FDA’s Guidance Describes the Subjectiveness of Benefit-Risk Assessments
(Thursday, September 30, 2021)
A new draft FDA guidance released this week describes all the factors that govern FDA’s decisions about market approval of new drugs and biologics, and it is apparent that the benefit-risk assessment of new products is far from black and white, but various shades of gray. The guidance appears more like an opinion article than advisory document but provides several carefully worded justifications for FDA’s past decisions and highlights key elements of the FDA internal processes going forward. FDA considers four categories of information for making its benefit-risk assessment. First is the data generated in clinical trials to understand the factual risk and benefit measures for a given product. The guidance is careful to mention that the benefit-risk assessment considers data both from pre- and post-market trials hence justifying less than perfect data from pre-market trials for initial decisions. The evidence in support of greater benefit over risk also includes non-clinical data, patient experience data (both in pre-market clinical trials, and post-market real world usage), reported adverse events, and epidemiologic data. Second consideration is the therapeutic context of the drug. This includes nature and severity of the target indication, and whether the new drug would address an unmet medical need. FDA is likely to have a higher tolerance for risk or toxicities for drugs intended to treat serious diseases with few or no treatment options compared to those that target diseases with other less risky treatment options. This should not be surprising for those following several FDA decisions in the last few years. The third consideration is the degree of uncertainty about the new drug’s benefits over risk. These include uncertainties due to heterogeneity of the disease manifestations in the real-world patient population compared to that observed in the clinical trial populations, statistical uncertainty, potential adverse drug-drug interactions that could not be tested in clinical trials, risk management strategies, meaningful assessment of patient input on potential benefits and acceptable risk, and new manufacturing technologies risk of which is not fully understood. FDA intends to accept higher uncertainty for rare diseases, and those with few or no treatment options, i.e., unmet medical needs. The last consideration is the regulatory options available to FDA to address deficiencies in the previous three areas of information. FDA can require additional clinical trials, post-marketing observational studies, enhanced pharmacovigilance, limiting labels, or REMS. The guidance describes the above four considerations in great detail providing examples and anecdotes to highlight considerations for risk-benefit planning. The guidance emphasizes the importance of FDA meetings, robust patient experience data, and appropriate presentation of the benefit-risk information. Sponsors should take a life-cycle development approach where various tangible and abstract factors are discussed with FDA to justify greater benefit over risk for a given new drug. The process may appear highly subjective because it is, and FDA is intent on keeping it that way, subjective that is to the wholistic considerations for the diseases and patients in context of the available options at the time of approval.
Dr. Mukesh Kumar
Founder & CEO, FDAMap
Linkedin: Mukesh Kumar, PhD, RAC