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

Abstract

PURPOSE Clinical trial evidence is routinely evaluated for initial drug approvals, yet the benefit of indication extensions remains uncertain. This study evaluates the clinical benefit supporting new cancer drugs' initial and supplemental US Food and Drug Administration (FDA) indication approval. PATIENTS AND METHODS Clinical trial evidence supporting each indication's FDA approval was collected from the Drugs@FDA database between 2003 and 2021. Drug, indication, and clinical trial characteristics are described. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk for tumor response were meta-analyzed. RESULTS Out of 124 FDA-approved drugs, 78 were approved across multiple indications. Out of 374 indications, 141 were approved as combination therapies, 255 for solid cancers, 121 with biomarkers, and 182 as first-line therapy. Approval was mostly supported by open-label (267 [71%]) phase III (238 [64%]) concurrent randomized controlled trials (248 [66%]) with a median of 331 enrolled patients (interquartile range [IQR], 123-665 patients). Across 234 randomized controlled trials with available data, drugs' HRs were 0.73 (95% 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 tumor response was 1.38 (95% CI, 1.33 to 1.42; I2 = 80.7%). Novel pharmaceuticals 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 trials for advanced-line monotherapies, than indication extensions. Initial approvals provided a higher PFS (HR, 0.48 v 0.58; P = .002) and tumor response (relative risk, 1.76 v 1.36; P < .001). CONCLUSION New cancer drugs substantially reduce the risk of death and tumor progression, yet only marginally extend patient survival. The FDA, physicians, patients, and insurers must evaluate and decide on a drug's safety and efficacy approval, pricing, coverage, and reimbursement on an indication-specific level.

The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020

“…Our results are overall consistent with previous less comprehensive reports on approval data for cancer drugs and their impact 5,14,16,29 . That OS plays only a minor role for approval and that most approvals are based on a surrogate endpoint has been shown by Davis et al for cancer drugs approved by the European Medicines Agency (2009‐13) 16 .…”

“…For almost all trials without control arm, TR was the primary endpoint; in RCTs, OS was the primary endpoint in only 28%, while the most frequent primary outcome was PFS (51%). Although this practice has been criticized for years, 4,5,14 we could not observe a trend during the last 20 years to employ RCTs to test novel cancer drugs or provide results on OS more often. Considering that several countries with small national regulators adopt FDA approvals or approve drugs in collaboration with the FDA, 27,28 the evidence base for approval of novel cancer drugs by the FDA has an impact beyond the borders of the US healthcare system.…”

“…However, once approved, drugs are often kept on the market despite the lack of evidence for a benefit beyond surrogate endpoints, 11,12 emphasizing the importance of high quality evidence at the date of approval. And even when there is evidence on survival benefits of novel cancer drugs, analyses on approval evidence showed that these are only modest with average survival gains in the range of a few months 4,5,13,14 . Considering the modest improvement of survival, the importance of data on quality of life (QoL) in the assessment of new cancer treatments has been emphasized 15 .…”

Cost-Effectiveness of Empagliflozin in Combination with Standard Care versus Standard Care Only in the Treatment of Heart Failure Patients in Finland

“…However, the finding of differing ICERs in HFrEF and HFpEF also add to the recent discussion on whether indication-specific pricing policies should be developed to reflect differential clinical and economic value in each indication. [32][33][34] Currently, the same price for a pharmaceutical product applies for all approved indications in Finland.…”

Does Therapeutic Repurposing in Cancer Meet the Expectations of Having Drugs at a Lower Price?

“…Paradoxically, most medical, scientific, and pharmaceutical organizations focus on improving treatments (tertiary prevention) by developing new molecular entities (NMEs). Unfortunately, the 124 NMEs approved by the US FDA between 2003 and 2021 increased the patient median survival by 2.8 months [ 8 ]. Although the benefits of globally reducing cancer mortality through tertiary prevention or treatment are limited, oncological research continues with this model.…”