Craig McLendon

Since the outbreak of COVID-19, there has been disruption to clinical trial management including missed patient visits and assessments, laboratory tests not being performed and submitted, and lapses in study drug administration. Investigative site closures and patient non-attendance will raise the issue of best practice for restarting studies and sample sizes may need to be reviewed with statistical guidance as possible gaps occur.  

	All of these factors pose risks to the integrity of trial data and it is expected that these challenges will impact clinical trials for at least four to five months. Whenever feasible, sponsors are both ethically and economically obliged to continue ongoing trials, and ensuring that decisions around protocol revisions and other trial adjustments are properly captured and documented is essential to the scientific integrity of the trial.

	What are the regulatory authorities advising?

	Competent authorities are urging sponsors to utilize data monitoring committees (DMCs), if not already part of the study design, and regulatory agencies are issuing new and updated guidance as the situation evolves. The European Medicines Agency (EMA) has recommended that trials without a DMC should establish one now to help monitor subject safety and trial disruptions caused by the pandemic.

	EMA has also suggested that ongoing studies consider undertaking an interim analysis, examining the validity of the trial by the DMC. The DMC should examine trial outcomes that have the potential to be impacted by the presence of different trial populations: 

		Some patients completed the trial before the start of the pandemic. 

		Some will have been ongoing during the pandemic and have been impacted by the associated measures. 

		Some will be enrolled as normal activities resume after the end of the pandemic. 

	These timings and measures will be country- and region-specific. Measures taken in relation to the COVID-19 pandemic may interfere with study treatments. An interim analysis would enable the DMC to identify and address such concerns. For instance, assessing the impact of missing primary endpoint data, treatment gaps and discontinuity, and serious adverse events related to hospitalization due to infection and missed imaging assessments. EMA has also recommended that existing DMCs consider updating their charters in order to broaden their scope and enhance their ability to effectively guide and steer the trial during these unprecedented events. FDA guidance on the conduct of clinical trials of medical products during COVID-19

 also indicated that since a primary responsibility of the DMC in any trial is to assess patient safety, then they are well-placed to assess the impact of modifications required due COVID-19 conditions. 

	A properly constructed and well-organized DMC is one of the best ways to ensure patient safety, data integrity, and appropriate analysis and interpretation of a clinical trial’s data. In addition, DMCs can support objective decision-making regarding the study, while minimizing potential bias. The DMC charters are focused on preserving the integrity of the trial, and clearly record and outline necessary protocol revisions and changes to the planned analysis that may be necessary, steps which FDA recommended in its guidance outline.

 They will also be vital in continuing to monitor patient safety in ongoing studies. 

	While it is important to assess each trial for suitability, a DMC could also potentially make recommendations on patients’ eligibility to remain in the study after missed visits or dosages, interactions from other medicines taken during the course of the trial, sample size adjustments, and other induced potential biases. 

	Depending on the therapeutic area targeted in the study, there may be a need for new table listings that would support DMC decision-making. The DMC has the ability to look across various subsets of the trial and different countries and regions to evaluate any differences in the treatment groups based on exposure and infection rates. 

	Looking ahead, having a DMC could also be instrumental in helping study teams navigate considerations in restarting trials as the pandemic recedes, by reviewing possible adjustments in sample size and protocol revisions. Many of the changes would have to be approved by local ethics, institutional review boards (IRBs), and regulatory agencies, but the input and documentation from DMCs could help pave the way for pragmatic approaches and solutions adapted to the circumstances.

	Furthermore, DMCs and associated adjudication committees could be important in evaluating cardiac events, as many COVID-19 patients are presenting with elevated cardiac markers and ECG tracings consistent with myocardial infarction changes that could confound the data.

 DMCs could also help in making sure that trial endpoint definitions were updated to include clear and stringent language when determining whether hospitalizations or other endpoint events were COVID-related or not. 

	By creating or revising a charter with good, well thought out, and tight definitions and applying these to source data from the site, the event adjudication committee (EAC) can make decisions that the trial team can be confident in and would support the final findings. 

	If a sponsor is unfamiliar with DMCs, it is advisable to seek advice on setting up and managing this activity effectively. This support can extend to access to proven processes in charter development and connectivity into an already established global network of recognized thought leaders and physicians to serve on these committees. All of this can save valuable time during this evolving and dynamic period. Outsourcing the DMC can also avoid perceived bias in analysis and interpretation of the trial results, which is important in maintaining data integrity.  

	The use of technology is another consideration. There are electronic adjudication systems on the market that have real-time status reporting, and this enables the delivery of a streamlined, efficient, and transparent process for accurate event collection, with high quality results in a timely fashion.

is Senior Director, Adjudication & Data Monitoring Management, ICON Clinical Research Services

	1. EMA Guidance Document: “Points to consider on implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials” EMA/158330/2020, March 25, 2020, page 3, first paragraph

	2. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic Guidance for Industry, Investigators, and Institutional Review Boards, March 18, 2020, 

https://www.fda.gov/drugs/coronavirus-covid-19-drugs/clinical-trial-conduct-during-covid-19-pandemic

	3. Xiaowen Wang, MD, and Deepak L. Bhatt MD, MPH. COVID-19: An Unintended Force for Medical Revolution. 

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