John Hubbard, PhD

	Drug safety is an especially challenging issue in emerging treatments for Alzheimer’s disease (AD), requiring pharmaceutical and biotechnology companies to refocus clinical trial design using patient-centric approaches that mitigate risk and manage adverse events. Current research indicates that AD is a complex disease with a long progression from early onset to the manifestation of clinical symptoms. Moreover, physicians can struggle with

 the clinical diagnosis of AD versus related dementias. Taken together, drug sponsors face the task of enrolling diverse patient populations, which they must carefully enrich and monitor throughout lengthy clinical trials. 

	Improvements in technology, an increased understanding of disease mechanisms, and enhanced clinical trial processes and systems are bringing new tools and resources with the potential to help researchers develop safe and effective drugs for this indication.

	In the era of personalized medicine, imaging and cerebrospinal fluid (CSF) biomarkers play an increasingly pivotal role in AD trials. The development and widespread use of positron emission tomography (PET) tracers enable clinicians and investigators to detect and measure key targets, including amyloid plaques and tau tangles, hallmarks of neurodegenerative disease. CSF biomarker assays are being developed with the goal of identifying and diagnosing patient cohorts in the earliest stages of AD, prior to structural changes in the brain and cognitive defects. 

	Biomarker approaches help direct tailored treatment options to patients most likely to respond, minimizing risk for patients unlikely to benefit from treatment. Moreover, the ability to image the brain of AD patients during the course of treatment provides a critical tool for detecting and monitoring amyloid-related imaging abnormalities (ARIA), including edema and microhemorrhages, often observed with immunotherapies targeting amyloid plaques. Early detection of ARIA in patients, combined with appropriate monitoring and management, is important for reducing patient risk during the course of a trial.

	Treating patients in the earlier stages of disease translates to treating a significantly younger population (on the order of decades), potentially decreasing the likelihood for certain adverse events and complications. Stratification of patient populations also increases the likelihood of observing disease-modifying activity, which may otherwise be obscured by overlapping patient populations in various stages of disease. 

	With over 500 open clinical trials for AD looking to enroll thousands of patients, one of the largest obstacles to developing new and safe treatments is patient recruitment.  Many AD trial participants are over the age of 65, may be undergoing treatment for other diseases (e.g., cardiovascular disease, metabolic disease), and may not meet inclusion criteria designed to ensure participant safety. Furthermore, the use of biomarkers for AD diagnoses may result in more stringent inclusion criteria for a trial.

	Today’s trials require specialized recruitment-retention strategies to enroll suitable patients, keep them safely in the trial, and minimize loss to follow up. To satisfy enrollment needs, specialized industry services aimed at ensuring the safety of patients over the duration of long, complex trials are becoming more popular among sponsors.

	Concerted patient-centric practices aligned with personalized medicine, biomarker use, and patient recruitment have already transformed the design of AD clinical trials. These efforts will continue to grow and ultimately contribute to the approval of the first disease- modifying therapy for this widespread disease.

, PhD, FCP, is President and CEO, BioClinica

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Aligning patient-centric approaches with personalized medicine and biomarker use is transforming the design of Alzheimer's trials.

John Hubbard, PhD

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Developing New Alzheimer’s Drugs With a Focus on Patient Safety