3rd Quarter 2007
By Jeffrey J. Stoddard, MD
The market for post-licensure drug development services continues to be shaped by an ongoing focus on drug safety. Regulatory, legal, political and sociologic influences heavily shape perceptions as well as reality regarding the need for heightened attention to post-marketing drug safety assessment. Covance Periapproval Inc.'s service line (which focuses on post-marketing commitments, registries and observational study services, risk management, drug safety services and pharmacovigilance) continues to be greatly affected by these forces.
Capturing many of these dynamics in an editorial entitled “Sidelining Safety—the FDA's Inadequate Response to the IOM” in the September 6, 2007 issue of the New England Journal of Medicine , Sheila Weiss Smith argues that the FDA's response to the now renowned IOM report, The Future of Drug Safety, has fallen short. Dr. Smith is an associate professor at the Center on Drugs and Public Policy, Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, and in the Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine.
Released in September 2006, the landmark IOM report called out weaknesses in the laws, regulations, resources, and practice of ensuring drug safety. Some of the IOM's recommendations were directed toward Congress, but most of the report outlined deficiencies that the FDA itself should correct. In its report, the IOM called upon the agency to "embrace a culture of safety".
Smith states in her editorial that “the FDA's official response falls far short of what the American public expects and deserves.” Smith frames her argument beginning with the premise that
‘the basic criterion for approval of a new drug is that its benefits outweigh its associated risks… In its response to the IOM report, however, the FDA described its "fundamental dilemma" as weighing the "tradeoff between safety and access." …The public expects the FDA to be the final arbiter of drug safety… . Accelerated development programs and expedited reviews hasten the introduction of lifesaving drugs, but they should not be an option for treatments intended for chronic conditions; these drugs should have safety standards that tolerate minimal uncertainty. By pitting safety directly against "access and innovation," the agency betrays its mandate to ensure that U.S. drugs are both safe and effective.'
Smith also argues in her editorial that the organizational structure of the FDA marginalizes safety, correctly pointing out that all meaningful regulatory authority lies within the drug evaluation divisions of the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER) staff members in these divisions evaluate and approve drugs, negotiate labeling, and request risk management programs and postmarketing studies. Notwithstanding the agency's heightened emphasis on pharmacoepidemiology, such expertise is all too often underrepresented within (or even absent from) these divisions. Smith cogently points out that the agency's safety experts work in a separate Office of Surveillance and Epidemiology (OSE) and serve merely as consultants to the review divisions, having no meaningful regulatory authority.
This organizational structure and functional approach is at odds with some of the IOM's recommendations regarding the importance of including safety experts as integral decisionmakers in the drug review process. More fundamentally, even with the engaged participation of safety experts and pharmacoepidemiologists in preapproval reviews, most pivotal clinical trials would have extremely limited ability to identify uncommon adverse events based on limited statistical power to detect such rare events. Well designed postmarketing surveillance programs to detect adverse events—including registries, observational studies, large simple trials, and other well designed studies-- are therefore crucial. However, although responsibility for these activities rests with OSE, all regulatory authority remains with the review division. Regarding postmarketing surveillance jurisdiction, the IOM recommended establishing joint OND/OSE regulatory authority. The agency has not conferred any formal regulatory authority to the OSE.
Smith concludes her commentary: “in my view, the FDA's response to the IOM report demonstrates a lack of understanding of the magnitude of the changes required to create a culture of safety.”
Covance Periapproval Services, Inc. continues to bear witness to many actions, reactions, and reverberative responses wrought by the shifting landscape and the evolving expectations coming to bear upon postmarketing drug safety surveillance. Moreover, ‘Peri,' through its firsthand experience in many of the leading edge trends in this arena, remains a market leader in proactive approaches that make sense.
Reference
Smith SW. Sidelining safety – The FDA's inadequate response to the IOM. N Engl J Med 2007 357;109: 960-963.
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