Please note that this is an early draft. There will be daily updates of the data contained within this paper, as well as the analysis and interpretation.

Introduction

In late 2019 and early 2020, an outbreak of a novel coronavirus named “SARS-CoV-2” causing a disease named “Coronavirus Disease 2019” (Covid-19)1 became a global pandemic that affected lives, families, industries and entire nations. Medical research on humans in clinical trials was also affected, with the FDA, the EMA and individual institutions publishing guidance regarding ongoing clinical trials that recommend, in some cases, that ongoing clinical trials be suspended, terminated or withdrawn due to Covid-19.1,2

Termination, suspension or withdrawal of clinical trials affects many different stakeholders in the enterprise of human research. Clinical trials stopping due to Covid-19 impacts the patients who were enrolled, as they may not receive the treatment they had anticipated, and their expectations regarding their contribution to new medical knowledge may also not be met. While many clinical trials were suspended with the intention of restarting after the Covid-19 pandemic, the prospect of starting again is far from certain for any clinical trial that has stopped, and even in cases where a clinical trial resumes after the pandemic, there may be reduced statistical power, more funding needed, or changes to the protocol to accommodate for the interruption. Clinical trials that were stopped and do not start again may be unable to answer the questions they set out to answer, and even in cases where they do start again, it may take greater resources to make up for data that can no longer be included in analysis due to the interruption. The large volume of stopped clinical trials due to Covid-19 also affects research institutions, investigators, researchers and other staff who run such trials. The Covid-19 pandemic has also caused a setback for entire programmes of human research, possibly delaying the advent of new drugs, evidence of drugs’ efficacy in new indications or combinations, or informative negative results.

There are several publications highlighting the extensive closures of clinical trials that have occurred due to Covid-19 policies, however the extent to which this has affected the human research enterprise is unclear.3–6 The following represents an attempt to quantify the number of clinical trials that have been terminated, suspended or withdrawn due to Covid-19 and their impact on different stakeholders in the project of clinical research on humans. We will capture the cohort of trials that stopped during the Covid-19 pandemic, identify ones that cited Covid-19 as the reason for stopping, and compare these against a comparator taken from the same timeframe, two years earlier, from which we will also estimate the baseline rate at which clinical trials that are terminated, suspended or withdrawn are re-started within 1 year, under normal circumstances. We will use actual and anticipated enrollment to quantify the impact on patients, number of trials stopped to estimate the impact on researchers and their institutions, and the number of unique drugs in trials that stopped due to Covid-19 as a proxy for the extent of the impact on drug development of terminations, suspensions and withdrawals due to Covid-19.

Methods

The Covid-19 arm of this study includes all clinical trial registry entries from ClinicalTrials.gov whose overall status changed to “Terminated”, “Suspended” or “Withdrawn” (“stopped”) since 2019-12-01. To collect this sample, all clinical trial registry records were that were updated since 2019-12-01 were downloaded, and this database was updated daily from ClinicalTrials.gov. Clinical trials that changed status to “Terminated”, “Suspended” or “Withdrawn” after 2019-12-01 were included. Clinical trials that were already stopped before this date were not included. The “Why stopped” field for every trial was manually screened for whether it mentions Covid-19 explicitly, including terms such as “Covid-19”, “COVID19”, “Covid”, “NCoV-2019”, “Coronavirus”, “Corona virus”, “Corona”, “The current pandemic”, and variations on “Institution suspended all clinical research not deemed medically essential.” Other trial details were extracted from the downloaded ClinicalTrials.gov XML files, such as title, summary and detailed description, primary completion date, actual or anticipated enrollment, phase number, study type, patient allocation, intervention model, primary purpose, masking, indications, interventions and sponsors.

To provide a baseline for comparison and an estimate of the base rate at which clinical trials re-start after stopping, we captured a comparator cohort of matched length of clinical trial registry entries whose status changed to “Terminated”, “Suspended” or “Withdrawn” from two years earlier, to allow for a full year of followup time that is unaffected by Covid-19 policies for the entire comparator cohort.

All clinical trials in both cohorts were automatically coded for inclusion non-exclusively in four broad indication areas: oncology, neurologic, cardiovascular and pain by a search for the conjunction of the set of trials on ClinicalTrials.gov that match a search for that indication area and the NCT number of the trial in question.

The names of drugs and biologicals listed as interventions in trials that stopped due to Covid-19 were manually curated to remove placebos and “standard of care” arms that do not list a particular drug. Brand names were standardized to generic names where possible, and details of administration were removed (e.g. quantities, routes, schedules) to allow for easier counting of unique drugs and biologicals.

Analysis plan, code and data

The protocol for this project was registered before data collection.7 The data sets that this report is based on are available at https://covid19.bgcarlisle.com, and will be moved to the Open Science Foundation upon completion. The code for data collection, screening and extraction that was used in this project are freely available.8

Statistics

All statistical tests were two-sided, and we considered \(p<0.05\) to be significant. We used a z-test to calculate test statistics for proportions of trials in between samples. We regard any tests to be exploratory only, and we did not correct for multiple testing.

Results

Among the 2522 clinical trial registry entries on ClinicalTrials.gov that were suspended, terminated or withdrawn (“stopped”) between 2019-12-01 and 2020-05-05, 1099 (44%) were closed with a reported reason that explicitly mentioned Covid-19. (See Figure 1, Table 1 and Covid-19 arm per-trial data set.) There was a combined enrollment of 39,405 patients in trials stopped due to Covid-19 that reported actual patient enrollment, and a combined enrollment of 4,092,344 patients in trials stopped due to Covid-19 that reported anticipated patient enrollment.

Figure 1. Clinical trials that were suspended, terminated or withdrawn since 2019-12-01. Green indicates clinical trials with a 'why stopped' field that gives an explicitly stated reason relating to Covid-19. Grey indicates clinical trials with a 'why stopped field that did not explicitly relate to Covid-19.

Figure 1. Clinical trials that were suspended, terminated or withdrawn since 2019-12-01. Green indicates clinical trials with a ‘why stopped’ field that gives an explicitly stated reason relating to Covid-19. Grey indicates clinical trials with a ’why stopped field that did not explicitly relate to Covid-19.

Table 1. Sample characteristics for all clinical trials in the Covid-19 arm regardless of reason for stopping, trials stopped with an explicitly stated reason citing Covid-19, and the comparator arm of clinical trials
Trials stopped 2019-12-01 to 2020-05-05 (any reason) Trials stopped 2019-12-01 to 2020-05-05 (due to Covid-19) Trials stopped 2017-12-01 to 2018-05-05 (comparator arm)
Trials 2522 1099 1233
Actual enrollment 612,280 39,405 83,773
Anticipated enrollment 4,336,304 4,092,344 19,839
Status when stopped
Suspended 1273 (50%) 1070 (97%) 226 (18%)
Terminated 812 (32%) 20 (2%) 585 (47%)
Withdrawn 437 (17%) 9 (1%) 422 (34%)
Phase number
Phase 1 343 (14%) 163 (15%) 169 (14%)
Phase 1-2 119 (5%) 33 (3%) 59 (5%)
Phase 2 384 (15%) 151 (14%) 224 (18%)
Phase 2-3 37 (1%) 10 (1%) 16 (1%)
Phase 3 168 (7%) 85 (8%) 107 (9%)
Phase 4 181 (7%) 63 (6%) 81 (7%)
N/A 910 (36%) 417 (38%) 393 (32%)
(Left blank) 380 (15%) 177 (16%) 184 (15%)
Patient allocation
Randomized 1263 (50%) 589 (54%) 586 (53%)
Non-Randomized 246 (10%) 100 (9%) 95 (9%)
Not stated 1013 (40%) 410 (37%) 552 (50%)
Study type
Interventional 2142 (85%) 922 (84%) 1049 (85%)
Observational 349 (14%) 163 (15%) 166 (13%)
Observational (patient registry) 31 (1%) 14 (1%) 18 (1%)

The comparator arm included 1233 clinical trials. (See Figure 2, and Comparator arm per-trial data set) There was a combined enrollment of 83,773 patients in trials in the comparator arm that reported actual patient enrollment, and a combined enrollment of 19,839 patients in trials in the comparator arm that reported anticipated patient enrollment.

Figure 2. Clinical trials that were suspended, terminated or withdrawn in a cohort of matched length to the Covid-19 arm, starting 2017-12-01.

Figure 2. Clinical trials that were suspended, terminated or withdrawn in a cohort of matched length to the Covid-19 arm, starting 2017-12-01.

Among trials in the comparator arm, 116 (9.4%) were started again within 1 year of the date when they were first stopped.

Effects on different broad indication areas

Table 2. Number of clinical trial registries, stratified by broad indication area among trials stopped due to Covid-19 and trials from a baseline comparator
Indication area Trials stopped by Covid-19 Trials stopped in Comparator p-value
Cardiovascular 125 (11%) 177 (14%) 0.016
Neurologic 93 (8.5%) 77 (6.2%) 0.02
Oncology 308 (28%) 398 (32%) 0.013
Pain 57 (5.2%) 66 (5.4%) 0.43

Drugs and biologicals whose testing was impacted by clinical trials stopping due to Covid-19

Among the clinical trials that were stopped with a reason citing Covid-19, 504 trials were testing drugs or biologicals; the remainder were testing procedures, devices, behavioural interventions, laboratory analyses, diagnostic tests, etc. A total of 538 unique drugs or biologicals were captured in our sample of clinical trials. (See Drugs and biologics in stopped trials data set.)

Acknowledgements

I would like to gratefully acknowledge Peter Grabitz, Carole Federico and Delwen Franzen for insightful conversations that inspired and guided this work.

References

1. Drug Evaluation and Research, C. for. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency. U.S. Food and Drug Administration Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency. (Accessed: 4th May 2020)

2. Czarska-Thorley, D. Implications of coronavirus disease (COVID-19) on methodological aspects ongoing clinical trials. European Medicines Agency (2020). Available at: https://www.ema.europa.eu/en/implications-coronavirus-disease-covid-19-methodological-aspects-ongoing-clinical-trials. (Accessed: 30th April 2020)

3. Ledford, H. Coronavirus shuts down trials of drugs for multiple other diseases. Nature 580, 15–16 (2020).

4. Mahase, E. Covid-19: Cancer Research urges mass testing to enable care to continue during pandemic. BMJ 369, (2020).

5. Mullard, A. COVID-19 brings drug development to a halt. Nature Reviews Drug Discovery (2020). doi:10.1038/d41573-020-00069-1

6. Adams, Ben. IQVIA: 80% of our trial sites are ’inaccessible’ due to pandemic, eyes Q4 for turnaround. FierceBiotech Available at: https://www.fiercebiotech.com/cro/iqvia-80-our-trial-sites-are-inaccessible-due-to-pandemic-eyes-q4-for-turnaround. (Accessed: 4th May 2020)

7. Carlisle, B. G. Clinical trials that were terminated, suspended or withdrawn due to Covid-19. (2020). doi:10.17605/OSF.IO/PRAFD

8. Carlisle, B. G. Covid-19 Trial Tracker. Codeberg.org Available at: https://codeberg.org/bgcarlisle/Covid-19TrialTracker. (Accessed: 4th May 2020)