32: Clinical Microbiology In Vitro Diagnostics in Japan

CHAPTER 32
Clinical Microbiology In Vitro Diagnostics in Japan: Regulatory Requirements and Product Information


Koji Kawakami and Yukie Yamauchi


Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Japan


32.1 The regulatory structure of pharmaceuticals and clinical trials in Japan


The current Japanese Pharmaceutical Affairs Law of 1960 (act no. 145) regulates licensed marketing business practice that routinely manufactures medicinal and pharmaceutical products and conducts national product distribution. Therefore, the regulated subjects of this Law are not research institutions such as universities, but rather commercial enterprises, including pharmaceutical companies. Under the regulation of the Pharmaceutical Affairs Law, clinical trials conducted for the purpose of marketing approval by the government (via the Minister of Health, Labour, and Welfare) are called “chiken,” (lit: treatment trials). Upon approval, an official price of the product is determined by the Government and then listed on the national health insurance price listing, which allows national medical institutions to use the product.


The Pharmaceuticals and Medical Devices Agency (PMDA) reviews the enforcement of chiken, as well as post-trial applications for marketing. Since the revision of the Japanese Pharmaceutical Affairs Law created several years ago, not only pharmaceutical companies, but also medical institutions, including academic hospitals, can also submit applications for investigator-initiated clinical trials to PMDA. However, there are exceptions for the regulatory requirements under the Japanese Pharmaceutical Affairs Law. With regards to novel molecular entities that are unapproved in any fields other than genetic and cellular therapies, the application and review process is not necessary if the new molecular entity is used as an investigational product for non-chiken clinical research (hereafter called “clinical research”, conducting development which is not for the purpose of marketing approval), conducted by institutions such as universities. The advantage of this clinical research is that the expenses are covered by the national Special Healthcare Expenditure system if a subject participates in clinical research at a designated institution. For all clinical research, ethical guidelines are required. Nonetheless, it is still easier for investigators to conduct clinical research than chiken because the clinical research does not mandate good clinical practice (GCP). On the other hand, the clinical data obtained through clinical research is often considered insufficient evidence. Hence, the data cannot be used to evaluate new products for marketing approval in Japan and other countries.


Further information can be found on the following websites of the Ministry of Health, Labour, and Welfare and PMDA: Ministry of Health, Labour, and Welfare – www.mhlw.go.jp/english/; Pharmaceuticals and Medical Devices Agency in Japan – www.pmda.go.jp/english/


32.2 The regulatory structure of in vitro diagnostic testing in Japan


In vitro diagnostic (IVD) reagents are described in Article 2, paragraph 13 of the Pharmaceutical Affairs Law of 1960. The term “in vitro diagnostic reagent” used in this law refers to a test, device, or reagent not directly applied to the human or animal body and exclusively used in the diagnosis of disease.


Diagnostic tests for infectious diseases are classified based on their risk (see Table 32.1). In contrast to Class I items (low-risk tests and reagents) or Class II items (relatively low-risk tests and reagents), which require no regulatory review by PMDA and are instead cleared by third party certification, certain diagnostic tests for infectious diseases are classified into Class III (relatively high-risk tests and reagents), which requires approval from the Minister of Health, Labour, and Welfare. The approval criteria are divided into two categories: reagents for detection (e.g., qualitative and semiquantitative tests) and reagents for measurement (e.g., quantitative tests). There is a specific testing method, control reagent, and statistical method determined for each reagent. The differences in the criteria for reagents for detection and reagents for measurement are the number of specimens tested and their analytical method.


Table 32.1 Classification of in vitro diagnostic reagents in Japan












































Class Outline Compliance with Standards Application process required Review authority
I Reagents that have lower risks as diagnostic information tools for making diagnoses and lower potential to produce life-threatening experiences than Class III. Certified reference materials or standard measurement methods are given on the bulletin for the reagent, which provide convenient manufacture control and quality assurance management. Nonprescription reagents (over-the-counter) are excluded, e.g., GPT, GOT, ALP, glucose, LDH, HbA1c, IgG, cholesterol, estradiol Compliant Marketing notification No review necessary
Noncompliant Marketing approval Pharmaceuticals and Medical Devices Agency
II Reagents that have relatively low risks as diagnostic information tools for making diagnoses and lower potential to produce life-threatening experiences than Class III. Nonprescription reagents (over-the-counter) are included, e.g., hematologic tests including hemoglobin and hematocrit, autoimmunology tests including anti-Sm antibody Compliant Marketing certification Registered certifying agency
Noncompliant Marketing certification Pharmaceuticals and Medical Devices Agency
III Reagents that have relatively high risks as diagnostic information tools for making diagnoses and high potential to produce life-threatening experiences, e.g., cancer, diagnostic tests for infectious diseases including HIV and HCV tests, genetic diagnostic reagents including NAT test, microbiology tests Compliant Marketing approval Pharmaceuticals and Medical Devices Agency
Noncompliant Marketing approval Pharmaceuticals and Medical Devices Agency
No standards Marketing approval Pharmaceuticals and Medical Devices Agency

An applicant may determine in which class the product for consideration is classified. In cases where the appropriate class is difficult to determine, an applicant may consult the PMDA. The application categories are divided as follows (see below): (1) new products that are to detect or measure a new product; (2) products with undetermined approval criteria; (3) products which meet existing approval criteria; and (4) products which do not meet approval criteria. The category for each product should be determined based on its characteristics and results of clinical trials. The fees for determining approval are different depending on the application category.


Categories:



  1. New product – application for marketing approval of IVD reagents that are to detect or measure a new product.
  2. Nonstandard approval product – Class III IVD reagents with undetermined approval criteria (e.g., HIV,HCV, HDV,HTLV,genetic testing items for pathogens, human genetic testing items).
  3. Conformity approval product – IVD reagents whose approval criteria have been determined and have also been met.
  4. Nonconforming approval product – IVD reagents whose approval criteria have been determined, but on testing against these approval criteria, fail to meet them.

All IVD testing for tests, devices and instruments, including domestic and imported products must follow these guidelines.


32.3 Marketing of IVD reagents in Japan


32.3.1 Marketing licenses


Marketing of IVD reagents is allowed only for licensed marketing approval holders who have submitted an application for marketing approval, marketing certification, or a notification of marketing on a product-by-product basis. These holders must receive approval or certification to start their practice. The regulations apply to all products used in Japan regardless of domestic or foreign origin. In addition to the marketing approval or certification, licensed marketing approval holders must also submit an application for quality management system (QMS) compliance inspection. Licensed marketing approval holders who wish to market IVD reagents are required to obtain a No. 2 type license for marketing.


The requirements for the No. 2 type license approval are as follows: complying with standards for quality control (GQP and QMS) and standards for postmarketing safety management (good vigilance practice; GVP). Marketing business licenses are granted by the prefectural governor at the location of the business’s principal office following submission of their application. Marketing business licenses are valid for 5 years and must be renewed before the expiration date.


32.3.2 Foreign manufacturers


Foreign manufacturers whose facilities are located outside Japan and who wish to export IVD reagents to Japan are required to obtain relevant accreditation of foreign manufacturers. The accreditation of foreign manufacturers is granted by the Minister of Health, Labour, and Welfare on a facility-by-facility basis. The application process for accreditation may be conducted by proxy by a licensed marketing approval holder of the drug or medical device on behalf of a foreign manufacturer. Accreditation of foreign manufacturers is valid for 5 years. The accreditation needs to be renewed before the expiration date.


In vitro diagnostic reagents are classified by generic names that are given to each individual reagent. These generic names are determined based on the nomenclature for IVD reagents from the ISO/TC120 Global Medical Device Nomenclature (GMDN) project.


The approval criteria for Class III IVD reagents are described as follows:



  1. Reagents for detection
Dec 10, 2017 | Posted by in MICROBIOLOGY | Comments Off on 32: Clinical Microbiology In Vitro Diagnostics in Japan
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