An analysis of evidence from clinical studies and efficacy that supported the initial and supplemental approval of 124 anticancer drugs for 374 indications by the US Food and Administration (FDA) showed that new anticancer drugs significantly reduced the risk of death by 27% and of tumour progression by 43% compared with control. However, overall survival (OS) and progression-free survival (PFS) were only prolonged by a median of 2.80 and 3.30 months. Initial approvals prevented more deaths, tumour progressions, and provided a greater tumour response than indication extensions, yet more frequently being supported by non-randomised studies. Daniel Tobias Michaeli of the University Hospital Mannheim, Heidelberg University in Mannheim and Schumpeter School of Business and Economics, University of Wuppertal in Wuppertal, Germany who published the findings on 3 August 2022 in the Journal of Clinical Oncology wrote that the FDA and oncologists should cautiously evaluate initial drug approvals with non-robust clinical evidence, which may overestimate efficacy outcomes.

Increased cost triggered public debate about the clinical benefit of anticancer drugs. The authors wrote in the background that although a survey of 4,316 US inhabitants reported that 39% mistakenly believed that the FDA approves only extremely effective drugs, previous meta-analyses demonstrated that novel anticancer drugs only marginally extend life by 2 to 3 months on average. However, these meta-analyses are limited to initial drug approvals. The purpose of this study was to perform a meta-analysis of clinical benefit of novel anticancer drugs across all FDA-approved indications from 2003 to 2021. The authors reported drug, indication, and clinical study characteristics and meta-analysis of hazard ratios (HR) for OS, PFS, and relative risk for tumour response outcomes.

Among 124 FDA-approved drugs during analysis period, 78 were approved across multiple indications. From 374 approved indications, 141 were approved as combination therapies, 255 for solid tumours, 121 with biomarkers, and 182 as first-line treatment. Approval was mostly supported by open-label (71%), phase III (64%) concurrent randomised controlled studies (66%) with a median of 331 enroled patients (interquartile range [IQR] 123-665 patients).

In 234 randomised controlled studies with available data, drugs’ HRs were 0.73 (95% confidence interval [CI] 0.72 to 0.75; I2 = 29.6%) for OS and 0.57 (95% CI 0.54 to 0.60; I2 = 90.6%) for PFS, whereas tumour response was 1.38 (95% CI 1.33 to 1.42; I2 = 80.7%). Novel drugs increased patient survival by a median of 2.80 months (IQR 1.97-4.60 months) for OS and 3.30 months (IQR 1.50-5.58 months) for PFS.

Initial indications more frequently received accelerated approval, supported by single-arm studies for advanced-line monotherapies, than indication extensions. Initial approvals provided a higher PFS (HR 0.48 versus 0.58; p = 0.002) and tumour response (relative risk 1.76 versus 1.36; p < 0.001).

The authors concluded that pharmaceutical innovation in oncology is driven by the development and use of anticancer drugs for multiple rather than single cancer entity. The analysis showed that novel anticancer drugs reduce the risk of death and tumour progression; however, quality of evidence and patient benefit vary across indications. They wrote that patients and physicians must be able to rely on the FDA’s competence to decide that a drug is safe and effective for all approved cancer entities. Patients and insurers should only pay for the clinical benefit that drug delivers in treatment for their cancer. The authors advise policymakers to explore indication-specific pricing, coverage, and reimbursement policies.


Michaeli DT, Michaeli T. Overall Survival, Progression-Free Survival, and Tumor Response Benefit Supporting Initial US Food and Drug Administration Approval and Indication Extension of New Cancer Drugs, 2003-2021. JCO; Published online 3 August 2022. DOI: 10.1200/JCO.22.00535