01 Jul 2008

See also Part 1 of this story.

Subject Protection Versus Research Progress: Debate Continues
There is an inherent dilemma in how best to ensure protection for cognitively vulnerable subjects without impeding research that promises better treatments for this population. It is one the U.S. has wrestled with for several decades, Jason Karlawish, an expert on decisional capacity at the University of Pennsylvania, Philadelphia, told the Alzforum. Since the first national bioethics commission in the U.S. was created in 1974, these deliberative bodies have issued protections for various research subject populations, including pregnant women, prisoners, and children. Later, similar laws were written to protect the mentally ill. It took another 15 to 20 years of advances in scholarship to recognize that subjects with impaired decisional capacity also warranted protection, Karlawish said.

The U.S. Government has made two efforts to pass laws that would protect people whose mental impairments preclude them from making informed decisions about research participation. Both efforts failed. The most recent set of recommendations was written by the National Bioethics Advisory Commission (NBAC) toward the end of the Clinton Administration. The proposed guidelines included standard procedures for assessing decisional capacity and identifying proxies. A study by Carol Stocking and colleagues at the University of Chicago, Illinois, surveyed dementia researchers to get a sense of how the NBAC guidelines might impact clinical research. The researchers reported that 45 to 64 percent of researchers thought the recommendations would increase subject protection, but 40 to 86 percent felt they would make research less feasible (Stocking et al., 2003). Those recommendations never became law. “In short, consensus on guidelines has been elusive because we are still working out what we are talking about,” wrote Karlawish in a chapter about research on cognitively impaired adults for the Oxford Handbook for Bioethics (2006).

In the meantime, public watchdog organizations such as the New York-based Alliance for Human Research Protection (AHRP) are doing their part to keep the issues alive—albeit not in ways that would help AD research. In a phone conversation with this reporter, AHRP president Vera Sharav shared her stance that seniors with impaired reasoning capacity should not be enrolled in drug trials of treatments for AD and related diseases. “Unless there are compelling reasons to do so, we would say no,” Sharav said. “The first question we would have is, Who is sponsoring the research? All commercial research is suspect. That is what research in psychiatry and neurology is. It’s commercial. It’s exploitation of populations who cannot say no. We would be very much opposed to that sort of use of the elderly who are frail and dependent—economically, socially, and every which way.”

Charging that companies have failed to disclose harmful side effects while promoting their antipsychotic drugs for off-label use, Sharav urged those running clinical trials that require subjects with dementia to “prove first that (a candidate drug) is safe and likely to be effective before you use this population because they are so vulnerable. It’s a conundrum, I know. If you can’t have access to these patients, then these patients won’t have treatments.”

The AHRP opposes ongoing efforts by some states to consider advanced directives for medical treatment and consent for research along a similar vein. “It is dishonest to pretend that research is equivalent to accepted medical practice. They’re two different things. Research is a gamble,” Sharav said. “A person in their right mind has to decide that they want to take the risk. Anyone who isn’t capable of making that kind of self-serving evaluation should not be in research.”

In a phone conversation with this reporter, Paul Aisen, director of the Alzheimer's Disease Cooperative Study (ADCS) at the University of California, San Diego, said he agreed with much of the sentiment behind the AHRP stance. “People with cognitive impairments are indeed vulnerable and frail, and incorporating such individuals into research studies requires a balance of considerations,” Aisen said. “That many people with cognitive impairments cannot provide informed consent is a major concern in the ethical conduct of such research. On the other hand, to decide therefore not to include such individuals in therapeutic research would deprive them of any valid assessment of safety and efficacy of treatments, and I believe this consideration clearly counterbalances the concern for their vulnerability.”

Setting the Stage for Federal Legislation
It is difficult to determine whether groups like the AHRP are swaying public attitudes about research participation and influencing guidelines on surrogate consent for cognitively impaired research subjects. What is known is that federal legislation in the latter domain has been stalled for more than three decades. That this has happened amid rising concern by IRBs about proper assessment of decision-making capacity suggests that much will be required to break the legislative standstill.

A nudge toward the goal of federal legislation allowing surrogate consent for cognitively impaired research subjects could come from research published this month in the American Journal of Geriatric Psychiatry (Karlawish et al., 2008). In a study of 60 AD patients and their study partners, who were enrolled at 13 sites in an 18-month trial of simvastatin, Karlawish and colleagues looked at how well the MacArthur Competency Assessment Tool for Clinical Research (MacCAT-CR) was able to gauge decision-making capability of the research subjects. Administration of this 15- to 20-minute interview varies from site to site, often from investigator to investigator, said Karlawish. Still, the recent study suggests that MacCAT-CR’s “understanding” subscale—which measures factual comprehension of disclosed information—can predict fairly well whether a person will be able give informed consent. Another study by this group, published earlier this year (Karlawish et al., 2008), confirms previous work showing that, in general, AD patients and their caregivers supported the use of proxy consent in situations where participants are incapable of giving their own consent to research participation.

In summary of this two-part news report, a small handful of papers published in recent months has shown that 1) people with MCI or mild AD already show impairment in decision-making; 2) there are standardized tests that do a reasonably good job of gauging a person’s decisional capacity; and 3) most AD patients and caregivers see the benefit of using proxy consent for trial enrollment. Taking these findings into account, Paul Appelbaum of Columbia University, New York, suggested that modification of the Common Rule (Subpart A of U.S. federal regulations governing the protection of human subjects in research) “would be the most effective way of facilitating AD research by clearly permitting surrogate consent.—Esther Landhuis

See also Part 1 of this story.

Comments

1. • J. Lucy Boyd
     
   • Posted: 09 Jul 2008

   Ms. Sharav's stance astounds me. Left unchecked, a patient with AD has little to no opportunity for improvement. By participating in a clinical trial, the patient at least has a chance of improvement in quality of life. Why deny that to this population? Common sense dictates that most, when given a virtual death sentence, would opt to try an experimental treatment if available. Those with AD should have the same rights to clinical trials as those with cancer, heart disease, or any other life-threatening illness. Next-of-kin should suffice for consent purposes, just as in most other medical situations.

   View all comments by J. Lucy Boyd
2. • Gary Sinoff
     
   • Posted: 22 Sep 2008

   The problem of consent has been troubling me in Israel for the last few years. At what stage do we have to stop performing research on demented persons, even with consent of family members? The local IRBs have been increasingly demanding that the demented have guardianship before signing a consent form. This has even been extended to having a guideline to include a proxy/guardian for persons only with MCI.

   Researchers worldwide have to find a means of bringing the problem to the forefront of dementia research.

   View all comments by Gary Sinoff

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References

News Citations

1. AD Research Participation: Informed Consent Complicates Trials, Part 1 29 Jun 2008

Therapeutics Citations

1. Simvastatin

Paper Citations

2. Karlawish J, Kim SY, Knopman D, van Dyck CH, James BD, Marson D. Interpreting the clinical significance of capacity scores for informed consent in Alzheimer disease clinical trials. Am J Geriatr Psychiatry. 2008 Jul;16(7):568-74. PubMed.
3. Karlawish J, Kim SY, Knopman D, van Dyck CH, James BD, Marson D. The views of Alzheimer disease patients and their study partners on proxy consent for clinical trial enrollment. Am J Geriatr Psychiatry. 2008 Mar;16(3):240-7. PubMed.

External Citations

1. Alliance for Human Research Protection (AHRP)
2. federal regulations

Further Reading

Papers

1. Karlawish J. Measuring decision-making capacity in cognitively impaired individuals. Neurosignals. 2008;16(1):91-8. PubMed.

News

1. AD Research Participation: Patients Want to Know 23 May 2008