The U.S. Food and Drug Administration (FDA) has several programs available that can expedite the development and regulatory review of a drug or biological product, including Accelerated Approval, which allows for approval of a drug or biologic based on surrogate or intermediate clinical endpoints while requiring the sponsor to develop additional clinical data postmarket to confirm efficacy. In the article below, we summarize FDA’s expedited program pathways, and analyze how the “Consolidated Appropriations Act, 2023” effectuates reforms to the Accelerated Approval regulatory framework. Most notably, the new legislation permits FDA to require sponsors of drugs or biologics submitted under the Accelerated Approval pathway to specify conditions for post-approval trials by the time their product is approved under that program.
Types of expedited programs
FDA has several programs designed to expedite development and regulatory review of a medical product that addresses an “unmet medical need” for a “serious condition.” First, a drug or biologic may be granted Fast Track Designation (FTD) if it is intended to treat a serious condition and nonclinical or clinical data demonstrate the potential for the product to address an unmet medical need. Drugs that receive FTD may be granted more frequent meetings and written communication with FDA, and rolling review. However, FTD may be rescinded if the agency determines the drug or biologic no longer meets the qualifying criteria for Fast Track.
Breakthrough Therapy Designation (BTD) from FDA helps expedite the development and review of new drugs and biologics for which there is preliminary clinical evidence that indicates that the drug or biologic may demonstrate “substantial improvement” over existing therapies on one or more clinically significant endpoints. In addition to the benefits of FTD, drugs granted BTD are also eligible for intensive guidance on an efficient drug development program, as well as involvement of FDA senior managers to expedite drug development. Like FTD, BTD may be rescinded if the agency determines the drug or biologic no longer meets the qualifying criteria for Fast Track. We recently analyzed online here how new FDA guidance signals the potential for closer agency scrutiny of BTDs.
Though Fast Track and Breakthrough Therapy designations are similar, they differ in the types of data needed to substantiate the request: FTD can be granted based on preliminary data, such as activity in a nonclinical model or pharmacological data, or a mechanistic rationale; in contrast, BTD must be based on preliminary clinical data, and therefore activity in a nonclinical model or a mechanistic rationale alone would not be sufficient. Drugs with FTD may also be granted BTD during the drug development process.
Unlike other expedited programs, Regenerative Medicine Advanced Therapy (RMAT) designation can only be obtained by regenerative medicine therapies – i.e., cell and gene therapies, therapeutic tissue engineering products, and human cell and tissue products – that address a serious or life-threatening disease or condition, are intended to treat, modify, reverse or cure a serious condition, and preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such condition. The RMAT program also allows for more leeway around the types of evidence that could confirm clinical benefit for regenerative therapies cleared under Accelerated Approval, which could include real-world evidence (RWE) and larger datasets from an existing clinical trial.
Priority Review directs FDA attention and resources to evaluating drugs or biologics that, if approved, would provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions over standard applications. Unlike the aforementioned programs, priority review does not expedite the development process. Rather, drugs and biologics receiving priority review benefit from having a 6-month goal date for the review of the application compared to the normal 10-month review goal date.
The most unique of the expedited programs, Accelerated Approval is an approval pathway rather than a designation. Accelerated approval allows for the use of a “surrogate endpoint” or an “intermediate clinical endpoint” that is not itself a measure of clinical benefit, but is instead a measure of a therapeutic effect that is considered “reasonably likely to predict” the clinical benefit of a drug. Using surrogate or intermediate clinical endpoints can bring drugs and biological products to the market far faster than applications supported by trials of direct clinical benefit. For example, instead of having to wait to learn if a drug actually extends survival for cancer patients, the FDA may approve a drug based on evidence that the drug shrinks tumors, because tumor shrinkage is considered reasonably likely to predict clinical benefit.
FDORA’s Accelerated Approval reform
The Accelerated Approval program has recently become the focal point of criticism from U.S. lawmakers due to concerns that FDA may not have efficient regulatory tools to remove ineffective drugs that entered the market through the expedited pathway. In response to these concerns, Accelerated Approval reforms were included as part of the recently enacted “Consolidated Appropriations Act, 2023,” a $1.7 trillion omnibus funding bill, which contains the Food and Drug Omnibus Reform Act (FDORA). Section 3210 of FDORA, “Modernizing Accelerated Approval,” includes the following:
FDA may require sponsors to specify conditions for post-approval trials no later than the date of Accelerated Approval, and if the agency does not require that the sponsor of a drug or biologic approved under Accelerated Approval conduct a post-approval trial, FDA must publish on its website the rationale for why such trial is not appropriate or necessary.
No later than the date of accelerated approval, FDA must specify the conditions for a post-approval trial or trials required to be conducted with respect to such drug or biologic, which may include enrollment targets, the trial protocol and milestones, including the target date of trial completion.
Accelerated Approval sponsors must submit progress reports every six months on required post-approval trials.
Sponsors retain certain rights prior to any withdrawal of accelerated approval, including the opportunity to appeal, and providing an opportunity for public comment on the proposed withdrawal.
Within one year of the bill’s enactment, HHS must establish an Accelerated Approval Council, comprised of more than ten directors of various offices within FDA, to ensure consistent and appropriate use of the accelerated approval process.
Within 18 months of the bill’s enactment, FDA must issue guidance documents covering Accelerated Approval related topics, including:
how sponsor questions related to the identification of novel surrogate or intermediate clinical endpoints may be addressed in early-stage development meetings with FDA,
the use of novel clinical trial designs that may be used to conduct appropriate post-approval trials, and
considerations related to the use of surrogate or intermediate clinical endpoints that may support the Accelerated Approval, including considerations in evaluating the evidence related to any such endpoints.
Critically, the language in FDORA says FDA “may require” that confirmatory post-approval trials be underway before approval, rather than that FDA “must” require this. It remains to be seen how CDER will implement this provision .
However, FDORA does expand the expedited procedures that FDA may utilize if a sponsor fails to conduct any required post-approval trial with “due diligence”; for example, under FDORA’s revised withdrawal procedures, sponsors who previously have faced an advisory committee on the withdrawal issue would not get a second advisory committee as part of that expedited process. We expect new guidance from the agency on how FDA plans to implement expedited withdrawal post-FDORA.
Notably omitted from the enacted legislation were measures from the draft bill that would have:
- Explicitly allowed pharmaceutical companies to use real-world evidence (e.g., data from medical claims and insurance information) as confirmatory evidence of effectiveness.
- Mandated that drug/biologic product labels disclose if they were granted Accelerated Approval.
We will continue to monitor changes to FDA’s expedited review programs and keep you apprised of any changes. In the meantime, feel free to reach out to your Hogan Lovells attorney or either of the authors of this alert with any questions you may have.
Authored by Lynn Mehler, Blake Wilson, and Sally Gu