One of the most discussed aspects of clinical trial conduct has been the importance of ensuring a diverse pool of participants that represents the real-world population. Racial and ethnic diversity were probably the first diversity facets to enter the stage, while sex diversity is still making its way, as the enduring underrepresentation of female participants in early-stage trials would attest. As the tolerance bar for excluding participants on the grounds of race and sex lowers significantly, exclusion based on cognitive disability still goes on, and very little work is done to address it, says Dr Victoria Shepherd, a senior research fellow at the Centre for Trials Research at Cardiff University.
A recently published study showed that almost 75% of late-stage NIH-funded trials had eligibility criteria that directly or indirectly excluded people with intellectual disability (ID). The current exclusion of this population goes back to the historical segregation and negative societal perception, says Katherine McDonald, PhD, associate dean and professor of public health at Syracuse University and one of the paper’s authors.
This population was also often viewed as “easy targets” for clinical research without benefit or even with harm to them, says Maya Sabatello, LLB, PhD, associate professor of medical sciences at Columbia University and another author of the paper. With historical examples, such as Nazi medical experiments on humans and Willowbrook State School’s experimentations of deliberate hepatitis B infections on children with ID, governments released laws and guidelines to address the harm and abuse. However, instead of creating rules for protection of vulnerable populations, they are often interpreted as exclusion, Sabatello explains.
But in the age of inclusivity and diversity, it should not be a question why it is important to ensure inclusion of people with cognitive disabilities, says Dr Mylynda Massart, medical director of The Primary Care Precision Medicine Center at the University of Pittsburgh. She adds that while it may be more challenging, it is important to have a fully diverse representation by every definition that is possible.
Excluding at the researcher’s discretion
One of the main reasons behind exclusion is the vague language in the eligibility criteria. Dr Willyanne DeCormier Plosky, program manager of the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard University, recently published a study looking at whether the study protocols contain exclusionary language for people in one or more of 10 disability-related domains, including cognitive disability.
The paper found that 85% of the analysed trials allowed investigators to exclude participants at their discretion. However, most of these protocols did not include a justification behind the exclusion prerogative or used vague reasoning, DeCormier Plosky explains. Some of the discretionary exclusions include “participants with serious or uncontrolled medical disorders,” “subject has any condition that confounds the ability to interpret data from the study,” or “any other reason the Investigator deems exclusionary.”
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Exclusion based on the researcher’s discretion can introduce bias when selecting the participants, Massart says. While it is a discretionary decision to some point, the judgment call needs to be based on reproducible concrete questions and formal assessments, she adds. However, there are no clear guidelines of what this discretion entails and what are the grounds for exclusion, Sabatello notes.
The exclusion of people with disabilities from clinical research without appropriate justification is discriminatory and counter to federal regulations and research guidelines, DeCormier Plosky says. She adds that eligibility criteria need to be clearer and more specific, including the reasoning behind investigator discretion.
Caveats in the consenting process
The pervasiveness of unjustified exclusion based on researchers’ discretion ties in with the lack of evaluation to determine if the person has the decisional capacity to consent. “If we’re not evaluating whether individuals have the capacity to consent, we’re essentially making decisions on a group level,” Sabatello says. The NIH’s policy outlines that evaluation of competency and decisional capacity has to be done on an individual basis, yet there is no clear guidance on how to do it, she adds.
This can bring the misconception that every person with a cognitive impairment needs support to consent. In fact, people tend to underestimate an individual’s capacity for decision making, Massart notes, adding that defining one’s decision capacity is difficult, and researchers need to be better at understanding how to do so.
Regardless of whether someone has a cognitive disability or not, informed consent is challenging due to the complexity of the information and medical or legal terminology, says Lauren McCormack, PhD, senior vice president of the Communication Practice Area at RTI International. She explains that the consent process needs to include more plain language and clear communication principles to be able to effectively support the process, which would also benefit people with no disabilities.
One way of easing the consent process is by introducing decision support tools to help the participant in decision making. McCormack was part of a study where such a tool was used and it included criteria of being able to understand relevant information, appreciate the situation and the consequences of those choices, and then ultimately communicate choice, even if that choice is a head nod.
However, not every clinical trial allows the inclusion of support tools. DeCormier Plosky’s paper found that only 18% of analysed protocols allowed the use of support, either supported decision making or assistive devices, to facilitate participation.
Role of a caregiver and decision making
If the person does require a third-party representative, the roles of consent and assent get complicated. When working with a third party, who presumably has the best interest of the person in mind, it’s possible that the caregiver may have their own biases that they bring to the decision, McCormack says.
Such gatekeeping may include the caregiver thinking that the investigational drug is a cure or not seeing the benefit at all, McDonald says. “As a researcher, you have to be ready for both of these situations and think really carefully about how you interact with guardians or support providers,” she adds.
In such situations, it is crucial to have meaningful assent procedures. The guardian’s decision is not final and the researchers need to create a protocol that gives that person with cognitive disability space to understand in their own way and work with the researchers free of the influence of others in their life, McDonald explains. It is important to look for signs of interest or disinterest, verbal and nonverbal signs, she notes.
However, in the UK there is more emphasis on dissent rather than assent, unlike in paediatric trials where assent is a strong component, Shepherd explains. There is no legal requirement to seek assent from adults who lack the capacity to consent. But researchers must seek the views of the person about whether they would want to take part in the research and if there are any signs of disapproval, the participant needs to be excluded.
The legal framework says that the surrogate decision maker should base it on the wishes and preferences of the person they’re representing, not their own. This is often included in participant information sheets to go to consultees or legal representatives. Shepard did an interview study asking people who have acted in that surrogate role about how they made a decision. The study identified a real need for caregivers to have more information on that decision making.
Adherence to the protocol
Even if the person with cognitive impairment gets past the gate of consenting or receives support to make a decision, they still might be excluded by researchers on the grounds of not being able to complete procedures, self-report measures, or adhere to medical regimes that are part of experimental treatment protocols, McDonald says.
Although, individuals who are assisted might be more likely to be adherent to the protocol because someone is facilitating the administration of the intervention, Massart notes. “If you have someone who puts your medication in a box and lines them up for you every day and includes the studied medicine, you are actually more likely to take it,” she explains.
If the trial protocol requires self-reported measures, a long questionnaire that is not accessible might be challenging to the person with cognitive disability. In such instance, sponsors should enable someone to get support to complete it or introduce proxy-recorded outcomes, Shepard says.
Importance of inclusivity
The legal framework around the inclusion of vulnerable populations might scare sponsors away. For example, sponsors in the UK need to justify the reasons why they are including people who lack the capacity to consent, Shepard explains. “There are lots of challenges around how that justification is presented and viewed by research ethics committees,” she adds. In the US, meanwhile, researchers need to provide evidence about the safeguards in place to protect more vulnerable populations, Massart notes.
While responsible inclusion is critical, sponsors and researchers also need to think about the dignity of risk, meaning that everyone should be entitled to take whatever risk they want, Sabatello says. For example, Massart is working on a study looking at the recruitment of adults with trisomy 21, also known as Down syndrome. The study was asking the participants which clinical trials would appeal to them. “The bottom line was that they just want to be included like everyone else and want the opportunity to make their own decision to participate in that study that that has meaning to them,” she explains.
Ultimately, if these patient populations are not included, then clinicians are left guessing what the effective treatments and potential side effects are. For example, people with Down syndrome have a very high rate of developing early-onset Alzheimer’s, but they have not yet typically been included in studies of Alzheimer’s drugs, DeCormier Plosky notes.
Also, clinical trials can have medical benefits for the participant. Some cancer treatments in clinical trials are the only available treatment. But if a person is not eligible to participate, they are not going to have the chance to receive that therapy, DeCormier Plosky explains.
Routine exclusion is discriminatory and leads to non-inclusive science. External generalisability is an important reason to have diversity in clinical trials, especially when so many people across the world have some type of impairment, McCormack says. Indeed, sponsors are putting a fortune into clinical trials and missing out on data generalisability will only exacerbate the health disparities in the future, Sabatello notes.
- Exclusion based on the researcher’s discretion and presumed inability to consent are the main reasons why people with ID are not allowed in clinical trials. There is a need for clearer guidelines for justified exclusion and training to assess a person’s capability to consent.
- Surrogate decision makers might introduce their own personal biases. Researchers need to introduce meaningful assent procedures and look for signs of interest or disinterest.
- Ensuring a responsible inclusion of participants with cognitive impairment supports external generalisability of efficacy and safety results and, in some occasions, allows access to therapies that are only available in a clinical development setting.