Recruitment of participants to a multiple sclerosis trial: The CombiRx experience

Abstract

Background and Purpose: Participant recruitment is central to all clinical trials. Any delay in recruitment affects the completion and ultimate success of the trial. We report our experience with patient screening and randomization in CombiRx, which may inform the design of other trials. CombiRx was a multi-center, phase III, double-blind, randomized clinical trial comparing the combined use of interferon beta-1a and glatiramer acetate to either agent alone in patients with relapsing-remitting multiple sclerosis (RRMS). This trial was launched in January 2005 in 69 centers in the U.S. and Canada under a co-operative agreement with the National Institute of Neurological Disorders and Stroke (NINDS). The goal was to recruit 1000 patients over 1.5 years after a 6 month startup period. Instead, the investigators required 4.25 years to enroll 1008 patients. Methods: During this trial, we assessed the effectiveness of various recruitment strategies, utility of rescreening prior screen failures, and potential factors and strategies used in study conduct, research and infrastructure, all of which affected recruitment of participants and ultimately time to completion of CombiRx. We particularly were interested in the variability in time to site initiation between academic centers and private practice sites. Results: Physicians who were directly involved in the medical care of patients with RRMS were the primary source of patients recruited to CombiRx. A flexible study design that allowed for re-screening of the initial screen failures after a period of time was useful due to the relapsing/remitting course of the disease. Academic centers took longer to implement the trial than the private practice centers, but once sites were approved for enrollment, there was no important difference in the number of participants enrolled. Limitations: The CombiRx trial was conducted during a period when multiple new medications were being tested, thus affecting the pace of recruitment and limiting ability to generalize our experiences. However, the lessons we learned about process are relevant. Conclusion: Participants can be enrolled successfully in a clinical trial for RRMS, but factors affecting the time to achieve the requirements needed to start screening can be unpredictable and problematic. Prospective planning by the sponsors and investigators, use of central IRBs, master trial agreements and secure remote desktop access to the trial database may expedite trial implementation and participant recruitment. A good scientific research question with flexible study design and active involvement of the clinicians are important factors driving recruitment. Clinical trials can be implemented successfully both in private practices and at academic centers, a consideration when selecting sites.

Long-term follow-up of a randomized study of combination interferon and glatiramer acetate in multiple sclerosis: Efficacy and safety results up to 7 years

“…At the start of the 3-year core study, eligible participants with a confirmed diagnosis of RRMS (by Poser or McDonald criteria), aged 18–60 years, with an Expanded Disability Status Scale (EDSS) score of ≤ 6, and with at least 2 relapses in the prior 3 years were randomized (2:1:1) to combination IFN+GA or each single agent plus matching placebo (Bhanushali et al, 2014). There was no dual placebo arm; all participants received at least one active agent.…”

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke–Supported Network for Excellence in Neuroscience Clinical Trials

“…Recruitment strategies used in this study were reported by Bartlett et al in 2018. In the NN102 study, the average enrollment rate was 0.51 per site per month, about twice as fast as enrollment in other NIH and industry-sponsored trials in multiple sclerosis (estimated from ClinicalTrial.gov EXPAND (NCT01665144), ORATORIO (NCT01194570), and ASCEND (NCT01416181) trials [Robert Fox, MD, Cleveland Clinic, oral and written communication, December 2016). The enrollment rate (0.1/site/mo) for the NN103 study was twice as fast as that reported for another myasthenia gravis trial .…”

“…In the first 7 years, the cIRB reviewed and approved 8 protocols, 133 site submissions, 18 continuing reviews, and 579 other amendments (eg, protocols, safety reports, deviations, staff changes). Across the first 8 studies, protocols were approved in a mean (SD) of 59 (21) days and sites in a mean (SD) of 22 (18) days after submission to the cIRB. The median time from cIRB approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96).…”

An evaluation of recruitment methods utilized for a clinical trial with periodontal and diabetes enrollment criteria: the Diabetes and Periodontal Therapy Trial

“…Because we were enrolling individuals with two chronic diseases that included a number of potentially changeable eligibility criteria, we were able to rescreen individuals who meet all but one of the eligibility criteria, such as requiring essential dental care prior to enrollment. A recent study reported on using a similar method of rescreening to recruit participants with multiple sclerosis [22]. Their study reported a 31% success rate from rescreening but did not note how many rescreens occurred.…”