OBJECTIVES: R-RCTs are pragmatic trials utilizing registry platforms for one or more vital trial functions such as case records, data collection, randomization, or follow-up. We investigated the use of R-RCTs for regulatory approval and access.

METHODS: A systematic search of ongoing and completed R-RCTs was conducted before January 12, 2023, using ClinicalTrials.gov, Citeline’s Trialtrove, and recent systematic reviews. Details of each trial were extracted from study protocols and publications, and included whether a clinical patient registry or administrative health registry was used (for one/several major functions for trial conduct and outcomes reporting). Trials were excluded if they were prematurely terminated, or if patient registries were only used for long-term post-trial follow-up or to ascertain vital status. Nonmedical interventions (outreach/advertising, policy changes) were only included if registered in ClinicalTrials.gov or Citeline’s Trialtrove.

RESULTS: In total, 112 R-RCTs were identified, of which 68 (60.7%) used a clinical patient registry. Interventions in the 112 trials included drugs (n=37; 33.0%), surgical/medical device related (n=33; 29.5%), screening (n=7; 6.3%), vaccines (n=6; 5.4%), and others (n=29; 25.9%; e.g., advertising, outreach, complex healthcare, patient education, oxygen therapy). Of the 37 trials with drug interventions, all used approved drugs, and one was industry initiated. Most trials were conducted in the Nordic countries (n=69; 61.6%), Canada (n=11; 9.8%), or the USA (n=8; 7.1%). Twelve trials (10.7%) were conducted in more than one country, of which five (4.5%) only used an R-RCT design in the Nordic sites. Four trials (3.6%) did not report which registries were used. None of the trials with drug interventions were identified for use as primary evidence for regulatory/reimbursement decisions.

CONCLUSIONS: So far, R-RCTs have only been conducted with approved drugs. Most were conducted in the Nordic countries, and multicountry trials were rare. R-RCTs are underutilized by industry and early drug development; this motivates further exploration.