A landmark for AD

FDA and EMA vet Critical Path Institute’s clinical trial simulation tool for Alzheimer’s disease

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TUCSON, Ariz.—In what may be a big step forward forAlzheimer's disease (AD) therapy development, both the U.S. Food and DrugAdministration (FDA) and the European Medicines Agency (EMA) have independentlyreached favorable decisions on the value of the Critical Path Institute's(C-Path) new disease simulation tool for improving trial design in mild andmoderate AD.

The first such instrument to ever receive this regulatory designation—deemed"fit for purpose" by the FDA and "suitable for use" by the EMA—the toolrepresents an enabling advance to improve the design of future clinical trialsin AD. The new tool applies computerized models to simulate "what-if" scenariosfor clinical trials, with the goal of serving as a public resource for sponsorsdesigning trials of new therapies.

The FDA issued its "fit for purpose" regulatory letter to the Critical PathInstitute's consortium, the Coalition Against Major Diseases (CAMD), in June.
"Model-based drug development was one of the goals definedin the FDA's 2004 Critical Path Initiative report, and this new tool sets thestage for applying new technologies to accelerating medical productdevelopment," says Dr. Janet Woodcock, director of the Center for DrugEvaluation and Research (CDER) at the FDA.

"The involvement of the FDA and the EMA for guidance on C-Path programs is ahallmark of C-Path/CAMD," says Dr. Diane Stephenson, executive director of theCAMD. She points out that C-Path programs frequently result in a formalregulatory qualification by FDA and EMA as drug development tools and novelmethodologies. The institute is an independent, nonprofit organizationestablished in 2005 with public and private philanthropic support from theArizona community, the Science Foundation Arizona (SFAz) and the FDA. Aninternational leader in forming collaborations to advance its mission ofimproving health and saving lives by accelerating the development of safe,effective medicines, C-Path has established global, public-private partnershipsthat currently include more than 1,000 scientists from government regulatoryagencies, academia, patient advocacy organizations and 35 major pharmaceuticalcompanies.

"The AD clinical trial simulation tool will make it possible to simulateclinical trials by integrating all relevant data so future studies will be moreefficient and more likely to be successful," states Stephenson. "The tool wasdeveloped by integrating diverse sources of data which helped with improvedreliability and confidence in the model."
The data sources used to develop the simulation include: Mild and moderate ADtrials from the CAMD database—3,200 patient-strong at the time the tool wasdeveloped; 6,500 to date.

"Pfizer, Abbott (now AbbVie), AstraZeneca, Sanofi and GlaxoSmithKline allcontributed data to the CAMD database," Stephenson notes. "There were ninetrials in total, representing the placebo arms of legacy clinical trials."

Other sources included natural history data from the large observational study, the Alzheimer's Disease Neuroimaging Initiative (ADNI) mild and moderate ADcohort, which was 284 patient-strong at the time the tool was developed, andliterature data from 73 publications of unique trials that represented morethan 72,000 patients.

In earlier work, Stephenson notes, C-Path identified the first preclinicalsafety biomarkers, qualified by the FDA, the EMA and the PMDA, that predictwhether a drug may affect kidney function and the first imaging biomarker fortrial enrichment qualified by EMA in which clinicians can identify thosepatients with memory loss that are most likely to progress to Alzheimer'sdisease by measuring hippocampal volume.

Dr. Richard Lalonde, vice president and global head of clinical pharmacology atPfizer, states, "this model was made possible because major pharmaceuticalcompanies participating in CAMD were willing to share de-identifiedpatient-level data for over 6,000 patients who previously participated in ADtrials. The data from these trials were the basis for this model, and the FDA'sdecision on this tool will allow sponsors to apply modeling and simulation andlaunch AD trials with a higher degree of confidence. This is a great example ofa rising tide lifting all boats."

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