Risk Management in Japan

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Chapter: Pharmacovigilance: Pharmacovigilance and Risk Management in Japan

According to the draft for ‘guideline on risk management system for medicinal products for human use’ published by the European Medicines Agency (EMEA) .


According to the draft for ‘guideline on risk management system for medicinal products for human use’ published by the European Medicines Agency (EMEA) in September 2005, a risk management system is defined as ‘a set of pharmacovigilance activities and interventions designed to proactively iden-tify, characterize, prevent or minimize risks relating to medicinal products’ (EMEA, 2005). The activity of the risk management system includes risk commu-nication and an assessment of the effectiveness of risk minimization interventions. As of late 2005, there has been no systematic approach in Japan to develop the official guideline specified for the risk management equivalent to the draft guideline issued by EMEA. However, some essential components of the risk management system are being gradually incor-porated into the new regulations adopted in Japan. For example, the GVP indicates that the pharmacovigi-lance supervisor has the responsibility for planning and execution of measures to ensure safety in the MAH and the ICH E2E guideline has been adopted in the regulation for the pharmacovigilance activity.

Risk communication is an important tool for risk minimization. According to PAL (Article 77-3), the MAH has an obligation to provide information on the appropriate use of a drug for doctors and other health professionals. The information includes the results of the ‘re-examination’ and ‘re-evaluation,’ emergency information, such as ‘dear doctor letter’ and revision of precautions. Notice on ‘Guideline for distribution of urgent safety information (Dear Doctor Letter)’ was introduced in October 1989. To enhance the legal requirement, the Federation of Pharmaceu-tical Manufacturers’ Association of Japan (FPMAJ) published the rules for enforced dissemination on the information during the post-approval period in 1994. The rules include the description of the box warn-ing and contraindication (including contraindicated concomitant use of the drug) as well as the distri-bution of the ‘Drug Safety Update’ (DSU) published by the FPMAJ to health professionals for prompt and complete communication of the revision of precau-tion statement (the DSU is currently available from the PMDA’s website (Drug Safety Update, 2005)). Notice on ‘The preparation of explanation materials on warning and precaution statements of new drugs’ was announced in June 1997.

In addition to the regulations enforced by the regu-latory body and voluntary rules made by the FPMAJ, the risk management plan can also involve academia and non-governmental bodies. One important exam-ple of this system is the regulatory guidelines for thalidomide. Thalidomide, marketed in the late 1950s in Europe, Canada and Japan as a treatment for morn-ing sickness, was banned worldwide because of its teratogenicity. Thalidomide was withdrawn from the Japanese market in 1962. However, the usefulness of thalidomide was reappraised in the mid-1960s when the drug was found to be effective in the treatment of erythema nodosum leprosum (ENL). The widespread ‘revival’ of thalidomide occurred in the 1990s when it was found to be effective in the treatment of a refrac-tory multiple myeloma and possibly several other diseases such as Behcet’s disease, graft versus host disease and inflammatory bowel disease. In 1998, thalidomide was approved for the treatment of ENL in the US. In Australia, New Zealand, Turkey and Israel, thalidomide is approved for the treatment of multiple myeloma after the failure of standard thera-pies as well as ENL. In the US, the risk of thalido-mide, particularly teratogenicity, is managed by the ‘System for Thalidomide Education and Prescribing Safety’ (STEPS), where all the patients and prescrib-ing doctors are registered to the MAH. In other coun-tries where thalidomide is approved, STEPS is also used with some modification.

Thalidomide is currently not an approved drug in Japan. In the late 1990s Japanese patients with multi-ple myeloma requested that thalidomide be used for their treatment. Since 2000, several thousand Japanese patients with multiple myeloma and other diseases have obtained thalidomide via the system of ‘personal importation’ for unapproved drugs. A clinical trial of thalidomide for multiple myeloma was started in 2005 and it is anticipated that thalidomide will be available as an approved drug in Japan from around 2006.

In December 2004, while thalidomide was not approved, the Japanese Society of Clinical Hematology (JSCH) published its own guidelines on the appropriate use of the drug for multiple myeloma. In the guidelines, it is indicated that doctors should register the patients prescribed thalidomide for multiple myeloma to the office of the JSCH. In addition, patients should be properly educated to understand the risks of terato-genicity and other adverse reactions due to treatment with thalidomide. Patients should be made aware of effective methods of contraception and the safe stor-age of thalidomide in the home. Furthermore, doctors should report serious adverse events to the JSCH. In late 2005 or early 2006, a new web system for thalidomide registry will be operated to enforce the JSCH guide-line. The website will be run by the ‘University hospi-tal Medical Information Network’ (UMIN), which is recognized as the infrastructure for academic activ-ities (UMIN, 2005). Upon approval of thalidomide, the MAH will be responsible for the risk management.

It is becoming increasingly easy for patients to obtain information via the Internet on a new drug that is not approved in their own country. In Japan, the approval of a new drug can often take several years after the original approval somewhere else in the world. Indeed, this is currently a major social issue in Japan. Although the regulatory body is making every effort to improve the situation, in particular by promoting clinical trials, the changes are being intro-duced slowly, mainly because improvements in the infrastructure needed to conduct the clinical studies are not yet in place. Prior to the commencement of clinical trials in Japan, the involvement of academia and non-governmental bodies in risk management may be required for patients using unapproved drugs, as well as for patients who are not covered by the clinical trials for new drug applications.

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