Good Postmarketing Study Practice (GPSP) and ICH E2E Guideline

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Chapter: Pharmacovigilance: Pharmacovigilance and Risk Management in Japan

The DUI has long been regarded as the major tool for collecting drug safety information in Japan.


The DUI has long been regarded as the major tool for collecting drug safety information in Japan. Thou-sands of patients who were prescribed a new prod-uct are registered by their physicians with DUI and followed up usually for up to 6 months, depending on its usual administration term. Until 2000, it was mandatory to apply the results of the DUI when the product was assessed in the ‘re-examination.’ The predecessor of DUI, known as the ‘Side Effect Inves-tigation,’ was formed in the late 1960s. Between 1973 and 2000, out of 874 ‘Side Effect Investi-gations’ or DUIs, a total of 7 180 188 patients or an average of 8215 (range 37–111 810) patients per study were monitored (Tanaka et al., 2002). Although the methodological requirements for the ‘Side Effect Investigation’ and DUI, including the number of patients being monitored, have altered many times, one of the main objectives of the DUIs was consis-tently defined as ‘the detection of unknown serious reactions.’ For example, in the notice issued in March 1997 associated with the ‘GPMSP’ enacted as a minis-terial ordinance in 1997, the target number of patients to monitor was said to be 3000. The reasoning for this regulation was explained by using the ‘rule of 3’ (Bégaud and Tubert-Bitter, 1993) and the notice read ‘the target number of the subjects should be decided according to the characteristics of the drug, but it should be normally set as 3000 in order to detect, with 95% confidence, unknown ADRs with the 0.1% or more of the frequency’ (Safety Division, Drug Affairs Bureau, 1997). Until recently, the number of sponta-neous domestic reports of ADRs was small and the DUI was thought to complement the SRS. However, in the amendment of the ‘GPMSP’ in 2000 the DUI was no longer a uniform requirement and was only carried out in certain cases, according to the char-acteristics of the drug. The MHLW explained that one of the reasons for this change in the regulation was the increase in the number of spontaneous reports via drug companies together with the increase in the size of clinical trials (Pharmaceutical and Food Safety Bureau, 2000).

In November 2004, an agreement between the EU, US and Japan was reached for the guideline of ‘Phar-macovigilance planning (PVP)’ (also known as the ‘E2E guideline’) in the ICH (E2E Pharmacovigi-lance Planning, 2004). The ‘ICH harmonised tripartite guideline’ was incorporated into Japanese regulation rules as the notice issued from the MHLW in Septem-ber 2005. According to the notice, the basic plan of post-marketing studies should be prepared according to the ICH E2E guideline. The notice also indicates that a plan for the post-approval investigation at the stage of new drug application should be made accord-ing to the ICH E2E guideline. In the ICH E2E guide-line, it is stated, ‘for products with important iden-tified risks, important potential risks or important missing information, the PVP should include addi-tional actions designed to address these concerns.’ For products where no special concerns have arisen, ‘routine pharmacovigilance should be sufficient for post-approval safety monitoring.’ In addition, accord-ing to the E2E guideline, ‘when choosing a method to address a safety concern, sponsors should employ the most appropriate design.’ Until 2000, the DUIs were conducted irrespective of whether the drug had any ‘special concerns’ because it was a uniform require-ment. This ‘uniformity’ was altered in 2000 and the trend was augmented when the E2E guideline was incorporated into Japanese regulation rules in 2005.

GPSP, being different from the GVP, are not license rules that the MAH must follow without exception. Rather, the GPSP is a ministerial ordinance stipulat-ing duty rules for post-approval investigations and trials conducted only when necessary. According to the GPSP, a PMS supervisor that is independent from the sales department should control the post-approval investigations and trials. The department may or may not be located in the same section as that for the safety control management stipulated in the GVP. In the current GPSP, the investigations and trials are, as in the former GMPSP, divided into three categories: ‘Drug Use Investigation (DUI),’ ‘DUI of Special Population’ and ‘Post-marketing clinical trial.’ In future, this classification may be rearranged to make it more compatible with the classification of ‘special concerns’ given in the E2E guidelines.

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