An Evaluation of Novel Oncology Approvals with a PMR/C for Assessing Data in Racial and Ethnic Populations Underrepresented in Premarket Clinical Trials

Ensuring clinical trials include patients who represent the demographics of the intended treatment population is necessary to support a comprehensive assessment of a therapy’s benefits and risks and inform optimal use. Recognizing this imperative, the federal government, including Congress and the U.S. Food and Drug Administration (FDA), has implemented policies to ensure clinical trials are more inclusive and representative of the general U.S. population and intended patient population based on characteristics such as race, ethnicity, sex, gender, socioeconomic status, and age. As part of these efforts, the FDA released several guidance documents detailing standards for collecting race and ethnicity data, launched clinical trial snapshots to improve transparency in reporting demographic variables for pivotal clinical trials, and, with their new authority provided under the Food and Drug Omnibus Reform Act (FDORA) of 2022, established the requirement for sponsors to submit diversity action plans which must include representative enrollment targets for registrational trials supporting new drug applications and biologics license applications (1–4).

The focus of these efforts is primarily on improving representation in premarket clinical trials; however, FDA may exercise regulatory flexibility and issue postmarketing requirements and/or commitments (PMR/Cs) to further evaluate a drug in situations where additional information is needed to ensure the safety, effectiveness, and quality of the drug after approval. Recent FDA guidance has clarified that in certain circumstances, PMR/Cs may be used to further characterize safety or efficacy in populations underrepresented in premarket clinical trials (5). Patients from certain racial and ethnic populations are disproportionately underrepresented in clinical research, including premarket pivotal trials supporting oncology approvals. To address this gap, in some cases, approvals were accompanied by PMR/Cs requesting additional data in underrepresented racial and ethnic populations (R/E PMR/C; refs. 6–8). This analysis evaluates the trends in oncology PMR/C studies from 2012 to 2023 focused on greater representation of race and ethnicity, assesses characteristics of pivotal trials that may prompt these studies to provide insights into FDA expectations, and informs the development of more effective diversity plans and premarket study designs.

Using publicly available information on Drugs@FDA and the Center for Biologics Evaluation and Research’s (CBER) page of Licensed Biological Products with Supporting Documents, a list of all PMR/Cs issued in the original approval letters of novel oncology drugs and biologics (referred to herein as “drugs”) approved by the FDA between 2012 and 2023 was compiled (9, 10). PMR/C descriptions, statutes under which the PMR/Cs were issued, and final report due dates were also collected from the original approval letters. To identify PMR/Cs that emphasized the need for data in a representative population, a key word search of PMR/C descriptions was conducted using the terms “represent,” “racial,” “race,” “ethnic,” and “ethnicity,” and matching PMR/C descriptions were reviewed to identify those that specifically addressed representation based on race and ethnicity (R/E PMR/Cs).

Publicly available review documents on Drugs@FDA and CBER’s web page of Licensed Biological Products with Supporting Documents were used to collect pivotal trial characteristics including trial size, design (single-arm vs. randomized), patient demographics by geographic region, race, and ethnicity and to assess results from efficacy, safety, dosing, and pharmacokinetics (PK) subgroup analyses based on race and ethnicity. Review documents were also used to identify instances where FDA commented whether the trial(s) supporting approval were representative of the racial and ethnic makeup of the intended patient population and/or U.S. population.

Between January 1, 2012, and December 31, 2023, the FDA approved 144 novel oncology drugs and issued PMR/Cs to 98% (141/144), 22 of which had a PMR/C specifying the need for additional data in a population representative of the racial and ethnic diversity of the U.S. and/or intended patient population (R/E PMR/C). Most drugs with a R/E PMR/C (21/22, 96%) were approved from 2021 to 2023. Prior to 2021 (2012–2020), only 1 of the 104 drugs approved had a R/E PMR/C (Fig. 1). Further analyses focused on the 40 novel oncology drug approvals between 2021 and 2023, of which 53% (21/40) had a R/E PMR/C (Fig. 1).

A total of 25 R/E PMR/Cs were issued across 21 drugs (three drugs had two R/E PMR/Cs). Most were PMCs subject to annual reporting requirements under section 506B of the Federal Food, Drug, and Cosmetic Act (13/25, 52%). The remaining 12 were Accelerated Approval (AA) requirements (8/25, 32%) or PMRs under 505(o) of the Federal Food, Drug, and Cosmetic Act (4/25, 16%) that assess serious risks or safety signals related to the use of the drug.

More than half of the drugs approved from 2021 to 2023 were AAs (21/40, 53%). Of these, the majority had a R/E PMR/C (16/21, 76%). In contrast, only 26% (5/19) of drugs approved through the traditional approval pathway had a R/E PMR/C (Table 1). Many approvals in this time frame received Priority Review (37/40, 93%), Orphan Drug Designation (29/40, 72%), Breakthrough Therapy Designation (22/40, 55%), and/or were first-in-class approvals (13/40, 33%)—this was true for both drugs with and without a R/E PMR/C.

Approvals supported by a single-arm pivotal trial (n = 31) were more likely to have a R/E PMR/C than approvals supported by a randomized controlled trial (RCT; n = 11). Two approvals were supported by one randomized trial and one single-arm trial and are included in the counts for both trial design categories. While 58% (18/31) of approvals supported by a single-arm trial had a R/E PMR/C, only 36% (4/11) of approvals supported by a RCT had a R/E PMR/C. Likely because of these differences in trial design (i.e., single-arm trials are on average smaller than RCTs), trials supporting approvals with a R/E PMR/C were smaller on average than trials supporting approvals without a R/E PMR/C (201 vs. 267). Notably, all AA drugs were supported by single-arm trials.

When considering cancer type, R/E PMR/Cs were assigned to drugs indicated for non–Hodgkin lymphoma (NHL; 6/8, 75% of drugs approved for the indication received R/E PMR/Cs), non–small cell lung cancer (NSCLC; 3/6, 50%), multiple myeloma (5/6, 83%), gynecologic cancers (1/3, 33%), gastrointestinal cancers (3/3, 100%), breast cancer (2/2, 100%), and nasopharyngeal cancer (1/1, 100%; Table 1).

The 40 drugs approved in 2021 to 2023 were supported by data from 43 pivotal clinical trials. For each pivotal trial, patient demographics (race, ethnicity, and U.S. enrollment) of the primary efficacy population used to support approval were compiled. Pivotal trial demographics for indications that had both drugs with and without a R/E PMR/C (i.e., NHL, NSCLC, multiple myeloma, and gynecologic cancers) were further evaluated to identify any differences in pivotal trial patient demographics for drugs with a R/E PMR/C (n = 15) versus those without a R/E PMR/C (n = 8; Table 2).

Most pivotal trials reported race using the categories White (23/23, 100%), Black or African American (21/23, 91%), and Asian (23/23, 100%). On average, pivotal trials supporting approvals with a R/E PMR/C enrolled 75.3% (36.8%–96%) White, 3.7% (0%–7.3%) Black or African American, and 12.5% (0.6%–59.6%) Asian patients compared to 74.4% (34%–95%) White, 6.6% (1%–18%) Black or African American, and 12.9% (1%–59%) Asian patients for drugs without a R/E PMR/C (Table 2). Other categories included for reporting of race were American Indian or Alaska Native (AI/AN; reported for 10/23 trials, 43%), Native Hawaiian or Other Pacific Islander (NHPI; 8/23, 35%), Multiple (5/23, 22%), and Other (13/23, 57%). Patients who identify as AI/AN or NHPI were on average less represented in pivotal trials for drugs with a R/E PMR/C [0.9% (0%–1.7%) and 0.5% (0.35%–1%)] than in pivotal trials for drugs without a R/E PMR/C [1.6% (0.7%–4.2%) and 1.3% (1%–1.6%)]. In addition to the reported categories, 78% (18/23) of pivotal trials reported some degree of missing data for race (Race Not Reported/Unknown/Missing). On average, pivotal trials for drugs with a R/E PMR/C had more missing data for race reporting compared to drugs without a R/E PMR/C (7.6% vs. 3.3%; Table 2).

Reporting of ethnicity (i.e., Hispanic/Latinx, Non-Hispanic/Latinx, Other Ethnicity, and Not Reported/Missing/Unknown) was also variable across pivotal trials (Table 2). Patients identifying as Hispanic/Latinx were less represented in pivotal trials supporting drugs with a R/E PMR/C [4.8% (0%–9.7%)] compared to drugs without a R/E PMR/C [10.5% (2.7%–35%)] (Table 2). Most pivotal trials had some degree of missing ethnicity data (18/23, 78%) and pivotal trials for drugs with a R/E PMR/C on average had a greater percentage of patients without ethnicity reported compared to drugs without a R/E PMR/C [14% (0%–21.9%) vs. 3.5% (0%–6.2%)] (Table 2).

For reporting by geographic region, on average, pivotal trials for drugs with a R/E PMR/C, reported fewer U.S. patients than pivotal trials for drugs without a R/E PMR/C. Pivotal trials supporting approvals without a R/E PMR/C were made up on average of 66% (14.9%–100%) U.S. patients, compared to an average of 41% (12%–73%) U.S. patients for approvals with a R/E PMR/C (Table 2).

Efficacy, safety, PK, and dosing subgroup analyses based on race and ethnicity were assessed for all 40 drugs approved from 2021 to 2023. Three review documents for drugs with a R/E PMR/C and one review for drugs without a R/E PMR/C included subgroup analyses for multiple cohorts or clinical trials. Each subgroup analysis was assessed leading to differences in the total subgroup analyses for drugs with a R/E PMR/C (n = 24) and without a R/E PMR/C (n = 20) compared with the total number of drugs in each group (n = 21 and n = 19, respectively). Review documents frequently noted insufficient data or small samples sizes which limited the ability to draw conclusions from subgroup analyses. More reviews for drugs with a R/E PMR/C noted there were limited data for efficacy (17/24, 71%), safety (14/24, 58%), PK (7/24, 29%), and dosing (6/24, 25%) subgroup analyses based on race/ethnicity compared reviews for drugs without a R/E PMR/C (Fig. 2A–D). A greater number of subgroup analyses for drugs with a R/E PMR/C indicated there was a potential difference across racial and/or ethnic subgroups than for drugs without a R/E PMR/C, although these differences may not have been clinically meaningful (Fig. 2A–D). Differences were observed most in safety subgroup analyses for 29% (7/24) of drugs with a R/E PMR/C and 25% (5/20) of drugs without a R/E PMR/C (Fig. 2B).

Clinical trials supporting oncology drug approvals frequently underrepresent diverse racial and ethnic populations. Prior to 2020, the FDA had not explicitly requested postmarket studies for novel oncology drugs be conducted in more representative populations to address this gap. However, since 2020, there has been a notable increase in the number of novel oncology approvals with a PMR/C specifying the study should be conducted in a population more representative of the racial and ethnic diversity of the U.S. population or intended use population. In the last 3 years (2021–2023), more than half of novel oncology approvals (21/40, 53%) were issued such a PMR/C. The timing of this increase in R/E PMR/Cs aligned with the release of FDA guidance and legislation aimed at enhancing representation in clinical trials. This analysis assessed differences between approval characteristics for drugs with a R/E PMR/C and those without a R/E PMR/C to identify factors that may contribute to a drug being issued a R/E PMR/C.

Most notably, drug approvals supported by a single-arm trial and/or that were accelerated approvals were more likely to receive a R/E PMR/C. All accelerated approvals during this period were based on a single-arm trial. Additionally, on average, trials for drugs with a R/E PMR/C reported more missing data for both race and ethnicity compared to trials without a R/E PMR/C. For indications in which there were drugs with a R/E PMR/C and without a R/E PMR/C (i.e., NHL, NSCLC, multiple myeloma, and gynecologic cancers) pivotal trial demographics were consistent with previous analyses of pivotal trial demographics that show a lack of representation of certain racial and ethnic groups, in particular, Black or African American and Hispanic/Latinx populations (7).

Despite efforts to standardize and improve transparency in reporting of demographic data for novel drugs (e.g., Clinical Trial Snapshots) there continues to be variable reporting of race and ethnicity data. For reporting of race, FDA recommends sponsors include, at a minimum, options to select AI/AN, Asian, Black or African American, NHPI and White, as well as directions clarifying that one or more of these may be selected (2). This analysis showed some reviews did not report enrollment for all recommended race and ethnicity categories, which may have been due to the timing of data collection for the clinical trials or because there were no patients who identified as the missing races or ethnicities; however, in some cases zero was reported if this was true. White and Asian were the only two demographic categories assessed that were reported in all review documents. Most trials included in this analysis were conducted globally, so the missing data may be related to global restrictions related to protected characteristics, such as race and ethnicity, that prevent collection and reporting of these data (11, 12). Among the 20 trials that included information on U.S. enrollment, trials for drugs with a R/E PMR/C had an average U.S. enrollment of 40.9% (12%–73%). In contrast, trials for drugs without a R/E PMR/C reported a higher average U.S. enrollment rate of 66.2% (14.9%–100%). Notably, there were four drugs supported by trials that enrolled only U.S. patients and these drugs did not receive a R/E PMR/C.

Another factor influencing whether FDA issues a R/E PMR/C is the presence of potential safety signals observed in subgroup analyses. Review documents posted in support of drug approvals often include subgroup analyses that assess whether there are differences in efficacy, safety, PK, and dosing based on intrinsic factors such as race and ethnicity. Review documents for drugs with a R/E PMR/C and those without a R/E PMR/C indicated subgroup analyses are often limited by small sample sizes and/or are incorporated as secondary/exploratory analyses, limiting the ability to draw conclusions about whether meaningful differences in efficacy, safety, dosing, or PK exist across racial and ethnic subgroups. Despite these limitations, subgroup analyses based on race and ethnicity occasionally identify potential signals of a difference. Safety subgroup analyses most often indicated a potential signal of a difference (n = 12). Of note, there were five instances where a safety subgroup analysis by race and/or ethnicity indicated a potential difference and no R/E PMR/C was issued.

The FDA’s commitment to ensure oncology trials reflect the diversity of the U.S. population should be considered with the evolving nature of oncology clinical trials, including enhanced research capabilities outside the U.S. Global clinical trial practices and regulatory expectations influence diversity efforts and reciprocally, U.S. diversity initiatives affect clinical trials worldwide. It will be important to know how many patients should be enrolled in the U.S. to be considered representative of the U.S. population, as well as how FDA considers patients enrolled outside of the U.S. when determining whether a trial is adequately representative. One PMC provided a benchmark for the number of patients to be enrolled in the U.S. requesting the sponsor, “conduct a clinical trial enrolling a total sample size of 100 patients in the U.S. and Canada, that includes a sufficient representation of patients in racial and ethnic minority subgroups and is reflective of the U.S. population of patients with nasopharyngeal carcinoma (NPC).” Another PMC specified a benchmark for what FDA considers appropriate representation of Black or African American patients for a trial in multiple myeloma stating, “Ensure that the representation of the African American subpopulation in the studies is reflective of the Black population in the geographical location/country. Therefore, approximately 15% of the population that is enrolled from the US should comprise of African Americans.” Additionally, there is a need for more consistent and transparent reporting of race and ethnicity. Varying global definitions and restrictions on reporting for protected characteristics, in particular race and ethnicity, can impact the ability to assess whether a trial is adequately representative. Efforts to have more uniform and complete reporting across clinical trials will help to accurately assess the extent of underrepresentation, inform effective strategies for enhancing diversity and inclusion in trials, and help with assessing progress toward equitable clinical trials. Approaches for addressing these gaps in data and global coordination around efforts to enhance clinical trial diversity can be useful for ensuring data necessary to assess differences across subgroups are available.

Finally, studies should be designed to assess effectiveness and safety in different populations. In several cases, reviews noted the subgroup analyses were limited due to small sample sizes. In certain instances, such as when there are known differences between populations or disparities in the disease burden, oversampling patients from underrepresented subgroups may be warranted to improve the ability to assess whether meaningful differences across subgroups exist. As such, it will be important to evaluate when to power studies adequately to assess whether meaningful differences in safety and efficacy exist across racial and ethnic or other underrepresented subgroups. When enrolling patients is challenging due to the rarity of the disease, regulatory flexibility can be applied to answer these questions following approval through PMR/Cs to avoid delaying patient access to promising therapies.

Greater representation in clinical trials can improve the generalizability of results to real-world patients who may need the drug, inform optimal use, and ensure equitable access and benefit from novel therapies. Our findings demonstrate that PMR/Cs are being used to ensure stakeholders conduct representative studies following approval; however, it is too early to assess whether this results in timely studies in more representative populations or if the results of these studies have an impact on labeling. While these types of PMR/Cs may be appropriate in certain instances, additional work is necessary to ensure premarket oncology clinical trials are representative of all patients. To achieve this goal, it will be essential to implement strategies that address barriers to participation and promote inclusivity. Although this analysis focuses on representation of racial and ethnic groups, the mandates in FDORA, such as the Diversity Action Plan requirement, also aim to address underrepresentation of populations based on characteristics such as sex, gender, age, geographic region, and other social determinants of health. As part of the effort to fulfill these mandates, trial sponsors have described strategies for setting representative enrollment goals, enrolling patients to meet these goals, and retaining these patients on clinical trials. For example, sponsors now incorporate diversity considerations into their trial planning processes by using epidemiologic data sources to assess disease burden and inform site selection. Trial sponsors are also working to lower barriers to participation when designing trials by incorporating decentralized elements and removing overly restrictive eligibility criteria. To address the financial burdens of participating, sponsors are offering reimbursement for travel, time, meals, and other costs incurred during trial participation. In addition to trial-specific efforts, sponsors are working to cultivate sustained partnerships with diverse communities and providers to build trust, better understand and address patient and provider needs, and more effectively communicate about trial opportunities (13). To continue this progress, it is critical that the future clinical trials, especially clinical trials conducted in the premarket setting used to support drug approvals, prioritize and enhance representation of diverse patient populations.

No disclosures were reported.

This work was supported by Friends of Cancer Research.