Promoting Diversity in Clinical Trials

Avastin is a medication approved by the FDA in 2004 for the treatment of colorectal cancer; it works by blocking the formation of new blood vessels allowing tumors to grow and metastasize. After four years on the market, in 2008, Avastin was granted accelerated approval by the FDA for the treatment of advanced breast cancer when used in combination with chemotherapy. However, shortly after market clearance there were concerns about the safety and effectiveness of Avastin’s newfound use for breast cancer patients. In just 2010 the FDA's Oncologic Drugs Advisory Committee voted to recommend that the approval be revoked, and in 2011 the FDA began the process of revoking their approval for Avastin’s use in the treatment of breast cancer. This was due to the results of a number of clinical studies on Avastin in treating breast cancer. The studies started to show that Avastin did not provide a significant benefit to patients with advanced breast cancer, in fact, it appeared to have serious adverse effects, including high blood pressure and bleeding. So, the question is, if the early studies on Avastin didn’t identify these issues why were these later stage studies unearthing so many issues?

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An earlier study, the AVADO trial, had subjects that did not reflect the actual demographics of the disease state. There was an underrepresentation of older women and women of color. While the AVADO trial showed that Avastin delayed the progression of breast cancer, it did not appear to improve overall survival significantly. Conversely, other trials, such as the RIBBON-1 trial, that had more diverse subject populations in terms of race, ethnicity, and geographic location did not show significant benefit from Avastin.

While the approval of Avastin was not explicitly revoked due to lack of diversity, if all of the clinical trials had been more diverse it is likely that the medication's effectiveness and side effects in the general population would have been better characterized and understood. Thus, more accurate and reliable data could have been collected and considered when assessing the medication’s safety and effectiveness. It is undeniable that including diverse populations in clinical trials can lead to a better understanding of medications and medical devices and ensure that medications are safe and effective for everyone who may use them.

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In 2022, the FDA released a guidance document for the industry titled "Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials." This intention of this new guidance is to not only encourage but assist both the pharmaceutical and medical device industry in increasing diversity in clinical trials, particularly with regards to racial and ethnic representation. The document acknowledges that certain patient populations have been historically excluded from and underrepresented in clinical studies. This has led to disparities in healthcare and worsened health outcomes for these groups. The FDA also details and emphasizes how the importance of diversity in clinical trials to ensure that the benefits and risks of medical products are understood across different patient populations.

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More specifically, the guidance document recommends that sponsors develop a Race and Ethnicity Diversity Plan for their product. A plan is recommended for products that require any of the following:

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• IND

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• IDE

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• Clinical studies to support a marketing submission for a BLA, NDA, 510(k), PMA, De Novo or HDE

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The plan should be submitted to the IND Application as soon as practicable, as part of the IDE, and/or as part of the marketing submission. Upon submission, the plan should be marked. “RACE AND ETHNICITY DIVERSITY PLAN” in large, bolded type in the cover letter.

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Fortunately, the FDA has provided the four key components that should be included in the plan:

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1.       Overview Of The Disease/Condition

a.       Describe available data on the pathophysiology of the disease or condition in underrepresented racial and ethnic populations. As appropriate, describe any differential application or use of currently available prevention, screening or diagnostic strategies and treatments, across racial and ethnic populations.

b.       Discuss the current understanding of and available evidence supporting any similarities and/or differences in the disease or condition under study that are associated with the underrepresented racial and ethnic populations in the United States.

2.       Scope Of Medical Product Development Program

Briefly describe the planned trials or studies that will product support the medical product’s safety, effectiveness and, if a drug, dosage in a future marketing submission. Outline the following:

a.       Study design, study population (including study eligibility criteria), endpoints and, the expected geographic locations of the trials or studies and how these aspects of the trial or study may specifically address inclusion of underrepresented racial and ethnic populations.

b.       As applicable, summarize any differential findings from clinical pharmacology studies (PK /PD data, pharmacogenomics) that may be associated with certain racial and ethnic populations and/or other relevant information.

3.       Goals For Enrollment Of Underrepresented Racial And Ethnic ParticipantsDefine and provide justification for the planned enrollment of participants from underrepresented racial and ethnic populations.

a.       Specify underrepresented racial and ethnic populations based on assessment in Category #1.

b.       Specify goals for enrollment of underrepresented racial and ethnic participants (e.g., based on the epidemiology of the disease and/or based on a priori information that may impact outcomes across racial and ethnic groups; and where appropriate, leverage pooled data sources or use demographic data in general population). In some cases, increased (i.e., greater than proportional) enrollment of certain populations may be needed to elucidate potential important differences.

4.       Specific Plan Of Action To Enroll And Retain Diverse Participants

a.       Describe in detail the operational measures that will be action to enroll implemented to enroll and retain underrepresented racial and ethnic participants in the planned trial(s) or studies, and the planned use of data to characterize safety, efficacy, and optimal dosage in these participants, when applicable.

b.       Describe specific trial enrollment and retention strategies, including but not limited to:

                                                               i.      site location and access (e.g., language assistance for persons with limited English proficiency, reasonable modifications for persons with disabilities, and other issues such as transportation);                                                             ii.      sustained community engagement (e.g., community advisory boards and navigators, community health workers, patient advocacy groups, local healthcare providers, etc.);                                                           iii.      reducing burdens due to trial/study design/conduct (e.g., number/frequency of study-related procedures, use of local laboratory/imaging, telehealth);

c.       Describe metrics to ensure that diverse participant enrollment goals are achieved and specify actions to be implemented during the conduct of the trial(s) or studies if planned enrollment goals are not met.

5.       Status Of Meeting Enrollment Goals (As Applicable)

a.       As the diversity plan is updated, the status of meeting enrollment goals should be evaluated. If the enrollment goals sponsor is not able to achieve enrollment goals despite best efforts, discuss a plan and justification for collecting data in the post-market setting.There are several steps that the industry can take to achieve better diversity in clinical trials:

1.       Identifying and addressing potential barriers to enrollment: Companies should identify potential barriers to enrollment for underrepresented groups, such as language barriers, lack of transportation, or distrust of medical research. Once identified, companies should develop strategies to address them. These may include providing language interpretation services, offering transportation assistance, or working with community organizations to build trust.

2.       Monitoring and Reporting demographic data: Companies should monitor and report demographic data for clinical trial subjects to assess in real time whether the trial population adequately represents the intended patient population. This data should also be considered when making decisions about the safety and efficacy of the medical product.

3.       Diverse locations of clinical sites: Companies should establish clinical study sites in areas that vary in geographical location to enhance the opportunity for the recruitment and retention of diverse clinical study subjects.

4.       Incentives for participation: Offering financial incentives or other benefits, such as transportation or childcare, can help to increase participation from underrepresented groups.

5.       Diversify the research team: Having a research team that reflects the diversity of the target population can help to build trust and improve communication with study participants.

6.       Collaborate with minority-serving institutions: Clinical trial sponsors can partner with minority-serving institutions such as Historically Black Colleges and Universities (HBCUs) and Hispanic-Serving Institutions (HSIs) to increase participation from underrepresented groups.

The lack of diversity in clinical trials has long been recognized as a serious issue, leading to unequal access to healthcare for underrepresented groups. While there has been progress in recent years towards increasing diversity, there is still much work to be done. This recent addition to the clinical pathway for medical products that aims to address this issue. While this new addition to the clinical pathway for medical products may be viewed as an additional burden, it is achievable. Just as all similar previous situations were achieved, companies must and will learn to adapt to this new requirement. In the end, it is undeniable that it will be a net positive.

More diverse clinical trials are essential to help to ensure that medical products are safe and effective for all populations. Increasing diversity in clinical trials, is an essential step towards ensuring equitable access to healthcare and improving health outcomes for all populations. It is important for the industry to recognize the value of diversity in clinical trials and work towards implementing strategies to increase diversity and representation in clinical research.