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document in their annual status report the COVID-19-related reason(s) for missing interim, trial completion, and/or final report submission milestone(s), and any steps taken to address COVID-19-related factors. Q23. My company is the NDA holder of an FDA-approved drug for a non-COVID-19 indication and is also the sponsor of an IND for the same drug being investigated to treat COVID-19. If I receive a spontaneous report of a serious adverse event that occurred with the approved drug being used in clinical practice for treatment of COVID-19, do I report that event to the IND for the COVID-19 investigational use? Reports of serious adverse events (SAE) that occur in clinical practice with the use of an approved drug or biological product, whether or not the use is included in the labeling for that product, must be reported in accordance with the applicable post-marketing reporting requirements under FDA regulations at 21 CFR 314.80 and 600.80. Reports of SAEs for approved vaccines are submitted to the Vaccine Adverse Events Reporting System (VAERS), while reports of SAEs for other approved drugs and biological products are submitted to the FDA Adverse Event Reporting System (FAERS). 60 Serious adverse events that occur during a clinical trial under an IND for an approved drug or biological product being investigated for a new use to treat COVID-19 must be reported as an IND safety report per FDA regulations at 21 CFR 312.32 if they are unexpected and the sponsor determines that there is a reasonable possibly that the drug caused the SAE. Regardless of whether an SAE occurs in the course of clinical practice or during a clinical trial, and regardless of where it is first reported, an NDA or BLA holder who is also the sponsor of an IND investigating the same drug for COVID-19 is responsible for monitoring the safety of its drug and evaluating all accumulating safety data.61 If accumulating safety data, including use in clinical practice, indicates a new serious risk associated with the drug, an IND safety report will need to be filed to the IND, and updates will likely need to be made to the investigator brochure and/or the informed consent document.62 For more information, see FDA’s guidance for 59 See section 506B of the FD&C Act (21 U.S.C. 356b), 21 CFR 314.81(b)(2)(vii), and 601.70(b). 60 For more information, see the Vaccine Adverse Event Reporting System, available at https://vaers.hhs.gov/reportevent.html, and the FDA Adverse Event Reporting System (FAERS) Public Dashboard, available at https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fdaadverse-event-reporting-system-faers-public-dashboard. 61 See 21 CFR 312.32(b). 62 See 21 CFR 312.32(c). Contains Nonbinding Recommendations 32 industry and investigators Safety Reporting Requirements for INDs and BA/BE Studies (December 2012).63 Q24. For a clinical trial that is not investigating treatments for COVID-19, if a trial participant diagnosed with COVID-19 experiences a serious adverse event associated with COVID-19 during the trial, should that be reported as an IND safety report? Should these events be reported to the IRB? Under FDA regulations at 21 CFR 312.32, a sponsor must report to FDA any serious adverse event (SAE) that is both unexpected and for which 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. Given the community spread of infection during the COVID-19 public health emergency, trial participants in a clinical trial may be diagnosed with COVID-19 and experience SAEs associated with the disease that are not causally related to the investigational drug. However, it also is possible that an investigational drug might be causally related to a SAE associated with COVID19 by making trial participants in the trial more susceptible to complications from COVID-19. Establishing this potential causal relationship likely requires more than a single or even a few cases. To determine whether a reasonably possible causal relationship exists between an investigational drug and an SAE in a randomized controlled trial, FDA recommends a comparison between the rate of observed SAEs among COVID-19 infected trial participants in the investigational drug arm to COVID-19 infected trial participants in the control arm. Given that such analyses entail examination of unblinded data, such assessments should be done only by a data monitoring committee that routinely reviews unblinded data or by a specially constituted safety committee that is appropriately “firewalled” and independent from those conducting the trial and performing other study analyses. If the latter, such a committee should review safety data only, not efficacy data. If the trial is not randomized, in some circumstances it may be warranted to determine whether there is an excess of SAEs in trial participants diagnosed with COVID-19 by comparing the rate of such events to an external similar population diagnosed with COVID-19, recognizing that the reported rates of SAEs and mortality in patients with COVID-19 have varied widely. In comparing the rate in the trial to the published literature, sponsors should consider reports in patients with similar comorbidities and levels of care. If the difference in SAEs across treatment arms or compared to an 

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