Safety Events Common in Newly Approved Drugs
Nearly one third of drugs newly approved by the US Food and Drug Administration (FDA) are affected by safety issues that were not known at the time of approval, a study has shown.
Biologic and psychiatric drugs, as well as those that received accelerated approval or were approved within 60 days of the statutory decision deadline, are the most vulnerable to postmarket safety events, Nicholas S. Downing, MD, from the Department of Medicine at Brigham and Women's Hospital in Boston, Massachusetts, and colleagues report. Their study was published online May 9 in JAMA.
The findings "are not surprising to those of us who have been following this for a while, but they do reflect a growing realization by the mainstream medical community that there are important differences between efficacy in randomized controlled trials and effectiveness once a drug hits the real world," Peter J. Pitts told Medscape Medical News. Pitts is a former FDA associate commissioner and current president of the Center for Medicine in the Public Interest, New York, New York. "It reinforces the basic truth that when you give people medicine, interesting things will happen — good and bad. Postmarket research is the continual search for understanding what these interesting things are in the real world," he added.
To determine the prevalence of postmarket safety events and the characteristics associated with the likelihood of their occurrence in newly approved drugs, the researchers used the Drugs@FDA database to identify all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010. They then separated the drugs on the basis on seven prespecified features: class (pharmaceutical, biologic), therapeutic area, priority review, accelerated approval, orphan product, near–regulatory deadline approval, and total review time.
Of 222 novel therapeutics identified, including 183 pharmaceuticals and 39 biologics, 71 (32%) were affected by a total of 123 postmarket safety events over a median 11.7 years of follow-up. The safety issues led to three drug withdrawals. The irritable bowel syndrome drugs valdecoxib and tegaserod were withdrawn in 2005 and 2007, respectively, as a result of adverse cardiovascular events. The psoriasis drug efalizumab was withdrawn in 2009 as a result of an observed increased risk for progressive multifocal leukoencephalopathy.
The approved drugs were also associated individually and class-wide with 61 incremental boxed warnings (43 drugs) and 59 safety communications (44 drugs).
Although safety events leading to market withdrawals were rare, "new boxed warnings, indicating that potentially life-threatening or preventable safety events had been observed in the postmarket period, and safety communications, which describe serious but non-life-threatening postmarket safety events, each occurred for approximately one-fifth of the novel therapeutics," the authors write.
The median time between drug approval and the first postmarket safety event was 4.2 years, and nearly one in three of the drugs had one or more safety events at 10 years, the authors write.
The researchers performed multivariate analyses looking at the relationship between each of the prespecified characteristics and postmarket safety events. They found an increased risk for safety issues among biologics compared with pharmaceuticals (incidence rate ratio [IRR], 1.93; 95% confidence interval [CI], 1.06 - 3.52; P = .03) and among drugs used to treat psychiatric conditions compared with cancer and hematologic therapeutics (IRR, 3.78; 95% CI, 1.77 - 8.06; P < .001). In addition, postmarket safety events were more prevalent among drugs that received accelerated approval (IRR, 2.20; 95% CI, 1.15 - 4.21; P = .02) and those approved near their regulatory deadline (IRR, 1.90; 95% CI, 1.19 - 3.05; P = .008).
Of interest, safety events were significantly less common among drugs with the shortest regulatory review times. This finding "conversely raises the possibility that some approval packages provide clearer evidence of safety, allowing for more rapid regulatory approval," the authors write. "An analysis of regulatory review documents from the European Medicines Agency indicated that safety risks that would ultimately prompt a postmarket safety event were not always evident in the premarket period, suggesting that additional premarket review might only delay approval without identifying therapeutics that pose a future safety concern."
"I agree with the authors' main point, which is that there are major gaps in our knowledge about the safety of drugs at the time that they are approved," Sean Hennessy, PharmD, PhD, told Medscape Medical News. Dr Hennessy is from the Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, and Department of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
"This isn't necessarily a bad thing, since requiring drug companies to perform the much larger studies that would need to be done to learn about rare adverse effects prior to approval would further increase the cost of drug development, which is already very expensive. Rather, we need to develop more robust systems to assess the safety of drugs after they are approved," Dr Hennessy explained.
Additional research is warranted to gain insight into the approval timeline and drug safety, the authors state. Further, they call for collaboration between stakeholders and the FDA "to develop and maintain an effective system for detecting postmarket safety events."
Stakeholder engagement is essential, Pitts told Medscape Medical News. "Although it's not taught in medical school, it's up to physicians and pharmacists to report adverse events, which is critical from a risk perspective and to mitigate potential problems with the use of approved medicines in everyday practice."
The good news, according to Pitts, is that "the FDA is taking this challenge to heart," by enhancing the capacity of its postmarket safety surveillance programs, and improving interactions with industry to achieve a better understanding of the performance of new drugs once they get into the market.The FDA's Sentinel Initiative, an integrated, national electronic monitoring system for active postmarket risk identification and analysis, is an important step in this direction, as is the sharing of premarket clinical trial data, the authors write. "[T]he integration of multiple data sources that include observations among large and diverse patient populations can facilitate the detection of postmarket safety events."
Previously, as reported by Medscape Medical News, the Government Accountability Office has questioned the sufficiency of the FDA's reporting of postmarket studies of approved drugs.
"I'm not as optimistic as the authors that the current system is working…. Sentinel, which I'm part of, is a great system, but has limited bandwidth. There aren't enough resources to use Sentinel as the only way to study the safety of every approved product, nor does FDA have the human resources to be primarily responsible for studying the safety of all products," Dr Hennessy explained.
"Industry needs to play a role. Unfortunately, FDA is limited by law in their ability to require companies to perform their own safety studies. Changing this would require an act of Congress," he added.
The authors acknowledge that even the most careful regulatory review and surveillance systems may not prevent all postmarket safety events. "[I]t may be impossible to detect other less common events until several years after approval, once the therapeutics are in broad use."
Dr Downing has disclosed no relevant financial relationships. One coauthor reports receiving personal fees from Cepton, OliverWyman, Roland Berger, McCann Health, Omnicom, Grey Healthcare, Saatchi & Saatchi, Sudler, TBWA, Havas, Agipharm, Mayoly Spindler, Teva, Menarini, Pierre Fabre, Merck, and AbbVie. One coauthor reports receiving a grant from the FDA; research agreements with Medtronic and Johnson & Johnson (Janssen) through Yale University; serving as chair of a cardiac scientific advisory board for UnitedHealth, being a founder of Hugo, being a participant and participant representative of the IBM Watson Health Life Sciences Board; and serving as an advisory board member of Element Science. One coauthor reports receiving grants from the FDA, Medtronic, Johnson & Johnson, the Centers for Medicare & Medicaid Services, Blue Cross Blue Shield Association, and the Laura and John Arnold Foundation. Mr Pitts serves as chief regulatory officer for Adherent Health Strategies. Dr Hennessy has disclosed no relevant financial relationships.