by Kei Mukohara, MD, Ph.D., Tsunetoshi Mogi, MD
COVID-19 REGISRY JAPAN（COVIREGI-JP, its official website [In Japanese]）is an ongoing government-funded national registry study conducted principally at the National Center for Global Health and Medicine in collaboration with Fujita Health University, Hokkaido University, National Institute of Infectious Diseases and pharmaceutical companies. To create a national registry, it is requesting participating institutions to provide clinical data on hospitalized patients with COVID-19. The study is enrolling patients retrospectively and prospectively from January 1, 2020 to January 31, 2021. One of its objectives is to investigate safety and effectiveness of experimental administration of various candidate medications for COVID-19 including favipiravir, lopinavir-ritonavir, interferons, neuraminidase inhibitors, remdesivir, and ciclesonide, all of which except remdesivir are not yet approved for use in patients with COVID-19 in Japan. The research protocol ver 1.0 February 27, 2020 (In Japanese) is available from COVIREGI-JP Research Office at the National Center for Global Health and Medicine upon request with conditions attached.
Despite its experimental aspects, COVIREGI-JP does not currently require obtaining informed consent from individual patients to study participation. The protocol explains that the study is non-interventional because candidate medications are administered not for the purpose of research but for the purpose of treating patients with COVID-19. It also explains that the study is retrospective because it uses existing data in medical records. However, if the study involves a specific medical product that has not yet received marketing authorization, it should be considered not as a non-interventional study but as a clinical trial. In addition, use of existing data in medical records itself does not guarantee that the study is retrospective. COVIREGI-JP has a prospective part as described above. At least for its prospective part, one could argue that COVIREGI-JP meets NIH’s definition of clinical trial: ‘a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes’ although interventions are assigned not by researchers but by clinicians treating patients on the ground.
As a substudy of COVIREGI-JP, the Favipiravir Observational Study (FOS) is being conducted at the Fujita Health University. One of its objectives is to investigate safety and effectiveness of off-label compassionate use of favipiravir for patients with COVID-19. It is enrolling patients with COVID-19 who receive favipiravir until December 31, 2020. Notably, the government made it mandatory for hospitals to participate in the FOS if they were to use favipiravir to patients with COVID-19 (an administrative communication document [In Japanese]). Consequently, both hospitals and patients who are to use favipiravir have no choice but to participate in the FOS for the public good. Since the FOS has no control group, it could be argued that the FOS is actually a prospective, multicenter, single-arm clinical trial according to the NIH’s definition of clinical trial, not a non-interventional retrospective observational study as described in the protocol (In Japanese). However, for the same reasons as with COVIREGI-JP (i.e., being a non-interventional retrospective observational study), the FOS does not currently require participating hospitals to obtain informed consent from individual patients to study participation.
On May 26, 2020, a preliminary report of the FOS was released on an official website of the Japanese Association for Infectious Diseases. The report described information on patients who received favipiravir including patient demographics, dosing of favipiravir, clinical outcomes and adverse events. However, readers of the preliminary report including patients may have a hard time understanding why the FOS is conducted because research purposes and objectives are not clearly described. Furthermore, throughout the report, there is no mention of its being ‘retrospective’ although it is written as such in the protocol (In Japanese). Meanwhile, in the methods section of the preliminary report, there is a following sentence: “The hospitals are asked at the time to join the Favipiravir Observational Study and provide information regarding the patient demographics, comorbidities, severity of illness, dose and duration of favipiravir, use of other medications targeting SARS-CoV-2, adverse events likely related to favipiravir use, clinical status 7 and 14 days from the start of the use of favipiravir and clinical outcome approximately one month after admission to the hospital [sic]” which implies that the FOS is indeed a prospective study.
To preserve integrity and well-intendedness of COVIREGI-JP and the FOS, the protocols should be modified and informed consent from individual patients to study participation should be obtained.