Failures in Alzheimer’s Disease (AD) clinical trials have been attributed to multiple factors, including an inadequate understanding of mechanisms of action and poor target engagement; however, other issues such as poor study design, wrong stage of AD matched to a particular drug, limited statistical power of endpoint measures, and inclusion of ineligible participants, also contribute. In fact, failure to meet entry criteria in randomized controlled studies focusing on cognition improvement is a fundamental aspect in study execution, leading to protracted timelines and increased costs. Appropriate study design and optimization of recruitment/screen failure rates are proving increasingly important as the field focuses on putative disease-modifying agents and patients that are early in the disease spectrum – studies which have notoriously high screen failure rates (with averages upwards of 85%) and low recruitment rates (with averages of 0.19 patients per site per month).
Studies of patient eligibility have established that as little as 10–27% of potential participants are trial-eligible.1-2 Unfortunately, few AD patients are aware of research opportunities and many are unable or unwilling to participate. Many older adults live alone and may not have access to a caregiver who can assist their participation. Indeed, AD trials require not one but two participants: the patient and a study partner, and enrollment of this dyad is imperative to success.
Selecting the right patients for a study and appropriately translating their medical data into a protocol-specific entry criteria, creates major challenges. Other obstacles include medical comorbidities, use of prescribed and OTC medications, and behavioural complications which can all be exclusionary.
Improving Screen Failure For Ad Clinical Trials
In terms of screen failure, the development of symptomatic treatment in mild to moderate AD has been associated with rates ranging between 15-35%. Although this range is manageable, it is not uncommon for trials to have twice the fail rates in early AD populations. To ameliorate these, a hierarchic approach to patient’s eligibility factors may be utilized, that takes into account all known and estimated screening variables. This hierarchy should be based on how costly and cumbersome various screening procedures are, with less costly and complex procedures occurring first. Following such a hierarchical procedure has been shown to reduce screen failures in an ongoing study from 80% to less than 50%.
It is more difficult to reduce failure rates caused by non-predictable factors such as amyloid level on CSF, amyloid-PET or safety brain MRI indicating ARIA. One promising technique utilizes statistical tools that predict the presence of amyloid/tau or even the eventual diagnostic conversion to AD. Typical techniques involve using multiple regression analyses to predict the presence or absence of beta amyloid or tau on imaging or in CSF, based on scores on earlier-obtained and easier to acquire screening measures such as demographics, cognitive test scores, genetic status, clinical signs/symptoms and structural MRI findings.
Another method has been proposed to minimize the cost of trials without compromising statistical power. Utilizing an adaptive design for data acquisition exploits harmonic analysis of a band-limited signal on a graph whose node corresponds to participants with the goal of fully recovering a multivariate signal on the nodes, given the full set of lower-cost features and a partial set of more expensive measurements.3
Analytical techniques offer the opportunity to predict which subjects will qualify for study participation in an adaptive manner, with each additional piece of screening information adding to the success of final predictions based on biomarkers. These methods, along with an increased familiarity of patient clinical status and the use of a hierarchical approach to screening, should help to minimize screen failure rates, improving overall recruitment rates in these notoriously difficult-to-enroll trials.
To learn more about how Worldwide Clinical Trials approaches AD clinical trials, click here.
Tomislav Babic, M.D., Ph.D., is Vice President of Medical and Scientific Affairs/Neuroscience at Worldwide Clinical Trials
Henry J. Riordan, Ph.D., is Executive Vice President, Medical & Scientific Affairs at Worldwide Clinical Trials
References
- Schneider LS, Olin JT, Lyness SA, et al. Eligibility of Alzheimer’s disease clinic patients for clinical trials. Journal of the American Geriatrics Society. 1997; 45(8):923–928.
- Treves TA, Verchovsky R, Klimovitsky S, et al. Recruitment rate to drug trials for dementia of the Alzheimer type. Alzheimer Disease and Associated Disorders. 2000; 14(4):209–211.
- Johnson, SC., Singh, V. Personal communication Aug 3, 2016.
