Substantial Evidence from 1 Trial Guidance
FDA has released a draft guidance entitled “Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence.” The document is intended to provide more context than previous guidances on meeting the substantial evidence standard based on one adequate and well-controlled clinical trial. The agency says it also complements the earlier guidances — the 2019 draft guidance “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products” and the 1998 guidance entitled “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.”
“When one adequate and well-controlled clinical investigation and confirmatory evidence are considered together to assess effectiveness, the quality and quantity of the confirmatory evidence are also important considerations,” FDA says. “Confirmatory evidence should be evidence generated from quality data derived from an appropriate source. The quantity of confirmatory evidence needed in a development program will be impacted by the features of, and results from, the single adequate and well-controlled clinical investigation that the confirmatory evidence is intended to substantiate.”
The new draft guidance describes the considerations in greater depth, and it provides examples of the types of evidence that could be considered confirmatory evidence. For example, it says evidence of a drug’s effectiveness from a clinical investigation for a particular indication can provide confirmatory evidence of effectiveness to support approval of the drug in a different but closely related indication. The agency also says that in some cases, strong mechanistic evidence of the drug’s treatment effect in a particular disease may be acceptable confirmatory evidence. “In such cases, (1) the pathophysiology of the disease should be well understood and (2) the drug’s mechanism of action should be both clearly understood and shown to directly target the major driver or drivers of the disease pathophysiology,” the guidance says.
FDA says that in some situations, data from an established animal model of disease could be used as confirmatory evidence, but sponsors should discuss with reviewers their plans for such nonclinical studies. “Whether data from an established animal model of disease would be suitable as confirmatory evidence,” the guidance explains, “depends on several factors, including similarity of pathophysiology and manifestations of the disease in the animal model and in humans, elucidation of the drug’s mechanism of action with evidence of similar pharmacology and pharmacodynamics in the animal model and humans with disease, and evidence that the results of efficacy studies conducted in the animal model reasonably support clinical benefits and outcomes in humans with disease (e.g., if the disease in humans leads to renal failure and the drug is intended to preserve renal function, showing that the animal model of disease also is characterized by renal failure and the drug reduces progression of renal failure when tested in the animal model).”
Another form of confirmatory evidence is data from other drugs in the same pharmacological class that are approved for the same indication. In this situation, FDA says the drugs should have the same mechanism of action and similar endpoints that were measured. Additionally, it says confirmatory evidence can come from real-world data (RWD) sources. “Whether an RWD source may be appropriate to develop RWE [real-world evidence] that serves as confirmatory evidence depends on several factors, including but not limited to the reliability and relevance of the RWD source and, when relevant, the quality of the study design and the use of appropriate prespecified statistical methods and analyses,” it says.