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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February 28, 2006

More on Outsourcing

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Posted by Derek

As it happens, I was looking through a recent New England Journal of Medicine yesterday after having posted that comment on outsourcing. (Yes, I do read it, even while whacking its editorial staff over the head about the VIGOR study).

There's a fine perspective in there on medical outsourcing, in this case the use of "nighthawk" firms that provide middle-of-the-night radiological opinions. After all, it's during the working day in Bangalore, and X-ray data is just a mass of binary digits like anything else that zips through the Internet, so why not?

The author lists some of the benefits to this (after all, radiologists need to sleep, too), and possible problems with these services, but concludes:

". . .it is easy to rail against this trend or to pray that it all happens after we retire. And observing the snail's pace of the quality, safety, and information-technology movements in health care one might predict that full-blown medical outsourcing is decades away. But judging by the speed with which high-tech call centers have migrated to Bangalore, the pace of change might actually be shockingly rapid.

People and institutions that are harmed by outsourcing will not take it sitting down, and I expect to see a flurry of initiatives to protect the status quo. Physicians and specialty societies will undoubtedly use the tools of legislation, licensure, certification, and reimbursement to thwart perceived threats to their livelihoods. Such efforts will nearly always be framed as protections of quality or patient safety, though some will be difficult to defend against charges of hypocrisy. . .

Though defensiveness and resistance are inevitable, I believe that a more productive strategy is for local caregivers, advocacy groups, and institutions to welcome - or at least accept - outsourcing that serves their patients' interests and to focus their attention on improving the quality and efficiency of the care they themselves deliver. . ."

Which, when you get down to it, is exactly what I was saying yesterday. I'll reiterate that I'm a free-trade advocate. I think that the free movement of goods and services is vital to economic prosperity. In turn, that economic prosperity is vital to keeping people alive and the world in what peace it has. Bastiat was right: when goods don't cross borders, soldiers will.

My opinions on the subject wouldn't be worth very much if they changed just because my industry is being affected. I think that American research firms can compete with anyone in the world, and if anyone would like to displace us as an engine of innovation, they are most welcome to try. We'll all be the better for it.

Comments (9) + TrackBacks (0) | Category: Business and Markets

February 27, 2006

But At My Back I Always Hear. . .

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Posted by Derek

I have an interesting article from Forbes to point out tonight: one of those lists of the best-selling drugs in the US, and a corresponding list of the fastest-growing ones.

A few things stand out. For one, five of the top ten drugs are showing declining sales. I suspect that this is close to the historical average, since some of these big sellers will always be things that are past their (gigantic) peak. Another striking feature is that the ten fastest-growing drugs include three antibodies and another protein. We small-molecule people tend to overlook these products because we're not the ones who do the research on them. But they're very big business indeed, and getting bigger every year. It would serve us organic chemists well, I think, to come up with ways that we can add something to the antibody field, because I think that we're going to want to be its friend.

And that brings up a conversation I was having with a colleague the other day. He was pointing out the huge amount of contract work that's being done in China and India these days. A lot of large and small companies are profitably outsourcing their chemical grunt work, and a lot of small firms outside the US are profitably taking it on. That got me to thinking again about a feeling that I just can't shake: that we medicinal chemists, individually and collectively, need to make sure that we are doing things that other people can't do for us.

Fifteen years ago, you could make a living banging out huge combichem libraries, but you can't do that any more. Ten years ago there were a lot of small outfits in the US that were doing custom synthesis, taking on all kinds of nickel-and-dime work, but if they've survived until now they've done it by branching out into things that the Indian and Chinese firms can't undercut them on. I think that the methyl-ethyl-butyl-futyl type of medicinal chemistry work is perhaps about to be loaded into the same hopper.

So, think about what you're doing for a living, fellow chemists. Is it something that someone easy to locate could do for a lot less money? It had better not be. Failing that, you'd better start to pick up some impressive new reasons to justify your paycheck.

Comments (22) + TrackBacks (0) | Category: Drug Industry History

February 26, 2006

Tied to the Mast

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Posted by Derek

Some readers will have already come across reports suggesting that some drugs for Parkinson's disease can lead to odd behavioral problems, including compulsive gambling. Given their effects on dopaminergic pathways, which seem to be involved in stimulus/reward behavior, it's a believable effect. (Actually, as I mentioned the other day, just about anything is a believable side effect with CNS drugs, especially at low rates of incidence).

Now (via Overlawyered) comes a case from Texas. A (once)-wealthy retiree named Max Wells is suing GlaxoSmithKline over their Requip drug (ropinirole), claiming that he wasn't warned that the drug could cause compulsive behavior. His particular compulsive behavior took place in Las Vegas, a city well equipped for it, and involved the loss of some 14 million dollars.

As the Austin newspaper story has it, Wells had started on another Parkinson's drug, Mirapex, in 2004 and lost several thousand dollars gambling, both online and in Vegas. (As it turns out, Boehringer Ingleheim is being sued over that drug, too, for similar reasons). He told his doctor about the problem, and was switched to Requip, which is when things apparently really started to roll.

Wells is also suing at least seven casinos, claiming that they knew that he was taking Parkinson's medication and should have been aware that he had a problem. I think these suits have even less of a chance, because casinos have been sued many times on similar "they should have stopped me" grounds. I recall a Philadelphia businessman in the early 1990s who took an Atlantic City casino to court because of his losses at his favorite game, which was high-stakes blackjack played with the aid of a bottle of bourbon. The casino, he contended, knew that he was impaired and should never have allowed him to continue. This argument didn't make much headway, as you'd probably guess.

This Parkinsonian case is a bit different, but I don't think it's going to get very far. It might bring up interesting questions about free will and human behavior, but no court is going to want to wade into that philosophical swamp. If the facts are as stated, the case will surely be decided on more practical grounds: why Wells didn't go back to his doctor when he started compulsively gambling again on the new medication instead of spending the next several months ripping through millions of dollars, and how casinos are not required to evaluate the motives of their customers.

Comments (6) + TrackBacks (0) | Category: The Central Nervous System

February 24, 2006

What's French for "Trust Us"?

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Posted by Derek

Well, Sanofi-Aventis has held their meeting with analysts and taken questions, and there's still not much to say about the Acomplia (rimonabant) situation. They still say that they plan to launch the drug later this year, and that they plan to talk with the FDA in March. A Bloomberg story says that they hope to resolve the issues "within months", which they'd better do if they're planning on 2006.

As far as I can determine, they still haven't come out and said just what the FDA's concerns are. And that, to me, has to be a bad sign. If the problems were inarguably small, the company would surely be motivated to tell everyone about them. But it looks more like: "We think we can launch this year. But if we told about you all the FDA's concerns, you might not think so yourselves. So we're not going to tell you."

If more details come out, I'll revise my opinion. But failing that, can anyone think of a reason why this isn't the right way to interpret this?

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity

February 23, 2006

Blogroll Revamp

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Posted by Derek

Well, I'm going to try to post tomorrow morning about the Sanofi-Aventis investors meeting, when we should (in fact, had darn well better) hear some more about the rimonabant situation. And the debate over the New England Journal of Medicine and Merck is going on briskly in the comments to yesterday's post, so please take a look over there if you haven't yet.

So tonight I'll take a few minutes to rework the blogroll. Welcome newcomers Terra Sigillata, Science, Shrimp and Grits, the Mass Spectrometry Blog, Tobias Sing's Bioinformatics Blog, Snowdeal, Cosmic Variance, On Pharma, and Oncology Updates.

And note also the new locations of Uncertain Principles, Adventures in Ethics and Science, Aetiology, Gene Expression, Pharyngula, and Respectful Insolence at Scienceblogs.

No doubt there are other sites I should be linking to - suggestions are welcome!

Comments (7) + TrackBacks (0) | Category: Blog Housekeeping

February 22, 2006

NEJM vs. Its Contributors, Round Two

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Posted by Derek

The original "Expression of Concern" editorial over the VIGOR Vioxx trial in the New England Journal of Medicine was an odd enough document already. But today brought an "Expression of Concern Reaffirmed" in the journal, along with replies from the VIGOR authors.

It's going to take some doing to get these folks together, as you'll see. The NEJM's editors, in their "reaffirmation", add a few details to their December 8th expression. Their position is still that there were three heart attacks in the Vioxx treatment group that were not in the data submitted to the journal. And they're not buying the explanation that these took place after the end of the study, either:

"The authors state that these events did occur during the trial but did not qualify for inclusion in the article because they were reported after a "prespecified cutoff date" for the reporting of cardiovascular events. This date, which the sponsor selected shortly before the trial ended, was one month earlier than the cutoff date for the reporting of adverse gastrointestinal events. This untenable feature of trial design, which inevitably skewed the results, was not disclosed to the editors or the academic authors of the study."

Those academic authors (11 of them from seven different countries, led by Claire Bombardier of Toronto) have a reply to all this in the same issue. Regarding those three MI events, they say:

"The VIGOR study was a double-blind, randomized outcomes study of upper gastrointestinal clinical events. We, as members of the steering committee, approved the study termination date of February 10, 2000, and the cutoff date of March 9, 2000, for reporting of gastrointestinal events to be included in the final analysis. Comparison of cardiovascular events was not a prespecified analysis for the VIGOR study. . .the independent committee charged with overseeing any potential safety concerns recommended to Merck that a data analysis plan be developed for serious cardiovascular events. . .As a result, a cardiovascular data analysis plan was developed by Merck. Merck indicated that they chose the study termination date of February 10, 2000, as the cutoff date. . .to allow sufficient time to adjudicate these events. . . (The three events) were neither in the locked database used in the analysis for the VIGOR paper no known to us during the review process. However, changing the analysis post hoc and after unblinding would not have been appropriate."

The authors go on to say that including the three heart attacks does not, in their view, change the interpretation of the safety data. They also take issue with the journal's contention that the three events were deleted from the manuscript, saying that the table of cardiovascular events in the presubmission draft of the paper never included them in the first place.

The two Merck authors on the paper, in a separate letter, make the same point, and also mention that there was an additional stroke in the naproxen-treated group that didn't make the paper for the same reasons. They reiterate that including the three heart attacks wouldn't have changed anything:

". . .The article clearly disclosed that there was a significant different in the rates of myocardial infarction in the Vioxx and naproxen arms of the study and reported these rates as 0.4 and 0.1, respectively, with a relative risk reported as 0.2. The inclusion of the post-cutoff data myocardial infarctions changes the Vioxx rate to 0.5 but does not meaningfully change the relative risk or the conclusion that there was a significant difference between the two arms of the study. Indeed, with such a small number of events (which were not a primary end point of the study) - and with such wide confidence intervals around them - it is difficult to imagine that this small numerical change could affect the interpretation of the data."

Looking at everything together, I'm still coming down on the side of Merck and their academic collaborators in this part of the fight. The post-launch cardiovascular data on Vioxx and its advertising and promotion are worth debating separately, but as for the VIGOR study, I think the NEJM is overreaching. Still, from Merck's viewpoint, I think the damage has already been done. . .

Update: Y'know, it occurs to me that there are a few people who aren't as upset about all this editorial wrangling: the editors of JAMA and the other top-ranked medical journals. They'll be getting some manuscripts that otherwise would have gone to NEJM.

Comments (25) + TrackBacks (2) | Category: Cardiovascular Disease | The Scientific Literature | Toxicology

February 21, 2006

Gold and Lasers

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Posted by Derek

There's been a lot of work in the last four or five years using nanoparticles of gold in biological systems. When they're are brought down to this size their electronic properties get quite unusual - in gold's case, the particles become huge absorbers and scatterers of certain wavelengths of light. They're thousands of times better then the kinds of dyes that organic chemists like me can crank out, which gives you potentially huge signal-to-noise in microscopy applications and assays.

Another exotic property these things have is that they convert the energy they absorb very efficiently into heat, and it didn't take long for people to have the idea of using this effect for cancer therapy. Heating cells, after all, kills them. Of course, you'd want to have some way to get the metal particles to stick only on to cancerous cells, and this has been realized by linking antibodies to the surfaces of both hollow and solid gold nanospheres.

The latest advance in this area has come from changing shapes. Rods are predicted to absorb more efficiently and at much different wavelengths than other shapes, and a joint Georgia Tech/UCSF team (who had worked earlier on the solid gold nanospheres) has verified these effects. They were able to grow rods of various sizes and aspect ratios and to conjugate them to anti-EGFR antibodies. EGFR, of course, is a well-known cancer target (via inhibition of angiogenesis), which is hit by several small molecules as well as antibodies like Imclone's Erbitux.

Each of these types of particle has its advantages. The gold nanosphere/antibody conjugates actually absorb at slightly different wavelengths when they interact with EGFR-expressing cancerous cells compared to noncancerous ones, which could make for a useful diagnostic assay. This can really only be done ex vivo, though, in thin preparations, because the wavelengths of light needed are also absorbed by the tissue itself.

The rods don't manage to show the differences between cells, although (as with the spheres) you can see the differences (scroll down on that page) qualitatively in how many particles are bound to the cell surfaces. But they do have a property that's potentially even more useful: their absorbing wavelengths are shifted to the near-infrared, which penetrates tissue much better (up to four inches)! You need green 520nm light for the spheres (with a convenient argon laser wavelength nearby at 514nm), but the rods need red 800nm light from a titanium/sapphire laser. When cell cultures are hit with that wavelength, the heating of the gold nanorods kills them off - and the EGFR-expressing cancerous cells can be killed by laser light of only half the strength needed for normal cells.

That's probably just barely enough of a gap to be therapeutically useful, for several reasons, not least because for tumors inside the body, I think that you'd be dosing the outer skin layers with too much wattage in order to hit the deeper tissues. No doubt work is already underway on widening the window between the two effects. I can certainly imagine some possible next steps as well: simultaneous treatment with conjugates of different antibodies, for example. Since many cancerous cell lines overexpress more than one type of cell surface protein, you might be able to hit them in several ways at the same time.

As much as I love small molecules (and the organic chemistry used to make them) I have to admit: they may not be able to hold their position against ideas like this. We can try to target things like EGFR that are overexpressed in many cancers, but we don't have much of a guarantee of success, because overexpression doesn't make a pathway crucial enough by itself. But overexpression alone is all you need with this technique, and the cellular pathways downstream don't matter a bit. It's a liberating thought. . .

Comments (13) + TrackBacks (0) | Category: Cancer

February 20, 2006

Rimonabant Bangs Into. . .Something

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Posted by Derek

Sanofi-Aventis basically has their future riding on their obesity therapy Acomplia (rimonabant), which was (until a day or two ago) expected to be approved before the middle of this year. But the FDA gave them one of those "Approvable, But. . ." letters which sow fear and confusion whenever they arrive.

The fear is self-explanatory, and the confusion comes because the letters don't have to be made public. No one knows what the FDA's concerns are, because Sanofi-Aventis doesn't have to say - yet. But in the case of a drug that was expected to be this big, and one that S-A's management was telling everyone just the other day was in fine, fine shape, they're going to have to come out with something soon or risk a complete loss of confidence and credibility.

There are quite a few possibilities, as this post at Pharmagossip lays out. I have to say, rimonabant has always made me a bit nervous, and that's not just hindsight talking. Back in 2004 I wrote about some possible bad side effects of the drug, and last year I worried in general about the problems of taking such a drug (huge buildup, huge market, totally new mechanism of action) to market.

You see, the problem is, I did the first half of my career in CNS drug discovery. Drugs that act on central nervous system receptors can do all kinds of odd stuff, and we most definitely do not know enough about brain chemistry to predict what those interesting surprises might be. The endocannabinoid receptor that rimonabant targets is very much an evolving story - it's even less worked out than the other brain targets. The thought of a CNS drug whose target is relatively less well understood than the others should be enough to make anyone gaze thoughtfully out the window for a bit.

The field has other brisk and tangy qualities. For example, the patient population tends to have an alarmingly heterogeneous response to CNS drugs, as a look at the antipsychotic and antidepressant markets will show you. Drugs that work fine for one person do nothing for another, and we don't yet know why. I can see no reason why rimonabant should be any different.

This FDA action may have borne out some of these fears, or it may be that Sanofi is just involved in an argument about a too-aggressive labeling proposal. Here's betting that they fill in some details real soon now. The longer they wait, the worse it'll be for them. By. . .Wednesday, I'd say?

Comments (5) + TrackBacks (0) | Category: Diabetes and Obesity

February 19, 2006

Because I Never Lie, and I'm Always Right

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Posted by Derek

Something recently made me think back to an undergraduate physics lab that I once had to do. This was elementary optics, so we had the standard collection of lenses on a beaten-up optical bench as we did our Newtonian thing. There would be little reason for me to remember it if it hadn't been for the comment of one of my lab partners.

We were setting up another phase of the experiment, and the instructions said for us to put the lenses in a set configuration and see if we got such-and-such effect. "That can't be right", this guy said, moving them to a different spot that he thought would work better. They didn't, and we ended up doing it the way the lab manual had laid out. But I've returned to that scene several times over the last twenty-five years, trying to figure out what bothered me about his response.

After all, a good researcher shouldn't just take someone else's word for everything, right? And if you have a hypothesis, and can test it, you should go ahead and do it, right? On the face of it, my old partner's attitude towards our lab that day shouldn't have gotten on my nerves, but it did. There was something wrong about it, but I kept trying to work out what it was - in a way that didn't put me on the just-follow-the-lab-book side of the argument, where I didn't want to be.

It finally dawned on me. My problem with the guy wasn't that he didn't trust the lab manual. It was that he trusted himself way too much. It would have been one thing to try what was in the book, then say "I wonder what happens if you move this lens out here?" That would actually be a good sign. But the statement "That can't be right"isn't one, especially not from an undergrad doing an optical demonstration whose results have been known for three hundred years.

Now, of course, I have a lot more room to maneuver as a scientist. Most of the experiments I run are things that no one has ever done before, not on these particular molecules in this particular way. I'm pretty sure I know what's going to happen, but I get surprised a lot. And when it comes to the effect of my compounds on cells and animals, I get surprised all the time.

But it's surprisingly easy to forget how little I know. After sixteen-plus years doing this, I have to watch my tendency to talk to younger colleagues as if I know what's going to happen with their ideas. I don't. I have my experience to draw on, of course, which makes me say things like "Are you sure you want to put a napthyl in that molecule?" or "Cyclohexyl groups are a metabolism magnet - that's going to get torn up". I'd say that a good solid majority of the time, those two statements are correct. But once in a while they're not, and most of the time I don't have as much evidence to back up my prejudices as I do with those two examples.

So now I know why I've never forgotten the guy who said "That can't be right". I've been trying, all this time, to keep from turning into him. The struggle continues.

Comments (5) + TrackBacks (0) | Category: Who Discovers and Why

February 16, 2006

What's It Worth to You?

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Posted by Derek

So now we come (again) to the topic of cancer drug pricing. The New York Times ran an article on this the other day which has gotten a lot of attention. In it, Alex Berenson points out that prescriptions for the antibody therapies like Avastin and Erbitux cost a huge amount of money.

This isn't news, unfortunately. See this 2004 article by Matthew Herper in Forbes, for example, or see my posts from around that time here and here. What the NYT article makes much of, though, is what it says is a new rationale for the costs:

"Until now, drug makers have typically defended high prices by noting the cost of developing new medicines. But executives at Genentech and its majority owner, Roche, are now using a separate argument — citing the inherent value of life-sustaining therapies.

If society wants the benefits, they say, it must be ready to spend more for treatments like Avastin and another of the company's cancer drugs, Herceptin, which sells for $40,000 a year. . ."

You won't catch me disagreeing about the value of pharmaceuticals. But this argument can only be taken so far, because (as those links from two years ago make clear) drugs like Avastin really only add a few months of life. That's nothing to make light of, but I fear that it's also not much of a basis for Genentech and Roche to talk about how society should be willing to pay for such outcomes. Can you fix a price for two extra months of life? We're going to have to.

The NYT article has an excellent example of someone who's done the calculation for himself:

"Ellis Minrath, who has pancreatic cancer, said he had chosen not to take Tarceva, a drug from Genentech that is approved for lung cancer and has shown promise in pancreatic cancer. He did so after learning that it would cost him about $1,000 a month in co-payments, even though he is covered by Medicare.

"If anybody came out and said, 'By God, this is the stuff. You want to get well, find a way to buy it,' that would be one thing," said Mr. Minrath, who is 87. "But that isn't the case. The forecast of how much it's going to do is not that wonderful. . .

I agree with Mr. Minrath's decision, and I strongly endorse his right to make it. As an 87-year-old with pancreatic cancer, he seems to have studied his situation objectively and realized the odds he faces. He is very, very likely to die within the next few months, and (although we've never met) I'll be sorry to see him go, because he sounds extremely sensible. Personally - and I hope I never have to work this decision out for real - I would lean toward a similar "leave more for my heirs" position. Other patients in different situations may well come to different conclusions, and that's up to them (and in the real world, up to their insurance companies) as well.

What we need, of course, is some cancer drugs that don't make us put prices on months. I'd rather be working out the value of whole years or decades. Therapies which can do that will be the place to make the "society should suck it up" argument, but making it for Avastin and the like seems rather premature. What will we do when we find something that's good?

Comments (29) + TrackBacks (1) | Category: Cancer | Drug Prices

February 15, 2006

Pfizer Takes a Deep Breath

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Posted by Derek

I haven't mentioned Pfizer's inhaled insulin project in a while, but a few weeks ago they got the stuff approved, at (very) long last. The development of Exubera, which is certainly a cheerful brand name, has been anything but uplifting, though Here's a piece I did three years ago, when the story already seemed to have been going on for a long time.

Insulin, of course, is the very definition of a well-established drug, but that's only if you inject it. Slowing things down have been problems which are unique to inhaled powders: the effect on lung function over time, the changes in dosage under suboptimal conditions (allergy, flu, etc.), and the reproducibility of the dose. These are particularly worrisome for insulin, which is a tough situation: it's vital to its users, and it has a lower margin for error (both under- and over-dosing) than most other drugs. As I put it in that 2003 post, if you take twice as much aspirin as you should, it'll be rough on your stomach. If you take twice as much insulin, you're going to end up on the floor (and there had better be someone around with a candy bar).

You can see this troubled history in the drug's labeling, which Frederick Cohen at Crownstone has been going over. To pick one interesting detail, patients will be required to have a baseline pulmonary function test before starting the drug, with monitoring thereafter. And this brings up the current worry: how much will Exubera (and its baggage) cost, and who's going to pay for it? The product won't be launched until mid-year, and no one knows quite what its price will be. Pfizer's just saying