Diversity in Clinical Trials — Patients with Disabilities
The public conversation regarding equity, access, inclusion, and diversity in clinical trials covers a wide spectrum of underrepresented communities, including race, ethnicity, socioeconomic status, sexual orientation, and gender identity. One population that receives less attention are patients with physical or cognitive disabilities. Including patients with cognitive disabilities in clinical trials poses special challenges. Among the challenges is the ability to assess the patient’s capacity to consent to participation in a research trial, or, if allowable under state or local law, allowing a legally authorized representative (LAR) to consent on behalf of a patient that is unable to consent for themselves. Whenever possible, the patient’s assent should be obtained in addition to consent from the LAR.
Granted, many clinical trials specifically evaluate drugs to treat patients with debilitating diseases, such as multiple sclerosis or Parkinson’s disease, that cause disability. Indeed, patient function and changes in disability are common primary or secondary endpoints in some Phase III drug trials. In other research, such as on learning disabilities, researchers measure the impact of non-drug interventions on specific patient populations.
What are the considerations for trials that do not specifically address a disability or impairment? How can institutions include these patients in the overall scope of recruitment and inclusion? How can investigators write protocols with inclusion or exclusion criteria that take into account the diversity of the study population? How do IRBs set policies and criteria for assessing risk versus benefit?
In 2018, as mandated by the FDA Reauthorization Act (FDARA), the FDA held a public meeting to discuss topics related to eligibility criteria in clinical trials, including:
(1) the rationale for, and potential barriers created by, inclusion and exclusion criteria;
(2) the benefit to appropriate study populations from trials with alternative designs;
(3) barriers to clinical trial participation;
(4) clinical trial designs that increase trial population diversity;
(5) how changes to trial inclusion and exclusion criteria could impact clinical trials; and
(6) how changes to eligibility criteria may impact the complexity and length of clinical trials.
Discussions at the public meeting informed subsequent guidance issued by the FDA that addressed several topics, including:
Broaden eligibility criteria
Some eligibility criteria have become commonly accepted over time or used as a template across trials, sometimes excluding certain populations from trials without strong clinical or scientific justification. Eligibility criteria should be carefully considered and not automatically defined by past practices.
Investigators should consider eligibility criteria that will result in a representative sample of the population for whom the treatment is intended. Likewise, exclusion criteria should be based on the safety of trial participants or the study objectives. For example, the risk to patients with certain advanced comorbidities require that they may be excluded. However, patients with the same, but less advanced, diagnosis may be included.
Likewise, exclusion criteria from Phase II trials might not be relevant in Phase III studies, when sponsors have a better understanding of adverse events, toxicity, and other factors.
Leverage adaptive trial design
An adaptive trial design is one that allows modifications to the trial and/or statistical procedures of the trial after its initiation without undermining its validity and integrity.
An adaptive design can start with a narrow population if there are concerns about safety and can expand to a broader population based on interim safety data from the trial that provide support for doing so.
IRBs must be particularly vigilant in reviewing adaptive trial designs. They should evaluate them based on patients’ safety and scientific validity, as well as whether the change reflects the target population.
A trial requiring participants to make frequent visits to specific sites may result in added burden for participants, especially disabled and cognitively impaired individuals who require transportation or caregiver assistance. Some patients with disabilities may require reasonable accommodations, such as physical access or sign language interpreters.
Institutions should consider mechanisms to ease these burdens. Examples of modifications include:
- Reducing the frequency of visits to those essential for monitoring safety and efficacy
- Allowing for flexibility in visit windows
- Including electronic or remote monitoring via video conference, email
- Considering digital health technology tools to monitor patients
- Hiring medical staff to conduct home visits for blood draws and other monitoring
Research budgets may include financial reimbursements for expenses associated with costs incurred by participation in clinical trials, such as travel or lodging expenses. The FDA does not consider reimbursement for reasonable travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.*
Incorporate patient-focused practices
Investigators and researchers can implement strategies for public outreach and education. They can engage with patient advocacy groups, medical associations, community-based advisory groups, and other organizations to identify opportunities for inclusion. These groups can also provide input at the protocol design stage by offering feedback on what elements of the protocol may discourage participation. These valuable insights into the challenges and burdens of patients with disabilities, as well as their caregivers, can inform improvements to the protocol.
Broadening eligibility criteria and minimizing barriers to participation in clinical trials can ensure that the study population is more representative of the community. This must be balanced with the obligation to also protect vulnerable populations and those who may not have the capacity to understand the risks and/or potential benefits associated with research. This, in turn, can improve the quality of the data collected and the research overall. With a careful eye toward evaluating the benefit versus the risk to patients with disabilities, IRBs play an important role in discerning this balance.
* See the information sheet guidance for institutional review boards and clinical investigators Payment and Reimbursement to Research Subjects (January 2018). See also 21 CFR 50.20.