Discussion
fits, dementia, word of mouth
DISEASE, RECRUITMENT
Many AD prevention trials require participants to have a genetic risk factor and/or biomarker evidence of disease. A risk factor with low prevalence, such as APOE ε4 homozygosity which is present in only 2-3% of the general population (approximately 4-5% of those with a first-degree family history of dementia) (The API Generation Program used a variety of recruitment and screening approaches, recognizing that there was not a “one size fits all” plan that could be applied to all countries and sites. This flexible, tailored approach was also found to be successful for a high-volume, non-interventional observational cohort study (The API Generation Program developed the ICF1a/ICFA prescreening program to support sites that did not have access to a local or national registry with APOE genotyped individuals or that preferred to handle the prescreening process themselves rather than refer interested individuals to registries. Although there are registries outside of the US that contain APOE results, few are set up like GeneMatch, which has the specific objective to connect with and invite its members to AD-focused studies based in part on their APOE results. In the US, sites differed in their perceptions of the ICF1a/ICFA prescreening option. Some indicated that the ICF1a/ICFA was more efficient and allowed them to develop their own registry at relatively low cost (to the site), whereas other sites preferred to direct interested individuals to programs such as GeneMatch and dedicate their staffing to the trial itself rather than the prescreening program. Some sites perceived GeneMatch to be inefficient and/or that it operated in manner that was not fully transparent to them. Globally, even sites were successful at consenting large numbers to the ICF1a/ICFA prescreening process and identifying APOE ε4 HMs experienced challenges at moving these participants to the next steps of screening (ICF1b/ICFB) and randomization. Sites did not share with the sponsor team the reason(s) for the lack of interest from these genetically eligible individuals (not all of whom were aware of their APOE genotype): we postulate that it may have been due the lag time between screening steps, lack of interest in joining a clinical trial of this nature, and/or some individuals may have used the prescreening process chiefly as a means of learning the APOE genotype.We acknowledge several limitations. The discussion and conclusions provided here are based on the data available at the time of termination. Had the program continued to the end of 2019 (when recruitment was projected to be complete), other strategies or tactics may have become more successful, and countries may have identified more APOE ε4 HMs. For instance, perhaps the ICF1a/ICFA prescreening in the US may have referred more APOE ε4 HMs for further screening, as sites implemented new outreach and recruitment strategies that were shared at the roundtables and recruitment meetings. Similarly, the partnership with advocacy groups to promote enrollment of individuals from traditionally underrepresented groups was implemented in spring 2019, just a few months before the trial was terminated. As a result, there are no metrics to describe the success of this effort. Another limitation is the scarce data available to retrospectively analyze the details of the ICF1a/ICFA prescreening program since data were entered into site databases rather than a central, study-level database. Without this data it is impossible to compare the characteristics of individuals who participated in the ICF1a/ICFA prescreening program to those in local or national registries, such as GeneMatch. Furthermore, sites were not consistent in tracking and reporting metrics associated with each recruitment strategy and tactic deployed at their site. In the future, sponsors may want to develop tracking systems that allow sites to easily collect and report referral sources, reasons for prescreening ineligibility, and other important metrics. Although we know the source of initial APOE genotyping (e.g., ICF1a/ICFA, GeneMatch, direct-to-consumer, etc.) at a study level for participants who consented to the disclosure step, we lack such information for participants who were not invited (i.e., noncarriers) or APOE ε4 carriers who did not respond to invitation for disclosure. It is not possible to know which tactic (e.g., newspaper article, trial website, word of mouth) alerted the participant to the trial and motivated their consent for APOE genotyping. Metrics were not collected systematically for many strategies and tactics, limiting our ability to draw specific conclusions about what works best at the site level (e.g., small-group community informational sessions compared to one-on-one sessions (Despite these and other limitations, we demonstrated that it is feasible to develop outreach and screening programs for cognitively unimpaired adults to identify and enroll APOE ε4 carriers, particularly APOE ε4 HMs, into a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Genetic testing registries (such as GeneMatch in the US), partnerships with genetic testing/genetic counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening, though the success of the ICF1a/ICFA prescreening process was greater outside of the US. The sponsor team recognized that a universal “one size fits all” recruitment plan would not be effective due to local, regional, and country-level differences. Collaborations between the sponsor team and individual trial sites were effective in supporting sites to be successful with their participant outreach, recruitment, and randomization goals. Frequent phone and email communication between the sponsor team and sites that was augmented by in-person meetings were instrumental in developing and maintaining the collaborative partnerships. The Generation Program provides a roadmap for developing and implementing outreach, recruitment, screening, and enrollment processes that may be applicable to future AD prevention studies or trials for other indications enrolling healthy adults based in part on the presence of one or more risk factors.