OBJECTIVES: To understand stakeholder perspectives on confirming drug benefit after “early" approval (including via the accelerated approval pathway) through postmarketing requirements (PMRs), with an emphasis on cancer and rare disease.

METHODS: Semi-structured interviews were conducted with: (1) current and former senior FDA officials; (2) scientific and regulatory leads at pharmaceutical companies and trade associations; (3) patient advocacy organization (PAO) leaders; and (4) current and former public and private sector payer representatives. Interviews covered barriers and facilitators to PMRs, responses to delay and ambiguous results, regulatory flexibility, and reforms. A codebook was developed including inductive and deductive themes and interviews were coded in Dedoose for analysis.

RESULTS: Participants noted common PMR barriers including disinterest from clinicians and patients, burdensome data collection, and midstream changes to the treatment landscape. Industry and PAO interviewees raised ethical and feasibility concerns about PMRs designed as new randomized placebo-controlled trials in the approved population. As an alternative, industry interviewees noted that successful PMRs typically must be conducted abroad, in a different indication, or in a single arm study. Many industry, PAO, and payer interviewees supported reliance on real world data (RWD) to confirm benefit. FDA interviewees encouraged confirmatory studies to be underway prior to accelerated approval while industry and PAO interviewees focused on rare disease worried about sponsor resources, small patient populations, and delayed access. Payers were willing to consider coverage and reimbursement levers toward enabling postmarket evidence generation, while industry and PAO interviewees feared that linking payment to approval pathway or PMR status could subvert early access.

CONCLUSIONS: Early drug approvals are granted with the expectation of later confirmation of benefit but feasible postmarket evidence generation may entail important sacrifices in quality, challenging the compromise. Recent reforms to begin confirmatory data collection prior to accelerated approval are promising but more work is needed to address the limitations of RWD.