European Project Mixes Adaptive Design with Trial-Ready Cohort

Series - G8 Dementia Summit:

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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References

News Citations

  1. Can Adaptive Trials Ride to the Rescue?
  2. As DIAN’s Scope Widens, Funding Narrows
  3. CTAD: Adaptive Antibody Trial to Try Bayesian Statistics

Paper Citations

  1. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther. 2009 Jul;86(1):97-100. Epub 2009 May 13 PubMed.

External Citations

  1. IMI
  2. call for proposals
  3. Pharma-Cog
  4. European Medical Information Framework
  5. here

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