Roughly 47 million people around the world are living with Alzheimer’s disease (AD) — a number that is expected to increase to 75 million by 2030 and 150 million by 2050. Researchers are pursuing a range of treatments: disease modifying, symptomatic treatment and therapy for behavioral issues. Yet no new therapy has been approved since 2003.
One holdup has been low enrollment in clinical trials. In the U.S., where most active trials are conducted, 85-90 percent of studies have delayed recruitment. One simple solution: expand trial sites to other nations worldwide. This is not a new idea; the 144 AD trials currently in progress are spread among 51 countries.
Of course, none is perfect.
- In South and Central America, Argentina and Mexico have the most active sites; however, the region typically requires long start-up timelines.
- In Western Europe, most sites are in the United Kingdom, France, Germany, Spain, and Italy. Due to their popularity among sponsors, they are now highly saturated with AD trials; sponsors are competing for access to the same clinical sites, which impacts enrollment.
- In Central and Eastern Europe, Poland is a leading host country, with many active trials and room for more.
- In Asia and the Pacific Region, the leading countries are Japan, South Korea, and Australia; they are especially successful for large phase three trials.
- China offers access to an enormous population, including naïve AD patients—which have proven hard to find in other countries. These advantages outweigh the complexities of local regulations, potential quality concerns and the typical 12-month wait for regulatory approval.
With no perfect solution, choosing the right country can seem daunting. Moreover, variations in population profiles and cultures can threaten to skew results when compared across countries. Some variations are inherent to a native population; others can be addressed through education and other trial support. Yet by recognizing and considering the following ten factors as you design and conduct a trial, a global trial becomes a feasible, effective answer to the enrollment issue.
- Education levels. In better-educated people, AD tends to progress more rapidly—yet education levels vary substantially from country to country. For instance, the average education level in the U.S. is 12 years, whereas in China it is 6.4 years.
- Exercise. People who exercise more have lower levels of amyloid deposits in the brain; again, typically levels are country dependent.
- Body size. Variations in body size (as well as mass) may affect drug metabolism and distribution, contributing to differences in brain exposure levels. Both larger body frames and obesity are more common in Western populations.
- Polymorphism. Varying substantially across ethnic groups, polymorphism can contribute to differences in drug metabolism, central nervous system drug exposure, and drug response. In particular, Asian populations typically metabolize more slowly.
- Genetic diversity. The biology of AD relevant to clinical trials—for instance, native apolipoprotein E (ApoE) levels—varies among ethnicities.
- Perception of AD symptoms. In Asian countries particularly, a shift in memory is less likely to be considered an abnormality, potentially leading to late diagnosis of AD.
- The role of caregiver. Since the presence of a reliable caregiver—a single person who spends at least 10 hours a week with a patient—is essential to most AD trials, cultural variability can pose an issue, especially in many developing nations where patients tend to live at home in extended families with multiple caregivers.
- The use of clinical trial instruments and equipment. Nearly all widely used clinical trial instruments for AD were developed in North America; as a result, the data collected from different countries may be affected by cultural and national influences. In general, Western countries and some Asian countries tend to be early adopters of new technology; sites in other countries may need additional support.
- — Biological measures: Asian patients are more reluctant to undergo invasive procedures and therefore less likely to participate in trials that include lumbar puncture, which may significantly affect enrollment if cerebrospinal fluid (CSF) is part of your screening process
— Biomarker capacity: This may vary dramatically among global sites.
— Phantom for image standardization and machine calibration: These may not be familiar to all sites; consider providing additional technical expertise to ensure quality. Centralized reading of brain images can minimize site-to-site variability in image interpretation.
— The availability of radioactive tracers: Limited access to new tracers slows enrollment and can force investigators to use lumbar puncture, again, limiting enrollment in Asian countries
- Overall experience of your scientists. When investigators and raters have limited experience in AD trials, the result is often substantial score variability and difficulty demonstrating the drug-placebo differential for an effective compound. Standardized training for raters, provided by a third-party vendor, and in-study rater surveillance programs (evaluating data in near real time) can help improve data quality.
- Regulatory and legal considerations. Strategies and requirements for everything from sample collection to product authorization to marketing differ across international markets. Consider each as you plan and execute your trial.
By carefully considering each of these ten factors as you choose trial sites and establish protocols, you can cast a far wider net for trial enrollment while normalizing results across countries, helping speed progress on critically needed treatments for Alzheimer’s disease. You can learn more about this topic by having a listen to our latest AD webinar.