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Rewriting the Rules of Informed Consent

December 30, 2021

A look at efforts to include individuals with intellectual and developmental disabilities in clinical research

When hematologist/oncologist Cecilia Arana Yi, MD, first saw George (name changed to protect identity) in her clinic at the University of New Mexico Cancer Center, she thought he would be an ideal candidate for a nationwide registry study. He'd been successfully treated for leukemia in his 30s but later developed pancytopenia. Dr. Arana Yi was eager to send his bone marrow aspirate to a central biobank so researchers could identify the molecular mechanisms underlying his cancer.

As it turned out, though, George was not eligible to participate in the study. His intellectual disability related to Down syndrome (DS) made him unable to complete the standardized quality-of-life measures required by the study protocol.

"We don't know much about the biology of secondary leukemias or adult-onset leukemias in people with DS and this is, in large part, because the adult trials for leukemia are very restrictive," Dr. Arana Yi told ASH Clinical News.

She couldn't enroll him in an interventional trial, either, even though his father and sister, who are his legal representatives, wanted him to participate. "In the pediatric setting, patients' parents make the decision to enroll children in a clinical trial, and the demands on the patients are less," Dr. Arana Yi explained. "But in adults, if patients are unable to consent or fulfill the protocol requirements, we can't enroll them, even if the treatment is potentially lifesaving."

Consent has three components: disclosure, capacity, and voluntariness. It sounds simple enough, but the application of this concept can be controversial, complicated, and vague, particularly for individuals with intellectual and developmental disabilities. ASH Clinical News spoke with experts in clinical research and ethics to gain a better understanding of the perceptions, attitudes, and impediments associated with enrolling this population into clinical trials – as well as some ways to make trials more inclusive.

Rewriting the Rules of Consent?

"Informed consent" is a universally recognized fundamental concept in medical ethics and medical law, designed to protect individuals from unwanted intrusion. This simple line item appears in every clinical trial protocol: It is unlawful to touch someone without explicit permission, and that permission can be granted only if the participant understands what is going to happen and gives consent voluntarily.

For conditions of informed consent to be met, the person providing consent must have the capacity to make the decision to receive care or not. In most situations, the absence of clear indication of incapacity is enough to assume capacity. (The terms "competence" and "capacity" are often used interchangeably; competence is a legal term, whereas capacity refers to a person's ability to make a reasoned medical decision.)

Recent research challenges the assumption that individuals with disabilities cannot provide informed consent.

In a 2013 study of 131 adults with intellectual disabilities, researchers used a brief questionnaire to assess the extent to which individuals understood key aspects of a low-risk (i.e., mildly interventional) health-promotion study.1 After meeting one-on-one with study staff, participants were asked six questions about the study's design and objective (e.g., "In your own words, what is this study about?"; "What can you do if you start the study but don't want to finish it?"; and "What are the risks of being in this study?"). More than half (57%) were able to answer all six questions correctly.

"Just because someone is not able to make good decisions about his or her finances or health does not necessarily mean he or she can't give informed consent about participating in a research trial," said Dora Raymaker, PhD, from Portland State University, who researches ways to improve the lives of adults on the autism spectrum and in other disability communities through community engagement, accessible technology, measurement adaptation, and other practices. "And just because an individual has someone else who holds power of attorney does not mean he or she can't participate in shared decision-making, or even be able to give the informed consent him- or herself."

Explaining the potential risks of the study proved the biggest challenge for the study participants in the 2013 study; this could be a larger stumbling block for more invasive and higher-risk interventional studies – like much of the research being conducted in the hematology/oncology space. With more at stake, the importance of clearly explaining risks increases and the bar for determining capacity rises.

However, Dr. Raymaker stressed that the rules of ethical research do not apply differently depending on the type of research being conducted. "The basic ethics are basic for all research with human subjects," she said.

“We need to make some exceptions to the rules to try to incorporate more patients with [disabilities] into adult clinical trials."
—Cecilia Arana Yi, MD

"People with intellectual disabilities are as likely – and more likely, in some cases – to develop any kind of health need or health condition as anyone else, so we need to make sure that our scientific record is inclusive of them," said Katherine E. McDonald, PhD, from Syracuse University in New York. "We need to know that the treatments work the same for them as they do for other people."

Dr. McDonald has studied and published extensively on the issue of research participation for adults with intellectual disabilities. She compares their systematic exclusion from clinical trials to the exclusion of women and ethnic minorities from research studies – something the research world has long grappled with. However, although United States federal funding agencies have mandated inclusion of women and racial minorities to ensure that studies are representative of the larger population, no such mandates exist regarding people with disabilities.

Individuals' social and physical environments also can affect their overall health, Dr. McDonald argued. "People with intellectual disabilities may be institutionalized, have lower education levels, and live in poverty, and can develop a host of preventable health conditions, giving us a strong rationale for thinking about inclusion."

Including patients with disabilities in clinical trials can uncover specific risk factors and even chemotherapy dose adjustments, as has been shown in patients with DS and leukemia: The incidences of acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) are approximately 10- to 20-fold higher in children with DS than in those without.

"About 15 percent of all pediatric patients with AML have DS," explained Jeffrey W. Taub, MD, a childhood leukemia researcher from Children's Hospital of Michigan at Wayne State University, "and about 3 percent of children enrolled in clinical trials for ALL have DS, even though they represent only about one in 700 children in the general population."

As Dr. Taub and colleagues reported in results from the Children's Oncology Group (COG) AAML0431 trial, though patients with DS and AML typically have favorable survival outcomes with standard chemotherapy regimens, their increased risk for treatment-related morbidity and mortality complicates decisions about optimal treatment intensity.2

In the 204 patients enrolled in the AAML0431 study (ranging in age from 0-4 years old), the researchers found that, as with patients with AML and without DS, minimal residual disease (MRD) status is a significant predictor of outcomes. Patients who were MRD positive after the first induction cycle had lower rates of five-year disease-free survival than MRD-negative patients (76.2% vs. 92.7%; p=0.01). "We actually were able to reduce the intensity of daunorubicin treatment by 25 percent [in patients who were MRD negative] to minimize side effects while maintaining high cure rates," Dr. Taub explained.

"Because we have research protocols specifically designed for patients with DS, or treatment arms specifically for individuals with DS, we now have treatment protocols that take into account their potentially increased risks of toxicity or, in the case of AML, their responses to treatment and improved prognosis," he added.

"About 15 percent of all pediatric patients with AML have DS, and about 3 percent of children enrolled in clinical trials for ALL have DS, even though they represent only about one in 700 children in the general population."
—Jeffrey W. Taub, MD

This is exactly the kind of research Dr. Arana Yi would like to see in the adult DS/leukemia population, she told ASH Clinical News, even though numbers of affected individuals are considerably smaller.

"If we incorporated even just five or six patients in a cohort of 1,000 patients, we would have some key information about the basic genetic and molecular mechanisms for this subset of patients, and we could better understand why they develop secondary leukemia or leukemia in adulthood," she said. "We need to make some exceptions to the rules to try to incorporate more patients with DS or other congenital genetic conditions or disabilities into adult clinical trials."

The pediatric research world doesn't hold all the answers, though. For instance, Dr. Taub noted that protocols for trials of relapsed disease often exclude children with DS because of potential or theoretical concerns about toxicity, which "from the parent's perspective, and from my perspective, doesn't seem fair." Because of this, he said, "new drugs for relapsed leukemias are not necessarily going to be available for children [with DS]."

Changing Attitudes

How do individuals with disabilities feel about participating in clinical research trials? According to research conducted by Dr. McDonald and colleagues, the message is clear: "We want in."

To understand the viewpoint of individuals with intellectual and developmental disabilities regarding participating in research, Dr. McDonald's group conducted individual interviews and focus groups with 16 adults.3 In general, the participants were interested and even excited about the possibility of participating in clinical research, with a few caveats – they wanted to learn about the research from people they trust, choose the people with whom they would discuss the research, and talk with peers about the decision to enroll or not.

"Some patients want to be included because they've so often felt excluded from other facets of community life, but they want to be seen as active, giving, civic-minded members of society," Dr. McDonald said. "Even when they understand they may not personally benefit from the research, they want to be able to help other people who are similar to them."

Like everyone weighing the decision of whether to enroll in a trial, though, they also want to know that the research is valuable. After reviewing a study with researchers, participants were asked questions to assess their level of understanding of the study's objective; if participants expressed that they felt the study would be void of benefit, they declined to enroll.

Trust also permeates the conversations Dr. Taub has with parents who are considering enrolling their children with DS in pediatric leukemia studies; a good reputation and experience in the area are also deciding factors.

"Parents of children with disabilities tend to talk to one another," he said. "If the parents know you have experience and are invested in finding answers to help their child and other children, they will likely be more receptive to the idea of having their children participate in a study. It assures them that you're not just ‘experimenting' on their child."

(Parents' hesitation to involve their children in clinical research – and, similarly, some researchers' hesitation to ask patients to participate – is rooted in the complicated history of research in this population. See the SIDEBAR for the historical and ethical perspectives on research for individuals with intellectual and developmental disabilities.)

The Downside of Overprotection

The attitudes of researchers, Institutional Review Board members, and those in charge of conducting and monitoring research play a substantial role in shaping the knowledge base about the treatment of individuals with disabilities. When Dr. McDonald and authors interviewed these "gatekeepers of science" about their opinions on greater trial inclusion, most want more people with disabilities to participate – again, with some caveats.4

All survey respondents agreed that, to consent to enroll in a clinical trial, participants need to understand "the prospect of encountering both benefits and burdens from participating in research" and have the necessary support to participate. However, respondents expressed varying levels of comfort with the degree of autonomy and protections that research participants should be granted.

"Gatekeepers who perceived greater similarity and shared humanity between people with and those without intellectual disability endorse opportunities for adults with intellectual disability to make decisions about and take part in research," the authors wrote. "Conversely, gatekeepers who support the protection of adults with intellectual disability in general perceived a greater need [for them] to receive support specifically in making decisions about research participation and want to see them more protected therein."

Competing factors are at work: Individuals with intellectual disabilities are potentially at risk for exploitation within the research process because of their limitations and relative social powerlessness. At the same time, avoiding these issues via blanket exclusion from research denies such individuals the opportunity to contribute to and benefit from scientific research.

The authors suggested that "the tendency to protect adults with intellectual disability by assuming reduced autonomy" may be doing more harm than good. "Restrictive attitudes may create subtle barriers to community inclusion," they wrote.

Facilitating Inclusion

Making the clinical trial recruitment and enrollment process more accessible and inclusive is a relatively straightforward process, Dr. Raymaker said. "It's really a question of figuring out how you tailor your process to accommodate a population that is outside of the originally intended population." But, she conceded, it "can be difficult work to do."

And, because the issue affects such a small percentage of the overall population, it can be hard to get people to care enough to try. Her hope is that the tools and tricks that have been developed by those intimately involved in this issue will "go viral." New researchers will learn from the work of experienced investigators, then pass along that knowledge to a few more researchers, and so on.

Enrolling individuals with intellectual disabilities takes extra time and effort; for instance, modifying informed-consent forms with pictures or simplified written explanations (see SIDEBAR). It can also require outside help, including family members or researchers who are specially trained to communicate with people with intellectual disabilities.

To open clinical trials to individuals with intellectual and developmental disabilities, researchers may need to modify their informed-consent processes. According to interviews with individuals with disabilities and their caregivers, Dr. McDonald suggests that materials:

  • are brief
  • use visuals
  • provide concrete descriptions
  • include feedback from other participants

Using information gathered from those interviews, Dr. McDonald and Colleen A. Kidney, PhD, from the Human Services Research Institute in Cambridge, Massachusetts, created a research toolkit for enrollment that emphasizes accessibility, flexibility, variety, and responsiveness.

For example, the "Visual Break Board" (FIGURE) to be used in the informed-consent process communicates, in text and graphics, three important options during participation in an interview: continuing the interview, taking a break, or stopping the interview.

Other visual aid resources from the toolkit explain the schedule for participating in a clinical trial, the informed consent process, and the interview process.

Kidney CA, McDonald KE. A toolkit for accessible and respectful engagement in research. Disabil Soc. 2014;29:1013-30.

A "Visual Break Board" that can be used to explain informed consent to participants with intellectual or developmental disabilities.

“Maybe participants just need time to discuss participation privately with their parents or guardians," Dr. Raymaker offered. "You need to give them the opportunity to do that."

Parents and legal guardians can also serve as a proxy for patients to provide their consent to participate in a trial, much like the "assent-consent process" that is used for enrolling children into clinical trials.

Above all, investigators should keep in mind that "the purpose of Informed consent is not to get individuals enrolled in the study, but rather to give them the information they need to make that decision for themselves," Dr. Raymaker said. —Debra L. Beck


  1. Horner-Johnson W, Bailey D. Assessing understanding and obtaining consent from adults with intellectual disabilities for a health promotion study. J Policy Prac Intellect Disabil. 2013;10(3).
  2. Taub JW, Berman JN, Hitzler JK, et al. Improvement outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial. Blood. 2017;129:3304-13.
  3. McDonald KE, Kidney CA, Patka M, et al. ‘You need to let your voice be heard': research participants' views on research. J Intellect Disabil Res. 2013;57:216-25.
  4. McDonald KE, Keys CB, Henry DB. Gatekeepers of science: attitudes toward the research participation of adults with intellectual disability. Am J Ment Retard. 2008;113:466-78.

Over the past 50 years, members of the Disability Rights Movement have advocated for equal opportunities and rights for all people with disabilities, from accessibility and safety in architecture to equal access to employment opportunities; in the case of clinical trials participation, they are reclaiming an area in which they were once victimized. Research involving individuals with intellectual and developmental disabilities has a complicated history. The horrors of Nazi medical experimentation on this population may seem buried in the past, but, as recently as the early 1970s, individuals with disabilities were used involuntarily as research subjects. This history is fresh in the minds of researchers who have a deeply ingrained wariness of risking – or even appearing to risk – taking advantage of individuals with disabilities.

"Ethicists are very protective because there was a long history of doing research on people who basically had no right to refuse, including handicapped children in state institutions," Jeffrey P. Spike, PhD, professor at the McGovern Center for Humanities and Ethics and former director of the Campus-Wide Ethics Program at the University of Texas Health Science Center in Houston, told ASH Clinical News.

Dr. Spike cited the Willowbrook State School in Staten Island, New York, as one example. From the late 1950s to the early 1970s, researchers at Willowbrook deliberately infected children with intellectual disabilities with live hepatitis virus to study the effects of gamma globulin treatment. They justified inoculating healthy children because 90 percent of the children in the school developed hepatitis soon after their arrival anyway.

Looking back at the Willowbrook experience, ethicists point out the immorality of the experimentation: Children were involuntarily injected with the virus, and they had no chance to benefit from the procedure – only the chance to be harmed.

"Conducting ethical trials in this population means striking a balance between protecting potential participants who might be easily manipulated and respecting their ability to make their own decisions like anyone else," Dr. Spike explained. In larger institutions, investigators might call for an ethics consultation to help determine a patient's capacity to consent or clarify a gray area in which participation in clinical research may be inappropriate.

"Everything hinges on whether individuals can understand and appreciate the risks they are taking," he added. "We never want participants to say afterwards that they really didn't know what could happen or that something could hurt this much, or for such a long time."

Robinson WM, Unruh BT (2008). The hepatitis experiments at the Willowbrook State School. In: The Oxford Textbook of Clinical Research Ethics (pp. 80). New York, NY: Oxford University Press.


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