FDA official updates on advancing RWE program, lists common reasons for rejection

Some of the main reasons the US Food and Drug Administration (FDA) rejects applicants from participating in its Advancing Real-World Evidence (RWE) Program include concerns that proposed real-world data (RWD) studies will use heterogeneous patient populations or that the studies will provide supportive, rather than primary evidence, to support regulatory decisions.

Kristen Miller, FDA health science policy advisor, shared this information during a 23 September workshop sponsored by the Duke Margolis Institute for Health Policy in Washington, DC. Her presentation explored initiatives to boost use of RWE through the latest Prescription Drug User Fee Act (PDUFA VII) agreement, the agency’s criteria for accepting applications into the program, and the reasons why some applications are rejected. (RELATED: FDA starts PDUFA VII programs for real-world evidence, innovative trial designs, Regulatory Focus 19 October 2022).

Under the program, drug and biological product sponsors collaborate with FDA to develop and use real-world data (RWD) to generate RWE to support regulatory decisions.

“The goal of the program is to identify approaches for generating real-world evidence that meets regulatory requirements,” said Miller.

To be eligible, sponsors must have an approved investigational new drug (IND) or pre-IND number for the medical product; and the proposed RWE is intended to meet regulatory requirements.

“When we select and evaluate the applications for acceptance, we consider both the technical and the regulatory standards and also the breadth and diversity of the different submissions. We look at whether or not the proposed data will be appropriate and sufficient for the intended regulatory purpose and that the study design is robust enough to be able to support the regulatory decision,” said Miller.

FDA accepts meeting requests twice a year, with submission deadlines on March 31 and September 30. The agency allows up to four submissions per review cycle and will meet with sponsors a maximum of four times annually.

Miller said that during the first five cycles of the program, a total of 26 initial meeting requests were received for the program. Out of these, five requests were accepted into the program. Two sponsors have completed the program and submitted applications using RWE while three sponsors are currently participating. Additionally, 21 requests were rejected from the program.

Miller laid out three main reasons that participants were denied from the program. The first centers around study interpretability concerns. She listed three factors that could make it difficult to interpret study data, including having heterogenous patient populations with variable clinical outcomes, treatment regimens that evolve based on clinical response, or in situations when significant channeling biases or large placebo effects are expected.

Miller also said the study’s role in the development program could preclude it from the program. For instance, studies that provide supportive, rather than primary evidence would not be appropriate and that method development and endpoint validation are outside the program’s scope.

Additionally, Miller said that participants are rejected if there are better engagement pathways available to them or they are already receiving review division feedback through another means.

One of the applications accepted into the program proposed a study to evaluate clinical outcomes in children during flu season. The study was intended to fulfill a post-marketing commitment (PMC) and support a new indication. The sponsors aimed to conduct a non-interventional retrospective cohort study using electronic health records (EHR) data.

Miller said that the program has met its goal of improving understanding of RWD study characteristics that can support regulatory decision-making. It has also fostered “better engagement” by providing constructive feedback to sponsors not just from the primary review division but also from across the agency.

Miller stated there are several upcoming milestones mandated by the PDUFA VII. By 31 December 2025, the FDA will hold a public workshop or meeting to discuss case studies focused on generating RWE that complies with regulatory requirements. By 31 December 2026, the FDA will apply the lessons learned from the Advancing RWE Program to either update existing RWE-related guidance documents or create new ones.

FDA official updates on advancing RWE program, lists common reasons for rejection

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