European Project Mixes Adaptive Design with Trial-Ready Cohort

11 Dec 2013

Today at the G8 Dementia Summit in London, officials announced that Alzheimer's disease will figure prominently in a European Innovative Medicines Initiative (IMI). IMI is a public-private partnership that facilitates cooperation between industry and outside partners. Its proposed €50 million program, called the European Platform for Proof of Concept for Prevention in Alzheimer’s Disease, EPOC-AD for short, aims to speed the field toward treatments by helping pharmaceutical companies share resources in the early phases of drug testing. Today, the IMI put out a call for proposals from public consortia that wish to join with industry to establish a registry of potential trial participants, characterize a subset of them with biomarker data, and develop innovative adaptive trial designs to move promising therapeutic candidates more quickly into Phase 3 trials.

"Our current approach to clinical trials in Alzheimer's disease is too slow and ineffective—frankly, it's not working," said Simon Lovestone, Kings College London. Lovestone co-coordinates another IMI project but was not involved in the development of EPOC-AD. "We have to do something different, and this is one approach to a solution."

Researchers across academia and industry agree that clinical trials in AD are slow, inefficient, and too expensive. Disappointment from a string of negative trials has highlighted the need to get answers sooner about whether a drug works. The IMI research program plans to jump-start drug discovery by making Phase 2 drug testing less onerous. For starters, the EPOC-AD registry will recruit around 24,000 people who are at risk for AD and interested in participating in clinical research. These can come from existing patient networks. IMI asks that EPOC-AD take neuropsychological and biomarker measurements from about 6,000 of these registrants for at least six months. These people would then have run-in data to enlist in a clinical trial immediately upon its start. "Normally, it takes a year to and a half to recruit patients for a clinical trial, and that's after the year it takes to get ethics approvals in place," said George Vradenburg of USAgainstAlzheimer's, based in Washington, D.C. Once such a phenotyped registry cohort exists, it could cut down on recruitment time considerably.

The registry could be used in other ways, as well. For instance, it could help validate biomarkers for the progression of AD, Vradenburg said. "We don't yet have a biomarker for presymptomatic stages that predicts the clinical outcome of this disease," he told Alzforum.

The third component of EPOC-AD, an adaptive trials platform, will make Phase 2 trials more efficient and less burdensome, according to IMI. Because adaptive trials modify study parameters as trial data comes in (see Mar 2011 news story), they need fewer placebo controls and can randomize a greater proportion of participants to treatment groups. In addition, adaptive trials can compare several therapeutics head-to-head, and then allow the trial to focus on the more promising therapies as it moves forward, while dropping the less effective ones and adding new candidates. The idea of adaptive trials for AD has been brewing for some years. AD researchers look to the I-SPY 2 trial as an example. It used interim biomarker analysis to adjust treatments for breast cancer (see Barker et al., 2009).

"We need to get to a point where we can run clinical trials in Alzheimer's disease at a reasonable cost," said Ryan Watts, Genentech, San Francisco, California, who was not involved with EPOC-AD's development. "If this type of consortium can cut those costs and allow companies to share risk with various partners, it will increase the likelihood that we'll move into Phase 3," he told Alzforum. While the consortium will ultimately decide which therapies are tested with this approach, EPOC-AD specifies that multiple industrial and public partners should test various compounds and non-pharmaceutical strategies, either alone or in combination. The Dominantly Inherited Alzheimer's Network (DIAN) prevention trial has incorporated adaptive trial elements into its protocol (see Apr 2013 conference story), and at least one adaptive trial in late-onset AD is already ongoing (see Nov 2012 conference story).

EPOC-AD will not be IMI's first foray into Alzheimer’s. Jointly funded by the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA), IMI issues periodic calls for proposals based on needs identified by EFPIA members, and funds them for a number of years. "The idea is to combine the very structured and step-wise approach of industry with the creativity and imagination of the public sector," said Michel Goldman, executive director of IMI. IMI currently funds Pharma-Cog, which combines past and current data to define a biomarker signature of AD progression, and the European Medical Information Framework (EMIF), which integrates data from disparate sources on the same patient into a common framework to help researchers gather more detailed information about diseases such as AD and obesity. Another upcoming project called AETIONOMY will launch in January of 2014. It plans to reclassify Alzheimer's and Parkinson's patients based on the underlying genetic or molecular causes of their disease, to help the biomedical community develop new diagnostic tests and treatments.

The deadline to submit preliminary proposals for EPOC-AD will fall in early April 2014. Details are available here. A single winner will work with the 12 participating EFPIA members to develop a full proposal, which will undergo academic review. After it is approved, the IMI will fund the project for an initial five years. IMI asks applicant consortia to propose a business model for sustaining the project beyond that timeframe.

At the outset, EPOC-AD will focus on European organizations, but IMI seeks to widen the cooperative scope globally, Goldman said. "It is very important that EPOC-AD does not end up siloed in Europe," Lovestone said. "I'm hoping that whoever coordinates the EPOC-AD study will look to Canada, the U.S., and elsewhere for collaborative opportunities."—Gwyneth Dickey Zakaib

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G8 Vows to Improve Care, Cure Dementia

12 Dec 2013

On December 11, leaders of the G8 countries met in London for the first-ever summit dedicated to dementia. Much as they did for AIDS nearly a decade ago, they made the disease a global priority. Having set the year 2025 as the official international goal for having a better treatment, the leaders pledged more money for research, discussed strategies to study the disease and care for patients, and laid out a blueprint for a continuing global approach. Jeremy Hunt, the U.K. Secretary of State for Health, announced that a new Global Innovation Envoy would be appointed to coordinate international efforts to attract new sources of finance for the support of dementia innovation worldwide (for a full list of summit outcomes, see the final G8 Summit Declaration).

"This disease steals lives, wrecks families, and breaks hearts," said U.K. Prime Minister David Cameron, who used his country's 2013 G8 presidency to draw attention to the looming global crisis of dementia (see May 2013 news story). The summit was broadcast live online. "I want people to remember December 11, 2013, as the day the global fight back really started."

The summit came less than a week after Alzheimer's Disease International published an update on global AD projections. It indicates that, by 2050, prevalence will rise higher than originally predicted in 2009, owing to new data from China and sub-Saharan Africa. These two regions had lacked clear data previously; new numbers suggest dementia rates there are similar to other countries, raising the estimated global prevalence to 76 million by 2030, and 135 million by 2050.

With that knowledge, health officials, researchers, pharmaceutical representatives, and other experts from the G8 countries gathered at Lancaster House in London's West End to discuss how to tackle this challenge. Organizers grounded the conference in the emotional plight of patients, highlighting the human aspect of dementia. Short films of people who had been diagnosed, along with their caregivers, were interspersed with talks. Former obstetrician and gynecologist Peter Dunlop, who has a diagnosis of early onset Alzheimer's, opened the event with a short speech. "We may not find a cure in time for myself and my family, but a huge number of people are looking at us today and hoping to have future research to improve the outcome," he concluded. "I'm sure you won't let us down." The audience gave him a standing ovation.

That energy animated the rest of the day. Chief among the subsequent discussion points was how best to collaborate on global research that clarifies disease mechanisms and speeds up drug development. Many individual initiatives are underway in different countries, but their leaders are finding it challenging to effectively cooperate and share resources and information. Officials from the European Innovative Medicines Initiative announced a call for proposals to develop a platform for adaptive trials and a registry of trial-ready participants (see Dec 2013 news story). Attendees requested more open access to international, publicly funded data to maximize research opportunities. At the same time, they encouraged governments to help re-incentivize pharmaceutical companies to develop dementia drugs by lowering their financial risk and raising their chances of success. Several experts emphasized the need for further studies on early prevention. While multiple projects are in the works (see, e.g., Sep 2012 news story), more are needed to determine which modifiable factors, such as cardiovascular disease and exercise, could help stem the tide of people who will develop dementia in the future, said Miia Kivipelto, Karolinska Institutet, Stockholm.

Care was also high on the agenda. Representatives from several countries, particularly Japan and the United Kingdom, talked about efforts to create dementia-friendly communities and reduce the stigma around this disease. Germany is implementing programs to help patients live at home longer; these could act as models for other countries, many speakers agreed. Others raised the problem of properly identifying the disease, which goes undiagnosed around 50 percent of the time. "We want [at least] two-thirds of people with dementia to get a formal diagnosis, so that they get the right support from our health care system," said Norman Lamb, U.K. Minister of State for Care and Support.

In addition to patients, caregivers repeatedly came up in discussions. Raj Long, GE Healthcare, suggested that carers could provide valuable data, both on patient outcomes and effective strategies for care. Their collective experiences could be compiled into a set of guidelines, a handbook for people who look after patients, she proposed.

While the Global Innovation Envoy will help coordinate these efforts, individual countries should take their own initiatives. "We need a concrete, action-oriented method so we can hold ourselves accountable," said George Vradenburg, USAgainstAlzheimer's. He suggested that to better measure progress, each country set goals and milestones, such as aiming to spend 1 percent of the cost of dementia care on research, and defining the number of patients to be enrolled in clinical trials. Many countries have yet to develop a dementia plan.

Francis Collins, director of the National Institutes of Health, encouraged funders to enter study information into the International Alzheimer's Disease Research Portfolio (see Oct 2013 news story) so that countries can better coordinate how they spend their budgets.

Some audience members expressed concern that the G8's enthusiasm might peter out. To allay those worries, Hunt announced that three follow-up meetings will take place in 2014. A U.K.-led meeting will focus on social impact investment, Japan will host a session about new care and prevention models, and Canada and France will host a conference about partnerships between academia and industry. In early 2015, G8 members will meet again in the United States with global experts to review progress. In the meantime, Cameron emphasized that dementia should make its way up the agenda at other international gatherings, such as that of the G20 and the U.N. General Assembly. "These meetings will help maintain the momentum we've started today," Lamb said.

Researchers at the conference seemed enthusiastic after the meeting. "We have to congratulate the U.K. for taking the lead, starting with David Cameron, who made dementia a pillar in his efforts," Michael Krams, Janssen Pharmaceuticals, told Alzforum. "To run a G8 summit around this topic is really quite something." The summit has heightened global awareness about the problem and mobilized players to interact at a higher level, he said.

Kristine Yaffe, University of California, San Francisco, agreed. "There is now a clear commitment to dementia, both in terms of research and care, from the highest political level," she said.—Gwyneth Dickey Zakaib

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