The credibility of the FDA.

The Food and Drug Administration (FDA) relies upon adverse event data collected during pharmaceutical trials to evaluate the safety of medications, but these trials often fail to permit an adequate assessment of safety. The FDA usually recommends that at least 1500 patients be exposed to a new drug. Such relatively small samples stand little chance of detecting serious safety risks. In addition, if pharmaceutical manufacturers conduct trials on relatively young and healthy subjects, the likelihood of identifying serious risks is lessened even more. Further exacerbating the problem, the FDA accepts surrogate markers, rather than morbidity and mortality data, for some drug approvals. According to Raymond Lipicky, MD, former Director, Division of Cardiovascular and Renal Products, FDA/Center for Drug Evaluation and Research, for drugs that do not prolong longevity (i.e. arthritis medications, analgesics, anxiolytics, antidepressants, decongestants, and migraine medications), what constitutes an adequate ‘safety’ database for approval has no easy answer and is currently poorly defined (personal communication). Post-marketing surveillance is a mechanism to help identify unsafe drugs, but it is an imperfect system. This is especially true when adverse events occur commonly, as is the case with heart attacks and strokes. For example, post-marketing surveillance had nothing to do with detecting the cardiovascular risk of rofecoxib (Vioxx). Rofecoxib is one of several medications taken off the market in recent years due to cardiovascular safety concerns. The list also includes: valdecoxib (Bextra); sibutramine (Meridia), a weight loss medication; and ephedrine alkaloids used in weight-loss products. Each of these drugs, rofecoxib included, raises blood pressure (BP). Drugs that raise BP predictably increase the risk of heart attacks and strokes. Moreover, if a drug increases BP, it is possible to calculate its risk of causing heart attacks and strokes. According to Norman Stockbridge, MD, PhD, Director, Division of Cardiovascular and Renal Products, FDA/Center for Drug Evaluation and Research, the FDA recognizes that a modest elevation in BP, even if it is undetectable in any given individual, increases the risk of heart attacks and strokes, but, in the absence of cardiovascular safety data for a specific medication, the FDA’s stance is that no regulatory action for the medication is indicated (personal communication). Regardless of the FDA’s stance, when a drug predictably increases the risk of adverse events, the FDA ought to ensure that appropriate safety data is obtained. This is simply common sense. Many drugs currently on the market raise BP, yet little or no cardiovascular safety data is available for most of these drugs. Table 1 lists medications that raise BP and indicates the regulatory status and cardiovascular safety data for each. That so many drugs are on the market without adequate cardiovascular safety data undermines the credibility of the FDA. Why doesn’t the FDA require the collection of cardiovascular safety data for medications that raise blood pressure? For new drug approvals, the FDA can require manufacturers to conduct safety trials after a drug is approved. Many of the drugs listed in Table 1 were approved so long ago that they are available generically. Even if the FDA desired the collection of safety data for these drugs, it is complicated to require manufacturers to obtain data for drugs that are available generically. The FDA lacks a legislative mandate to conduct research. Consequently, the FDA lacks the financial resources to support prospective drug trials. For the drugs listed in Table 1 for which safety data are inadequate, the FDA might be able to support retrospective studies. There is precedent for this approach. In collaboration with the Agency for Healthcare Research and Quality, the FDA supported two recently published retrospective studies regarding the cardiovascular safety of attention deficit disorder medications. The credibility of the FDA has been damaged by multiple drug approvals that occurred despite inadequate safety data. Restoring the FDA’s credibility