New safety threats identified in one-third of drugs post-approval

Nearly one-third of drugs approved by the U.S. Food and Drug Administration spark safety warnings or recalls on issues that aren't identified until after they hit the market, according to a new study.

About 32% of the 222 drugs approved by the FDA from 2001 to 2010 were subject to recalls on safety risks that weren't discovered during pre-approval clinical trials, the study published Tuesday in JAMA found. More rigorous monitoring of drug treatment is needed to reduce the number of post-approval safety threats, said lead author Dr. Joseph Ross, an associate professor of medicine and public health at Yale University.

Biologics, drugs used for psychiatric diseases and drugs that were approved close to their regulatory deadline correlated with higher rates of safety issues, the study found.

Safety warnings and recalls of drugs can cost providers, manufacturers and payers millions. Developing a system to manage safety warnings or recalls; providing care to patients using unsafe drugs; and returning drugs to manufacturers and replacing them with alternatives come with significant costs, healthcare experts said.

There has been industrywide pressure to reduce review and approval times for drugs and medical devices in order to lower costs. The key is for the FDA to strike an appropriate balance between efficient drug approval times while ensuring medications are safe, said Erin Fox, director of drug information at University of Utah Health's Drug Information Service.

"The more we move toward smaller trials and approving drugs studied in smaller and smaller numbers of people, the more frequently we will discover safety concerns post-approval," she said. "What is incredibly important are post-marketing studies. . . . Those post-approval studies are not always happening."

Fox was not surprised that adverse effects are discovered after approval given that many drugs are only studied in a limited number of patients and some side effects are quite rare, she said.

David Rosen, a partner and public policy lawyer with Foley & Lardner, echoed that sentiment, adding that patients have more access to drug information and are likely more aware of adverse events.

The debate on FDA user fees is central to this issue. The Senate Health, Education, Labor & Pensions Committee will discuss the potential reauthorization of the FDA's ability to collect user fees from drugmakers on Wednesday, which could streamline the administration's product approval process. The proposed agreement calls for more than $400 million in additional user fees in the next year that would allow the FDA to hire more staff and speed up approvals. Healthcare companies could streamline operations, supporters argue, while critics claim that the rising fees disproportionately affect smaller companies that cannot accommodate the fee hike.

But the proposed user fee review deadlines don't jeopardize the safety of approved drugs, Rosen said.

"I don't think that the user fee time deadlines really have an impact; it doesn't mean that the FDA is putting out drugs that are less safe," he said. "The FDA takes safety very seriously and does the best job it can in making sure labels show the proper risk and benefits and are updated."

Researchers did not come to a conclusion on whether the special accelerated approval and priority review pathways were correlated to greater safety risks.

They studied drugs classified as autoimmune, musculoskeletal and dermatology; cancer and hematology; cardiovascular disease, diabetes and hyperlipidemia; genitourinary and renal; infectious disease; neurology; and psychiatry.

Of the 123 incidents involving 71 drugs that were reported after approval, three resulted in withdrawal, 61 led to black-box warnings included in the packaging and 59 involved communication with doctors and patients. FDA actions came a median time of 4.2 years after approval, according to the study.

Patient safety could be improved by identifying potential safety issues at the time of FDA approval and focusing oversight on at-risk drugs to facilitate earlier detection, the study said.