Group Head Quantitative Safety and Epidemiology Novartis Pharma AG, Switzerland
Background: The European Medicines Agency defines registry-based randomized clinical trials (RRCTs) as RCTs embedded in the data collection infrastructure of one or several patient registries. Advantages of RRCTs versus RCTs include increased external validity, decreased loss to follow-up, and an effective inclusion of a large number of patients. To our knowledge, a comprehensive overview of RRCTs and the contribution of used registries is lacking.
Objectives: To review publications on RRCTs with a focus on the registries’ contribution.
Methods: A literature review was conducted in PubMed, applying a comprehensive search strategy to identify publications on RRCTs in English. General information on the RRCTs’ methodology was sought based on the published articles and clinicaltrials.gov. Type, country of origin, and the specific contribution of registries were described.
Results: 69 publications reporting on 82 RRCTs were included in the review. The majority of RRCTs (53.7%) were conducted in European Nordic countries. Registries (population registers in 49.0%, disease registries in 46.4%, and surgical/clinical procedure registries in 21.7% of publications) contributed mainly to data collection and study follow-up (87.0% of publications), patient recruitment (62.3%), and randomization (40.6%). More than 75% of publications reported a mixed RRCT approach with additional data collection beyond the registry. Study visits, questionnaires, or review of medical records were used to capture missing data on baseline characteristics, patient-reported outcome measures and exposure, or potential confounders. A commonly reported limitation of used registries was the need of external central adjudication of endpoints. Randomization within the registry, if described, was mainly done on patient level and relied on integrated web-based tools.
Conclusions: Data collection outside of registries was often needed to meet the objectives of the RRCTs, highlighting the value of fit-for-purpose registries and preliminary feasibility assessments. To improve the suitability of registries for RRCTs, integration of randomization tools, validation of outcomes, and standardized processes to add missing data elements should be considered. Moreover, future efforts towards uniform data collection between registries would allow for multinational RRCTs with higher external validity. Forthcoming discussions should include transparent reporting of RRCT methods and the potential impact on the reusability of the collected data (e.g., how registry data collected as part of RRCTs deviate from standard of care under the assigned intervention).
