Japan's aggregate safety reports
Japan's pharmacovigilance legislation requires aggregate safety reports before and after approval. The Japanese development safety update report and periodic benefit-risk evaluation report follow the ICH reports and add elements specific to Japan, and three post-approval reports are specific to the post-marketing experience in Japan: the non-serious unexpected periodic report, the infection periodic report and the early post-marketing phase vigilance report.
The reports and their deadlines
In Japan, aggregate safety reports give a structured and comprehensive assessment of a drug's evolving safety profile by integrating global and domestic clinical trial and post-marketing data. Principles of the International Council for Harmonisation (ICH) guidelines can be applied to the Japanese development safety update report (J-DSUR) and periodic benefit-risk evaluation report (J-PBRER), but the legislation requires those reports to incorporate elements specific to the clinical development and post-marketing experience in Japan. The legislation also describes post-approval aggregate reports specific to the post-marketing experience in Japan: the non-serious unexpected periodic report (NUPR), the infection periodic report (IPR) and the early post-marketing phase vigilance (EPPV) report. Sponsors of clinical trials and marketing authorisation holders in Japan should ensure they comply with the current legislation, both to evaluate their products' safety effectively and to fulfil their obligations for preparing and submitting aggregate safety reports.
| Stage | Report | Period covered | Submitted within (from the period end) |
|---|---|---|---|
| Pre-approval | J-DSUR | 1 year | 60 days |
| Post-approval | J-PBRER | 6 months or 1 year | 70 days (3 months if data not in Japanese) |
| Post-approval | NUPR | 6 months or 1 year | 2 months (3 months if data not in Japanese) |
| Post-approval | IPR | 6 months | 1 month (2 months if data not in Japanese) |
| Post-approval | EPPV | 6 months | 2 months |
The Japanese development safety update report
ICH E2F, the ICH guideline on the development safety update report (DSUR), was implemented in Japanese pharmacovigilance legislation in December 2012.
The requirement for periodic reporting on the safety of investigational drugs in Japan sits in Article 80-2 of the Pharmaceuticals and Medical Devices Act and Article 273(4) of the Enforcement of the Act. A sponsor must prepare and submit a J-DSUR for each investigational drug it tests in clinical trials in Japan. For fixed combinations and multi-drug therapies, a J-DSUR is prepared and submitted for each investigational drug in the combination, although E2F allows a single global DSUR for the combination. The J-DSUR obligation runs from the sponsor's initial clinical trial notification to marketing approval of the drug or a notification from the sponsor that development has been discontinued.
In line with E2F, the J-DSUR periodicity is set by the development international birth date. For an approved product with an ongoing clinical development programme, the reporting period can be aligned with the international birth date, which synchronises it with the J-PBRER. As part of the J-DSUR submission, sponsors must submit the global DSUR with Japan-specific elements: a summary of the DSUR, including the sponsor's conclusions and safety actions from the overall assessment of the period's clinical, non-clinical and post-marketing safety data, and details of the serious adverse reactions reported from trials in Japan during the period. J-DSURs are submitted annually within 60 days of the end of the reporting period.
The Japanese periodic benefit-risk evaluation report
ICH E2C(R2), the ICH guideline on the periodic benefit-risk evaluation report, was implemented in Japanese pharmacovigilance legislation in May 2013.
Under Article 63 of the Act's enforcement regulations, J-PBRERs are required for every product subject to re-examination as designated by the Ministry of Health, Labour and Welfare at approval. Re-examination, under Articles 14-4 and 23-29 of the Act, is the re-evaluation and confirmation of a product's clinical usefulness over a specified period after approval. It is part of the product's post-marketing surveillance and rests on the efficacy and safety information collected since approval, and the ministry designates its period, which can vary by product. The J-PBRER obligation runs from marketing approval to submission of the re-examination application. J-PBRERs go to the Pharmaceuticals and Medical Devices Agency every six months for the first two years from the date the ministry designates, then annually until the re-examination application is submitted, and this frequency is expected whether or not the product is marketed. Each is due within 70 days of the end of the interval, or within three months where the data are in a language other than Japanese.
The J-PBRER is accompanied by Japan-specific elements: an overview of the implementation status of the product's risk management plan, including the effectiveness of risk minimisation measures; details of the adverse reactions and infections reported from the trials before approval and during post-marketing surveillance; and a description of any safety measures planned on the results of that surveillance.
The non-serious unexpected periodic report
Article 228-20(1)(iii) of the enforcement regulations requires marketing authorisation holders to report periodically on non-serious adverse reactions that are unknown — not described in the approved Japanese package insert — at the time of reporting. The NUPR is required for every product approved in Japan, whether or not it is subject to re-examination. Besides the details of every non-serious unexpected adverse reaction reported in Japan during the interval, it assesses the impact of each on the product's overall safety profile, for the interval and cumulatively. It also describes whether the holder took any actions for safety reasons during the interval, such as changes to the precautions for use or information disseminated to healthcare professionals.
For a product subject to re-examination the NUPR follows the J-PBRER's periodicity — every six months for the first two years from the date the ministry designates at approval, then annually until the re-examination application is submitted. For a product not subject to re-examination it is submitted annually. It is due within two months of the end of the interval, or within three months where the data are in a language other than Japanese.
The infection periodic report
Under Articles 68-14 and 68-24 of the Act, marketing authorisation holders of regenerative medicinal products and biologically derived products in Japan must periodically analyse the data on infectious diseases associated with these products and report the results to the ministry. The requirement was introduced in 2003 after a series of AIDS and Creutzfeldt-Jakob disease cases caused by contaminated blood coagulation factors. Article 2 of the Act defines regenerative medicinal products as cellular and tissue-based products used to reconstruct, repair or form structures or functions of the body and to treat or prevent disease, or as gene therapy. It defines biological products as drugs, quasi-drugs (products with mild pharmacological effects that fall between cosmetics and drugs), cosmetics or medical devices manufactured from materials derived from humans or from organisms other than plants. A subcategory, specified biological products, covers those for which additional measures are needed to prevent the onset and increase of public health risk after they are provided or administered.
The IPR focuses on diseases transmissible or infectious to humans from regenerative medicinal products and biologically derived products or their individual components: newly reported infections, including increases in their incidence, newly recognised routes of infection, and serious infections associated with the product. Besides an overview of the infection adverse reactions reported in the interval, it summarises information from the literature on infections suspected to be caused by the product, measures concerning infectious diseases related to the product taken in Japan and abroad, a critical evaluation of the collected data and actions proposed from the overall safety assessment. It is submitted every six months from the marketing approval date, within one month of the end of the interval, or within two months where the data are in a language other than Japanese.
The early post-marketing phase vigilance report
Early post-marketing phase vigilance is implemented in Japan to promote proper use of a product and the collection of its safety information for the first six months after its launch, or after its approval for an additional indication. The agency often makes it a condition of marketing approval during the regulatory review, though there may be instances when it is not required, such as a newly approved indication for an already approved product on which sufficient safety information has been collected over time and whose safety profile is not expected to change.
The vigilance is based on a plan the holder develops under Article 10(1) of Ministerial Ordinance 135/2004, giving its purpose, the period covered, the number of healthcare institutions subject to it, and most importantly its method: how and how often information on the product's proper use is provided to the institutions, cooperation with the institutions that will use the product, and notification of any emerging safety issues with it. In practice the holder's medical representatives visit the institutions every two weeks for the first two months of the period to provide the necessary explanations and ask that important safety information be reported promptly, then monthly until six months after launch.
The report goes to the agency within two months of the end of the six-month period. It gives the product's trade name, active substance, approval number and date and therapeutic category, the launch date, the period covered, the institutions involved, the estimated patient exposure, an overview of the serious adverse reactions reported and any safety actions taken during the period. It is accompanied by the information materials provided to the institutions and materials on the progress of the vigilance at them.