By participating in research projects, people with Alzheimer disease and other forms of dementia can provide valuable data that could lead to better treatments or even a cure. But if they have dementia, how can they understand the risks – and give informed consent to participate? Should a spouse or other trusted family member be allowed to provide consent for the demented subject?
Last year Scott YH Kim, MD, PhD, Assistant Professor of Psychiatry at the University of Michigan Medical School in Ann Arbor and a member of the facility's Bioethics Program, called for research that might provide an objective basis for resolving such ethical quandaries. The paper, “Evidence-Based Ethics for Neurology and Psychiatry Research,” was published in the July 1, 2004 issue of NeuroRx, the journal of the American Society for Experimental NeuroTherapeutics.
Now Dr. Kim has attempted to provide that evidence by seeking the opinions of people who may actually face this ethical question. In a November 8th paper in Neurology (2005;65:1395–1401), Dr. Kim asks: “What do people at risk for Alzheimer disease think about surrogate consent for research?”
Most people he surveyed said they would be willing to participate in research projects if they were unable to give consent themselves, as long as a trusted spouse or family member provided permission.
A ‘COMPASSIONATE, COMMON SENSE APPROACH’
However, they would be more cautious about providing surrogate consent themselves for incompetent loved ones to undergo the same procedures. Dr. Kim viewed the results as a compassionate, common sense approach to the question of surrogate consent.
“You wouldn't want that result to be reversed,” he said. “You wouldn't want them to say, ‘I would be willing to decide for someone else, but I wouldn't want someone else deciding for me.’”
Efforts to establish guidelines governing surrogate consent have repeatedly foundered on a fundamental ethical question: When people cannot give informed consent, how much risk should they be exposed to? The ethical implications deepen when the research data will provide no direct benefit to study participants.
“For three decades we've had expert panels trying to come up with regulations, but they have never been able to adopt any,” Dr. Kim said. “The federal regulations governing research say you can have a legally authorized representative for research subjects, but then they say the definition of a legally authorized representative should be established by local and state authorities, who usually do not do this. So there are different standards among states. What may be legal in California may not be legal in Virginia.
“Investigators and their institutions do their best, but in most states they don't get much guidance from policy makers. We should eventually have a uniform policy that reflects our society's values. To do that, we should incorporate the views of those who are likely to be affected by such policies.”
Dr. Kim sent surveys to 259 people enrolled in the Alzheimer's Disease Anti-inflammatory Prevention Trial. He received completed surveys from 229, or 88 percent.
The participants were at least 70 years old and did not show signs of overt cognitive impairment. Since they all had at least one first-degree relative with probable dementia, they were facing a higher-than-average risk of developing Alzheimer disease.
The survey described 10 research scenarios, in ascending order of risk. The first scenario described a study that would involve merely observing participants who lived in a nursing facility. Others involved taking blood samples, doing a lumbar puncture, a drug challenge study, or at the higher end of the spectrum, a brain biopsy and gene transfer study that would require neurosurgery to insert genetic material into the brain of research subjects.
The first seven scenarios provided no immediate benefit to participants but might give valuable information that could lead to effective therapy. The last three – a new drug study, a vaccine study, and the gene transfer study – could conceivably provide some benefit.
More than 90 percent of respondents approved of the relatively low-risk studies involving observation, interviews, and blood samples, as well as the drug trials. Even at the high end of the risk spectrum, 56 percent supported research involving a brain biopsy, and 54 percent supported a gene transfer study that would involve neurosurgery. While support for the various research scenarios decreased as the risk increased, support remained robust.
However, the willingness to provide surrogate consent for a loved one decreased at a greater rate. For example, while 197 said they probably or definitely would participate in a project that required an MRI, only 184 – 13 percent fewer – would provide surrogate consent for a loved one to undergo a biopsy. And while 125 would submit to the surgery required by a gene transfer study, only 96 – 22.5 percent fewer – would agree to have a loved one undergo the surgery.
These results, according to Dr. Kim, reveal “strong support for surrogate-based research with relatively low risk, even when there is no potential for direct benefit to the subjects.” Even when risk is greater, he added, “a majority still found the policy of surrogate consent acceptable. Of course, this also means that a substantial minority found the highest risk studies unacceptable.”
These findings should provide some guidance for policy-makers attempting to devise guidelines for research with demented patients, said Jason Karlawish, MD, Assistant Professor in the Division of Geriatrics, a Fellow in the Institute on Aging, and a member of the Center for Bioethics at the University of Pennsylvania.
“We need to clarify the acceptable levels of risk that would be appropriate to expose people to,” he said. “This paper goes a long way toward getting the public perception of those risks.”
THE CHALLENGES OF ASSESSING RISK
What makes this tricky is that almost any research project carries some risk, and risk is highly relative. “Suppose people who have carotid artery stenosis, but no symptoms, are enrolled in a study that involves a procedure with a 1 to 2 percent complication rate,” said James F. Toole, MD, Director of the Stroke and Vascular Dementia Center at Wake Forest University School of Medicine in Winston-Salem, NC. “A 2 percent complication rate may not sound bad. Drug companies might say that's pretty good for one of their drugs, but if airplanes crashed 2 percent of the time, people would be up in arms.”
Leon J. Thal, MD, PhD, Chair and Professor of Neurosciences at the University of California-San Diego, where he is Director of the Alzheimer's Disease Research Center, contends that Dr. Kim's survey shows that ordinary people are capable of assessing for themselves as well as for loved ones the amount of risk posed by a research project.
“I believe these views are generally representative of the American population,” Dr. Thal said in an e-mail to Neurology Today. “They represent a thoughtful balancing of risks and benefits of clinical research in Alzheimer disease.”
Dr. Kim's study builds on previous studies, such as the one conducted by David Wendler, PhD, of the NIH, which was published in the April 2002 issue of The American Journal of Psychiatry.
Dr. Wendler reported that a majority of nearly 250 people with a family history of Alzheimer disease said they would be willing to participate in research even if they lost their ability to consent. Most also would allow family members to make research decisions for them.
Dr. Karlawish said he was hopeful that this accumulated evidence will lead to research guidelines that are flexible enough to promote research, but firm enough to prevent exploitation of incapacitated patients. Two previous attempts to create such guidelines, he noted, were spurred by questionable research practices.
“In the 1970s some research subjects who were probably demented received injections of cancer cells to test their immune response,” Dr. Karlawish said. “In the 1990s some investigators did challenge studies on people with psychosis that involved inducing symptoms. Now well-meaning investigators are trying to do research that involves these kinds of participants, and unfortunately they're meeting a lot of resistance from institutional review boards, and not getting adequate guidance.”
Such questionable research procedures have led to proposed guidelines that would allow certain kinds of research on demented patients only if those patients have executed an advance directive specifically allowing their participation.
“No one's going to do that,” said Dr. Karlawish. “That doesn't respect how people regard proxy decision-making. Dr. Kim's research, and studies our group is doing, shows that people accept proxy consent for research if the proxy is someone they trust and have close relationship with.”
ARTICLE IN BRIEF
- ✓ A survey indicated that among those at high-risk for dementia, more than 90 percent approved of having a surrogate enroll them in relatively low-risk studies involving observation, interview, and blood samples, as well as the drug trials; more than 50 percent would agree to have a surrogate enroll them in studies involving a brain biopsy and a gene transfer study that would involve neurosurgery.