Substantial Evidence of Effectiveness—How Much Is Enough? A Brief History of the FDA’s Single-Study Pathways to Approval
In 1938, President Franklin Delano Roosevelt signed the Food, Drug, and Cosmetic Act into law. The Act mandated that drug manufacturers would have to prove that a product was safe. The Act also prohibited the advertisement of false therapeutic claims. Unfortunately, the Act did not require drug manufacturers to prove that their products were effective.
Adequate and Well-Controlled Studies
To correct this omission, the Food, Drug, and Cosmetic Act was amended in 1962. The amendment required drug manufacturers to prove effectiveness, that is, to demonstrate substantial evidence of efficacy before a drug could be approved for marketing. Substantial effectiveness could be demonstrated by conducting adequate and well-controlled clinical studies to evaluate the efficacy of the new drug. The results of these studies would prove that that the product would have the effect stated by the manufacturer.
The United States Food and Drug Administration (FDA) interpreted the amended Act to mean that at least two adequate and well-controlled studies yielding positive results were required to demonstrate a beneficial outcome for patients. Consequently, the two-study pathway became the “standard” approach to new drug and biological product approvals.
A Flexible Standard
Today, the two-study pathway to approval remains the FDA’s evidentiary standard for prevalent, non–life-threatening diseases. Establishing its flexibility in meeting the substantial evidence standard, the FDA recognized in its early 1997 draft guidance a single-study pathway whereby one statistically very persuasive study could meet the statutory requirement to demonstrate substantial evidence of effectiveness for rare (orphan), life-threatening diseases that lacked effective treatment.
In practice, however, the FDA provides another option, a single-study pathway. In late 1997, an amendment to the FDA Modernization Act (FDAMA) indicated that the substantial evidence requirement for demonstrating effectiveness that “had generally been interpreted as calling for two adequate and well-controlled trials, could also be met by a single trial plus confirmatory evidence.”
In light of the FDAMA amendment, the FDA finalized its guidance in 1998 (Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products). In 2019, the FDA made available another draft guidance for industry titled Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products that complements and expands on the 1998 guidance.
Flexibility to meet evolving needs
The FDA’s 2019 draft guidance regarding substantial evidence provides a degree of clarity on confirmatory evidence, which could support a single study in the approval process that was lacking in the final 1998 guidance.
Notably, the 2019 draft guidance confirms that the FDA’s evidentiary standard for effectiveness has not changed since 1998, but it has been updated to account for the advances in science, technology, and medicine that have occurred during the last 2 decades.
You are encouraged to read the 2019 draft guidance as well as the articles in the bibliography. The articles delve into the precedent-setting actions of the FDA that demonstrate its commitment to the clinical development of drug and biological products. This commitment supports the needs of patients who are living with rare and serious, life-threatening diseases that lack effective treatments.
Bibliography
Raver CG, Sasinowski FJ, Valentine JE. Is confirmatory evidence having a moment? October 11, 2022. FDA Law Blog . Accessed March 3, 2023. https://www.thefdalawblog.com/2022/10/is-confirmatory-evidence-having-a-moment
Sasinowski FJ, Butler ML. Single-study approvals: quantum of evidence required [published online ahead of print, 2019 Sep 26]. Ther Innov Regul Sci. 2019;2168479019873918. doi:10.1177/2168479019873918
U.S. Food and Drug Administration. Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products. Draft guidance. December 2019. Accessed March 3, 2023. https://www.fda.gov/media/133660/download
U.S. Food and Drug Administration. Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products; Draft Guidance for Industry; Availability. Federal Register. Vol 84, No 245, p 170196. FR Doc. 2019-27524. December 20, 2019. Accessed March 3, 2023. https://www.govinfo.gov/content/pkg/FR-2019-12-20/pdf/2019-27524.pdf
U.S. Food and Drug Administration. Guidance for Industry. Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. Clinical 6. May 1998. Accessed March 3, 2023. https://www.fda.gov/media/71655/download
About the author
Gene S. Lysko is a senior medical writer at Artcraft Health.