12 Aug 2016

Part 3 of a three-part series.

“A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be.”

At the Alzheimer’s Association’s International Conference, held July 22-28 in Toronto, this quote by Ontario’s native son Wayne Gretzky echoed in the hallways as clinicians discussed upgrading their infrastructure and operations in anticipation of a clinical trials platform being set up by the European Prevention of Alzheimer’s Disease (EPAD) and Global Alzheimer’s Platform (GAP) Net (see Parts 1 and 2 of this series). A crucial component of these initiatives that is currently moving into place is the clinical site networks on either side of the Atlantic Ocean. EPAD is certifying a network of 30 sites throughout Europe; in the United States, GAP is expanding a pilot of 11 sites to add 20 sites this year, and 30 more in 2017. “Eighty sites, both academic and commercial ones, have expressed interest to join,” GAP founder George Vradenburg told Alzforum. GAP Net is a not-for-profit site management organization that is independent of trial sponsors or specific drugs. Both GAP and EPAD are public-private partnerships.

There is much room for improvement in how clinical trials in Alzheimer’s disease are being run today. A sponsor finds, contracts, and activates hundreds of sites separately every time a new drug program starts. When a program fails, teams disband, people are let go, and the whole process starts anew when a sponsor comes along with a new drug. Sites, and sponsors, use different contract language, ethics boards, and training methods. Besides slowing things down, these inefficiencies make it difficult for sites to maintain a steady work flow and budget personnel and infrastructure, and they drive up the cost for sponsors.

Some sites take three months to process contracts and institutional review board (IRB) assessment, others up to a year, and their performance varies greatly on other measures, as well. Variability leads to noisy data, requiring larger trials—it’s a familiar problem to Alzheimerologists. “Current trials are slow, redundant, inefficient, expensive. If a biotech has to make a decision between a cancer drug and an AD drug, they will choose the former because it is cheaper to test. We need change,” said Jeffrey Cummings of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Nevada.

EPAD dealt with this problem by establishing its network of certified sites, which it calls trial delivery centers, or TDCs. A TDC must be located near a hotspot of the EPAD Register, and its ability to serve as an EPAD TDC is tested in feasibility runs as the register begins to recruit locally. They need to have PET scanners nearby, and must be able to recruit 200 people into the EPAD cohort and 50 of those into the first EPAD proof-of-concept trial. The sites must have experience running Phase 2 trials and sign best practice agreements. The sites will open in three waves, as EPAD works out the kinks of the system, said José Luis Molinuevo of Barcelonaβeta Brain Research Center in Barcelona, Spain. This summer, EPAD is bringing on the second wave.

GAP is starting up GAP Net. In a pilot study with 11 U.S. sites in the past year, GAP leaders asked the sites to name their worst “pain points.” They heard about lack of recruitment personnel, having exhausted limited site staff in pre-screening large numbers of trial candidates, four out of five of whom are rejected. They also heard about too much paperwork for contracts and ethics approval. In turn, each site received $100,000 from GAP to spend as it saw fit and to report back. At a GAP Net site expansion meeting at AAIC, Richard Mohs of GAP told site leaders from across North America that just by hiring an outreach or recruitment coordinator, administrative support, and taking out advertisements, the pilot sites had doubled the number of people they were able to screen and enroll. Some sites started trials up faster, had fewer discontinuations, or were able to accommodate additional trials.

Going forward, however, GAP will not simply fund sites locally. Its leaders also want to bring sites into line by mandating common “best practice” procedures across the network. GAP leaders intend to institute templates to streamline budgeting, agreed-upon common contract language, and administrative tasks. GAP Net sites will have to train raters annually through a central company, though this will eliminate the current burden of having to train them anew, and differently, for each drug program. Sites will use the CDISC2 data standards to support pooling, sharing, and, importantly, regulatory submission, Vradenburg said. They will also have to provide some concierge services to patients, Cummings said. This includes not just helping with parking but also with finding one’s way around the study site and general personal assistance to make study visits less stressful, perhaps even pleasant. There is a business feel to GAP Net, with an emphasis on performance expectations and monitoring. Quantitative performance data as well as qualitative considerations will guide the selection of the next batch of 20 GAP Net sites from the 80 applications that have come in, Cummings told the audience at the GAP Net meeting in Toronto.

GAP Net will require its sites to switch from using their own IRBs to a central, nationwide IRB. While some institutions may initially resist giving up local control of ethics oversight, others may welcome the simplification. A survey of 45 academic sites commissioned by GAP indicates that the majority have already used a central IRB for other trials. On June 21, the National Institutes of Health mandated use of a single IRB for multi-center research funded by the federal government starting in May 2017. “The goal of this policy is to enhance and streamline the IRB review process in the context of multi-site research so that research can proceed as effectively and expeditiously as possible. Eliminating duplicative IRB review is expected to reduce unnecessary administrative burdens and systemic inefficiencies without diminishing human subject protections,” the policy declares. 

Large IRB organizations exist to provide this service. One of them was commissioned for the White House’s Cancer Moonshot 2020 initiative to run Phase 2 cancer immunotherapy trials in 20,000 patients within the next three years, which was championed by Vice President Joe Biden. In a recent series, The New York Times chronicled a history of cancer immunotherapy replete with early setbacks and side effects, but with tremendous potential going forward. At AAIC, immunotherapy presentations evoked a field at an earlier stage, but perhaps with similar potential.  

“We have to do this. The central IRB, and funding for a permanent recruiting staff alone can really speed things up,” said Pierre Tariot of the Banner Alzheimer’s Institute in Phoenix.

Whether all participating sites, in both the United States and Europe, fall fully in line with the new plan remains to be seen. “To make this successful, centers have to be completely engaged. This is not business as usual. This is creating and executing a new paradigm for how to do AD trials. It takes extra energy, and everyone has to be fully committed,” Molinuevo told Alzforum.

Similar initiatives to broaden recruitment and reform clinical trials are forming around the world. [Courtesy of GAP.]

Different Countries, Same Idea
Other countries are developing similar initiatives, and they are communicating with GAP and EPAD to harmonize the overall approach, if not the details. For example, the Canadian Consortium on Neurodegeneration and Aging, led by Howard Chertkow at McGill University in Montreal, is that country’s national dementia initiative. With five years’ worth of government funding, CCNA is charged with engaging 350 Canadian researchers and clinicians to advance research, treatment, and care. CCNA provides resources to establish registries and a cohort of 1,600 people with various neurodegenerative diseases called COMPASS-ND. To be fully enrolled by 2018, this cohort will deliver deeply phenotyped people for prevention or prodromal trials, Chertkow said at an AAIC pre-meeting. To add the trials and the sites that would make COMPASS-ND a full equivalent of EPAD— aka Canadian Pipeline for AD Therapeutics, or cPAD—Howard Feldman earlier this year submitted a grant to the Canadian government. Feldman moved to University of California, San Diego, this past April (see Jan 2016 news), but stayed affiliated with the University of British Columbia in Vancouver. He proposes a master protocol to evaluate multiple compounds through Phase 2 adaptive proof-of-concept trials; this would be done with a network of up to 30 C5R sites. As does GAP, Feldman’s proposal emphasizes broad-based recruitment efforts through family practice and provincial health networks, as well as patient engagement to keep presymptomatic or only mildly impaired people interested in participating in research for long periods of time. 

Across the Pacific, Australian researchers have applied for government funding to transition the Australian Imaging, Biomarkers, and Lifestyle Study of Aging into becoming a trial-readiness cohort. AIBL will change its name to Australian Prevention of Alzheimer’s Disease Partnership, APAD for short. The AIBL longitudinal cohort started in 2006 with 1,822 participants, 1,201 of them cognitively normal at the time, and is currently conducting 90-month (7.5-year) follow-up assessments. To date, 642 people have died or withdrawn, but 503 are left, 419 of them still cognitively normal. With these deeply phenotyped people, AIBL has not only produced highly regarded progression data, but is also now recruiting some of them into early stage trials, including A4 and EARLY.

More broadly, for APAD, Australia currently has 14,000 people in a cognitive-disorders registry, 2,000 people screened for a longitudinal readiness cohort, and 500 in a deeply phenotyped trial-ready cohort. The capital cities of all Australian territories participate in APAD, Colin Masters of Melbourne University said at AAIC.

Japan, which expects 7 million dementia cases by 2025, in 2015 established a nationwide clinical register. Its name is a mouthful: Organized Registration for the Assessment of dementia on Nationwide General consortium toward Effective treatment. ORANGE, for short, unites existing registries, such as the multi-site Japan Gerontological Evaluation Study cohort, which is expected to soon double its current size of 3,000 people with preclinical AD. It is funded by the Japan Agency for Medical Research and Development, AMED. In 2015, AMED announced funding until 2020 for ORANGE2, a beefed-up, more comprehensive platform for prevention and drug discovery research similar to EPAD and GAP, whereby registrants are followed longitudinally, funneled into a trial-ready cohort, and enrolled in prevention drug trials. The organization to support this process, for those readers who can take on board yet another acronym, is called J-DCS, or Japanese Dementia Clinical study Support. In J-DCS, leading Japanese researchers Atsushi Iwata and Takeshi Iwatsubo consider advice from international colleagues at ADNI, DIAN-TU, and GAP.

“Similar processes are beginning to be built in all these countries, and they are all aiming to prevent Alzheimer’s disease at greater speed, lesser cost, and better-quality data,” said Vradenburg.

Can these international initiatives come together? They won’t all merge into one global effort. For their part, GAP and EPAD hold joint meetings to make sure the two initiatives are developing compatible components so they will be able to run global trials, said Luc Truyen of Janssen Research & Development. Both initiatives maintain formal contacts. For example, Truyen is on EPAD’s executive committee and in this role answers to EPAD’s funder, Innovative Medicines Initiative, while also heading GAP’s management advisory council. Likewise, Simon Lovestone at the University of Oxford is EPAD’s academic co-lead and also serves as EPAD liaison for GAP. Eisai’s Andy Satlin is on the EPAD executive committee as well as in a GAP trials development group, and has worked with Cummings and others to develop ADCOMS, a clinical outcome measure derived from the ADAS-cog (Wang et al., 2016). 

With Canada, Australia, and Japan, the idea is for each initiative to obtain funding regionally and set up their own governing structure, but to consult with the other initiatives and build similar capacities where possible. In a field known for strong personalities, as well as a history of debates and at times even truculence, the growing sense of consensus and a shared commitment marks a notable change. Molinuevo summed it up this way: “Some people say this is an ‘interesting project.’ It is not just an interesting project. I believe very strongly that this is the future. Around the world, we have to be ‘all in.’ As we would say in Barcelona, ‘You have to put all the meat in the pan.’”—Gabrielle Strobel

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References

News Citations

1. Howard Feldman to Breathe New Life Into ADCS 21 Jan 2016

Paper Citations

1. Wang J, Logovinsky V, Hendrix SB, Stanworth SH, Perdomo C, Xu L, Dhadda S, Do I, Rabe M, Luthman J, Cummings J, Satlin A. ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry. 2016 Sep;87(9):993-9. Epub 2016 Mar 23 PubMed.

External Citations

1. mandated 
2. Cancer Moonshot 2020
3. recent series
4. C5R sites

Further Reading

No Available Further Reading