Postmarketing Studies Lag After FDA Approvals.


Of the 20 new drugs approved for marketing by the US Food and Drug Administration (FDA) in 2008, 8 received expedited reviews after significantly fewer patients were studied, according to an article published online October 28 in JAMA Internal Medicine. In addition, 50 of 85 postmarketing study commitments, included as conditions for approvals, remained unfulfilled as of January 2013.

Thomas J. Moore, AB, from the Institute for Safe Medication Practices, Alexandria, Virginia, and Curt D. Furberg, MD, PhD, from the Wake Forest School of Medicine, Winston-Salem, North Carolina, conducted a descriptive study of 2008 FDA new molecular entity approvals using FDA documents, drug information databases, prescribing information, and other data sources.

They found that the drugs approved under the accelerated approval program received approval after a median of 5.1 years (range, 1.6 – 10.6 years) compared with 7.5 years (range, 4.7 – 19.4 years) for drugs approved under the standard review process (P = .05). Moreover, approvals for expedited-review drugs came after efficacy testing in a median of 104 patients (range, 23 – 599 patients) compared with a median of 580 patients (range, 75 – 1207 patients) for standard-review drugs (P = .003).

The 20 drugs approved in 2008 were split evenly between inpatient and outpatient use. Seven of the drugs were approved with orphan drug status for rare diseases, including 6 of those that received expedited review. (The FDA also approved 4 diagnostic tests in 2008, which the researchers did not include in their current analysis.)

All 20 drugs were still marketed as of January 2013. However, drug sponsors had completed just 26 of 85 (31%) postmarketing studies and submitted data for FDA review for another 8 (9%). In other words, drug sponsors had not yet met their commitments for 50 of the 83 postmarketing commitments that were required by the agency as part of the approval process.

Interestingly, commitments remained unfulfilled for both drugs that received accelerated approval (18/48 [38%]) and those that received standard approval (23/37 [48%]).

The researchers note that postmarketing commitments occur a median of 11 years after approval; their study only covered 4 years. Of 48 studies that were scheduled for completion by study time, 34 (71%) had been submitted.

At the time of approval, 5 of the 20 drugs carried a boxed warning of a significant safety risk, 8 carried a requirement of special risk management, and 8 carried a warning or contraindication for hypersensitivity. Since approval, 5 drugs received a new or expanded boxed warning, raising the total number to 7 drugs. One drug received new contraindications, and 4 drugs received additional warnings or precautions.

Shifting Situation

“The testing of new drugs has shifted from a situation in which most testing was conducted prior to initial approval to a situation in which many innovative drugs are more rapidly approved after a small trial in a narrower patient population, with extensive additional testing conducted after approval,” the researchers conclude. “Our findings suggest that the shift has made it more difficult to balance the benefits and risks of new drugs.”

The seriousness of the problem can hardly be overstated, according to Daniel Carpenter, PhD, from the Radcliffe Institute for Advanced Study, Harvard University, Cambridge, Massachusetts. “If the FDA’s requirements for new drugs, both premarket and postmarket, are weakened, trust in both the efficacy and safety of prescription drugs is likely to be weakened,” he writes in an accompanying commentary. “The stakes of the current policy debates could not be higher. There is scarcely a feature of the American health care system that does not depend on evidence-based trust in prescription drugs, ratified and enforced by the FDA.”