Clinical Trial Diversity: An Emerging Paradigm in Outcomes Research

“The enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition”

– Dr Tedros Adhanom Ghebreyesus
Director-General, World Health Organization

‘Right to heath’ and universal health coverage has been a World Health Organization mandate since its establishment. This brings up a primary and integral aspect of universal health coverage- clinical trials, a diverse population in clinical trials provides assorted data and ensures an inclusive ‘research for all’ approach.
The safety and efficacy of investigational products and novel clinical interventions may vary depending on the population characteristics such as age, gender, race, ethnicity, and geography. A varied population acts as a diverse sample and a more accurate representation of the final target population. It can pave the way for researchers to study even atypical treatment responses unique to subpopulations. This in turn provides robust trial data- a cardinal parameter for the success of any drug in the post-marketing arena.
For example, heart failure trials have shown a poor representation of African – American, women and other minorities which caused preclusion of meaningful subgroup analyses and missing out the opportunities to define the mechanisms for important population differences.¹

Let’s take an example of the COVID-19 research data. According to Centers for Disease Control and Prevention (CDC), African – American, American Indian, and Asian population had 1.0x, 1.5x, and 0.7x higher prevalence of COVID-19 infection respectively than the White population.² Emphasizing this concept on diversity, equity, and inclusion (DE&I), the recent phase 3 Pfizer & Moderna Coronavirus Disease (COVID)-19 trial included African – American (9.3% & 9.7%), Asian (4.3% & 4.7%), American Indian (0.6% and 0.8%), and Hispanics (28% & 20%), respectively, despite its expeditious nature.^3,4 Although the numbers do not fully approximate all the minor population in the US, they came closer to other US vaccine trials to some extent.

Acknowledging the importance of a diverse sample and its subsequent benefit on patients and their rights, global vistas in clinical research is ‘Diversity, Equity, and Inclusion’ (DE&I).

How DE&I influence clinical outcomes and subsequent care decisions?

Genpro’s evidence synthesis specialists bring to you interesting insights on how DE&I can influence clinical outcomes and their consequences. The summary given below is on a rapid evidence synthesis performed using our state-of-the-art artificial intelligence (AI) powered tool MaiA (machine assisted intelligent authoring platform, Genpro Research Inc.), within just one business day.
Oncology trials in last decade have reported a predominance of the white population.⁶ Although African – American people have a higher incidence of cancer (myeloma, colorectal, hepatic, prostate); their likelihood to receive therapy is less compared to White or Caucasians.⁷ This might be due to the underrepresentation of a race in the study sample. Non-small cell lung cancer (NSCLC) patients of the ‘African – American’ race showed lower treatment response and worse overall survival (OS) compared to those ‘White’ race. A subgroup analysis revealed that age >70 years, male gender, and African – American race showed lower incidence of survival.

Racial disparities were observed in other diseases with terminal outcomes. As per the CDC report, African Americans have higher asthma-related morbidity and mortality compared to non-Hispanic Whites.⁸ Opposingly, no difference was reported in mortality rates of African – American, Hispanics, and Whites in a cardiology trial.⁹ This highlights an urgent need for diversity research to arrive at conclusive and credible evidence.

Clinical Trial Diversity: Global Footprints

“Identifying health inequalities and their drivers is essential for achieving health equity”

WHO Thirteenth Global Programme of Work (GPW13)

In the recent past, we have witnessed a rigorous drive to reflect DE&I principles in CT practice which include proactive steps from regulatory authorities, pharma companies, and academia across the globe.
FDA, in November 2020, released a guidance document titled, “Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrolment Practices, and Trial Design (2020)”.10 The guidance document discusses three core recommendations for sponsors of CTs to improve the enrolment of underrepresented population.

“Going forward, achieving greater diversity will be a key focus throughout the FDA to facilitate the development of better treatments and better ways to fight diseases that often
disproportionately impact diverse communities.”

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Robert M Califf,
FDA Commissioner

In synchrony with the trial diversity-related advocacy efforts, FDA released industry guidance on 13^th April 2022 titled “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials: Draft Guidance for Industry”.¹¹ This guidance aims to provide recommendations to stakeholders, especially sponsors to develop and submit a Race and Ethnicity Diversity Plan to enrol representative numbers of participants from underrepresented racial and ethnic populations in the United States in clinical trials. It is an extension to the earlier FDA guidance (Oct 2016) focusing on the data collection related to race and ethnicity in clinical trials.¹² The key summary points from the latest FDA guidance documents are as follows:

Key challenges:

Advantages of the Diversity Plan:

Who may be included

Timepoint for the Diversity Plan from Sponsor:

As a part of IND application following discussion with FDA, plan to be submitted no later than pivotal trial(s) related feedback period (EOP2 milestone meeting package)

As recommended in this guidance, a diversity plan from the sponsor is recommended by
FDA at the following junctures:

Desirable Outcomes:

Operational Recommendations to ensure clinical trial diversity:

Recommended elements in the Diversity Plan:

Similarly, for the first time, Pharmaceutical Research and Manufacturers of America (PhRMA) committed towards diversity in CTs through its industry-wide principles.¹³ Four major dimensions were covered in these principles: education and awareness of CTs, reduction of access barriers, real-world data on diverse populations, and DE&I in CTs as a whole.
Although the implementation of these principles is voluntary, when put in practice PhRMA foresees a positive impact and better reflection of the intended treatment in an underrepresented population.
In the United Kingdom, the National Institute for Health Research (NIHR) launched the project ‘INCLUDE’- Innovations in Clinical Trial Design and Delivery for the Under-served. This acts as a roadmap for inclusive representation in research focused on those most in need.¹⁴ This strategic document includes characteristics of ‘under-served’ groups, reasons for underrepresentation, and a list of priorities for inclusive research. The project also aims to develop means to support the under-served groups and build awareness on INCLUDE among stakeholders.

Notably, all major global pharmaceutical companies are striving toward bridging DE&I gaps by committing actionable steps and allocating investments. This includes strategic roadmaps, academia-industry partnerships, data leverage and digitalization, and innovative enrolment procedures to ensure inclusive representation

Digitalizing Diversity Initiatives

Minority populations e.g., African Americans are active on several social media platforms like Twitter and Facebook. In an act to harness this potential, focused social media campaigns and online, open courses on recruitment strategies for minorities are being doled out.¹⁸ These aim to improve participation of marginalized and underrepresented patient groups in CTs.
However, every digital intervention requires cautious implementation and diversity research is also not here an exception. Poor health literacy or accessibility barriers to digital recruitment tools are the biggest challenges one must consider. A John Hopkins study reported that two-thirds of the African – American population responded only to paper advertisements and direct mail and not through digital patient portals.¹⁹ The finding implies that overreliance on electronic-based methods could exclude the underrepresented population. Instead, a hybrid strategy has shown potential to reduce disparity in CT. A study published in Clinical Trials journal featured a hybrid strategy (EMR + mailing) to be cost-effective and increase participation of minor groups. This strategy provides a promising approach for the broader inclusion of a representative population.

Need expert guidance on an inclusive and diverse representation in your research?

We at Genpro, can provide a one stop solution for all your diversity-related needs. We can quickly and efficiently transform your research initiatives with our state-of-the-art artificial intelligence- machine learning augmented platform. Our expertise and insights on inclusive and effective study enrolment strategies and real-world analyses on differential outcomes can be the game changer you are looking for.

Please feel free to write us at mw.info@genproresearch.com for expert insights on DE&I and to propel your research ahead! A copy of the full evidence synthesis report on DE&I created using MaiA by our team can be provided on request.

References:

1. Taylor AL, Wright JT. Importance of Race/Ethnicity in Clinical Trials. Circulation. 2005 Dec 6;112(23):3654–66.
2. Risk for COVID-19 Infection, Hospitalization, and Death By Race/Ethnicity [Internet]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-race-ethnicity.html
3. FDA Briefing Document Moderna COVID-19 Vaccine [Internet]. [cited 2022 Apr 8]. Available from: https://www.fda.gov/media/144434/download
4. FDA Briefing Document Pfizer-BioNTech COVID-19 Vaccine [Internet]. [cited 2022 Apr 8]. Available from: https://www.fda.gov/media/144245/download
5. US statistics 2021 [Internet]. [cited 2022 Apr 8]. Available from: https://www.census.gov/quickfacts/US
6. Loree JM, Anand S, Dasari A, Unger JM, Gothwal A, Ellis LM, et al. Disparity of Race Reporting and Representation in Clinical Trials Leading to Cancer Drug Approvals From 2008 to 2018. JAMA Oncol. 2019 Oct 10;5(10):e191870.
7. Cancer Facts & Figures for African American/African – American People 2022-2024 | American Cancer Society [Internet]. Available from: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/cancer-facts-and-figures-for-african-americans/2022-2024-cff-aa.pdf
8. Asthma as the Underlying Cause of Death | CDC [Internet]. Available from: https://www.cdc.gov/asthma/asthma_stats/asthma_underlying_death.html
9. Mochari-Greenberger H, Mosca L. Racial/Ethnic Differences in Medication Uptake and Clinical Outcomes Among Hospitalized Cardiovascular Patients With Hypertension and Diabetes. Am J Hypertens. 2015 Jan 1;28(1):106–12.
10. Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrolment Practices, and Trial Designs [Internet]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enhancing-diversity-clinical-trial-populations-eligibility-criteria-enrollment-practices-and-trial
11. Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials Guidance for Industry [Internet]. Available from: https://www.fda.gov/media/157635/download
12. Collection of Race and Ethnicity Data in Clinical Trials [Internet]. Available from: https://www.fda.gov/media/75453/download
13. PhRMA Announces First-Ever, Industry-Wide Principles on Clinical Trial Diversity [Internet]. Available from: https://phrma.org/Equity/PhRMA-Announces-First-Ever-Industry-Wide-Principles-on-Clinical-Trial-Diversity
14. INCLUDE Roadmap can help researchers make trials more inclusive [Internet]. Available from: https://evidence.nihr.ac.uk/alert/include-roadmap-can-help-researchers-make-trials-more-inclusive/
15. J&J joins Bristol Myers Squibb with $100M commitment to diversity efforts [Internet]. Available from: https://endpts.com/sp/the-four-steps-fujifilm-diosynth-biotechnologies-is-taking-to-impact-the-future-of-biopharma-manufacturing/
16. Columbia University and Pfizer to Establish Clinical Trials Diversity Initiative [Internet]. Available from: https://www.cuimc.columbia.edu/news/columbia-university-and-pfizer-establish-clinical-trials-diversity-initiative
17. Novartis inks 10-year pledge to improve equiy in health [Internet]. Available from: https://www.outsourcing-pharma.com/Article/2021/07/20/Novartis-inks-10-year-pledge-to-improve-equity-in-health
18. At the Crossroads of Social Media and Clinical Trials | NIH [Internet]. Available from: https://www.cancer.gov/research/key-initiatives/moonshot-cancer-initiative/implementation/patient-engagement/social-media-clinical-trials-workshop-workshop-summary.pdf
19. Miller HN, Charleston J, Wu B, Gleason K, White K, Dennison Himmelfarb CR, et al. Use of electronic recruitment methods in a clinical trial of adults with gout. Clin Trials. 2021 Feb 15;18(1):92–103.

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