To the Editor
The demands of social distancing during the novel coronavirus 2019 (COVID-19) pandemic have upended standard healthcare workflows through travel limitations, site closures, and interruptions of medication supply chains (U.S. Food & Drug Administration, 2020). These changes have impacted the conduct of highly choreographed clinical trials, which require timely visits and assessments to maintain scientific validity in evaluating the safety and efficacy of new medications (European Medicines Agency, 2020; U.S. Food & Drug Administration, 2020).
In response to the logistic and economic uncertainties of the current times, some clinical trials have been suspended or will not begin as originally planned because of the global pandemic (Ledford, 2020). We aimed to investigate the impact of the COVID-19 outbreak on dermatology-related clinical trials by examining the publicly available clinical trials data.
Methods
We queried ClinicalTrials.gov, a global repository of privately and publicly funded clinical studies, to identify the clinical trials related to dermatologic conditions using the search terms dermatologic diseases, skin diseases, and skin disorders from 1 April 2019 to 31 May 2020. For interventional trials listed as withdrawn, suspended, or terminated, the date the trial listing was last updated was used as a proxy for when the trial’s status was changed. We excluded trials that were not related to dermatology, listed as completed, had not posted updates, or had not been verified by ClinicalTrials.gov within the past 2 years. We also excluded trials that had been withdrawn, terminated, or suspended before 1 March 2019.
Information on the trial’s name, related condition(s), estimated enrollment, last update, and current status (suspended, withdrawn, terminated, active not recruiting, recruiting, and enrolling by invitation) were collected. Active, not recruiting trials include ongoing studies with participants who are receiving an intervention or being examined, but potential participants are not currently being recruited or enrolled. For any trials suspended in March, April, or May 2020, we reviewed any listed reasons for trial closures and documented if this reason was specifically attributed to COVID-19.
Although we were unable to ascertain the total number of ongoing dermatology trials in 2019, we performed a sensitivity analysis using chi-square analysis to determine the minimum number of ongoing trials required in 2019 to ensure that the change in the proportion of trial suspensions, terminations, and withdrawals in March–May 2019 was different than the proportion of trial suspensions, terminations, and withdrawals in March–May 2020 (defined as P < 0.05).
Results
We identified 1,010 active (not recruiting), recruiting, and enrolling by invitation trials for dermatologic conditions, with an estimated enrollment of 284,881 patients. In total, 293 (29%) of trials were listed as active (not recruiting) with an enrollment of 121,310 patients. In addition, 92 of 1,010 trials (9.1% of the ongoing dermatology-related clinical trials) had been suspended, withdrawn, or terminated. Over half of the suspensions, terminations, and withdrawals occurred in March, April, and May of 2020 (n = 57 of 92, 62%; Figure 1 ), with an estimated enrollment of 7,141 patients (7,141 of 292,022; 2.4% of all the patients enrolled in the dermatology trials). There were 17, 21, and 7 excess dermatology trial suspensions, terminations, and withdrawals that occurred in March, April, and May of 2020, respectively, as compared with March, April, and May of 2019 (Table 1 ).
Figure 1.
Trials for dermatologic conditions that were suspended, withdrawn, or terminated between 1 April 2019 and 31 May 2020. Suspended trials: the study has stopped early but may start again. Terminated trials: the study has stopped early and will not start again. Participants are no longer being examined or treated. Withdrawn trials: the study stopped early, before enrolling its first participant.
Table 1.
Excess Trial Suspensions, Withdrawals, and Terminations in March–May 2019 Relative to Suspensions, Withdrawals, and Terminations in March–May 2020
| March | April | May | Total | |
|---|---|---|---|---|
| Suspensions, withdrawals, and terminations 2019, number of trials | number of patients | 2 | 90 | 7 | 0 | 3 | 450 | 12 | 540 |
| Suspensions, withdrawals, and terminations 2020, number of trials | number of patients | 19 | 1,545 | 28 | 4,680 | 10 | 916 | 57 | 7,839 |
| Excess suspensions, withdrawals, and terminations, number of trials | number of patients | 17 | 1,455 | 21 | 4,680 | 7 | 466 | 45 | 6,601 |
Among the affected trials, 5,607 patients (79%) were enrolled in 32 trials (56%) listed as suspended specifically because of the COVID-19 pandemic. The most common COVID-19 trial suspensions were for atopic dermatitis (n = 7), psoriasis (n = 7), and hidradenitis suppurativa (n = 5). Most (63%, 20 of 32) of the COVID-19 affected trials were phase 2 and 3 trials. A total of 44% (14 of 32) of the COVID-19–affected trials had an estimated enrollment of more than 100 patients.
Our sensitivity analysis revealed that the proportion of trial suspensions, withdrawals, and terminations in March, April, and May of 2020 (N = 57) was significantly more than the proportion of trial suspensions, withdrawals, and terminations occurring in March, April, and May of 2019 (N = 12, P < 0.05), assuming that the number of active, not recruiting, recruiting, and enrolling trials (e.g., ongoing trials) in 2019 did not fall below 398 (61% less than the number of ongoing trials in 2020).
Discussion
We observed an increase in the suspension, withdrawal, and termination of clinical trials for dermatologic conditions during the initial months of the COVID-19 pandemic, many of which were attributed specifically to the coronavirus outbreak. These changes have substantial implications on the currently enrolled patients, as clinical trials provide patients with skin disorder treatments that can significantly improve their clinical outcomes and QOL (Torre and Shahriari, 2017).
The reverberations of clinical trial closures will not only affect patients during the pandemic but will also extend well beyond this timeframe. Halting clinical trials, which serve as the basis for regulatory approval of new treatments (U.S. Food & Drug Administration, 2019), can create considerable delays in drug development.
Barriers to the treatment and timely assessment of trial enrollees may also threaten the integrity of clinical trials data and limit their interpretation (McDermott and Newman, 2020). Furthermore, the financial impact of trial closures and reassignment of study personnel may alter the available infrastructure for future trials. Additional studies are necessary to investigate the impact of trial closures on both trial integrity and infrastructure.
The results of our study must be interpreted within the context of our study design. Our sensitivity analysis was simple and unadjusted. Although ClinicalTrials.gov requires responsible parties to update their records within 30 days of a change to an individual site and overall recruitment status (ClinicalTrials.gov, 2020), it is possible that some sponsors do not change the status of their studies in a timely manner (Tse et. al., 2018). In addition, a multisite trial’s overall recruitment status may have remained unchanged if only a subset of its sites experienced closures. Our study may therefore underestimate the number of trials affected.
Although our data show a spike in trial suspensions, withdrawals, and terminations over the past 3 months, longitudinal data are required to determine the complete scope of the impact of COVID-19 on the dermatology trials. Until then, the development and dissemination of best practices to maintain patient safety and trial integrity are essential in maintaining the progress of therapeutic development within dermatology.
Data availability statement
Datasets related to this article can be found at https://clinicaltrials.gov/, an online data repository hosted at ClinicalTrials.gov (Home - ClinicalTrials.gov. Clinicaltrials.gov. https://clinicaltrials.gov/. Published 2020. Accessed May 15, 2020).
ORCIDs
Sheena Desai: http://orcid.org/0000-0001-6590-0809
Priya Manjaly: https://orcid.org/0000-0001-8162-6256
Karen J. Lee: http://orcid.org/0000-0003-4255-8355
Sara J. Li: http://orcid.org/0000-0002-0964-5935
Cyriac Manjaly: http://orcid.org/0000-0001-7076-2463
Arash Mostaghimi: http://orcid.org/0000-0002-6084-5617
Conflict of Interest
The authors state no conflicts of interest.
Acknowledgments
Institutional review board approval was not required for this study as all the data were publicly available.
Author Contributions
Conceptualization: AM; Data Curation: SD, CM; Formal Analysis: SD, PM; Investigation: SD; Methodology: AM, SD; Project Administration: AM; Resources: CM; Supervision: AM; Visualization: AM; Writing - Original Draft Preparation: SD; Writing - Review and Editing: SD, PM, KJL, SJL, CM, AM.
Accepted manuscript published online 14 August 2020; corrected proof published online 24 September 2020
References
- ClinicalTrials.gov How to edit your study record. https://clinicaltrials.gov/ct2/manage-recs/how-edit 2020 (accessed 5 June 2020)
- European Medicines Agency Guidance on the management of clinical trials during the COVID-19 (coronavirus) pandemic, version 3. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf 2020 (accessed 6 May 2020)
- Ledford H. Coronavirus shuts down trials of drugs for multiple other diseases. Nature News. https://www.nature.com/articles/d41586-020-00889-6 2020 (accessed 27 April 2020) [DOI] [PubMed]
- McDermott M.M., Newman A.B. Preserving clinical trial integrity during the coronavirus pandemic. JAMA. 2020;323:2135–2136. doi: 10.1001/jama.2020.4689. [DOI] [PubMed] [Google Scholar]
- Torre K., Shahriari M. Clinical trials in dermatology. Int J Womens Dermatol. 2017;3:180–183. doi: 10.1016/j.ijwd.2016.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tse T., Fain K.M., Zarin D.A. How to avoid common problems when using ClinicalTrials.gov in research: 10 issues to consider. BMJ. 2018;361:k1452. doi: 10.1136/bmj.k1452. [DOI] [PMC free article] [PubMed] [Google Scholar]
- U.S. Food and Drug Administration Coronavirus (COVID-19) update: FDA issues guidance for conducting clinical trials. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-guidance-conducting-clinical-trials 2020 (accessed 6 May 2020)
- U.S. Food & Drug Administration Development & approval process: drugs. https://www.fda.gov/drugs/development-approval-process-drugs 2019 (accessed 4 May 2020)
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Datasets related to this article can be found at https://clinicaltrials.gov/, an online data repository hosted at ClinicalTrials.gov (Home - ClinicalTrials.gov. Clinicaltrials.gov. https://clinicaltrials.gov/. Published 2020. Accessed May 15, 2020).