Enhancing Drug Safety:

Creating an Independent Office of Drug Safety

Overview

Tens of millions Americans rely on FDA-approved drugs to safeguard their health. In fact, two-thirds of all adults report taking one or more prescription medications to treat chronic conditions.

But revelations over the past 12 months have both shattered public confidence and raised significant questions about FDA’s ability to ensure the safety of the drugs it approves. In a number of instances, though clinical studies have raised significant safety questions about FDA-approved drugs, FDA has failed to take timely action to warn doctors and patients about those issues. The agency lacks authority to require and enforce risk mitigation measures after a drug is approved. Of equal concern, some scientists at FDA report that their own findings regarding drug safety have been suppressed. Finally, in most cases, FDA lacks authority to require important post-approval safety studies that provide the data required to balance risks with benefits.

To restore public confidence and eliminate the conflicts of interest and regulatory failures plaguing FDA, Congress should authorize and fully fund an independent Office of Drug Safety with new regulatory authorities to require post-approval studies and take corrective action when data show that drugs pose an unreasonable risk to public health.

The Problem

FDA drug safety review processes, both prior to and after approval, are beset with problems, ranging from inadequate pre-approval reviews, insufficient post-approval safety monitoring and internal conflicts of interest that prevent the agency from acting.

Inadequate Pre-approval Review Process: Tight pre-approval deadlines for consideration of new drug applications do not allow time for adequate review. Nearly one-third of FDA reviewers say the review process has gotten worse in terms of allowing for in-depth scientific reviews. And more than one-third say they are either only "somewhat confident" or "not at all confident" that final decisions adequately assess drug safety.

Of perhaps greater concern, nearly 20% of FDA reviewers report that they have felt pressured to approve a drug despite their reservations about safety, efficacy or quality.

To correct these problems without impeding approval times, FDA must improve post-market safety monitoring.

Insufficient Pre-Approval Clinical Trial Data: Though pre-approval clinical trials that drug companies conduct may adequately assess efficacy, they are rarely large enough or conducted for a sufficient duration to determine the safety of drugs, particularly those that may be taken over a lifetime. Other shortcomings may include too few subjects or testing on a homogeneous population in terms of age, illness, and other factors. In fact, FDA regulations allow for drug approval with evidence from a single clinical trial demonstrating effectiveness. In too many cases, safety concerns emerge only after a drug has gone on the market and millions of patients begin using it.

Inadequate Post-Marketing Safety Monitoring: Unfortunately, FDA does not have authority to require drug sponsors to conduct additional safety or efficacy drug trials except as a condition of approval and in other very limited circumstances. Even then, study requirements are the subject of negotiations with the drug sponsor. Once a drug has been approved, FDA has little ability mandate additional studies.

Drug companies can and do conduct their own post-marketing studies, but rarely for the purposes of examining safety. It’s not surprising then that nearly one fifth of FDA reviewers lack confidence that FDA adequately monitors safety after a drug is approved. Another 47% say they are only "somewhat confident."

Delays in Post-Marketing Studies: Drug companies routinely drag out completion of required post-marketing studies. FDA has few tools to prevent this. Of nearly 1,200 current post-marketing drug studies, only 12% have been submitted; 68% have not yet begun.

FDA’s only tool to enforce agency requests for submission of post-marketing study commitments is to threaten to withdraw approval. Even that penalty is available only for failure to submit studies required under accelerated approval. FDA has never withdrawn a drug for failure to submit post marketing study commitments.

Delays in Mitigating Safety Risks: Even when FDA attempts to take corrective action to mitigate a drug safety risk—such as labeling changes, use restrictions, and advertising limitations—it must negotiate extensively with the drug sponsors, delaying delivery of safety information and implementation of risk management steps. The label change warning of cardiovascular risks for Vioxx was finalized more than 18 months after study results raising that concern were released. Of those 18 months, 7 were consumed by negotiations with Merck on the content of the label change.

Organizational Conflicts: FDA’s Center for Drug Evaluation & Research (CDER) includes both the Office of New Drugs (OND), which approves new drugs, and the Office of Drug Safety (ODS), responsible for post-approval safety monitoring of all drugs. The offices are not organizational peers and do not share comparable regulatory authority.

Despite ODS’s role in identifying safety concerns, it lacks regulatory authority to act on those findings. Only OND can take regulatory action when safety questions arise, creating a situation in which those who approve the drugs are responsible for admitting their own mistakes. Ongoing reports also suggest that OND staff have the last word on reviews and analyses conducted by the ODS. In recent cases, ODS scientists allege their safety findings have been suppressed by OND and CDER officials.

Resource Imbalances: The Office of New Drugs accounts for half of the Center’s $456 million budget and nearly half of its staff. Meanwhile, the Office of Drug Safety accounts for just 5 percent of the Center’s funding and staff.

Between 1991 and 2000, OND approved 1,090 new drug applications, generating 1,737 study commitments addressing clinical safety and efficacy that ODS must monitor with its small staff. This is on top of ODS’s responsibility to evaluate some 400,000 adverse event reports annually. The burden on ODS has only increased as FDA has accelerated approval times to meet Prescription Drug User Fee Act deadlines and provide fast-track approval for serious or life-threatening conditions.

The Solution: An Independent Office of Drug Safety

Congress should pass new legislation creating an independent Office of Drug Safety to improve pre-approval and post-market safety reviews. The new Office should have:

Complete independence from the Center for Drug Evaluation and Research—the FDA division that approves new drugs;
Authority to review the safety of a drug before it is approved and require labeling, marketing or distribution restrictions as well as additional post-approval studies when safety concerns exist;
Authority to subject new drugs to "provisional approval" pending completion of additional safety reviews, with additional authority to withdraw approval at the end of a provisional period if the drug poses an unreasonable safety risk;
Authority to review, prior to dissemination, advertising and other promotional materials for drugs with outstanding safety questions;
Authority to, at any time, require additional studies to further evaluate the safety of drugs, both before and after they are approved;
Authority to set the terms, standards and deadlines for post-approval studies;
Authority to make determinations regarding the safety of a drug at any time;
Authority to take corrective action to mitigate unreasonable risks to public health posed by a drug and to withdraw approval of a drug if corrective action cannot mitigate safety risks;
Authority to impose civil penalties on drug companies that fail to submit required studies or take corrective action as directed by the Office;and

Full funding to carry out its duties.