Use of Single-Arm Trials for US Food and Drug Administration Drug Approval in Oncology, 2002-2021.

Importance: Single-arm trials have allowed for transformative therapies to be made available to patients expeditiously. However, using single-arm trials to support drug approval presents several challenges that must be carefully considered. Observations: Between January 1, 2002, and December 31, 2021, the US Food and Drug Administration granted 176 new malignant hematology and oncology indications based on single-arm trials, including 116 accelerated approvals (AAs) and 60 traditional approvals. Overall, 87 approvals (49%) were for new molecular entities or original biologics and 89 (51%) were supplemental indications. Response rate (RR) was the most common end point used to support approval in these single-arm trials (173 of 176 [98%]). Of the 116 AAs based on single-arm trials, 45 (38%) fulfilled their postmarketing requirement to verify clinical benefit, 61 (52%) are pending verification of benefit, and 10 (9%) were withdrawn from the market as of December 31, 2021. Most (56 of 61 [92%]) AAs based on single-arm trials pending verification of benefit occurred during the previous 5 years and have ongoing confirmatory trials as of December 2021. Conclusions and Relevance: Single-arm trials have been a common development strategy to support regulatory approval as early-stage expansion cohorts with promising durable RRs have become more prevalent. In the appropriate context, single-arm trials using durable RRs can allow patients expedited access to novel therapies and will continue to serve a role in advancing drug development in oncology. However, single-arm trials have a smaller noncomparative safety data set, inability to use time-to-event end points, and other limitations that require careful consideration within the context of the disease and available therapies. The randomized clinical trial remains the preferred approach in clinical investigation.

Oncology Expanded Access and FDA's Project Facilitate.

The Oncology Center of Excellence at the U.S. Food and Drug Administration launched Project Facilitate on May 31, 2019, to assist oncology health care providers with Expanded Access requests for investigational drugs. Expanded Access, sometimes called "compassionate use," is a regulatory pathway for physicians caring for patients who have a life-threatening condition or a serious disease to gain access to an investigational drug for treatment when no comparable or satisfactory alternative treatment options are available. Herein we describe the Project Facilitate program and the process for requesting Expanded Access to an investigational drug.

U.S. Food and Drug Administration: Initial Experience with the Real-Time Oncology Review Program.

The FDA Oncology Center of Excellence commenced the Real-Time Oncology Review (RTOR) pilot project in February 2018 to facilitate earlier submission of topline results and datasets to support an earlier start to the FDA application review. RTOR was initially begun to support supplemental drug applications to add new indications, dosing regimens, or other clinical information to the prescribing information, but was later expanded to include original new drug applications and biological license applications for new molecular entities (NME). From February 2018 to April 2020, RTOR was used to support the submission and review of drug approvals for 20 oncology applications (11 for solid tumor and nine for hematologic malignancy indications). Two were NME drug approvals and 18 were supplemental approvals. All of the applications received priority review and nine (45%) applications had received breakthrough therapy designation status. FDA received the RTOR submissions a median of 5.7 weeks (range 1.7-16.2 weeks) prior to the full application submission. The median time from application submission to FDA approval was 3.3 months (range 0.4-5.9 months). RTOR was also integrated with other review programs including the Assessment Aid and Project Orbis programs. Innovative regulatory processes are critical to expedite the rigorous review of impactful products across the FDA.

Overview of Oncology and Hematology Drug Approvals at US Food and Drug Administration Between 2008 and 2016.

BACKGROUND: We previously conducted an overview of oncology products reviewed by the Office of Oncology Drug Products in the Center for Drug Evaluation and Research at the US Food and Drug Administration for marketing approval and the regulatory actions taken during July 2005 to December 2007. There is a need to understand if the changes in the laws, regulations, and the organization that occurred after 2007 had any impact on the regulatory drug approvals. We present a detailed overview of hematology and oncology products reviewed by Office of Oncology Drug Products and Office of Hematology and Oncology Drug Products. METHODS: We identified all oncology-hematology applications that were submitted to the US Food and Drug Administration from January 1, 2008 through December 31, 2016, and reviewed the approval actions taken. RESULTS: During the study period, the Office of Hematology and Oncology Products approved 239 applications that supported 260 new indications. Of the 239 applications approved, 141 were approved via priority review and 98 were approved via standard review. Fifty-three of these applications were granted accelerated approval, 29 were converted from accelerated approval to regular approval, and 157 received regular approval. Since its promulgation in 2013, breakthrough designation status has been granted to 25.7% of applications. A variety of endpoints were used to support these approvals. CONCLUSION: During the study period, despite changes in the regulations and organization, the Office of Hematology and Oncology Products consistently utilized regulatory mechanisms that expedite the development and approval of promising oncology and hematology drug products resulting in the approval of 260 new indications.

A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review.

Importance: Accelerated approval (AA) is a US Food and Drug Administration (FDA) expedited program intended to speed the approval of drugs and biologics that may demonstrate a meaningful advantage over available therapies for diseases that are serious or life-threatening. Observations: This review describes all malignant hematology and oncology AAs from inception of the program on December 11, 1992, to May 31, 2017. During this period, the FDA granted AA to 64 malignant hematology and oncology products for 93 new indications. Of these AAs, 53 were for new molecular entities. Overall, the end point of response rate, including hematologic response rates, accounted for most AAs (81 [87%]), followed by time-to-event end points of progression-free survival or time to progression (8 [9%]) and disease-free survival or recurrence-free survival (4 [4%]). Single-arm trial designs provided the data for 67 (72%) of the initial AA indications. Of the 93 AAs, 51 (55%) have fulfilled their postmarketing requirement and verified benefit in a median of 3.4 years after their initial AA. Thirty-seven (40%) indications have not yet completed confirmatory trial(s) or verified benefit, and 5 indications receiving AA (5%) have been withdrawn from the market. Conclusions and Relevance: The use of the AA program during the past 25 years has increased over time, and only a small portion of indications under the AA program fail to verify clinical benefit. For patients with serious or life-threatening oncologic diseases, AA brings products to the market years before confirmatory trials are typically completed.

Expansion Cohorts in First-in-Human Solid Tumor Oncology Trials.

In 1962, the passage of the Kefauver-Harris Amendment to the 1938 Food, Drug, and Cosmetic Act required that sponsors seeking approval of new drugs demonstrate the drug's efficacy, in addition to its safety, through a formal process that includes "adequate and well-controlled" clinical trials as the basis to support claims of effectiveness. As a result of this amendment, FDA formalized in regulation the definitions of various phases of clinical investigations (i.e., phase I, phase II, and phase III). The clinical drug development paradigm for anticancer drugs intended to support marketing approval has historically followed this "phased" approach with sequential, stand-alone trials, with an increasing number of patients exposed to an investigational drug with each trial in order to fulfill the objectives of that particular stage in development. Increasingly, it is the Office of Hematology and Oncology Products' experience that commercial sponsors of solid tumor oncology drug development programs are amending ongoing phase I trials to add expansion cohorts designed to evaluate study objectives typical of later-phase trials. For investigational anticancer drugs that demonstrate preliminary clinical evidence of substantial antitumor activity early in clinical testing, use of expansion cohorts as a component of the solid tumor oncology drug development pathway, with appropriate measures to mitigate the risks of this approach, may fit in well with the goals and concepts described by FDA's expedited programs for serious conditions.