FDA expands types of acceptable confirmatory evidence in new guidance

In a new draft guidance, the US Food and Drug Administration (FDA) outlined the types of confirmatory evidence it will accept from sponsors that want to use one adequate and well-controlled clinical investigation to demonstrate drug effectiveness.

FDA announced that the guidance “provides additional information on the flexibility in the amount and type of evidence needed to establish their effectiveness.” The change is meant to accommodate more products for serious diseases that lack effective treatments.

The guidance was jointly issued by FDA’s Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Oncology Center of Excellence (OCE). It complements draft guidance issued in 2019 (RELATED: FDA draft guidance on demonstrating substantial evidence of effectiveness, Regulatory Focus 19 December 2019).

The 2019 guidance was based on an earlier 1998 guidance and responded to the statutory changes brought by the Food and Drug Administration Modernization Act of 1997 (FDAMA). The law made clear that substantial evidence could be demonstrated by “one adequate and well-controlled clinical investigation plus confirmatory evidence” instead of two clinical trials.

The agency announced that “although FDA’s standard for demonstrating effectiveness has not changed since the publication of the 1998 guidance, drug and biologic development and science has evolved, leading to changes in the types of product development programs submitted to the agency.”

In the guidance, FDA outlines seven types of acceptable confirmatory evidence, including:

Clinical evidence from a related indication
Mechanistic or pharmacodynamics evidence
Evidence from a relevant animal model
Evidence from other members of the same pharmacologic class
Evidence from natural history
Real world data/evidence
Evidence from expanded use of an investigational drug

The draft guidance expands on the 2019 version, which included just four approaches for establishing confirmatory evidence with a single adequate and well-controlled study. The latest additions are evidence from a relevant animal model, evidence from real world data, and evidence from expanded access use of an investigational drug.

However, FDA noted in the guidance that this list is not meant to be exhaustive. “Whether confirmatory evidence and the adequate and well-controlled clinical investigation provide substantial evidence of effectiveness is determined case by case, for each application, in the context of the application as a whole,” FDA wrote.

The quality and quantity of confirmatory evidence are important considerations, and this evidence should be “generated from quality data derived from an appropriate source,” according to FDA.

The guidance notes that “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.”

FDA also recommends early consultations with sponsors if they plan to use any of these methods for establishing confirmatory evidence. Sponsors should provide a “strong scientific rationale to support the use of a single clinical investigation and confirmatory evidence for their specific drug development program, taking into account the considerations outlined in section III of this document,” the agency wrote.

These meetings should be held during the pre-investigational new drug (IND) meetings or at the end of Phase 2 meetings.

The public comment deadline is 18 December 2023. Submit comments here.

Draft guidance and notice , Announcement

FDA expands types of acceptable confirmatory evidence in new guidance

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