Food And Drug Administration

While I'm talking about changes to cherished institutions, let's talk about the FDA.  There needs to be some control regarding drug distribution and claims about drugs, but I'm far from convinced that the FDA's current approach is anything near the optimal approach.  Mark A.R. Kleiman (a liberal I respect but often disagree with) is apparently thinking along the same lines.  In a thought provoking post  he suggests a number of changes to the structure of the FDA.  I do of course suggest that you read it all, but here is an interesting passage:

In the wake of the Vioxx/Celebrex flap, there's been lots of finger-pointing, but it seems to me not enough consideration of what principles ought to guide policy when it comes to approving new drugs or ordering existing drugs off the market.

Given patient-to-patient variability, the idea that a drug is "safe and efficacious" (or not) generically can't really be right. What if a drug is helpful to some patients and harmful to others and the difference between the two groups is observable, either in advance or by monitoring the patient during a trial period? There are almost certainly patients who, given the alternatives, would be better off staying on Celebrex rather than switching to the older generation of NSAIDs. But there's no guarantee that those are the patients who will actually be continued on the drug if it isn't yanked from the market.

...

Some know much more than others about pharmacology generally, or about a specific drug or class of drugs. While it makes sense to have a regulator in the middle to protect the less-knowledgeable from the persuasive powers of the drug companies, it make no sense to overrule the decisions of doctors and patients who may be as knowledgeable about a drug as the FDA regulators themselves, and are certainly more knowledgeable about the details of a particular case.

The SEC came up with a fix for the analogous problem in capital markets: the "sophisticated investor" rule. In the securities case, "sophistication" means no more than deep pockets and experience in high-risk investing. But in the case of drugs, why not craft categories of "sophisticated" doctors and patients who could, by passing examinations, win for themselves the right to prescribe, or to use, drugs not yet approved for marketing to the general public?

It would be reasonable to require, as a condition of participation in the program, agreement to collect and submit appropriate information about the use of the drug and its outcomes to the drug-review process. That would somewhat compensate for what might otherwise be the reduced pressure to participate in clinical trials.

Of course, mistakes would continue to be made. But is there any reason to think that, given the option of using non-approved drugs, truly knowledgeable physicians and patients would in fact make choices that led to worse outcomes rather than better ones? None that I can think of.

This is a key insight.  Americans have a funny idea about risk.  The same people who worry about getting cancer from high tension lines drive every day in their car.  Getting electricity and using personal transportation are both very useful facets of modern life.  For some reason people are willing to focus on the super-tiny risk (if it exists at all, studies seem to show that it is below the statistical significance threshold) of living near high tension wires, while they are willing to bear the much larger risk of driving to the mall.  (Please don't draw parallels between this and terrorist risks.  There are arguments to be made about intentional violent acts and societal trust that I just don't want to get sidetracked with in this post.)  Back to medicine.  Many people seem to have developed the strange idea that medicine is or ought to be a risk free endeavour.  We've come a long way, but we are nowhere near a deep enough understanding of individuals' bodies to be able to realisitically think of advanced medicine in that way.  It would be helpful to engage in a societal discussion of useful risk taking with respect to medicine.  It might be good to allow informed patients and informed doctors to take more risks if tailored to the specific patient.  Many risks might be very manageable if they were well monitored during treatment.  It is commonly said that aspirin wouldn't make it past the FDA nowadays.  But aspirin turns out to be an extremely useful drug, with real but manageable side-effects.  It isn't reccommended for some people, but for many it works very well. 

There used to be an old tort principle called assumption of risk.  It used to relieve manufacturers and other potential defendants of liability if the damaged party engaged in certain activity despite a risk that they could see.  A policy somewhat informed by a similar notion might be very useful in the drug arena.  We could get a lot more drugs out their which could help quite a few people, if we didn't have unrealistic expectations about drug safety and if we were better able to manage the fact that some drugs are safe and effective for some people even if they aren't safe and effective for everyone. 

A further comment about this post appears in Lines in the Sand:

After basic testing for general safety, the FDA could issue a provisional approval that pharmacists would have to stay up on to remain certified.  That would allow the FDA apply even more rigorous testing for final approval without delaying availability, and could provide a larger statistical base for that testing.

I agree with Kleiman that the FDA is a great place to collect statistics and do testing, but giving them absolute authority for approval has questionable value.  This approach moves the prescription decision closer to the the patient's unique situation without resorting to drug by drug certification.

I agree that could be a useful way of looking at it. 

Comments

[blogbudsman]

Well there must be a (not so) new tort principle, Kill the Golden Goose. Our local (small market even) newspaper and TV stations are running ads from lawyers seeking Vioxx victims. I thought I read recently where the risk level of taking this medicine would only be reached if the patient exceeded the stated dosage recommendations. I don't have a link, sorry. What we'll get is some statistical analysis where three old ladies in Hoboken, two of which chain smoked and ate pork fat daily, suffered heart failure six months after OD'ing on Vioxx. Since there was only six heart attacks in the county that week, there's a 50% risk factor 'proving' the FDA and the pharmaceutical company knowingly marketed a killer drug.

Streamlining, customizing and de-politicizing the process is an excellent endeavor. There are wonderful things on the horizon studying DNA proteins and there impact on our most devastating dementia diseases of our generation. Any oversight of the drug approval process must parallel and serious debate on torts and trial lawyers.

[votermom]

Random thoughts:
Why are drug companies allowed to advertise prescription drug directly to patients?

Should there be some manadatory beta-test period for new drugs, where doctors are allowed to prescribe them under stricter protocols than regular drugs?

[heet]

Why are drug companies allowed to advertise prescription drug directly to patients?

I think you know the answer to this one. But it does more than encourage patients to ask their doctors about medicines and fill the pockets of big pharma. It is useful to have a communication channel for drug information that bypasses doctors. Many docs are old, set in their ways, and are not up on the newest literature. On the other side of that coin, many (most all) patients are not knowledgeable about available drugs for their particular illness without advertisements.

There is plenty of opportunity for abuse by the companies, as I'm sure everyone can appreciate. Tricking consumers into self-diagnosing and therefore creating demand for a drug is a big one in my eyes. The commercial for Zoloft kills me -- if you have ever been afraid of talking in front of groups, meeting new people, or talking to your boss, you are normal.

What's funny is the pharm industry used to spend tons more money on the doctors themselves. They'd send them on cruises, fly them to Hawaii for "conferences", etc... After a while, they realized they weren't buying much for their money. Doctors, non-specialty internal med especially, try very hard to police themselves in this regard with some success. The companies found it was much more cost effective to just advertise to potential patients.

[hilzoy]

heet -- that money is still being spent on marketing to doctors; it has just been supplemented by even more money spent marketing to consumers. Myself, I agree with you that it's good to have a way for patients to get information about drugs that bypasses their doctors, but I don't agree that drug company marketing is a good version of this 'way', most particularly because it has nothing to do with accuracy. Moreover, I think the web is stepping in to provide the info patients need. Direct-to-patient marketing is, in my view, a tremendous waste of money. And if the drug companies were just spending this money without passing it along to consumers, thereby adding a lot to the rising cost of prescription drugs, that would be fine, but as things stand we are ultimately paying for it all.

To anticipate possible future objections: in a normal market, I'd say: hey, let a thousand flowers bloom. I have no analogous objection to shampoo ads, and I don't think they play a particularly useful social role either. But the market for prescription drugs is not a normal one, both because the user, the prescriber, and the payer are different people with very different incentives, and because they have vastly different levels of information which invite market failures. For these reasons, and because not having a medication you badly need is not like not having shampoo, the drug market does not function 'normally', as a result of our own policy choices; and thus my normal objection to things like ruling out advertising does not seem to me to apply here.

[heet]

Hey, I'm all for restricting drug ads to consumers, believe me. The pharmacutical market is full of failures of information. It isn't perfect by any means.

In the America I know, you will never be able to completely keep an industry from advertising to its consumers. Just isn't going to happen. What should never happen, though, is a patient deciding his own treatment. Docs still have the final word and it should stay that way for reasons of liability and propriety.

[Sebastian Holsclaw]

I think the competing information claims make Kleiman's concept a good one. You design a mechanism whereby people and especially doctors demonstrate their knowledge on specific drug areas if they want to prescribe/use some of the more dangerous drugs. I think a lot of the problem is that the tort industry has deformed the idea of risk. It is perfectly normal to expect that some very useful drugs might have some very noticeable risks--and I mean risks other than the 'dry mouth' or 'could cause dizziness' that exist for nearly every drug.

[chuchundra]

Yes, it is reasonable to expect that drugs may have strong and even dangerous side effects. It is also reasonable to expect that new drugs will be properly tested so that the side effects can be explained to physicians and patients so they can weigh the risks and the benefits of taking these drugs.

What Merck and other pharma companies have been doing is using the FDA's "fast track" approval process, one that they asked for for potentially life saving drugs, for drugs that don't merit it, like Vioxx. By the late 1990's, over 68% of new drug approvals were using the FDA's priority system, potentially putting tens of millions of Americans at risk from insufficiently tested drugs.

Conservatives and right-wing partisans want to spin this as a failure of the tort system, but the tort system is working like it's supposed to.

People have been harmed because Merck wanted a shorter time to market so they could make more profit. As well, there were followup studies as early as 2000 that Merck fought the FDA to keep from being disclosed. Now Merck is going to have to pay for that. I'm not a lawyer, but it seems to me that that's how the system should work.

Strong drugs may have strong side effects. If you're taking a drug that controls your HIV or cancer, you accept that it the side effects could be dangerous or even fatal. For the nearly 140,000 people who suffered major or even fatal complications because they took an arthritis drug that didn't upset their stomach as much, that's probably a bad deal.

[Sebastian Holsclaw]

"For the nearly 140,000 people who suffered major or even fatal complications"

Is this an accurate assessment of the Vioxx problem? I haven't found any useful numbers on the actual risk.

[chuchundra]

Well, TheStreet is doing a series on the Vioxx debacle this week, the latest article is

http://www.thestreet.com/_tscana/stocks/melissadavid/10201869.html

and it links back to the other three articles from this week. That's where I got my numbers, although I'm sure Merck might disagree.

TheStreet articles are very, very damning, alledging that Merck knew that Vioxx was likely to have serious cardiac side effects and that their clinical trials were designed to minimize the reported danger.

Also, if you're interested you can read the actual testmony in the Vioxx Drug Safety Hearings before the U.S. Senate Finance Committee over at FindLaw

Here's a little snippet of the testimony by Dr. David J. Graham, Associate Director for Science, Office of Drug Safety:

Dr. Eric Topol at the Cleveland Clinic recently estimated up to 160,000 cases of heart attacks and strokes due to Vioxx, in an article published in the New England Journal of Medicine.

P.S. I tried to put in actual links and my post was flagged as "comment spam". WTF?

[Bernard Yomtov]

why not craft categories of "sophisticated" doctors and patients who could, by passing examinations, win for themselves the right to prescribe, or to use, drugs not yet approved for marketing to the general public?

I'm a little confused here. What do you and Kleiman mean by unapproved drugs? If it means drugs that have not been through clinical trials how will even the cleverest doctors and patients be able to make intelligent decisions?

[Sebastian Holsclaw]

I'm not a Merck defender, I don't know anything one way or another about their corporate practices. But if you have been reading here long you know that I am skeptical of reporter claims to summarize statistics that are in the format of "Dr. Eric Topol at the Cleveland Clinic recently estimated up to 160,000 cases of heart attacks and strokes due to Vioxx, in an article published in the New England Journal of Medicine." It is too bad that wasn't a blog or they would have linked to the NEJoM article. :)

So, I'm off to look it up.

[Sebastian Holsclaw]

Bernard, drugs that wouldn't make it through the current process because for example they have difficult side effects.

[Bernard Yomtov]

Sebastian,

So you are talking about drugs that have been through clinical trials, but did not meet FDA approval standards. Is that right?

[Sebastian Holsclaw]

Among others.

[Bernard Yomtov]

Among others?

Again, without solid data, how can physicians make intelligent judgments? And how many physicians have the statistical knowledge needed to make judgments about a drug based on the results of clinical tests without some good guidance?

It looks to me like you're aiming at an awful small target - drugs that would help some people but whose side effects are such that they are so unsuited for others as to not qualify for approval. Drugs with serious side effects are often approved, after all, and the side effects are monitored. I take cholesterol medicine, to cite just one example, and have regular blood tests to check for possible liver damage - an occasional and potentially serious side effect.

My main concern is that there be thorough and accurate testing, and that decisons be made by those who understand the results. If you want to argue that the FDA is too conservative then go ahead, but I've heard the opposite from knowledgeable physicians. They make judgment calls. Sometimes those are wrong, but are they truly biased?

As for Vioxx and torts, there does seem to be an argument that Merck distorted its tests. That is an entirely different issue than the one you discuss. I don't know if they did or didn't - neither do you. But suppose they did? What consequences do you think they should bear?

[Sebastian Holsclaw]

"But suppose they did? What consequences do you think they should bear?"

Of course if they committed some kind of fraud they should get slammed. I have no problem with strongly hitting a company which intentionally violates trust. I'm just using it as a springboard to talk about things.

As for the idea that I'm aiming at a small target, I don't think so at all. There are lots of drugs which can and do have serious side effects but which properly controlled would be fine. Vioxx, for instance, seems to have a 2% increase in heart attacks. That could be a very manageable risk for some people--so long as closely monitored. It could also be dealt with by taking aspirin concurrently. I'm reminded of a great prescription anti-histimane in the 1980s (I had horrible sinus trouble as a child) which was pulled because of a very low incidence of Erythromycin interaction which was linked to heart attacks. Instead of pulling the drug it would have been much better if there could be strong warnings against using it with Erythromycin. (Or was it tetracycline?) And once again, if its manufacturers were hiding something, slam down on them.

I'm making a broader point about risk. It isn't ridiculous to suggest that many drugs which increase the chance of heart attack by 2% while on the drug might still be worth it.

[Bernard Yomtov]

I have no problem with strongly hitting a company which intentionally violates trust.

Then what is the objection to using the tort system to go after them?

I'm making a broader point about risk. It isn't ridiculous to suggest that many drugs which increase the chance of heart attack by 2% while on the drug might still be worth it.

No it's not. But there seem to be a couple of issues here. Are you saying you simply think the FDA is too conservative in its approval policies? You would find a lot of disagreement from those more knowledgeable than I. (I know that's not an argument. I'm just saying I'm not equipped to debate the point, but I doubt you have an automatic winner). In any case, there will always be drugs at the margin. There will always be some drug that is not approved that you, or others less risk-averse, will think should be OK.

But suppose you get around this, somehow. You establish your super-doc system. Now you still need the trial data. How are you going to get it? Once the side effects start to show up you can't just continue the trials, can you? Certainly not without informed consent from the subjects. And if the subjects are as risk-averse in these matters as you say, (and you are right, they are) how will we get valid data for the super-docs?

I guess what I'm saying is that I don't see, as a practical matter, what change you are proposing other than urging the FDA to loosen up a bit.