Thông tư 10/2020/TT-BYT

CIRCULAR

BIOEQUIVALENCE STUDIES FOR DRUGS

Pursuant to the Law on pharmacy No. 105/2016/QH13 dated April 06, 2016;

Pursuant to the Government’s Decree No. 75/2017/ND-CP dated June 20, 2017 defining functions, tasks, powers and organizational structure of the Ministry of Health;

At the request of the Director General of the Administration of Science Technology and Training;

The Minister of Health promulgates a Circular prescribing the bioequivalence studies for drugs.

Article 1. Scope and regulated entities

1. This Circular introduces regulations on inspection of fulfillment of eligibility requirements by facilities that conduct bioequivalence studies for drugs, guidance on bioequivalence studies for drugs, and bioequivalence study dossiers and procedures.

2. This Circular applies to facilities that conduct bioequivalence studies for drugs (hereinafter referred to as “bioequivalence study facility”) and other organizations and individuals involved in bioequivalence studies for drugs.

3. Bioequivalence study facilities subject to this Circular are facilities that meet facilities, equipment and personnel requirements laid down in Point g Clause 1 Article 33 of the Law on pharmacy, including:

a) Facilities that meet GLP (Good Laboratory Practices) principles and standards as set forth in the Circular No. 04/2018/TT-BYT dated February 09, 2018 of the Minister of Health on Good Laboratory Practices (hereinafter referred to as “Circular No. 04/2018/TT-BYT”) and GCP (Good Clinical Practice) principles and standards for phase 1 clinical trial as set forth in the Circular No. 29/2018/TT-BYT dated October 29, 2018 of the Minister of Health (hereinafter referred to as “Circular No. 29/2018/TT-BYT”).

b) Facilities that meet GLP requirements as prescribed in the Circular No. 04/2018/TT-BYT, do not have areas for monitoring drug users serving bioequivalence studies, and have signed cooperation contracts with clinical trial facilities that meet GCP requirements for phase 1 clinical trial as prescribed in the Circular No. 29/2018/TT-BYT;

c) Facilities that meet GLP requirements as prescribed in the Circular No. 04/2018/TT-BYT, have areas for monitoring drug users serving bioequivalence studies, that meet GCP principles and standards as prescribed in the Appendix enclosed herewith, and have signed cooperation contracts with clinical trial facilities that meet GCP requirements as prescribed in the Circular No. 29/2018/TT-BYT for conducting clinical trial in support of the bioequivalence study for drugs.

Article 2. Application for inspection of fulfillment of eligibility requirements by bioequivalence study facilities

1. The facility prescribed in Point a Clause 3 Article 1 hereof shall submit 01 set of application which includes:

a) The documents prescribed in Article 5 of the Circular No. 04/2018/TT-BYT serving the inspection of GLP compliance and the documents in Article 8 of the Circular No. 29/2018/TT-BYT serving the inspection of GCP compliance. Where a facility has been issued with a Certificate of GLP compliance or GLP compliance inspection report, it shall only submit the documents prescribed in Article 8 of the Circular No. 29/2018/TT-BYT for inspection of GCP compliance.

b) If a facility has been issued with Certificate of GLP compliance and Certificate of GCP compliance or GLP and GCP compliance inspection reports, it shall only submit an application for the Certificate of eligibility for pharmacy business according to the Form prescribed in Clause 1 Article 32 of the Government’s Decree No. 54/2017/ND-CP dated May 08, 2017 for implementation of the Law on pharmacy (for bioequivalence study service providers), in which the availability of Certificate of GLP compliance and Certificate of GCP compliance or GLP and GCP compliance inspection reports must be clearly stated. A non-commercial bioequivalence study facility shall only submit an application for approval for bioequivalence studies for drugs according to Form No. 01 enclosed herewith.

2. The facility prescribed in Point b Clause 3 Article 1 hereof shall submit 01 set of application as prescribed in Article 5 of the Circular No. 04/2018/TT-BYT (if applying for inspection of GLP compliance) or an application as prescribed in Point b Clause 1 of this Article (if it has been issued with the Certificate of GLP compliance) and the following technical documents:

a) The cooperation contract signed with the health facility that meets GCP requirements for phase 1 clinical trial;

b) The copy of the Certificate of GCP compliance for phase 1 clinical trial of the cooperating health facility or the GCP compliance inspection report for phase 1 clinical trial;

3. The facility prescribed in Point c Clause 3 Article 1 hereof shall submit 01 set of application as prescribed in Article 5 of the Circular No. 04/2018/TT-BYT (if applying for inspection of GLP compliance) or an application as prescribed in Point b Clause 1 of this Article (if it has been issued with the Certificate of GLP compliance) and the following technical documents:

a) The list of material, technical and first aid facilities of the bioequivalence study facility;

b) The cooperation contract signed with the health facility that meets GCP requirements;

c) The copy of the Certificate of GCP compliance of the cooperating health facility or the GCP compliance inspection report.

Article 3. Procedures for inspection of fulfillment of eligibility requirements by bioequivalence study facilities

1. The bioequivalence study facility shall submit 01 set of application as prescribed for each corresponding case in Article 2 hereof, accompanied by the application fees, to the Drug Administration of Vietnam affiliated to the Ministry of Health.

2. For a facility prescribed in Point a Clause 3 Article 1 hereof:

a) The Drug Administration of Vietnam shall cooperate with the Administration of Science Technology and Training to carry out the inspection of GLP and GCP compliance according to the procedures in Circular No. 04/2018/TT-BYT and/or Circular No. 29/2018/TT-BYT.

b) If the bioequivalence study facility has been issued with the Certificate of GLP compliance or GLP compliance inspection report, the Drug Administration of Vietnam shall cooperate with the Administration of Science Technology and Training to carry out the inspection of GCP compliance according to the procedures in Circular No. 29/2018/TT-BYT.

c) If the bioequivalence study facility has been issued with the Certificate of GLP compliance and Certificate of GCP compliance or GLP and GCP compliance inspection reports, the Drug Administration of Vietnam shall cooperate with the Administration of Science Technology and Training to receive and carry out the inspection of application.

3. For a facility prescribed in Point b Clause 3 Article 1 hereof:

a) If the bioequivalence study facility does not have Certificate of GLP compliance or GLP compliance inspection report, the Drug Administration of Vietnam shall cooperate with the Administration of Science Technology and Training to carry out the inspection of GLP compliance according to the procedures in Circular No. 04/2018/TT-BYT.

b) If the bioequivalence study facility has been issued with the Certificate of GLP compliance or GLP compliance inspection report, the Drug Administration of Vietnam shall cooperate with the Administration of Science Technology and Training to receive and carry out the inspection of application.

4. For a facility prescribed in Point c Clause 3 Article 1 hereof:

a) If the bioequivalence study facility does not have Certificate of GLP compliance or GLP compliance inspection report, the Drug Administration of Vietnam shall cooperate with the Administration of Science Technology and Training to carry out the inspection of GLP compliance and the area for monitoring drug users serving bioequivalence study according to the procedures in Circular No. 04/2018/TT-BYT.

b) If the bioequivalence study facility has been issued with the Certificate of GLP compliance or GLP compliance inspection report, the Drug Administration of Vietnam shall cooperate with the Administration of Science Technology and Training to carry out the inspection of the area for monitoring drug users serving bioequivalence study and first aid facilities within 15 days from receipt of the adequate application.

Article 4. Processing results of inspection of fulfillment of eligibility requirements by bioequivalence study facilities

1. For a facility prescribed in Point a Clause 3 Article 1 hereof:

a) Processing of inspection results and issuance of Certificate of eligibility for pharmacy business that allows the bioequivalence study for drugs (for bioequivalence study service providers), Certificate of GLP compliance and Certificate of GCP compliance or refusal to issue these certificates shall comply with the provisions in Article 8 of the Circular No. 04/2018/TT-BYT or Article 11 of the Circular No. 29/2018/TT-BYT.

b) If a bioequivalence study facility is not required to obtain a Certificate of eligibility for pharmacy business, Certificate of GLP compliance and Certificate of GCP compliance or GLP and GCP compliance inspection reports are used as the basis for conducting bioequivalence study for drugs.

c) If a bioequivalence study facility has been issued with the Certificate of GLP compliance and Certificate of GCP compliance or GLP and GCP compliance inspection reports, after completion of the inspection of the received application, the Drug Administration of Vietnam affiliated to the Ministry of Health shall request the Minister of Health to issue the Certificate of eligibility for pharmacy business that allows the bioequivalence study for drugs (for bioequivalence study service providers) or give a notification of fulfillment of eligibility requirements by the bioequivalence study facility according to Form No. 02 enclosed herewith within 15 days from receipt of an adequate application.

2. For a facility prescribed in Point b Clause 3 Article 1 hereof:

a) If a facility does not have a Certificate of GLP compliance or GLP compliance inspection report, the processing of inspection results and issuance of Certificate of eligibility for pharmacy business that allows the bioequivalence study for drugs (for bioequivalence study service providers), Certificate of GLP compliance or refusal to issue these certificates shall comply with the provisions in Article 8 of the Circular No. 04/2018/TT-BYT.

If a bioequivalence study facility is not required to obtain a Certificate of eligibility for pharmacy business, the Drug Administration of Vietnam affiliated to the Ministry of Health shall give a notification of fulfillment of eligibility requirements by the bioequivalence study facility according to Form No. 02 enclosed herewith when issuing the Certificate of GLP compliance.

b) If a facility has been issued with the Certificate of GLP compliance or GLP compliance inspection report, after completion of inspection of the received application, the Drug Administration of Vietnam affiliated to the Ministry of Health shall request the Minister of Health to issue the Certificate of eligibility for pharmacy business that allows the bioequivalence study for drugs (for bioequivalence study service providers) or give a notification of fulfillment of eligibility requirements by the bioequivalence study facility according to Form No. 02 enclosed herewith within 15 days from receipt of an adequate application.

3. For a facility prescribed in Point c Clause 3 Article 1 hereof:

a) If a facility does not have a Certificate of GLP compliance or GLP compliance inspection report, the processing of inspection results shall comply with the provisions in Point a Clause 2 of this Article.

b) With regard to a facility that has been issued with the Certificate of GLP compliance or GLP compliance inspection report:

- If the inspection report indicates that the bioequivalence study facility meets the requirements in terms of the area for drug users serving bioequivalence study and first aid facilities as prescribed in the Appendix enclosed herewith, the Drug Administration of Vietnam affiliated to the Ministry of Health shall request the Minister of Health to issue the Certificate of eligibility for pharmacy business that allows the bioequivalence study for drugs (for bioequivalence study service providers) or give a notification of fulfillment of eligibility requirements by the bioequivalence study facility according to Form No. 02 enclosed herewith within 10 days from the date on which the inspection report is signed.

- If the inspection report indicates that the bioequivalence study facility needs to carry out remedial actions, within 05 working days from the date on which the site inspection at the premises of the bioequivalence study facility is completed and the inspection report is signed, the Drug Administration of Vietnam shall request the bioequivalence study facility in writing to carry out remedial actions against deficiencies specified in the inspection report.

Upon completion of remedial actions, the bioequivalence study facility shall provide a written report on remedial actions, accompanied by evidences of its completion of such remedial actions against the deficiencies specified in the inspection report (including documents, photos, videos and/or certifications);

Within 20 days from receipt of the report on remedial actions, the Drug Administration of Vietnam shall cooperate with the Administration of Science Technology and Training to assess the results of remedial actions implemented by the bioequivalence study facility and draw conclusions on the fulfillment of eligibility requirements by the bioequivalence study facility.

If results of remedial actions taken by the bioequivalence study facility are satisfactory, the Drug Administration of Vietnam affiliated to the Ministry of Health shall request the Minister of Health to issue the Certificate of eligibility for pharmacy business that allows the bioequivalence study for drugs (for bioequivalence study service providers) or give a notification of fulfillment of eligibility requirements by the bioequivalence study facility according to Form No. 02 enclosed herewith;

If results of remedial actions taken by the bioequivalence study facility are not satisfactory, the Drug Administration of Vietnam shall provide the applicant with written reasons.

Within 06 months from receipt of the written request from the Drug Administration of Vietnam for modification of the application, the bioequivalence study facility shall submit the application which has been modified as requested. Over this time limit, if the bioequivalence study facility fails to modify the application, or after 12 months from the date of first submission of the application which has been assessed unsatisfactory, the submitted application shall be no longer valid.

- If the inspection report indicates that the bioequivalence study facility fails to meet the requirements in terms of the area for drug users serving bioequivalence study and first aid facilities as prescribed in the Appendix enclosed herewith, within 05 days from the date on which the site inspection at the premises of the bioequivalence study facility is completed and the inspection report is signed, the Drug Administration of Vietnam shall give a notification of failure to meet eligibility requirements by the bioequivalence study facility, accompanied by the inspection report, to the applicant.

4. Within 05 working days from the date of issue of the Certificate of eligibility for pharmacy business that allows the bioequivalence study for drugs or Certificate of GLP compliance, Certificate of GCP compliance, notification of fulfillment of eligibility requirements by the bioequivalence study facility, the Drug Administration of Vietnam shall publish the following information on its website and the web portal of the Ministry of Health, including:

a) Name and address of the bioequivalence study facility;

b) Full name of the chief pharmacist, number of his/her pharmacy practice certificate;

c) Numbers of Certificate of eligibility for pharmacy business and Certificate of GLP compliance, Certificate of GCP compliance (if any);

d) Validity of inspection of fulfillment of eligibility requirements by the bioequivalence study facility and date of the next periodic inspection;

dd) Scope of operations of the bioequivalence study facility.

Article 5. Inspection of maintenance of fulfillment of eligibility requirements by bioequivalence study facilities

Periodic inspection, processing of periodic inspection results, control of changes and ad hoc inspection of maintenance of fulfillment of eligibility requirements by bioequivalence study facilities shall comply with the provisions in Chapter IV of the Circular No. 04/2018/TT-BYT and Chapter V of the Circular No. 29/2018/TT-BYT.

Article 6. Guidance on bioequivalence studies for drugs

Bioequivalence studies for drugs must be conducted in accordance with guidelines in Appendix 1 enclosed with Circular No. 32/2018/TT-BYT dated November 12, 2018 on marketing authorization of drugs and medicinal ingredients, Circular No. 08/2010/TT–BYT dated April 26, 2010 of the Minister of Health regarding reporting on bioavailability/bioequivalence study data in registration of drugs, and list of reference drugs promulgated by the Minister of Health.

Article 7. Bioequivalence study dossiers

Bioequivalence study dossier is a technical dossier, including application for registration of bioequivalence study, application for approval for bioequivalence study, and application for approval for bioequivalence study result. To be specific:

1. An application for registration of bioequivalence study includes:

a) An application form made according to Form No. 03 enclosed herewith;

b) Documents containing information about the drug undergoing the bioequivalence study such as names of drug and active ingredient, ingredients, concentration/content, dosage form and other relevant information (if any).

2. An application for approval for bioequivalence study includes:

a) An application form made by the bioequivalence study facility according to Form No. 04 enclosed herewith and submitted to the internal biomedical ethics committee.

b) Documents containing information about the drug undergoing the bioequivalence study, including drug study documents: composition, origin of medicinal ingredients, abbreviated manufacturing chart/process, quality standards, drug test report (issued by a manufacturer that meets GMP requirements or by a testing laboratory that meets GLP requirements), and pharmaceutical development document/dossier of the bioequivalence study facility;

c) Legal documents about the drug undergoing the bioequivalence study, including:

- The package inserts of the reference drug, which has been licensed for marketing, and of the drug undergoing the bioequivalence study (if any);

- The contract for cooperation in the bioequivalence study for drug signed between the facility owning the drug and the bioequivalence study facility; the cooperation contract signed between the organization or individual owning the drug and the bioequivalence study support unit (if any).

d) The bioequivalence study outline, including:

- A description of the bioequivalence study outline;

- Case Report Form (CRF);

dd) The academic résumé and copies of certificates of completion of training courses in GLP and/or safety reporting, issued by the Ministry of Health or GCP training institutions, of the principal investigator;

e) The bioequivalence study information sheet and informed consent forms of the participants in the bioequivalence study;

g) The label of the drug undergoing the bioequivalence study, indicating information about names of the drug and active ingredient, concentration/content, dosage form, batch number, expiry date, name and address of manufacturer. Labels of drugs granted certificates of drug registration shall comply with the provisions in Circular No. 01/2018/TT-BYT dated January 18, 2018 of the Minister of Health on labeling and package inserts of drugs and medicinal ingredients.

3. An application for approval for bioequivalence study result includes:

a) An application form made according to Form No. 05 enclosed herewith;

b) Report on the bioequivalence study for drug.

Article 8. Bioequivalence study procedures

Procedures for the bioequivalence study for drug shall be carried out in accordance with Article 100 and Article 101 of the Law on pharmacy. To be specific:

1. Registration of the bioequivalence study:

a) The facility that owns the drug undergoing the bioequivalence study shall submit 01 set of application for registration of bioequivalence study as prescribed in Clause 1 Article 7 hereof to the bioequivalence study facility.

b) The bioequivalence study facility shall consider accepting the application and entering into a bioequivalence study service contract with the facility owning the drug.

2. Approval for the bioequivalence study:

a) The bioequivalence study facility shall prepare 01 set of application as prescribed in Clause 2 Article 7 hereof, and send it to the internal biomedical ethics committee.

b) The internal biomedical ethics committee shall hold a meeting for inspection of the bioequivalence study outline within 10 days from receipt of an adequate application, and issue an inspection record.

c) Within 05 days from the date on which the inspection record is given by the internal biomedical ethics committee, the person in charge of professional expertise of the bioequivalence study facility shall decide to give approval for the bioequivalence study outline if it is satisfactory.

d) If the bioequivalence study outline needs to be modified, the bioequivalence study facility shall modify the bioequivalence study outline within 20 days from receipt of the inspection record given by the internal biomedical ethics committee. Over this period, procedures for approval for the bioequivalence study outline shall be repeated from the first step.

dd) Within 05 days from receipt of the complete bioequivalence study outline, the person in charge of professional expertise of the bioequivalence study facility shall give approval for the bioequivalence study outline.

3. Conduct of the bioequivalence study:

The bioequivalence study facility shall carry out bioequivalence study phases at its own premises or relevant units according to the approved bioequivalence study outline.

4. Assessment and approval for bioequivalence study result:

a) The principal investigator shall submit 01 set of application for assessment of bioequivalence study result as prescribed in Clause 3 Article 7 hereof to the internal biomedical ethics committee.

b) Within 10 days from receipt of an adequate application, the internal biomedical ethics committee shall hold a meeting for assessment of bioequivalence study result and give an assessment report indicating that the bioequivalence study result is satisfactory, partially satisfactory or unsatisfactory.

c) Within 05 days from the date on which the internal biomedical ethics committee gives an assessment report indicating that the bioequivalence study result is satisfactory, the person in charge of professional expertise of the bioequivalence study facility shall give approval for the bioequivalence study report.

d) If the assessment report indicates that the bioequivalence study result is satisfactory but needs modifications, the bioequivalence study facility shall complete the application within a maximum period of 25 days from receipt of written notification. Over this period, procedures for approval for the bioequivalence study result shall be repeated from the first step.

dd) Within 05 days from receipt of the complete application which has been modified as requested, the person in charge of professional expertise of the bioequivalence study facility shall decide to give approval for the bioequivalence study report.

Article 9. Amendments to Appendix I of Circular No. 29/2018/TT-BYT

Appendix I on Good Clinical Practices enclosed with the Circular No. 29/2018/TT-BYT is amended as in the Appendix enclosed herewith.

Article 10. Effect

This Circular comes into force from August 10, 2020.

Appendix I on Good Clinical Practices (GCP) enclosed with the Circular No. 29/2018/TT-BYT shall be annulled from the effective date of this Circular.

Article 11. Transition

If legislative documents referred to herein are superseded or amended, the new ones shall apply.

Article 12. Responsibility for implementation

1. The Administration of Science Technology and Training shall:

a) cooperate with the Drug Administration of Vietnam and relevant units affiliated to the Ministry of Health in instructing and organizing the implementation of this Circular;

b) participate in the inspection of fulfillment of eligibility requirements by bioequivalence study facilities;

c) publish updated GCP documents concerning the bioequivalence study on its website and web portal of the Ministry of Health;

d) cooperate with the Inspector of the Ministry of Health and relevant units affiliated to the Ministry of Health in carrying out inspection of GCP compliance by bioequivalence study facilities, take actions, within its competence, or request competent authorities to take actions against violations;

dd) cooperate with the Drug Administration of Vietnam in publishing updated administrative procedures which are integrated into prevailing procedures for the purpose of facilitating completion of administrative procedures.

2. The Drug Administration of Vietnam shall:

a) cooperate with the Administration of Science Technology and Training in instructing the implementation of this Circular.

b) cooperate with the Administration of Science Technology and Training in receiving applications for and carrying out inspection of fulfillment of eligibility requirements by bioequivalence study facilities in accordance with regulations herein.

3. Each bioequivalence study facility shall:

a) carry out bioequivalence studies for drugs within scope of its licensed operations and in accordance with regulations herein;

b) comply with the inspection of fulfillment of eligibility requirements to conduct bioequivalence studies for drugs in accordance with regulations herein;

c) conduct bioequivalence studies for drugs according to bioequivalence study dossiers and procedures laid down herein;

d) prepare documents as prescribed in this Circular, present them to the internal biomedical ethics committee for consideration and assessment, and retain documents as prescribed by law.

dd) bear the inspection, including ad hoc inspection, of maintenance of fulfillment of GCP compliance by competent authorities as prescribed by law.

Difficulties that arise during the implementation of this Circular should be promptly reported to the Ministry of Health (via the Drug Administration of Vietnam or the Administration of Science Technology and Training) for consideration./.