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information added to the cover letter in the subject line: PROTOCOL AMENDMENT – COVID-19 TITLE OF PROTOCOL Sponsors should summarize the major changes made to the protocol related to COVID-19 in the cover letter and should include a tracked changes version of the protocol to facilitate review. As with other protocol amendments, sponsors may implement protocol amendments due to COVID19 upon submission to FDA if approved by the IRB. Sponsors seeking FDA input prior to implementation should indicate that in the cover letter. For IDE studies, the sponsor should submit a supplement to its existing IDE, with the following information added to the cover letter in the subject line: CHANGE IN PROTOCOL SUPPLEMENT – COVID-19 or NOTICE OF IDE CHANGE – COVID-19, as applicable TITLE OF PROTOCOL The submission to the IDE should contain a tracked changes version of the protocol to facilitate review. Q5. Can a sponsor initiate virtual clinical trial visits for monitoring patients without contacting FDA if there is an assessment by the sponsor and investigator that these visits are necessary for the safety of the trial participant and it will not impact data integrity? FDA regulations allow for changes to be made to the investigational plan or protocol without prior FDA review or approval, if the change is intended to eliminate an apparent immediate 10 See 21 CFR 812.35(a)(2). Contains Nonbinding Recommendations 12 hazard or to protect the life and well-being of trial participants.11 Therefore, changes in protocol conduct necessary to immediately assure patient safety, such as conducting telephone or video contact visits for safety monitoring rather than on-site visits, can be immediately implemented with subsequent review by the IRB and notification to FDA. Since this reflects a protocol deviation (until the amendment is approved), documentation of the required deviations, as described above, would generally be acceptable (i.e., a document that lists each deviation, study reference ID, patient ID, and date). For example, documenting that all protocol-specified visits will be done by telephone contact rather than on-site visits, and that procedures requiring inperson visits will either not be conducted, or performed by other means (specified, as appropriate). Since the change to telephone or video contact visits would likely result in some protocol-required procedures not being conducted (e.g., vital signs, blood samples for safety laboratory studies), the sponsor must evaluate the potential impact on patient safety, and consider how to mitigate risks to patients, including the need to discontinue the investigational product. For IDE studies, sponsors are required to report deviations implemented to address the imminent safety risk to FDA within 5 working days after learning of the deviations. We recognize that challenges related to the COVID-19 pandemic may make it difficult to meet this timeframe. Sponsors may consolidate implemented deviations when submitting 5-day reports and should update FDA as soon as possible. Q6. With the rapid changes in clinical trial conduct that may occur due to the COVID19 public health emergency, including multiple deviations to address patient safety, what is the best way for sponsors and investigators to capture these data? As noted in the main body of this guidance, it is important to capture specific information for individual participants that explains the basis for missing protocol-specified information that includes the relationship to COVID-19 (e.g., from missed study visits or study discontinuations due to COVID-19). This information, summarized in the clinical study report, will be helpful to the sponsor and FDA. If it is not possible to capture this information in the case report form(s), sponsors may develop processes that enable systematic capture of these data across the sites in a manner that enables the appropriate analysis when the data are submitted to FDA. Sponsors may also develop processes to capture site-level status, site-level or vendor-level protocol deviations, and process deviations. Q7. If patients are currently dispensed investigational product through a pharmacy at the clinical trial site for self-administration at home, can a sponsor switch that to home delivery without amending the protocol? If there is concern about risk of exposure to COVID-19, home delivery of investigational product that would not raise any new safety risks may be implemented to protect patients from coming to clinical trial sites. In all cases, requirements under FDA regulations for maintaining required investigational product storage conditions and investigational product accountability remain; these requirements must be addressed and documented. 12 If the protocol indicates pharmacy dispensing for self-administration at home, and this is changed to direct-to-patient shipments, 11 See 21 CFR 56.108(a)(4), 312.30(b)(2)(ii), and 812.35(a)(2). 12 See 21 CFR 312.60, 312.62, and 812.140. Contains Nonbinding Recommendations 13 then a protocol amendment would be required to permit home delivery of investigational product.13 If the extent of home delivery is limited to certain participants and not the entire population described in the protocol, documenting the change in the mechanisms of distribution of investigational product administration through 

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