1.0 INTRODUCTION
The COVID‑19 pandemic has added an unprecedented set of challenges to the conduct of clinical trials including quarantines, travel limitations, site closures, and interruptions in the supply chain of investigational products. In acknowledgement of these challenges, the Food and Drug Administration (FDA) recognizes that protocol modifications may be required and protocol deviations may be unavoidable. FDA initially issued FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID‑19 Public Health Emergency – Guidance for Industry, Investigators, and Institutional Review Boards on 18 March 20 with subsequent updates in late March and mid-April. This guidance outlines considerations to assist sponsors in the conduct of clinical trials during the COVID‑19 pandemic and offers recommendations to manage protocol amendments and deviations and document changes to the conduct of the trial to ensure patient safety, compliance with GCP, and minimize impact on trial integrity.
2.0 CONSIDERATIONS FOR ONGOING CLINICAL TRIALS
During the COVID‑19 pandemic, it is important for sponsors to consider the specific circumstances of each clinical study, including the nature of the investigational product and the disease under study, the ability to conduct appropriate safety monitoring, and possible impacts on the investigational impact of the study. It is critical that trial participants are kept informed of all changes and steps are taken to appropriately document changes through protocol amendments and in the clinical study report.
2.1 Trial Recruitment and Participation: Halt or Continue?
The FDA recognizes that the current crisis is going to disrupt ongoing treatment of trial participants, recruitment of new participants, and participant monitoring. When deciding to continue, modify, or halt a trial, sponsors are encouraged to carefully evaluate the impact on participants and clearly communicate any changes to trial participants. When making this decision, sponsors must consider the risk and benefits to study participants during under the circumstances of the pandemic, the ability to collect meaningful and complete data, the feasibility of any modifications including appropriate documentation and reporting to regulatory authorities, and availability of alternative approaches to adequately monitor subject safety. The safety of clinical trial participants much be central to any decisions regarding trial conduct. At CATO SMS, we can help sponsors navigate these decisions and we believe that many studies can continue, safely and ethically.
2.2 Subjects cannot travel to study site: Bringing the Trial to the Participant.
Regardless of the impact of COVID‑19 on a clinical trial, the safety of trial participants paramount. Due to travel restrictions or risk of COVID‑19 exposure, subjects that are enrolled in trials may not be able to travel to sites for medical assessments. The FDA guidance directs sponsors to consider alternative means to remotely conduct safety evaluations. Maintaining active communication with trial participants is essential and must continue. Virtual visits and decentralized trial activities will demonstrate remarkable value during the pandemic. When considering alternative approaches to safety assessments, sponsors must consider the feasibility and availability of alternative means to effectively conduct appropriate safety assessments. A decentralized research platform such as offered by THREAD (www.THREADresearch.com) can allow trial activities normally conducted in the clinic to move to a remote setting.
THREAD is a leader in providing decentralized study technology platform and services including Virtual Visits. Virtual Visits allow investigators to observe participants, instruct them to complete assessments, and record their observations directly into a Data Capture/eSource form. The technology required to accomplish greater participant convenience is provided securely, through one unified platform.
2.3 Maintaining access to Investigational Product and Trial Supplies when Access to Study Site is Limited
It is imperative that sponsors conduct ongoing risk evaluations when deciding to continue treatment with investigational product. In many cases, the benefits of treatment outweigh the risks presented by the COVID‑19 crisis. Sponsors should consider whether home delivery of investigational product and other trial supplies is feasible for each study. This decision should include acknowledgement of requirements for shipment and storage of investigational product in addition to the existing regulatory requirements for accountability and distribution of investigational product. Additionally, appropriate documentation of all changes is required.
The FDA recognizes that in some circumstances, including supply chain interruptions or the inability to ensure the safe use of investigational product, it may be necessary to discontinue use of investigational product. In these cases, the sponsor should consider amending the protocol to limit investigational product use to those participants with apparent benefit and discontinue investigational product use to other participants. If a participant discontinues use of investigational product, it is essential that subject communication and appropriate safety monitoring is maintained after discontinuation.
2.4 Site Management and Modifications to Monitoring
The FDA acknowledges that on‑site monitoring visits may not be possible during the current crisis. Sponsors should work to find alternative ways to maintain trial subject safety and ensure trial data quality and integrity such as enhanced central monitoring, telephone contact with sites, or remote monitoring of individual trial participants. While FDA recognizes that delays in on‑site monitoring may result in delayed identification of GCP non‑compliance, it is critical for sponsors and monitors to carefully document all limited access or delayed monitoring situations. Changes in protocol conduct necessary to immediately assure participant safety can be immediately implemented with subsequent review by the IRB and notification to FDA.
In these unprecedented circumstances it is essential that sponsors work to assure the safety of all trial participants and maintain standards of good clinical practice, while minimizing risks to trial integrity. At CATO SMS, we have the technology, experience, and expertise to support and navigate sponsors through the challenges presented by the current global pandemic.
2.5 Impacts to the Study Report
It is expected that all sponsors, investigators, and IRBs/IECs make robust efforts to maintain the safety of trial participants and integrity of trial data and these measures should be clearly documented in the clinical study report. For all trials impacted by the COVID‑19 pandemic, sponsors should describe in the clinical study report (or in a separate study‑specific document) the following information:
- A description of all contingency measures implemented to manage trial conduct and disruptions as a result of pandemic‑related control measures.
- A listing of all participants affected by COVID‑19 related disruption by subject identifier and study site, and a description of how the subject’s participation was impacted
- Analyses and discussions that address the impact of implemented contingency measures on the safety and efficacy results reported for the study
In addition to the above, all changes to a trial as a result of the COVID‑19 pandemic must be clearly documented in the clinical study report. These changes include modified visit schedules, missed visits, or subject discontinuations. FDA acknowledges that these changes will likely lead to missing information. It is important for sponsors to capture specific details in the case report form to explain the reason for the missing information, including the relationship to COVID‑19. If it is not possible for sponsors to capture this information in the case report form, FDA recommends that sponsors develop processes to systematically capture this information across sites in a way that allows appropriate analysis when the data are submitted to FDA. Additionally, FDA suggests sponsors may also develop methods to capture site‑level status, site‑level or vendor‑level protocol deviations, and process deviations.