When Informed Consent Is Impossible

The promise of the Alzheimer's vaccine -- that it could slow, or even reverse, Alzheimer's disease -- was powerful enough to persuade 300 patients to volunteer for a study of the experimental therapy in 2001.

Scientists thought the vaccine might stimulate the body's immune system to clear up the toxic plaques that destroy brain cells in Alzheimer's patients.

Four months after the study began, however, a safety board shut it down. Several patients had suffered a life-threatening side effect: encephalitis, a dangerous swelling of the brain.

The story is proof that research can be dangerous, even deadly.

Other studies of promising treatments for Alzheimer's disease have ended in less drama than the vaccine study, but with equal disappointment.

Since Alzheimer's disease clinical trials began about 20 years ago, thousands of patients have sacrificed their time and effort to attend frequent visits for studies lasting as long as two years.

For many studies, the result was the same: a promising drug failed to treat the disease.

How do researchers justify exposing people with Alzheimer's disease to these risks, hassles and disappointments?

A core justification is informed consent, a term that describes a competent subject who agrees to join a study after the investigator discloses all the relevant details about the research, such as its risks and benefit.

But informed consent -- that core justification -- is a challenge in research that enrolls persons with Alzheimer's disease.

Informed Consent Not Always Possible

By definition, Alzheimer's patients have trouble with memory, concentration and attention. They may not be competent to give an informed consent.

Without the patient's informed consent, how do we ethically enroll patients with Alzheimer's disease in research?

In the United States, the answer to this question remains the source of a loud and still unresolved debate. We have rules for researchers who study so-called vulnerable populations, children, prisoners and pregnant women. We do not have rules for research that involves people with Alzheimer's disease.

Jason Karlawish is associate professor of medicine at the University of Pennsylvania.

The debate centers around the use of proxy consent -- when one person provides informed consent on behalf of someone who cannot give his own consent. For example, the adult child of an Alzheimer's patient might offer proxy consent.

Some ethicists want strict limits on this practice. For example, the proxy could only enroll a patient in research if he or she had clear guidance from that person that they would want to be in research. Perhaps several years ago the patient wrote down what kinds of research they did or did not want to participate in. Their concerns include that a proxy will act according to their own interests, rather than according to the patient's best interests.

Others disagree with this position. They argue that to restrict research enrollment only to people who are either competent to give consent or who previously expressed a willingness to participate limits the number of potential research subjects. This will in turn slow the progress of discovering better treatments.

Each side in this debate has it merits. But neither side addresses adequately the critical questions: Who should be a patient's proxy? What limits, if any, should we place on the risks of research that enrolls patients with proxy informed consent?

The answers to these questions require a principled argument, but evidence must inform how we apply those principles.

Caregiver May Be Best Proxy

The proxies of people with Alzheimer's disease are not strangers or family members who have dropped in from out of town to enroll their demented relative in research. They are caregivers. These are spouses, partners and adult children who shoulder a number of roles. They take the person to doctor visits, talk to the doctor about how their patient is doing, and help their loved one to cope with their disabilities.

Caregivers take these roles quite seriously and with great emotion. They understand that not only the benefits, but also the risks, of research affect themselves and their relative.

Jason Karlawish is associate professor of medicine at the University of Pennsylvania.

Caregivers are not self-interested strangers. They are trusted companions. They know that if research harms a patient, it harms the caregiver as well. The caregiver will face not only the burden of a decision that turned out bad but also the task of caring for a now injured loved one.

The bond between patient and caregiver supports why caregivers should be the proxy for a patient with Alzheimer's disease who is not competent to consent. What we should focus on is reducing the risks of research proxies and patients face. But what risks?

Some caregivers and patients consider Alzheimer's a dreadful disease. They are willing to take risks for the potential benefits of a promising experimental drug in the same manner as persons with cancer.

Bringing Crucial Studies Home

There is no reason why we should restrict a proxy from enrolling a loved one in a study that tests a risky but promising experimental treatment, even treatments with risks like encephalitis. Instead, we should focus on reducing the risks of research procedures.

Caregivers and patients say that one of the biggest risks and hassles of research are the frequent trips to the study site. Getting a person with Alzheimer's disease ready for a trip to the study site, driving there, and getting home are not easy tasks. And caregivers, many of them elderly, have their own health issues as well.

The solution? Study visits should be at the patients' homes. This may not be possible for all study visits. Some studies require hospital visits for tests and procedures. But just as physicians can see their patients at their homes -- and Medicare pays them to do that -- so, too, can physician-scientists come to their research participant's home to gather their data.

Jason Karlawish is associate professor of medicine at the University of Pennsylvania.