Diversity in Cancer Clinical Trials: Issues and Solutions

Summary in Thirty Seconds

• Ethnic minorities and women have been underrepresented in cancer clinical trials for many years. Trials have not consistently reported participant demographics, and without reporting such data, the lack of diversity will not change.

• Diversity in trials matters because of the differential mortality rates, immune responses, and genetic compositions of various demographic groups.

• There are multiple barriers to clinical trial participation amongst underrepresented groups, including community, sponsor/trial systemic, and individual factors.

• Many proposals have been put forth to improve cancer clinical trial representation, including amplifying awareness of clinical trials, identifying eligible patients more effectively, and co-facilitating decision-making about trial participation can improve diversity in cancer clinical trials.

• Additional recommendations include designing trials with a focus on reducing barriers and enhancing inclusiveness; evaluating protocol inclusions and exclusions that affect ethnic minorities; educating trial staff to enhance cross-cultural competencies and communication; and forming partnerships with patient advocacy groups and community leaders to help increase access for under-represented populations and increase awareness of clinical trials.

Project Equity

It has been almost a year since Project Equity drafted the FDA initiative to increase the diversity of clinical trial participants in the U.S.[1] This initiative has three goals:

• Develop policies to ensure adequate enrollment of underrepresented/vulnerable subgroups in cancer clinical trials;

• Engage with stakeholders on various initiatives to promote access to and equity in clinical trials;

• Analyze data generated through clinical trials to evaluate outcomes across these underrepresented/vulnerable subgroups.

Underrepresentation in Cancer Clinical Trials

1. Inconsistent Demographic Reporting

Why is such an initiative necessary? First, reporting of the ethnic/racial composition of clinical trial participants is often lacking. A 2018 retrospective study of clinicaltrials.gov[2] assessed over 1,000 completed cancer clinical trials between 2003 and 2016 and found only 31% reported ethnicity, while a review of 230 cancer clinical trials conducted between 2008 and 2018 involving over 100,000 participants found that 63% reported racial demographics with this reporting essentially unchanged over the studied decade.[3] If demographic data is not reported in clinical trials, it is impossible to assess levels of representation nor will diversity shortcomings change.

2. Poor Diversity in Trials

Second, the lack of diversity in cancer clinical trials is a well-established problem.[4] The image on the left is a snapshot of the 18 oncology drugs approved by the FDA in 2020.[5]

Three large review studies describe this problem. An evaluation of FDA oncology drug approvals over a decade found that compared to cancer incidence, Black and Hispanic participants were significantly underrepresented in clinical trials (22% and 44% respectively under incidence).[6] A similar study of 149 clinical trials and almost 60,000 participants demonstrated under-representation of women in cancer clinical trials (60% men/40% women in trials vs. 55% men/45% women cancer incidence).[7] More specifically, women were most underrepresented in thyroid cancer and liver cancer trials; whereas, men were underrepresented in soft tissue cancer and bladder cancer trials. The 2018 retrospective study of clinicaltrials.gov[8] (described above) found cancer clinical trial participants more likely to be White (83%) than prevalence would predict, and younger than 65 (63%), with low recruitment of females, particularly in melanoma, pancreatic cancer, and lung cancer trials. Additionally, industry-sponsored trials were less likely to incorporate Black participants versus NIH/NCI and academic trials. Unexpectedly, the representation of Black and Native American participants dropped slightly in the later years of the trials studied. A 2020 study evaluated 358 cancer clinical trials for 15 cancer types[9] and found the proportion of Black participants in pharmaceutical-company–sponsored trials was 2.9% while the proportion of Black patients with cancer in the US population is 12.1%. These findings were generally consistent across individual cancer types. This finding is particularly notable because pharmaceutical company-sponsored trials test the newest available therapies; thus, limited access to these trials represents a disparity in access to potential breakthrough therapies.

Why Representation Matters

Research suggests that particular populations may be at greater risk for specific diseases (e.g., oncologic[10] and neurologic[11]). It has been estimated that one-fifth of new drugs demonstrate differences in exposure and/or response across racial and ethnic groups.[12] For example, research involving 1 million patients with cancer in the U.S. showed that Black patients have a 28% higher cancer-specific mortality compared with White patients. This survival gap is independent of socioeconomic factors, disease stage, and access to treatment.[13] Additionally, immune responses to cancer have been shown to vary by race. An analysis of prostate cancer samples obtained from White and Black patients showed differences by race in the immune composition of both the tumor and the surrounding tissue.[14] An analysis of breast cancer samples showed differential immune responses in Black patients versus White patients.[15] Such differences in immune response patterns are important to recognize when evaluating diversity in clinical trials and the prescription of immunotherapeutic agents.[16]

When specific ethnic/racial populations are underrepresented in clinical studies, then the genetic and/or socioeconomic factors driving the diseases may not be included in the very studies designed to understand those diseases and develop new treatments. Additionally, a lack of diversity results in a divide between the clinical trial populations and the real-world patients who will ultimately receive the treatments.[17]

The following image gives a summary of the multiple sources of barriers leading to the underrepresentation of ethnic minorities in clinical trials:[18]

Proposed Solutions to Improve Diversity

As the image above demonstrates, there are multiple potential issues leading to a lack of diversity in clinical trials. This image suggests at least three addressable issues:

1. Collecting sociodemographic data;

2. Improving clinical trial infrastructure, (e.g., providing interpreter services, addressing logistical barriers in low-resource settings);

3. Understanding how health beliefs, patient comprehension, communication, and perceptions of clinical research influence clinical trial enrollment decisions among diverse populations.

An international coalition of cancer experts suggested that amplifying awareness of clinical trials, identifying eligible patients more effectively, and co-facilitating decision-making about trial participation can improve diversity in cancer clinical trials.[19] Recommendations to improve diversity in cancer clinical trials from ASCO,[20] the US Cancer Centers of Excellence,[21] and the Government Accounting Office[22] can be summarized as follows:

1. Proactively design and implement trials with a focus on reducing barriers and enhancing inclusiveness, and work with sites to conduct trials in ways that recruit and increase participation of under-represented populations.

2. Evaluate protocol inclusions and exclusions, including non-clinically relevant criteria, that disproportionately affect ethnic minorities.

3. Include prospective support/logistics measures for patients to enhance their understanding of and trust in what is available to them in the recruiting stage.

4. Conduct recurring education, training, and evaluation for anyone designing or conducting trials to build cross-cultural competencies, mitigate bias, and build effective communication.

5. Form partnerships with patients, patient advocacy groups, and community leaders and ambassadors to help increase access for under-represented populations and increase awareness of clinical trials.

6. Collect and publish data on the racial, ethnic, and gender demographics of trial participants when reporting results of trials, programs, and interventions intended to increase clinical trial representation.

[1] Diversity Plans to Improve Enrollment of Participants From Underrepresented Racial and Ethnic Populations in Clinical Trials; Draft Guidance for Industry; Availability | FDA [2] Journal of Oncology Practice. 2018; 14(1):e1-e10 [3] JAMA Oncol. 2019; 5(10):e191870 [4] J Natl Cancer Inst. 2002; 94(5):334-357 [5] 2020 Drug Trials Snapshots Summary Report (fda.gov) [6] JAMA Oncol. 2019; 5(10):e191870 [7] Cancer. 2021; 127(17):3156-3162 [8] Journal of Oncology Practice. 2018; 14(1):e1-e10 [9] JNCI Cancer Spectrum. 2020; 4(4):pkaa034 [10] Blood Cancer J. 2020; 10:19 [11] Alzheimers Dement. 2019; 15:17-24 [12] PLoS ONE 18(2):e0281940 [13] Cancer. 2014; 120:1532-1539 [14] Int J Cancer. 2014;134:81-91 [15] PLoS One. 2009; 4:e4531l [16] ASCO Educational Book. 2019 :39, 3-10 [17] Cancer. 2017; 74:89-95 [18] Cancer. 2022; 128(2):216-221 [19] Nature Medicine 2022; 28:620–626 [20] Journal of Clin. Onc. 2022; 40(19):2163-2171 [21] Journal of Oncology Pract. 2019; 15:4:e289-e299 [22] Cancer Clinical Trials: Federal Actions and Selected Non-Federal Practices to Facilitate Diversity of Patients | U.S. GAO