About this Author
College chemistry, 1983
The 2002 Model
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: firstname.lastname@example.org
May 31, 2007
GlaxoSmithKline is breaking out the data to respond to the Nissen and Wolski NEJM paper on the possible cardiovascular risks of Avandia (rosiglitazone). In a letter published by The Lancet (PDF), the company's chief medical officer, Ronald Krall, defends the drug (and the company):
"GlaxoSmithKline did similar meta-analyses in 2005 and 2006 and found hazard ratios in the same direction as Nissen and Wolski. However, all these results are highly dependent on the methods used and the studies included, given the small number of events reported. For example, the actual number of myocardial infarctions in the Nissen and Wolski meta-analysis yields a very low frequency of events (0·6%), and the absolute difference in rates of myocardial infarctions between rosiglitazone and controls is less than 0·1%.
These observations support a view expressed by Nissen and Wolski them-selves: “a meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest.”
He then goes back over the data in the three large trials that bear on the question. Reanalyzed data from the ADOPT study still do not show a statistically meaningful cardiovascular risk for rosiglitazone versus the other two diabetes drugs in the trial (metformin and glibenclamide). (There's no placebo group - this is one of those head-to-head comparisons of a drug versus its strongest competitors, a type of study that some people believe never takes place). The second completed study, DREAM, looked at co-administration of rosiglitazone and the ACE inhibitor ramapril. There were four groups - placebo only, rosi and placebo, ramapril and placebo, and rosi plus ramapril. The first three showed no difference in cardiovascular events, but the last one did, for unknown reasons.
These two studies are in the Nissen/Wolski meta-analysis, of course, but as I noted originally, it was the sum of the smaller studies that gave them their cardiovascular warning. But when the statistically less powerful trials show one thing that isn't borne out by the larger ones, the issue is (at the very least) still in doubt. The letter also points out that the company's database mining of managed-care patients taking rosi has shown no increase in cardiovascular risks.
Other controlled studies are ongoing, the (now highly awaited) RECORD and another one called ACCORD. Both are designed from the start to address cardiovascular outcomes (which are a major complication in diabetic patients). Krall's letter lifts the veil a tiny bit on RECORD, saying that the independent review board has now completed an interim analysis of its cardiovascular data and concluded that the trial should continue. This would not be the case, you'd have to presume, were the numbers to clearly show increased CV deaths in the treatment group.
My take on this is that the company has a pretty strong case so far, certainly strong enough to wait for the ongoing trials to settle the issue. What never fails to disappoint me, though, is the way that stories like this are jammed into ready-made templates. Depending on the editorial writer, the appearance of the NEJM paper became "FDA Corrupt, Broken: Snores While Dangerous Drugs Kill Thousands", or "Giant Drug Company Sells Heart Attack Poison, Doesn't Give Hoot". Or maybe just "Drug Approval System Completely Broken - Again".
Now, Steve Nissen does sound the alarm a lot, but I have no doubt that his intentions are honorable. His paper, to me, was the equivalent of saying "Hey, you people may have a problem here. Did you know that?" GSK's response, then is "Yeah, we've looked at that, too, but we don't see it. Are you sure your numbers are good?" Meanwhile, the studies which should answer the question for good are already years into their runs. If this is our standard for a broken drug approval system, we've certainly become mighty fastidious over the years. For what it's worth, The Lancet agrees.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Press Coverage
May 29, 2007
Here's a question for people working in the industry: when you see your own company's press releases, just how close to reality do you feel they come? Could someone wanting to invest in your company's stock form an accurate picture of your drug pipeline's potential by reading them, or not?
I ask because (in my experience) the answer to that second question is very much in doubt. There are several reasons: First, from what I've seen, many companies have their official pipelines cluttered with compounds that aren't being developed - at least, not in the same way that the really important ones are. (Projects can get sent "into the clinic" for many reasons, not all of them productive). And canceled projects often linger on the list before they're removed, too. A dedicated reader of the company's SEC filings and press releases can work some of these things out, but no one makes it easy.
Then there are the press releases about specific projects, which. . .well, they're press releases, if you know what I mean. The bad news is skulking in a subordinate clause somewhere in the fifth paragraph, while the good news is up on stage, expensive spotlights reflecting off its refined makeup and tasteful clothes. This isn't a particular failing of the drug industry; it's a failing of press releases (or, more likely, of human nature).
This has a bearing on the issue of disclosure of clinical trial information, naturally. I think that we're moving toward some sort of standardized disclosure, and that there's little that can be done (in the long run) to stop it. I think the positives outweigh the negatives, although it's not as easy a match to score as you'd guess. (Lack of knowledge of statistics, to pick one big issue, could make the whole thing a pile of dry wood for fools to make bonfires of). More on this in a future post. . .
+ TrackBacks (0) | Category: Business and Markets | Clinical Trials
May 25, 2007
Insider, author of the Pharmagossip site, sent along this link to an article on Avandia at the Health Care Renewal site, flagged as "essential reading". After looking it over, I don't think I agree, and I thought it might be worthwhile to explain why.
The HCR piece quotes extensively from this New York Times article, headlined "Years Ago, Agency Was Warned of a Drug's Risks". Its focus is a letter that Dr. John Buse of UNC (now president-elect of the American Diabetes Association) sent to the FDA in 2000 on the possible cardiovascular risks of Avandia. Reading HCR's summary is a somewhat different experience than reading the original article, though - for one thing, you miss out on the part about how even now Dr. Buse isn't calling for Avandia to be be taken off the market. Rather than finding the Nissen New England Journal of Medicine paper to be the smoking gun he's been waiting for, he advocates waiting for the GSK cardiovascular risk study to be completed before making any decisions.
The HCR article has some good points in it, but to my ear they're phrased oddly. For example, it advocates a skeptical attitude toward the marketing claims made by drug companies, which is very good advice. But that's very good advice for evaluating the marketing claims of companies in every other industry, too. They're trying to sell you something. They will present their product in the most favorable light possible, whether that product is a car, a diabetes drug, or a burrito.
And that's the part that drives some people crazy, because it seems wrong to have potential life-saving drugs handled the same way as pickup trucks and enchiladas. They're not, though: the reason we can argue about drug company marketing is that drugs already have something that almost no other product has, which is a body of statistically valid comparison data. No data exist as to the long-term advantages and disadvantages of consuming a given brand of burrito versus its competition or versus an alternative meal. Cars are somewhat more data-rich, thanks to government and insurance company testing, and frequency-of-repair databases like those kept by Consumer Reports. But that's about the highest standard for comparison data outside of the drug industry, and you'll look in vain for P values and other tests of statistical significance, because there aren't any. In short, marketing claims in virtually every other industry can go relatively unchallenged, because there's little to measure them against.
So, that's why one of the things that I dislike about the Health Care Renewal piece is the hand-rubbing now-we've-got-'em tone that I detect in it. You don't have to go far to find it from plenty of other sources, either, which is why people like me are perhaps too touchy on the subject.
+ TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Press Coverage | Why Everyone Loves Us
May 24, 2007
Steve Nissen has (once again) made waves with an analysis of cardiovascular risk. This time the subject is Avandia (rosiglitazone), a therapy for diabetes that's the oldest PPAR-gamma drug on the market. A meta-analysis of 42 reported clinical trials of the drug led to the conclusion that rosiglitazone is associated with a statistically significant risk of cardiac events.
The similarities to the Vioxx situation are what have made headlines (and what sent GlaxoSmithKline's stock down about 8% on the day the paper was released). But there are some important differences. Merck's ran into the Vioxx numbers in their own clinical data - the arguing has been whether they recognized the effects earlier (or should have), but it was a specific trial of theirs that led to the statistics that sank the drug. A meta-analysis is a much different beast, since you're trying to fit a large number of different trials, run in different ways for different reasons, into the same framework. Not everyone trusts them, even when the analysis is performed by someone as competent as Nissen, who does mention the limitations of the approach in the paper:
"Our study has important limitations. We pooled the results of a group of trials that were not originally intended to explore cardiovascular outcomes. Most trials did not centrally adjudicate cardiovascular outcomes, and the definitions of myocardial infarction were not available. Many of these trials were small and short-term, resulting in few adverse cardiovascular events or deaths. Accordingly, the confidence intervals for the odds ratios for myocardial infarction and death from cardiovascular causes are wide, resulting in considerable uncertainty about the magnitude of the observed hazard. Furthermore, we did not have access to original source data for any of these trials. Thus, we based the analysis on available data from publicly disclosed summaries of events. The lack of availability of source data did not allow the use of more statistically powerful time-to-event analysis. A meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest."
And that's what's happening here. A number of people at large diabetes treatment centers aren't ready to buy into a cardiovascular risk for Avandia yet, because they're wary of the statistics. There's a large cardiovascular outcome trial of the drug going on now, which won't wrap up until 2009, but several people seem to want to wait for that as a more definitive answer.
If Nissen's data hold up - and statistically, I'm definitely not up to the task of evaluating his approach - then we might be looking at a Vioxx-like risk level. Out of some 14,000 patients on the drug in the various studies, there were 86 heart attacks in the treatment groups, and 72 in the controls. That comes out to be statistically significant, but (as you can see) the problem is that Type II diabetics have a high background rate of CV problems. Looking at Nissen's Table IV, it also seems clear that most of the significance he's found comes from the pooling of the smaller studies. The larger trials are nowhere near as clear-cut, which makes you wonder if this effect is real or an artifact.
I'm certainly not prepared to say one way or another, and I just hope that the ongoing trial settles the question. It's certainly not unreasonable to imagine a PPAR gamma drug having this side effect, but if this were a strong mechanism-based phenomenon the numbers would surely be stronger. If a risk is confirmed, though, we'll then be faced with a risk-benefit question. Does the glycemic control that Avandia provides lead to enough good outcomes to offset any cardiovascular risk over a large population? If you think getting the current numbers is a tough job, wait until you try to work that one out.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Toxicology
May 23, 2007
It might not always be obvious from the blog, but I've been rather literature-deprived lately. I'm not talking literature-literature, naturally - my favorites are all over here on the shelf to my left (For anyone who's interested, those would include Nabokov's wonderful Pale Fire, Brad Leithauser's underappreciated Hence, Martin Amis's best, which is Money, his father Kingsley's immortal Lucky Jim, Chesterton's The Man Who Was Thursday, and Evelyn Waugh's Decline and Fall). No, what I'm beginning to starve a bit for is full-text scientific literature, which is understandable, given that (a) I've been unemployed since the beginning of February, and (b) full-text subscriptions to all the major journals would cost me cash that I'd rather hose away on frivolities like my mortgage.
I do have some recourse to the local universities, where I've gone, uh, periodically to catch up on things. The same processes I saw at work in the Wonder Drug Factory's library are at work in these, too, of course: dwindling shelf space for paper journals and increasing numbers of flat screen displays in their place. It's a bit of a shame for a person like me, who grew up in the era of dead tree journals, because I still like to pick them up in my hands (and because the experience of reading them online still isn't as pleasant as it no doubt will be eventually).
What I've noticed is that the most widely read ones remain in paper as well as digital subscriptions. It's becoming a clear sign of respect for a journal's influence. That means Science, Nature and the like are always still to be had physically. Chemistry libraries always seem to have JACS, Angewandte Chemie and, interestingly, Organic Letters in hard copy, which is probably a good sign for the latter.
So I've been making due with the open-access journals, few of which have strong chemistry ties as yet, and with abstracts and individual free-access articles from the others. Which reminds me - does the ACS ever make anything from its journals open access? Fly-by-night rags like the NEJM or PNAS will open up the most-discussed papers in each of their issues to give them wider exposure, but I've never heard of that happening with, say, JACS. Maybe they figure that the most-discussed articles there are going to be read largely by people that they can get to pay for them, anyway, so why bother?
+ TrackBacks (0) | Category: The Scientific Literature
May 22, 2007
As the cost of sequencing goes down, a lot of once-crazy experiments become feasible. There's a good case in point this week in the preprint section of PNAS. A team of researchers looked at a single patient undergoing treatment with vancomycin for a serious infection. (Just saying "vancomycin" makes the "serious infection" part redundant, since it's often the last resort). They periodically isolated Staphylococcus aureus bacteria from the patient's blood during the course of the treatment to look at how resistance to the antibiotic developed.
Fine, fine - except the way they watched the process was to sequence the whole genome of each bacterial isolate. What they found were a total of 35 mutations, which developed sequentially as the treatment continued (and the levels of resistance rose). Here's natural selection, operating in real time, under the strongest magnifying glass available. And it's in the service of a potentially serious problem, since resistant bacteria are no joke. (Reading between the lines of the PNAS abstract, for example, it appears that the patient involved in this study may well not have survived).
The technology involved here is worth thinking about. Even now, this was a rather costly experiment as these things go, and it's worth a paper in a good journal. But a few years ago, needless to say, it would have been a borderline-insane idea, and a few years before that it would have been flatly impossible. A few years from now it'll be routine, and a few years after that it probably won't be done at all, having been superseded by something more elegant that no one's come up with yet. But for now, we're entering the age where wildly sequence-intensive experiments, many of which no one even bothered to think about before, will start to run.
+ TrackBacks (0) | Category: Infectious Diseases
May 20, 2007
I became entangled in a discussion - well, OK, argument - in another blog's comment section a few years ago, and the person I was having it out with said something that stopped my fingers cold right on the keyboard. I'm not sure any more how this came up - probably something Platonist about whether physical laws were discovered, or invented - but the comment was made that well, of course these things had to be invented, because "there's only people, and what they do".
I felt as if I had encountered alien life. It would be hard to find a statement further away from what I believe, and I'm pretty sure that being a scientist has something to do with that. I mentioned in that Nature blog interview that when I was a boy I used to spend a lot of time with the microscope and telescope: well, through both of those instruments you can observe a lot of things that have nothing to do with humans at all. It's a useful perspective, and how my sparring partner could have missed experiencing it, I just can't imagine.
I mention this because I've had both instruments out recently. The past few days I've been showing a lot of microscopic life forms to my kids (and using the same microscope I used 35 years ago to do it - it's an old, rock-solid Bausch & Lomb). The rotifers and Vorticella look exactly the way they did when I was ten years old; they've been at it all this time with no help from me. (And does that stream across the road have a lot of Synura in it, or what?)
And at night, I've been taking advantage of some clear skies and lack of moonlight over the last week or ten days, hunting through the shoals of spring galaxies in Virgo and Coma Berenices. They look the same way they did when I was ten, too; nothing less likely to be disturbed by human activity comes to my mind just now.
All this is one of the things I like about science. So much of what we see and study is indifferent to human concerns. In the chemistry lab, I can (and will) do what I can to get a reaction to work, but in the end, the molecules are going to do what they do and they're not going to consult me. That goes at least double for later in the game when compounds are tried out in mice and rats. The moving finger (moving paw?) writes at that point, and there's nothing you can do about it if the experiment was the correct one, done correctly.
All this takes you down a peg, which isn't a bad thing. People get rather inflated views of themselves, their ideas, and the importance of both. M100 and the rotifers don't care. (And to show this whole post can be served up in light verse, let me recommend "Canopus"!)
+ TrackBacks (0) | Category: Who Discovers and Why
May 18, 2007
Over at Nature's Sceptical Chymist blog they have a Friday interview feature, and this week you can see them interrogate me. (The blog's name is lifted from Robert Boyle, one that I liked so much that I also wrote it on the front of one of my undergraduate lab notebooks.) Note: I had this post up for a couple of hours attributing the title to Robert Hooke instead. It was early in the morning, really.)
+ TrackBacks (0) | Category: Blog Housekeeping
May 17, 2007
(My apologies for no update today - it's been hectic around here, for reasons that I hope to be able to reveal soon).
Some of the first work I did in the industry was on Alzheimer's disease. It's hard stuff to deal with, and it was even hard seventeen years ago, I can tell you. You may have noticed that there isn't much that anyone can do about AD, even now, and there's most definitely a reason for that: it's a hard disease in a hard field.
One of the most promising areas (for an unnervingly long time) has been the inhibition of the formation of beta-amyloid, long thought (though not by everyone) to be a primary cause of Alzheimer's pathology. (There's no doubt that AD patients show abundant deposits of beta-amyloid plaques in their brain tissue - the argument has been about whether amyloid gives you Alzheimer's, or if Alzheimer's gives you amyloid). The protein is clipped off a larger precursor protein (APP, which is an acronym for just what you think), and back when I started in the field, the major race was on to find out which proteases did the clipping.
That's been worked out in the intervening years. One of them, the beta-secretase enzyme BACE1, has been a target of a lot of work for quite a while now. Getting good, selective, non-peptidic inhibitors hasn't been easy, though, but here's some from Merck, and there have been other reports. Will one of these be the Alzheimer's drug that everyone's been waiting for?
Well. . .maybe not. A recent PNAS paper from a large academic/industrial collaboration has raised a disturbing possibility. They found that mice that produced extra APP (but did not show beta-amyloid pathology) had improved spatial memory. Disrupting their beta-secretase was downright harmful to their performance, as well, suggesting that some of the beta-secretase cleavage products might actually be beneficial. It would be just like the natural world to have beta-amyloid turn out to be memory-enhancing in smaller quantities, but no one's sure if it's the player here - it could also be the intracellular hunk of APP that's also liberated by the secretase.
The authors finish the paper with an unmissable warning:
"A practical implication of this work involves safety considerations for experimental therapies of AD. To ensure that experimental therapies do not prevent BACE1-mediated facilitation of memory by APP, preclinical studies of experimental beta-secretase inhibitors should be done not only in animal models of AD, but also in natural animals to evaluate their effects on normal cognitive function."
One wonders what GlaxoSmithKline has made of this, in light of their recent paper on in vivo dosing of a BACE1 inhibitor. And there may be others. . .
+ TrackBacks (0) | Category: Alzheimer's Disease
May 16, 2007
A comment on the most recent post got me thinking about photochemistry. I've done that, but just for one project, and I'll bet that many other chemists have had the same pattern.
A lot of people who've never done light-powered chemistry find the idea neat - no nasty reagents, no masses of inorganic salts to remove, just shine a light on the flask and you're done. It seems like Chemistry Of The Future - you feel as if you should be wearing some sort of white jumpsuit with padded shoulders if you ever get around to setting some up.
The idea is appealing, but the reality is less so. Photochemistry often isn't as clean as you picture it being - a look at your clear starting solution gradually turning orange and brown under the punishing glare of the UV lamp tips you off about that. Things get hot in those setups, too, which also doesn't fit the sleek, cool, futuristic template. When you take a hot flask of darkened gunk off the lamp, it's hard not to wonder what would have happened if you'd just cooked it in the oil bath the old-fashioned way.
Probably not what happened under illumination, though. Light does do some odd stuff, and there are some neat-looking reactions that can be run that way. The problem is, many of those neat reactions are free-radical mechanisms, and that's what leads to a lot of that colorful crud. There are a lot of concerted mechanisms that can be driven photochemically, and those should (in theory) be cleaner, but in my experience, it can be hard to keep a lot of radical chemistry from going on, and it can swamp the cleaner stuff right out.
Radical reactions were all the trend back when I was in grad school (get off my lawn!), but while they've never disappeared, they've never caught on to become an essential part of every organic chemist's toolkit. There are several well-used reactions that run (or can run) by single-electron processes, but as a class, free radicals still have an exotic, slightly disreputable look to them. People will look at a potential transformation on the board, and say "Hmm, I bet I could do that by a dipolar cycloaddition", or "I'll bet that I'll able to do an olefin metathesis to get that". There are dozens of reaction classes that you reach for without thinking twice: metal-catalyzed coupling, epoxide opening, reductive amination, electrophilic ring substitution. But do you reach for a free-radical closure to a five-membered ring, a well-trodden radical process if ever there was one? Well, I don't, anyway - and I've done the things. Do you?
+ TrackBacks (0) | Category: Life in the Drug Labs
May 15, 2007
I had an e-mail the other day from a reader who pointed out that when anyone tells you something is simple or obvious in indole chemistry, that you should run for cover. He expressed similar worries about amino acids, and I take his point. There are some areas of organic chemistry that have huge encrustations of literature all over them, which can be a warning sign.
One way you get a literature jungle is for few general methods to work. That's always been my impression of indole chemistry - each reaction has its limited area of jurisdiction, but if you start messing around you find yourself in the lawless borderlands pretty quickly. I did my PhD work using carbohydrates for natural product synthesis, and I have to say that they've got the same problem. All kinds of interesting, funky things start happening when you do something so (apparently) innocent as using a galactose scaffold instead of glucose.
Of course, there's another way to pile up a lot of different reactions, which is for most all of them to work, more or less. I think that's been the situation for many years in the palladium-catalyzed reaction field. As I've said before, I believe that just about any Pd coupling can be made to work, if you're willing to devote enough of your life to tweaking the conditions. Can you imagine a comprehensive review of some of these reactions? You'd need a special nine-volume run of Organic Reactions to even have a hope, and where would you find the maniacs to write it all?
Readers are invited to submit other examples of literature swamps - another one I can think of, from the old days, are all those steroid transformations. But I know that there are others lurking out there. . .
+ TrackBacks (0) | Category: The Scientific Literature
May 14, 2007
Perverse incentives can work in any direction you choose. I was talking here the other week about lab safety, and how it's a good thing to know where the fire extinguishers are. But what if you're working in a place where discharging one of those extinguishers sets off an avalanche of paperwork and committee meetings? Do you use the thing, or does the vision of all that wasted time give you pause, while the flames leap around your glassware?
If it's a seriously nasty fire, you're probably going to pull the pin and worry about the consequences later (and for a fire like that, it's good to remember that going for that second extinguisher is usually a bad idea, compared to, say, diving for the stairs). But what if it's just medium bad, and if you're not sure if it's going to get worse? Other things being equal, you should probably do the most effective thing you can to put it out. But other things aren't always equal in industry.
I've worked where the safety culture was limited to occasional warnings not to blow yourself up, and I've worked under intrusive, no-sparrow-shall-fall regimes. Neither of those, as far as I could see, kept me safer than the other. The problem is, if you're going to aggressively document every possible incident and near miss, to be entered into the massive database and discussed in detail at the mandatory regular safety meetings (attendance taken and computed into the year-end bonus formula). . .well, people are going to sit on most of the ones that they think that they can get away with. The harder you work to log every lapse, the more of them you'll miss.
Once people have reached a certain level of competence and experience, lab safety is largely a matter of thinking about what you're doing, realizing what you know and what you don't know, and planning ahead. These are all highly desirable qualities, both in and out of the lab, and they cannot be expressed by decree. No safety committee is going to make people smarter, and no multi-page web form will make them more alert. In this world, actually, the opposite is much more likely. . .
+ TrackBacks (0) | Category: Life in the Drug Labs
May 10, 2007
If you'd like some more proof that investing in pharma and biotech stocks on the basis of pending FDA rulings is a strategy best suited for clowns, take a look at Dendreon. Remember them? Everyone's shoulda-bought-that stock from a few weeks ago, prostate cancer vaccine, unexpectedly favorable FDA panel ruling?
Well, now they've been handed the dread "approvable" letter by the agency, asking for more efficacy data. The stock. . .ah, the stock didn't take it well. If you look at the chart over the last couple of months, you find that on March 28, DNDN was at 5.22. On April 4, it broke 15, and on the 9th it closed at about 23 1/2. Champagne, waiter! It hovered between 15 and 20 after that, and as of last Tuesday was at a nice solid 17.74. Thursday's close, though, was 5.54, completing a spectacular hair-bleaching round trip in just over a month.
Not quite a round trip, actually. . .if you'd bought at the March 28th close, and held on through the whole power wash and spin cycle, after the onlookers pried your fingers out of the wallboard you'd have found yourself with what is still a very respectable return. No, I mean it - 5.54 versus 5.22 is just over 6 per cent, and six per cent per month would make you very, very rich were you able somehow to lock it in. It sure doesn't seem that way when you've just experienced four or five hundred per cent in a month, but it's true.
At any rate, my condolences to those who bought the stock in the double digits. You really had no business doing that, but I'm sorry for you, anyway. The problem is, most of the near-term gains (in case of an approval) were probably in the stock already, while the risk of what just happened was always there. It's worth repeating: betting on FDA rulings is rubber-nose, midget-car, rainbow-wig clown territory. No matter how tempting it looks. . .
+ TrackBacks (0) | Category: Business and Markets
May 9, 2007
You'd think that I'd have more to say on the new bill giving the FDA a broader drug safety mandate. It's certainly all over the news as I write. But this seems (to me, anyway) to be a change in degree more than anything else. Congress is asking the agency to do what it does - monitor drug safety, change label wordings if necessary, etc. - but to do more of it. I don't have a problem with that, because this sort of thing will be all the execution, and we don't know how that's going to go yet.
And the other reason I'm not as revved-up as I could be about this is that I know that the raw material for everything the FDA does isn't changing a bit. By that I mean all the drugs that get sent in for approval, as well as the ones already on the market. Altering the way that data is collected isn't going to change the underlying data. I don't see how the pharmacopeia is going to be much safer (or much more dangerous) compared to how it is today. Perhaps some safety decisions will be made more quickly, but it's also possible that a flood of new information might obscure some things in the noise.
We know just as much about toxicology as we did yesterday - a lot, from one perspective, but not nearly enough, from another. People who believe that this regulatory change are more likely to believe that we know a lot about side effects and toxicity, and that if we just pay more attention we'll improve the situation greatly. But this isn't a view that I can endorse. As far as I can see, regulatory oversight isn't the limiting reagent here. It's knowledge, and that comes on slowly and in defiance of every lawmaker that ever was.
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May 7, 2007
A comment in the last post pointed me to an op-ed in today's New York Times by Suketu Mehta. It's on India and intellectual property, specifically the idea of patenting yoga techniques. Mehta finds this both laughable and troubling, while noting that most of the applicants are overseas Indians themselves. I'm no yoga expert (maybe Michael Blowhard can, uh, enlighten us on the issue), but as it goes on, Mehta's piece gets off some remarkably cloth-headed observations on drug patents:
"Western pharmaceutical companies make billions on drugs that are often first discovered in developing countries — but herbal remedies like bitter gourd or turmeric, which are known to be effective against everything from diabetes to piles, earn nothing for the country whose sages first isolated their virtues. The Indian government estimates that worldwide, 2000 patents are issued a year based on traditional Indian medicines.
Drugs and hatha yoga have the same aim: to help us lead healthier lives. India has given the world yoga for free. No wonder so many in the country feel that the world should return the favor by making lifesaving drugs available at reduced prices, or at least letting Indian companies make cheap generics. If padmasana — a k a the lotus position — belongs to all mankind, so should the formula for Gleevec. . ."
There's more where that came from, and if you wish you can drink from this fount of wisdom yourself. Rinse thoroughly. OK, where to start? The whole piece is a panoramic view of the fallacy that chewing a leaf (or finding out what leaves the natives chew) is equivalent to discovering a drug. That skips over some rather intricate and expensive steps - isolating the active fractions of the original medicine, determining what compounds are in there and what their structures are, figuring out what they do and how they do it, improving them to make them less toxic and more efficacious, and figuring out how to dose them. Then there's the little matter of scores of millions of dollars to be spent on clinical trials.
Perhaps I could start by asking for a list of those patents - granted patents, mind you, not applications - that apparently issued in complete ignorance of all that well-established prior art? Sure, I'm game. Anyone who has the 2006 list of the two thousand patents ripping off traditional Indian medicine, send it along. If no one has last year's roundup yet, I'll take the list from 2005 - another two thousand! How many are there in reality, do you think? How many of them come from real drug companies?
If not that, I'd be glad to hear about those drugs that were "often" first discovered in developing countries. How often is that, exactly? While there are examples, I'm rather hard pressed to come up with many recent ones. Despite what you might think from the editorial, Gleevec is not one of them, unless Switzerland is your idea of a developing country. Besides, we're skipping all those steps again if we decide that Madagascar gets all the credit for, say, vincristine. As for bitter gourd and turmeric, even if those ancient sages had filed for proto-patents of some sort, wouldn't their terms have, y'know, expired by now? Patents aren't forever, although you wouldn't know this from reading this stuff.
That brings us up to that "yoga is free, and Gleevec should be, too" argument. Again, I hardly know which handle to grasp. There's always the very basic argument, which I will advance in a small, weary voice, that if Gleevec and other medications were given away for free that it might be difficult to persuade people to spend hundreds of millions of dollars developing them.
But enough logic! Let's Mehta up some similar arguments and see how they fly: because the idea of pasta was given to the world for free, no Italian restaurant should be able to charge money for it. Not bad. . .how about, because my daughter gives me a drawing for free to put on my wall, no one should ever charge anything to see a painting? Here we go - what about those darn Sumerians and their writing? How can the publishing industry show its face, when cuneiform was released straight into the public domain? Oh, I like this, it's a lot easier than science - which I think is the point, right there. . .
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Back in 2005, the government of Brazil threatened to break the patent on Abbott's HIV medication Kaletra if the price didn't come down (see here and here). But after a lot of arm-wrestling, a deal was reached. Now it's Merck's turn, with their efavirenz, and this time things went all the way: on Friday, Brazil's president issued a compulsory license to produce the drug outside Merck's patent.
My problem with this, other than the obvious problem I have with expropriation of someone else's property, is that Brazil is trying to have things both ways. The government spends much of its time talking about how the country is an emerging power, with the 12th-largest economy in the world, huge natural resources, its own successful aircraft industry and space program, and so on. But when it comes time to pay for HIV medications, which are important both medically and politically, suddenly they're a poor third-world country being exploited by the evil multinational drugmakers. A look back at the second blog link above, with its quotes from Brazil's Minister of Health on how nationalizing drug patents would help the country's industry, shows that this issue probably has more to do with the first worldview than the second one.
During the Kaletra dispute, I asked a question:
I've known some pretty good Brazilian scientists, but the country isn't up to being able to discover and develop its own new ones. (Very few countries are; you can count them on your fingers.) So I've saved my usual justification for last: if Brazil decides to grab an HIV medication that other people discovered, tested, and won approval for, who's going to make the next one for them?
And now Merck is basically asking Brazil the same thing:
"Research and development-based pharmaceutical companies like Merck simply cannot sustain a situation in which the developed countries alone are expected to bear the cost for essential drugs in both least-developed countries and emerging markets. As such, we believe it is essential to price our medicines according to a country's level of development and HIV burden, thereby ensuring equitable access as well as our ability to invest in future innovative medicines. As the world's 12th largest economy, Brazil has a greater capacity to pay for HIV medicines than countries that are poorer or harder hit by the disease.
This decision by the Government of Brazil will have a negative impact on Brazil's reputation as an industrialized country seeking to attract inward investment, and thus its ability to build world-class research and development."
It should have, anyway. Look, intellectual property law is not pretty, and doesn't give anyone a warm feeling. It's not meant to. But the alternative Jolly-Roger world is even worse, and anything that takes us toward that is a bad move.
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May 3, 2007
If you work in an organic chemistry lab, odds are excellent that eventually you're going to have to handle some sort of emergency. There are so many energetic materials used, and so many flammable substances around to go up with them, that sooner or later every working chemist has (or is close to) a fire or explosion.
I don't want to sound too alarmist, because most of these are small affairs that go out quickly. Some of them, though, are small affairs that should go out quickly, but get transformed by bad decisions into large, exciting ones. And once in a while you get one that starts off large and just keeps building, and good luck to all concerned. Here's the question, though: how do you behave?
There's no way to know a priori, and there's no way to know about your labmates, either. You can place some bets: a person who's normally level-headed has a better chance of remaining true to type in a sudden emergency (as does a person who's usually jumpy, for that matter), but there are no guarantees. You have to wait until a situation develops to find out. Some folks are going to surprise you, in either a positive or negative way.
The biggest problem many people have is that they freeze up, unable to think of the best course of action. In my experience, doing nothing in a lab crisis is a much likelier problem than doing something immediate, forceful, and wrong. (Immediate action is usually a sign that the person involved has thought about their options in advance). It always pays, when setting up some chemistry that might turn lively, to picture yourself bolting for the nearest fire extinguisher. That'll at least fix its location in your mind, not to mention concentrating your attention a bit on what you're doing. If a fire extinguisher isn't the answer to your potential problem (which it is, in many cases), then by all means imagine doing whatever else you'll need to do if things go wild - heaving in buckets of sand or handfuls of ice, shutting off valves, what have you.
The problem with freezing up (or with its equivalent, running around in circles), is that not only are you not doing anything about the problem at hand, you're probably interfering with the efforts of anyone who is. You'd be surprised at how many times you have to push someone aside to get a clear shot with an extinguisher, for instance. Doing something is the first choice, but getting out of the way for someone else to do something is not to be disparaged.
In some twenty-five years in academic and industrial labs, I've probably been in the vicinity for about six incidents which were serious trouble, either real or potential, and several others that could have turned that way, but didn't. It's been a while since the last one, though, and that's how I like it. But once I get back into the lab, you can be sure that I'll be checking to see where the fire extinguisher is, because you never know.
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May 2, 2007
The Supreme Court doesn't take too many patent cases, but when they rule on one, it's news. This week they handed down a decision in KSR v. Teleflex, and most pharma/biotech readers can be forgiven if their immediate reaction is "Who they?"
But you'll hear about them, all right. This case turned on the definition of obviousness, which is Section 103(a) for lovers of patent law. The standard, ever since the Graham decision many years ago, has been that a patent claim can't be rejected on obviousness grounds unless there's some "TSM" (teaching, suggestion, or motivation) in the prior art, something that would have lead a person of ordinary skill in the art to take that step. (Update - not quite. I've conflated the original Graham stuff with later decisions - see below). That's the sort of thinking behind this earlier post, for example, and it's the way we've all thought about drug patents.
You see where this is headed. The Supreme Court has (by a 9-0 vote) redefined this criterion. (Interested fanatics can get the full decision here). Here's a key section that gets across the spirit of the thing:
". . .Helpful insights, however, need not become rigid and mandatory formulas. If it is so applied, the TSM test is incompatible with this Court’s precedents. The diversity of inventive pursuits and of modern technology counsels against confining the obviousness analysis by a formalistic conception of the words teaching, suggestion, and motivation, or by overemphasizing the importance of published articles and the explicit content of issued patents. In many fields there may be little discussion of obvious techniques or combinations, and market demand, rather than scientific literature, may often drive design trends. Granting patent protection to advances that would occur in the ordinary course without real innovation retards progress and may, for patents combining previously known elements, deprive prior inventions of their value or utility."
In other words, the Graham tests are history. (Update - not so fast! TSM was a construct of the CAFC, the Court of Appeals for the Federal Circuit, in an attempt to come up with an mechanism to apply the Graham decision). What replaces them? There's language in the ruling about "predictable" combinations of the prior art as opposed to "real innovation", but in the end, this is going to have to be thrashed out by years of lawsuits. If this had been a legislative act instead of a judicial ruling, it would be called the "Intellectual Property Lawyer's Perpetual Employment Act of 2007". Here's a post on the ruling from PatentBaristas (who also have an excellent roundup of other takes here).
What will this mean for pharma? Eventually (and this will take a while), it looks to me like it's going to be harder to do the sort of patent-extending moves with formulations, enantiomers, and such that we've seen so much of. Some of these are surely going to end up on the wrong side of the new obviousness line, when it gets drawn. That's going to be the biggest effect, I'd say, and overall, I'm not going to be sorry to see some of that stuff go.
I know that this ruling is going to be seen as a blow to the drug companies, and financially, that's what it's going to be. But in the long run, I think we're better off without incentives to dink and tweak existing drugs to extend their patent lives. It's profitable, and given our success rate in the clinic, we could use the money. But without the temptation to do this kind of thing, which is basically a moral hazard, we'll be forced to work on more substantial things. If some of these modifications really are an advance, then presumably they'll fall on the protected side of the patentability line, so we won't miss out on the really good stuff. The now-with-the-great-taste-of-fish innovations, though, I think we're better off without. It's not going to be easy to give them up, but hey, it's not an easy industry.
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