Japan differs somewhat from the other countries included in this chapter in that it is a signatory to the ICH, and although a degree of variation does exist, Japan utilizes similar pharmacovigilance documents to those relied upon in the EU and the US. Pharmacovigilance in Japan is governed by the Pharmaceutical Affairs Law, in parallel to oversight provided by the Ministry for Health, Labor and Welfare (MHLW).

7.2.1 Pharmacovigilance Medical Writing for Clinical Trials

Until 2009, and in contrast to the EU and US regions, there were no requirements for periodic reports of safety data from clinical trials undertaken in Japan. However, since 2009, the Japanese authorities have requested submission of a 6-monthly periodic report of safety data from investigational medicinal products, including:

• all reports of expected and unexpected suspected adverse drug reactions in clinical development (i.e. including studies outside Japan);
  
• the number of events for the 6-month review period and cumulatively since April 2009;
  
• the sponsor’s overall assessment of the reviewed safety data.

However, as with the EU Annual Safety Report (ASR), the Japanese 6-monthly periodic report for investigational medicinal products may be replaced by the Development Safety Update Report (DSUR). Full details of the DSUR and associated preparation activities can be found in Section 2.3 of Chapter 2 (Pharmacovigilance Medical Writing for Clinical Trials).

As a signatory to the ICH, the Japanese authorities accept submission of Common Technical Documentation (CTD) modules, including the Summary of Clinical Safety (SCS), also utilized in the EU and US regions. Full details of the SCS and associated preparation activities can be found in Chapter 3 (Pharmacovigilance Medical Writing for Marketing Authorization) of this book.

7.2.2 Pharmacovigilance Medical Writing for Marketed Products

In common with the EU and in line with ICH guidelines, a PSUR consistent with ICH E2C (R1) is submitted to the Japanese MHLW for marketed products. PSURs are submitted to the MHLW every 6 months for the first 2 years from the time of product approval/registration, akin to the EU schedule. However, in contrast to the EU, the 6-monthly PSURs are followed by annual PSURs for the entirety of the specified re-examination period (which can range from 4–10 years, depending on the type of medicinal product and is defined as the period after approval during which the efficacy and safety of the product is re-confirmed) [2].

The Japanese authorities stipulate that the country of origin be specified for data in PSURs for products marketed outside Japan, as well as details regarding any actions taken for reasons of safety by the associated (i.e. foreign) regulatory authorities.

As with the EU, the Japanese authorities retain the right to re-set the clock and re-start submission on 6-monthly PSURs if warranted, such as in cases of approval of a new indication or changes to the components of the medicinal product.

Full details of the PSUR and associated preparation activities can be found in Section 5.2 of Chapter 5 (Pharmacovigilance Medical Writing for Marketed Products) of this book.

However, it is worth noting that, unlike the EU region, the ICH E2C (R1) compliant PSUR is not all that is required in terms of periodic reporting for authorized medicinal products in Japan. In fact, the ICH E2C (R1) PSUR only constitutes part of the Japanese Periodic Safety Report, which also includes findings from local post-marketing studies [2, 3]:

• reports of unknown non-serious adverse drug reactions (ADRs);
  
• all reports of infections (for biological products);
  
• information from the ‘drug use–results survey’ and a summary of future measures planned based on the surveillance findings;
  
• status on post-marketing studies, including the number of recruited patients.

Although Canada is not a signatory to the ICH, its regulatory authority, Health Canada [4], describes itself as an ‘official observer to and active participant in the ICH, committed to adoption and implementation of ICH guidance and standards.’

7.3.1 Pharmacovigilance Medical Writing for Clinical Trials

Thus far, there has been no requirement to submit a periodic report of safety data arising from investigational medicinal products to the Canadian authorities. However, Canada is set to accept submission of the new DSUR, thereby creating parity with the EU, US, and Japan with respect to pharmacovigilance medical writing for clinical trials.

Full details of the DSUR and associated preparation activities can be found in Section 2.3 of Chapter 2 (Pharmacovigilance Medical Writing for Clinical Trials).

7.3.2 Pharmacovigilance Medical Writing for Marketed Products

With respect to periodic reporting for authorized medicinal products, there is a stipulation in Section C.01.016 of Division 1 of the Food and Drug Regulations for the preparation of an annual safety report [5]. Although submission of these annual reports to the Canadian authorities is voluntary, the MAH is expected to hold them on file, inform the authorities when data analysis reveals new safety signals warranting further action, and be ready to submit the reports within 30 days of request.

As an observer of the ICH guidance, Health Canada recommends that the annual post-marketing safety reports be consistent with the ICH E2C (R1) format used in the EU [6].

Full details of the PSUR and associated preparation activities can be found in Section 5.2 of Chapter 5 (Pharmacovigilance Medical Writing for Marketed Products).

Akin to Canada, Australia and New Zealand are not signatories to the ICH, yet both regions generally follow ICH guidance and format for pharmacovigilance reports accepted under a joint scheme, the Australia New Zealand Therapeutic Products Authority, which was formed through an alliance of the Australian Therapeutic Goods Administration and New Zealand Medicines and Medical Devices Safety Authority.

7.4.1 Pharmacovigilance Medical Writing for Clinical Trials

During clinical development of medicinal products, Australia requires submission of an annual report to the Human Research Ethics Committees, in the format of the EU ASR [7]. Although the ASR is now redundant in the EU, having been replaced with the DSUR in August 2011, summary details of this report are available in Section 2.2 of Chapter 2 (Pharmacovigilance Medical Writing for Clinical Trials) of this book.

As this region follows ICH guidance, it is likely that the DSUR will be implemented in the near future. Full details of the DSUR and associated preparation activities can be found in Section 2.3 of Chapter 2 (Pharmacovigilance Medical Writing for Clinical Trials).

7.4.2 Pharmacovigilance Medical Writing for Marketed Products

Submission of 6-monthly PSURs is required for a period of 3 years following product approval/registration, in a format consistent with the ICH E2C (R1) structure utilized in the EU.

Full details of the PSUR and associated preparation activities can be found in Section 5.2 of Chapter 5 (Pharmacovigilance Medical Writing for Marketed Products).

Pharmacovigilance activities in India are governed by Schedule Y of the Drugs and Cosmetics Act of 1945 [8] and enforced by the Central Drugs Standards Control Organization, which provides oversight for the National Pharmacovigilance Program that, since 2005, has been tasked with surveillance of the safety of medicinal products marketed in India [9].

7.5.1 Pharmacovigilance Medical Writing for Clinical Trials

In contrast to the ICH regions of the EU, US, and Japan, and notwithstanding that a large proportion of clinical trials for multinational pharmaceutical companies are undertaken in India, there are currently no requirements for periodic and aggregate reporting for investigational medicinal products in India. However, this situation is likely to change in the coming years as there are calls for the Indian authorities to adopt the DSUR or implement a similar report [10].

7.5.2 Pharmacovigilance Medical Writing for Marketed Products

Submission of PSURs consistent with the ICH E2C (R1) format is required for medicinal products marketed in India. Like the EU region, the mandated scheduling is every 6 months for the first 2 years after initiation of product marketing and then annually for the subsequent 2 years [9].

Full details of the ICH E2C (R1) PSUR format and associated preparation activities can be found in Section 5.2 of Chapter 5 (Pharmacovigilance Medical Writing for Marketed Products) of this book.

However, it is worth noting that although the Indian authorities accept the ICH E2C (R1) PSUR format, there are some differences when compared to the EU, in that submissions of PSURs are expected within 30 days of the DLP, in contrast to the 60-day preparation window permitted by the EU regulators. In addition, Indian legislation in the form of Schedule Y allows companies to delay submission of the first PSUR if the medicinal product has been approved but has not yet been launched into the marketplace – this is in contrast to the EU, where the PSUR clock starts ticking from the day of product approval, irrespective of whether the product launch has taken place [9].

Pharmacovigilance in Singapore and Taiwan falls under the jurisdiction of the Health Sciences Authority and the Department of Health, respectively.

7.6.1 Pharmacovigilance Medical Writing for Clinical Trials

Singapore and Taiwan currently have no mandatory requirements necessitating the submission of periodic reports of safety data for investigational medicinal products.

7.6.2 Pharmacovigilance Medical Writing for Marketed Products

Although pharmacovigilance in these regions could be regarded as still in its infancy compared to the EU and US, both Singapore and Taiwan have legislation requiring the submission of PSURs for medicinal products marketed in their territories.

Since September 2004, the Taiwanese Department of Health has required submission of 6-monthly PSURs during the first 2 years after license approval, followed by annual PSURs for the next 3 years [11,12]. The recommended PSUR format is consistent with the ICH E2C (R1) format utilized in the EU, although the Taiwanese authorities require that domestic data (safety as well as patient exposure) be presented separately from that gathered from the international market.

Similarly, Singapore’s Health Sciences Authority requires submission of a PSUR, for specified medicinal products, every 6 months during the first 2 years after product approval/registration, followed by annual PSURs for the subsequent 3 years [13]. Furthermore, Singaporean authorities advise that for products not mandated for the submission of PSURs, a similar report nonetheless be prepared and held on file by the license holder, in readiness to submit to the authorities within 30 days of demand. With regard to the format of the submitted PSURs, the Health Sciences Authority requests adoption of the ICH E2C (R1) format used in the EU [13].

Full details of the ICH E2C (R1) PSUR format and associated preparation activities can be found in Section 5.2 of Chapter 5 (Pharmacovigilance Medical Writing for Marketed Products) of this book.

1. Pirmohamed, M., Atuah, K., Dodoo, A., and Winstanley, P. (2007) Pharmacovigilance in Developing Countries. British Journal of Medicine, 335: 462.