Chapter II. Standards for Preparing Clinical Trials. Section 1.

Standards for Preparing Clinical Trials by Persons Who Intend to Sponsor Clinical Trials: 'Ministerial Ordinance on Good Clinical Practice for Drugs', PMDA Japan

Article 4. Operating Procedures, etc.

1. A person who intends to sponsor a clinical trial shall prepare written operating procedures for the duties related to sponsoring and managing the clinical trial such as preparation of the protocol, selection of medical institutions and investigators, control/accountability of investigational products, collection of information on adverse drug reactions, record keeping.

2. The person who intends to sponsor a clinical trial shall secure professionals with adequate expertise to fulfill the duties related to sponsoring and managing the clinical trial, such as physicians, dentists, and pharmacists.

Article 5. Conduct of Toxicity Studies etc.

The person who intends to sponsor a clinical trial shall have completed studies on the quality, toxicity and pharmacological effects of the test drug and other studies required for sponsoring the clinical trial.

Article 6. Selection of Medical Institution.

The person who intends to sponsor a clinical trial shall select a medical institution that meets the qualifications specified in Article 35 and an investigator who meets the qualifications specified in Article 42.

Article 7. Protocol.

1. The person who intends to sponsor a clinical trial shall prepare a protocol that should include the following information:

(1) Name and address of the person who intends to sponsor a clinical trial (or, in the case of a corporation, company name [the same shall apply in this item, the following item, Article 13, Paragraph 1, Items (2) and (3); Article 15-4, Paragraph 1, Items (2), (3) and (7); and Article 16, Paragraph 1, Item (2)] and address of its principal office [the same shall apply in this item; the following item; Article 13, Paragraph 1, Items (2) and (3); Article 15; Article 15-4, Paragraph 1, Items (2), (3) and (7); Article 16, Paragraph 1, Item (2); and Article 26, Paragraph 2]) (or, if the person resides outside Japan, then his or her name and name of the country where the person is located, and name and address of the clinical trial in-country representative pursuant to Article 15; the same shall apply in Article 13, Paragraph 1, Item (2))

(2) When all or any of the duties related to the clinical trial are outsourced to another person or organization (hereinafter referred to as "contractor" in this chapter), name and address of the contractor and the scope of the duties outsourced
(3) Name(s) and address(es) of medical institution(s)
(4) Name(s) and title(s) of the person(s) to be appointed as the investigator(s)
(5) Objectives of the clinical trial
(6) Summary of the test drug
(7) Clinical trial design
(8) Description of subject selection
(9) Description of direct access to source documents
(10) Description of record (including data) keeping
(11) Name(s) and title(s) of coordinating investigator(s) to whom the responsibilities for coordination are assigned, if applicable
(12) Names and titles of physicians or dentists constituting a coordinating committee to which the responsibilities for coordination are assigned, if applicable
(13) If an Efficacy and Safety Assessment Committee is established pursuant to Article 19, then a note to that effect.

2. The person who intends to sponsor a clinical trial shall state in the protocol, if applicable, that the investigational product affords no intended clinical benefit to the subject, and that some subjects are to be enrolled in the clinical trial although it would be difficult to obtain their own consent under Article 50, Paragraph 1. The protocol should also include the following information:

(1) Reasons why some subjects are to be enrolled in the clinical trial although it would be difficult to obtain their own consent under Article 50, Paragraph 1

(2) Explanation that the potential disadvantages which the subject may incur in the clinical trial are minimized

3. The person who intends to sponsor a clinical trial shall state in the protocol that, if applicable, some subjects are to be enrolled in the clinical trial although it would be difficult to obtain their own consent under Article 50, Paragraphs 1 and 2. The protocol should also include the following information:
(1) Explanation that an application for marketing approval of the test drug is intended to be submitted so that the drug will be used for emergency treatment to save lives of patients in a life-threatening condition
(2) Explanation that currently available treatments are unlikely to achieve sufficient therapeutic effects in the prospective subject
(3) Explanation that there is a sufficient possibility of saving the life of the prospective subject by using the test drug
(4) A note that an Efficacy and Safety Assessment Committee under Article 19 has been established for the clinical trial

4. When preparing a protocol pursuant to Paragraph 1, the person who intends to sponsor a clinical trial shall gain agreement with a person to be appointed as an investigator on the content of the protocol and that the clinical trial be conducted in compliance with the protocol.

5. The person who intends to sponsor a clinical trial shall revise the protocol as necessary whenever important new information becomes available that may be relevant to the proper conduct of the clinical trial, such as information on the quality, efficacy and safety of the test drug. In this case, the provisions of the preceding paragraph shall apply mutatis mutandis.

Article 8. Investigator’s Brochure (IB)

1. The person who intends to sponsor a clinical trial shall prepare an Investigator’s Brochure that states the following information, based on the data obtained in the studies specified in Article 5 and the information on the quality, efficacy and safety of the test drug:

(1) Chemical name or identification code of the test drug
(2) Information on the test drug, such as its quality, toxicity, and pharmaceutical effects
(3) Results of clinical studies of the investigational product, if any has been conducted

2. The person who intends to sponsor a clinical trial shall revise the Investigator’s Brochure as necessary whenever important new information becomes available that may be relevant to the proper conduct of the clinical trial, such as information on the quality, efficacy and safety of the test drug.

Article 9. Request for Preparation of Written Information

The person who intends to sponsor a clinical trial shall request the prospective investigator to prepare documents for providing the explanation as specified in Article 50, Paragraph 1 (hereinafter referred to as "written information").

Article 10. Prior Submission of Documents to the Head of Medical Institution

1. The person who intends to sponsor a clinical trial shall beforehand submit the following documents to the head of the medical institution:

(1) Protocol (including its amendments pursuant to Article 7, Paragraph 5)
(2) Investigator’s Brochure (including its amendments pursuant to Article 8, Paragraph 2)
(3) Sample of the case report form
(4) Written information
(5) List of prospective investigators and subinvestigators (hereinafter collectively referred to as “investigators etc”).
(6) Documents on the burden of expenses for the clinical trial
(7) Document explaining compensation to the subject in the event of trial-related injuries

2. A person who intends to sponsor a clinical trial may, in lieu of submitting the documents as stipulated in the preceding paragraph, send the information that must be submitted in writing as stipulated in the preceding paragraph by using electronic data processing system or other information-communication technologies specified below (hereinafter referred to as "electromagnetic means") pursuant to Paragraph 5, with the
consent of the head of the medical institution. In this case, the person who intends to sponsor a clinical trial shall be deemed to have submitted the documents.
(1) A method of using an electronic data processing system of either (a) or (b):
     (a) A method where the information is transmitted from a computer used by the person who intends to sponsor a clinical trial to a computer used by the head of the medical institution via a telecommunication line connecting the computers, and the information is recorded in a file on the computer used by the recipient.
     (b) A method where the information stipulated in the preceding paragraph that is recorded in a file on a computer used by the person who intends to sponsor a clinical trial is made available for access by the head of the medical institution, and the information as stipulated in the preceding paragraph is recorded in a file on the computer used by the head of the medical institution (if the head of the medical institution notifies the person who intends to sponsor a clinical trial of the decision on whether or not to accept the transmission of documents by electromagnetic means, then including the method of recording the notification in a file on the computer used by the person who intends to sponsor a clinical trial).

(2) A method of delivering the information as stipulated in the preceding paragraph recorded in a file on a magnetic disk, CD-ROM, or other storage media that can securely store the specified information.

3. The method as stipulated in the preceding paragraph must allow the head of the medical institution to prepare the documents by printing out the data recorded in the file.

4. The term "electronic data processing system" used in Paragraph 2, Item (1) refers to an electronic data processing system where a computer used by the person who intends to sponsor a clinical trial is connected via a telecommunication line with a computer used by the head of the medical institution.

5. When the person who intends to sponsor a clinical trial submits the documents as stipulated in Paragraph 1 pursuant to Paragraph 2, he or she shall beforehand inform the head of the medical institution of the type and description of the electromagnetic means shown below and obtain consent from the head of medical institution in writing or by electromagnetic means.

(1) Among the methods stipulated in Paragraph 2, the method used by the person who intends to sponsor a clinical trial
(2) File format

6. When notified by the head of the medical institution, either in writing or by
electromagnetic means, that notification by electromagnetic means is unacceptable, even if the consent has been obtained once as stipulated in the preceding paragraph, the person who intends to sponsor a clinical trial shall not submit the documents stipulated Paragraph 1 by electromagnetic means to the head of the medical institution, except when the head of the medical institution gives another consent pursuant to the preceding
paragraph later.

Article 11. Prohibition of Prior Supply of Investigational Products

The person who intends to sponsor a clinical trial shall not supply medical institutions with investigational products before the clinical trial contract is concluded.

Article 12. Outsourcing Duties

1. The person who intends to sponsor a clinical trial shall conclude a contract with a contractor by means of a document specifying the following information when outsourcing all or any of the duties related to sponsoring and managing the clinical trial:
(1) Scope of the duties outsourced
(2) Description of the operating procedures for the duties outsourced
(3) Statement that the person who intends to sponsor a clinical trial is entitled to ascertain whether the duties outsourced are conducted properly and smoothly in compliance with the operating procedures specified in the preceding item
(4) Description of instructions to the contractor
(5) Statement that if the instructions specified in the preceding item are given, the person who intends to sponsor a clinical trial is entitled to ascertain whether appropriate measures are taken in response to the instructions
(6) Description of reports to be submitted by the contractor to the person who intends to sponsor a clinical trial
(7) Description of measures specified in Article 14 relating to the duties outsourced
(8) Other necessary matters related to the duties outsourced

2. A person who intends to sponsor a clinical trial may, in lieu of making a written contract as stipulated in the preceding paragraph, conclude a contract specifying the matters as stipulated in the preceding paragraph by using an electronic data processing system or other information-communication technologies specified below (hereinafter referred to
as "electromagnetic means" in this Article), pursuant to Paragraph 5, with the consent of the contractor as stipulated in the preceding paragraph (hereinafter referred to as "contractor" in this Article). In this case, the person who intends to sponsor a clinical trial shall be deemed to have concluded a written contract.

(1) A method of using an electronic data processing system of either (a) or (b):

    (a) A method where the information is transmitted between a computer used by the person who intends to sponsor a clinical trial and a computer used by the contractor via a telecommunication line connecting the computers, and the information is recorded in a file on the computer used by either party.
   (b) A method where the information stipulated in the preceding paragraph that is recorded in a file on a computer used by the person who intends to sponsor a clinical trial is made available for access by the contractor, and the information as stipulated in the preceding paragraph is recorded in a file on the computer used by the contractor (if the contractor notifies the person who intends to sponsor a clinical trial of the decision on whether or not to accept the conclusion of a contract by electromagnetic means, then including the method of recording the notification in a file on the computer used by the person who intends to sponsor a clinical trial).

(2) A method of delivering the information as stipulated in the preceding paragraph is recorded in a file on a magnetic disk, CD-ROM, or other storage media that can securely store the specified information.

3. The method as specified in the preceding paragraph must conform to the technical standards below.

(1) The method must allow the person who intends to sponsor a clinical trial and the contractor to prepare the documents by printing out data recorded in a file.
(2) The method must employ a means by which one can confirm that the information in the documents recorded in the file has not been modified.

4. The term "electronic data processing system" used in Paragraph 2, Item (1) refers to an electronic data processing system where a computer used by the person who intends to sponsor a clinical trial is connected via a telecommunication line with a computer used by the contractor.

5. When the person who intends to sponsor a clinical trial concludes a contract specifying the matters as stipulated in Paragraph 1 pursuant to Paragraph 2, he or she shall  beforehand inform the contractor of the type and description of the electromagnetic means shown below, and obtain consent from the contractor in writing or by electromagnetic means.

(1) Among the methods stipulated in Paragraph 2, the method used by the person who intends to sponsor a clinical trial
(2) File format

6. When notified by the contractor, either in writing or by electromagnetic means, that the conclusion of the contract by electromagnetic means is unacceptable, even if the consent has been obtained once as stipulated in the preceding paragraph, the person who intends to sponsor a clinical trial shall not conclude the contract stipulated Paragraph 1 by electromagnetic means with the contractor, except when the contractor gives another
consent pursuant to the preceding paragraph later.

Article 13. Clinical Trial Contract

1. A clinical trial contract shall be concluded by means of a document specifying the following information between the person who intends to sponsor a clinical trial and medical institutions (or among the person who intends to sponsor a clinical trial, contractor(s), and medical institution when all or any of the duties are outsourced pursuant to the preceding Article):
(1) Date of concluding the contract
(2) Name and address of the person who intends to sponsor a clinical trial
(3) Name(s) and address(es) of the contractor(s) and the scope of the duties outsourced, if all or any of the duties are outsourced pursuant to the preceding article
(4) Name(s) and address(es) of the medical institution(s)
(5) Name(s) and title(s) of the person(s) in charge of the contract from each party
(6) Name(s) of the investigator(s)
(7) Duration of the clinical trial
(8) Description of the control/accountability of investigational products
(9) Description of record keeping (including data)
(10) Description of notifications given by the sponsor and the personnel of the medical institution in accordance with this Ministerial Ordinance
(11) Description of maintenance of the confidentiality of the subjects
(12) Description of the expense for the clinical trial
(13) Statement that the medical institution conducts the clinical trial in compliance with the protocol
(14) Statement that the medical institution will provide the sponsor with direct access to the records (including documents) specified in Article 41, Paragraph 2, upon request by the sponsor
(15) Statement that the sponsor may cancel the contract if it is found that the medical institution has violated this Ministerial Ordinance, the protocol, or the relevant contract, resulting in interference with the proper conduct of the clinical trial (excluding cases stipulated in Article 46)
(16) Description of compensation to the subject in the event of trial-related injuries
(17) Other matters necessary to ensure that the clinical trial is conducted properly and smoothly

2. The provisions of Article 12, Paragraphs 2 through 6 shall apply mutatis mutandis to the written contract as stipulated in the preceding paragraph. In this case, “the contractor as stipulated in the preceding paragraph” in Article 12, Paragraph 2 and "contractor" in Article 12, Paragraph 2, Items (1); Paragraph 3, Item (1); and Paragraphs 4 through 6, shall be read as "the medical institution" (the medical institution and the contractor, if all
or any of the duties are outsourced pursuant to this article) (hereinafter referred to as the "medical institutions etc.”) and "medical institutions etc.," respectively.

Article 14. Compensation to Subjects

The person who intends to sponsor a clinical trial shall beforehand take necessary measures such as purchasing insurance in preparation for compensation to the subject in the event of trial-related injuries (including those attributable to the duties performed by the contractor).

Article 15. Clinical Trial In-Country Representative

In order to take the necessary measures to prevent the occurrence or spread of health hazards due to investigational products, the person who intends to sponsor a clinical trial and resides outside Japan shall appoint a person eligible for sponsoring the clinical trial on behalf of the person who intends to sponsor a clinical trial from among persons residing in Japan (including the head of a Japanese business office of a foreign company) to have him or her (hereinafter referred to as "clinical trial in-country representative") conduct the procedures for sponsoring the clinical trial.

 

Ministerial Ordinance on Good Clinical Practice for Drugs:  Pharmaceuticals and Medical Devices Agency, Japan

 

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