COVID-19 has had far-reaching social, economic and regulatory impacts. Nearly all companies (private and public, large and small) have had reason to more frequently convene their boards of directors to review and monitor COVID-19’s impact on the company. For life sciences companies conducting ongoing clinical trials, the necessity of additional engagement with the board of directors must be viewed through the lens of the recent Delaware Court of Chancery decision in re Clovis Oncology, Inc. Derivative Litigation (2019 WL 4850188 (Del. Ch. Oct. 1, 2019) (Clovis).
In October 2019, the Delaware Court of Chancery denied a motion to dismiss a stockholder derivative suit, applying the “duty to monitor” doctrine expanded early in 2019 by the Delaware Supreme Court. Clovis stockholders brought a Caremark claim (In re Caremark Int’l Inc. Deriv. Litig., 698 A.2d 959 (Del. Ch. 1996)) alleging that the board of directors ignored red flags in the testing of the company’s sole product in development. The clinical trials for the sole product failed to follow standard protocol, which would prevent the drug from gaining approval from the U.S. Food and Drug Administration (the FDA). Clovis allegedly made public statements about the success of trials that were inconsistent with the information the board of directors received (and information management would have had access to as part of the clinical trial). When Clovis withdrew the drug from FDA consideration, the stock price plummeted. The Delaware Court of Chancery interpreted prior precedent as requiring a higher level of board of directors oversight in industries where “externally imposed regulations govern its ‘mission critical operations’” (which would be the case for all life sciences companies engaged with the FDA during ongoing clinical trials).
As the COVID-19 pandemic continues, life sciences companies will continue to be impacted by clinical trial delays, interruptions and unforeseen issues relating to supply chain and manufacturing uncertainties. Directors of these life sciences companies should stay apprised of the FDA’s guidance for companies’ conduct of clinical trials during the COVID-19 pandemic, which continue to be updated as the pandemic and implications stemming therefrom continue to evolve. Below, we outline the existing FDA guidance on the conduct of clinical trials during the pendency of the COVID-19 pandemic to assist directors in staying informed of regulatory changes that impact life sciences companies they oversee.
The FDA initially issued guidance on the conduct of clinical trials during the COVID-19 pandemic on March 18, 2020, and has subsequently provided updates on March 27, 2020, April 16, 2020, and June 3, 2020 (the guidance and updates through the date of this Insight is referred to herein as the Guidance). In the Guidance, the FDA outlines a number of considerations for assuring the safety of clinical trial participants, maintaining compliance with good clinical practice and minimizing risks to clinical trial integrity and provides a Q&A appendix. The Guidance also acknowledges the fluidity of the continuing public health crisis and the case-by-case nature of COVID-19 impacts on clinical trials and their sponsors. The Guidance was immediately effective and implemented without a public comment period given the public health emergency resulting from the COVID-19 pandemic. A summary of the Guidance is as follows:
- Subject safety; informing subjects of changes. Safety of clinical trial participants is of paramount importance. Sponsors should consider each circumstance, focusing on the potential impact on the safety of clinical trial participants, and modify study conduct accordingly. Clinical trial participants should be kept informed of changes to the study and monitoring plans that could impact them.
- Continuing or discontinuing existing participants. Sponsors, in consultation with investigators and institutional review boards (IRBs), may determine that the protection of a participant’s safety, welfare and rights is best served by (i) continuing a study participant in the clinical trial or (ii) discontinuing the administration or use of the investigational product or even participation in the clinical trial. Factors to consider include the nature of the investigational product, the ability to conduct appropriate safety monitoring, the potential impact on the investigational product supply chain and the nature of the disease under study in the clinical trial.
- Altering safety assessments or increasing safety monitoring. Sponsors should evaluate whether alternative methods for safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) could be implemented when necessary and feasible, and whether these measures would be sufficient to assure the safety of clinical trial participants. Additionally, further safety monitoring may be needed in the case of clinical trial participants who no longer have access to the investigational product or clinical trial site.
- Switching to central or remote monitoring. If on-site monitoring is no longer possible under the circumstances, sponsors should consider central and remote monitoring options to maintain oversight of clinical trial sites.
- Altering administration of investigational products. If the study involves investigational products that are administered in health care facilities, the FDA recommends considering, in consultation with the applicable FDA review divisions, the possibility of alternative administration methods (e.g., home nursing or alternative sites by trained but non-study personnel). If investigational products may be self-administered during a site visit, alterative secure delivery methods may be possible.
- Changing efficacy endpoint collection. The FDA recommends consultation with the appropriate FDA review division regarding protocol amendments for the collection of efficacy endpoints, such as virtual assessments or delays in assessments. If efficacy assessments cannot be collected in particular situations, the specific COVID-19 limitation should be documented.
- Amending data management or statistical analysis plans. The FDA recommends consultation with the appropriate FDA review division (CDER, CBER, CDRH) if changes in the protocol will lead to amending data management and/or statistical analysis plans. Prior to database lock, sponsors should ensure that the statistical analysis plan addresses how protocol deviations related to COVID-19 will be handled for the pre-specified analyses.
- COVID-19 screenings. COVID-19 screening procedures that may be mandated by clinical trial sites do not need to be reported as protocol amendments, unless the sponsor is incorporating the data collected as part of a new research objective.
- Efficacy endpoints. As noted above, where efficacy endpoints cannot be collected, sponsors should document the reasons specifically (e.g., identifying the specific limitation imposed by COVID-19 leading to the inability to perform the protocol-specified assessment).
- Documenting missing data. The Guidance highlights the importance of capturing specific information in the case report form that explains missing data (e.g., from missed study visits or study discontinuations due to COVID-19).
- Other protocol deviations. Changes to the protocol or study plan to minimize or eliminate immediate hazards or to protect the life and well-being of research participants (e.g., to limit exposure to COVID-19) may be implemented without IRB approval or before filing an amendment to the IND or IDE, but are required to be reported later. The FDA encourages sponsors and investigators to work with their IRBs to develop procedures for prioritizing reporting of deviations that may impact participant safety.
- Take action if policies and procedures are not already in place. Sponsors, clinical investigators and IRBs should consider establishing and implementing policies and procedures to address the impact of COVID-19 on the informed consent process, study visits and procedures, data collection, study monitoring, adverse event reporting and changes in investigator(s), site staff and/or monitor(s) secondary to travel restrictions, quarantine measures or the COVID-19 illness itself.
- Clinical study reports. Clinical study reports (or other study-specific documents) should be updated to address: (i) contingency measures implemented to manage study conduct during disruption of the study as a result of COVID-19 control measures; (ii) a listing of all participants affected by the COVID-19 related study disruption by unique subject number identifier and by site, and a description of how the individual’s participation was altered; and (iii) analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., trial participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the study.
- The Guidance also includes an appendix with a number of Q&As that continue to be updated.
Directors should be vigilant in understanding the changing landscape relating to the conduct of clinical trials during the pendency of the COVID-19 pandemic and should ensure management has continued to conduct clinical trials in a manner consistent with the most up-to-date FDA guidance.