key: cord-325391-tgli4k5i authors: Perez, Tamra; Perez, Rafael L.; Roman, Jesse title: Conducting clinical research in the era of Covid-19 date: 2020-06-10 journal: Am J Med Sci DOI: 10.1016/j.amjms.2020.06.011 sha: doc_id: 325391 cord_uid: tgli4k5i nan CoV-2 virus in Wuhan, China in December 2019, raised many challenges to clinical research. Even now, investigators, industry sponsors, and institutional review boards/ethical committees (IRB/EC) struggle to maintain the safety of trial participants and researchers, while promoting the continuity of ongoing clinical studies. COVID-19 has spread to more than 215 countries, infected more than 6.6 million people, and caused close to 400,000 deaths globally as of this submission. 1 The United States (US) is caring for the largest number of cases, currently at 1.5 million, with over 100,000 deaths. 2 Without a proven vaccine or treatment, the mortality rate in the US is projected to be as high as 135,000 -140,000 by August 2020. By comparison, the H1N1 influenza pandemic of 2009 infected 60.8 million individuals and resulted in 12,469 deaths in over 12 months in the US (Centers for Disease Control and Prevention, CDC, estimation). 3 In general, it is estimated that a person infected with COVID-19 can infect three others while an individual with the H1N1 influenza virus infected 1.4 to 1.6 and those with the seasonal influenza infected about two. 4, 5 Clearly, the transmission and mortality rates are what makes COVID-19 a global concern and a source of disquietude. The conduct of clinical studies changed soon after the U.S. Department of Health & Human Services (HHS) issued a COVID-19 Public Health Emergency on January 31, 2020. 6 The FDA, investigators, industry sponsors, and IRBs/ECs, among others, were required to act quickly to assess the status of ongoing studies and restructure research processes accordingly. Unanticipated deviations to protocols became unavoidable, as subjects were unable to attend study visits due to travel restrictions, clinic closures, and quarantine requirements. Elective surgeries and protocol-specified procedures were postponed to diminish environmental contamination and to preserve limited personal protective equipment (PPE). Research staff were instructed to work remotely and study enrollment was only allowed for trials required for a participant's health (e.g. oncology treatment protocol). Other challenges included possible interruptions in the supply of investigational product and other clinical trial shipments. The Guidelines regarding who should be tested for the COVID-19 virus have been provided, but confusion remains and the decision is ultimately at the discretion of the treating physician. 2 Industry sponsors are just now becoming aware that in order for research sites to begin to reopen their sites, COVID-19 testing may become a requirement for subjects as they are seen inperson for clinical visits as well as protocol-specified procedures. This raises questions such as where will testing be done and who bears the cost of the testing (the subject, industry sponsor, or the research site). Informed consents will need to be revised to add the new information as it will involve another procedure and possibly change the risk to the subject. 10 "In the midst of chaos, there is also opportunity"-Sun-Tzu, The Art of War. No one knows for sure when we will be able to get back to business as usual. Considering that an effective vaccine is not expected to be available for another 12 to 18 month, the probability that the virus will still be with us in 2021 and beyond is likely. Nevertheless, we should be recognized that we no longer need to be in the same physical space to have investigator training meetings thanks to web-based applications that can accommodate large numbers of people for a virtual presentation. Centralized IRBs/ECs are already using a virtual meeting format. We can also adopt new technologies to reduce travel burden on subjects with 6 the use of home monitoring technologies and the use of secure web portals for patient reported outcome questionnaires and diaries. While a number of procedures and assessments can be completed off-site, some will continue to require face-to-face contact, like collecting blood or other specimen samples. The COVID-19 pandemic has emphasized the need for flexibility in conducting clinical research that cannot be done without human volunteers. Drastically reducing or halting important studies of diseases yet to be controlled or conquered is not an option. The COVID-19 pandemic will not be the last. We must be prepared to meet the next challenge quickly with the lessons learned from this pandemic, to adjust to unforeseen threats brought by the new challenge, and to promote relentlessly the preservation of human health and life. Oversight • Investigators should determine if it is in the best interest of the subject to continue in a trial and/or continue the use of a trial drug. • In accordance with research informed consent requirements, the subject should be informed of any protocol changes that could affect their participation, as this is new relevant information. • Industry sponsors should be in contact with each investigative site to provide guidance on safety procedures to be continued such as labs or other vital status measurements. • IRBs/ECs may need to change their review processes if they are accustomed to meeting in person or submissions are still on paper. Some central IRBs/ECs already have electronic submissions in place and committee members meet via a secure teleconference format. • Alternative means of obtaining data may need to be incorporated after approval from the FDA or IRB/EC. For example, telehealth visits (telephone calls and video conferencing) can be substituted for in-person visits. • A process for the safe shipment of the investigational product or trial drug directly to the subject that meets sponsor approval as well as local, state, and federal laws can be developed. • Similarly, contingency measures to maintain the manufacture and supply of study drug to research sites during a pandemic or other emergency should be implemented. • Some protocol-specified assessments for efficacy will most likely be delayed or missed and could affect the integrity of the study. However, protocol specified procedures that put the subject or research staff at risk for contracting the virus should be postponed to a later date. These include situations that require close respiratory/facial contact and/or aerosol generating procedures (e.g., pulmonary function testing, nebulization, bronchoscopy, collection of sputum samples, intubation). • Sponsors should seek guidance from the FDA when such protocol changes are considered to affect proposed study endpoints and/or statistical analysis. • In accordance with research informed consent requirements, investigators should maintain contact with trial subjects and keep them informed of protocol changes that could affect their participation (new information). • Sponsors should be in contact with each investigative site to provide guidance on safety procedures to be continued such as labs or other vital status measurements. • Sponsors and investigators are required to document and maintain a log of all missing data and protocol deviations in the study regulatory files. • Any deviations and changes to the protocol should be reported to the local or centralized IRB/EC as soon as possible. As it relates to COVID-19, the documentation should include a description of the deviation/missing data, its relationship to COVID-19, subject ID (if applicable), and any mitigation instituted. • IRB/ECs should acknowledge and render a decision as to whether it is safe for subjects to continue in a clinical trial. • Sponsors should provide additional information in the final clinical study report to the FDA. The report should include contingency measures that were put in place to manage study conduct during the COVID-19 crisis, a log of all trial participants affected by COVID-19 (to include subject ID, clinical site, and the deviation), the justification for the changes implemented, and the impact of the changes on the data results and safety. Centers for Disease Control (CDC). 2009 H1N1 Pandemic (H1N1pdm09 virus Pandemic Potential of a Strain of Influenza A (H1N1): Early Findings Modeling influenza epidemics and pandemics: insights into the future of swine flu (H1N1) Department of Health & Human Services. Secretary Azar Declares Public Health Emergency for United States for Public Health Emergency Guidance for Industry, Investigators, and Institutional Review Boards Draft Informed Consent Information Sheet: Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors