30 June 2008. Compared with decades past, the clinical pipeline for investigational Alzheimer disease therapies is ready to burst. This is, of course, a good problem for the field on many accounts. It raises hope that researchers are closing in on the first drug to safely and effectively treat the underlying disease instead of merely alleviating symptoms as do currently available drugs such as donepezil and similar drugs in its class, or memantine.

However, given that human testing is the penultimate—and often lengthiest and costliest—step in a drug’s journey from lab bench to patients at large, the swollen AD clinical pipeline raises a troubling question: are trials of the new generation of mechanism-based drugs getting enough participants?

This is the second story in an occasional Alzforum series exploring different factors that influence AD research participation. Our first story examined physician outreach and results disclosure. In this article, we take a look at thorny issues that arise in clinical trials involving subjects whose disease-related impairments render them unable to give informed consent for participation in the research. The controversy falls within two general domains: how to measure decision-making capacity, and who should provide surrogate consent to research for adults found to lack this capacity? Many people involved in running AD trials do not see current legal ambiguity surrounding decisional capacity as a bottleneck for low enrollment rates. But most agree that clearer guidelines on how to gauge decision-making capacity and obtain informed consent for impaired subjects would smooth the AD trials process.

When Does Decisional Capacity Fade?
With increasing recognition that earlier intervention holds out the greatest—and perhaps only—hope for curbing pathogenesis, AD trials want subjects at increasingly earlier disease stages where cognitive symptoms are minimal or absent. Given this trend, one would think that decisional capacity becomes less of a concern. Not necessarily, suggests a study published last month in the Journal of the American Geriatrics Society (Jefferson et al., 2008). Led by Jason Karlawish, an expert on decisional capacity at the University of Pennsylvania, Philadelphia, the researchers reported that among 40 participants with mild cognitive impairment (MCI), 16 were judged incapable of giving informed consent for research participation. In the study, subjects recruited from the Boston University Alzheimer’s Disease Core Center research registry were asked to participate in a Phase 3 trial of a hypothetical drug designed to treat or prevent memory decline. Subjects were told the study would involve multiple visits, MRI brain imaging, neuropsychological testing, blood draws, and other procedures typical of double-blind, placebo-controlled AD trials.

“What looks like a pretty intact patient may be compromised when it comes to predicting the outcomes of their actions,” noted Jeffrey Cummings, director of the Alzheimer Disease Research Center at the University of California, Los Angeles, in an Alzforum interview. Declines in executive function are known to be an early sign of AD.

The gist of the findings by Karlawish and colleagues was echoed by a recent study performed at Imperial College London. James Warner and colleagues found that 76 percent of mild to moderate dementia patients were unable to give informed consent for participation in a randomized, controlled trial of Ginkgo biloba as a dementia treatment. Their study appeared in the March issue of the Journal of Medical Ethics (Warner et al., 2008). These studies highlight the need for clear guidelines on who is allowed to make decisions about research participation on behalf of adults whose disease prevents them from being able to do so themselves.

Coping With Legal Ambiguity
California and Virginia are among the few states in the U.S. with laws that specifically define a hierarchy of substitute decision makers—a spouse, then children, and so forth. California’s law was changed a few years ago to say that whoever could give consent for medical care could also give consent for research participation. “The person who can make decisions about your health presumably is also going to make protective decisions—decisions that are in the interest of and on behalf of the person participating in research,” Cummings told ARF. “It's a reasonable decision-making framework.”

Yet in most other states, these sorts of rules do not exist. “Researchers are left in a legal gray zone when it comes to assessing the legitimacy of turning to family members for consent,” explained Paul Appelbaum of Columbia University, New York, who studies the impact of legal and ethical rules on medical research.

In the state of New York, investigators running clinical trials for AD and other dementia conditions face an unusually restrictive legal code. State laws do not recognize surrogate consent even for medical treatment—an arena where potential patient benefit is often more clear-cut than it would be in a placebo-controlled clinical trial. For example, in New York, family members cannot consent to life-support termination without clear prior indication of the patient’s desires, wrote Appelbaum in an e-mail to ARF. Apart from rare instances of court-appointed guardianship, New York laws do not spell out any form of “legal” surrogate consent for research participation.

As a result, clinical trials with dementia patients at some conservative institutions are suffering. “Even though the studies are designed for mild to moderate AD patients, in our state the people on the moderate end get shut out because they cannot give informed consent,” said Karen Bell, director of Columbia’s Alzheimer’s Disease Clinical Trials Group.

Because state laws are silent on the issue of surrogate research consent, some New York institutions have formulated their own guidelines. At the New York University (NYU) School of Medicine, those who enroll in the clinical core of the Alzheimer’s Disease Center are encouraged to complete a standard health care proxy form where they can specify substitute decision makers for research participation. Steven Ferris, the center’s director, estimates that with this procedure, less than 20 percent of otherwise eligible clinical trial candidates end up getting excluded from trials due to impaired decisional capacity. This is because roughly 50 percent of AD patients are found to lack consent capacity, and more than half of these folks have a pre-existing proxy, Ferris explained in an e-mail to ARF. “Thus, while some patients cannot enroll and our rate of enrollment is slowed to some extent, it would be much worse if proxy consent were not allowed at our institution.”

Mary Sano, director of the Alzheimer’s Disease Research Center at Mount Sinai School of Medicine, New York, does not think the state’s legal silence on surrogate consent has posed problems for AD trials at Mount Sinai. In a phone interview with this reporter, Sano said that the key is educating the institutional review boards (IRBs) on the potential risks and benefits associated with the clinical procedures in the research. “If the procedure clearly has potential for direct benefit, it makes it easier for the IRB to consider using surrogate consent.”

Regardless of how individual institutions have chosen to handle surrogate consent in research where potential subjects have impaired decisional capacity, IRBs are now paying closer attention to how this capability is assessed. For some time, it appeared that IRBs practically took for granted that investigators would get informed consent from trial participants. “Two years ago, they took what you said at face value,” Bell said. “Now you have to give chapter and verse. They’re paying much more attention to how you're assessing decisional capacity. They have also been asking how you will assess decisional capacity as the study continues, because trials tend to be longer now than they used to be.” To learn about legislative efforts in this area, please see Part 2 of this story.—Esther Landhuis.

See also Part 2 of this story.

References:
Jefferson AL, Lambe S, Moser DJ, Byerly LK, Ozonoff A, Karlawish JH. Decisional Capacity for Research Participation in Individuals with Mild Cognitive Impairment. J Am Geriatr Soc. 2008 May 12; Abstract

Warner J, McCarney R, Griffin M, Hill K, Fisher P. Participation in dementia research: rates and correlates of capacity to give informed consent. J Med Ethics. 2008 Mar;34(3):167-70. Abstract