perceived rush to approve drugs without sufficient attention to safety, and press coverage of internal problems in CDER may have contributed to a deterioration of public confidence in FDA. Academics, consumer organizations, professional societies, and legislators debated the possible causes and solutions of what was seen by many as a major problem (Consumers Union, 2005; Grassley, 2005; NCL, 2005; US PIRG, 2006). FDA and the Department of Health and Human Services (DHHS) announced a series of steps to address drug safety, including asking the Institute of Medicine (IOM) to convene a committee to assess the US drug safety system and to make recommendations to improve risk assessment, surveillance, and the safe use of drugs.

In its report, the committee considered the drug safety system as the sum of all activities conducted by FDA and other stakeholders to monitor, evaluate, improve, and ensure drug safety. (See the committee’s Statement of Task in Box S-1.) Although much of the committee’s work was focused on drug review, safety surveillance, and related activities of CDER, the committee also reviewed some key aspects of the roles and considered the potential contributions of the pharmaceutical industry, the academic research enterprise, Congress, the health care delivery system, patients, and the public.

Some observers believe that drug withdrawals (which are only one potential indicator of drug safety) represent de facto failures of the drug regulatory system, or that newly identified unusual and serious adverse events indicate that someone made a mistake in approving the drug. This is not so. FDA approval does not represent a lifetime guarantee of safety and efficacy, and what is newest is not always the best. For several related reasons, even the best drug safety system would not prevent adverse reactions to pharmaceuticals on the market. It is impossible to know everything about a drug at the point of approval because drugs’ mechanisms of action are complex, and because the clinical testing that happens before approval is generally conducted in controlled settings in defined, carefully selected populations that may not fully represent the wide range of patients who will use the drug after approval, some chronically, and in combination with other drugs. Thus, the understanding of a drug’s risk-benefit profile necessarily evolves over the drug’s lifecycle. CDER staff who review regulatory submissions, such as new drug applications, must strike a delicate balance in judging the drug’s risks and benefits, and whether the need for more study to increase certainty before approval warrants delaying the release of the drug into the marketplace and into the hands of health care providers and their patients.

Legitimate questions have arisen about CDER’s handling of drug safety. Are safety signals recognized and addressed in a timely fashion? Is the public informed about safety problems in a clear and timely manner? Do the interactions of pre- and postmarketing center staff facilitate effective action



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