Postmarketing surveillance--lack of vigilance, lack of trust.

PHYSICIANS AND PATIENTS EXPECT THAT WHEN MEDIcations are prescribed correctly for labeled indications and are used as directed, these medications generally will have beneficial effects and will not cause significant harm. This confidence in pharmaceutical products reflects trust in the effectiveness and integrity of the drug approval and monitoring process. However, the current approval process for drugs and biological agents in the United States has come under intense scrutiny, most notably because of concerns about influence from industry. For instance, since adoption of the 1992 Prescription Drug User Fee Act, which augmented the budget of the Food and Drug Administration (FDA) by charging “user fees” to pharmaceutical firms, the FDA has received approximately $825 million in fees from drug and biologic manufacturers from fiscal years 1993 through 2001. During that time, median approval times for standard (ie, “nonpriority”) drugs decreased from 27 months in 1993 to 14 months in 2001, but as an inevitable consequence of faster approvals, drug recalls following approval increased from 1.56% for 1993-1996 to 5.35% for 19972001. In addition, an investigation of 18 FDA expert advisory panels revealed that more than half of the members of these panels had direct financial interests in the drug or topic they were evaluating and for which they were making recommendations. The drug review process has been described as structurally similar to many decisions made by other regulatory agencies, such that it is characterized by high uncertainty, avoidance of observable error, and low (reputational) reversibility, with drug recalls harming the reputation of the FDA for a faulty approval decision, and often severely affecting the manufacturer. Given that new products are the financial lifeblood of pharmaceutical companies, the stakes are raised higher due to intense lobbying by interested parties such as health professionals and patient advocacy groups, as well as pharmaceutical and technology companies, so it is no wonder that, in 2003, the pharmaceutical industry earmarked $4.9 million to lobby the FDA. While these concerns are noteworthy, they pale in comparison to the shortcomings and failures of the current imperfect system for postmarketing surveillance. This system is intended to detect adverse drug events and reactions once new products are in widespread use, and thereby limit exposure of the public to hazards of new medications. The inadequacies of the postmarketing surveillance system (ie, FDA’s MedWatch program with passive collection of spontaneous reports of adverse drug reactions) for ensuring safety are well known and include: reliance on voluntary reporting of adverse events by physicians and other health care professionals; poor quality of submitted reports, often with inadequate documentation and detail; underreporting of adverse outcomes with capture of only a small fraction of adverse events that actually occur; difficulty in calculating rates of adverse events because of incomplete numerator data on events, together with unreliable denominator data on exposure; limited ability for spontaneous reports to establish causal relationships; and difficulty in determining whether the adverse event resulted from the drug or the disease it was intended to treat. Yet the major problem with the current system for ensuring the safety of medications is that drug manufacturers are largely responsible for collecting, evaluating, and reporting data from postmarketing studies of their own products. This approach has many inherent problems. For instance, it appears that fewer than half of the postmarketing studies that manufacturers have made commitments to undertake as a condition of approval have been completed and many have not even been initiated. Moreover, despite the mandatory adverse event reporting system for companies subject to the FDA’s postmarketing safety reporting regulations, drug manufacturers may be tempted to conceal available data that may signal the possibility of major risks. In some cases, the FDA and drug manufacturers may fail to act on that information and fail to conduct appropriate studies to examine a potential risk rigorously and promptly. The well known saga of the link between the selective serotonin reuptake inhibitors and teenage suicide was notable