Managing the Risks of Medicines: An Examination of FDA's Application of Criteria for Requiring a REMS.

BACKGROUND: In September 2016, the Food and Drug Administration (FDA) published a draft guidance for industry, FDA's Application of Statutory Factors in Determining When a REMS Is Necessary, that detailed the factors the Agency considers in determining when a Risk Evaluation and Mitigation Strategy (REMS) is necessary. The objective of this study was to determine how the FDA has applied these criteria for newly approved drugs. METHODS: For the 3-year period, 2015-2017, which included a full year of FDA approvals both before and after the issuance of the draft guidance, publicly available FDA reviews were analyzed for all 113 approved products using the criteria outlined in the guidance. RESULTS: Of the 113 products approved, 5 required a REMS. The most cited reasons for not requiring a REMS for the remaining 108 drugs were that risks could be managed via professional labeling (87%), physicians (primarily specialists) were familiar with the management of the risks (76%), the risk profile was similar to other non-REMS marketed products (45%), products were used in a controlled setting (inpatient, infusion center) (30%), and/or safety concerns would be further evaluated by a postmarket study (14%). CONCLUSIONS: A review of Agency risk evaluations indicate that whether physicians are sufficiently familiar with and capable of managing a risk and that the health care setting where the product is administered is conducive to such management are leading factors in determining whether or not to require a REMS.

Risk Evaluation and Mitigation Strategies With Elements to Assure Safe Use: Alignment of the Goals With the Tools to Manage Risk.

The Food and Drug Administration Amendments Act of 2007 gave the FDA the authority to require drug sponsors to submit a risk evaluation and mitigation strategies (REMS) program for those medicines with serious risks such that failure to effectively manage these risks would tip the benefit-risk balance. As of August 8, 2013, the 34 distinct individual and shared REMS programs that have specific elements to assure safe use (ETASU) were reviewed to ascertain the types of risks managed, the goals of the REMS, and the tools that were employed targeting prescribers, health care facilities, pharmacists, and particular conditions for safe use. Most REMS (65%) have a combination of risk mitigation and educational goals, but 4 REMS programs (12%) have exclusively educational goals. Preventing fetotoxicity (25%) is the most common risk managed by REMS with ETASU. Seventy-nine percent of ETASU REMS employ prescriber-based tools that include performing laboratory testing (eg, pregnancy, hepatic enzymes) or monitoring (eg, ophthalmologic examinations, documenting vaccination). The goals of REMS programs should focus on measurable behaviors that directly reduce risk. The tools that are employed should create the appropriate conditions for safe use. With the number of programs and the plethora of tools applied, serious consideration should be given to better integration of risk management into health care and pharmacy systems that are best equipped to manage such risks.

Using controlled clinical trials to learn more about acute drug-induced liver injury.

Drug-induced liver injury (DILI) is of major interest to hepatologists and clinicians in general, patients, government regulators, and the pharmaceutical industry. Understanding why this form of injury occurs only in certain individuals has major implications for the development and availability of drug therapies and in the prevention of these events. A single controlled clinical trial may be unlikely to show cases of such rare events, but in the aggregate, clinical trials offer a unique resource for learning more about individual susceptibility and developing truly predictive new biomarkers for DILI. We pose the question as to whether clinical trials could be modified or improved to provide data that would better answer some of the outstanding issues. At a recent (March 2008) public meeting, experts from academia, industry, and regulatory bodies discussed several major issues regarding liver safety in clinical trials including: what signals of liver injury should justify stopping administration of study drug or allowing it to continue; if deliberate rechallenge should be done and under what circumstances; whether patients with liver disease should be included in clinical trials; and what kinds of new biomarkers will be needed to answer these questions more clearly. Past clinical trials have not provided data to settle those issues, and reliance has defaulted to consensus of expert opinions. Modified and better clinical trials with standardized collection of data and biospecimens are probably the best source of new and potentially valuable information to supplant current rules based on consensus of expert opinions and to understand by what mechanisms and how to distinguish those individuals who are susceptible to severe DILI.