The US Food and Drug Administration (FDA) approves cancer drugs based on (1) overall survival (OS) or patient reported outcomes, (2) progression-free survival, the time until cancer recurs or worsens, or (3) response rate (RR), the percent of patients experiencing tumor shrinkage. Response rate and complete response rate are typically ascertained in uncontrolled, non-randomized studies. Because these trials have no comparator arm, drug-related adverse events may be missed among symptomatic patients because they may be mistakenly attributed to their underlying cancer. There is also uncertainty about whether and to what degree these drugs improve survival or quality of life.

The FDA has noted that a high RR in early phase trials justifies granting expedited approval. The agency has stated, “for drugs demonstrating unprecedented activity in early clinical development in cancers with few effective options, the ability to randomly allocate patients to either an agent with markedly improved durable response rates or to a toxic and marginally effective comparator may not be feasible because equipoise may not exist.” The FDA has used response rate to justify both accelerated and regular (traditional) approval. The accelerated approval program is often based on response rate and duration of response in a single-arm study. For accelerated approval, the FDA generally mandates postmarketing efficacy requirements be fulfilled by subsequent randomized clinical trials in the same treatment setting or in an earlier disease course setting, but the agency has also accepted larger single-arm studies using RR. This is different from the regular approval pathway where postmarketing commitments generally only address drug-drug interactions, dosing based on hepatic and renal impairment, short-term and long-term drug safety, and efficacy in special or subgroup populations, and not further evidence of general efficacy...