Regulatory update: What the Omnibus FDA Amendments Mean for Real-World Evidence
Chief Legal and Regulatory Officer
Associate Regulatory Counsel
On December 29, 2022, President Biden signed the Consolidated Appropriations Act, 2023, a $1.7 trillion omnibus spending package that will fund the federal government for the 2023 fiscal year. The bipartisan legislation includes many substantive legal changes, including important amendments to the laws governing the Food and Drug Administration. These amendments — called the Food and Drug Omnibus Reform Act of 2022, or FDORA (pronounced “fedora,” like the hat) — will have effects across FDA’s portfolio, including its real-world evidence (RWE) program.
We expect FDORA will help advance the use of real-world data (RWD) and RWE in regulatory decision-making in several important ways. Below we discuss the key provisions and what they mean for RWD and RWE.
New Guidance and Report on RWD and RWE
The provision speaking most directly to RWD/E is a requirement that FDA issue (1) new (or revised) guidance and (2) a report to Congress, both addressing the use of RWD/E in approving products that were first marketed under an emergency use authorization (EUA).
This is significant because many products marketed under EUA during the COVID-19 public health emergency will, in the coming months and years, be seeking full approval, licensure, or clearance. Given the substantial real-world use of many of these EUA products, RWD/E is likely to figure prominently in many of these coming submissions.
Congress specified that the new guidance, which is due by December 2023, must include:
- Considerations for including RWD/E in applications and submissions for drugs, biologics, and devices when the RWD/E was collected as a result of the product’s use under EUA; and
- Information on standards and methodologies for collecting and analyzing such RWD/E when it is included in applications and submissions.
This guidance is worth watching even for products that have not been marketed under EUA. The principles FDA applies when relying upon RWE in this context could become precedent for the use of RWE in other settings, and clearer guidance will be helpful for all. Hopefully the guidance will also address specific questions that have arisen in the context of EUA products, such as how requirements for Institutional Review Board review apply to purely observational studies involving products solely available under EUA.
In addition to requiring guidance, Congress also required that FDA submit a report to Congress (due two years after the end of the COVID-19 public health emergency) on the use of RWE in submissions for products that had been marketed under EUA. The report will include information on the number of submissions for which RWE was and was not used to support a regulatory decision, along with information as to why. As with the guidance, this report is worth watching for anyone interested in the regulatory use of RWE, as it may shed light on broader issues.
FDA’s Rare Disease Endpoint Advancement Pilot Program
To advance the development of endpoints for drugs intended to treat rare diseases, Congress required FDA to
- host up to three public workshops related to the development of endpoints for rare diseases, and
- establish a pilot program enabling increased discussion between FDA and sponsors about the development of efficacy endpoints for rare diseases.
Notably, the workshops will “as appropriate, focus on the use of real world evidence and real world data to support the validation of efficacy endpoints, including surrogate and intermediate endpoints.”
We expect these required actions to benefit patients with rare diseases by providing greater regulatory clarity around how to identify and measure outcomes of interest when developing treatments for rare diseases. RWD/E can play an important role in these efforts. In addition, a greater focus on using RWD/E to validate endpoints in this context will hopefully help to advance methods and understanding for using RWD/E in endpoint validation more broadly.
Modernizing Accelerated Approval
One of the most discussed provisions in FDORA is an amendment to the accelerated approval pathway.
Under the accelerated approval program, a drug that treats a serious condition and fills an unmet need can be approved earlier than they might be otherwise, based on a surrogate endpoint that predicts clinical benefit but is not itself evidence of benefit. Sponsors generally must commit to conducting post-approval studies to try to generate confirmatory evidence of clinical benefit. Increasingly, we are seeing confirmatory studies that leverage RWE to help demonstrate clinical benefit, and FDA has relied on evidence including RWE to support a finding of benefit.
FDORA modified the accelerated approval program in several key respects. Among other things, it:
- Authorized FDA to require that confirmatory trials be underway at the time of approval or shortly thereafter;
- Required sponsors to provide a status report every 6 months on the progress made in confirmatory trials;
- Streamlined the process by which FDA can withdraw approval for a drug that fails, or does not make progress on, its confirmatory trial, including by replacing the right to a hearing with a right to a meeting;
- Required FDA to promulgate guidance on topics such as identifying novel endpoints and using novel study designs to conduct confirmatory studies; and
- Required FDA to establish an internal agency coordinating council to advise on the accelerated approval program.
The accelerated approval provision is also notable for what it does not contain: Any reference to RWD or RWE. This is significant because earlier, unenacted drafts of the provision included a parenthetical that noted a sponsor’s ability to use RWE to augment or support a post-approval study. We understand that this parenthetical was initially included as an endorsement of FDA’s existing practice of including RWE among potential sources of confirmatory evidence, but that committee staff ultimately removed the parenthetical from the final draft because of concerns that it could be misinterpreted as limiting FDA’s existing authority (i.e., by restricting the use of RWE to only situations where the RWE is “supporting” or “augmenting” a post-approval study).
By striking this parenthetical, Congress preserved the status quo on the use of RWE in confirmatory studies. FDA’s existing practice is to rely on RWE as part of the confirmatory evidence package, and there remains no legal limit on the type of reliance that FDA may place on RWE in this setting. We expect the role of RWE in confirmatory studies will continue to grow in the years to come. We may also see more concrete guidance from FDA on how to leverage real-world data sources in confirmatory studies — perhaps as part of the required guidance on novel confirmatory study designs.
Other Provisions Related to RWE
FDORA contains a number of provisions that do not directly reference RWE but nonetheless may have an impact on RWE and offer new areas for advancement in the field. These provisions include, for example:
- Diversity Action Plans. FDORA includes a requirement that sponsors of certain drug and device studies develop and implement a diversity action plan. There is an important role for RWD and RWE to play in addressing clinical trial diversity. For example, it can be a helpful tool in enrollment, provide a more representative view of a patient population, provide context to recruitment challenges, or supplement trials that are unable to achieve a study population that is representative of the overall patient population;
- Platform Technologies. Congress established a program to expedite the development and review of platform technologies that meet certain criteria. The criteria include preliminary evidence from the sponsor that the technology “has a reasonable likelihood to bring significant efficiencies to the drug development or manufacturing process and to the review process.” RWE can play a powerful role in supporting these conversations, such as around the known safety profile of a platform technology.
- Report on Review of Rare Disease Submissions. Congress mandated that FDA report on policies, practices, and programs with respect to review of applications for drugs and biologics intended to treat rare diseases and conditions, including consideration of patient-experience data.
This legislation builds on top of a strong emerging framework for the use of RWD and RWE in regulatory decision-making. This includes the RWE provisions in the 21st Century Cures Act, FDA’s RWE framework and associated guidance, a growing body of FDA approval decisions that leverage RWE, and, most recently, FDA’s commitments to advancing RWE as part of the 2022 user fee process. We anticipate much more to come as the field continues to evolve in the near- and mid-term future.
If you would like to learn more about RWE best practices, please view our recent webinar, Making Sense of FDA’s 2021 Real-World Evidence Guidance. To connect with one of our scientific experts at Aetion, please email: email@example.com.