David R. Henderson  

Three Great Comments on My FDA Post

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Three people, Jim Glass, Dan Klein, and db, made important comments on my FDA post yesterday.

First, Jim Glass:

How the patent system and the FDA discourage study of cancer prevention (quoting...)

"R & D on cancer prevention and treatment of early-stage cancer is very socially valuable," the authors told me in an email, "yet our work shows that society provides private firms -- perhaps inadvertently -- with surprisingly few incentives to conduct this kind of research."

To secure F.D.A. approval, after patenting a drug, drug companies race the clock to show that their product is safe and effective. The more quickly they can complete those studies, the longer they have until the patent runs out, which is the period of time during which profit margins are highest. Developing drugs to treat late-stage disease is usually much faster than developing drugs to treat early-stage disease or prevention, because late-stage disease is aggressive and progresses rapidly. This allows companies to see results in clinical trials more quickly, even if those results are only small improvements in survival.

This very lesson is taught in some medicinal chemistry textbooks. For instance, one notes that "some compounds are never developed [into drugs] because the patent protected production time available to recoup the cost of development is too short."...

Between 1973 and 2011 ... there were over 17,000 trials of patients with the lowest chance of survival (those with recurrent cancers) but only 500 for cancer prevention, which confer the longest survival gains....


I was unfamiliar with the article that Jim Glass links to--and I shouldn't have been.

Now Dan Klein:

Nice post. One comment: The focus of the NYT article is on shaving months off the decision on a new drug application. But the real issue is the extremely protracted many-years-long process of testing that precedes even submitting the application, a process ruled over by the FDA.

It's great that Pazdur shaves a month or two off the final step, but the real issue is the regimented system of requirements preceding the application.

Debating the speed with which the FDA decides new drug applications is a bit like debating how quickly a state Bar examination is graded.


Good point. I was aware of this when I read the NYT piece, noting that the time has been cut by one month. Of course my focus was on the motivation of Dr. Pazdur and then, given that, on whether there is a better way.

But Dan's point is important. Simply by going back to pre-1962 law and not requiring a test for efficacy in particular uses would shave not months, but years, off the process. And Dan's analogy with grading the state bar exam is spot on.

Now db, making the point that there is precedent for my proposal in federal regulation of another potentially dangerous product:

This would be similar (but on a much larger scale than) the regulations allowing for homebuilt aircraft. The FAA regulations allow for an aircraft to be built for personal use and educational/recreational uses by a non-certified builder. There is a thriving industry in building components and equipment for such aircraft. The whole thing is predicated on the idea of placing the risk on the builder/pilot/passengers. Indeed, the regulations require that all such aircraft be marked "EXPERIMENTAL" and have a placard visible to passengers that reads to the effect of "THIS AIRCRAFT HAS NOT BEEN CERTIFICATED BY THE FAA AND DOES NOT MEET REGULATORY STANDARDS FOR CERTIFICATED AIRCRAFT"

Often, builders suffix the required language with "...IT EXCEEDS THEM."

Professional aircraft mechanics can work on such aircraft without endangering their certificates or taking on any more liability than they would working on a certificated aircraft. This would provide an analog to licensed doctors experimenting with unapproved drugs.

It may be wise to set the liability standards a bit higher for medical experimentation, but there is a precedent in federal regulations for allowing this type of action in an otherwise extremely overregulated industry.


Comments and Sharing


CATEGORIES: Regulation




COMMENTS (24 to date)
Stuart Buck writes:

"Not requiring a test for efficacy...would shave not months but years off the process"

So without any incentive for anyone to spend millions on clinical trials, we would no longer have reliable information on whether the latest $80,000 cancer drug even worked at all. But hey, we would have much quicker access to overpriced snake oil.

David R. Henderson writes:

@Stuart Buck,
Your conclusion presumes that the only incentive companies have to test for efficacy is a government requirement that they do so.

Michael Byrnes writes:

I think Jim Glass is partly right but he is also describing more of a second order effect. I would argue that the main reason why we don't see more early stage or preventative therapies in development is just due to the logistical requirements and uncertainty involved in such trials.

Imagine a dug that might prevent some type of cancer. To run a clinical trial for that, you would first need to start by enrolling a large number of patients - enough so that in the absence of treatment, a sufficient number of patients would go on to develop the cancer to support a statistical analysis of the impact of treatment on cancer risk. For a low incidence cancer, that could be a huge number of patients. On top of that, it could be necessary to follow those patients for years to decades before an effect on cancer incidence could be detected.

I'm sure issues such as patient duration etc are a factor in some situations, but mostly on the margins.

Anonymous writes:

Regarding snake oil, it seems to me that the reason it historically existed is because medicine that actually works is a relatively recent invention. A couple centuries ago, all the regulation in the world couldn't cause the snake oil to stop and real medicine to be made in its place, because there was no real medicine - the necessary scientific knowledge just hadn't been built up yet.

Regarding uncertified aircraft, I would be interested to know whether those who approve of the FDA, in roughly the form it exists now, would prefer for the law to be tightened up in this area too - for all planes to require licencing, private or not. This seems to me more justified than drug regulation. In both cases, allowing people to use unregulated products will cause some injury and death, via those with poor judgement using dangerous products when they shouldn't. But at least unlicensed drugs used correctly will save lives. Unlicensed planes will... allow some people to have fun a little more cheaply than they would have otherwise? If you support drug licensing then surely unlicensed planes are indefensible?

If you don't feel this way then is it possible that your support for the existing system, in both cases, might be caused to an extent by status quo bias?

Kevin writes:

I like the FAA example. I think we should allow this in a ton of industries and mark them as product X or something that everyone knows has not been government "certified" but is free of many regulations. Cars that are category X that don't meet safety guidelines (but are lighter and get much better gas milage), drugs not cleared by the FDA that people want to try and use, banks that are essentially wildcat category X but have no oversight except the market.

The real problem, is over time, many things would be dominated by category X and many people would not feel comfortable (for themselves maybe, for others no) and the opportunities for graft go way down.

Anonymous writes:

Another point, one I've made before on this blog but will make again - an implication of having support for paternalistic laws is that you must surely be grateful that democracy doesn't really work. Just imagine if the elected leaders really did implement people's preferences, rather than mostly ignoring them. Consent of the governed existing for real, rather than just as a cute sounding idea. Then we'd really have something to worry about - people getting the laws they want! Who would take care of them and stop them choosing laws that aren't good for them?

Thomas B writes:

To Anonymous,

"Unlicensed planes" as you call them don't just allow some people to have fun a little more cheaply; they cut the cost by about 75%, and with a normally certificated airplane costing $500k, that's a big deal.

The FAA, realizing that its regulatory system has brought it to the brink of soon having no small planes to regulate, has been sporadically looking for ways to reduce the regulatory burden - but in some respects is now trailing behind Europe (of all places) in the process.

But, as you say, those who demand "more regulation" will not be satisfied by mere customer satisfaction or acceptable levels of safety. I applaud the FAA for its vision in trying to be sensible anyway.

john hare writes:
The real problem, is over time, many things would be dominated by category X and many people would not feel comfortable (for themselves maybe, for others no) and the opportunities for graft go way down.

An information organization could do wonders for this problem. Underwriters Laboratories I have noticed on many products.

Stuart Buck writes: "Not requiring a test for efficacy...would shave not months but years off the process"

So without any incentive for anyone to spend millions on clinical trials, we would no longer have reliable information on whether the latest $80,000 cancer drug even worked at all. But hey, we would have much quicker access to overpriced snake oil.

It might be $800.00 instead of $80,000.00 if there weren't all those hoops to jump through.

Thomas B writes:

Folks who worry about the FAA and airplanes would do well to remember that every year thousands of children and teens take to the water in unregulated sailboats and on unregulated kitesurfing boards - and often they modify their own! Adults take trusting friends and family members out on unregulated yachts. There must be literally millions of children riding unregulated bicycles in this country - many of them on public roads, within inches of cars moving at high speed.

Stuart Buck writes:

David,

I do not think anyone has an incentive to do expensive clinical trials absent a regulatory requirement to show that the drug actually does what is claimed.

We can look, for example, at off label uses of drugs, which are everywhere. Do companies or anyone else sponsor $50 million efficacy trials for those uses? Barely ever, if at all. They are happy to sell drugs to doctors, and doctors are happy to prescribe them, without any real evidence of efficacy.

Or we could look at other markets where people sell products or services that purport to have some effect -- for example, brain training software or teacher professional development programs. Do the sellers of those products perform rigorous randomized trials that might run the risk of showing inefficacy? Again, no. They happily peddle their wares on the basis of bogus research and people happily buy it because the vast majority of people couldn't explain why a well powered RCT gives more causal inference than a pre-post study with a comparison group picked by some unknown criteria that are contaminated with selection bias.

Even with the FDA'S supposedly onerous requirements (never mind that many drugs come through accelerated approval routes that are far quicker and less demanding), there are still oodles of cases of bias in RCTs, including outcome switching, failure to report results at all, post hoc subgroup analysis, etc. One only has to look at homeopathy to see what all of our drug markets would look like if no one had any authority to expect better evidence.

Michael Byrnes writes:

In absence of FDA efficacy requirements, the incentive to do clinical trials would come from the insurers. How many health insurers are going to pony up $1,000/pill for Sovaldi without convicing evidence that it actually works?

Stuart Buck writes:

Is that what you observe happening in the off-label market right now?

David R. Henderson writes:

@Stuart Buck,
I do not think anyone has an incentive to do expensive clinical trials absent a regulatory requirement to show that the drug actually does what is claimed.
It’s certainly correct that they have less incentive.
We can look, for example, at off label uses of drugs, which are everywhere. Do companies or anyone else sponsor $50 million efficacy trials for those uses? Barely ever, if at all. They are happy to sell drugs to doctors, and doctors are happy to prescribe them, without any real evidence of efficacy.
You chose a particularly good example and your reasoning is excellent until the last line. The way it often works is that doctors get experimental with drugs and find that they work. So think of Prozac, for example, which doctors found worked with PMS. Eli Lilly was happy to sell it for that use and it worked so well that Eli Lilly bothered to do the expensive testing so that they could advertise it for PMS. But that’s the exception. And that’s the problem. I’m saying that Eli Lilly should have been able to advertise it for PMS without FDA permission. And many more women would have known about it much sooner.

Stuart Buck writes:

Only in rare cases are effect sizes large enough that doctors' anecdotal experience could make randomized trials unnecessary. The median cancer drug approved over the past 12 years (if I recall) had a survival benefit of 2.1 months. Absent clinical trials that are very meticulous, no one would have any idea how well these drugs work.

Michael Byrnes writes:

The off-label use of drugs is itself a reason to question the value of FDA efficacy requirements. A drug must be approved for a specific indication, but, once approved, a doctor can prescribe it for anything (with some limited exceptions).

So we are fine with the use of drugs in indications for which they have not been approved. Botox, for one, is used off-label for all sorts of stuff. Avastin, a borderline effective cancer therapy, is used off label to prevent blindness caused by wet age-related macular degeneration. 10-20% of prescriptions are for off label uses. If we're really ok with off-label uses of prescription drugs, then the FDA efficacy requirement seems sort of misguided.

Charley Hooper writes:

@Stuart Buck,

I do not think anyone has an incentive to do expensive clinical trials absent a regulatory requirement to show that the drug actually does what is claimed.

You might argue that it's a regulatory requirement, but drug companies do this all the time. If a drug is approved for X, often the company will test it for Y in hopes of receiving approval for Y. Gilead Sciences did this with Sovaldi and Harvoni for the different hepatitis C genotypes. Gilead did it with Viread for HBV and HIV. Genentech has done this with many drugs, for instance, Rituxan and Avastin.

But your point raises a bigger issue. What is the real value of randomized, double-blind, placebo-controlled clinical trials? A properly done trial might find that 40% of patients see a benefit with the drug while only 10% see a benefit with the placebo. That's great, but if I take this drug, will I be in the 40% group or the 60% group? I have no way of knowing. I still need to take the drug to see how it works for me.

Stuart Buck writes:

"You might argue that it's a regulatory requirement, but drug companies do this all the time. "

I might argue this indeed, because that's precisely what is happening. Companies do clinical trials when they want to get a new approval and have to comply with the regulatory requirements, but are not likely to do so otherwise. So the off-label market demonstrates that the marketplace does not, in general, provide enough of an incentive for most companies to perform rigorous clinical trials on most drugs.

If you're fine with the entire drug market for cancer, heart, diabetes, etc., being as full of unsubstantiated claims by hucksters as we see w/r/t to vitamin supplements, then so be it. I happen to think that for all its flaws, the system we have for pharmaceuticals is the best way of producing rigorous evidence on a systematic basis that has ever existed, in any field in all of history. It would be a shame to ditch that and replace it with anecdotes and bogus observational research.

Charley Hooper writes:

@Stuart Buck,

My point is that if clinical trails provide compelling evidence, drug companies will conduct them whether they are required to or not. What better way to convince someone to prescribe, pay for, take, and keep taking your drug?

If clinical trials do not provide compelling evidence, then drug companies only conduct them because they are required to by the FDA. And the FDA is wasting everyone's time and money because the results aren't persuasive anyway.

I would like you to explain why clinical trials provide persuasive evidence but drug companies will still not voluntarily conduct them.

Mark Bahner writes:
So without any incentive for anyone to spend millions on clinical trials, we would no longer have reliable information on whether the latest $80,000 cancer drug even worked at all. But hey, we would have much quicker access to overpriced snake oil.

A site like Patients Like Me can perform efficacy testing.

But much more importantly, no one should be allowed to tell mentally competent adults what they can and can't put in their bodies.

I wish politicians like Rand Paul would properly frame this as a moral issue.

Charley Hooper writes:

I'll answer my own question.

Drug companies must conduct clinical trials for each drug's first indication, as per FDA requirements. All subsequent clinical trials are evaluated based on a cost/benefit analysis. How expensive will the trials be? What's the chance of a positive outcome? How big is the market? What costs will be involved in promoting the drug to doctors and patients in that market? What other competitors are in that market and what is being developed?

For cases where the benefits exceed the costs, the clinical trials are run. For the other cases, they aren't run. So when you look at off-label situations where no clinical trial has been conducted, it was probably due to a company seeing high costs and limited value or perhaps high opportunity costs.

Stuart Buck writes:

Mark:

"no one should be allowed to tell mentally competent adults what they can and can't put in their bodies."

The FDA does not regulate what doctors prescribe or what people ingest. It regulates what can be marketed based on what evidential claims.

Charley:

"I would like you to explain why clinical trials provide persuasive evidence but drug companies will still not voluntarily conduct them."

Clinical trials provide the best possible evidence. Unfortunately, the vast majority of people do not know whether they are reading the results of a rigorous randomized trial or whether the "study" in question was a much cheaper and much less reliable observational study. So the latter may be just as "persuasive" to the public.

If you think doctors are too smart to be persuaded by less reliable evidence, look at the history of hormone supplementation and the Women's Health Initiative clinical trials. Doctors were prescribing hormone supplementation to literally millions of women, putting them at higher risk of heart disease, stroke, and breast cancer, all based on seemingly sophisticated epidemiological evidence. I would not want unreliable epidemiology to replace clinical trials.

Charley Hooper writes:
The FDA does not regulate what doctors prescribe or what people ingest. It regulates what can be marketed based on what evidential claims.

If a drug cannot be marketed, people cannot ingest it. Therefore the FDA tells mentally competent adults what they cannot put in their bodies.

Ken P writes:

Often, the FDA requires that drugs under development be tested on only the sickest patients and/or patients in which all other medicines have failed.

This has been a particularly troublesome issue for testing the efficacy of many immunotherapeutics, since the currently used chemotherapies as well as late stage disease often go hand in hand with a compromised immune system. Therapies that rely on an engaged immune system are not given a fair chance to demonstrate what efficacy they can potentially provide.

R Richard Schweitzer writes:

It has been a long term puzzle as to why there can not be provisions to extend the term of patents for a period equal to the time required for regulatory approval for actual use.

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