One of the things I like about Midwestbusiness.com is that the articles are often accompanied by a reader poll, the results of which can be quite informative. 

The earlier article “FDA: Tortoise, Hare or Something Else Entirely?” was one of those columns which included a reader poll and, indeed, the results are quite interesting.

To summarize: the article used the Avandia issue as a springboard to discussing the issue of drug safety and FDA reform.  Because of the safety issues with Avandia as well as Vioxx, defibrillators, Fen-Phen some have argued for a slower, more deliberate FDA approval process.  To these critics, the FDA should be - metaphorically - a "tortoise."  Many others – from Ivory Tower physician-scientists to in-the-streets activists – have, in contrast, demanded a faster FDA in order to bring new medicines faster to market.  To these critics, the FDA should be a "hare."  In my mind, the choice is neither and rather the FDA should be something else entirely – one that shifts the priority and focus away from efficacy and more towards the core mandate of safety and in this way accomplish both goals of safer drugs, faster to market.

With respect to the reader poll, here’s what you said:

The FDA should be a “Tortoise”

Only about 4% of you felt that the FDA should actually slow down the approval process.  In the wake of all the safety controversies, this is indeed a surprising verdict.  It’s somewhat like the phrase “have your cake and eat it too” in that we increasingly demand safer drugs but do not want to slow down the process in achieving that. 

The FDA should be a “Hare”

Over 12% - three times the number that wanted a slower FDA- felt that the agency should approve drugs faster.  This means that despite all the safety concerns, we do want new medicines to reach market faster than is presently the case.

The FDA should be “Something else entirely”

The overwhelming majority (over 70%) desire a redesigned FDA which implies that FDA reform is not just a matter of tweaking the current system but rather potentially a complete redesign or paradigm shift.  This is the point-of-view argued in the article and in other writings on the topic.  “Something else entirely” does not mean a slightly slower or slightly faster FDA but rather one that approaches its mandate through a different lens and a different set of priorities.

The FDA is “fine as it is”

A minority – though not an insignificant one – voted to retain the FDA as it is.  However, if we add up all those who seek FDA reform (or redesign) that adds up to over 87% of the vote.  87% is not a number to ignore and hence the desire for FDA reform is definitely not something to ignore.

FDA Reform – FDA Redesign

This blog has published several articles on the topic of FDA Reform.  And to the extent that “something else entirely” implies a more significant change we can even call this FDA Redesign.  A summary list of these articles are:

Boston Scientific, Medtronic settle some defibrillator suits; is the device safety storm over?

Financial Incentives Can Drive New Pharmaceutical & Medical Technology Adoption: What are the Implications?

FDA Reform Redux: On Business Models, Regulatory Reform and Safety

FDA: Tortoise, Hare or Something Else

Drug /Device Safety Debate to Yield Big Changes, Grow More Controversial

And to summarize the main thrust of the FDA Reform proposal is to shift the agency’s priority away from efficacy: 

"The requirement to demonstrate efficacy as mandated by the Kefauver-Harris amendment of 1962 is a major contributor to the complexity and duration of new drug approvals.  In addition, an unintended consequence of the efficacy requirement may be a compromise in the priority for safety.  Because efficacy is so important for approval, priority goes to proving efficacy in large, statistically significant clinical trials which is a long, arduous and costly process.  In a world of limited resources, the emphasis on efficacy means that, despite good intentions, less thought and effort is necessarily given to evaluating safety – ending up being largely relegated to post-market surveillance.  In order to speed up drug approval as well as devote more resources to comprehensive as well as pre-market safety studies, it is proposed that the Kefauver-Harris efficacy requirement be scrapped or at least significantly reduced in importance.  In fact, with the advent of personalized medicine whereby large, randomized, double-blind and controlled clinical trials become increasingly more difficult to meaningfully design and with our present internet age, in which it is much easier for the market to determine and share information about efficacy, the efficacy requirement has, indeed, become less relevant.  Finally, it should be recognized that with the rapidity by which new technologies are developed, efficacy results may, in fact, often be obsolete and irrelevant by the time they are obtained.  Efficacy is a relative truth; safety is a durable truth."

And with respect to increasing the agency’s emphasis on safety, a quote from one of yesterday’s posted comments helps explain this further:

"Therein lies the problem, namely that everyone assumes that extensive safety studies require large numbers of patients and the regulatory authorities throw up their hands and say nothing more can be done.  And, quite frankly, it is convenient for industry to go along with that.  When I mention devoting more resources to safety studies, I mean just that: namely putting the best minds and the smartest ideas to work.  Which means coming up with innovative ways to evaluate safety – computer simulations, worst-case scenario planning, extensive animal testing, factorial patient sampling (e.g. working with a diversity of patients), human factors studies (for the surgical techniques to implant the devices), etc. etc. All of these “tricks” are used to obtain that all-important efficacy endpoint.  No one says simply “increase the sample size” in order to get a better efficacy result – even though that would, of course, be the most obvious solution.  Instead, much thought and effort goes into inclusion and exclusion criteria, optimizing the indication (which often means confining it to an increasingly minute slice of the population), analyzing surrogate endpoints, sophisticated statistical analyses, etc. etc.  I’m not saying it’s a game but clearly all sorts of innovative techniques are utilized to obtain efficacy results from as few patients as possible. The problem (as also outlined in the article “Avandia, the Drug Safety Debate and How to Get a Nobel Prize”) is that such safety studies are decidedly unglamorous and not a fast track to career success in the sciences.  In fact, when a prominent scientist such as Dr. Steven Nissen investigates safety some people are apt to question his motives more than the validity of his motives.  The same would be unlikely if he were confining his studies to the more glamorous, yet less politicized efficacy questions."

What do you think? 

Ogan Gurel, MD
gurel@aesisgroup.com
http://blog.aesisgroup.com

Drug safety efficacy FDA reform Avandia Vioxx Aesis Research Group Ogan Gurel MD