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 28, 2004

No Defense

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Posted by Derek

In case anyone has me pegged as a reliable apologist for the pharmaceutical industry, I'd like to direct you to this article in the Sunday New York Times. It details marketing practices (in this case, from Schering-Plough) that, if reported accurately, amount to little more than programmatic bribery of physicians. I can't defend this stuff, nor do I want to.

I have a brief message for anyone involved in this kind of thing. We're having a rough enough time in the industry already, don't you think? As you're doing your job, ask yourself if your work is the sort of thing you'd care to have spread all over the business pages of the newspaper. It had better be.

Comments (7) + TrackBacks (0) | Category: The Dark Side | Why Everyone Loves Us

June 27, 2004

Loose Lips

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Posted by Derek

A recent comment to the "Dumpster Diving for Data" post below mentioned a rumor that a supplier of oligonucleotides was comparing orders against GenBank sequences. For those outside the field, what all that means is that supposedly a company that makes custom small sequences of DNA was looking through a public DNA database, trying to guess what its customers might be up to.

Is that possible? Well, yeah. But is it likely? I have to wonder. Cui bono? I'm not sure how the supplier might benefit - what are they going to do, turn around and sell the information to another company? All that means is that anyone they make the offer to will never order DNA from them again - why risk having that information peddled to someone else? Pretty soon, no one would order from them at all. Actually, this rumor sounds more like something the oligonucleotide firm's rivals might deliberately spread in order to ruin their business.

In the chemical end of things, we expect the major suppliers (Aldrich, Lancaster, Acros, etc.) will keep our orders completely confidential, and I've never heard of a case where they didn't. They fear just the sort of backlash I described - nothing they could make from the order information is worth it.

Now, I have to admit, an off-the-main-road supplier did let slip something to me one time. They were pretty much the only world source for a particular class of compounds, and we needed to get some starting material to take a look at some patented compounds from a competing company (and to appropraite some of their chemical structure, if it fit into what we were working on.) I called this outfit up to ask about the price, and they wanted to know what application we had in mind.

When I told them, frankly, that we were evaluating some compounds from the competition, the fellow on the other end laughed and said, "I think I know who you're talking about - some people in (name of town, name of state.)" That at least let me know that they'd spoken with this company, too, which wasn't particularly valuable information by itself, but more than I would have known otherwise. And even so, it's still a lot more than Aldrich or Maybridge would tell you.

Comments (4) + TrackBacks (0) | Category: Drug Industry History

June 24, 2004

Summer Hours

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Posted by Derek

I'm only going to be at the Wonder Drug Factory for a half day on Friday, and there's not much time to post tonight, either. I wanted to let everyone know that I'm not going to hit the once-a-day update schedule reliably during the summer, what with all the summery activities going on (and with two small children, I'll be seeing plenty.)

I also hope to be working on some chemistry/pharma writing that will bring in some actual income - inquiries and suggestions are welcome. That's as opposed to blogging, which runs on the Free Ice Cream model (or some days, admittedly, Free Pickled Lemons.)

Next week looks like it'll feature some more drug-price blogging, to judge from the comments piling up below (and thanks for the links, from (among others) Marginal Revolution and LeftCenterLeft.

Comments (1) + TrackBacks (0) | Category: Blog Housekeeping

June 23, 2004

It'll Cost You

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Posted by Derek

Over at Slate, NBC's Robert Bazell takes on the drug pricing issue, focusing on the newer oncology therapies. There's no denying that some of them are really costly, and that this is a situation that probably can't continue under the current system (which, to exaggerate only slightly, works like this: every cancer patient gets to try everything, and insurance/Medicare pays for it no matter what.) But the problem with Bazell's article is that it bungles enough other points that his main ones are obscured. One of them goes like this:

"Why are these drugs so expensive? It's hard to know exactly, since drug pricing is a sacred prerogative protected by acts of Congress and the details remain shrouded in trade secrets. But the simplest answer is that drug companies can charge whatever price they want. "

Ahem. That's as opposed to the perfectly transparent pricing mechanisms for, say, cars, toothpaste, and fish sandwiches, I guess. And those aren't even "sacred prerogatives"! Imagine what those things would cost if the businesses that provided them could charge whatever prices they wanted to! Good thing we don't let them. (And yes, I know that cancer drugs aren't exactly discretionary purchases - we'll come back to that one.) Bazell goes on:

"Erbitux and Avastin are both laboratory-produced antibodies (Erbitux blocks a chemical signal that tells cells to grow; Avastin cuts off blood supply to tumors). True, these antibodies are more expensive to produce than most pills, but only slightly-the technology can be replicated in any college biology lab. Production costs amount to few dollars a dose at most."

I hate to put myself in the position of defending Imclone and Erbitux, but this argument is exaggerated to the point of nonsense. I know what he's trying to say - that making monoclonal antibodies is an established technology - and up to a point, it is. But Bazell makes it sound like a bunch of undergraduates could whip up a batch of Erbitux for fifty bucks or so, and that is, to use a term of the pharmaceutical art, complete bullshit. Antibodies are actually a lot more expensive to produce than small molecules. Getting reproducible purity and performance from them is a completely different problem than with small synthetic molecules, and once made, they're significantly harder to formulate, store, and handle. (That's one reason why Iressa, for example, is cheaper by a factor of ten than Erbitux.)

Here's a challenge for Robert Bazell: Let's pick a random college biology lab or two by riffling through a directory, and see if they could produce a steady supply of GMP-grade doses of Erbitux (or any other antibody therapy). Let's just call them up and ask them! Anyone want to put some money down on the results? Bazell goes on:

". . .Like all pharmaceutical companies, BMS and Genentech cite research costs and the huge risks involved in drug development (many drugs fail; clinical trials are expensive ... but haven't we heard it all?) as explanations for the high prices of their drugs. But the real reason is that market forces do not apply to drugs."

I'm sorry that we're boring him. Unfortunately, those explanations get trotted out over and over again because they're true.

"Few individuals purchase these drugs as they would a head of lettuce, say, or a refrigerator. In the case of cancer drugs, health-insurance companies are the consumers. For those lucky enough to have insurance, their plan might pay; and indeed, oncologists say that, surprisingly, so far few have balked."

Now we're down to that nondiscretionary spending issue. It's a real one, and it applies not just to pharmaceuticals, but to every sort of health care. People value their health very highly, as they should. And it's not that market forces don't apply to drugs, it's that no one seems to want them to. If they did so more directly, insurance companies would indeed start to balk, and drug companies would have to decide if they could lower the prices of their new therapies coming through the research pipeline. And if they couldn't, they would have to decide not to take them through clinical trials at all. We would end up with fewer therapeutic options than we have now.

But a therapy that no one can afford is arguably about the same as no therapy at all, so that's not as much of a tragedy as it sounds. And it's certainly true, as the article goes on to point out, that many of these new cancer treatments aren't as effective as everyone would like. Unfortunately, the only way to find that out was to go ahead and spend the money and time to develop them, and take them all the way through clinical trials and regulatory approval. That's when you find out that your wonder drug isn't as wonderful as you'd hoped. But I'll stop right there; I can hear Robert Bazell starting to yawn. Here he comes again:

"But even the current meager benefit will encourage all cancer patients to seek (these drugs), and those who cannot get them, because they lack health insurance or their plan won't pay, to feel cheated. And a marketplace with absolutely no price control will only propel the drug companies to charge even more for future drugs, some of which may offer even less benefit."

Why, exactly, would we enter the market with something that's demonstrably worse than what's already out there? I know that the industry gets hammered for me-too drugs, but those work at least as well as the existing therapies, and they need some selling point that lets you argue that they're even better. I can testify, from personal experience, that projects get killed all the time in the drug industry because we can't beat the competition, either what's already on the market or in clinical trials. I've helped kill them. This hasn't been as big an issue in oncology, but it does happen, and it's going to be happening more often.

And the answer to all this, presumably, is price controls. Hard to say, since that's where Bazell's article ends, but that seems to be the prescription. I can just imagine what kind of price a group of elected officials will decide what is fair. We'll be tied up, top to bottom. It's not clear to me - it never has been - how forcing companies to earn less money from their drugs will cause them to produce better ones. (Think how much Imclone could charge if Erbitux actually worked better than it does.)

If you want a more detailed take on the cancer drug pricing issue, go back a couple of weeks to Matthew Herper's article in Forbes. It covers the same ground, but in a clearer fashion. Ultimately, I think what's going to happen is that there will be patients who will not get some of these drugs, largely because they won't do very much good - or none at all. If we get past the treat-everyone-with-everything style in oncology, it'll force us in the drug industry to modify our projections of market size, and we'll have to come up with a way to deal with it. Pushback from the insurance companies and physicans is a better check on the drug industry, to my mind, than a Central Office of Pharmaceutical Pricing could ever be.

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

June 21, 2004

Primum Non Nocere, Eh?

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Posted by Derek

The placebo effect is a real problem in some clinical trials. It varies, but in things like antidepressants it's a major factor (while with, say, pancreatic cancer it doesn't change the results too much.) In a given sample of depressed patients, there are a fair number of people (20 or thirty percent) who will respond if you give them 50 milligrams of confectioner's sugar which they truly believe to be an efficacious drug.

Of course, the majority will respond as if you'd given them, well, confectioner's sugar, but that group of placebo responders will blow your statistical workup to pieces. This is one of the reasons that you see multiple trials for antidepressants, because the trials themselves often just produce noisy data. Of course, one way to interpret this is that the antidepressants themselves are fairly worthless. That's a tempting conclusion, and for some people, they clearly don't do much good. But you can find others that truly appear to have been helped. Depressed patients, even ones who may look and act similarly, are clearly a heterogeneous population.

What if those strong placebo-responders could be weeded out of the patient population before you even started the clinical trial? This question is a good test of a person's attitude toward the drug industry. Many folks will hear that idea and cry "Fraud! Stacking the deck!" But think about it. If you could find the people who will improve when given a sugar pill, then you could pull them aside and just go ahead and give 'em the sugar pill. Hey, it's effective therapy, and that's what counts, right? And they'll miss out on the side effects of the antidepressant drugs themselves, and every drug has side effects at some level - every single one.

Meanwhile, once those folks have been sorted out, you're left with a cohort of patients who need all the help they can get, and now you're in a statistical position to see if you can really provide any. As far as I can see, everyone comes out ahead.

It turns out that there may be ways to see who's a strong placebo effect candidate and who isn't. There have been several studies in the last few years that show some real correlations in brain activity during placebo situations, and this has lead to the idea of a test for it.

If this goes on, though, there could be some interesting developments. What if everyone becomes aware of the test to see if you're going to get a placebo? Will the responders still respond if they thing there's a reasonable chance that they didn't get a "real" drug? I think that what we'll need to do is present the test as a standard procedure, to help figure out which therapy would work the best - not a method to see if you get a drug or not, but a method to see which drug you should get. That should keep things working.

Comments (5) + TrackBacks (0) | Category: Clinical Trials

Le Dernier Cri

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Posted by Derek

Mentioning all the nanostructure papers in the journals brings up the topic of fashions in chemistry. We've got 'em, all right. Waves like this tend to wash over the literature every few years. (I can only speak for organic chemistry, but I assume that it's the same in the other disciplines.)

For example, only in the last couple of years have we begun to escape from the olefin metathesis craze. That's a useful reaction, and I can't make fun of it on its face. But a few years ago, it seemed that everyone with two alkenes in their lab was finding a way to get them in the same flask with some Grubbs catalyst or whatnot. People looked at the reaction and said "Hey, that's neat. I could do that", and they did.

Of course, people also look at these things and think "Hey, that's neat. I could publish that" or "Hey, that's neat. I could get funded for that", and those reasons carry a lot of weight. So journal editors and the reviewers at granting agencies carry some responsibility for these fads, but they're just as human as the rest of us. Most of the time.

These bursts of activity can serve a useful purpose. The state of the art advances rapidly when everyone's trying to improve it, as you'd figure. The best examples of waves of interest have a can-you-top-this quality in them; the worst have a bunch of chemists just doing the same thing because everyone else is doing it.

There are even fashionable molecules, ones that have been synthesized over and over again, because they come in handy to show that your new synthetic method is good for something. (That's not a line of argument that I find very compelling, but it's a common one.) An insect attractant called brevicomin is a good example. I'm sure that I've seen six or eight synthetic routes to that, and it's not like I've been collecting them, either. Twenty years or so ago, the jokes were about a molecule called cis-jasmone, which turned up over and over again when someone wanted to prove their synthetic moves.

But since we're talking about fashion, I should note that the whole field of natural product total synthesis isn't as fashionable as it used to be. That's a larger topic worth a post of its own, but it's something that's had its practioners a bit worried and defensive the last few years.

Comments (2) + TrackBacks (0) | Category: The Scientific Literature

June 17, 2004

You'd Think It Was An Election Year or Something

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Posted by Derek

There are several Canadian drug reimportation bills floating around in the House and Senate, and it's anyone's guess whether one of them will come up for a vote this session. The AARP has just weighed in in favor of S. 2328, sponsored by Bill Dorgan and Olympia Snowe - and if you're an elected official, the AARP is not to be taken lightly. Of course, neither is the drug industry, so we're set up for a fine Godzilla-versus-Rodan spectacle if the bill ever gets to the floor.

You can see the maneuvering going on. In addition to the AARP's statement, the General Accounting Office has released a study where they tried out dozens of online pharmacies. This one can be spun both ways, depending on where you stand: "US, Canadian Web Pharmacies Generally Safe" or "Many Online Drugs Fake, Study Says." Both headlines are accurate, as far as I can see. The GAO was ordering from as far afield as Turkey, which requires (no offense to the Turkish pharmacy distributors in the audience) a bit of a leap of faith.

I continue to think that the drug-safety argument is a long-term loser for the industry, because it's a problem that can be addressed. The Dorgan-Snowe bill has plenty of provisions to do just that, along with some to prevent drug companies from cutting down supplies to non-US pharmacies. The bill can be summarized as: We have ways of making you sell at the prices we like.

But do they have ways of making us discover and market drugs more cheaply? Or is that going to be our department? I realize that we in the drug business need faster, cheaper methods of finding new therapies - but you know, it's not like we lack incentives - green folding ones - to do that already. And we've been throwing substantial sums at those problems, without all that much to show for it. Would price controls have helped us, do you think?

No, the real arguments against reimportation are economic, and if you don't believe me on that one, believe an economist, Alex Tabarrok over at Marginal Revolution:

Price controls or other such plans such as reimportation may bring cheaper pharmaceuticals for a short period but we will then have a much smaller supply of new drugs forever. Only the shortsighted would buy that prescription.

Comments (9) + TrackBacks (0) | Category: Drug Prices

June 16, 2004

The Dull Edge of Nanotech

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Posted by Derek

There's a type of paper that's showing up often in the major chemistry journals these days, and it's a type that didn't even exist a few years ago. I can't count the number of reports of nanometer-sized structures that have been described recently. Rods, filaments, sheets, cylinders, shells - you name it and someone's got it. That inorganic salt plugging up your filter? Turns out it's not just an annoyance, it's a publishable nanostructure!

On one level you can see why this happens, with all the publicity that nanotechnology has these days. But that's not what most of the papers are really about. No particular use or general principles are suggested, for the most part, just "We found these things, and they look like this." (You can spot these papers quickly in the abstracts at the front of the journals, because they're invariably illustrated with a photomicrograph of the new structure.)

There's a place for that kind of paper, naturally, but are there dozens of places? Some of these things may turn out to be useful, or at least point the way to something useful, but for now they're largely just being described as curiosities, and they're being published because - well, because they can be. Perhaps some of these groups are hoping that someone, someday, will make a breakthrough that makes their paper look ahead of its time.

The techniques to look for these structures have been around for some years, so it's not like we're just now able to see them. It's just that up until recently, no one has cared all that much. I have to wonder what would have happened if someone had submitted a paper to JACS fifteen years ago about, say, scandium salts that form nanoscale helices when precipitated out just so. Would the editors and reviewers have known what to make of it? Or would they have tossed it back, telling the authors to come back when they had more to say?

There's a lot of serious nanotech work being done in chemistry, but this stuff isn't it. I have to think that these papers are going to look a bit strange and dated in coming years, once this stamp-collecting phase passes. When will the editors at the likes of the Journal of the American Chemical Society, the Journal of Organic Chemistry, Organic Letters,and Angewandte Chemiecall a halt?

Comments (5) + TrackBacks (0) | Category: General Scientific News | The Scientific Literature

June 15, 2004

The Journals Fight Back

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Posted by Derek

So it turns out that the major medical journals have their own plan for bringing on a clinical trial database: they're going to require companies to register trials before they'll allow publication of their results. I was taken aback at not having heard anything about this idea, until I saw that no one else in the drug industry seems to have, either.

I don't really have a problem with this at all. For one thing, it's better than having the state sue you into doing something - this is a good old free-market fight. Most of the major medical journals need revenue from pharmaceutical advertising, and the companies need the prestige of publishing in them. Come, then, let us reason together.

And the first step here, merely registering the fact of a trial, will sidestep some of the issues I brought up the other day with how to report the final data. I know that there will be pressure to include that data as well, and if we can find a way to deal with those reporting issues, we should. But even a registry of trials would show that something had been tried, naturally leading to questions about how things came out. (That's important for the medical editors' side of this dispute, because the studies that companies don't want to talk about aren't going to be submitted for publication, anyway - the journals have no other leverage at that point.)

Now, one way around this would be for companies to forsake publication in the journals involved (a tough thing to do, mind you) and just present the data with a big splash at a prestigious meeting or two. If you see more professional societies joining this trial-registry movement, especially ones that don't publish their own journals but still sponsor large meetings, then I think the outcome will have become clear.

I think, though, that people have some odd ideas about how clinical trials work and how many of them there are. Consider columnist Michelle Malkin, who wrote about this story today:

From Statistics 101 we know that if a product is as effective as a placebo, 1 in 20 trials will produce a statistically significant finding due to random chance. Since companies run dozens of trials on each major compound, it is not too hard to produce at least one positive, statistically significant finding suitable for publication. The rest are buried in the "circular file." This is great marketing but it is not science.

Um, we don't actually run "dozens" of trials on every major compound. We don't have enough money to do that, as hard as that may be to believe, and in many cases there just aren't enough patients to go around. So we just don't get to play with the statistics in this way. It would be irresponsible, she's right about that, but we don't do it.

And that argument would only hold if all 20 trials were run the exact same way (Statistics 101, you know.) Twenty different trials, each run a different way on different patient groups, can produce results all over the map. Trying to do metastatistics over the whole group is not a job you want; it's often not even possible. And besides, even if they were all the same, the level of statistical significance that Malkin's talking about (1 in 20 by random chance) isn't very high at all. A clinical trial has to be a lot more significant than that to convince anyone at either the FDA or the company itself.

Comments (5) + TrackBacks (0) | Category: Clinical Trials

June 14, 2004

Wipe Down

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Posted by Derek

Family activities prohibit much blogging tonight, but I wanted to bring up a couple of other issues about secrecy in the drug business. One effect of all the proprietary information running around inside our buildings is that it's rather unusual to have someone from a rival drug firm visit another one. If they do, then it's likely to be for a seminar or symposium, and they'll be confined to the public meeting areas of the site.

The only times you see any people from another company up in the lab areas are when some sort of research deal has been signed, or (more commonly!) when someone is slipping over to interview for a job. Those are certainly the only times I've ever seen the inside of another drug company, and quite right. I wouldn't let me upstairs, either.

It's not like I'm going to be snooping around, but it would be impossible not to see something revealing. There isn't going to be any sensitive information lying around in the cafeteria or the main conference rooms - there had better not be - but there's nothing but sensitive stuff all over the labs: notebooks, spectra, printouts, structures and reactions all over the blackboards and the sliding glass of the fume hoods.

All that can stay up if there's a high school group coming through on a tour. But two or three times in my career, I've been in labs where we had to sanitize the place ahead of scientifically adept outside visitors (a busload of miscellaneous academics, say) and it was a pain. It's odd to look through hood sashes that aren't full of blue and black heiroglyphics for once.

Comments (1) + TrackBacks (0) | Category: Life in the Drug Labs

June 13, 2004

Dumpster Diving for Data?

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Posted by Derek

A comment to the last post wondered if drug companies ever do active intelligence against each other (as opposed to the passive kinds I mentioned). Active means would be rooting through dumpsters and the like, and the answer is - almost invariably - no.

That sort of thing is more trouble than it's worth, because it's easy to find out what's public knowledge at a given time and what isn't. If you dig around for nonpublic information, it doesn't do you much good unless you act on it. And if you act on it, you've admitted having something that you shouldn't, and you're faced with having to explain your psychic powers.

The same problem occurs in military and governmental intelligence gathering, on a rather larger scale. But there the theater the intelligence is gathered in is the same one where any repercussions will occur (in diplomatic relations or on the battlefield). In business, the retaliation will come through the courts, which is a completely different problem, and generally one you don't want.

If someone talks more than they should during a meeting, well, that's their problem. The listeners always have the defense that they didn't think that this was truly proprietary information, because if it was, the speaker wouldn't have let it out, right? But that said, I can't think of any major slip-ups of this kind - perhaps some of my readers know of a few.

The only active intelligence gathering I've heard was in a story that broke a few years ago. It seems that one or more large European pharma companies were trying to figure out what some of the patent-ignoring generic drug firms in Cyprus were up to, and hired some folks to sneak into some offices to see if their drugs were being pirated. A couple of people got caught in a break-in. I haven't seen a follow-up in some time, so I don't know what eventually happened. There was an interesting article in Fortune in 1998 or 1999 on the case, but it isn't online.

Comments (1) + TrackBacks (0) | Category: Drug Industry History

June 11, 2004

The Agents Report Back

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Posted by Derek

Now that ASCO's wrapped up (and the American Diabetes Association meeting as well) every attendee from the drug industry has gone back to report on the news: copies of poster presentations, handwritten notes from the talks, and (most importantly) information that was only given verbally. That would be in answers to questions after a talk, in conversation around a poster, or in small gatherings all over the place.

That sort of stuff is often the real gold from a large meeting. No one is going to spill anything vital, but you can often learn more than is strictly contained in the official presentations, and everything helps. The drug industry being what it is, we have plenty of things we'd like to know about what the competition is up to: Are they still interested in compound X? Have they moved on to another one? What's better about it? Is that side effect something that's showing up in the whole class of compounds? How did they ever dose that stuff at those levels, anyway? Are they in Phase II? In what sort of patients?

It's a well-known psychological effect in the business that we treat new information as something that's just happened. But you have to keep in mind that the information in these meeting presentations is at best several months old, and maybe older than that. (At least it's better than getting excited about a paper that's just shown up in the literature.) That's another reason for all the one-on-one questioning, naturally - we want to know, for once, what's happening right now.

Comments (1) + TrackBacks (0) | Category: The Scientific Literature

June 9, 2004

Your One-Stop Clinical Data Superstore?

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Posted by Derek

There have been plans, over the years, for some sort of data repository for clinical trials. Nothing's ever worked out. The only place that all of this is collected is at the FDA, and they only have the ones that companies have submitted because they were requesting a new approval or a new indication. If companies run studies but they give up on regulatory filing, the data can never see the outside world at all.

That's the heart of the New York - GSK suit, as I was discussing yesterday (although, as I pointed out, in this case the data were made public, although nowhere near to the extent that the more positive study was). Presumably, the ideal that Eliot Spitzer seeks would be a central database of all clinical studies conducted on marketed drugs - along with, it seems, a requirement to go into the results of all of them in marketing presentations. (Actually, I think the ideal that Eliot Spitzer seeks is a world in which he is a senator from or the governor of New York, but that's another story. . .)

This sounds like a reasonably clear mandate, but in practice it's quite tricky. It's worth thinking about what a clinical data repository would look like. You'd have to include the statistical workup from the end of the trial, that's for sure. The raw data makes for quite a heap, and extracting the useful conclusions from it is not the work of a moment. You have to be well informed about how and why the trial was designed to even know where to start, and you have to be well informed about statistics to know when to stop.

Even with all the conclusions attached, an open raw-data repository would be a real invitation to cranks of all kinds to go in and massage the data. I've spoken about this issue before, because companies themselves can be guilty of trying to extract more conclusions than the data will support. Imagine the ax-grinding subgroup analysis and selective data mining that would go on - for one thing, the trial lawyers would be adding statisticians to their staffs to do nothing but comb through the numbers all day, looking for tort-worthy tangles.

Even if you just have the worked-up data in the repository, you still face the problem of data overload. Heavily studied drugs can have a long list of differently designed trials attached to them, all of which are either asking different questions or asking the same one in different ways. Digging through them is not something you can do on your lunch break.

An even tougher problem is what to do about poorly designed or poorly executed studies. That seems to be the case with the Paxil 377 data I spoke about yesterday, which is why one of the study's co-authors wanted to publicize it in the first place. Who gets to decide if a particular study is valid? Whose comments and conclusions will be attached to the results? Who gets to weight them against the other results collected on the same drug?

These are the sorts of issues that are wrangled about in the regulatory approval process, and the disagreements can be heated, even in a roomful of people who all know what they're doing. How many physicians would be willing to consult a Central Clinical Trial Database and do the wrestling themselves? How many would even have the time? For the most part, practioners have as their default setting to trust the FDA, since they've analyzed the data already.

As for what companies can say to doctors, limits in this area have banged right into free-speech considerations in the courts. Attorney General Spitzer's on-message response to this is that you can't use a First Amendment argument to justify fraud, and I'll let that one go by without swinging at it. But what would he have disclosure look like? Should it be verbal (and in that case, how would it be enforced?) Should it be a written handout on the total clinical data generated for a new drug? That makes more sense, but then we get back to the question of how summarized the results should be, and who gets to write the summaries.

The thing is, I think that a clinical data repository would be useful. I know that I'd like to go data-mining through previous studies, looking for things that are relevant to my current projects. And I'd like to see what happened in failed trials so we can be sure not to run ours in the same fashion (which was Dr. Miner's point about the 377 Paxil study). It could be worth trying, but I worry that it might require the world to be a little better than it really is to work. We'll see.

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

June 8, 2004

Cue the Music

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Posted by Derek

New York Attorney General Eliot Spitzer has found what must look like another target-rich environment: the pharmaceutical industry. As many readers will have seen, he's initiated a lawsuit against GlaxoSmithKline for their handling of clinical trial data for the antidepressant Paxil (paroxetine). As far as anyone can tell, this suit is the first of its kind.

There's a specific side to this story, and a there's general one about the handling of all clinical trial data. I think I'm going to end up splitting the difference, but first things first: in this case, SmithKline (as it was at the time) ran different studies on the effectiveness of Paxil in adolescent patients. One study (#329) had positive results, and another (#377, slightly later) showed no benefit versus placebo. Spitzer points out that the successful first study was widely publicized, presented at several scientific meetings, and eventually published. SmithKline (and later GSK) made it part of their sales pitch to physicians.

Meanwhile, the 377 study was presented once, at the annual meeting of that same academy, and never showed up as a full paper in the literature. The presentation wasn't SmithKline's idea; they weren't going to publish or present at all. It was suggested by two of their academic collaborators (Robert Milin and Jovan Simeon). And as you can imagine, it has not been a feature of GSK's promotional literature.

All this, in the eyes of Attorney General Spitzer, adds up to an indictment for fraud - and yes, that's exactly the word he uses. Here we have all the elements of a great case: buried information that would have been harmful to a large corporation, and a whistleblower who brought it to light. It sounds more like a screenplay - as you read about it, you can start mentally casting the movie.

But there are complications. For one thing, SmithKline made no objection when Dr. Milin told them of his plans to present the 377 study. I don't know what the terms of the research agreement were in this case, but often enough the company can exercise a veto in such cases, since they paid for the study. And second, Milin himself is, according to Barry Meier's story in the New York Times last week, a strong believer in the use of Paxil in adolescents. He considers the 377 study to have failed because of a flawed design, not because the drug isn't useful. And as for publishing the results in a journal, that would have actually been quite difficult. Inconclusive or negative results are very hard to publish in general, and in this case even the positive study wasn't the easiest thing to get into the literature. According the Times article, the paper probably bounced around a couple of times before finding a home. It ended up in the Journal of the American Academy of Child and Adolescent Psychiatry, and appropriate venue but hardly the highest-impact journal in the world. And finally, GSK provided details of both studies to the FDA, as it is required to do.

So hiding information, which is the basis of the fraud allegation, lies in the way that GSK detailed physicians. I wouldn't expect them to go out of their way to present data showing that the drug didn't work, but if one of the study's own authors felt that it was flawed, then I really wouldn't expect them to talk about it much. I can see what Spitzer's trying to do, all right, and I can see what he thinks he has. But I don't think that's what's really there.

All this, presumably, is supposed to further the cause of releasing clinical trial data. Under the current system, the company can show it only to the FDA (or other regulatory agencies) if it chooses, and if they give up on the compound, no one has to see it at all. There have been calls over the years to establish a clinical trial database, but nothing's ever come together.

And you know, I actually think that a general trial database could be a good idea. (It could also be a disaster, and the industry has chosen to avoid the latter rather than seek the former - we'll go into some of the complications tomorrow.) But I think that Eliot Spitzer may have picked the wrong grandstand to make a speech from, and should have thought twice before striking up the band. Then again, that's not the sort of behavior that got him to where he is now. . .

Comments (0) + TrackBacks (0) | Category: Clinical Trials

June 7, 2004

Vox Populi

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Posted by Derek

I wasn't planning on returning to this topic today, but tonight's e-mail seems to deserve a speedy reply. Says a loyal reader, one "Busterbuckeye":

You gave me a very impolite back hand slap in the above referenced blog. . .(on May 12) I posted in response to your April 28 blog in which you quoted Travers with approval: "Travers did indeed estimate Erbitux revenues at "peak" based solely on its one current crc indication. Your own April 29 response admits at least the possibility of other indications. After careful thought and perhaps after this coming ASCO, I invite you to reconsider adopting Travers' "peak" revenue estimates, and perhaps one of us (sic) my dine on crow."

In light of IMCL's ASCO data on Head & Neck, nsclc, and pancreatic cancer, you should be prepared to abandon Mr. Travers "peak" estimates and apologize for your rude treatment. . .

Let's take these points one at a time, skipping (for the moment) the back of the hand. Charley Travers of the Motley Fool did run his numbers based on the colon cancer indication. And in my April 29th post, "Yahoots", I did mention the possibility of other indications.

But take a look at the context in which I mentioned them. Here's the key part:

". . .don't let those shimmering waves of greed blind you to the facts: in their clinical trials, Imclone, BMS, and Merck-Darmstadt carefully picked the tumor types that would be expected to give the most robust response. That's how you get a drug approved, by going to the agencies with the best data you can get. Erbitux has already been tested in the areas where it's likely to gain the most market share and make the most profit."

Head and neck cancer, for example, is one of those carefully picked areas I was referring to. There's a good chance of a therapy targeted against EGFR showing efficacy against that kind of tumor, and it's an underserved patient population (although not an especially large one.) That's why they picked it for the clinical trial. It's not a new indication out of the blue.

So, let's remedy the situation. The numbers I linked to in yesterday's post speak of an SG Cowen estimate of a "$150 million market" for Imclone in head and neck cancer. It's unclear if that's the total market size, or the net to Imclone after they pay their royalties to BMS and Merck-Darmstadt. Let's be generous and say it's the latter. And let's double that figure, just to get in that optimistic frame of mind.

So, adding another $300 million means that it doubles the sales numbers that Travers estimated. The trouble is, by his figures, Imclone stock was already between 50% and 100% overvalued when he wrote his piece, and it's gone up more since then.

I'm prepared to modify my views, then: instead of saying that Imclone is that much overvalued, I'll put on my rose-colored glasses and say that under current conditions, it's valued about where it should be at its peak sales - a few years from now, mind you. Now, Imclone can pick up some sales in the more competitive NSCLC market, and some in pancreatic cancer too (a small market, but a cruelly underserved one.) But long before then, you Imclonites will have pushed the stock price up to take care of that slack, too. Hey, what am I talking about? You'll have the share price up there next week at this rate. Sell!

From a drug-company perspective, you're working on the assumption that everything will go perfectly. There will be no safety problems in any of these new indications, and no manufacturing or regulatory hitches. And you're choosing not to think too much about other new compounds hitting the market over the next few years. Some of them will take some market share, you know. For one thing, they won't cost $10,000 a month.

Now for the last point, that "apology" for "rude behavior". It's not happening. For one thing, my behavior was the expression of an opinion about the stock price of Imclone, and of those people who are willing to pay it. If you've made money on Imclone, that should be all the compensation you could ever want. I've lost money on them, myself, and believing that I'm right is of only limited consolation in such situations.

I have my opinions; you have yours. You don't have to read (or comment on) mine, and I probably wouldn't read yours on a salary. Perhaps you should start an Imclonocentric blog of your own - you'd probably get more traffic than I do, considering the fanatic following the company has.

Comments (3) + TrackBacks (0) | Category: Business and Markets | Cancer

June 6, 2004

As Goes ASCO. . .

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Posted by Derek

The American Society of Clinical Oncology meeting is taking place as you read this. ASCO is a pretty high-pressure venue, because key clinical results for cancer therapies are often unveiled there. The audience has a much higher percentage of journalists and financial analysts than you'll see at most meetings. It's a sandstorm of hype, all right - try this news search for a blast of it.

The Imclonites have already started filling my inbox, since I'd taken a crack at the company's stock valuation a couple of months ago. Imclone's just presented data at this ASCO showing that their antibody extends survival time significantly in patients with head and neck cancer. That's good news for the patients, who could use some, and I'm sure that IMCL shareholders figure it's great news for them, too.

But that market is in the low tens of thousands of patients. Even with sizable market penetration, I still think that Imclone stock is no bargain at 70-odd dollars a share. Mind you, that's what it was on Friday. It'll be worth taking a look during Monday's trading to see what it's been inflated to since this news came out. My advice to IMCL shareholders continues to be: cash in and run laughing to the bank. That's what Carl Icahn is doing, guys.

But feel free to ignore me, of course, and go take the other end of Icahn's trades for him. And don't forget to write and tell me what a knuckle-dragging throwback I am. It's not like I catch any abuse at work - I have to depend on my weblog to generate some, don't you know.

Comments (4) + TrackBacks (0) | Category: Business and Markets | Cancer

June 3, 2004

Doublets, Triplets, Whateverlets

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Posted by Derek

Another day spent rooting around in the archives, trying to appease the rapacious Taiwanese patent office. One more day should about do it, and not a moment too soon. I'm now unearthing NMR spectral data for compounds, and translating those to print is not enjoyable.

For those outside the field, an NMR spectrum of a typical organic molecule is a rather complex linear plot of multiple lines and peaks. After staring at it a while, it gets rendered into text as something like "1.63, t, 3H; 2.34, s, 3H; 3.1 - 3.39, m, 4H. . ." In plain text, that's "At 1.63 and 2.34, there are a triplet signals that represent three protons each, and between 3.1 and 3.39 there's a messy multiplet that adds up to four protons' worth. . ."

If you really want to get into it, you list the coupling constants, the spacings between the individual peaks of those triplets and etc. No thanks. A typical spectrum will go on for a reasonable paragraph in this way, and the Taiwanese would like nothing better than several pages of this sort of thing, or so they maintain. What they'll is get as much as I can stand.

I'll try to lead off next week with a discussion of today's news about everyone's pal, Elliot Spitzer, and his suit against GSK. It's a wide-ranging topic, and there wasn't enough time to wrestle it to the ground today.

Comments (2) + TrackBacks (0) | Category: Analytical Chemistry | Patents and IP

June 2, 2004

This Isn't the Kind of Office Action You're Thinking Of

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Posted by Derek

I've had enough staring at the computer monitor for one day, so this will be short. I've been dealing with an "office action" from Taiwan's patent office. They're reviewing an application on which I'm the lead inventor, so this one lands on my desk. Taiwan isn't a member of the Patent Cooperation Treaty; you have to file a separate application. And they have their own standards, which they lose few chances to demonstrate.

According to their examiner, we need to provide more biological data and more chemical characterization data for the compounds in the patent, which is not particularly enjoyable since these compounds were all made three or four years ago. Everyone in the drug industry is supposed to have data handling systems that make such queries light and breezy, but just try putting them to the test. It's all there, but you have to know which rock it's hiding under. And the numbering of the compounds in the patent is totally different from any of the numbering schemes used in our record keeping, and so on. You know the sort of thing.

The data provided have been perfectly acceptable to the patent offices in Europe and the US so far, but that cuts no ice in Taipei. I'm just glad that the other non-PCT countries don't engage in this sort of thing. Separate office actions, one after the other, from the likes of Peru, Pakistan, Thailand and Venezuela would probably push me over the edge. Like Taiwan, though, they have their own special application paperwork, which is enough of a racket as it is.

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Industry vs. Academia: The Mental Aspect

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Posted by Derek

It's been a while since I returned to this topic. Many differences remain for me to talk about, but I though that it was time to address the biggest one, which is psychological. Some of you probably thought that the biggest difference was money. Can't ignore that one - it probably contributes to some of the effects I'll be talking about. But there's a separate mental component to graduate school that never really recurs, which should be good news to my readers who are working on their degrees.

Some of this is due to age, naturally enough. The research cohort out in industry ranges from fresh-out-of-school to greybeards in their fifties and sixties. (I can say that, since I'm in my early forties, the color changes in my own short beard notwithstanding.) Everyone in graduate school is a transient of one sort of another, usually someone whose life is still just getting going. But in the workplace, most people are more settled in their lives and careers. There are still some unsettling waves that move through industry, mergers and layoffs and reorganizations. But people respond to them differently than they would in their 20s - often better, sometimes worse, but differently.

And not all your co-workers in grad school are actually stable individuals, either. Some of these people wash out of the field for very good reasons, and you don't see as many of the outer fringes later on in your career. It's not that we don't have some odd people in the industrial labs, believe me. But the variance isn't as high as it is in school. Some of those folks are off by so many standard deviations that they fall right off the edge of the table.

Another factor is something I've already spoken about, the way that most graduate careers come down to one make-or-break research project. The only industrial equivalents are in the most grad-school atmospheric edge of the field, small startup companies that have one shot to make it with an important project. But in most companies, no matter how big a project gets, there's always another one coming along. Clinical candidate went down in flames? Terrible news, but you're working on another one by then. There's a flow to the research environment that gives things more stability.

The finish-the-project-or-die environment of graduate study leads to the well-known working hours in many departments. Those will derange you after a while: days, nights, weekends, holidays, Saturday nights and Sunday mornings. I worked 'em all myself when I was trying to finish my PhD, but I don't now. If a project is very interesting or important, I'll stay late, or once in a while work during a weekend. But otherwise, I arrange my work so that I go home at night. For one thing, I have a wife and two small children who'd much rather have me there, but even when I was single I found many more things to do than work grad-school hours. It took me some months after defending my dissertation before I could decompress, but I did. Having a life outside the lab is valuable, but it's a net that graduate students often have to work without.

But beyond all these, there's one great big reason for why grad school feels so strange in retrospect, and I've saved it for last: your research advisor. There's no other time when you're so dependent on one person's opinion of your work. (At least, there had better not be!) If your advisor is competent and even-tempered, your graduate studies are going to be a lot smoother. If you pick one who turns out to have some psychological sinkholes, though, then you're in for a rough ride and there's not much that can be done about it. Everyone has a fund of horror stories and cautionary tales, and there's a reason for that: there are too damn many of these people around.

Naturally, there are bad bosses in the industrial world. But, for the most part, they don't get quite as crazy as the academic ones can (there's that variance at work again). And they generally aren't the only thing running (or ruining) your life, either. There's the much-maligned HR department, which can in fact help bail you out if things get really bad. Moving from group to group is a lot easier at most companies than it can ever be in graduate school, and it's not like you lose time off the big ticking clock when you do it.

I can see in retrospect that I was a lot harder to get along with when I was in grad school. I responded to the pressure by getting more ornery, and I think that many other personalities deformed similarly. When I've met up with my fellow grad students in the years since, we seem to be different people, and with good reason. It isn't just the years.

Comments (1) + TrackBacks (0) | Category: Academia (vs. Industry) | Graduate School