Study: Oncology accelerated approvals are often based on non-comparative trials evaluating response rate

Most oncology products granted accelerated approval by the US Food and Drug Administration (FDA) tend to rely on non-comparative single or multi-arm trials that use response rate as a primary endpoint, according to recent research published in the Journal of Pharmaceutical Innovation.

Satoshi Kato and Shunsuke Ono, of the laboratory of pharmaceutical regulatory science at The University of Tokyo, said there were “considerable variations” in the requirements for post-accelerated approval requirements as well as flexibility in how FDA determined a product’s path to full approval.

The researchers analyzed 157 oncology products granted accelerated approval between 1992 and 2001, identifying product characteristics such as their properties, post-approval requirements, rationale for approval, and the evidence prior to accelerated approval including the trial count, design, sample size, and ratio of effect size to the standard of care. They also evaluated whether the products granted accelerated approval had received breakthrough therapy, priority review, and fast track designations.

Of the products granted accelerated approval over that timeframe, there were approvals for 39 cancer types, with the most common being non-small cell lung cancer (11%), breast cancer (8.3%), and chronic myeloid leukemia (7.0%). A majority of accelerated approvals were granted from a single trial (76%) and non-comparative single or multi-arm trials (79%) where response rate was the primary or secondary endpoint (94%). Across 119 trials, 88 products achieved the median duration of response in a trial and had a range of 3.8 months to 21.7 months.

FDA approved oncology products based on a favorable benefit-risk profile for 60 accelerated approvals (38%) “without referring to existing products.” The agency granted 26 approvals based on superior efficacy and/or safety (17%), the researchers said, with 6 accelerated approvals having comparative trial results, and the rest relying on use of historical evidence. FDA granted 13 accelerated approvals (8%) despite efficacy and safety requirements for regular approval not being met, the researchers noted, and 39 accelerated approvals (25%) did not contain a rationale for approval.

Accelerated approval products were also often given other regulatory designations such as orphan drug (67%), priority review (55%), breakthrough therapy (36%), and fast track designations. Products that were deemed to have an acceptable benefit-risk profile were more likely to have another regulatory designation (89%) compared to products with a favorable benefit-risk profile (73%).

Post-approval requirements

Overall, FDA issued 232 post-accelerated approval requirements for 157 accelerated approvals, 189 post-marketing requirements, and 284 post-marketing commitments, with 162 post-marketing commitments having reporting requirements.

Nearly all post-accelerated approval requirements (94%) noted supplemental trials and follow-up of pre-accelerated approval trials were needed, and some asked for more data on safety and efficacy in adults and children like those with hepatic and renal impairment (29%) or in drug-drug interactions (22%). For post-marketing commitments that contained reporting requirements, common descriptions included supplemental clinical evidence (36%), device development (15%), and drug-drug interactions (15%), while general post-marketing commitments mostly included chemistry manufacturing and controls (CMC) tests (88%).

Accelerated approval was granted based on results from one trial in 84 cases (54%) with a requirement for an additional trial to convert the accelerated approval to regular approval, while 21 accelerated approvals (13%) were granted approval from one trial and had two trials required for conversion to full approval. All but two accelerated approvals (99%) had requirements for at least one supplemental clinical trial or a clinical trial follow-up subject to post-accelerated approval requirement, post-marketing requirement, or post-marketing commitment; in these cases, the trial with the “most robust study design” was described, such as a randomized controlled trial (RCT) with overall survival (OS) as a primary outcome.

Using a Poisson regression analysis, the researchers found the larger the number of pre-accelerated approval trials, the lower the ratio of supplemental trials required for regular approval (P < .001), and increasing pre-accelerated approval trials by one led to a 20% decrease in FDA-required supplemental trials. The researchers also found breakthrough therapy status was significantly associated with an increased number of supplemental trials (P = .039), while factors that were significantly associated with fewer supplemental trials compared to hematologic cancers included drugs with a respiratory indication (P = .035) and drugs for female cancers (P = .016).

When analyzing primary endpoints, 57 accelerated approvals (36%) were granted in situations where a single or multiple-arm non-comparative trial was conducted with response rate as a primary endpoint that also carried a requirement for one or more RCTs where time-to-event (TTE) was a primary endpoint for a regular approval. There were 33 accelerated approvals (21%) where single or multiple-arm non-comparative trials served as the basis for approval and there was also a requirement for one or more RCTs where OS was a primary endpoint.

“The present study showed that the FDA did not necessarily mandate confirmatory OS-RCTs upon granting accelerated approval to enable earlier access to oncology products and determined post-accelerated approval requirements in a flexible manner, considering product profiles and expectations to fill the evidence gap for regular approval, although investigation of overall survival in a randomized setting is considered the gold standard for developing oncology products,” Kato and Ono wrote.

Factors that significantly influenced a primary endpoint in a post-accelerated approval trial being more rust included an accelerated approval for a more common cancer (P = .02), and less robust when participants received the treatment in a trial prior to accelerated approval (P = .002), respiratory cancers granted accelerated approval (P = .069), skin cancers (P = .007), “other” cancers (P = .029), and cancers with a higher 5-year survival rate (P = .007).

“The accelerated approval program may lower the operational hurdles for launching the above-mentioned products by allowing studies with surrogate endpoints to be reviewed for early approval, in which the sample size is smaller and the results are available more expeditiously than studies with true endpoints,” the researchers wrote. “However, this does not necessarily mean that the program offers a discount on the overall evidence for granting regular approval. Further research is warranted to characterize approval through the respective pathways.”

J Pharm Innov Kato et al.

Study: Oncology accelerated approvals are often based on non-comparative trials evaluating response rate

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