Author + information
- Anthony N. DeMaria, MD, Editor-in-Chief, Journal of the American College of Cardiology* ()
- ↵*Address correspondence to:
Dr. Anthony N. DeMaria, Editor-in-Chief, Journal of the American College of Cardiology, 3655 Nobel Drive, Suite 630, San Diego, California 92112
I was having a discussion about one of my pet peeves, the exportation of clinical research (1), when the general topic of the Food and Drug Administration (FDA) and medical innovation came up. The FDA is responsible for the approval and continued availability of cardiac drugs, biologicals, and devices, and its processes have recently received considerable attention in both the medical and lay press. My initial instinct was to regard the agency as an impediment to innovation. However, after having gone back and read some of the press pieces, it has become obvious that the role of the FDA is neither simple nor clear. The agency has the dual charge of seeing that effective therapies are made available to patients as rapidly as possible while simultaneously ensuring that those therapies are safe over the product lifecycle. In “a catch 22”, the FDA has received criticism for both delaying the availability of new therapies and for allowing drugs and devices to be approved before fully documenting their safety.
Although the FDA has long been criticized for over-regulation, more recently the predominant concern has been under-regulation. These concerns have particularly been fueled by high-profile drug withdrawals, such as Vioxx. Concern regarding under-regulation was perhaps best exemplified by a report on pharmaceutical regulation by the Institute of Medicine (IOM) in 2006. This document indicated that “the drug safety system is impaired,” and described “the perception of crisis that has compromised the credibility of the FDA and the pharmaceutical industry” (2). The recommendations included changes in organizational culture, a strengthening of science and expertise, an increase in regulatory authority, and an improvement in communication. Given the stature of the IOM and the careful and extensive process to create the report, these recommendations carried considerable weight.
Lately, worry of under-regulation has expanded to include the potential of undue influence by industry. In a 2006 survey (3), nearly 20% of scientists employed by the FDA indicated that they had been requested to use nonscientific considerations in creating scientific documents. More recently, FDA scientist Dr. David Graham (the whistleblower in the Vioxx affair), claimed that a report he had generated regarding possible adverse effects from rosiglitazone was delayed from journal submission (4). Questions were raised as to whether the manufacturer (GlaxoSmithKline) knew of and communicated the potential side effects in a timely manner, and whether in general the same agency that approved a drug should be responsible for determining whether it should be withdrawn. Past panels recommending drug approval or writing guidelines for usage were frequently reported to have relations with the industry under consideration. Last year Dr. Sanjay Kaul was abruptly dismissed from an advisory panel after the maker of the drug to be considered called the FDA to express concern regarding potential intellectual bias on his part about study results that supported approval. The net effect of the above events has been to suggest that, far from over-regulation, the FDA may be unduly loose in its oversight of medical therapies.
In contrast to the recent foregoing issues, concerns that over-regulation by the FDA delays and perhaps even stifles the discovery and approval of new therapies have been expressed nearly continuously for many years. It has been “guesstimated” that only 20% of investigational drugs that enter clinical trials actually achieve approval, and these at a cost of over $1 million. The process often requires many years and several large clinical trials, and the length of a typical FDA review when all data are completed takes 6 to 12 months. Approval, when achieved, often carries with it the requirement for specific product detailing and/or the need for additional post-market studies. Anecdotes exist regarding the changing of FDA personnel or of criteria during the development of new agents. The pathway for devices is similar, and both differ radically from that of surgical procedures, which do not have a prescribed approval process. Accordingly, the discovery and development of new therapeutics is a high-risk financial undertaking. Of significance, the nature of the approval process is somewhat different in Europe, as has been evidenced by the availability of new devices, such as drug-eluting stents and percutaneous heart valves, on that continent.
As daunting as is the demonstration of efficacy, the issue of proving safety is often more so. Proving a negative, that is, that the therapy is free of adverse events, is always challenging. In fact, given the limited number of highly-specified patients enrolled in most studies, it is difficult to be certain of how an agent will behave in a larger, general population. This, of course, is as great a challenge to the FDA as it is to the company developing the agent or device. As has been pointed out on numerous occasions, the penalty for delaying or prohibiting the approval of an effective agent is nearly always much less than that of making one available with significant toxicity. And so, the wheels sometimes seem to grind extremely fine, but very slowly. The net effect of the foregoing is a sense that the approval process represents a degree of over-regulation that could be lessened and accelerated.
Of perhaps greater relevance in regard to freedom from adverse events is the question of how safe a new pharmaceutical or device has to be. We in medicine live with risk/benefit ratios all of the time, and we make reasoned judgments accordingly. We understand that, in alleviating one problem, an agent may increase the chances of another (e.g., thrombolytic agents and stroke). Many get the impression that, in the quest for near absolute safety, the FDA may neglect the potential of benefit. I personally know of a number of physicians who hoarded as much Vioxx as they could find upon hearing that it would be removed from the market. They felt that at a low dose the benefit more than outweighed the risk. It is often quipped that aspirin could not be approved at the current time, and that penicillin, with a potential for allergic reactions, might have a difficult time as well. Of course, we may well have foisted this posture on the FDA, since the occurrence of side effects draws much more attention than the treatment of disease. It is in this sense that I worry about the potential for over-regulation by the FDA because there exists a possible under-emphasis of efficacy versus safety.
I have often heard it said that if both sides of an issue are unhappy, you must be doing something right. I certainly admire the dedicated scientists and staff of the FDA, and I respect the very difficult task that they perform well on a daily basis. They have their hands full balancing the efficacy and safety of new diagnostics and therapeutics, and striving for rapid benefits at minimal risk. They must walk the tightrope between over- and under-regulation. It is probably not surprising that, in attempting to achieve the proper balance, they disappoint parties on both sides. They are truly between a rock and a hard place. In my view, one concern is that the agency not overly emphasize risk over benefit. We count on them to provide us with a well-defined profile of both potential toxicity and efficacy. It should then be up to us and our patients to make the most reasonable decision as to when and how to use the treatment.
- American College of Cardiology Foundation
- DeMaria A.N.
- Baciu A.,
- Stratton K.,
- Burke S.
- Union of Concerned Scientists
- ↵Top Stories in Business. Wall Street Journal. June 11, 2010.