Most Novel Cancer Drug Approvals Based on Limited Evidence

Over the past 2 decades, novel cancer drugs have increasingly received priority review by the US Food and Drug Administration (FDA), but these drugs are often approved on the basis of a single clinical trial in which surrogate endpoints were measured and in which there was no control group, a new analysis found.

The authors found that over 80% of approvals were based on a single clinical trial, and most were based on surrogate endpoints, such as progression-free survival. Overall survival was an endpoint in only 14% of trials, which cited a median survival benefit of just over 2.5 months. Quality-of-life data were available in 25% of trials.

The findings add to mounting concerns that regulatory pathways to speed up the approval of novel cancer drugs may increase uncertainty about survival and quality-of-life benefits, the researchers say.

The report was published online last month in the International Journal of Cancer.

Ongoing efforts to accelerate the approval of cancer drugs have led to concerns about the quality of evidence supporting the use of these drugs.

To assess the quality of evidence, the study authors analyzed all pivotal clinical trials and nonpivotal randomized controlled trials (RCTs) for cancer drugs the FDA approved for the first time between 2000 and 2020.

During this time, the FDA approved 145 novel cancer drugs for 156 indications. The approvals were based on 190 clinical trials. Overall, 62% of indications were for solid malignancies, and 38% were for blood cancers. Most indications involved first-line (38%) or second-line (42%) treatments. For 36% of the indications, the FDA required a specific biomarker.

The FDA granted priority review to 82% of the indications, breakthrough therapy designation to 28%, orphan drug status to 68%, and accelerated approval to 46%, with a general trend toward increasing use of these designations over time.

Most indications (81%) were supported by only a single clinical trial, and nearly half of the indications (49%) were approved without supporting evidence from an RCT. Only 11 indications (7%) were approved with evidence from two RCTs. The clinical trials that led to approval were typically small, with fewer than 250 patients.

The researchers note that despite the “large volume” of novel cancer drug approvals, the benefits for patients seemed “modest.”

Among all 190 trials, overall survival was the primary endpoint in only 14%. Progression-free survival and tumor response were the primary endpoints in 26% and 54% of trials, respectively.

While the approved novel cancer drugs showed strong effect sizes for surrogate endpoints, such as progression-free survival (mean hazard ratio [HR], 0.51) and tumor response (relative risk, 2.14), the effect on overall survival was more modest. Novel drugs improved overall survival relatively by 25% (mean HR, 0.75), with an absolute median overall survival increase of 2.55 months.

The median improvement in overall survival did increase over time, with gains of 5.65 months between 2016 and 2020 compared with 2.4 months from 2006 to 2010 and 2.8 months from 2000 to 2005.

However, this finding “should be interpreted cautiously” because it was not supported by linear regressions across all years and was largely driven by the 2016 approval of olaratumab for soft-tissue sarcoma, which was subsequently withdrawn.

And while the authors observed a trend to measure quality of life more often, only a small minority of cancer drugs (5%) appeared to improve quality of life in an RCT.

“Across all indications, novel cancer drugs have modest beneficial effects on [overall survival], and [quality of life] plays only a minor role in their regulatory assessment,” the researchers conclude.

The study was supported by a grant from the Swiss Cancer League. One author received an educational grant from Janssen-Cilag AG and support for conference attendance from Novartis. All other authors have disclosed no relevant financial relationships.

Int J Cancer. Published online February 13, 2023. Full text

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