Retention and Compliance in a Multicenter, Open-Label Clinical Trial
Successful retention and compliance of patients in clinical trials are significant challenges in the arduous path to drug approval1,2. Missing outcome data caused by patient dropout and poor compliance not only jeopardize the scientific validity of a study but also comes at a high financial cost to study sponsors. Technology and behavioral science offer potential solutions that can address these challenges through the patient-centric design of tools such as the Linkt mobile application. This case study examines retention and compliance in a multi-center, open-label clinical trial (N=36).
Our app was used to deliver two electronic patient-reported outcomes (ePROs), repeated at five points throughout a 12-week active treatment period (see Fig. 1, top). Baseline assessments were completed by participants on-site, while the remaining assessments were completed remotely within variable time windows of 3 to 7 days.
Patient Retention
We defined retention as the proportion of participants remaining until the study close, the close occurring on the 88th day. The standard attrition rate of 28 days without activity was applied, defining action as completing at least one ePRO instrument within 28 days. For Visits 4 and 5, we modified attrition slightly to accommodate a prolonged gap (> 28 days) between assessments.
We excluded four early treatment termination (ETT) participants to focus the analyses on retention within the context of the Linkt app. The research showed that we retained 28 of the 32 participants throughout the study. The survival analysis to model study attrition using a Kaplan-Meier estimator (KM estimate) showed a probability of 0.88 of retention through the study end.
Figure 1. Survival analysis model of the probability of retention throughout the study. The solid blue line shows the KM estimate. The shaded region shows error.
Trail COMPLIANCE
Using the Linkt app, percent compliance was calculated as a proportion between completed ePROs and delivered ePROs. While we plot compliance for the 4 ETT participants in Fig. 2-A, analyses of overall compliance and compliance by site and visit exclude ETT participants.
The overall compliance rate across participants and assessments was 89%. Moreover, there was higher overall compliance of 95% among retained participants. Individually, 28 participants had 80% or more, 24 had compliance of 90% or more, and 20 of 100% compliance (see Fig. 2-A). Throughout the study (i.e., from one visit to the next), there was a slight, expected reduction in compliance following the baseline on-site assessment; however, compliance leveled off and remained high with subsequent assessments (see Fig. 2-B).
ROLE OF SITES IN RETENTION AND COMPLIANCE
There were also differences in retention and compliance by site (Fig 2-C). Site-specific behaviors had an important influence on participant retention and compliance. Retention and compliance varied widely by site; multiple sites achieved perfect compliance, whereas one site had very poor compliance. Sites play an essential role in the success of a clinical trial, particularly patient trial retention. For example, consistent site communication may encourage participant engagement early in a study, whereas site-specific issues may discourage study participation.
A qualitative review found that initial site staff enthusiasm in adopting and implementing the Linkt platform varied. While all sites in the study had limited-to-no experience with ePRO or electronic clinical outcome assessments (eCOA), a few reported negative past experiences with other ePRO/eCOA platforms. In addition, sites that had already integrated various types of technology into their processes tended to be more receptive to ePRO adoption.
Site & Training variations
Datacubed provided training and worked with the Sponsor to ensure reference materials were available to site staff throughout the trial. Still, there were differences across sites in site staff attendance at the training sessions. Whereas some sites sent the entire study team (at all levels) for training, others did not send a single representative. These variations appeared to contribute to whether sites reported ePRO administration issues, such as using paper or missing ePROs.
To investigate whether these site-level variations impacted participant retention and compliance, two sites that did not send staff for training and administered PROs in paper format and two sites that did not administer both PROs during the initial on-site visit (i.e., Visit 1) were examined. Statistical analyses of compliance and retention revealed that participants at these flagged sites (N = 14) had both lower retention and compliance compared to participants at the other sites (N = 18).
For compliance, a t-test showed significantly reduced compliance at sites with ePRO administration issues (80.7 ± 6.7%) compared to sites without issues (95.5% ± 1.8%) (t = -2.28, p = 0.02). For retention, a chi-squared test showed a trend towards reduced retention at sites with ePRO administration issues (71.4%) compared to sites without issues (100%) (χ = 3.6, p = 0.06). Notably, the sites with 100% compliance also enrolled the most participants. Site differences in retention and compliance highlight the importance of comprehensive site training, validation of site proficiency, reference materials, and the value of implementing engaging ePRO platforms for study success.
CONCLUSION
Overall, at the study end, site investigator feedback regarding the Linkt platform was largely positive, even from site staff who were somewhat hesitant to deviate from traditional paper PRO administration initially.
This paper reports on retention and compliance with ePRO completion in a multicenter, open-label clinical trial. The trial had a high rate of compliance of 95% among retained participants, and compliance of 89% across both retained and attritted participants over the course of the study. Furthermore, 88% of participants were retained through the study end and completed both of the primary study endpoints at Visit 1 and Visit 5. Finally, retention and compliance can be impacted by site practices, and with adequate training and support, high-enrolling sites can achieve perfect compliance even when using an ePRO platform for the first time. Overall, retention and compliance using the Linkt mobile app were very high and exceeded industry standards.
REFERENCES
1. Fogel DB. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemp Clin Trials Commun. 2018;11:156-164. Published 2018 Aug 7.
2. Zweben A, Fucito LM, O’Malley SS. Effective Strategies for Maintaining Research Participation in Clinical Trials. Drug Inf J. 2009;43(4):10.1177/009286150904300411.
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