Aug. 14, 2014 -- In the years since the FDA sped up its drug-approval process, the rate of black box warnings on prescription drugs, as well drug withdrawals, has increased, according to an article in the August issue of Health Affairs. The agency imposes black box warnings to highlight side effects that could be disabling or life-threatening.
Cassie Frank, MD, an instructor of medicine at Cambridge Health Alliance in Massachusetts, and colleagues looked at the history of 748 new drugs approved by the FDA between 1975 and 2009.
They compared the records of those approved before and after the 1992 passage of the Prescription Drug User Fee Act (PDUFA). That law allowed the FDA to collect fees from pharmaceutical companies to pay for resources needed to speed up the drug-approval process. PDUFA has been renewed four times since 1992.
Of the new drugs approved for the entire period, 114 (15.2%) had received one or more black box warnings, and 32 (4.3%) were withdrawn from the market for safety reasons.
In total, label changes for all black box warnings plus withdrawals came to 208 (27.8%). Half of the warnings were issued within 12 years of approval, and half of the withdrawals happened within 5 years of approval.
The researchers found that drugs approved after enactment of PDUFA were more likely to be withdrawn or to receive a black box warning. The rate of warning or withdrawal climbed from 21.2 per 100 drugs before PDUFA to 26.7 per 100 afterward.
"New drugs have a one-in-three chance of acquiring a new black-box warning or being withdrawn for safety reasons within twenty-five years of approval," the researchers conclude.
"We believe that the ultimate solution is stronger U.S. drug approval standards. In the interim, with the rare exception of truly breakthrough therapies, doctors should preferentially prescribe drugs that have been on the market longer and hence have a more established track record of safety."
FDA, Industry Counter Findings
The FDA issued a two-paragraph statement in response to the article: "PDUFA has enhanced pre-market review and created a modern post-market drug safety system that follows products across their full life cycle. Specifically, PDUFA provides FDA revenue to hire additional reviewers and support staff and upgrade its information technology systems to maximize the efficiency of the application review process for new drugs and biological products without compromising FDA's high standards for approval.
"Additionally, PDUFA funding has helped the FDA modernize and transform the post-market drug safety surveillance system. It has helped ensure the safety of drugs after they are approved for as long as they remain on the market and [has] increased FDA's drug safety surveillance capacity. FDA has been able to adopt new scientific approaches and improve the utility of existing tools for the detection and prevention of adverse events, including obtaining access to the best available databases to better analyze drug safety signals."
Similarly, Robert Zirkelbach, senior vice president of communications for Pharmaceutical Research and Manufacturers of America, emphasizes the benefits of the updated system.
"Prior to 1992, the drug review process was unpredictable, lagging behind other countries and stalling patient access to critical new medicines," he says in a statement. "Providing the FDA with stable, consistent funding, PDUFA revolutionized the [drug review] process and strengthened the agency's high safety and efficacy standards."
He continued: "Since its enactment in 1992, PDUFA has sped up patient access to over 1,500 new medicines, including treatments combating some of our nation's most deadly diseases. By injecting greater consistency, transparency, and predictability into the drug review process, PDUFA has played a crucial role in improving public health."
To improve people's safety, the researchers suggest several actions that could be taken.
For instance, doctors and patients could consider whether a new drug is a “breakthrough,” and consider alternatives if it's not. A symbol on labels or marketing materials could identify newly approved drugs. And the FDA could focus more on doing follow-up studies on available drugs, looking for any side effects that didn’t show up while the drugs were getting reviewed for approval.
Drugs taken off the market before PDUFA "had an average review time for submission and approval of 3 years. The ones that were taken off after had an average review time of 1 year," says study coauthor Sidney M. Wolfe, MD, founder and senior adviser at the Health Research Group, Public Citizen, Washington, D.C. "That was certainly one of the purposes of PDUFA, but the failure to really treat these two groups of drugs [breakthrough and non-breakthrough] differently is what the problem is."
"I'd like to say that the primary mission of the FDA is to ensure patients' safety,” Frank says. “Our study raises concerns about how well the FDA is doing this. The FDA needs to make sure drugs are safe before they're approved, not rush to judgment in order to meet artificial deadlines. In the meantime, doctors and patients should avoid new drugs, especially when older, safer drugs are available."