Background: This presentation describes the U.S. Food and Drug Administration’s (FDA) experience in establishing a dedicated mailbox, and in publishing related guidance, to address concerns among interested parties regarding the conduct of clinical trials during the COVID-19 public health emergency (PHE). At the start of the pandemic, numerous external inquiries were coming into different FDA offices without any coordinated FDA effort. The Office of Medical Policy set up a dedicated Clinicaltrialconduct-COVID19 mailbox for stakeholders to seek expedited help with conducting clinical trials around the world during the COVID-19 PHE. Method: 634 mailbox inquiries received by FDA from March 2020 through February 2022 were reviewed for trends and lessons learned. Qualitative methods were used to provide a structured description of, and identify common themes among, these inquiries. Results: Most inquiries came from U.S.-based interested parties, including sponsors, industry trade associations, academic institutions, hospitals, clinics, research sites, trial participants, and individual persons. Approximately one-fifth of questions were related directly to COVID-19 (e.g., proposals for treatment); other inquiries were related to conduct of routine trial-related activities, and concerns were often focused on maintaining compliance with good clinical practice. In March 2020, FDA published a guidance titled, Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency; the document was subsequently revised eight times based in part on issues raised in mailbox inquiries. Conclusions: The dedicated mailbox enabled expedited communication among invested parties during the COVID-19 PHE; FDA also provided updates of the aforementioned guidance. These efforts supported the continuance of ongoing clinical trials and the initiation of new trials during the PHE in accordance with good clinical practice guidelines, thereby helping to ensure the safety of trial participants while maintaining the quality of trial data. By soliciting and responding to trial-related inquiries and addressing corresponding needs and concerns, FDA improved transparency and communication. Impact on the Federal Health Enterprise include regulatory flexibility and coordination, as well as adoption of digital health tools. For example, the COVID-19 PHE demonstrated the necessity for flexibility in clinical trials, such as remote monitoring and electronic consent. Agencies such as the Department of Defense and Veterans Affairs, which conduct numerous clinical studies, could integrate these findings to ensure that their research protocol are resilient to disruptions such as pandemics or other emergencies. Further, impact on beneficiaries include improved access and safety in clinical trials and protection of trial data and participants’ welfare. In summary, the findings of the report offer a foundation for improving preparedness and coordination during future health emergencies, particularly in the areas of clinical trial continuity, regulatory flexibility, and the adoption of digital tools.