Project Confirm is an initiative of the FDA Oncology Center of Excellence to promote the transparency of outcomes related to Accelerated Approvals for oncology indications. The project provides a framework to foster discussion, research and innovation in approval and post-marketing processes, with the goal to enhance the balance of access and verification of benefit for therapies available to patients with cancer and hematologic malignancies.
The following web pages provide concise information on the status of Accelerated Approvals for cancer and hematologic malignancies.
- Ongoing Accelerated Approvals
- Accelerated Approvals with verified clinical benefit
- Accelerated Approvals that have been withdrawn
Accelerated Approval, developed in 1992 in response to the HIV/AIDS crisis, has led to expedited drug and biologic approvals in several disease areas across the FDA. The program was codified into law under the Food and Drug Safety and Innovation Act (FDASIA) in 2012. Accelerated Approval allows for earlier access to drugs and biologics based on initial evidence of safety and effectiveness, and while confirmatory studies required to verify clinical benefit are ongoing.
To accomplish this, Accelerated Approvals are granted on the basis that products have an effect on “a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments” (FDASIA, 21 USC §301).
Since 1992, the majority of Accelerated Approvals have been granted for oncology and hematology indications. This has led to access to life-saving anti-cancer therapies an average of 3.4 years before they would have been available otherwise.
Q: How does FDA let patients and providers know that a product was approved under Accelerated Approval?
A: If a product is approved under Accelerated Approval, this status is described in the Indications and Usage Section (Section 1) of the Prescription Drug Labeling (US Prescribing Information, USPI). The USPI will convey the following text: This indication is approved under accelerated approval based on [the accelerated approval endpoint]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Q: Are specific endpoints used to support Accelerated Approvals in oncology? Are these different from the endpoints used to support Traditional Approvals?
A: In oncology, Accelerated Approval has frequently relied on the endpoint known as overall response rate (ORR), which is a measure of whether tumors shrink or are eradicated after treatment. These reductions in tumor size need to occur in a sufficient number of patients and for a sufficient period of time (Duration of Response [DOR]). Infrequently, other endpoints (e.g., pathologic complete response, progression-free survival, and disease-free survival) have also been used to support Accelerated Approval in oncology and hematologic malignancies.
As an endpoint to support marketing authorization ORR is not limited to Accelerated Approval. In fact, in specific rare cancers, cancers with long survivorship, and cases where randomized studies are otherwise impractical, ORR with supportive DOR has been used to support Traditional Approval in oncology.
Q: What are the postmarketing requirements for Accelerated Approvals?
A: As a condition of Accelerated Approval, the applicant should conduct confirmatory trials to verify the clinical benefit of the drug or demonstrate an effect on irreversible morbidity or mortality. If these trials completed post-approval verify the clinical benefit of an indication granted Accelerated Approval, the indication is granted Traditional Approval.
Q: Are these postmarketing confirmatory trials always performed in the same indication?
A: After Accelerated Approval is granted, the marketing authorization and availability of the approved drug or biologic product may limit enrollment and limit equipoise in randomized trials for the same indication. In other words, patients may not want to enroll in a trial with a control or placebo arm if an effective therapy is already available on the market (the indication approved through Accelerated Approval). For this reason, confirmatory trials are often conducted in earlier lines of therapy than the original indication for which Accelerated Approval was granted.
Q: Are there deadlines for postmarketing requirements to be completed?
A: Yes. At the time of Accelerated Approval, postmarketing requirements are agreed to by the company and FDA. These agreements include the projected date by which the post-approval confirmatory trial(s) will be completed and the projected date by which the final report of these studies will be submitted to FDA. FDA strongly recommends that the confirmatory trial(s) be well underway if not fully enrolled at the time of Accelerated Approval. These completion deadlines are based on unique considerations related to the indication and confirmatory trial design. Confirmatory trials that are in progress at the time of Accelerated Approval are more likely to result in a timely verification of benefit. In certain cases, post-approval studies can be affected by enrollment challenges, changes in the oncology treatment landscape, or other practical considerations that occur during the conduct of these trials.
Q: What happens if these confirmatory trials don’t verify clinical benefit?
A: Products approved under the Accelerated Approval program may be withdrawn voluntarily by the company or may be withdrawn by FDA after a public hearing.
Q: What are “Dangling” Accelerated Approvals?
A: The term “dangling” Accelerated Approval has been used to describe approvals for which confirmatory trials did not verify clinical benefit, but for which marketing authorization continues. FDA is continuously evaluating these approvals to ensure the safety and effectiveness of approved products and whether a “dangling” Accelerated Approval indication should remain approved. In certain cases where there are continued unmet medical needs and there are reasons for a confirmatory trial not verifying clinical benefit an indication may remain on the market while another confirmatory trial is completed.
Q: Are products granted Accelerated Approval considered “available therapies” for regulatory purposes?
A: Drugs granted Accelerated Approval are not considered “available therapy,” as their clinical benefit for the specific indication has not been verified. This promotes continued development for the given indication. For more information on “available therapies” see FDA Guidance For Industry: Expedited Programs for Serious Conditions – Drugs and Biologics.
Q: Do other countries have accelerated approval programs?
A: Several Regulatory Health Authorities (RHAs) in other countries have established expedited approval programs based on the AA program in the US. These programs have key differences including the endpoints or analysis used to support approval, built-in time limits to verify benefit, and whether they apply to original products (new molecular entities) and/or new indications for previously approved products.
Q: Does Accelerated Approval have anything to do with drug pricing?
- Mehta GU, de Claro RA, Pazdur R. Accelerated Approval Is Not Conditional Approval: Insights From International Expedited Approval Programs [published online ahead of print, 2022 Jan 20]. JAMA Oncol. 2022;10.1001/jamaoncol.2021.6854. doi:10.1001/jamaoncol.2021.6854
- Beaver JA, Pazdur R. The Wild West of Checkpoint Inhibitor Development [published online ahead of print, 2021 Dec 15]. N Engl J Med. 2021;10.1056/NEJMp2116863. doi:10.1056/NEJMp2116863
- Beaver JA, Pazdur R. "Dangling" Accelerated Approvals in Oncology. N Engl J Med. 2021;384(18):e68. doi:10.1056/NEJMp2104846
- Beaver JA, Howie LJ, Pelosof L, et al. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol. 2018;4(6):849-856. doi:10.1001/jamaoncol.2017.5618