19 Dec 2008

While those who design clinical trials puzzle over eligibility criteria, drug doses, and statistical power, a few researchers have turned their attention to an oft-neglected component of these studies—the participants themselves. In a recent analysis of clinical trial considerations that matter most to caregivers of Alzheimer’s patients, travel hardship topped the list, even dwarfing potential safety issues. Another study found that participants of an industry-sponsored Huntington disease trial placed a high premium on learning study results through phone calls, rather than letters or press releases. Though not particularly earth-shattering, the findings highlight the need to consider caregiver burden and results disclosure as significant factors in recruiting and retaining clinical trial participants—an intensifying challenge in AD trials.

With the growing number of AD experimental treatments entering the clinical pipeline, low trial enrollment rates have become a key bottleneck in the drug development process. One way to explore what keeps more patients and caregivers from opting in is to view the clinical trial as a product with features that can be optimized. “When we make decisions about a product—a car, a soda, or a clinical trial—they’re based on putting together all the attributes and saying, ‘I think it's worth it.’ Products mix attributes, and you want to figure out which ones are most important to people,” said lead author Jason Karlawish of the University of Pennsylvania, Philadelphia, whose study on AD trial design appeared in the 2 December issue of Neurology.

Using conjoint analysis—a statistical tool used in business for new product design—Karlawish and colleagues asked 108 caregivers of mild to severe AD patients how likely they would be to participate in clinical trials that vary four key attributes: risk, home visits, car service, and increased chance of receiving intervention. All caregivers came from the PENN Memory Center cohort. Most—probably more than 80 percent, Karlawish said—had not participated in a clinical trial. In the new investigation, the caregivers rated their willingness to have their relative enroll in a hypothetical 18-month trial of an oral drug being tested for its ability to slow the rate of AD progression. Only 17 percent were willing to participate in the barebones trial—that is, with equal chances of receiving drug or placebo, 10 study visits at the institution, and a 2 percent risk of cardiac damage. If study staff offered to come to the patient’s home for eight of 10 study visits, the predicted participation rate rose to 27 percent. When home visits were combined with lower potential side effects (standard list minus the cardiac damage risk) and greater likelihood of receiving the study drug (2:1 instead of 1:1 randomization), willingness to enroll more than tripled, to 60 percent.

“That's not a surprise,” Karlawish told ARF in a phone interview. “What's more interesting is that the value of reducing the hassles of travel essentially washed out the lack of value of drug risk.” The researchers also found that caregivers of patients with more severe cognitive and behavioral symptoms placed a greater value on travel relief. Travel amenities could thus extend the study’s appeal to family members of more impaired patients, potentially drawing a broader spectrum of participants, Karlawish noted.

Many AD research centers already reimburse for travel and offer home evaluations in ad hoc situations, where patients have declined enough to make transport to and from the clinic difficult. The conjoint analysis suggests that recruitment might pick up if such enhancements were offered up front. “He is demonstrating that these convenience features do matter,” said Lon Schneider, University of Southern California, Los Angeles, of the new investigation. “When we're sending people out to patients' homes, or when we're paying them for travel, we can know it is making a difference.”

Based on local mileages and professional salaries, Karlawish and colleagues calculated the relative cost of adding various amenities to the basic trial. On top of a $5,000 baseline cost per subject, home visits would require an additional $600 per subject. Combining home visits with a 2:1 drug:placebo randomization brought the additional per-subject cost up to $1,200. “That sounds to me low, but if it were in that range I think it would certainly be feasible [to incorporate those amenities],” said Paul Aisen, University of California, San Diego, who heads the NIA-funded Alzheimer’s Disease Cooperative Study (ADCS)).

Even without economic constraints, though, routinely offering such enhancements remains a big challenge. “We already have to have unusually large staff for AD trial therapeutics,” said Rachelle Doody of Baylor College of Medicine in Houston, Texas, noting that most trials require multiple raters, as well as trained staff to do physical assessments and monitor adverse events—many of whom need to be blinded to the others’ evaluations. “If you have to potentially send all of those people out to the home, it would just be very inefficient.”

In a study in this month’s Archives of Neurology, researchers led by Ira Shoulson at the University of Rochester Medical Center, New York, looked at results disclosure—another aspect of clinical trials that could affect a study’s appeal to prospective participants. “Companies are often under obligation to disclose information to investors, but there aren't similar obligations to disclose those results to participants who volunteer to participate in a study and put themselves at risk,” lead author E. Ray Dorsey said in an interview with ARF. “There are new requirements for clinical trials to be registered, and increasingly for those results to be posted. But posting and informing are two different things.”

Dorsey’s study surveyed more than two-thirds of the 316 Huntington disease patients in a recent trial of ethyl-eicosapentaenoic acid (ethyl-EPA)—an omega-3 fatty acid that showed no efficacy for HD over six months and questionable benefits at 12 months (Huntington Study Group TREND-HD Investigators, 2008). Dorsey, Shoulson, and colleagues worked with the study’s sponsor, Dublin, Ireland-based Amarin Corporation, to develop a sponsor-funded plan to communicate the study results to research participants using three means: a media release posted on the Huntington Study Group’s public website; a phone call from site staff; and a conference call involving investigators, sponsor, and participants. In a 13-question postal survey, participants indicated when they first learned the study results, where they got the information, and their satisfaction with those sources.

Of the 217 surveyed, just over half (114) responded. They were older, received HD diagnoses at an older age, and had fewer psychiatric symptoms and better functional capacity than non-responders. Nearly half of the respondents said they learned of the study results within a day of the sponsor’s press release, most often through the phone call from site staff. They much preferred the phone call and conference call (89 and 82 percent of respondents satisfied, respectively) to the press release (50 percent). From these communications, more than three-fourths felt they had a good grasp of the drug’s risks and benefits, and their next steps for participation in the research. Almost 60 percent indicated a preference for thorough review of results before disclosure, even if this delayed dissemination.

Despite the absence of specific mandates on disclosing study results to participants, many research centers routinely provide this information to participants through mailed letters, conversations during site visits, phone calls from site staff, or some combination of these methods. Conference calls are rare.

The new study did not address whether the phone-based means of communicating results might actually boost trial recruitment. Nevertheless, Dorsey noted that appealing to participants in this regard should at the very least be cost-effective. Taking into account the time required for salaried staff to inform patients of study results individually and through the conference call, he placed the cost of the ethyl-EPA study’s communication plan at “certainly less than 5 percent of the total cost of the trial.”

Though it remains to be seen how feasible it will be to implement the features that mattered to participants in these two new studies, experts do see the need to acknowledge patients and caregivers as active stakeholders in clinical research. “Participating in AD clinical trials is obviously essential for any progress, and yet it places a huge burden on families,” Aisen said. “I think we need to pay attention to factors that are important to trial participants.”—Esther Landhuis

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References

Paper Citations

1. Randomized controlled trial of ethyl-eicosapentaenoic acid in Huntington disease: the TREND-HD study. Arch Neurol. 2008 Dec;65(12):1582-9. PubMed.

External Citations

1. Alzheimer’s Disease Cooperative Study (ADCS)
2. recent trial
3. public website

Further Reading

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.

News

1. AD Research Participation: Informed Consent Complicates Trials, Part 1 29 Jun 2008
2. AD Research Participation: Patients Want to Know 23 May 2008