not willing to pay, your drug will go nowhere. In the US, you’re going to want to sound out the big health insurance companies for the same kind of reality check.

And I don’t see how GSK showed these officials anything that you wouldn’t see (or haven’t seen) at an investor’s conference – otherwise, we’d have seen some Regulation FD disclosures, since the company’s stock is listed on the NYSE. This seems to have been a one-stop rundown of what’s already been disclosed about the whole pipeline, but with opinions specifically solicited along the way– and the company’s not obliged to say what those opinions were or what they’re doing in response to them. GSK got a lot more previously unavailable information out of this process than the health care officials did.

How much, though, will this help? For one thing, I suspect that the officials didn’t say much that GSK didn’t know about what everyone wants for a new drug. They want it to work better than anything that’s currently on the market, with fewer side effects, and for less money. (There, that was easy). And predicting the future doesn’t always work too well. The medical landscape could always change by the time the drugs make it up to the regulatory stage. There will also be a lot more information (good and bad) about the compounds themselves by that time, much of which could make these earlier discussions moot. “Remember that oncology drug we were developing? Well, turns out that it doesn’t work against quite as many different tumors as we were hoping, but. . .” or “Remember that CNS drug we were telling you about back in ’08? Well, turns out that it also has this little cardiovascular thing going, too, and. . .” In the end, the drugs will do what they will in the clinic, and the company will have to bring what it has, not what the regulators asked for.

And even though companies are already supposed to be doing this kind of legwork, there are still some spectacular disconnects. Sanofi-Aventis, for example, did manage to get Acomplia (rimonabant) on the market in Europe (which is more than they ever managed in the US), but they didn’t get the national health care to pay for it. More recently, as in "yesterday", the UK's health care system just told Glaxo itself that they're not going to pay for Tykerb/Tyverb (lapatinib), because they don't see the benefit for the price. And when we’re talking about totally mistaken ideas about market size and acceptance, how can we not mention Pfizer’s Exubera?

Comments (10) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Regulatory Affairs