The warning of the risk of diabetes and cognitive dysfunction recently added to the safety information of statin drugs by the Food and Drug Administration (FDA) reinforced my impression that there is now an excessive focus upon the adverse effects of drugs and devices. This impression has gradually formed over a number of years, fostered in part by the media attention accompanying the withdrawal of drugs, such as rofecoxib, and the delayed approval of therapeutic devices, such as transcatheter valves. So I decided to confirm this suspicion by researching the topic. As is so often the case, I was surprised at the considerable literature on the risk–benefit ratio, and that the issue was much more complex than I had envisioned. Although an Editor's Page is inadequate to address the subject adequately, it can certainly serve to convey some general thoughts.

In the process of researching the literature, I encountered an enlightening and very entertaining article by Louis Lasagna that I highly recommend (1). He points out that outrageous medications and claims of benefits were quite prevalent in the distant past, including Mrs. Winslow's Soothing Syrup to relax children that contained morphine, and the advertisement regarding Hamlin's Wizard Oil that “there was no sore that it will not heal, no pain it will not subdue.” The Food and Drug Act of 1906 established the agency to address dangerous practices in meat processing and the preparation and use of pharmaceutical agents. In 1962, following the adverse effects of thalidomide, the Act was amended and the attention of Congress regarding the FDA became focused on safety. In fact, it was not until the AIDS epidemic that the issue of the availability of medications came to the forefront. It should not be surprising, therefore, if the FDA were more disposed to the sin of omission of not approving an effective modality than to the sin of commission of approving one with serious adverse effects.

Despite the suspicions of an excessive emphasis upon safety engendered by the foregoing, the clearly stated mission of the FDA is to assure the safety, efficacy, and security of human drugs, biological products, and medical devices and to help speed innovations that make medicines more effective, safer, and more affordable. In this regard, the concept of safety does not include the freedom from adverse effects, but rather that any risk is outweighed by the benefit produced. However, the means by which this is decided is not clear cut, and certainly very complex. There is no established quantitative method for this determination, and at least 12 approaches exist in the literature (2), including net number needed to treat or harm, the risk–benefit plane and contour, multicriteria decision analysis, and the stated preference method. However, after extensive examination and analysis of these methods, all that investigators could conclude was that “multiple risk–benefit assessment approaches across different therapeutic indications and treatment populations should be undertaken to bound the risk–benefit profile (2).”

An interesting paper by Cohen and Neumann (3) illustrates the variables inherent in risk–benefit assessment by comparing the danger of taking aspirin to that of driving a car. Regarding risk, the authors indicated there is typically limited information prior to drug approval, and post-marketing data are often insufficiently comprehensive for this determination. Drug therapy may be mandatory or discretional. The magnitude of any adverse event can vary considerably, as can the number of side effects. The risk of adverse event may be near- or far-term, and the duration and intensity of administration required for risk may differ considerably. The characteristics of the individual, including age, comorbidities, and so on, may greatly influence the risk involved in any intervention. The perception and acceptability of risk may differ substantially among individuals, including the perceived catastrophic nature and “dread” of the event, its newness or familiarity, and the degree of public attention that it attracts. Inherent in this last issue is the supremely important factor of the freedom to accept any given risk, and the differences that individuals exhibit in this characteristic. Taking these variables into consideration as much as possible, the Cohen and Neumann (3) paper concluded that the mortality risk of aspirin (via stroke) was equivalent to that of driving a car.

Not considered in the above analysis, of course, was the benefit of any action or intervention. Just as the risk intrinsic to any medical treatment has multiple variables, so does the benefit. Obviously, the more severe the outcome of the condition being treated, the greater the risk that is warranted for the benefit of its remedy. The benefit sought may be partial or complete, and may have a high or low degree of certainty of occurring. As is true of risk, comprehensive data regarding the likelihood of benefit throughout a wide population is often lacking. Again, individuals may differ widely in the degree of distress that they experience with any signs or symptoms of a disorder, and the degree of risk they are willing to take to eliminate or reduce them.

It is apparent that the FDA, or any other international agency charged with the task, faces a formidable challenge in assuring the safety and efficacy of medical interventions. It is not surprising, therefore, that no uniform quantitative methodology is regularly employed in making these assessments. This does raise the specter, however, that subconscious bias could lead to greater emphasis upon risk than benefit, and to a somewhat cautious approach to drug and device approval. The regulatory process of the FDA in the United States seems to be more rigorous than elsewhere in the world, a policy for which valid arguments can be advanced. While the value of this rigor may be debated, it does have the potential to delay the availability of effective therapies to patients. The greatest impact occurs when the FDA makes a decision for society as a whole that a drug or device is not to be approved and, therefore, is not available. Those decisions hopefully provide protection from dangerous interventions for individuals who are incapable of or unwilling to make risk–benefit assessments. However, they deny the option of choice to those who desire to and can make such evaluations, and also can have the potential to dampen the willingness of innovators to try to bring their discoveries to the marketplace.

As stated in the opening paragraph, determination of the risk–benefit ratio of any medical intervention is complex at best, always challenging, and continues to be a frequently discussed in the literature. I believe that the professionals of the FDA who are charged with making these decisions are hard working and dedicated. Thank goodness that I do not have to make the judgments that are required of them. Not uncommonly they must reach verdicts in the absence of absolute certainty, and in the setting of external pressures. Society can help them in this regard by recognizing that safe does not mean without adverse events, but rather that the benefits outweigh the risks. While the occurence of significant adverse effects will almost certainly attract more attention than the absence of an effective therapy, the impact upon society of the latter may be much greater. We have to be willing to accept that a few may be injured so that many may be benefited.