Last Minute Drug Approvals Linked to Postmarket Safety Issues

Drugs approved by the FDA just before mandated deadlines are more likely to have safety issues after entering the market than those approved at other times, according to a study in the March 27 New England Journal of Medicine.¹ Coincidentally, on that date, the FDA announced the first group of marketed medications, including the atypical antipsychotic clozapine(Drug information on clozapine) (Clozaril), for which it is requiring additional safety plans under the FDA Amendments Act of 2007.

With the seeming spate of drug warnings and recalls, the adequacy of the agency’s safety and effectiveness evaluations has come under question. Some reforms have been implemented, and additional authority has been granted the FDA to conduct postmarket regulatory interventions. The impact of the Prescription Drug User Fee Act (PDUFA) of 1992 on the approval process and drug safety has received particular scrutiny.

The PDUFA levies fees on applicant pharmaceutical manufacturers to help fund drug evaluations and mandates, with the threat of funding cuts, that the FDA make a determination within 12 months on most new drug applications. Subsequent legislation reduced this to 10 months, and high-priority applications for drugs that treat serious illnesses for which there is no adequate alternative treatment are to be evaluated within 6 months.

In their NEJM article, Daniel Carpenter, PhD, professor of government at Harvard University, and colleagues at Harvard Medical School observed that after the PDUFA, a disproportionate number of approvals occurred within 2 months before mandated deadlines. Compared with drugs that were deemed approvable earlier in the evaluation period or that were assessed for periods beyond the deadline, their study found that drugs approved close to the impending deadline were 2 to 3 times more likely to be recalled for safety concerns, 2 to 7 times more likely to require addition of a black box warning to the approved labeling, and 2 to 7 times more likely to have 1 or more dosage forms discontinued voluntarily by the manufacturer.

These drugs were not deemed inherently more risky by the investigators because they were not more likely to be “first in class,” to have required advisory committee assessment, or to have primary indications with high rates of hospitalization. The common risk factor appeared to be mandated deadlines, which the investigators associate with a change in the pattern of FDA decision making.

Carpenter and colleagues characterize the constraints of deadlines as a “blunt tool with which to accelerate review.” They opine that the PDUFA might have hastened drug reviews with fewer subsequent safety problems if it had simply imposed the fees and used the proceeds to hire more FDA staff scientists.

Previous assessments of the PDUFA have differed in concluding whether it has added to or detracted from the effectiveness of drug safety screens. Carpenter and colleagues, however, consider that some earlier assessments of the impact of the PDUFA on drug safety have been too broad. They claim that in the approval deadlines, they have identified a factor that is a “much more specific and plausible mechanism” of affecting drug screening and the related consequences.

FDA Requires Postmarket Safety Plans

Although the FDA could rescind approval of a product and require it to be withdrawn from the market, there were few other actions it could take on marketed products without voluntary compliance of the manufacturer. Even when drug approvals had been qualified by requirements for postmarket study, there was little consequence when the studies were delayed or incomplete.

The agency gained additional authority to act on marketed products from the 2007 FDA Amendments Act, including the capacity to require safety plans for products deemed to pose particular risks and to enforce manufacturer compliance. If a satisfactory safety plan is not received or adhered to, the agency can impose civil monetary penalties on the manufacturer or deem the product to be misbranded. On March 27, the FDA announced the first group of drugs and biologic products for which it would require Risk Evaluation and Mitigation Strategy (REMS) plans.² Clozapine is among the 25 products in the group, as is the antiprogestational agent, mifepristone(Drug information on mifepristone) (Mifeprex), which has been investigated in treatment of postpartum depression, and the retinoid isotretinoin(Drug information on isotretinoin) (Accutane)—a known teratogen whose adverse effects include a range of psychiatric symptoms.

The REMS must contain “elements to assure safe use,” and it is possible that the elaborate monitoring system that has been used in psychiatry for clozapine could serve as a model for REMS adherence. The elements of safety as described in the statutes can include restriction to patients with evidence of safe use, steps such as laboratory monitoring, and patient enrollment in a central registry.

Increased FDA capacity to intervene postmarket is warranted for the unforeseen drug reactions and interactions that can occur when the limited investigational drug use is increased after market release. Carpenter and colleagues point out, however, that more should be done in premarket assessment. “Relying more on staffing and less on deadlines would result in the same degree of review efficiency without increasing the risk . . . of unanticipated drug-safety problems,” they argue.