22 Mar 2019

In their grand project to hasten the start-up of therapy trials, the Global Alzheimer’s Platform trial network (GAP-Net) is looking to unclog procedural bottlenecks. Part 1 of this report of the GAP-Net Site Optimization conference, held February 27–March 1 in Nashville, Tennessee, summarized innovation in recruitment. Other sessions discussed progress in using a central institutional review board (IRB) to speed regulatory approvals for sites. Efforts to fill a shortage of qualified clinical raters have not progressed as hoped, however.

IRBs safeguard the rights and welfare of research participants, but they also cause long delays and site-to-site variation in the time it takes a trial to begin enrolling. To accelerate IRB approval, GAP requires sites to accept review by a single organization, a so-called central IRB. GAP chose Advarra, the largest IRB consulting service in North America. Built for speed, Advarra maintains standing committees that meet multiple times a day and process applications within days, far faster than most academic IRBs.

Sixty-one of the GAP-Net sites have signed agreements with Advarra, though not all use its services effectively yet. After observing sites and analyzing metrics for IRB processes, GAP’s Gabe Goldfeder concluded that half the sites use the service well while the other sites remain slow due to confusion about paperwork requirements and duplicate submissions to both Advarra and local IRBs. According to data Goldfeder presented, the former sites halved their time to IRB approval compared to the latter. In one trial, for example, time to approval averaged 85 days in the former group versus 183 days in the latter; in the second, the difference was 71 versus 130 days. GAP is now creating a best-practice guide for IRB use modeled on the “full optimization” sites, and coaching less-efficient sites for improvement.

Goldfeder said getting academic institutions to loosen their grip on the process and sign on to a central IRB is a major undertaking. They’d better get used to it, said Bethany Johnson, director of the human research protection program at Indiana University. She believes central IRBs are here to stay. The National Institutes of Health now require all multicenter proposals to include a plan for single IRB review. Starting in 2020, all cooperative research subject to federal rules for protection of human subjects will require a single IRB review for all sites, and the FDA is expected to update their regulations soon to require the same.

IRB approval is but one bottleneck. Contract and budget negotiations drag on, and communication between sites and sponsors or their contract research organizations can be slow. GAP developed a common contract template, and is working on one for budgeting, too. Goldfeder said that GAP’s liaisons—facilitators who advocate on behalf of sites and participants to sponsors or their CROs—also foster quicker communication and problem resolution.

Early data suggest the efforts are working: GAP-Net sites on the three ongoing studies on average started up in 4.8 months, compared with 5.8 for non-GAP sites on the same trials. And fast start-up predicted better results: The faster sites screened 25 percent more people and randomized 71 percent more into the trial.

For their part, investigators appreciate GAP-Net’s help. Several told Alzforum they would rather work on a GAP-Net study than non-network studies. “I have four study proposals on my desk right now and I want to make a good business choice. I feel the (GAP-Net trial) collaboration has been largely positive, so if we can work together again, I would like to prioritize those studies,” wrote one site research manager to GAP by way of feedback. Of all the sites accepted into GAP-Net, only one has withdrawn, John Dwyer, president of the GAP Foundation, told Alzforum.

Ready, set, retrain?
Another problem in expanding therapy evaluation in AD is a shortage of raters whom pharma sponsors will accept as qualified to administer the cognitive tests and scales used to measure trial outcomes. Richard Mohs, now at GAP after a career at Eli Lilly, said that one-third of GAP-Net sites have had to turn down studies because they lacked qualified raters.

Why is that? Trial instruments differ from the tests doctors do in the clinic, and that means few people get trained on the CDR-SB or ADAS-Cog, to name but two. For those who gain the requisite experience, no generally accepted certification scheme exists. Sponsors rarely recognize prior training, hence even expert raters end up taking the same courses over and over for different sponsors, sometimes for each trial by the same sponsor. Imagine being asked to repeat a school year over and over, regardless of how well you did in class? At sites, duplicative training saps staff morale and takes time away from trial work.

Added to that, currently the field has no clear-cut path to produce new raters. A circular logic bedevils the system, whereby trial protocols require raters to have extensive experience but there is no way to get the experience except to have worked on a trial. “There is no place to go and get trained, yet industry demands training,” said Mohs.

This is not a new problem, and it still resists solution. “Everybody wants change, but no one wants to change,” Mohs said. GAP plans to create a rater-certification program and a central database of qualified raters. Certification would be done scale by scale, and sponsors would need to agree to accept raters qualified for each scale in a given trial, without requiring retraining.

It hasn’t been easy. After years of discussion with GAP-Net sites, academic trial consortia, a training company, and a large CRO, in Nashville Mohs reported some progress toward defining what constitutes a proven rater that any sponsor should accept. Alas, there’s no consensus yet.

What will it take? GAP needs buy-in from all groups involved in trials, said Mohs. That’s a challenge because pharma companies are fundamentally conservative and looking to minimize risk, while training companies have a financial incentive to maintain use of their services. “We want one of our commercial sponsors to step up and say, ‘We will accept this program. If you provide the database, we will accept the raters.’ It’s going to take one courageous sponsor to do that,” Mohs said.

Arthur Simen of Takeda Pharmaceuticals thinks that sponsors will accept new raters once they have been rigorously evaluated. “From the sponsor’s point of view, we need better metrics for assessing raters,” he said. Jason Bork of the GAP Foundation told Alzforum that at the senior management levels, pharma companies express support, but at the level of a given drug program, no one wants to shoulder the perceived risk. In Nashville, Dwyer told the audience, “This is our biggest miss. We are two years behind, and aren’t going to be happy if we don’t get this done.”

Besides big initiatives, GAP has an eye on details, too. Even after trials are up a and running, sites need help to keep volunteers coming back for all their appointments. Now, through the ride-share service Lyft, GAP provides free transportation to clinical sites for participants in their three studies, and also gives transportation grants to every site to use even in non-GAP trials. Steve Satek, Great Lakes Clinical Trials, Chicago, says that’s important at his urban site, where many seniors don’t drive. “It comes down to what matters to the patients, and getting them to the clinic. These little things can make all the difference,” he said.—Pat McCaffrey

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References

News Citations

1. In Year Three, GAP Trial Network Is Starting to Hum 21 Mar 2019

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