An Overview of Cancer Drugs Approved by the US Food and Drug Administration Based on the Surrogate End Point of Response Rate

Abstract

IMPORTANCE Approximately one-third of cancer drugs are approved based on response rate (RR)-the percentage of patients whose tumors shrink beyond an arbitrary thresholdtypically assessed in a single-arm study. OBJECTIVE To characterize RR end points used by the US Food and Drug Administration (FDA) for cancer drug approval. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of FDA-approved drug indications in oncology from 2006 to 2018. EXPOSURES Data related to cancer type, line of therapy (first-line, second-line, or third-or-later-line treatment for advanced/metastatic disease), type of FDA approval pathway, trial design, sample size, and level of innovation were extracted. MAIN OUTCOMES AND MEASURES The primary outcome was the RR used as the basis for FDA approval. The secondary outcome was rate of complete response. RESULTS Eighty-five indications for 59 cancer drugs were identified, 32 (38%) received regular approval, and 53 (62%) were granted accelerated approval. Twenty-nine (55%) accelerated approvals were later converted to regular approval. Of these, 6 (21%) approvals showed overall survival benefit, 16 (55%) later established progression-free survival benefit, and 7 (24%) continued to use RR but gained regular approval. The median RR among the 85 indications was 41% (interquartile range [IQR], 27%-58%). Among them, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%. The median complete RR for 81 participants was 6% (IQR, 2%-22%). The median sample size among studies leading to approval was 117 (IQR, 76-182; range, 18-1052 participants). Drugs with accelerated approval pending confirmatory data had lower RR compared with drugs that have completed most postmarketing efficacy requirements (median, 28%; IQR, 15%-50% vs median, 42%; IQR, 31%-58%; P = .02). CONCLUSIONS AND RELEVANCE Many cancer drugs approved on the basis of response rate offer numerically low or modest response rates. Most premarket studies accrue more than 100 patients. Some of these drugs could potentially be tested in premarket randomized clinical trials measuring directly end points that demonstrate clinical benefit.

Generating comparative evidence on new drugs and devices before approval

“…102 Over half of "single-group" studies in a recent review of cancer drug approvals had sufficiently large sample sizes to include control groups. 103 RCTs with active comparators should be more routinely used for drug and device approval. 104 Regulators should routinely investigate the availability, validity, and completeness of outcome data in existing clinical registries to facilitate embedding active-comparator trials.…”

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“…Randomized controlled trials (RCTs) are the gold standard to investigate efficacy of novel drug therapies and, therefore, RCTs are pivotal for drug marketing authorization applications 1–3 . However, in the accelerated approval pathway of the US Food and Drug Administration (FDA) and in the conditional marketing approval pathway of the European Medicines Agency (EMA), new and mostly expensive anticancer drugs are increasingly approved based upon studies with surrogate end points such as progression‐free survival (PFS) or objective response rate, and a large part of these studies lack a standard‐of‐care control arm 4 . Consequently, the treatment effect in terms of overall survival (OS) is unclear at approval by the authorities.…”

Generating comparative evidence on new drugs and devices after approval

“…22 Cancer drugs approved by the FDA based on the surrogate endpoint of response rate were often tested in post-marketing studies that captured other similar surrogate endpoints. 29 Among high-risk therapeutic devices approved via FDA's most stringent pathway for medical devices, implementation of post-approval studies has been challenging. 30 According to one review, only approximately 13% of initiated post-marketing studies were completed between three and five years after FDA approval.…”