AD Research Participation: Patients Want to Know

Each day for one and a half years, 78-year-old Alan Wahlner popped four pink pills—two in the morning, two in the evening. Diagnosed with Alzheimer disease in early 2004, he was hoping the tablets were Flurizan (tarenflurbil), an investigational treatment for mild AD developed by Myriad Pharmaceuticals, Inc. The retired Hughes Aircraft purchasing agent was participating in Phase 3 clinical trials of the small-molecule compound at the University of California, Irvine—a 40-minute drive from his home.

Wahlner will never know whether he had gotten Flurizan or placebo pills throughout the 18-month trial that ended in late 2007. Yet he and his wife, Mary Ann, dutifully participated in what many hope is the final stage of testing for the Myriad drug thought to work by reducing levels of Aβ42 peptide. Before enrolling in the trial, the Wahlners signed an agreement stating they would not find out what was in the pills they took home. “That’s why most Alzheimer’s patients I know don’t participate—they don’t want to have the placebo,” said Mary Ann, 75, a retired research manager for California’s Employment Development Department. “My response is, how are you ever going to know if a drug actually works if you don’t have in the trials people who are not taking it? I understand the process and rationale behind double-blind studies, and I’m willing to be one of the participants.”

Clinical scientists in the field generally agree that research participation rates in AD are low—too low to enable speedy testing of a growing number of candidate drugs companies have developed in recent years. The reasons are manifold, ranging from concern about the ability of cognitively impaired people to give informed consent, to the burden placed on patient and caregiver, to reluctance about taking placebo. Moreover, many people simply do not know they have the option of enrolling in a trial.

How do people learn about the clinical trials process? Probably not from their doctors, according to a new survey released 13 May by the Society for Women’s Health Research, a national nonprofit organization based in Washington, DC. Of more than 2,000 U.S. adults 18 and older who did the phone survey, 94 percent said a physician had never talked with them about taking part in clinical research. Fewer than 10 percent said they had ever participated in a medical research study. Those who had taken part in research cited desires to advance medicine and help others with a disease as the top two reasons for participating, and more than 70 percent of these folks said they would definitely or probably participate again if asked.

The survey findings did not surprise Eric Siemers, medical director for the Alzheimer disease research team at Eli Lilly and Company in Indianapolis. “Doctors are really pushed in the amount of time they can spend on individual patients,” he said. “They don't have as much time as they would like to have for things like sitting down and talking to a patient for a half hour about participating in clinical trials. It's probably not a lack of desire but more about being very busy people.”

Other factors might also play into the reluctance of some doctors to put their patients forward for trials. “This arises, I believe, from a mixture of not wanting to be bothered with the perceived extra workload that may be cascaded down to a physician whose patient enters a trial and in some cases a feeling that vulnerable patients need to be protected from having their established treatment disrupted in a way that will offer little benefit and potential risk,” wrote Robert Howard, King’s College London, in an e-mail to ARF (see extended comment below). Howard was lead investigator on the CALM-AD trial, which tested the effect of an acetylcholinesterase inhibitor on neuropsychiatric problems associated with AD (Howard et al., 2007; ARF related news story). He is currently directing the DOMINO-AD trial, a large, publicly funded UK trial, independent of pharmaceutical companies, to study medications for people with moderate to severe Alzheimer disease.

Beyond that, there may be deeper reasons for why doctors aren’t telling patients about research opportunities, at least in the U.S. Rachelle Doody directs the Alzheimer's Disease and Memory Disorder Center at Baylor College of Medicine in Houston, Texas. “It’s a systemic problem that has arisen in our country that we’ve allowed our centers of research expertise to become separate from our centers for clinical care,” she told the Alzforum. “People are out there talking to their family doctor or community neurologist. Those are not the people engaged in research.”

The split between research and clinical care has made it increasingly difficult for primary care physicians and community specialists to stay attuned to clinical trials in their region. “How would they know—for even one disease, let alone multiple ones—what’s going on? A lot of practicing physicians don’t read specialty-type journals,” said Doody, who collaborates with many biotech and industry sponsors in developing experimental strategies for treating AD. “Do you put the onus on the practicing doctors to find out about research opportunities and convey them to the patient? Do you make it the researchers’ responsibility to try to inform the vast public of doctors? Do you make it the patients’ responsibility to try to contact the agency or look on sites like clinicaltrials.gov for trials info?”

To make matters worse, those who do take the initiative to find out about medical research can find themselves misguided, said Paul Aisen, who directs the Alzheimer's Disease Cooperative Study (ADCS) at the University of California, San Diego. “I think too many people have the idea that scientists make a discovery, the media covers it, and then people rush out to get the treatment. That's not the process,” he told this reporter, citing a recent case report touting apparent therapeutic effects of an FDA-approved arthritis drug in a single California patient with probable AD (Tobinick and Gross, 2008). Upon publication in the January 9 Journal of Neuroinflammation, the presumed anti-AD effects of the drug (etanercept), a tumor necrosis factor α blocker marketed under the name Enbrel, were hyped by the media, Aisen said (see ARF related news story). “Every clinician I know in the field was inundated with questions that wasted time, interfered with patient-doctor relationships, and were quite damaging,” Aisen said. “People were flying out to California to get that treatment.”

Clinical testing is time-consuming, expensive, and often fails; it’s the rate-limiting step in bringing new AD treatments to the public, Aisen said. Yet it must be done. “There is no avoiding the huge effort in establishing the safety and efficacy of a new treatment based on a scientific discovery. If people appreciated that, we would have greater numbers of volunteers in our clinical trials,” he told ARF. “And at the same time, all of us working on clinical trials need to pay close attention to the interest of the participants.”

A paper published last week in the open-access journal PLoS Medicine addresses one such concern. Reviewing 28 studies on communicating clinical research results to participants, David Shalowitz, University of Michigan Medical School, Ann Arbor; and Franklin Miller, National Institutes of Health, Bethesda, Maryland, found that most people participating in medical research want to know the results of the trial, even if receiving this information might cause distress or anxiety. This “bad news is better than no news” sentiment seems to echo the findings of a study published in March suggesting that a dementia diagnosis actually brings relief to people with AD or mild cognitive impairment (Carpenter et al., 2008).

Siemers of Eli Lilly pointed out that while most lab and neuropsychological test results collected during an AD treatment trial are readily available to participants, the question of whether they received active drug or placebo often cannot be disclosed until months, sometimes years, after the trial has ended. Phase 2 and 3 trials are always double-blind, placebo-controlled studies, he said. This means neither the participants nor the investigators know who got drug or placebo—a key feature for avoiding bias when interpreting trial data.

Disclosure of whether a patient received drug or placebo in trials of Eli Lilly therapies can only happen once all data from the study have been “locked” and carefully analyzed—usually months after a trial has ended, Siemers said. Some studies have an open-label extension, during which all participants know they are receiving active drug and collection of key data continues. This feature can attract patients because it reassures them that even if they got randomized to placebo during the blinded period, they will receive active drug afterward. To maintain scientific integrity in these cases, investigators cannot disclose treatment assignments until the open-label extension has ended, and in some cases as late as several years later when the drug is launched, Siemers said.

That said, Siemers offers this charge to people who are deciding whether to take part in clinical research. “[Study participants] get a lot of very careful general medical attention,” he said, noting the battery of lab tests, x-rays, EKGs, and other procedures required for trials of many investigative AD therapies. “I can’t tell you the number of times we just happened to find an elevated cholesterol or something else that was completely unrelated to the disease but helpful for the patient’s overall medical condition,” said Siemers. He recalled two patients whose EKGs, taken during Phase 2 trials of Lilly Alzheimer compounds, showed they were having a silent heart attack.—Esther Landhuis

Comments

  1. “Participation in medical research" really means participating in a clinical trial—either as a specific subject or as the caregiver of someone who enrolls in a clinical trial. We know that patients who take part in trials—certainly in psychiatry and neurology—do better than patients who aren't involved in trials, even if they are randomized to receive placebo. This is presumably because of placebo effects (which are real and measurable and formed the basis of much of the apparent efficacy of medical treatments available until 50 years ago) and a positive effect of the attention received during assessments and more general effects associated with the hope and feeling of purpose engendered by participation. Knowing the results of the trial—both in terms of personal individual response and that of the whole group—is an important part of this, too.

    Having said this, there are often reasons why it is difficult to give information about the outcome of a trial until several months have passed following an individual participant's involvement. This may be part of the trial design to protect against unblinding or due to the delays involved in completing data collection, cleaning, and analyzing the data before a final analysis can reveal the results. My own experience is that the people with dementia and their caregivers who have participated in our large-scale trials have been very understanding about the limitations that are placed upon us by these factors and are positive about waiting for the results to be made available so long as they understand that we will let them know the final results as soon as we have them.

    A theme that arises again and again in the UK—sadly, in my view—is that clinicians are often reluctant to put their patients forward for trials—despite the clear benefits that I have alluded to above. This arises, I believe, from a mixture of not wanting to be bothered with the perceived extra workload that may be cascaded down to a physician whose patient enters a trial and in some cases a feeling that vulnerable patients need to be protected from having their established treatment disrupted in a way that will offer little benefit and potential risk. I think that researchers like myself have a job to do in persuading our colleagues to change their attitudes and behavior in this area!

    View all comments by Robert Howard

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References

Therapeutics Citations

  1. Flurizan™

News Citations

  1. Donepezil BeCALMed? Drug Fails to Relieve Agitation
  2. Breakthrough or False Hope? Etanercept Case Report Draws Scrutiny

Paper Citations

  1. Howard RJ, Juszczak E, Ballard CG, Bentham P, Brown RG, Bullock R, Burns AS, Holmes C, Jacoby R, Johnson T, Knapp M, Lindesay J, O'Brien JT, Wilcock G, Katona C, Jones RW, DeCesare J, Rodger M, . Donepezil for the treatment of agitation in Alzheimer's disease. N Engl J Med. 2007 Oct 4;357(14):1382-92. PubMed.
  2. Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation. 2008;5:2. PubMed.
  3. Carpenter BD, Xiong C, Porensky EK, Lee MM, Brown PJ, Coats M, Johnson D, Morris JC. Reaction to a dementia diagnosis in individuals with Alzheimer's disease and mild cognitive impairment. J Am Geriatr Soc. 2008 Mar;56(3):405-12. PubMed.

External Citations

  1. Myriad Pharmaceuticals, Inc.
  2. new survey
  3. Society for Women’s Health Research
  4. Eli Lilly and Company
  5. DOMINO-AD trial
  6. clinicaltrials.gov
  7. ADCS

Further Reading

Papers

  1. Carpenter BD, Xiong C, Porensky EK, Lee MM, Brown PJ, Coats M, Johnson D, Morris JC. Reaction to a dementia diagnosis in individuals with Alzheimer's disease and mild cognitive impairment. J Am Geriatr Soc. 2008 Mar;56(3):405-12. PubMed.

Primary Papers

  1. Shalowitz DI, Miller FG. Communicating the results of clinical research to participants: attitudes, practices, and future directions. PLoS Med. 2008 May 13;5(5):e91. PubMed.

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