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

Abstract

Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non‐pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression‐free survival and tumor response were summarized in meta‐analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33‐4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72‐0.79, I2 = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000‐2005; 41% in 2016‐2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.

An empirical analysis of overall survival in drug approvals by the US FDA (2006–2023)

“…Compared to other studies, we similarly found that the percentage of drug approvals based on OS was small, 19 and almost one‐third of approvals are via the accelerated pathway that requires post‐marketing studies 20 . However, our study extends these findings by evaluating the fate of these approvals to see how many provide further evidence of OS efficacy, even among drugs receiving accelerated approval.…”

Global inequalities in availability of systemic therapies for cancer care and strategies to address them

“…While drug approvals are based on statistical significance of the endpoint achieved, this need not always be clinically significant. The average improvement in overall survival for 86 drugs approved between 2006 and 2017 was a paltry 2.5 months 28 …”

“…The average improvement in overall survival for 86 drugs approved between 2006 and 2017 was a paltry 2.5 months. 28 With skyrocketing prices of cancer drugs and the modest benefits that these interventions add, it is important to define value-based care. The value of any therapeutic strategy is determined by the magnitude of clinical benefit balanced against its costs.…”

Is Target-Based Drug Discovery Efficient? Discovery and “Off-Target” Mechanisms of All Drugs

“…Moreover, many approved drugs that have been considered to be successful have been the subject of criticism by experts and available evidence. A considerable number are suggested to exert minimal effects, − offering almost no benefit compared to previously approved drugs, − or have been approved only based on surrogate end points ,,− or flawed and limited evidence. − ,,,− Compared to placebo, many approved drugs probably offer at best only marginal benefit and may even lower a patient’s quality of life and survival. ,− ,− …”