“Do the studies in our program meet the FDA standards for demonstrating effectiveness?” is a question that sponsors frequently ask here at Rho. Demonstrating the efficacy of your product is an integral component of an application, but the flexibility surrounding what qualifies as substantial evidence from the FDA’s perspective can often leave you scratching your head. In the 1962 US Federal Food, Drug, and Cosmetic Act, “substantial evidence” is defined by the FDA as:

evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.

Since then, the FDA’s stance has been that establishing effectiveness equates to two adequate and well‑controlled studies that are independently convincing.  While this has remained the standard for demonstrating efficacy of a product, the FDA allows for a broad interpretation of this requirement and has provided three guidances across the decades to help clarify what constitutes as substantial evidence considering the rapid advancement of science, product development, and clinical evaluation:  “Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products” in 1998, “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products” in 2019, and recently “Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence” in September of 2023. Through the 1998 guidance, the FDA elucidates the quantitative and qualitative standards for demonstrating effectiveness, upon which the 2019 and 2023 guidances build and expand.  Across these guidances, the quantity of clinical evidence to establish effectiveness may be derived from (1) two adequate and well-controlled trials, (2) one adequate and well-controlled large multicenter trial that can provide a substantial amount of evidence of effectiveness, (3) one adequate and well-controlled trial plus confirmatory evidence, or (4) reliance on a previous finding of effectiveness of an approved drug when scientifically justified and legally permissible.

Here, we hit another subjective consideration: what does the FDA consider to be confirmatory evidence? Thankfully, the new 2023 guidance expands upon just that. In the guidance, the FDA presents 7 categories of evidence that have the potential to substantiate the results of one adequate and well‑controlled trial:

• Clinical evidence from a related indication
• Mechanistic or pharmacodynamic evidence
• Evidence from a relevant animal model
• Evidence from other members of the same pharmacological class
• Natural history evidence
• Real-world data/evidence
• Evidence from expanded access use of an investigational drug

These categories are not comprehensive. Ultimately, whether substantial evidence of effectiveness has been presented using one adequate and well-controlled trial plus confirmatory evidence is determined for each application independently with consideration of the context. One thing is certain – sponsors looking to confirm they have established effectiveness in support of their application should consult the FDA to discuss whether this is the best approach for their specific development program. In the meantime, we have compiled a tabular summary of the examples of confirmatory evidence presented in the new guidance as a reference tool to guide your considerations for what your program may rely on for demonstrating substantial effectiveness. If you would like the tabular summary or more help presenting your substantial evidence of effectiveness in your next application, be sure to contact Rho!

Casey Steadman, Ph.D., Regulatory Scientist, is an experienced Regulatory Scientist at Rho. She has 11 years of experience in writing and editing scientific documents and publications across a variety of neurological, biological, clinical, and regulatory fields, which includes several publications in peer reviewed scientific journals. She has experience leading and managing regulatory and scientific authoring teams and has participated in the authoring and preparation of modules of regulatory submissions (IND, NDA, BLA, etc.), briefing packages to support regulatory meetings, clinical study protocols, informed consent documents, clinical study reports, and other regulatory documents. Dr. Steadman has experience across a variety of integrated product development projects in various phases of development, including early phase (pre INDs and INDs) and late phase submissions (NDAs and BLAs). Her therapeutic area experience includes, but is not limited to, analgesia, dermatology, and psychiatric disorders. Dr. Steadman received her PhD in Anatomical Sciences and Neurobiology at the University of Louisville, where her research focused on the impacts of spinal cord injury on erectile function. Prior to joining Rho, she was a postdoctoral researcher at Duke University, where her research focused on the effects of spinal neuromodulation on lower urinary tract function. Dr. Steadman is a current member of the Regulatory Affairs Professionals Society (RAPS) and the North Carolina Regulatory Affairs Forum (NCRAF).