Sunday, September 13, 2009

He is right, but greater safety is not synonymous with more stringent regulation. In fact, net benefit to patients is often compromised by excessively risk-averse regulatory policies that hinder the use of important products or unnecessarily delay their availability. That is evident today in current trends in the regulation of pharmaceuticals.

Earlier this month, the Food and Drug Administration revised a black-box warning, the most severe at its disposal, on the labels of an important class of drugs used to treat inflammatory diseases such as rheumatoid arthritis, Crohn’s disease and inflammatory bowel disease.

The cancer risk of these drugs, called TNF inhibitors, has been known for years, but regulators wanted the labels to highlight cancer risks in children and adolescents. The new warning signals only a change in perception of risk, not new information about heightened risk.

In recent years, the FDA has been using — some would say overusing — black-box labels with increasing frequency. Between 2003 and 2007, the number of new or revised black-box labels increased almost fourfold. This proliferation of warnings has its own negative effects.

Consider, for example, the risk-benefit calculation for use of the drug to treat inflammatory diseases. The prominent black-box labels certainly deter both physicians and patients from resorting to drugs that carry these warnings.

If the drugs are underused because of heightened concerns elicited by the new additional cancer warning, might patients with inflammatory bowel disease face a higher risk of colon cancer as a result of years of inflammation of the colon, as well as the morbidity of undertreatment of the disease?

You won’t see those risks in bold print, but they are just as real. That is precisely the problem with the trend at the FDA toward erring on the side of more warnings and more risk aversion in general.

An unequivocal example of ill-advised caution is the FDA’s warning last month about the safety of a product called e-cigarettes, which many smokers use to give up real cigarettes. These devices supply users with vaporized nicotine and look like cigarettes; some even boast an LED light at the tip. They contain no tobacco and are noncombustible, and they lack most of the risks of smoking.

For the vast majority of smokers unable to quit even with the help of drugs and counseling, e-cigarettes could be lifesavers — but because the FDA found tiny levels of carcinogens in the product, the agency warned smokers to stay away, essentially telling them to go back to deadly cigarettes. Regulators appear not to understand comparative risk assessment.

The trend toward more black-box warnings illustrates that as the agency weighs benefits versus risks of drugs and medical devices, the risk side will dominate. Nowhere is this more evident than in the FDA’s Risk Evaluation and Mitigation Strategies (REMS), which the agency can impose on new drugs whenever it wishes.

These REMS include “elements to assure safe use” of the drug, which may encompass restriction of the drug to specified patient populations, distribution only by certain specialty pharmacies, required laboratory findings/monitoring in all patients who get the drug, advertising permitted only to certain physician specialists, and patient enrollment in a central registry. These restrictions and requirements amount to “limited” approvals of a new drug, which will have the effect of constraining the prescribing and use of the medicine.

The swinging of the pendulum at the FDA toward greater risk aversion and more stultifying regulation itself has side effects:

c Fewer patients will get the treatment they need, out of an “abundance of caution” and physicians’ fear of litigation or their aversion to red tape.

c The proliferation of black-box warnings, originally meant for only the most dangerous drugs, has discounted the impact of these warnings and made them less meaningful.

c The FDA’s new regulatory power over tobacco actually makes it harder for people to quit smoking cigarettes.

c Investors and industry researchers have less incentive to pursue new medications whose markets are constrained by regulatory policy.

Are we becoming too “safe” for our own good?

Dr. Henry I. Miller, a physician and fellow at Stanford University’s Hoover Institution, was an official at the Food and Drug Administration from 1979 to 1994. He is the author of “To America’s Health: A Proposal to Reform the FDA.” Jeff Stier is an associate director of the American Council on Science and Health.

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