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P64: Safety Initiative for Multi-Drug Regimens: Guiding Principles for Identification, Management, and Reporting of Safety Issues

Poster Presenter

William O'Brien

Senior Director, Medical Safety Assessment Physician
Bristol-Myers Squibb Company
United States

Objectives

Multi-drug regimens are often more efficacious than monotherapies, but safety risks can be complicated by variable contribution of components. This initiative aims to provide potential guiding principles to address identification, management and reporting of safety interests in multi-drug regimens

Method

We reviewed publicly available regulations and company processes to develop methodologies for clinical development, aggregate reporting, risk management, and signal detection, to facilitate systematic and comprehensive safety review and reporting during development of multi-drug regimens (MDRs). Co-authors: Nina Johnson, Chris Bond, Jenny Hamilton, Robyn James, Aryeh Fischer, Cynthia Wojtaszek, Hewei Li, Jeff Lockman, Barret Giese, Linda Lum, Daniel Seekins

Results

For clinical development, a systematic approach to the assessment of the safety of combination therapies includes consideration of each drug’s safety, drug interactions, mechanism of action, overlapping or synergistic toxicities, and experience with other drugs in class. For signal detection, appropriate historical monotherapy groups can be utilized, with delineation of subset/cohort rules to establish time-dependent threshold values for adverse events. Rules should provide flexibility to allow the best comparators and thresholds for various combinations. For aggregate documents, MDR information in Periodic Safety Aggregate Reports can be added to the Periodic Benefit-Risk Evaluation Report and Developmental Safety Update Report documents. Safety aggregate report content can be aligned with known class effects of the MDR, which may help inform drug labeling decisions. In addition, known pharmacodynamic, pharmacokinetic, pharmacologic, and toxicologic impacts may be included. The approach taken for the risk management plan (RMP) is determined by the type of treatment combination: fixed-dose combination versus MDR. A fixed-dose combination product is considered a single drug; drugs that are part of an MDR each have their own RMP, for which the marketing authorization holder (MAH) is responsible. For drugs that are part of MDRs, a flexible approach is required for the presentation of safety concerns in RMPs because of drug-specific differences, including extent of treatment experience and available safety data. Drug-drug interactions and overlapping or synergistic toxicities may need to be added to the RMP. Finally, the safety profile of a drug used as part of an MDR must be considered in the context of the experience with other drugs in the MDR.

Conclusion

Approval of MDRs has been on the rise across therapeutic areas, especially in immuno-oncology. Clinical trials using MDRs increased from 50% in 2016 to 76% in 2020. [1,2] However, to our knowledge, optimized guidance is not available to MAHs on how to address combination therapies in regulatory submission documents and safety processes, including signal detection and risk management plans. This lack of guidance can have an impact on the quality of submissions and feedback from regulators and can result in increased document complexity when addressing safety issues. We have proposed an approach for comprehensive evaluation of safety interests. The overarching goal is to establish guiding principles to address identification, management and reporting of safety interests in combination therapies and to produce a robust package of safety information for use by healthcare providers and health authorities. Additional assessment of the effectiveness of these principles will continue; however, initial experience suggests greater consistency and efficiency within the organization, and a reduction in health authority feedback on aggregate documents related to MDRs. This research demonstrates the feasibility of developing a set of principles to apply to processes affecting safety for MDRs, which could be useful for shaping guidance at an industry level. References: 1. Albrecht B. et al. The next wave of innovation in oncology. McKinsey Cancer Center. September 2016. 2. Yu JX et al. Nat Rev Drug Discov. 2020;19(3):163-4.