FDA does, and should, stick to only science

In a welcome reversal of a key politics-driven Bush era mandate, the FDA has approved the Plan B morning-after emergency contraception pill for 17-year olds. Previously the reluctance of FDA to approve the product had led a senior official to rightly resign. Not surprisingly, this decision drew wrath from conservative groups who say that the pill would "encourage promiscuity". This statement is rather typical of conservative statements opposing abortion and promotion of contraceptive measures in school, in spite of the fact that abstinence-only programs have been shown to essentially cause no change or even an increase in "promiscuity".

But here's the thing, and it should be clear all along; the FDA should stick to science and nothing else. Just as the conservative FDA officials during the Bush era were utterly out of line opposing Plan B because of political and religious interests, so should liberals also not applaud the FDA decision as a moral value judgement. The business of the FDA is to determine the efficacy and safety of medical products, period. The moment it starts to pontificate on the moral or political value of its decision its immediately sets itself on a slippery slope.

So just like the National Academy of Sciences and the National Center for Science Education should stick to demonstrating the evidence for evolution and lack of evidence for ID/creationism and not pass judgement on whether science and religion are compatible, so should the FDA stick to the science behind the approval of medical products. Not making political or religious statements, either conservative or liberal, would be in the safe and best interests of both the FDA and society.

VYTORIN: NEW PROBLEMS FOR A NEW ERA

The NYT has a piece today in which it describes the problems riddling Vytorin, a combination of ezetimibe and simvastatin, which is taken by 3 million around the world and makes 5 billion for its owners, Schering-Plough and Merck. The piece says that in spite of such widespread usage, there is apparently no clinical trial data that demonstrates that the second piece of the cocktail- ezetimibe- is efficacious. Much more concerning is the fact that there may be a link between ezetimibe and cancer, although the link looks fragile at best right now.

Statins have been the wonder drugs of our time, with Atorvastatin (Lipitor) being the best-selling drug in the world. Their efficacy in reducing heart attacks has been demonstrated in large-scale trials. Ezetimibe which blocks cholesterol absorption in the intestine and reduces LDL has much more tenuous effects. Recent large-scale studies found that while ezetimibe does reduce LDL, it's effect on the variables that actually matter are far less certain; there was no evidence that it actually reduces heart attacks. Yet it continues to be prescribed by thousands of doctors around the country, with patients shelling out considerable amounts for it.

However, the article raises the much bigger issue of knowing exactly when a drug is efficacious. According to the article, utility of a drug is usually gauged by "surrogate endpoints", that is, endpoints which indicate reductionist type effects rather than an actual increase in life-span or quality of lives. Take cancer for example. For most cancer drugs, tumor shrinkage is a convincing endpoint, not an actual increase in life-span. Or take cholesterol medications. The causal link between LDL cholesterol lowering and reduced heart attacks is apparently well-proven. Yet the body is complex enough for this causal link to be questioned; such questions arise most often in truly large sample studies, when the drug is on the market. Clearly the only true indication of side-effects or efficacy will come from such large-scale studies.

But there's a dilemma here as far as I can see it. The reason why surrogate endpoints are used seems clear to me; it's simply much more easy to look for such effects and ascribe them to drug action than effects like "increase in life-span" which can be controlled by multiple factors. Let's say two men who are the same age have been prescribed the same cancer medication. Both show shrinkage in tumors. Apparently the medicine works. But can this be translated into an observation about the difference in their life-spans, which can be attributed to so many different factors. Especially if the general health of one of the patients is worse than the other, then the cancer medicine can basically be an adjuvant and not the primary cause for his prolonged survival. How do we know that it's the cancer medicine and not his general health condition that actually increased his life-span? Naturally a reduced incidence of heart attacks is much easier to analyze than an increase in life-span. But even there it seems that so many factors can be responsible for a heart attack that it would be a problem trying to attribute specific effects to the medication, or especially the lack thereof of its effects.

The article also says that the FDA has become stringent about medications that address chronic problems like heart disease. The stringent bar set for a true study of efficacy seems to be about 10,000 patients over about four or five years. If every pharmaceutical company needs to do such a study to get approval, they might as well start digging their grave right away. Drug development is already so risky and expensive that putting a drug through 10,000 patients over five years and having the FDA almost certainly reject it after that would spell doom for all drug makers. Yet it is clearly unethical for doctors to keep on prescribing medication whose efficacy has not been demonstrated.

There does not seem to be an easy way out of this problem. To me right now it seems that, with all the compromises and problems it entails, the best bet might be to set such a stringent bar for medications for which good alternatives exist (and medications for chronic heart disease seem to fall into that category now) but relax the need for such large-scale trials for unmet and critical needs for which no good drugs exist. I am pretty sure the FDA is not going to set the bar for cancer so high.

So what's the way out for companies? To me the soundest scheme for now seems to be for doctors to provide information on the label saying that the drug did not show efficacy in a fair number of patients, and let the patient decide for himself or herself. It would be ridiculous in my opinion for the FDA to demand that the company withdraw the drug. Also, as a general thought, I think that both the FDA and public opinion need to get over their obsession of approving drugs only if they show efficacy in 100% or even 90% patients. What if a drug shows efficacy in 50% of patients? The rational thing would be for doctors and companies to explicitly say this on their label and let the consumer decide. That's the kind of thing that should happen in a liberal society.

Note: Over at The Pipeline, Derek has quite a few posts on this

LIBERTARIANISM AND THE FDA

Chetan alerted me to this video of Milton Friedman where the stalwart economist introduces libertarian ideas and basically counters every matter advocating government intervention that the questioner puts in front of him.

At one point, the questioner asks him if having the FDA around does not prevent tragedies like the Thalidomide tragedy, where it was the FDA that kept a drug with devastating effects away from the US market on the grounds of insufficient testing. Friedman's answer is not surprising to those who are familiar with libertarianism; he says that it is in the interests of the FDA to delay the approval of drugs for fear of backlash from ill-approved drugs. The solution? Again predictable; let the companies themselves do the testing. They won't dare to get a drug with harmful side-effects into the market because then their share-holders will be displeased and they might even go bankrupt from all that class action legislation.

Does this actually work? When I told this second argument to a veteran in the drug industry who has many years of experience with both the business and science of making drugs, without batting an eyelid he answered, "That simply does not happen. For companies, most out-of-court settlements constitute a fraction of the profit they make from drugs. For a company, bringing a product with a side-effect on the market does not carry a very great risk, because any cost they may have to pay in the form of fines or court settlements usually is much lesser than the profit which they make". Plus, exactly why are shareholders going to bring down the company? Surely not because of morality. Did shareholders stop buying Union Carbide products because of Bhopal? They only care what the shares look like. For a giant drug company, a temporary setback does not affect the long-term value of their shares. Even if such a company loses a few customers temporarily, it can gain many more customers in the future.

So Friedman's contention that customers will regulate the company (or rather, that the free market will regulate itself) may work in principle, but it is hard to imagine it working in practice. And there are examples in the real world where it has not worked. And not just with drug companies. Let's take companies which have extensively polluted the environment. Have these companies stopped their practices because of litigation? No, in most cases they have simply paid the fine and moved on with the same practices. That's the point; for companies, everything is a business decision, and many times paying punitive damages is much less expensive than changing manufacturing practices or testing drugs extensively.

This is the problem I have with some of these libertarian ideas; while I agree on many points with libertarians, to me their solutions often sound theoretical and many times generalised, with real-life examples providing plenty of counterexamples. Now when you point out these counterexamples, they will say "Yes, but you wouldn't have had these counterexamples in a perfect, libertarian world" But that's the point; the world is not perfect, even if we should continue to strive to make it so. In the real world, not everyone has property rights to shield themselves from corporate malpractices. Many people simply don't have the financial and political muscle to go to court against corporations. I always cite the example of Pacific Islanders facing sea-level rise from climate change. How many oil companies will they sue and how? And will the oil companies change their practices even then? The problem I have with some libertarian views is that they are extreme; they assume that government in any and every form is evil in any and every time, and that it is anethema to even think of any degree of government regulation. With governments of the kind that we have in India, I can sympathize with their viewpoint. But isn't there a second perspective here? Until their perfect libertarian world materialises, sometimes to me government regulation seems like the only option, even if it may be a necessary evil. We should certainly strive to give everyone property rights, but until that can happen we need to have some way of preventing catastrophe and disasters. Moreover, there are bad government agencies and good government agencies. Wouldn't a moderate standpoint be to advocate increasing the efficiency of some government agencies rather than simply doing away with them? Why doesn's anyone talk about improving systems rather than advocating getting rid of them by default?

I feel sad because libertarians often take an extreme stance and espouse a catch-all viewpoint. There is one fundamental rule of debate or analysis; don't adopt an extreme viewpoint, because then you automatically open yourself up to criticism. But in this case, I would go a step further and say that with their extreme viewpoints, libertarians force others who agree with much of what they say to become their critics.

P.S. The really galling question is, what do you do if government itself is more evil than anyone else? That's a tough nut to crack. Who do the people turn to then?

ETHANOL: SAVIOUR OF THE UNFORTUNATE...AND THE STUPID

Ethanol, the much reviled yet irresistible satanic temptation that has plagued the human world for centuries, can actually be a giver of life in some situations...

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