Groups seek changes to FDA’s single-trial effectiveness guidance

Stakeholders urged the US Food and Drug Administration (FDA) to provide more examples of how real-world data (RWD) can be leveraged to support confirmatory studies to demonstrate effectiveness when only conducting a single adequate and well-controlled clinical investigation to support approval.

Comments also asked the agency to expand on the types of confirmatory evidence it will accept and petitioned the agency to accommodate other types of non-clinical data, such as in silico modeling, to support confirmatory studies.

The comments were made in response to FDA’s call for feedback on draft guidance outlining the types of confirmatory evidence it will accept from sponsors that want to use one adequate and well-controlled clinical investigation to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. The draft guidance, issued in September 2023, is meant to facilitate the development of products for serious diseases that lack effective treatments. (RELATED: FDA expands types of acceptable confirmatory evidence in new guidance, Regulatory Focus 19 September 2023)

The document complements draft guidance issued in 2019, and responds to the statutory changes brought by the Food and Drug Administration Modernization Act of 1997 (FDAMA).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.

ARM and Duke-Margolis Center want more examples of RWD

Two groups, the Alliance for Regenerative Medicine (ARM) and the Duke-Margolis Center for Health Policy, suggested FDA provide more examples of how RWD can be used to support confirmatory evidence.

ARM said that “examples would be helpful to illustrate situations in which confirmatory evidence developed from an RWD source, such as a post-market registry, combined with one adequate and well-controlled clinical investigation, could be considered sufficient to meet expectations for substantial evidence of effectiveness.”

The guidance makes brief mention of using RWD to support confirmatory studies. It states that “whether an RWD source may be appropriate to develop RWE 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. FDA recommends that sponsors discuss with the relevant review divisions any plans to use RWE as confirmatory evidence in a drug development program.”

Duke-Margolis similarly recommended FDA provide more guidance on RWD can be used to obtain confirmatory evidence.

Such guidance could focus on “various pragmatic, decentralized, and point-of-care trial approaches leveraging electronic health records, wearables, or other RWD sources could be implemented in post-market settings to provide real-world insight on the benefits and risks of therapies originally approved using one adequate and well controlled study. Guidance from FDA on how best to leverage these approaches to provide actionable insights on newly approved therapies would be helpful.”

The center also recommended the final guidance address strategies for leveraging the use of patient and disease registries that are designed to capture fit-for-purpose RWD on treatment outcomes and provide ongoing confirmatory evidence for newly approved therapies based on one adequate and well controlled study.

AstraZeneca wants more examples of confirmatory evidence

In its comments, AstraZeneca recommended the agency provide more examples of the seven different types of confirmatory evidence described in the guidance.

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, RWD and RWE, and evidence from expanded use of an investigational drug.

“We suggest the agency could go further in its descriptions of all the types of evidence described. In particular and for example, it is somewhat unclear if a situation with one trial with effect on established endpoints plus one trial demonstrating effect on a disease-related intermediate or surrogate endpoint would be sufficient,” said AstraZeneca. “Or indeed if other early types of evidence are in scope. Please could the agency clarify, consider expansion, and provide examples.”

ARM wants more flexibility for animal studies

ARM also requests FDA allow more flexibility and use of animal studies to support drug safety and efficacy when human data for rare disease treatments is lacking.

“We recommend extending the consideration of animal data as confirmatory evidence in circumstances that challenge the ability to gather additional human data, such as for products for rare diseases.”

FDA said that it will allow sponsors to use data from established animal models for confirmatory studies in limited circumstances, but that “sponsors should discuss in advance these planned nonclinical studies with the appropriate FDA review division.”

AstraZeneca suggests use of in silico data

AstraZeneca also suggested that FDA include in silico models as a type of nonclinical data it will accept as confirmatory evidence.

“We strongly encourage the Agency to also include in this section the growing sources of non-clinical evidence that are developing at a fast pace, including those being explore by the Agency through public-private partnerships. These include but are not limited to in silico technologies and models, as well as organ-in-chip methodologies that allow to the replacement and reduction (to some extent) of animal models as sources of confirmatory evidence.”

Clarification needed on related indications

In other areas, ARM said FDA should clarify what is meant by a related indication. In the guidance, FDA states that “under certain circumstances, evidence of effectiveness of a drug 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.”

ARM said that “while the guidance provides some factors that affect the determination of what a related indication is, further definition would be helpful of what a related indication is and what kind of data, evidence or rationale FDA would expect for a sponsor to sufficiently demonstrate that a given indication is related to another for the purpose of using one trial as confirmatory evidence for another.”

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Groups seek changes to FDA’s single-trial effectiveness guidance

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