By Marjorie Zettler, Ph.D., MPH, senior director, clinical science, Accutar Biotech
1-4 Adequate representation of the patient populations who will eventually receive the therapy is crucial to accurately detect possible differences in both efficacy and safety in subpopulations. More inclusive clinical trials produce results with greater generalizability and that better reflect the treatment effects that can be expected with real-world use.
Over the past few years, FDA has produced multiple guidance documents related to broadening patient populations in clinical trials. In addition to the general guidance encouraging inclusion of clinical trial participants representative of the overall population of patients who will be exposed to a marketed drug in clinical practice (issued to satisfy the FDA Reauthorization Act of 2017 mandate),5 FDA published a series of guidance documents specifically for cancer clinical trials. These guidances focus on restrictive eligibility criteria in trials of cancer therapies and include three documents related to the age of the participants (pediatric, adolescent, and older adults)6-8 and three related to comorbid conditions (human immunodeficiency virus, hepatitis B virus, or hepatitis C virus infections; organ dysfunction or prior or concurrent malignancies; and brain metastases).9-11
But beyond issuing guidance documents, what action has FDA taken to ensure inclusion of relevant patient populations in cancer clinical trials? And what has been the impact? This article outlines three observations regarding FDA’s recent efforts toward improving diversity in trials supporting approval of cancer therapies.
1. Lack Of Diversity In Trial Patient Populations Can Factor Into Approval Decisions
In a briefing document ahead of a June 24, 2021, Oncologic Drugs Advisory Committee (ODAC) meeting for retifanlimab (a PD-1 inhibitor under review for the treatment of adult patients with locally advanced or metastatic squamous cell carcinoma of the anal canal, who have progressed on, or who are intolerant of, platinum-based chemotherapy), one of the review issues noted by FDA was the lack of diversity among the patient population in the supporting clinical trial, PODIUM-202: “Members of racial minority groups relevant to who would receive the drug in the U.S. were under-represented in PODIUM-202, with only 1 Black patient and 4 Hispanic or Latino patients among the patients for whom race or ethnicity were reported.”12 At the meeting, the committee voted 13 to 4 for the deferral of the approval, and FDA ultimately rejected the retifanlimab marketing application.
Similarly, prior to a Feb. 10, 2022, ODAC meeting for sintilimab (a PD-1 inhibitor under review for first-line treatment of non-squamous non-small cell lung cancer, in combination with pemetrexed and platinum-based chemotherapy), FDA’s briefing document included the following concern regarding the Phase 3 trial (ORIENT-11) supporting the application: “ORIENT-11 was conducted exclusively in China and enrolled a patient population which lacks the racial and ethnic diversity of the U.S. population, notably with regards to currently underserved groups.”13 The committee voted 14 to 1 that FDA should require additional studies demonstrating applicability to patients in the U.S. and U.S. medical care before making a regulatory decision on the application. Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, spoke about the FDA’s commitment to diversity and stated at the meeting, “Single country submission is a step backward in achieving the racial diversity that we need in the United States.” The FDA had not yet made a final decision about the sintilimab marketing application at the time of this writing.
While neither of these cases hinged solely on the demographics of the trial patient populations, these examples indicate that FDA is paying attention to diversity and taking it into account when evaluating marketing applications.
2. Post-Marketing Requirements & Commitments Represent Another Mechanism By Which FDA Can Request Data On Broader Patient Populations
An increasing number of cancer therapy approvals are accompanied by post-marketing requirements or commitments for additional studies or analyses that include a diverse patient population. For example, the May 28, 2021, accelerated approval of infigratinib (for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with fibroblast growth factor receptor 2 [FGFR2] gene fusions or other rearrangement) was accompanied by the post-marketing requirement for a confirmatory randomized clinical trial. The requirement specified that the sponsor should “Ensure that racial and ethnic minority subjects are adequately represented in the trial population, at a minimum, proportional to the prevalence of FGFR2 alterations in these subgroups in the U.S. population.”14
Likewise, umbralisib received accelerated approval on Feb. 5, 2021, for the treatment of adult patients with relapsed or refractory marginal zone lymphoma who have received at least one prior anti-CD20-based regimen and for the treatment of adult patients with relapsed or refractory follicular lymphoma who have received at least three prior lines of systemic therapy. In addition to a requirement for a Phase 3 trial that “… should include sufficient numbers of racial and ethnic minority patients to better reflect the U.S. patient population and allow for interpretation of the results in these patient populations”, a post-marketing commitment was also issued at the time of approval for “… a final report containing data from clinical trials, post-marketing reports, compassionate use/expanded access program, real-world evidence, and other sources to further characterize the safety and efficacy of umbralisib monotherapy and in combination with immunotherapy among U.S. racial and ethnic minority patients with follicular lymphoma or marginal zone lymphoma.”15
These examples highlight an alternative mechanism by which FDA may require sponsors to provide data from a patient population more representative of the disease population as a whole and identify the use of real-world data as one means through which this requirement may be met.
3. More Applications For Pediatric Oncology Indications Are Being Approved Than Ever Before
A growing number of cancer clinical trial protocols have opened up enrollment to adolescents, as recommended in the FDA guidance documents, Cancer Clinical Trial Eligibility Criteria: Minimum Age Considerations for Inclusion of Pediatric Patients6 and Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials.7 Upon approval, FDA has granted these therapies indications based on the broader patient population.
For example, the eligibility criteria for the LIBRETTO-001 trial, which evaluated selpercatinib in patients with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer, included ages 12 years and older.16 This age range was reflected in the indication approved May 8, 2020, for the drug (for adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, or radioactive iodine-refractory thyroid cancer, if radioactive iodine is appropriate).17
These adolescent-inclusive approvals are part of a larger trend toward increased approvals for pediatric cancer indications in recent years. An FDA analysis found that only 38 applications for pediatric oncology indications had been approved in the 65-year period between 1953 and 2018.18 In contrast, a search of the FDA’s Oncology/Hematologic Malignancies Approval Notifications database found 16 approvals for pediatric indications in just the two-year period 2020-2021.19 This pattern is likely to continue, as the Research to Accelerate Cures and Equity (RACE) for Children Act, which came into effect Aug. 18, 2020, authorized the FDA to require pediatric studies for new therapies intended for the treatment of an adult cancer, if the molecular target is relevant to a pediatric cancer. This legislation has already resulted in the FDA issuing pediatric study requirements for multiple therapies that would previously have been exempt due to orphan drug designation or had the requirement waived due to the indication rarely or never occurring in children.20
Taken together, these examples demonstrate that FDA recognizes the critical importance of diversity in cancer clinical trials and has implemented multiple strategies to address the current challenges. These strategies represent a shift in thinking with respect to diversity in clinical trials of oncology medical products, from aspirational to actionable. As FDA’s thinking has evolved, so has their approach. Measurable progress has already been made in the inclusion of pediatric patients in trials of cancer therapies, and with the introduction of two new initiatives in 2021 (Project Equity, to ensure that supporting data submitted to the FDA with marketing applications are reflective of the actual demographics of the patient population who will receive the therapy;21 and Project Silver, to increase representation of older adults in cancer clinical trials22), there is further reason for optimism going forward.
- Loree JM, Anand S, Dasari A, Unger JM, Gothwal A, Ellis LM, Varadhachary G, Kopetz S, Overman MJ, Raghav K. Disparity of Race Reporting and Representation in Clinical Trials Leading to Cancer Drug Approvals From 2008 to 2018. JAMA Oncol. 2019 Oct 1;5(10):e191870. https://jamanetwork.com/journals/jamaoncology/fullarticle/2748395
- Zettler M, Feinberg BA, Kish J, Gajra A. Gender-based disparities in clinical trials supporting FDA approval of oncology drugs. Journal of Clinical Oncology 2020;38(15) suppl: 2058. https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.2058
- Gajra A, Zettler ME. Age-based disparities in clinical trials supporting FDA approval of therapies for solid tumors. Journal of Clinical Oncology 2021;39(15) suppl: e18534. https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.e18534
- Gajra A, Zettler ME, Phillips, Jr EG, Feinberg B. Age-Based Disparities in Clinical Trials Supporting FDA Approval of Therapies for Hematologic Malignancies. Blood 2020;136 (Supplement 1): 21–22. https://ashpublications.org/blood/article/136/Supplement%201/21/474059/Age-Based-Disparities-in-Clinical-Trials
- United States Food and Drug Administration. Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry. Guidance for Industry. November 2020. https://www.fda.gov/media/127712/download
- United States Food and Drug Administration. Cancer Clinical Trial Eligibility Criteria: Minimum Age Considerations for Inclusion of Pediatric Patients. Guidance for Industry and IRBs. July 2020. https://www.fda.gov/media/121318/download
- United States Food and Drug Administration. Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials. Guidance for Industry. March 2019. https://www.fda.gov/media/113499/download
- United States Food and Drug Administration. Inclusion of Older Adults in Cancer Clinical Trials. Guidance for Industry. March 2020. https://www.fda.gov/media/135804/download
- United States Food and Drug Administration. Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, or Hepatitis C Virus Infections. Guidance for Industry. July 2020. https://www.fda.gov/media/121319/download
- United States Food and Drug Administration. Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies. Guidance for Industry. July 2020. https://www.fda.gov/media/123745/download
- United States Food and Drug Administration. Cancer Clinical Trial Eligibility Criteria: Brain Metastases. Guidance for Industry. July 2020. https://www.fda.gov/media/121317/download
- FDA Briefing Document, Oncologic Drugs Advisory Committee Meeting BLA 761209 (retifanlimab-dlwr infusion, Incyte Corporation). June 24, 2021. https://www.fda.gov/media/150251/download
- FDA Briefing Document, Oncologic Drugs Advisory Committee Meeting BLA 761222 (sintilimab, Innovent Biologics (Suzhou) Co., Ltd.) February 10, 2022. https://www.fda.gov/media/156021/download
- United States Food and Drug Administration. Approval letter for infigratinib. May 28, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/214622O rig1s000ltr.pdf
- United States Food and Drug Administration. Approval letter for umbralisib. February 5, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/213176
- ClinicalTrials.gov. A Study of LOXO-292 in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001). https://clinicaltrials.gov/ct2/show/NCT03157128
- United States Food and Drug Administration. Approval letter for selpercatinib. May 8, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/213246Orig1s000ltr.pdf
- Barone A, Casey D, McKee AE, Reaman G. Cancer drugs approved for use in children: Impact of legislative initiatives and future opportunities. Pediatr Blood Cancer. 2019 Aug;66(8):e27809. https://onlinelibrary.wiley.com/doi/10.1002/pbc.27809
- United States Food and Drug Administration. Oncology (Cancer) / Hematologic Malignancies Approval Notifications database. https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications
- Zettler ME. The RACE for children act at one year: progress in pediatric development of molecularly targeted oncology drugs. Expert Rev Anticancer Ther. 2022 Jan 24:1-5. https://www.tandfonline.com/doi/full/10.1080/14737140.2022.2032664
- United States Food and Drug Administration. Project Equity. August 16, 2021. https://www.fda.gov/about-fda/oncology-center-excellence/project-equity
- United States Food and Drug Administration. Project Silver. October 5, 2021. https://www.fda.gov/about-fda/oncology-center-excellence/project-silver
About The Author:
Marjorie Zettler, Ph.D., MPH is director of clinical science at Regor Pharmaceuticals, Inc. An industry veteran with nearly two decades’ experience in the pharma and healthcare sector, her work has focused on clinical research, drug development, and regulatory strategy. She has published more than 100 abstracts, manuscripts, and patents.