Clinical trials, particularly for Alzheimer’s disease, often struggle to find participants fast enough and retain them until the trial is over. As more drugs move into Phase 3, this is increasingly seen as a major bottleneck in the movement toward new treatments. To brainstorm solutions to this problem, about 30 stakeholders from academia, industry, and clinical and advocacy groups met November 1–2 at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. They agreed that trials are evolving and that technology plays a role in that process. By harnessing the power of Internet registries and online patient communities, trial sponsors can better reach potential participants. Initiatives have sprung up to reach new populations, especially minorities who are often underrepresented in trials. Speakers also discussed ways to keep people in studies, such as providing incentives and help with transportation to study sites (see part two of this series).

Above all, speakers stressed the importance of listening to patients. Their feedback can inform both the design of the trial and the selection of outcome measures that matter most to patients. In addition, participants often want to be kept in the loop about the results. Since many people enroll in trials for altruistic reasons, trial sponsors should share what was learned so participants can see what their generosity produced, said keynote speaker Freda Lewis-Hall, chief medical officer at Pfizer Inc. Pfizer has started to share trial information, and has received enthusiastic feedback from volunteers about it, Lewis-Hall added.

The conference sparked ideas and produced new collaborations, with the Lou Ruvo Center staff expressing interest in partnering with several Internet registries. However, it remains to be seen if any of these strategies will truly solve the long-standing problem of AD trial recruitment. At the conference’s end, Jeffrey Cummings, who heads the Lou Ruvo Center, said, “What most excited me was the idea of giving patients a voice in clinical trials.”

What Ails Trials?
Enrollment problems are common to clinical trials in all areas of medicine, according to a recent report from Tufts University. Overall, about one-third of sites worldwide fail to meet enrollment goals, and 10 percent fail to sign up any patients. Moreover, the pace of recruitment creeps along, often taking twice as long as projected, the report found. Most sites recruit less than a single patient per month, Cummings noted. This means that recruitment for large trials can drag on for several years.

AD trials face particular challenges. For one thing, as few as 10 percent of AD patients may qualify for a given trial due to strict inclusion and exclusion criteria (see Treves et al., 2000; Grill et al., 2012). Many studies reject people who take certain prescription drugs or who have various co-morbidities, yet people older than 65 take an average of 14 medications per year, and frequently have other conditions such as diabetes, noted Joshua Grill, who leads recruitment at the Mary S. Easton Center for Alzheimer’s Disease Research at the University of California, Los Angeles. Trial sponsors often screen 10,000 potential participants or more by telephone to end up with a few hundred people in a study, noted Robert Berman, who directs clinical neuroscience research at Bristol-Myers Squibb. This translates to a 1 to 2 percent success rate.

In addition, patients who do get into a trial hardly represent the general AD population. Grill noted that enrollees tend to be younger and more educated, and are more likely to be married than the average Alzheimer’s patient. About 90 percent of participants in the United States are Caucasian, despite the fact that minorities such as African-Americans and Hispanics have higher odds of developing AD than do whites. This means study results may not be generalizable to these populations. “Drugs are made for people who participate in clinical trials,” noted Stephanie Monroe, director of the newly launched African American Network Against Alzheimer’s, a branch of the advocacy group USAgainstAlzheimers.

With some 5 million Americans suffering from AD, how could it be so hard to find some 10,000 or 20,000 participants in an expeditious timeframe? Researchers at the meeting agreed it is largely because too few people know about the opportunities to take part in clinical research and the benefits of being in a clinical study. The majority of physicians who see aging patients have never referred a patient to a clinical trial, speakers pointed out, and Lewis-Hall said fewer than 3 percent of Americans take part in studies each year. In the early stages of AD, patients may have no diagnosis yet and are often not referred to memory clinics where they could hear about a trial.

There are also logistical barriers. In the later stages of the disease, caregivers usually decide whether their loved one will participate. They may be overwhelmed with responsibilities already and unable to take on more, or they may worry about the effect trial procedures will have on the patient. Older, less educated, and single patients tend to have little support and struggle with planning and transportation and costs. Also, because relatively few centers in the United States conduct AD trials, their catchment areas limit the pool of potential participants who can reasonably come to a nearby site for repeat visits.

Reaching New Participants
How can trial sponsors raise awareness of their studies and connect with more people who might qualify? Community events can be effective, speakers agreed. The African American Network Against Alzheimer’s, for example, has held events in churches and enlisted the aid of businesses, sororities, and other community organizations to spread the word, Monroe said. The group even sponsored an Alzheimer’s-themed play, Forget Me Not, which featured a black cast and ran in conjunction with other AD awareness events.

Likewise, Dorian Mendoza at the University of Pennsylvania, Philadelphia, noted that the Texas Alzheimer’s Research and Care Consortium recruited more than 500 Hispanic participants through targeted outreach to that community. Several speakers promoted the benefits of holding health fairs with the help of local research centers to let people know about clinical trials. Early memory loss and AD support groups are also great venues for contacting patients, Grill said. Different tactics work best in different parts of the country and for particular patient groups, noted Ed Watson, who developed oncology programs at Acurian in Horsham, Pennsylvania. In densely populated urban areas, print ads on public transit may give more bang for the buck than expensive TV spots, Watson said, while to reach an older demographic in a more rural area, television ads during morning talk shows may be the most cost-effective strategy. Acurian is a for-profit company that specializes in providing patient recruitment and retention programs for clinical trials.

Recruitment through primary-care physicians has been less successful thus far. Most patients say they would consider entering a trial recommended by their doctor, but several speakers said that outreach by trial sponsors to physicians falls flat. Grill described an educational symposium on AD research that drew 2,800 physicians but resulted in only a handful of referrals. A published study found that a community event brought in 69 participants, while targeting physicians brought in none (see Carr et al., 2010). Doctors have little time with patients and are focused on direct patient care rather than trial recruitment, speakers noted.

The best way to use doctors’ offices might be to provide brochures that patients can take home, Monroe suggested. Claire Meunier manages the clinical trial strategies team at the Michael J Fox Foundation for Parkinson’s Research. She noted that in her group’s experience, these materials “go like hotcakes. Patients are hungry for this information.” MJFF recently challenged physicians to hand out pocket cards that encourage patients to sign up on an online registry. The site that registers the most new patients will win a Parkinson’s-related educational event. Since its inception last September, nearly 600 new patients referred from 21 clinics have signed up to be matched with Parkinson’s trials, Meunier told Alzforum.

The Internet stands poised to play an ever-bigger role in trial recruitment. Speakers noted the importance of having a trial website to serve as a “landing zone” where patients can get information. Trial sponsors can reach potential participants through social media, banner ads, and healthcare networks. Currently, Acurian enrolls about 10 percent of its participants, including those for Alzheimer’s trials, through online outreach, Watson said. However, he noted that online strategies are not always cost-effective; sometimes a simple billboard or direct mailings can bring in the same number of participants for less money. For more information on the role of the Internet, see part two of this series.—Madolyn Bowman Rogers.

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  1. This comment is submitted by a layperson who has done considerable research on clinical trials for AD and is a caregiver for a partner who has been a participant in trials for more than a year. In addition to examining the reluctance of people with AD to join trials and the methods of communicating trial information to potential recruits, professionals should look to the criteria of the trials themselves and consider what changes or compromises research must make to enable even the most willing and cooperative participants to enroll. In the early stage AD population there is disillusionment about trials generally. Many trial centers are profit-making institutions that exist solely as "trial factories." Many are not populated by researchers but are run as additional income sources for enterprising physicians or psychologists who then outsource subjects to local hospitals for testing that the "centers" are not equipped to administer. These sites run multiple trials concurrently and are unable to provide quality information to enable a potential recruit to make an intelligent (or at least a comfortable) decision about which trial could be more suitable for him or her. I have found that in such centers it is almost impossible to make contact with anyone who can provide guidance or basic information about the trial medication, how it works, or the specific research goals. While some of this information appears on clinicaltrials.gov, it is not necessarily clear to a layperson, nor is it the same as talking to a human being who can answer follow-up questions. A second problem for us has been the various wash-out periods between trials, or from the time a prescribed medication is taken to the time of eligibility for a given trial. While it is scientifically understandable that the researcher must be confident his or her results are not corrupted by earlier medication, I question whether the length of the wash-out periods is determined in consideration of the patient. There is a terrible anxiety arising from the patient’s and caregiver’s inability to know how the disease will progress and how much time (s)he has before it is too late. Some of the washout periods seem unreasonably long. In one instance we articulated this criticism to a principal investigator, who responded by saying she would be willing to shorten it to secure the potential recruit. How often can the washout period actually be shortened without compromising the study? In my personal experience, clinical neurologists, no matter how knowledgeable or compassionate, have little information about specific research trials. If the patient has questions, it is up to him or her to indicate interest in one, two, or more trials, at which time the physician may examine literature the patient submits. If the neurologist has the time or the heart to really consider the alternatives (and in my experience many do not), the patient may get a response, but the response will only relate to the specific questions the patient/caregiver knew to ask; neurologists generally do not provide additional information or advise on other trials that may be more promising. The Alzheimer's Association Trial Match help line is very conscientious, but in my experience the staffers only appear to be able to respond to general questions. They do not know specifics about trials, nor can they provide meaningful alternatives. Is it any wonder that less-educated, less-connected, and underserved populations cannot drill through the morass to be persuaded to enroll in a trial? As an attorney I have done research throughout my professional life, yet even with personal connections in the world of "experts" on AD, and fairly good knowledge of where to search, I found no way to put the pieces together. There is no central location from which to explore the various moving parts of the clinical trials, such as wash-out timing, length of study, location in a genuine medical facility and not a "trial factory," sponsorship, pharmaceutical backing, likelihood of continuation of funding, sub-classes being targeted, and so on. The integration of information and access to expert knowledge, not only on the particular trial which is his or her project, but on the other possibilities that seem promising, would help bring in recruits. Open trials in which appropriate medication remains available to participants in between phases would be an invaluable means of persuasion. There is no depression quite like that of a participant who has been on a medication (or even placebo) who has a real feeling that his or her symptoms have stabilized or improved, only to reach the end of the study period, lose the medication, and be told it could be six months to a year before recruitment for the next phase starts. Pair that with being unable to enter the next-promising trial that has appeared, because of wash-out periods, and one can see why people afflicted with a progressive disease with no known time frame of progression would rather not go through all the examination, radiation, puncturing, testing, and waiting and waiting and waiting. I suggest the professional community lower the barriers that dissuade potential recruits from participation and work out a way to disseminate real and intellectually persuasive information for a person afflicted with this disease to walk in the door.

References

Paper Citations

  1. . Recruitment rate to drug trials for dementia of the Alzheimer type. Alzheimer Dis Assoc Disord. 14(4):209-11. PubMed.
  2. . Are patients whose study partners are spouses more likely to be eligible for Alzheimer's disease clinical trials?. Dement Geriatr Cogn Disord. 2012;33(5):334-40. PubMed.
  3. . Comparison of recruitment efforts targeted at primary care physicians versus the community at large for participation in Alzheimer disease clinical trials. Alzheimer Dis Assoc Disord. 2010 Apr-Jun;24(2):165-70. PubMed.

External Citations

  1. report from Tufts University
  2. African American Network Against Alzheimer’s
  3. sponsored an Alzheimer’s-themed play
  4. challenged

Further Reading

No Available Further Reading