Competition for recruitment in SARS-CoV-2 Trials in the United States: a longitudinal cohort analysis.

OBJECTIVE: Competition among trials for patient enrollment can impede recruitment. We hypothesized that this occurred early in the COVID-19 pandemic, when an unprecedented number of clinical trials were launched. We performed a simple and multivariable regression analysis evaluating the relationship between the proportion of SARS-CoV-2 investigational trial sites within each USA state with unsuccessful patient-participant recruitment and: (i) the proportion of cases required to reach state recruitment goals; (ii) state population based on data from the US Census; and, (iii) number of trial sites per state. RESULTS: Our study included 151 clinical trials. The proportion of trials with successful recruitment was 72.19% (109 of 151 trials). We did not find a significant relationship between unsuccessful patient-participant recruitment, state recruitment goals, state population or the number of trial sites per state in both our simple and multivariable regression analyses. Our results do not suggest that early in the COVID-19 pandemic, competition for patient-participants impeded successful recruitment in SARS-CoV-2 trials. This may reflect the unique circumstances of the first few months of the pandemic in the United States, in which the number and location of SARS-CoV-2 cases was sufficient to meet trial recruitment requirements, despite the large number of trials launched.

How informative were early SARS-CoV-2 treatment and prevention trials? a longitudinal cohort analysis of trials registered on ClinicalTrials.gov.

BACKGROUND: Early in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic. METHODS: Based on prespecified eligibility criteria, we created a cohort of Phase 1/2, Phase 2, Phase 2/3 and Phase 3 SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We excluded trials evaluating behavioural interventions and natural products, which are not regulated by the U.S. Food and Drug Administration (FDA). We evaluated trials on 3 criteria of informativeness: potential redundancy (comparing trial phase, type, patient-participant characteristics, treatment regimen, comparator arms and primary outcome), trials design (according to the recommendations set-out in the May 2020 FDA guidance document on SARS-CoV-2 treatment and prevention trials) and feasibility of patient-participant recruitment (based on timeliness and success of recruitment). RESULTS: We included all 500 eligible trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.9% (95% Confidence Interval 23.7-36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%. CONCLUSIONS: Less than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic.

Probability of Success and Timelines for the Development of Vaccines for Emerging and Reemerged Viral Infectious Diseases.

BACKGROUND: Anticipated success rates and timelines for COVID-19 vaccine development vary. Recent experience with developing and testing viral vaccine candidates can inform expectations regarding the development of safe and effective vaccines. OBJECTIVE: To estimate timelines and probabilities of success for recent vaccine candidates. DESIGN: ClinicalTrials.gov was searched to identify trials testing viral vaccines that had not advanced to phase 2 before 2005, and the progress of each vaccine from phase 1 through to U.S. Food and Drug Administration (FDA) licensure was tracked. Trial characteristics were double-coded. (Registration: Open Science Framework [https://osf.io/dmuzx/]). SETTING: Trials launched between January 2005 and March 2020. PARTICIPANTS: Preventive viral vaccine candidates for 23 emerging or reemerged viral infectious diseases. MEASUREMENTS: The primary end point was the probability of vaccines advancing from launch of phase 2 to FDA licensure within 10 years. RESULTS: In total, 606 clinical trials forming 220 distinct development trajectories (267 343 enrolled participants) were identified. The probability of vaccines progressing from phase 2 to licensure within 10 years was 10.0% (95% CI, 2.6% to 16.9%), with most approvals representing H1N1 or H5N1 vaccines. The average timeline from phase 2 to approval was 4.4 years (range, 6.4 weeks to 13.9 years). The probabilities of advancing from phase 1 to 2, phase 2 to 3, and phase 3 to licensure within the total available follow-up time were 38.2% (CI, 30.7% to 45.0%), 38.3% (CI, 23.1% to 50.5%), and 61.1% (CI, 3.7% to 84.3%), respectively. LIMITATIONS: The study did not account for preclinical development and relied primarily on ClinicalTrials.gov and FDA resources. Success probabilities do not capture the varied reasons why vaccines fail to advance to regulatory approval. CONCLUSION: Success probabilities and timelines varied widely across different vaccine types and diseases. If a SARS-CoV-2 vaccine is licensed within 18 months of the start of the pandemic, it will mark an unprecedented achievement for noninfluenza viral vaccine development. PRIMARY FUNDING SOURCE: McGill Interdisciplinary Initiative in Infection and Immunity (MI4) Emergency COVID-19 Research Funding program.