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external population suggests a causal relationship between the investigational product and the SAEs in trial participants diagnosed with COVID-19, this finding must be submitted to FDA as an IND safety report in accordance with 21 CFR 312.32. FDA had provided additional information about aggregate safety assessment and reporting for INDs in the guidance for industry and investigators, Safety Reporting Requirements for INDs and BA/BE Studies (December 2012),64 and has proposed recommendations in the draft guidance for industry Safety Assessment for IND Safety Reporting (December 2015).65 63 Available on the FDA guidance web page. 64 Available on the FDA guidance web page. 65 Available on the FDA guidance web page. When finalized, this guidance will represent FDA’s current thinking on these issues. Contains Nonbinding Recommendations 33 Where an IND safety report is required to be submitted to FDA under 21 CFR 312.32, the investigator must also send that IND safety report to the IRB.66 The IRB may have additional reporting requirements regarding COVID-19 during the clinical trial. Q25. Trial participants with COVID-19 may experience a number of serious and unexpected adverse clinical events, which may increase the volume of corresponding IND safety reports. If an investigator receives an IND safety report from a sponsor, is it acceptable to review only reports that the sponsor indicates will result in a change to the investigator brochure, informed consent, or protocol? Which IND safety reports must an investigator send to the IRB? No, it is not acceptable for an investigator to review only certain IND safety reports. Under 21 CFR 312.60, investigators are responsible for protecting the safety of trial participants in a clinical investigation. IND safety reports must be sent by the sponsor to FDA and all participating investigators67 when the sponsor determines that a serious adverse event is unexpected and there is a reasonable possibility that the drug caused the serious adverse event, i.e., there is evidence to suggest a causal relationship between the drug and the adverse event.68 Reviewing IND safety reports is essential for protecting the safety of trial participants because a serious and unexpected adverse event represents a new potential risk associated with the investigational product. FDA considers the review of all IND safety reports critical to fulfilling investigators’ responsibility to protect the safety of trial participants in a clinical investigation. 69 In addition, investigators are required under 21 CFR 312.66 to report all “unanticipated problems involving risk to human subjects or others” to the IRB. FDA considers a serious and unexpected adverse event that meets the criteria for sponsor reporting to FDA and all investigators in an IND safety report under 21 CFR 312.32, and would generally consider a serious adverse event that meets the criteria for safety reporting for an IND-exempt bioavailability/bioequivalence study under 21 CFR 320.31(d)(3), to be an “unanticipated [problem] involving risk to human subjects or others” that therefore must be reported to the IRB by the investigator.70,71 66 See 21 CFR 312.53(c)(1)(vii) and 312.66. See also the guidance for clinical investigators, sponsors, and IRBs Adverse Event Reporting to IRBs—Improving Human Subject Protection (January 2009), available on the FDA guidance web page. 67 See 21 CFR 312.32(c)(1). 68 See 21 CFR 312.32. IND safety reports must be submitted as soon as possible, but no later than 15 calendar days after the sponsor determines that the information qualifies for reporting. Unexpected fatal or life-threatening suspected adverse reactions must be submitted no later than 7 calendar days after the sponsor’s initial receipt of the information (21 CFR 312.32(c)(2)). 69 See 21 CFR 312.60. 70 See 21 CFR 312.66. 71 Many study protocols specify that the sponsor will submit IND safety reports to the IRB on the investigator’s behalf. In these situations, where the investigator receives confirmation that the report has been sent to the IRB (e.g., the investigator is copied on the report sent to the IRB by the sponsor), FDA does not intend to object to the sponsor submitting the report to the IRB on the investigator’s behalf and would not expect an investigator to provide the IRB with a duplicate copy of the report. Contains Nonbinding Recommendations 34 For more information about safety reporting, see FDA’s guidances Safety Reporting Requirements for INDs and BA/BE Studies (December 2012)72 and Adverse Event Reporting to IRBs—Improving Human Subject Protection (January 2009).73 Q26. What considerations apply to the electronic systems used to generate electronic signatures on clinical trial records, including informed consent documents, during the COVID-19 public health emergency? Electronic systems74 used to generate electronic signatures75 on clinical trial records, including informed consent documents, during the COVID-19 public health emergency must comply with the requirements outlined in FDA regulations at 21 CFR part 11 (Part 11) when applicable.76, 77 FDA is aware that there are multiple commercial off-the-shelf (COTS) software systems providing electronic signature services for clinical trial records. FDA does not certify individual electronic systems or methods to 

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