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Abstract

Backgrounds/Aims:

To secure market authorization, the Food and Drug Administration requires that drug manufacturers demonstrate product safety and efficacy for an indicated use based on two adequate and well-controlled studies, known as pivotal clinical trials. A single pivotal trial may also be sufficient for product approval, however, if safety and efficacy is clearly and convincingly demonstrated, or if accompanied by confirmatory evidence. We examined all original drug and biologic indication approvals by the Food and Drug Administration between 2015 and 2023 to determine what proportion of those approved on the basis of a single pivotal trial were accompanied by confirmatory evidence, the type and strength of this evidence, and whether confirmatory evidence was cited more frequently after December 2019, when the Food and Drug Administration released draft guidance clarifying issues related to confirmatory evidence.

Methods:

Information was extracted from publicly available Food and Drug Administration documents, and we used descriptive statistics to characterize the sample and chi-square tests to compare the frequency with which confirmatory evidence was cited before and after December 2019.

Results:

Overall, the Food and Drug Administration approved 441 original drug and biologic indications between 2015 and 2023; 40 of which were excluded. Of the remaining, 181 (41%) were based on 2 or more pivotal trials, 35 (7.9%) on a single pivotal trial with at least one clinical primary efficacy endpoint without orphan designation, and 185 (42%) on a single pivotal trial. Among the final category of approvals, the Food and Drug Administration explicitly referenced confirmatory evidence for 36 (19.5%) single pivotal trial approvals and implicitly referenced confirmatory evidence for 4 (2.2%) others. These 40 approvals referenced 99 unique sources of confirmatory evidence, most commonly pharmacodynamic/mechanistic (n = 49) and other (n = 32). Reference to confirmatory evidence was greater after the Food and Drug Administration issued clarifying guidance in December 2019 (pre: 7% vs post: 34%; p < 0.0001).

Conclusions:

Given the rising number of the Food and Drug Administration approvals based on a single pivotal trial, greater clarity on confirmatory evidence standards and communication of its use could be considered.

Keywords

Confirmatory evidence single pivotal trial approval single pivotal trial supportive evidence supporting evidence pharmaceutical pivotal trials FDA approval

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References

U.S. Food and Drug Administration. Demonstrating substantial evidence of effectiveness with one adequate and well-controlled clinical investigation and confirmatory evidence: draft guidance for industry [Internet]. Silver Spring, MD: U.S. Food and Drug Administration, September, 2023 [cited 2024 Nov 18]. Available at: https://www.fda.gov/media/172166/download (accessed 18 November 2024).

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U.S. Food and Drug Administration. Demonstrating substantial evidence of effectiveness with one adequate and well-controlled clinical investigation and confirmatory evidence: draft guidance for industry. Silver Spring, MD: U.S. Food and Drug Administration, September, 2023 (accessed 18 November 2024), https://www.fda.gov/media/172166/download

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Confirmatory evidence supporting single pivotal trial new drug approvals by the Food and Drug Administration,2015 through 2023