In recent years, the utilization of health care databases has been increasing worldwide. It is expected that Real World Data (RWD) will soon be effectively used for clinical research in Japan. On the other hand, database studies that use accumulated existing data such as electronic medical records, Diagnosis Procedure Combinations (DPCs), and health insurance claims, require extremely high loads of data preprocessing before statistical analysis is possible. So far, there is insufficient literature that describes the challenges of RWD preprocessing from an academic point of view. In this review paper, the challenges of database study are classified into three categories：（1）data content,（2）data structure, and（3）large-volume data handling. We then investigated existing preprocessing research and systematically introduced them. Most data preprocessing research targeted the improvement and reliability of the database itself through supplementing data contents required for each clinical research. There is very little research with the primary purpose of solving problems related to data structures and large-volume data processing. As the use of RWD for clinical research increases, the importance of the data preprocessing field will be recognized. In the future, we expect to see more research focused on RWD, which can enable the growth of clinical researches using RWD.

The COVID-19 vaccines have been used under the special temporary vaccination based on the Immunization Act, which stipulates the same report framework of symptoms suspected to be caused by the routine or the special temporary vaccinations. As for the safety analysis, the results of these reports have been evaluated at Council meetings held more frequently than usual. In addition, a research group, established by the Ministry of Health, Labour and Welfare, collected information about the symptoms suspected to be caused by COVID-19 vaccination.

Focusing on the electronic system for the COVID-19 vaccines, during the period of the special temporary vaccination, the Vaccination Record System (VRS), established by the Digital Agency, is used for individual COVID-19 vaccination history, and the Vaccination-System (V-SYS) established by the Ministry of Health, Labour and Welfare is used for recording COVID-19 vaccines distribution, so that the number of vaccine recipients, lot numbers of delivered vaccine, etc., which are the basis for safety assessment, can be confirmed easily.

Looking ahead, further progress is expected in the development of the infrastructure for evaluating vaccine safety. For example, the online insurance eligibility confirmation system will be expanded to a nationwide platform for sharing and exchanging information on immunizations and electronic medical records, etc. After the platform is completed, we will be able to analyze in conjunction with the database of information on immunization and specific medical examinations, etc.

Cohort Survey at the Beginning of SARS-CoV-2 Vaccination in Japan was planned as an administrative promotion survey project for the purpose of promptly disclosing safety information on SARS-CoV-2 vaccination to the council of the Ministry of Health, Labor and Welfare.

The cohort survey of initial series of Pfizer Comirnaty was started on February 17, 2021. In order to conduct the multi-institutional joint research as an observational study in compliance with the ethical guidelines for medical research on human subjects, we used a commercial IRB. We prepared for a research platform including an EDC, research management services, and cooperation with Organization headquarters. Comirnaty was vaccinated on approximately 20,000 healthcare workers over a nine-day period and the first interim report was published on March at the council of the MHLW. Then the cohort survey of initial series of Moderna Spikevax on SDF personnel and AstraZeneca VAXZEVRIA on the general public were started on May and August 2021, respectively. In addition, investigations on the third additional vaccination from December 2021, vaccines for children aged 5-11 years from March 2022, and Takeda/Novavax vaccines from May 2022 and the fourth additional vaccination from May 2022 were not only conducted as safety investigations, but also the changes in antibody titers of some of the subjects were examined. The results have been reported 23 times (as of July 8, 2022) to the council of the MHLW. The database includes specific adverse events such as fever, local pain, fatigue, and headache etc. and MedDRA-coded free-text adverse events, number of sick leave, number of drugs used for adverse reactions, antibody titer trends, and serious adverse events including PMDA reports.

Due to the rapid pandemic of the new coronavirus infection, a state of emergency was declared in Japan in April 2020, which had a great impact on people's lives. Under these circumstances, the development of COVID‒19 Vaccine (ChAdOx1‒S［recombinant］) (Vaxzevria^TM Intramuscular Injection) was started by Oxford University for the purpose of preventing COVID-19, and then AstraZeneca took over it. That vaccine was approved in the UK in December 2020. In Japan, an application for manufacturing and marketing approval was submitted in February 2021, and granted a Special Approval for Emergency for the indication of “prevention of infectious diseases caused by SARS-CoV-2” for people aged 18 or older in May 2021. For post-marketing safety measures conducted in COVID-19 pandemic, it includes the Early Post-marketing Phase Vigilance (EPPV), General Use Result Study following the priority survey (by the Scientific Research Group of the Ministry of Health, Labour and Welfare) at the initial stage of administration of the COVID-19 vaccination, Specific Use Result Study targeting vaccinated people with the special background, and the periodic submission of data about post-marketing safety information in and outside Japan. This contribution will describe the safety measures conducted by an unconventional method in the post-marketing setting. Especially, in COVID-19 pandemic, conducting EPPV via Medical Representative (MR) as usual is assumed to lead to a risk to increase the threat of infection to the overwhelmed healthcare professionals； therefore, the interactive EPPV avoiding the direct contact with the healthcare professionals was conducted on the basis of discussion with the regulatory authority prior to the approval, and would be introduced here.

Epidemic of SARS-CoV-2 affected the human society, with multidimensional impact. COVID-19 vaccine was developed as an important tool for public health which can change epidemic situation. In early 2021, products got an approved and become available in Japan also. Several difficulty from development to approval which was overcame by collaborative work of several stakeholders, have been already known. As same as this, in post-marketing phase, there were several challenging situation. MR visit to health care institute was quite restricted. The duration from product approval to product use, was quite short. Vaccine distribution was controlled by government to keep nationwide optimization, and vaccination was done based on prioritization. To expand vaccination site, large scale vaccination sites and occupational vaccination sites which differed from usual health care institute, was opened. Under these situation, we made various effort to do several actions aligned with several related rules like pharmaceutical and Medical Device acts. For timely information delivery and information collection, internet technology was utilized. Post-marketing survey plan was revised from usual survey to database survey, because product used basically at occupational vaccination site. In this material, we would like to report what we did as Early Post-marketing Phase Vigilance (EPPV), safety monitoring and post-marketing survey under COVID-19 situation. We hope this report can be utilized to discuss what we should do under resemble situation.