RWE There Yet? FDA’s New Pilot Program Seeks to Help Usher in a New Era for Real World Evidence

Making use of real-world data has long been of interest to stakeholders as having tremendous potential value.  These data are routinely collected from a variety of sources, such as electronic health records, providing information on health and healthcare in actual patients, rather than in the controlled environment of a clinical trial.  This value is potentially even greater for rare diseases, where there are limited sources of data.  These data exist and are being collected – it is up to the stakeholders to figure out how to leverage them to realize this potential.

However, translating real-world data into real-world evidence (“RWE”) has proved to be a challenge.  While some sponsors have succeeded in using RWE, typically as external controls, few have been able to use RWE as even supportive evidence of effectiveness for approvals (FDA’s 2021 approval of Prograf (tacrolimus) for a new indication based on a non-interventional study using real-world data from a registry of transplant recipients appears to be the largest role for RWE thus far).

To encourage efforts in this arena, Congress, in the 21st Century Cures Act’s Section 3022, codified at 21 U.S.C. § 355g(a), directed FDA to “establish a program to evaluate the potential use of real world evidence” both “to help to support the approval of a new indication” and “to help to support or satisfy postapproval study requirements.”  FDA announced its intentions to do just that in its PDUFA VII Goals Letter, which described a commitment to establish this pilot program by December 31, 2022.  On October 20, 2022, FDA issued a Federal Register notice announcing the establishment of the “Advancing Real-World Evidence (RWE) Program” as the culmination of this commitment.

The Federal Register notice states that the Advancing RWE Program “seeks to identify approaches for generating RWE that meet the regulatory requirements in support of labeling for effectiveness (e.g., new indications, populations, dosing information) or for meeting post-approval study requirements.”  The notice makes clear that this is an optional pathway for sponsors submitting RWE proposals; established procedures will continue to be available for non-participants.

Applicants accepted into the program will have the opportunity to meet with Agency staff prior to protocol development or study initiation to discuss the use of RWE in development.  Such sponsors will be granted up to four meetings to “discuss approaches for generating RWE that can meet regulatory requirements.”

The Federal Register notice also announced a new website for the program with additional details.  The website describes three eligibility criteria:

• The sponsor has an IND or pre-IND number for the medical product;
• The proposed RWE is intended to meet regulatory requirements in support of labeling for effectiveness or to meet post-approval study requirements; and
• The sponsor and FDA reach agreement on the study design information to be publicly disclosed.

FDA will select submissions meeting these criteria “based on their potential regarding fit-for-use data, adequate study design, and appropriate regulatory conduct.”  Other considerations include “promoting diversity of data sources, study designs, analytical methodologies, and regulatory indications, as well as to diversity of diseases.”

However, as an important goal of the program is “[t]o promote awareness of characteristics of RWE that can support regulatory decisions,” sponsors should be aware that “study designs discussed through the program may be presented by FDA in a public forum.”  An agreement between FDA and the sponsor on the information FDA may disclose publicly is a prerequisite to participation in the program.  However, certain specifics are excluded from disclosure, including the sponsor’s name, product name/molecular structure, a complete description of study eligibility criteria, and patient-level data.

There will be two submission deadlines per year on March 31 and September 30, through March 31, 2027.  The website describes the required content and format of the initial request for a meeting under the Advancing RWE Program.  The scope of the requested information is aligned with the goal of soliciting proposals before the sponsor makes final decisions on study design.  The request should also specify elements of the study design the sponsor considers non-disclosable along with a rationale for exclusion.  For follow-up meetings, the request should include any major changes, new information, or decisions made since the preceding meeting.

FDA will review all initial meeting requests received in the preceding 6-month cycle following each submission deadline.  Based on the criteria above, FDA will accept one to two primary meeting requests and up to two alternates per submission cycle in FY 2023-2024, and one to four primary meeting requests and up to four alternates per submission cycle in FY 2025-2027.  Sponsors who submit requests will be notified of the determination approximately 45 days after the submission deadline.  For each meeting request granted, FDA will conduct an initial meeting, and, as mentioned above, up to three follow-up meetings, as requested.

The initial meeting is intended to be held 30 days following FDA’s notification of acceptance (and 75 days following the preceding submission deadline) and follow-up meetings 45 days following requests.  After each meeting, a meeting summary will be sent to the requester within 30 days.

The website notes that any public presentations based on study designs developed through the program will “focus on those elements relevant to the understanding of the RWE and its potential use,” but may be presented prior to approval or completion of the post-marketing study.  “When feasible,” FDA intends to notify a sponsor in advance of such disclosure.