Biopharmaceutical companies seeking FDA approval based on a single clinical trial must provide comprehensive and transparent data, including both positive and negative findings, according to new draft guidance released by the agency. While the FDA generally requires two studies to demonstrate efficacy and safety for drug approvals, Congress allows for regulatory flexibility in cases where conducting more than one trial before approval is challenging or impossible.
The FDA’s draft guidance, building on a 2019 document, emphasizes the importance of the quality and quantity of data from one adequate and well-controlled clinical trial and the need for confirmatory evidence. The FDA recommends that drug sponsors provide a description and analysis of all relevant safety and efficacy data, whether domestic or foreign and whether positive or negative, to avoid cherry-picking evidence that supports a predetermined conclusion.
Companies are urged to consider the clinical context of the drug, such as unmet medical needs or specific disease characteristics, when deciding on a single-trial approach. Early communication with regulators, particularly during a pre-investigational new drug meeting, is encouraged to justify why a single-trial design is necessary and to determine whether it will be sufficient for establishing substantial evidence of effectiveness.
“It may be possible for a highly persuasive adequate and well-controlled clinical investigation to be supported by a lesser quantity of confirmatory evidence, whereas a less-persuasive adequate and well-controlled clinical investigation may require a greater quantity of compelling confirmatory evidence to allow for a conclusion of substantial evidence of effectiveness. The results of a clinical investigation or confirmatory evidence can be called into question by conflicting evidence unless there is a sufficient scientific justification that may explain the disparate findings.”
To demonstrate confirmatory evidence, drug sponsors have multiple options, some of which are typically generated during a standard clinical development program. These options include using efficacy evidence from previously submitted or approved indications for the drug, preclinical data from established animal models, evidence from drugs in the same pharmacological class, natural history data, real-world evidence, data from expanded access programs, and evidence on the drug’s mechanism of action when the disease’s pathophysiology is well understood, especially for diseases caused by a single gene or enzyme defect. Comments on the proposed guidance can be submitted to the FDA until December 18.