The COVID-19 pandemic levied significant challenges for the effective delivery of clinical care and research operations. However, to date, the pandemic’s impact on cardiovascular trials has been primarily characterized in the context of single-trial experiences. We leveraged the unique, multisponsor membership of the Heart Failure Collaboratory (HFC) to assess recruitment metrics across active heart failure trials during the pandemic, including enrollment and visit information, and COVID-19–related adverse events.
The HFC is a multistakeholder, public-private partnership with the U.S. Food and Drug Administration, academic investigators, and industry representatives. Clinical trial sponsors participating in the HFC contributed aggregate data from active trials from February 2019 to May 2021.
For the purposes of this analysis, we compared trial metrics between pre-pandemic (September 2019 to February 2020), early pandemic (March to May 2020), and mid-pandemic periods (June to November 2020). Outcomes assessed included: 1) monthly enrollment rates; and 2) study visit completion rates. Monthly enrollment rate was defined as the percentage of total trial enrollment (or total planned enrollment for ongoing trials) recruited each month. Study visits were categorized as conducted in-person, converted to virtual formats, or missed. Rates were summarized as monthly percentages; Kruskal-Wallis and chi-square tests were used to assess differences between groups, and a value of P < 0.05 was considered significant. This analysis did not contain any participant identifiers or participant-level data and was exempt from ethics approval.
Data from 10 trials (4 drug, 6 device), including 19,645 participants across 1,927 sites on 5 continents, were pooled across 8 participating sponsors; 48% of participants were enrolled from February 2019 to May 2021 and previously enrolled participants were followed during this period. Three drug trials allowed enrollment/randomization during hospitalization. Three trials (2 device, 1 drug) paused recruitment due to the pandemic between March and June 2020 (Figure 1 ).
Figure 1.
Recruitment Timeline, Enrollment Rates, and Visit Information Among Participating Trials
In the pre-pandemic period, average monthly randomizations comprised 4.3% of total or planned enrollment. During the early pandemic period, average monthly enrollment declined to 1.1%, representing a 75.5% relative decline from pre-pandemic levels (P < 0.01). The monthly enrollment rate was 2.0%, 0.6%, and 0.6% in March, April, and May 2020, respectively (Figure 1). In June to November 2020, the monthly enrollment rate increased to 2.3%.
There were 92,856 planned visits over the study period; 18,735 (20.2%) were converted to virtual formats and 7,042 (7.6%) were missed. Virtual study visits rose from 11.4% in the pre-pandemic period to 51.7% during the early pandemic period, representing a 353.5% relative increase (P < 0.01). From June to November 2020, the percentage of virtual visits was 25.4%, representing a 14.0% absolute increase from pre-pandemic levels and a 26.3% absolute decrease from early pandemic levels. Missed visits rose modestly, from 6.0% (pre-pandemic) to 7.8% during the early pandemic (8.4%, 7.6%, and 7.5% in March, April, and May 2020, respectively). By May 2021, there were 581 COVID-19 cases, 249 hospitalizations, and 115 deaths related to COVID-19 reported across contributing trials.
We found significant declines in trial enrollment during the early pandemic. Reasons for such declines are likely multifactorial, including: 1) reallocation of resources away from research programs; 2) logistical challenges in administering screening protocols; 3) inability to have on-site sponsor staff (eg, for interventional device trials); and 4) the redeployment of clinical research staff to other care functions as necessitated by the pandemic, among others. Furthermore, reports demonstrated declines in hospitalizations for acute cardiovascular conditions,1 which preferentially may have impacted trials enrolling patients during or early after hospitalization.
We observed a rebound in enrollment just after the early pandemic period, and despite a sharp fall in enrollment rates during the early pandemic, we found that scheduled visits were quickly adapted to virtual formats with only modest rises in missed visits in the early pandemic period. These findings indicate the potential for adaptation measures aimed at sustaining trial operations. Consortia-based efforts offering a standardized approach to “disaster-proof” trial protocols may allow for better prospective contingency planning and more resilient clinical research. Such efforts may include standardized approaches to drug supply and shipment, safety event monitoring, flexible visit modalities, and prespecified analytical approaches to handle unexpected, postrandomization events.2
This study has several limitations. Demographic, regional, and site data were not systematically reported, precluding our ability to assess whether enrollment declines were particularly evident among specific demographic cohorts. Differences in recruitment capability, infrastructure, and access to virtual platforms may have varied across region, country, and socioeconomic status. This study also did not assess delays in trial initiations or missed deadlines due to the pandemic. Data on event rates and treatment effects were not available in the pre-pandemic and pandemic periods. Finally, COVID-19 reporting varied by trial protocol amendments and local standards; criteria for a COVID-19–related adverse event were not standardized. In a large, multi-sponsor, global experience of active HF trials, recruitment fell sharply early during the early pandemic, rebounding after May 2020. Study visits were readily converted to virtual platforms, suggesting rapid adaptation among trial sponsors and sites. Identifying optimal strategies to improve clinical trial resiliency is a central goal across major stakeholders.
Footnotes
The authors thank Dr Andrew Farb, Dr Norman Stockbridge, Dr Ellis Unger, and Dr Bram Zuckerman from the U.S. Food and Drug Administration for their support of the Heart Failure Collaboratory and this initiative. The authors further thank Abiomed, Impulse Dynamics, Dr Roberta Bogaev, and Ms Angela Stagg for their contributions. Dr Bhatt was supported by National Heart, Lung, and Blood Institute T32 postdoctoral training grant T32HL007604. Dr Bhatt has received consulting fees from Sanofi Pasteur. Dr Vaduganathan has received research grant support from or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; has held speaker engagements with AstraZeneca, Novartis, and Roche Diagnostics; and served on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Vardeny has received institutional research support for DELIVER from AstraZeneca; and received institutional research support from Bayer. Dr Divanji is an employee of Cytokinetics, Inc. Dr Komtebedde is an employee of Corvia Medical, Inc. Dr Lefkowitz is an employee of Novartis. Drs Nkulikiyinka and Roessig are employees of Bayer AG. Dr Petersson is an employee of AstraZeneca. Dr Schaber is an employee of Medtronic, Inc. Dr O’Connor has received grant or research support from Merck; and consulting fees from Merck, Bayer, and Abiomed. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has served as a consultant for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Akros. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Barry Greenberg, MD, served as Guest Editor-in-Chief for this paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
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