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Is Regulatory Transformation for Alzheimer’s Therapies Needed?

July 1, 2014
BIO 2014's  session titled ” Regulatory Transformation: As Alzheimer's Disease Science, Research and Advocacy Move Toward Earlier Detection and Intervention, How Will Researchers Adapt to this Evolution?” discussed progress and challenges facing researchers and the collaborative efforts between the Food and Drug Administration (FDA) and patient advocacy groups to help them find a cure. The discussion centered on recent FDA Draft Guidance for Early Stage Alzheimer’s Disease Drug Development which allows for an accelerated approval process for drugs which show that they have an effect on cognition, which is an early indicator of the disease. Since 1998 only 3 of 104 Alzheimer’s drugs have made it through clinical trials, and all drugs on the market only treat the symptoms and do not stop the slow progression of the disease.

The FDA’s decision to accelerate the approval of earlier acting drugs will help improve the success rate and will hopefully lead to drugs which prevent the disease, which is expected to inflict 40 million in the US by the year 2050. The panel, which consisted of two Alzheimer research experts and one patient advocacy group representative, discussed the history of Alzheimer’s diagnosis, working with the FDA, and the future of drug development. The panel was moderated by Melissa Stevens, Deputy Executive Director of FasterCures, a nonprofit think tank which seeks to improve the drug discovery, development and delivery processes. The session was sponsored by Eli Lilly, who are actively pursuing development of Alzheimer’s drugs. The panel referred to the figure in this review of the FDA draft guidance to frame the discussion.

Dr. Richard Mohs, Distinguished Research Fellow, Neuroscience and Medical Research at Eli Lilly and Company, said that he saw his first Alzheimer’s patient in 1976. At that time, it was found that patients had a cholinergic deficiency, and drug development in this area began. In those early days, the dual outcome criteria were developed for clinical validation. The two criteria were based on improvement of cognitive abilities, as determined by a test given to the patient, and a decrease in functional impairment as evidenced by interviews with the patient’s family members. At this stage of the drug development timeline, most patients were in the advanced stages of the disease, and the criteria worked well. However, earlier detection of Alzheimer’s disease became possible through biomarkers and brain imaging before mild cognitive impairment (MCI), the original hallmark of the disease, is evidenced. Since functional impairment occurs even after MCI, it was clear that new clinical validation standards were needed.

Lon Schneider, Director, USC Alzheimer's Disease Research Center, went on to describe that there are three preclinical Alzheimer’s stages that occur before a patient has MCI which provide opportunities to prevent the progression of the disease. Schneider is encouraged by the FDA guidance which will allow for development of drugs for these stages. Cynthia Bens, Vice President, Public Policy for the Alliance for Aging Research represents Alzheimer’s patients and described their efforts with the FDA that resulted in the draft guidance. Bens’ group organized annual meetings with the FDA starting in 2008, and may have prompted the FDA to publish the draft guidance. Bens said her organization also worked with the Critical Path Institute on developing strategies for combination therapies and composite measures for Alzheimer’s clinical trials.

When asked how clinical trial results could be improved, Schneider indicated that the key lies in disrupting the pathology of the disease, and that this is a complex process that might be best targeted with combination therapies. To achieve this, companies would need to collaborate on a clinical trial, or for a single company to develop drugs in parallel. Because each trial is so expensive, and recruiting is one of the major expenses, patient registries may help to facilitate as well as to segment the populations for cohort studies.

The FDA, European Medicines Agency (EMA), and patient advocacy groups are working together with researchers to improve the drug development process. The panel suggested that relaxing of the rigidity of clinical trials, implementing more statistical analyses, development of better clinical endpoints, and more communication with patient groups would further facilitate development of more and better Alzheimer’s drugs. The take home message is that the underlying issue with the paucity of Alzheimer’s drugs lies in scientific advances that are needed. As Mohs stated, “A mandate from the FDA is not a substitute for knowledge.” Of course, this is a very active area of research being carried out by groups such as the Alzheimer’s Disease Neuroimaging Institute (ADNI).

Mary Canady, Ph.D. is the founder of the life science marketing consulting firm Comprendia as well as the San Diego Biotechnology Network. Mary and her teams use digital and social media to facilitate better communication between life science companies and researchers, resulting in improved product development processes.