The Bureaucratization of Safety and Effectiveness
On June 30 the self-applause of The Beltway will be deafening, and not merely because it falls on a day hallowed above all others by government employees, to wit, a Friday beginning a long holiday weekend. No, that date marks the 100th anniversary of the FDA, an agency now synonymous with the bureaucratized analysis of the safety and effectiveness of pharmaceuticals.
And what better way to celebrate than with an expansion in FDA regulatory powers? Forget flowers, chocolates, and jewelry: Congress is awash in proposals to increase FDA authority and resources to monitor drug safety. In the wake of the recent Vioxx tragedy, Congress is anxious to expand the agency's already Promethean ability to regulate new medicines, and the media stand eager to offer congratulations for imposing more restraints on medical progress.
And seldom—make that never—will be heard a discouraging word, specifically, that the traditional FDA regulatory model increasingly will become an anachronism in the 21st century. Like all government agencies, the FDA by necessity must deal with aggregates, with averages, and with a determination to make one size fit all. But the increasing size of patient populations means automatically that heterogeneity will become the rule in terms of diagnoses and treatments, and technological advance will facilitate precisely that sort of differentiation.
The traditional FDA approach of one-size-fits-all evaluation—safety and effectiveness as determined in statistical trials both small and large—will be forced to swim against that stronger tide of personalized medicine, and it is doubtful that this traditional approach can prevail against powerful incentives of individual patients and their physicians to find individualized treatment protocols when available technologies allow them to do so.
Let us begin at the beginning: No human activity is safe: not even lingering in bed on a Sunday morning. After all, the ceiling might cave in with some probability greater than zero, and a hard hat worn in bed would interfere with more than mere sleep. Similarly, nothing that we consume is safe, and no activity undertaken in the pursuit of safety is safe either. Every endeavor, every good, everything that we confront, accept, pursue, and eschew yields outcomes simultaneously beneficial and adverse, and a good description of life is the endless series of choices among greater and lesser opportunities and evils offering varying combinations of benefits and joys, risks and adversities. The Garden of Eden, sadly, is an option no more.
Now, this is so obvious that it hardly seems worthy of repetition. But in that alternative universe inhabited by The Beltway, the eternal vanity not actually believed by anyone, except the mainstream journalists and the plaintiff attorneys, is that safety and effectiveness are absolute goals worthy unto themselves, mutually independent and subject to analysis in isolation.
Even the Beltway administrators have not succumbed to anything so silly. The FDA is explicit in its understanding that some adverse side effects of pharmaceuticals are inevitable, and that the singleminded pursuit of safety would yield a world literally without drugs at all, including aspirin, that is, without the huge medical and financial benefits attendant upon their use. The question, then, simultaneously is simple and complex: What is the right tradeoff between safety and effectiveness?
Actually, that is not quite the right question. The real question is: Who should decide what the right tradeoff is, that is, who should decide what risks are acceptable in pursuit of what potential benefits? And so we have, broadly speaking, two alternative answers. There is the top-down approach of the FDA, in which centralized analyses of aggregated data, along with highly subjective decisions about the quality of life and the value of weeks, months, and years, yield decisions about the relevant tradeoffs, that is, about which drugs are to be approved for use.
And then there is the bottom-up approach inherent in market processes, in which drugs would be developed and promoted by producers with a powerful interest in the protection of their brand names, after which trial and error by doctors and their patients over time would yield lessons for clinical practice, caveats for individual patients and patient categories, and the evaluation of the relevant tradeoffs undistorted by political pressures.
We return to that frightening "trial and error" below. For now, let us consider the respective incentives inherent in the top-down and bottom-up approaches. For the FDA, indeed for the most humane, public-spirited, and caring public official imaginable, loud headlines about an unexpected adverse side effect of a drug already approved bring with them the grandstanding of the politicians, the television cameras of the Congressional hearings, the picket signs of the "consumer" groups, the public tears of the families, the opprobrium of Oprah, and the finger-pointing of the bureaucracy. Not to mention the tragic loss of another long holiday weekend spent at the office.
Only regulatory delay offers relief from such horrors, delay predicated upon a purported need for more data, more analyses, more clinical trials, and more costs. And, inexorably, more patients who suffer and die as they endure the delays attendant upon the expanded approval process, the end of which offers the supreme benefit of reduced political risks for the FDA administrators. Do you remember the headlines about the thousands of patients who died in the months and years before a given drug was approved? Neither do I, and neither does anyone else, except for a very few drugs for which powerful patient groups exerted overwhelming pressures; this is a fact of life that cannot but distort the evaluation of risks and benefits as perceived in a top-down approach for drug approvals. When the FDA announces approval for a new drug, and estimates the thousands of life-years that will be saved, it is useful to ask how many were not saved in, say, the last year of regulatory delay.
Consider instead the incentives inherent in a market-based bottom-up approach. Doctors have substantial incentives to find out and to explain both the benefits and risks of a proposed drug regimen, information that profit-seeking pharmaceutical producers have incentives to provide, as a means of protecting the economic value of their brand name capital. More to the point, patients have incentives to evaluate the benefits and side effects of drugs without the distortions inevitable in a political environment.
Yes, to a degree, this would be trial and error; some patients will suffer adverse effects worse or will enjoy benefits smaller than anticipated. Others will receive net benefits larger than expected. But the larger point is that the decisions about which risks are worth bearing would be made in the absence of the pressures afflicting life in The Beltway. This is precisely the nature of off-label drug prescription, which the FDA can do little to constrain other than by limiting the availability of information, a pursuit that can serve only the interests of the administrators rather than those of the patients.
And let us not forget that the top-down approach, again, by its very nature must focus on averages for given patient populations; one-size-fits-all simply is the nature of government. But in a world of increasingly individualized medicine, with technologies, procedures, and medicines developed in the context of particular DNA profiles and patient-specific information, the top-down approach increasingly will become both an obstruction and an anachronism, as patients prove increasingly unwilling to wait for The Beltway to complete all the paperwork after returning from the latest long holiday weekend.
So: Onward with the second century of the FDA. But as has been the case with so many other regulated sectors, in which distortions impose heavy costs upon certain groups, market forces have combined with technological advance to make the role of the regulators increasingly irrelevant. "Bottoms up" is a happy phrase in more ways than one.
This piece originally appeared in Medical Progress Today
This piece originally appeared in Medical Progress Today