On Wednesday, March 18, the U.S. Food and Drug Administration published the guidance “Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic." The guidance aims to assist sponsors of clinical studies of medical products in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to data integrity, in spite of the challenges created by the novel coronavirus outbreak. FDA notes that clinical study disruptions may include site closures, quarantines, travel limitations, and supply chain issues. Critically, the guidance suggests greater agency flexibility for researchers and entities conducting clinical studies to alter protocols without first seeking institutional review board (IRB) approval, especially when those changes are necessary to protect participants’ health and safety. We analyzed many related issues in a client alert on March 16, and consider them again here in light of the new agency guidance.
Overall, the new FDA guidance shows increasing tolerance for protocol deviations and study changes in light of the new challenges created by the COVID-19 pandemic. The guidance provides a number of specific recommendations and describes certain accommodations by FDA, including the following:
- Changes for immediate hazard. In accordance with 21 CFR 56.108(a)(4) , 21 CFR 312.30(b)(2)(ii), and 21 CFR 812.35(a)(2), changes to the protocol or investigational plan to minimize or eliminate immediate hazards or to protect the life and well-being of research participants may be implemented without IRB/ethics committee (EC) approval, or filing an amendment to the applicable investigational new drug application (IND) or investigational device exemption (IDE). Such changes must be reported to FDA afterwards.
- Continued study conduct. Sponsors, investigators, and IRBs/ECs should consider whether study subjects’ safety, welfare, and rights are best served by continuing in the study, discontinuing use of investigational products, or withdrawing from the study altogether. This will likely be a fact-specific assessment, which should consider the nature of the investigational product, the nature of the disease being studied, the ability to conduct appropriate safety monitoring, and the potential impact on the investigational product supply chain.
- Site-imposed screening. COVID-19-related screening procedures mandated by study sites do not require a protocol amendment, unless the sponsor is incorporating the data collected as part of new research objective.
- Alternatives to in-person activities. Sponsors should consider alternative methods for in-person study visits, monitoring, safety assessments, and other in-person activities. Safety of subjects must be considered above all else, and sponsors should consider whether any proposed alternative methods (e.g., using phone or virtual visits, using alternative locations for assessments such as local labs) are sufficient to assure the safety of study subjects. For example, there may be instances where in-person visits are considered to be necessary to assess safety or the safe and appropriate use of the investigational product, in which case alternative methods may not be acceptable. Alternative processes should be consistent with the protocol to the extent possible.
- Other study changes. Sponsors may need to implement new or modified processes for a study, such as whether it is appropriate to delay certain study assessments, or – if the study cannot be properly conducted under the existing protocol or a reasonably revised protocol – whether to stop ongoing recruitment or withdraw study subjects. If subjects are withdrawn from the study, the sponsor should assess the need for wind-down from the investigational product and for additional safety monitoring (including using virtual or other alternative monitoring methods). Alternative processes should be consistent with the protocol to the extent possible.
- Providing investigational products. Some investigational products, such as those typically distributed for self-administration, may be able to be sent directly to study subjects’ residences or may be amenable to other secure delivery methods. For others, such as investigational products normally administered in a health care setting, sponsors are encouraged to consult the applicable FDA review division on plans for alternative administration. All accountability and other regulatory requirements remain applicable.
- Efficacy assessments and statistical analyses. Sponsors are encouraged to consult with the applicable FDA review division regarding protocol modifications related to efficacy data collection and analyses, and should document the reasons for any failures to obtain efficacy assessment data. In particular, sponsors should document the specific limitation imposed by COVID-19 leading to the inability to perform the protocol-specified assessment. Any protocol changes that impact data management or statistical analysis plans should be discussed with the applicable FDA review division. Sponsors should address how COVID-19-related protocol deviations will be handled for pre-specified analyses in the statistical analysis plan, prior to locking the database.
- Keeping subjects informed. As changes are made to the study, sponsors should keep subjects informed of changes to the study and monitoring plans that could impact them.
As changes to clinical trial protocols may lead to missing information, the guidance emphasizes that it “will be important to capture specific information in the case report form that explains the basis of the missing data.” FDA expects sponsors, investigators, and IRBs/ECs to take robust efforts to maintain the safety of subjects and the integrity of study data and, importantly, all such efforts should be documented.
Additionally, the guidance encourages sponsors to describe in the appropriate sections of the clinical study report or a separate study-specific document:
- Contingency measures implemented to manage study conduct
- A listing of all participants affected by the COVID-19 related study disruption by unique subject number identifier and by investigational site
- Analyses and corresponding discussions that address the impact of implemented contingency measures on the safety and efficacy results reported for the study
- For individual instances where efficacy endpoints are not collected, the reasons for failing to obtain the efficacy assessment in cases where efficacy endpoints are not collected
In efforts to prepare for clinical trial disruption, the guidance states that, for clinical trials where policies and procedures are not already in place, “[s]ponsors, clinical investigators, and IRBs should consider establishing and implementing policy and procedures, or revise existing policy and procedures, to describe approaches to be used to protect trial participants and manage study conduct during possible disruption of the study as a result of COVID-19 control measures at study sites.” When contemplating their approach, sponsors should take care to assess current regional and national policies related to the management and control of COVID-19, as well as policies that may be implemented in the future. For instance, use of an alternative location for study assessments may not be allowed in cities that implement “shelter-in-place” orders.
In a press release announcing the guidance, FDA Deputy Commissioner for Medical and Scientific Affairs Anand Shah, M.D. said that “FDA released this guidance to emphasize that at all times, patients’ safety should continue to be at the forefront of considerations.” Unlike normal agency guidance, which undergoes and a draft review and comment period before being finalized, this guidance is being implemented immediately without prior public comment because FDA said it “has determined that prior public participation for this guidance is not feasible or appropriate.” However, the guidance remains subject to comment in accordance with FDA’s good guidance practices.
The guidance comes as the National Institutes of Health (NIH) has initiated the first COVID-19 vaccine Phase 1 trial, and said Monday it would be willing to extend some budget deadlines and request reimbursement for unanticipated costs related to COVID-19. As several biotechnology companies are already halting clinical trials due to challenges associated with the novel coronavirus, it’s critical that pharmaceutical companies and medical device sponsors carefully consider emerging FDA guidance, which may aid them in continuing their studies in order to prevent the progress of experimental drugs from slowing.