The Futile Cycle

Via Pharmalot, apparently Pfizer is going to court to try to force the NEJM to release its confidential reviews of articles on Celebrex and Bextra, two of Pfizer’s products that have been targeted for lawsuits on their side effects.

Now, I’m not saying either way whether Pfizer is guilty of misinformation and such on Celebrex and Bextra, but this subpoena is just wrong. The scientific peer-review process has traditionally depended on confidentially to ensure candid and honest statements about the quality of research without fear of repercussions or retribution. It’s not perfect, but it’s sure a hell of a lot better than going without a peer-review system, and trying to break the confidential review system is like trying to force journalists to open up their sources. It stops the flow of good journalism, and it stops the flow of proper science.

Pfizer isn’t doing itself or the rest of the drug industry any favors, either. For whatever reason, people hate drug companies even more than they hate other companies (except maybe Big Tobacco), perhaps because they think that drug companies are evil machines sucking money out of sick and desperate people. That’s not true, and there are many noble people, including doctors and scientists, working hard out there in the drug industry to find the latest drugs to help people, but these kinds of antics from the top are just awful. I don’t envy the researchers at Pfizer, as they don’t deserve society’s scorn for all of this.

Derek Lowe has an excellent blog post on the scam of touting “natural” remedies as somehow better than “artificial” ones. Shame on the New York Times for not doing its groundwork; then again, what do you expect of the mainstream media, facts?

I am now moved in to my new room in graduate school. Classes have yet to start, but the weather is nice, the rooms are spacious, and the campus is very beautiful. It’s a bit weird to settle into a new campus this fall instead of returning to the old undergraduate campus, but I’m very excited about what’s to come. I’m also nervous that I’ve gotten soft during the summer, so I’m currently reviewing a bit of genetics, but in the meantime, I stumbled upon this interesting article on treating HIV by raising its mutation rate.

This is an interesting idea, since one would normally think that raising mutation rates on an organism would just increase the opportunities for it to become more virulent, more resistant, etc. But HIV is a pretty high-mutation rate virus already (any specific one letter mutation will arise more than 20,000 times per day); by the estimate of Martin Nowak, it’s mutation rate is currently the highest possible rate that allows for efficient adaptation and natural selection, in that if the mutation rate were lower, the virus would not adapt as quickly to adverse conditions (e.g. drugs), and if the mutation rate were higher, the virus would mutate so much that it would find it difficult to maintain any beneficial mutations. It’s at the cusp, the so-called “error threshold” (which is roughly the reciprocal of the genome length). So, by raising the mutation rate of HIV even higher, one could tip HIV over the error threshold and make the HIV quasi-species unstable enough to hamper its spread.

I only wonder, however, what kind of cancerous havoc it might raise in the human body. The drug doesn’t look flat enough to incorporate into anything but the most error-prone of DNA polymerases (e.g. HIV reverse transcriptase), but still, clinical study might show high rates of skin cancer and congenital defects for fetuses. The lack of a double bond on the major groove side of the nucleoside should prevent too many cycloadducts from forming with UV light, but then again, I’m no expert in heterocycle photochemistry, seeing as almost all the heterocycle-forming reactions I’ve ever tried to do ended with awful black tar on the bottom of my tiny flask.

Clifford J. Rosen has written a perspective in the New England Journal of Medicine summarizing his views on the FDA Advisory meeting on rosiglitazone (a.k.a. Avandia), which he was chair of.

I agree with his main conclusion, that rosiglitazone is probably not as good as some alternatives, but I have to say, his article’s stance on observational studies and meta-analyses was rather poorly presented. The main data he cites for showing that pioglitazone is better than rosiglitazone for cardiovascular risk is Gerrits et al., basically an observational meta-analysis. On the other hand, he essentially seems to dismiss the observaitional studies by Wellpoint, a health care insurer, which was much larger. I’m giving him the benefit of the doubt that he’s being self-consistent, but the way the article is written wrongly portrays his references. Consider that he says,

Moreover, we are facing a troubling paradox: preliminary data that were presented at the meeting and published by Gerrits et al. suggest that among the thiazolidinediones — a class of drugs that has been shown to improve metabolic control — rosiglitazone may increase cardiovascular risk whereas pioglitazone may reduce it.

Later on, when he mentions the Wellpoint study, he concludes,

The contrasts among the levels of evidence and the results regarding the safety of rosiglitazone raised new questions about relative and absolute risks but also highlighted the weaknesses of observational studies examining events that are common and whose rates are likely to be increased only slightly by a given drug, even in a large cohort (such as that used by WellPoint, which comprised 160,000 patient records).

Note that he never mentions that the Gerrits study is essentially an observational study, too, comprised of data pulled from a large health care insurer. So, the way he wrote the article casts a falsely bad impression on the studies showing little increase in cardiovascular risk for rosiglitazone compared to the alternatives, while not casting the same sort of critical eye at the studies that seem to support his conclusions.

A better (and I find, more convincing) argument would have been that pioglitazone has been demonstrated, in a clinical trial, to have fewer cardiovascular events than placebo, whereas rosiglitazone has not been shown conclusively to have less or more. So, if faced with a choice, it’s easy to recommend pioglitazone over rosiglitazone.

That argument would be much clearer than what he did, which was to simply cite a whole slough of meta-analyses and observational studies (the only non-meta-analysis data he cites at all are two clinical trials, both basically mum on cardiovascular risk), cast doubt on some of them, and then leave the reader to weigh one against the other while making the (unwarrented) conclusion that “a new ‘wonder drug,’ approved prematurely and for the wrong reasons by a weakened and underfunded government agency subjected to pressure from industry, had caused undue harm to patients.” Weighing meta-analyses that conflict with each other is for Ph.D. level statisticians, and I (nor, do I think, most of the readers of the NEJM) am not up to it. I’m still not terribly convinced that rosiglitazone has absolutely hurt patients; I think it’s premature to say so (otherwise, why not pull it from the market?), but certainly there are much more effective alternatives. Clifford Rosen just didn’t make a good case for it.

In the latest entry into the whole Avandia (a.k.a. rosiglitazone) deal, yet another meta-analysis published in the Annals of Internal Medicine shows no statistically significant increase in cardiovascular risk from Avandia, further giving weight to the quote from Ernest Rutherford, “if your experiment needs statistics, you ought to have done a better experiment.” Or weight to any number of other quotes, including Mark Twain’s, “there are three kinds of lies: lies, damned lies, and statistics.”

So, in conclusion, drugs have side effects, sometimes which are risky. (oooh.) Maybe Avandia has some, too, but no one knows. All Steve Nissen’s study shows is that we should conduct a clinical trial specifically to address this issue before making any more definitive conclusions.

Via Medpundit, an article in Scientific American arguing against race-based medicine. I spoke about this on an aside in a post a few days ago, but now I feel like I have to respond to the Scientific American article. Note that I’m not defending BiDil here, but the concept of race-based medicine in general.

I don’t think the trend for race or ethnicity targeted drugs is a bad thing, overall, because first, we wouldn’t have a shortage of new drugs for everyone, since drug companies would only try for subpopulation-targeted drugs in a case where the drug has failed in a larger population. They want profits; they’re not going to limit the scope of any drug to a subpopulation — race-based or genetics-based or whatever — unless they had no choice; just look at how much they try to expand the indications of already approved drugs. And research produces so many drugs that fail clinical trials anyway that it might as well behoove industry to try drugs on sub-populations, since they’ve brought the drugs so far through the clinical process. So nothing to worry about on the economic side of things.

Secondly, taking race into account is better than not doing so, I think. It is simply wrong and counter-productive to claim that people can’t be grouped into ethnicity based on genetic polymorphisms. There are strong sub-population differences on polymorphisms of drug metabolizing enzymes, so what is toxic to one group may not be to the other. And saying that only 10 drugs or so have evidence to back up race-based indications doesn’t mean that we won’t see more in the future, now that more biological understanding is coming out about such things. But until personal genome sequencing and profiling becomes a lot less expensive and a lot faster than it is now, ethnicity, or even race, is a better substitute than nothing. After all, humans have, on a population scale, very homogeneous genetics, and the variation from continent to continent is pretty clear, with minor exceptions, so ethnicity is a valid and easily detectable, though crude, genetic marker. (Ironically, “black”, which is what BiDil was approved for, is probably the crudest and most meaningless sub-population indicator, since Africa has the most diverse genetic variation in the world.)

I do, however, hope that the FDA does not go lax with its requirements of efficacy. After all, race-targeted or not, the drug still has to work. I don’t believe that a head-to-head of one race versus another would be strictly necessary before approval of a drug, since that brings in ethical issues (testing a drug in populations where researchers expect the drug to fail). Anyway, if a drug really is effective in a larger population, post-approval clinical trials would be a lot easier to test, as they would already have gone through the three previous trials for efficacy and toxicity, and so it would be advantageous to allow the drug company to seek approval based on a limited subset first.

Basically, I see race-based or ethnicity-based medicine as part of the whole “personalized medicine” endeavor. Even though it’s crude, it’s still the first step, and it’s what we have to work with right now. We have drugs targeted based on age and sex already, and biologists very well know that age from birth is just a surrogate for “real” aging, and sex is just a surrogate for “real” hormonal levels, developmental history, and so on. Until we have better biological markers, age, sex, and even race and ethnicity, are good starting points for tailoring medicine to each person. We already do it, so why not with pharmaceuticals, too?

UPDATE: A nice New York Times article on natural selection on human subpopulations.

I was in the middle of an interesting article on two documentary film-makers doing an exposé of Michael Moore, when I saw this sentence:

They were kicked out of Moore’s Traverse City (Mich.) Film Festival after questioning his nonprofit’s investments in defense contractor Halliburton and drug maker Eli Lilly.

Now, I understand that the main point is about Michael Moore’s hypocrisy, but I didn’t think I’d see the day where “Eli Lilly” and “Halliburton” were uttered in the same breath. I mean, as bad as drug companies can be, can one really compare them to a defense contractor?

There are a lot of prominent trials (or trials to be) involving Pharmaceutical companies right now, so here are two that have caught my eye over the past week (well, one of them was just pounded into my head over and over by the media).

From the TortsPorf Blog, Wyeth lost in a lawsuit against them in the Vermont Supreme Court in which a woman got gangrene from an accidental injection of a drug (”Phenergan”, a.k.a. promethazine) into her artery. Thing is, the drug’s label (approved by the FDA) “repeatedly and prominently warned” that gangrene is a risk if the drug is accidentally injected into an artery as opposed to a vein (alternatively, a doctor could choose to administer the drug, say, orally, which apparently works slower). A woman lost her arm because of a mistake, and so Wyeth lost the lawsuit. As Ben says, “If that’s the case, why don’t we sue gun manufacturers for every accidental death that guns cause?” I’d like to add, why don’t we sue car manufacturers for every injury sustained from not using seat belts?

Steve Nissen’s Meta-analysis of Avandia (a.k.a. rosiglitazone) is all over the news. Unfortunately, it’s being blown up to be a much bigger deal than it should be. In the Pipeline has a good overview about the caveats on the paper, from Steve Nissen himself as well as a good description about what meta-analyses are, and their inherent problems. Meanwhile, (from Pharmalot), lawyers are already holding conferences on how to sue GlaxoSmithKline. Pharmalot has a good post on the reactions to the NEJM article and the editorial that came with it, including a response editorial from the Lancet (PDF), and the various company affiliations that commenters have (e.g. Steve Haffner, who has been critical of the media frenzy, has gotten speaking fees from pharma companies in the past, and the NEJM editorialists have been paid as expert witnesses by plaintiffs’ lawyers in pharmaceutical trials). Orac has a set of links to good blog post articles on the article. The Examining Room of Dr. Charles has a good post on some unanswered questions about the methodology of the study.

First, the direct-to-consumer side of things. A recent NEJM article raises a good point about the legal feasibility of congress banning direct-to-consumer ads; there’s the first amendment, after all, and there’s a history of the Supreme Court overturning federal bans on the advertising of a variety of substances in the interest of public health, including alcohol, tobacco, and so on.

I, for one, don’t believe that direct-to-consumer ads have any educational value whatsoever, but the preservation of the freedom to advertise in a public forum is very important. We want to make sure that there is enough freedom for things like political advertising, but we also want to make sure that advertising that lowers the overall societal welfare, such as direct-to-consumer ads, get regulated, or even banned. After all, the first amendment is primarily oriented towards politically motivated speech.

Another article, from a few weeks back, was “Following the Script”, from the April issue of PLoS Medicine. It reveals a window into the world of pharmaceutical drug representatives (Drug Reps), who market pharmaceuticals to doctors. Of course, drug marketing is very similar to other business-to-business marketing, in that there is endless networking, false smiles, gifts, hand-shaking, memorization of personal details, tailoring of the message to the target, and so on. Still, the article does show how these are applied specifically to doctors. I really enjoyed reading the table showing how the marketing is tailored to the doctor’s personality. Particularly interesting is the way they approach the “Aloof and skeptical” doctor:

I visit the office with journal articles that specifically counter the doctor’s perceptions of the shortcoming of my drug. Armed with the articles and having hopefully scheduled a 20 minute appointment (so the doc can’t escape), I play dumb and have the doc explain to me the significance of my article.

The intent of the marketing is not education, no matter what the drug companies might claim. Marketing is always about sales. After all, (as the article says) “If detailing were an educational service, it would be provided to all physicians, not just those who affect market share.” Still, one cannot deny that there is currently no good substitute for drug education by drug companies. Even though studies show that doctors still accept gifts from drug companies, drug reps do accomplish getting the name of obscure drugs out, and they do distribute scientific literature. Doctors are busy people; they don’t have time to trawl through the literature all day, as it takes time away from patients. A short blurb from a drug rep can be better than nothing.

In addition, the whole situation marketing situation is a giant prisoner’s dilemma; if a drug company decides to be “noble” and not market to doctors, it will lose sales pretty quickly to the drug companies that don’t have such idealism. There’s really no good incentive for drug companies to stop marketing. If one has to criticize anyone, perhaps one should criticize the doctors for being so easily swayed; but doctors are human, after all, and marketers are very, very good.

Perhaps the group the public should really criticize is the AMA, which for all its statements of ethical guidelines for gifts to physicians, still sells a demographic database to drug companies for more than $40 million a year that allows drug reps to figure out the prescription habits of each individual doctor.

The BIO convention that’s been going on in Boston has started a few posts on drug pricing recently. The topic always seems to bring the crazies out of the woodwork, including Marcia Angell (former NEJM editor-in-chief, though she seems to absolutely lack any knowledge of public health or economics). Here are Derek Lowe’s and the Omics! Omics! takes on the subject. I like the anecdote that Omics! Omics! gives, as it provides a very real sense for how biotech responds to money incentives. Derek Lowe has written very insightfully many a time before on drug pricing.