By Waqas Haque1, Muzzammil Ahmadzada2
Affiliations: 1University of Texas Southwestern Medical School; 2Johns Hopkins University Disclosures: The authors have no financial conflicts of interest.
Clinical trials form the basis by which researchers assess the efficacy and safety of promising medical treatments to improve patient outcomes into the future. The process and validity of the clinical trials used to scrutinize various medications has great influence on patient safety, particularly for specific population demographics that get left by the wayside in clinical trial enrollment.1 While clinical trial diversity may not appear to be a salient patient safety issue at first glance, misapplication of trial findings may lead to drugs having suboptimal efficacy and ramifications for conducting risk-benefit analyses for patients with multiple comorbidities. This is important especially in the wake of the COVID-19 pandemic vaccine clinical trials, which have underrepresented minority groups in their study samples that account for a proportionally increased number of COVID-19 cases and deaths.2
Not incorporating vulnerable populations into trial design may result in skewed data and threaten the generalizability of trial findings. As an example, large-scale genetic studies and multiple trials show the varying effects of statin medications on Western and Asian populations, which includes side-effects such as myopathy and hepatotoxicity.3 To address this, the 1993 National Institutes of Health Revitalization Act of 1993 states as one of its goals to “ensure that women and members of minorities and their subpopulations are included in all human research”.4 Thus, it is important to investigate the patient recruitment, informed consent process, and design of clinical trials in understanding the causes and impacts of trial population homogeneity.5
There are three primary contributing factors to the lack of diversity in clinical trial recruitment. First, many providers do not have a robust patient engagement plan. Doctors may lack time to teach patients about the nuances of a clinical trial in a ten-minute office visit or may feel comfortable answering the patient’s questions about specific details of the trial.6 Second, the continuing need for medical innovation in the pharmaceutical industry has led to many expedited pathways for approval that may not lend itself to making diverse enrollment a priority. Third, specific groups of patients may be unwilling or distrustful about participation for reasons that will be discussed later.
Magnitude of the problem
The magnitude of the issue of trial diversity has been shown repeatedly in the baseline characteristics of trials and other diversity reports. A 2017 FDA report finds that only 48% of trial populations include women, and that merely 7% of trial participants are of African-American descent.7 The lack of diversity is also reflected by the fact that white patients comprise over three-fourths of trial patients, while patients over the age of 65 – a key demographic for most medications and increased mortality burden from coronavirus – represent just 21% of trial populations.8
To offer a granular example, it was found that 91% of patients participating in a trial testing Nuplazid (pimavanserin) – the only FDA-approved medication for treating hallucinations in Parkinson’s disease – happen to be white males.8 Contrast this with 36% of trial patients who were female, and only 1% who were African-American.8 For an African-American female experiencing Parkinson’s-induced hallucinations, how relatable will the trial findings turn out to be?
A more recent and relevant example is the demographic of the study sample for the COVID-19 treatment trials. Black Americans constituted only 20% of the 1063 patients in the placebo-controlled Adaptive COVID-19 Treatment Trial (ACCT-1) funded by the National Institute of Allergy and Infectious Diseases (NIAID), and only 11% of the 397 patients randomly assigned to 5 or 10 days of remdesivir in the Gilead-funded study (GS-YOU.S.-540-5773). The proportions of Latinx and Native American patients were only provided for the ACCT-1 and were 23% and 0.7%, respectively.2 This is despite research evidence displaying that minority populations are dying from COVID-19 at rates disproportionate to their representation in the United States population.2
Impact on Patient Safety
The lack of clinical trial diversity has several ramifications for patient safety. First, there is a negative impact on not being able to fully explore patient outcomes and future trial innovation. For example, Ranganathan et al. analyzed 31 cardiovascular cohort studies in North America, finding that 18 of these studies did not further assess ethnicity, or only restricted sampling to white patients, despite the stark difference in cardiovascular health outcomes between ethnic groups.5 Another review of randomized controlled trials taking place in the United Kingdom found that only 55% of the trials enrolled the target sample size,10 and that 45% of the trials needed extra funds to meet goals of recruitment. In regard to the future of targeted gene therapies, over There have been calls to use Bayesian statistical methods to analyze data on patient safety in trials to anticipate any impending patient safety issues.12 But it may be difficult to incorporate features such as an early safety signal detection system for minorities until there are enough minorities enrolled in trials in the first place.
Second, inadequately powered clinical research undermines trust in the healthcare system. The pharmaceutical industry already has a poor reputation among the general public, rivaling that of politicians. A qualitative stakeholder study identifies mistrust, discomfort with the process, lack of information, time and resource constraints, and lack of awareness as the major impediments to underrepresented groups participating in clinical trials.13
There are four potential solutions to improving diversity in clinical trials to improve patient safety in the short and long term. First, pharmaceutical companies need to become more involved in the community. The National Institutes of Health’s Precision Medicine Cohort to the All of Us Research Program provides $5 million grants to collaborate with community organizations for purposes of recruiting a wide demographic of patients into trials.14 A grassroots effort such as this may make individuals feel as if they are contributing to the advancement of science. Receiving information from projects where the patients’ data has been utilized will also increase trust in the healthcare system. The NIH initiative is the first of its kind, so it is unclear if it will be successful in the long-term.14
The second potential solution involves implementing mobile health (mHealth) applications and flexible trial design to promote trial diversity. This can reduce the frequency of study visits and make patients more amenable to financial reimbursement for participation. One analysis has found that leveraging snowball and word of mouth recruitment techniques has been effective.15 For example, a nutrition study16 used an mHealth approach to recruit 201 female adults into the study, with 48% non-white participants of multiple ethnic groups; one strategy that was particularly effective was collaborating with trial sites known to have a diverse assembly of patients.
mHealth has also shown great promise in response to the current COVID-19 pandemic. Care Access Research announced in early October 2020 that it is collaborating with Eli Lilly and Company to manage the system of decentralized, mobile clinical COVID-19 trials. This has been initiated at nursing homes, a community especially susceptible to the virus. The trial is truly mobile with the deployment of traveling teams of trucks, RVs, and personnel on the road simultaneously. The mobile research teams are capable of providing complex in-person patient care, and have access to a fully functioning lab fitted with centrifuges, lab kits, and medical supplies. The aim of the project is to accelerate clinical trials and reach over 2,000 participants in a matter of months.17
In addition to mobile trials for COVID treatment, mHealth has also shown promise in patient monitoring. In a July 2020 study, participation in a remote patient monitoring solution called GetWell Loop was offered to patients with COVID-19 symptoms. The program engaged patients and provided educational materials, while allowing any potential patient alerts to be resolved through a virtual care workforce of providers and medical students. Out of 3701 patients with COVID symptoms, 2255 (60.93%) chose to enroll, resulting in 2303 alerts, 4613 messages, 13 hospital admissions, and 91 emergency room visits. A satisfaction survey given to 300 of the patient respondents yielded 74% positive responses.18
Another piece of evidence is the case of research teams advertising on a mobile app with a study description on the app’s home screen, with a secure link to a patient enrollment portal.19, 20 The study far exceeded enrollment goals and achieved a population more representative of the United States population and overall insurance status. mHealth assists in minority recruitment and retention due to flexible visit schedules, remote data monitoring, and ensuring of privacy.16
Third, tailoring information and materials to underrepresented groups may increase trial participation. The FDA has started numerous initiatives, including the Drug Trials Snapshots and Office of Women’s Health, to increase transparency and the types of resources available to make patients feel comfortable about enrolling.21 Going to the Snapshots webpage does show promising results, such as 48% female and 11% Asian representation among 22 CDER-approved novel drugs; however, there is only 7% in African-American representation and only 21% of enrollees are age 65 or older. Offering educational modules that teach patients about the trial before enrolling also allows the patient to learn more about the nuances of a research study, including how to communicate any issues with the healthcare provider and understanding the intervention rationale.22
Fourth, using social media to recruit patients has also proven to be a successful strategy. One study used the platform Facebook to recruit women, where the trial’s Principal Investigator posted in private Facebook groups. By focusing on parent discussion groups and sell/trade/jobs pages, the team enrolled 82 participants in 48 days across 61 private Facebook groups.23
Within the applications and software systems themselves, it has been acknowledged that reinforcing an emphasis on personal health and safety, confirming clear information useful for decision-making, appreciation for involvement, and emphasis of available support are all core messages that should be incorporated into these platforms.23
In conclusion, clinical trials allow us to validate new advancements in patient care, but they must be able to do it for patients who come from all walks of life, without a one-size-fits all approach. While broadening eligibility criteria or loosening exclusion criteria may increase risk of adverse drug reactions, adaptive designs that ensure patients satisfy safety markers will allow trial design teams to recruit diverse groups of patients.24 The hope is that such efforts will make patient safety a forefront concern for underrepresented clinical study groups, especially as the race to develop a vaccine or medication for coronavirus moves forward.
- Food and Drug Administration. “New Drug Therapy Approvals 2019”. Accessible at: https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019. Retrieved 25 January 2020.
- Chastain, Daniel B., Sharmon P. Osae, Andrés F. Henao-Martínez, Carlos Franco-Paredes, Joeanna S. Chastain, and Henry N. Young. 2020. “Racial Disproportionality in Covid Clinical Trials.” New England Journal of Medicine 383 (9): e59. https://doi.org/10.1056/nejmp2021971.
- Naito R, Miyauchi K, Daida H. Racial Differences in the Cholesterol-Lowering Effect of Statin. J Atheroscler Thromb. 2017;24(1):19–25. doi:10.5551/jat.RV16004
- Sheikh A, Halani L, Bhopal R, et al. Facilitating the Recruitment of Minority Ethnic People into Research: Qualitative Case Study of South Asians and Asthma. Plos Medicine. 2009;6(10):e100148.
- Caplan A, Friesen P. Health disparities and clinical trial recruitment: Is there a duty to tweet?. PLoS Biol. 2017 Mar 1;15(3):e2002040. doi: 10.1371/journal.pbio.2002040.
- Gibson N. 25 April 2019. Addressing the diversity challenge in clinical trials. PharmaTimes. Accessible at: http://www.pharmatimes.com/web_exclusives/addressing_the_diversity_challenge_in_clinical_trials_1285691. Accessed 26 January 2020.
- Beaton T. 15 February 2017. Are Clinical Trials Diverse Enough to Ensure Patient Safety? Accessible at: https://healthitanalytics.com/news/are-clinical-trials-diverse-enough-to-ensure-patient-safety. Accessed 27 January 2020.
- Sellers, J., Darby, R.R., Farooque, A. et al. Drugs Aging (2019) 36: 647. https://doi.org/10.1007/s40266-019-00655-y
- Haddad RI, Chan AT, Vermorken JB. Barriers to clinical trial recruitment in head and neck cancer. Oral Oncol. 2015 Mar;51(3):203-11. doi: 10.1016/j.oraloncology.2014.12.007.
- Sully, B.G.O., Julious, S.A. & Nicholl, J. A reinvestigation of recruitment to randomised, controlled, multicenter trials: a review of trials funded by two UK funding agencies. Trials 14, 166 (2013). https://doi.org/10.1186/1745-6215-14-166
- Delgado J, Abrahams E. 17 January 2019. Diversity in clinical trials defines good science and better medicine. Stat. Accessible at: https://www.statnews.com/2019/01/17/diversity-clinical-trials-good-science-better-medicine/. Accessed 27 January 2020.
- Yao B, Zhu L, Jiang Q, Xia HA. Safety monitoring in clinical trials. Pharmaceutics. 2013;5(1):94–106. Published 2013 Jan 17. doi:10.3390/pharmaceutics5010094
- Clark LT, Watkins L, Pina IL, et a. Increasing diversity in clinical trials: overcoming critical barriers. Current Problems in Cardiology. 2019;44(5):148-172.
- Beaton T. 7 February 2017. NIH Renames Precision Medicine Cohort, Urges Patient Engagement. Accessible at: https://healthitanalytics.com/news/nih-renames-precision-medicine-cohort-urges-patient-engagement. Accessed 28 Janaury 2020.
- Wicklund E. 9 November 2016. mHealth is Fitting Nicely into Pharma’s Patient Engagement Strategies. mHealth Intelligence. https://mhealthintelligence.com/news/mhealth-is-fitting-nicely-into-pharmas-patient-engagement-strategies. Accessed 28 January 2020.
- Rodgers RF, Donovan E, Cousineau TM, et al. Ethnic and racial diversity in eating disorder prevention trials. Eating Disorders. 2019;27(2):168-182.
- “Care Access Research Partners on Mobile Trial for COVID-19 Treatment.” 2020. Applied Clinical Trials Online. October 1, 2020. https://www.appliedclinicaltrialsonline.com/view/care-access-research-partners-on-mobile-trial-for-covid-19-treatment.
- Annis, Tucker, Susan Pleasants, Gretchen Hultman, Elizabeth Lindemann, Joshua A Thompson, Stephanie Billecke, Sameer Badlani, and Genevieve B Melton. 2020. “Rapid Implementation of a COVID-19 Remote Patient Monitoring Program.” Journal of the American Medical Informatics Association 27 (8): 1326–30. https://doi.org/10.1093/jamia/ocaa097.
- Balakrishnan AS, Palmer NR, Fergus K. Minority Recruitment Trends in Phase III Prostate Cancer Clinical Trials (2003 to 2014): Progress and Critical Areas for Improvement. J Urol. 2019 Feb;201(2):259-267. doi: 10.1016/j.juro.2018.09.029
- Vignato J, Landau E, Duffecy J. Using mobile health applications for the rapid recruitment of perinatal women. Archive of Women’s Mental Health. 2019;22(2):305-308.
- Food and Drug Administration. 31 December 2016. Drug Trials Snapshots Summary Report (2015 and 2016). Accessible at: https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-summary-report-2015-and-2016. Accessed 30 January 2020.
- Amorrortu RP, Arevalo M, Vernon SW, et al. Recruitment of racial and ethnic minorities to clinical trials conducted within specialty clinics: an intervention mapping approach. Trials. 2018;19(1):115. Published 2018 Feb 17. doi:10.1186/s13063-018-2507-9
- Herbell K. Using Facebook To Recruit Pregnant Women for Research. Nurs Res. 2019 May/Jun;68(3):242-245. doi: 10.1097/NNR.0000000000000353.
- Kent J. 10 June 2019. FDA Issues Draft Guidance to Enhance Clinical Trial Diversity. Accessible at https://healthitanalytics.com/news/fda-issues-draft-guidance-to-enhance-clinical-trial-diversity. Accessed 1 February 2020.