When I first read the guideline, Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions Due to Disasters and Public Health Emergencies, which FDA issued in September 2023, my initial reaction was, ‘do we really need such a guideline?’ We have just gotten over the impact of the COVID pandemic on clinical trials, and business is getting back to usual or normal or whatever we want to call our new normal. That said, I found some interesting and very useful information in this guidance. Having lived through one pandemic, one thing I have learned is that we need to be prepared for the unexpected. While I hope that I will not experience another pandemic, other natural disasters and disruptions in clinical trial are increasingly more likely, especially in our current environment of global clinical studies.
We must always keep in mind that the safety of the participants and study staff in our trials always comes first. With this in mind, when faced with the question of continuing a study or continuing a study at a certain site or in a region, the first questions must always be safety-oriented. Are there modifications and/or risk mitigation steps that will allow participants to continue in the study? Keep in mind that there may be different considerations with starting a new study or site versus continuing a study which was in progress at the time of the disruption.
If the answer to whether safety can be maintained is yes, we can safely continue or start the study, then the next questions one needs to ask are whether the study objectives can be maintained and whether the investigational product (IP) can be safely administered. While the specific circumstances of the disruption and the site(s) will dictate what can be done, the decisions will depend on the trial, the IP, the nature of the disease or condition under study, and the ability to complete study assessments and safety monitoring.
When the Sponsor concludes that it is in the best interest of the participants to continue the study, the next step is to consider the protocol and study changes necessary. FDA recommends that if protocol amendments will result in changes in conduct of primary efficacy or safety assessments, data management, planned analyses, and/or statistical analysis plans, discussions with the review division should be included in the process.
Proposed adaptations may include switching to local laboratories or sites for blood work or imaging, or moving to virtual assessments. One needs to review carefully how these changes are implemented and the impact on the interpretation of study results. In looking at the FDA approval documents of products for which the clinical programs were conducted during the COVID pandemic, I have noted comments from FDA reviewers on assessments that were not done or were altered. If the missing or altered data had an impact on the review and potential approval decision, this was also highlighted by the reviewer. While it may be clear why it is not possible to collect certain data, the Sponsor needs to provide assurance that the omission of these data, or collecting them in a different way, will not negatively impact the review and approval of a marketing application which that study is meant to support. It is important to note that new/modified data handling and analysis processes need to be codified in the statistical analysis plan before database lock. These considerations point to the importance of a discussion with FDA during the modification process.
In addition to the documentation of the impacts of a natural disaster or public health emergency in the existing study documents such as SAP, it is important to provide a description of the impacts on study conduct in a study-specific document. This is a new document, further described in the guidance. The descriptions should include measures that were taken to minimize impact on trial integrity and the reasons for protocol deviations, and should reference those parts of the analysis and discussion in the Clinical Study Report (CSR) that were impacted by the modifications.
Lastly, this guidance includes questions and answers on specific topics that provide clear and important practical guidance to Sponsors. For example, valuable information is provided on remote visits using teleconferencing, some practical guidance on how to conduct these visits, and the clear statement that they are considered live exchange of information between the trial personnel and trial participants and would not be considered electronic records subject to 21 CFR part 11. Practical advice is also provided on remote monitoring; advice that also is applicable under normal trial circumstances as more and more Sponsors are implementing some type of remote monitoring in every clinical trial. Important suggestions for the handling and administration of IP are found in the guidance. For example, use of commercial product, considerations for shipping to sites other than the original site, administration of IP by a non-study healthcare professional, and whether these individuals would be responsible for activities (e.g., assessments, blood draws) other than IP administration.
From an administrative standpoint, this guideline is applicable to clinical studies of drugs, biologics and devices. One needs to keep in mind that some of the requirements for devices are different than those for drugs and biologics. The most significant difference in device regulations is the requirement for the submission of protocol amendments and deviations within 5 business days of the implementation of the change. Changes within a 5-day period can be batched, but Sponsors need to be aware of this additional burden during the protocol modification process.
In conclusion, this guidance provides very useful and practical information on how we should address our clinical programs in light of a natural disaster or public health emergency.
While we all hope that there will not be another global pandemic, the practical information provided in this guidance will be very useful if we find our trials or specific trial sites dealing with unexpected major disruptions. Sponsors should also consider reviewing this information as they plan all clinical trials.
