The Danger of Too Much Caution

Congress has a long and ignoble history of exaggerated legislative responses to perceived health crises. They seem to be at it again.<?xml:namespace prefix = o ns = “urn:schemas-microsoft-com:office:office” />


In 1938, after a hastily marketed drug containing an untested solvent (diethylene glycol, a potent poison) killed more than a hundred people within a few days, Congress introduced a requirement for the pre-marketing demonstration of safety (but not effectiveness) for new drugs.


The next pivotal event in <?xml:namespace prefix = st1 ns = “urn:schemas-microsoft-com:office:smarttags” />U.S. drug regulation came a quarter-century later in response to the birth defects caused by the sedative Thalidomide—although the drug was never approved for marketing in the United States, and the vast majority of adverse events occurred in Europe. Whereas under the 1938 statute a product could be marketed unless the FDA actually denied approval of the new drug application (NDA), the 1962 legislation imposed important new constraints and requirements on drug sponsors: For the first time, all human testing of new drugs, all drug advertising, and all labeling had to be reviewed and pre-cleared by the FDA, and the FDA promulgated regulations for Good Manufacturing Practices.


Research and development of drugs in the United States have never been the same, and the costs of drug development have skyrocketed—direct and indirect expenses now exceed $800 million dollars to bring an average drug to market.


Recent events again have shifted the Congress into crisis mode. First the FDA was blind-sided by Chiron Corporation's inability to provide flu vaccine this season due to contamination at its manufacturing facility, depriving Americans of half the usual supply. That led Congressman Henry Waxman (D-CA), for whom no amount of regulation is ever sufficient, to excoriate the FDA: “The agency ignored glaring problems at the [contaminated] facility and missed repeated opportunities to correct them,” he said, concluding, “There is no better example of what's wrong at FDA than its failures at the Chiron vaccine facility.”


Then came Merck's withdrawal from the market of its blockbuster anti-inflammatory drug, Vioxx, because of an increase in side effects, including heart attacks and strokes. This led one of FDA's medical officers, in November testimony before the Senate Finance Committee, to accuse his own colleagues of discounting recommendations from the agency's safety researchers, and of consistently being in denial when data indicates safety problems from an approved drug.


The FDA is a favorite target of critics, who variously accuse regulators of excessive risk-aversion and delay of approvals, or of too cozy a relationship with the drug industry. Former FDA Commissioner Frank E. Young once characterized his agency as “a slow-moving target that bleeds profusely when hit.”


Senator Charles E. Grassley (R-Iowa), the chairman of the Senate Finance Committee, which held hearings in November, chided the agency, “The health and safety of the public must be the FDA's first and only concern.” He is right, but particularly when governmental pre-marketing approval of a product is required, greater safety is not synonymous with more stringent regulation. In fact, net benefit to patients often suffers because of an obscure regulatory anomaly: the asymmetry of outcomes from the two types of mistakes that regulators can make. A regulator can commit an error by permitting something bad to happen (approving a harmful product, a Type I error in risk-analysis parlance), or by preventing something good from becoming available (not approving a beneficial product, a Type II error). Both outcomes are bad for the public, but the consequences for the regulator are very different.


The first kind of error is highly visible, causing the regulators to be attacked by the media and patient groups, and to be investigated by congress. But the second kind of error—keeping a potentially important product out of consumers' hands — is usually a non-event, eliciting little attention, let alone outrage.


FDA's approval process for new drugs has long struggled with the Type I/Type II error dichotomy. Consider the FDA's approval in 1976 of the swine flu vaccine, generally perceived to have been a Type I error, because although the vaccine was effective at preventing influenza, it had a major side effect that was unknown at the time of approval—532 cases of paralysis, including thirty-two deaths, from Guillain-Barré syndrome.


The mistaken approval of such a product is highly visible and has immediate consequences: the media pounces, the public denounces, and Congress pronounces. The developers of the product and the regulators who allowed it to be marketed are excoriated and punished in such modern-day pillories as congressional hearings, television newsmagazines, and newspaper editorials. Because a regulatory official's career might be damaged irreparably by the good faith but mistaken approval of a high-profile product, decisions are often made defensively—in other words, to avoid Type I errors at any cost.


Type II errors, in the form of excessive governmental requirements and unreasonable decisions, can delay commercialization of a new product, lessen competition to produce it, and inflate its ultimate price. The detrimental effects of FDA delays in approving certain new drugs already approved in other industrialized countries are well documented. These include the greater than three-year delay in the approval of misoprostol, a drug for the treatment of gastric bleeding, which is estimated to have cost between eight and fifteen thousand lives per year; and the lag in the approval of streptokinase for the treatment of occluded coronary arteries, which may have caused the loss of more than ten thousand lives per year.


Although they can profoundly compromise public health, Type II errors caused by a regulator's bad judgment, timidity, or anxiety seldom gain public attention. Often, only the employees of the company that makes the product and a few stock market analysts and investors are likely to be aware of them.


Likewise, if a regulator's mistake precipitates a corporate decision to abandon a product, the cause and effect are seldom connected in the public mind. The companies themselves are loath to complain publicly about FDA misjudgments, because the agency wields so much discretionary control over their ability to test and market products. As a consequence, there may be little direct evidence or data to document the lost societal benefits or of the culpability of regulatory officials.


Former FDA Commissioner Alexander Schmidt aptly summarized the regulator's conundrum: “In all our FDA history, we are unable to find a single instance where a Congressional committee investigated the failure of FDA to approve a new drug. But the times when hearings have been held to criticize our approval of a new drug have been so frequent that we have not been able to count them. The message to FDA staff could not be clearer.”


As a result, regulators make decisions defensively–in other words, to avoid approvals of harmful products at any cost—so they tend to delay or reject new products of all sorts, from fat substitutes to vaccines and painkillers. That's bad for public health and for consumers' freedom to choose.


The FDA is not unique in this regard. All regulatory agencies are subject to social and political tensions that cause them to be castigated for the dangerous products that make it to market (often even if those products produce net benefits) but to escape blame when they keep beneficial products out of the hands of consumers.


Congressional oversight is supposed to provide a check on regulators' performance, but as observed by Commissioner Schmidt, rarely does it focus on their unnecessarily delaying product approvals. After all, a premature or mistaken approval makes for more exciting hearings, with injured patients and their families paraded before the cameras. Even when regulators' inappropriate delays are exposed, they can fall back on the “erring on the side of caution, better safe than sorry” defense. Too often, legislators, the media, and the public accept these euphemisms uncritically, making our system of pharmaceutical oversight progressively less accountable and less relevant to the public interest.


If we are to balance drug safety, innovation in research and development, and the availability and price of new medicines, we must find a way to make regulators accountable for costly errors of all kinds. One way would be to create a vigorous, independent agency ombudsman that could compel regulators to act in the public interest. The office would have to possess the following attributes: (1) independence from the agency and the FDA commissioner; (2) access to independent expertise in relevant disciplines, including medicine, pharmacology, science, regulation, and law; and (3) the power to levy sanctions against FDA employees found to be responsible, individually or collectively, for flawed decisions or policies that constitute severe, avoidable errors.


This proposal differs in critical ways from those of critics of the FDA who have called for the creation of a new regulatory agency wholly separate from the FDA that would focus on the safety of already-approved drugs. (They seem to have lost sight of the fact that patients are just as dead if they're killed by the delay of a life-saving drug—misoprostol, streptokinase, and Heptavax come to mind — as by an adverse event from an approved one.) The existence of an agency with such a narrow focus would make it easier for drugs to be withdrawn from the market, even if they were highly cost-effective for a certain narrow population (e.g., Accutane). It could also lead to more frequent use of absurdly restrictive and expensive distribution mechanisms, such as that for Thalomid (formerly, Thalidomide), which is controlled as though it were highly enriched uranium that could be made into nuclear weapons. We should have learned from bitter experience the outcome of regulation that focuses narrowly on “safety,” to the exclusion of benefit: for example, the EPA's over-zealous, anti-consumer, anti-innovation oversight of pesticides and other chemicals.


In contrast to the creation of a new entity narrowly concerned with the safety of marketed drugs, the ombudsman panel described above would redress errors of both over- and under-regulation, a more balanced and effective approach that would make regulators more accountable for their actions. (Such a mechanism could also be of value for improving the performance of non-regulatory agencies, such as the CDC, which admitted in November that it erred significantly in making a widely publicized calculation of how many people died from obesity in the last decade.)


Americans are, literally, dying for regulatory reform. And once Congress gets around to it, it would behoove them to remember that where regulation is concerned, sometimes less is more.