Hematologic Malignancies and the Food and Drug Administration’s Accelerated Approval Program

The U.S. Food and Drug Administration’s (FDA) Accelerated Approval Program is an expedited drug development pathway that aims to bring promising agents to patients earlier in the development process. To qualify for accelerated approval, a product must treat a serious condition, offer meaningful advantage over available therapy, and demonstrate an effect on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. As a condition of accelerated approval, a postmarketing confirmatory trial verifying clinical benefit may be required; if it is required, the study must be completed with due diligence. Either the FDA or the sponsor may withdraw accelerated approval indications if a product fails to verify clinical benefit in the confirmatory trial, if the sponsor fails to conduct any required postapproval trials, or if accumulating evidence demonstrates that the product is not safe.¹ 

In the early years of the Accelerated Approval Program, from its launch in 1992 to 2010, accelerated approval indications were roughly split between non-oncology (~47%) and oncology (~53%) products.^2,3  Between 2010 and 2020, roughly 85% of accelerated approvals were for indications in cancer.⁴  Within oncology, between December 1992 and February 2023, there have been 180 indications granted accelerated approval. Sixty-eight of these indications (37%) across 53 unique agents were for hematologic malignancies. Of that number, 33 indications ultimately had confirmed clinical benefit, 25 indications have unconfirmed clinical benefit, and 10 indications have been withdrawn (Table). For indications with verified clinical benefit, the median time to verify clinical benefit was 3.5 years (range = 0.5-17.6). For agents receiving accelerated approval in the past 10 years, the median time to verification of clinical benefit was 2.2 years (range = 0.5-3.6).

The pharmaceutical industry has successfully used the Accelerated Approval Program in hematologic malignancies to introduce novel product classes for patients. For example, gemtuzumab ozogamicin, the first antibody-drug conjugate approved by the FDA, received accelerated approval in 2000 for acute myeloid leukemia.^5,6  Imatinib, the first tyrosine kinase inhibitor approved by the FDA, received accelerated approval for patients with chronic myeloid leukemia in 2001.⁷  Blinatumomab, the first bispecific antibody approved by the FDA, received accelerated approval for patients with acute lymphoblastic leukemia in 2014.⁸  Of the 68 accelerated approval indications in hematologic malignancies, 17 were unique antibody-based agents (6 antibody-drug conjugates, 6 monoclonal antibodies, 3 bispecific antibodies, and 2 radiotherapeutic antibodies), and 3 were cellular therapy agents. Thirty-two agents were small molecules, including 6 BCR-ABL inhibitors, 4 BTK inhibitors, 4 PI3K inhibitors, and 3 HDAC inhibitors.

While the Accelerated Approval Program has successfully brought patients new agents earlier in development, the current paradigm of developing novel therapies in the late-line setting has had challenges. Most indications under accelerated approval in hematologic malignancies thus far have been in the relapsed/refractory setting, at 58. Only 10 indications have been for newly diagnosed disease (7 for leukemia, 1 for lymphoma, and 2 for multiple myeloma). Historically, accelerated approval in oncology has relied on single-arm clinical trials with response rate serving as an early endpoint in these late-line settings.⁹  Confirmation of clinical benefit from single-arm trials is then based on a subsequent randomized trial where clinical benefit endpoints such as progression-free survival or overall survival can be assessed. Such an approach poses a risk of delaying confirmation of clinical benefit if the confirmatory trial is not initiated or if there are enrollment challenges. The FDA’s Oncology Center of Excellence (OCE) initiated Project FrontRunner to encourage development of novel therapies upfront in earlier lines of therapy.¹⁰  In earlier-line settings, randomized controlled trials are more feasible; the same trial can be used to grant accelerated approval based on an intermediate endpoint and then followed longitudinally to confirm clinical benefit, thus encapsulating accelerated approval and regular approval under the same clinical trial.

Ten accelerated approval indications in hematologic malignancies have been withdrawn. A total of six indications were withdrawn because of the inability to initiate or complete a confirmatory trial for an indication under accelerated approval, with a median time on the market of 7.3 years (range = 3.0- 9.7). For the 24 indications currently approved with unconfirmed clinical benefit, the median time on the market is 2.7 years (range = 0.05-13.4). Across oncology as a whole, indications with ongoing confirmatory trials at the time of accelerated approval had a median time to benefit verification of 3.1 years, compared to a median of 5.5 years for those without ongoing confirmatory trials.⁹  The delay in conducting confirmatory trials across the entire Accelerated Approval Program in oncology led to the creation of OCE’s Project Confirm, an initiative to promote transparency of outcomes in oncology accelerated approvals, enhance research and innovation in approval and postmarketing processes, and foster additional discussion regarding the program.¹¹  Furthermore, as part of the Consolidated Appropriations Act of 2022, the Food and Drug Omnibus Reform Act (FDORA) empowers the FDA with stronger regulatory oversight regarding the initiation and completion of confirmatory trials for accelerated approval, in addition to simplified withdrawal procedures.¹² 

Of the 37 indications with completed trial results in hematologic malignancies, four (11%) were withdrawn due to failure to confirm clinical benefit in their confirmatory trials, with a median time to withdrawal of 5.7 years (range = 1.3-11.5).

While failure to confirm clinical benefit in a confirmatory trial is often multifactorial, dose selection is an important aspect to consider in the development and benefit-risk assessment of an agent. Because an early endpoint such as response rate has been used to support approvals in single-arm trials, such a strategy may focus on efficacy over toxicity.¹³  In later stages of development, when more patients are enrolled and endpoints evolve to progression-free or overall survival in randomized trials, toxicity may become a dominating factor in a trial’s success or failure. Concerns regarding dose selection have arisen during the terminal stages of a product’s development several times in the history of accelerated approvals for hematologic malignancies. In the past 10 years, 40 indications in hematologic malignancies (among 30 unique agents) have received accelerated approval, and for eight of those agents (27%), dose selection has been discussed as part of an Oncology Drugs Advisory Committee meeting at the FDA. Because dose may impact tolerance, toxicity, and ultimately clinical benefit, the FDA’s OCE launched Project Optimus to reform the dose optimization and dose selection paradigm in oncologic drug development.¹⁴ 

The Accelerated Approval Program has proven successful in introducing promising agents to patients with hematologic malignancies. However, recent trial results and withdrawals that have occurred under the program point to opportunities to calibrate the development process so therapies are more efficiently made available for patients.