December 12, 2022
Clinical trial inclusivity strengthens analyses, speeds trial completion and Food and Drug Administration (FDA) approvals, and lowers administrative costs of clinical studies. However, a mounting body of evidence shows that eligibility criteria often limit enrollment inclusivity and compromise trial data.
For example, a retrospective review of 302 drug submissions to the FDA examined the impact of insufficient data on drug approvals. Nearly 16% of the reviewed studies had insufficient data to determine safe dosages, and over 13% revealed inconsistent results when alternative endpoints were tested. Over 11% had inconsistent results between study sites, and about 13% failed to demonstrate statistically significant benefits (1). As a result, only one product out of every six candidates ultimately gains FDA approval (2).
Growing evidence indicates that a lack of diversity among clinical trial participants is a primary cause of inadequate study data and inconsistencies. The good news is that community-based clinical trial sites now can be harnessed by pharmaceutical companies to address the problem. By leveraging online platforms to expand access to community trial sites — and to the broader, more diverse patient populations that they reach — pharmaceutical companies can overcome barriers to inclusivity, accelerating trials and improving the quality of their results.
Unintentional Exclusions
Aspects of today’s standard clinical trial inclusion and exclusion criteria arose from the need to prevent repetition of civil rights violations that occurred in the name of science — notoriously, the Nazi, Tuskegee, and human-radiation experimentation projects. Such criteria serve to protect vulnerable populations that are unable to give informed consent and/or those easily influenced by coercive, guileful, and forceful methods to obtain such consent (3).
Without question, strict inclusivity protocols prevent patient violations and protect and sustain the integrity of clinical trials. Establishing inclusion and exclusion criteria for study participants ensures high-quality research protocols — standards that form a bedrock of trust in and of the pharmaceutical industry. However, they also produce the unintended consequence of results with limited external validity. In short, when population samples are restricted (regardless of the reason), the efficacy and side effects of the drugs studied are less generalizable to the broad, diverse populations that they are designed to treat.
Diversity Is Essential
Some people argue that improving diversity in population samples goes beyond the generalizability of results; it has risen to the level of ethical and scientific imperative (4). Expanding clinical trials into diverse communities can increase data diversity. The FDA, National Institutes of Health (NIH), clinical investigators, data analytics companies, and patient-advocacy groups all concur that the following can increase clinical trial participation by underrepresented populations:
• increasing community engagement by use of patient-centric sites
• using digital tools to enhance the accessibility of clinical research
• employing diverse staff to better represent and communicate with clinical trial participants.
An important point is that agencies and organizations are acting on their own advice. For example, a published clinical trial review from 2022 found that in general, trials funded by the NIH set fewer age caps compared with those funded by non-NIH sources. That, according to the authors, “provides optimism that inclusivity can be feasible for all trials” (5).
The FDA also has begun reviewing its own inclusion/exclusion criteria, including one recent evaluation that identified pregnancy, lactation/breast feeding, renal and hepatic abnormalities, and specific infectious diseases as the most frequent exclusion criteria. The review also found a preponderance of men in FDA studies, indicating that factors other than exclusion criteria affect enrollment. Those findings bring crucial awareness to gender disparities in clinical trials that, once addressed, can help balance population samples (6).
Leveling the Playing Field
Designing trials around patients is a solution to increasing diversity, an approach being incorporated by clinical trial sponsors in tandem with advances in remote patient monitoring and telemedicine technologies. Such technologies enable enrollment of patients outside the physical boundaries of traditional clinical research facilities. The challenge, however, is that physicians still must be directly involved, particularly in complex trials.
Engaging community research sites is the best way to overcome that limitation and optimize the potential for patient-centric trials. This is where cloud-based platforms come into play. Designed to connect trial sponsors with eligible community sites, such platforms help improve representative data collection on a global scale and, in some cases, salvage existing trials that are struggling with enrollment. As part of a patient-centric approach, community research sites enable worldwide access to patients, including those populations that historically have lacked access to clinical research, allowing investigators to collect data from much larger populations in the real world.
In traditional clinical trial design, the intermediary (a term that colloquially includes the team of specially trained study coordinators, research assistants, nurses, and physicians) is responsible for meeting with a patient to collect and compile data according to the guidelines for good clinical practice (GCP) (7). The long travel distances required for patients to meet with those teams and the costs involved with an intermediary’s travel between study sites can be exorbitant, significantly slowing the pace of a clinical trial and, ultimately, time to FDA approval.
Leveraging online platforms helps to
• enroll a greater number of patients for a more robust (and accurate) analysis
• reduce administrative, intermediary, and clinical site costs
• more efficiently capture the individual patient experiences in real-world settings
• improve patient recruitment, retention, engagement, and adherence
• enhance data collection, aggregation, and analyses.
By increasing the number of trials available in communities, such platforms also remove the financial barriers to participation that are felt the hardest by vulnerable populations (8).
Real-World Impacts
The business case already is being made for leveraging the broader reach of community sites through online platforms that address diversity in trial enrollment.
Meeting Enrollment Timelines: One example is a sponsor’s experience with a phase 3 clinical trial for treating agitation in patients with Alzheimer’s dementia (AAD). Slow enrollment had forced many AAD study sites to close and convinced the study team that nearly all the patient pools in key AAD geographies had been exhausted. With remaining sites experiencing a screening success rate of just 21% and the 18-month enrollment deadline rapidly approaching, the trial sponsor decided to leverage the Inato clinical trial platform to connect with experienced sites with the capacity to enroll qualified patients. Within three weeks, 20 new sites were added (9).
Because Inato sites could activate quickly, moving to the platform in the final two months of its enrollment window gave the sponsor the final push needed to meet its objectives. Ultimately, Inato sites contributed an overall 13% of patients to the trial. Sites identified on the platform also screened eight times more patients and enrolled 16 times more patients per month than nonplatform sites. Ultimately, taking a community approach allowed the AAD study to achieve enrollment timelines and proceed with its critical research.
A second business case demonstrates how the engagement of online platforms allows trial sponsors to pivot quickly when unexpected or unprecedented developments threaten to shut things down — in this case, the COVID-19 pandemic.
Accessing Broader Patient Populations: For one global trial sponsor, the pandemic ratcheted up competition for academic research centers to conduct its trials and dramatically decreased the enrollment pool when patients scaled back doctor appointments and illness reports. In search of alternative access to a broadened patient population to speed up trial timelines, meet diversity goals, and patch up the delays brought on by COVID-19, the sponsor decided to use a platform for eight clinical trials across a number of disease areas including multiple sclerosis (MS), asthma, and chronic obstructive pulmonary disease (COPD) — traditionally complicated disease areas for trial enrollment.
Leveraging the marketplace platform, the sponsor connected with qualified community-based sites worldwide. The result was an accelerated start-up timeline, which, for one trial, saw patients screened within the first week of activation. Since implementing the platform, the sponsor has selected 62 sites in nine countries and secured enrollment commitments for 124 MS patients, 70 COPD patients, and 48 asthma patients (10).
Proven Impacts
The real-world body of evidence is growing steadily on the need to resolve diversity challenges that can hamper clinical trials. Technology platforms form one piece of the puzzle as important enablers. However, the most essential components continue to be the community doctors and care teams that patients trust. Those researchers play a vital role in engaging with, enrolling, and retaining underserved patients and will be a critical part of the solution to increase clinical trial diversity.
References
1 Sacks LV, et al. Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012. JAMA. 311(4) 2014: 378–384; https:/doi.org/10.1001/jama.2013.282542.
2 DiMasi JA, et al. Trends in Risks Associated with New Drug Development: Success Rates for Investigational Drugs. Clin. Pharmacol. Ther. 87(3) 2010: 272-277; https:/doi.org/10.1038/clpt.2009.295.
3 Shivayogi P. Vulnerable Population and Methods for Their Safeguard. Perspect. Clin. Res. 4(1) 2013; 53–57;https://doi.org/10.4103/2229-3485.106389.
4 Michelle D, et al. Inclusion and Diversity in Clinical Trials: Actionable Steps to Drive Lasting Change. Contemp. Clin. Trials 116, 2022: 106740; https://doi.org/10.1016/j.cct.2022.106740.
5 Nguyen D, Mika G, Ninh A. Age-Based Exclusions in Clinical Trials: A Review and New Perspectives. Contemp. Clin. Trials 114, 2022: 106683; https://doi.org/10.1016/j.cct.2022.106683.
6 Duggal M, Sacks L, Vasisht KP. Eligibility Criteria and Clinical Trials: An FDA Perspective. Contemp. Clin. Trials 109, 2021: 106515; https://doi.org/10.1016/j.cct.2021.106515.
7 Van Norman GA. Decentralized Clinical Trials: The Future of Medical Product Development? JACC: Basic Transl. Sci. 6(4) 2021: 384–387; https://doi.org/10.1016/j.jacbts.2021.01.011.
8 Khozin S, Coravos A. Decentralized Trials in the Age of Real-World Evidence and Inclusivity in Clinical Investigations. Clin. Pharmacol. Ther. 106(1) 2019: 25–27; https://doi.org/10.1002/cpt.1441.
9 Koch J. Site Insights: How Two Florida Sites Were Able to Increase Trial Access for Their Patients. Inato Blog, 15 December 2021; https://inato.com/blog/site-insights-how-two-florida-sites-were-able-to-increase-trial-access-for-their-patients.
10 Fallon K. A Closer Look at SCOPE 2022. Inato Blog, 22 February 2022; https://inato.com/blog/a-closer-look-at-scope-2022.
Liz Beatty is chief strategy officer with Inato, 800 Village Walk, Suite 198, Guilford, CT 06437, 203-350-3125; [email protected].
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