Use of Patient Preferences Data Regarding Multiple Risks to Inform Regulatory Decisions.

Background and Objectives. Risk-tolerance measures from patient-preference studies typically focus on individual adverse events. We recently introduced an approach that extends maximum acceptable risk (MAR) calculations to simultaneous maximum acceptable risk thresholds (SMART) for multiple treatment-related risks. We extend these methods to include the computation and display of confidence intervals and apply the approach to 3 published discrete-choice experiments to evaluate its utility to inform regulatory decisions. Methods. We generate MAR estimates and SMART curves and compare them with trial-based benefit-risk profiles of select treatments for depression, psoriasis, and thyroid cancer. Results. In the depression study, SMART curves with 70% to 95% confidence intervals portray which combinations of 2 adverse events would be considered acceptable. In the psoriasis example, the asymmetric confidence intervals for the SMART curve indicate that relying on independent MARs versus SMART curves when there are nonlinear preferences can lead to decisions that could expose patients to greater risks than they would accept. The thyroid cancer application shows an example in which the clinical incidence of each of 3 adverse events is lower than the single-event MARs for the expected treatment benefit, yet the collective risk profile surpasses acceptable levels when considered jointly. Limitations. Nonrandom sample of studies. Conclusions. When evaluating conventional MARs in which the observed incidences are near the estimated MARs or where preferences demonstrate diminishing marginal disutility of risk, conventional MAR estimates will overstate risk acceptance, which could lead to misinformed decisions, potentially placing patients at greater risk of adverse events than they would accept. Implications. The SMART method, herein extended to include confidence intervals, provides a reproducible, transparent evidence-based approach to enable decision makers to use data from discrete-choice experiments to account for multiple adverse events.

Highlights: Estimates of maximum acceptable risk (MAR) for a defined treatment benefit can be useful to inform regulatory decisions; however, the conventional metric considers one adverse event at a time.This article applies a new approach known as SMART (simultaneous maximum acceptable risk thresholds) that accounts for multiple adverse events to 3 published discrete-choice experiments.Findings reveal that conventional MARs could lead decision makers to accept a treatment based on individual risks that would not be acceptable if multiple risks are considered simultaneously.