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if necessary. FDA recognizes that in some circumstances it may be necessary (e.g., based on lack of product supply or inability to administer or ensure the safe use of the investigational product) to discontinue investigational product administration in a trial. If there are individual trial participants for whom discontinuing the investigational product might present a substantial risk (e.g., trial participants perceived by the investigator as having a clinical benefit from the investigational product), the sponsor should consider amending the protocol, after discussion with the relevant review division, to limit investigational product use to those patients with apparent benefit and discontinue investigational product use to other participants. In all cases, if a trial participant is discontinued from an investigational therapy, it is important that there be appropriate management after discontinuation. Contains Nonbinding Recommendations 10 Q3. How should sponsors manage protocol deviations and amendments to ongoing trials during the COVID-19 public health emergency? FDA recognizes that during the COVID-19 public health emergency, sponsors of clinical trials may need to modify protocol-specified procedures. As is discussed in the main body of this guidance, for protocol deviations necessitated by the impact of the current COVID-19 public health emergency, the sponsor should document the specific protocol deviation and the reason for the deviation. The sponsor can document protocol deviations using its standard processes, or given the larger expected number of such deviations, use alternative documentation approaches. For example, if visits are to be conducted by telephone/video contact rather than at the investigational site as specified in the protocol, documentation that provides a listing of all study visits (e.g., listing study reference number, patient ID, date of visit) that are deviations from the protocol due to the current COVID-19 situation generally would be acceptable. Protocol deviations should be included in final study reports and may also be included in annual reports. For a study-wide change in protocol conduct, under the IND regulations protocol amendments that are necessary to prevent imminent hazards to trial participants can generally be immediately implemented with subsequent submission and formal approval by the IRB and notification to FDA through filing a protocol amendment to the IND.7 For studies under an IND, 21 CFR 312.30(b) specifies that sponsors must submit a protocol amendment to the IND describing any change in a phase 1 protocol that significantly affects the safety of trial participants or any change in a phase 2 and 3 protocol that significantly affects the safety of trial participants, the scope of the investigation, or the scientific quality of the study. Pausing enrollment in a trial to decrease potential exposure to COVID-19 would not generally be expected to significantly affect trial participant safety, the scope of the investigation, or the scientific quality of the study; therefore, submitting a protocol amendment would not be required under the regulation for such a pause. Protocol amendments that are not required to prevent imminent safety risks to patients can be implemented after they are submitted to FDA and IRB approval has occurred.8 FDA recognizes that during the rapidly evolving circumstances of the current COVID-19 public health emergency, a sequence of changes may be needed to address those circumstances. Clinical investigators must document as protocol deviations any modifications to protocolspecified procedures that occur prior to IRB approval and submission of the protocol amendment implementing the modification.9 Consolidating several protocol modifications in a single protocol amendment would be acceptable but should be submitted expeditiously. For studies under an IDE, 21 CFR 812.35(a) generally requires prior FDA approval before implementing changes to the investigational plan. These requirements do not apply to changes made to protect the life or physical well-being of a trial participant in an emergency, including 7 See 21 CFR 56.108(a)(4) and 312.30(b)(2)(ii). 8 See 21 CFR 312.30(b)(2). 9 See 21 CFR 312.62. Contains Nonbinding Recommendations 11 study-wide changes, but such deviations must be reported to FDA within 5 working days.10 In addition, under 21 CFR 812.35(a)(3), changes to the protocol that the sponsor determines, based on credible information, do not affect the validity of the results from the study, the likely patient risk-to-benefit relationship, the scientific soundness of the investigational plan, or the rights, safety, or welfare of the trial participants may be made without prior FDA approval, if the sponsor reports the modifications to the agency within 5 days of implementing the changes. Because of the unique and evolving circumstances surrounding the impact of COVID-19, we understand that it may be challenging to submit 5-day reports/notices within the required timeframe. Sponsors may consolidate implemented changes when submitting 5-day reports/notices and should update the IDE as soon as possible. Q4. How should a sponsor submit a change in protocol that results from challenges related to the COVID-19 public health emergency? For IND studies, the sponsor should submit a formal amendment to its IND, with the following 

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