2nd Report of the Market Access Ombudsman Council (March 14, 1995)

2-(1) Simplification of approval procedures etc. for in-vitro diagnostics

1. Complainant: European Business Council, German Embassy

2. Ministry concerned: Ministry of Health and Welfare

3. Complaint:

According to the Pharmaceutical Affairs Law, when manufacturing and importing drugs or medical instruments, approval to manufacture (import) and license to manufacture (import generally) is required for each product.

In-vitro diagnostics belong to diagnostic drugs used in clinical tests and are used to detect or measure substances from samples taken from humans.

Although the approval and license are also required for manufacturing and importing of in-vitro diagnostics as other drugs, approval and licensing procedures for them are being simplified through cabinet ordinances, ministerial ordinances and notices.

The complainants state that since in-vitro diagnostics and medical instruments used with them are not regulated as drugs or medical instrument in many European countries, additional costs and are required when they plan to sell in-vitro diagnostics and medical instruments use with them developed in Europe in Japan, because of such Japanese regulation additional costs and time are required. Therefore they raised the following problems:

(1) The Pharmaceutical Affairs Law should be amended to place in-vitro diagnostics and medical instruments used with them in a separate category to simplify their handling in a basic and systematic way instead of the current system of partial simplification of procedures through cabinet ordinances, ministerial ordinances and notices.

(2) Further, even during this period, approval (licensing) procedures (requirements) should be simplified under the current system.

4. Results of deliberation:

It goes without saying that in-vitro diagnostics and instruments for them are used to diagnose diseases and establish treatment methods and that it is important that they be safe, of good quality, and used appropriately. However, they are different from other drugs and medical instruments since they are not used directly on the human body and the most important consideration is their function (efficacy). Given these characteristics, the concerned ministry has streamlined approval procedures by simplifying the documentation required to be attached and by shortening standard clerical processing time through cabinet ordinances, ministerial ordinances and notices and will continue to simplify procedures as much as possible. Where medical instruments used with them is concerned, the ministry is also studying eliminating approval procedures, except for new equipment.

In connection with the study of this question, a draft EU Committee order is being studied, which establishes a third category separate from drugs and medical instruments for in-vitro diagnostic products while the main European countries producing in-vitro diagnostics currently regulate these in various classifications. This difference in classification of such products in Japan and in Europe and the United States is behind this complaint. Therefore, it is essential in order to improve market access in this area to make the practical burden for approval be similar to U.S. and European levels by international harmonization of the system, while ensuring the function of the in-vitro diagnostics in question. The following measures are needed:

(1) The ministry concerned is taking steps to simplify approval procedures while ensuring the function of in-vitro diagnostic drugs. In this process, the gradual preparation of standards for in-vitro diagnostics, in consultation with the concerned parties including the complainants, and the establishment of the range of in-vitro diagnostics for which approval is not rewired and other measures, should be considered and implemented at early date as possible under the condition that necessary function of in-vitro diagnostics is ensured, so that the actual clerical burden in connection with approval examination is brought to U.S. and European levels. Regarding the question raised of establishing a separate classification from drugs and medical instruments for in-vitro diagnostics, the systems used in Europe and the United States will be studied to contribute to the consideration of above-mentioned measure.

It is expected that promoting these measures, together with the ministry's already established policy of not requiring approval for in-vitro diagnostic medical equipment except for new equipment, will be found satisfactory by the complainants.

(2) In order to simplify approval (license) procedures (requirements) further under the current system, the following measures should be taken immediately, taking into consideration the complaint raised.

1) When approval examination for in-vitro diagnostics takes place, depending on the product, this is sometimes subject to deliberation by or consultation with the Central Pharmaceutical Affairs Council, or documentation on test results from the National Institute of Health Institute must be attached. Criteria are currently established for conditions under which products are subject to deliberation by or consultation with the Central Pharmaceutical Affairs Council, or for which tests must be requested from the National Institute of Health, and some categories are given as examples. However, because complainants have mentioned that there are cases where it is difficult to know beforehand whether a product falls in the criteria, standards should be further clarified during FY1995, in consultation with the complainants, and the categories affected listed as far as possible and announced.
2) One of the requirements for a license to manufacture (import) drugs is that each manufacturing plants (import business office) establishment have a supervisor (pharmacist), and that when biological products are handled there be a separate supervisor with knowledge of microbiology (when in-vitro diagnostics are handled, there should be a separate supervisor with experience as a pharmacist). In cases where in-vitro diagnostics are handled, given their characteristics, the requirement for separate supervisors for biological and non-biological products should be simplified during FY1995 so that one pharmacist may assume both duties.
3) Data on stability tests are required to be attached when application for approval of in-vitro diagnostics is made. The ministry concerned will grant approval even in cases where the established validity period is under six months, if there are rational reasons for this. The notices concerning this should be amended during FY1995 to make it clear that periods shorter than six months are acceptable. When this is done, the meaning of "rational reasons" should be clarified as far as possible.
4) The standard clerical processing period for approval for in-vitro diagnostics is six months. Because this is considered by other countries to be a kind of promise, in order to complete the process, from receipt of application to actual delivery of the approval certificate to the applicant, within a six-month period, clerical process will be improved, with applications on floppy disk scheduled for introduction in FY1995, a computer on-line system to be set up between the Ministry and each prefecture, and others.

Government decision (March 28, 1995)

2-(1) Simplification of approval procedures for in-vitro diagnostics

(1) Based on the opinions of parties involved, gradual preparation of standards for in-vitro diagnostics and the establishment of a range for in-vitro diagnostics not requiring approval and other measures will be considered so that these measures will be implemented at an early date under the condition that necessary function of in-vitro diagnostics is made sure. Research and study on the systems in Europe and the United States will be undertaken to contribute to this study.

(2) The following steps will be taken immediately for further simplification of procedures and requirements for approval and license under the current system:

* For categories subject to deliberation or consultation by the Central Pharmaceutical Affairs Council and categories for the commission of testing to the National Institute of Health, the categories will be further clarified and the products in the categories in question will be listed and posted as far as possible during FY1995.

* Regarding the requirement to have a supervisor at each manufacturing plant (import business office) for in-vitro diagnostics, during FY1995 this requirement will be simplified taking the nature of in-vitro diagnostics into consideration, so that one pharmacist may assume the duties of supervisor for both biological and non-biological products.

* Regarding the established period of validity for in-vitro diagnostics, in order to clarify that approval will be granted even for periods of under six months if rational reasons are shown, the notification on the rule will be amended during FY1995. When doing so the meaning of "rational reasons" will be clarified as much as possible.

* The clerical process for approval will be improved, by enabling applications on floppy disk from FY1995, by establishing an on-line system with each prefecture and Ministry of Health and Welfare, and by other measures so that the clerical processing for approval can be made within the standard processing periods, i.e. six months.

Follow-up (May 27,1996)

2-(1) Simplification of approval procedures etc. for in-vitro diagnostics

(1)
1) Based on consultations with the EBC and other concerned bodies, a notice from the Director of the Examination Division, Pharmaceutical Affairs Bureau, was issued in March 1996 regarding the scope of products for which approval will not be required. This notice states that as long as function is not affected, changes in ingredients or quantities which are not involved in the reaction, or changes in the dosage form of the constituent reagents, may be made without requiring approval for changes in the items of approval granted. Further consultations will be held with the concerned parties concerning other areas where changes may be allowed without requiring approval, in order to reduce the burden on applicants.
2) A survey of systems in EU countries and US will be undertaken in FY1996 in order to study classifying in-vitro diagnostics separately from drugs.

(For reference)
Regarding the Ministry of Health and Welfare's already established policy of not requiring approval for medical equipment used for in-vitro diagnostics, except for new equipment. The regulations of the Pharmaceutical Affairs Law, amended in June 1995 (effect in July 1995), specify many types of medical equipment, including medical equipment for in-vitro diagnostics, except for new equipment, as types without approval by product.

(2)
1) Based on consultations with the EBC and others, a notice from the Director of the Examination Division, Pharmaceutical Affairs Bureau issued in March 1996 listed in-vitro diagnostics for HIV, HCV, and others and clarified which are subject to deliberation by or consultation with the Central Pharmaceutical Affairs Council, or for which tests must be requested from the National Institute of Health.
2) A notice from the Director General of the Pharmaceutical Affairs Bureau issued in December 1995 allows supervisory duties for biological and non-biological in-vitro diagnostics to be handled by one pharmacist allocated in each manufacturing plant (import business office).
3) A notice from the Director General of the Pharmaceutical Affairs Bureau in March 1996 clarifies that established validity periods of less than six months for data on stability tests are acceptable.
4) A notice from the Director of the Examination Division, Pharmaceutical Affairs Bureau was issued in June 1995 announcing that applications on floppy disks would be accepted and that an on-line system with each prefecture would be set up in order to improve clerical processing.

Further Follow-up (May 12, 1997)

2-(1) Simplification of approval procedures etc. for in-vitro diagnostics

(1)
1) To simplify approval procedures for in-vitro diagnostics while ensuring their function, based on specific requests made by the concerned parties, the ministry introduced a new category which does not require a change in approval if some changes are made in the preparation method for the reagent used, as long as there is no effect on the product's function.
Regarding the type of material to be measured, the issue of streamlining the documentation required for application for approval for products using ingredients for which there is a set international evaluation (standard products, etc.) will be studied and implemented in FY1997. Further, based on specific requests, study will be continued regarding reducing the clerical burden imposed in connection with application for approval to levels similar to those in the United States and Europe.
2) A delegated research committee consisting of experts in clinical testing will continue to study how the function of in-vitro diagnostics is ensured in the United States and Europe.