PHỤ LỤC II Thông tư 29/2018/TT-BYT: HỒ SƠ TỔNG THỂ VỀ CƠ SỞ THỬ THUỐC TRÊN LÂM SÀNG

CIRCULAR

CLINICAL TRIAL OF 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, entitlements and organizational structure of the Ministry of Health;

At the request of the Director of the Administration of Science Technology and Training; the Minister of Health hereby promulgates a Circular on clinical trial of drugs.

Chapter I

GENERAL PROVISIONS

Article 1. Scope

1. This Circular provides for promulgation and application of Good Clinical Practice; Good Clinical Practice (GCP) compliance assessment and applications and procedures for clinical trial of drugs (hereinafter referred to as “clinical trial”).

2. In addition to the regulations of this Circular, clinical trials related to medical examination and treatment shall comply with regulations of the law on medical examination and treatment.

Article 2. Regulated entities

This Circular applies to:

1. Trial facilities, including:

a) Providers of clinical trial services that are issued with the certificate of eligibility for pharmacy business which allows clinical trial.

b) Providers of bioequivalence study services that are issued with the certificate of eligibility for pharmacy business which allows bioequivalence study of drugs (hereinafter referred to as “bioequivalence study”).

c) Facilities not required to obtain certificates of eligibility for pharmacy business in Clause 1 Article 35 of the Law on Pharmacy that are health facilities, scientific research institutions conducting clinical trials or bioequivalence studies and other trial facilities or bioequivalence study facilities.

2. Organizations and individuals related to clinical trial.

Article 3. Definitions

1. “clinical trial” means a scientific research study on human volunteers performed to discover or verify the safety and efficacy of a drug; identify any adverse drug reactions; study the absorption, distribution, metabolism, and excretion of a drug.

2. “Good Clinical Practice” (GCP) means a set of principles and standards for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.

3. “international clinical trial regulations recognized by the Ministry of Health” are Guidelines for Good Clinical Practice provided in the Guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human use - ICH, Guidelines for Good Clinical Practice of the World Health Organization - WHO and guidelines for clinical trial of reference authorities specified in Clause 5 of this Article.

4. “Investigator’s Brochure” (IB) means a document containing preclinical and clinical data on the study drug.

5. “reference authorities” specified in this Circular include reference authorities of United States, Japan, France, Germany, Sweden, United Kingdom, Switzerland, Australia, Canada, Belgium, Austria, Ireland, Denmark and the Netherlands, e.g. European Medicines Agency (EMA), etc.

6. “Case Report Form” (CRF) means a paper or electronic document designed to record data on each trial subject.

Chapter II

PROMULGATION AND APPLICATION OF GOOD CLINICAL PRACTICE

Article 4. GCP principles

1. GCP principles are provided in the Appendix I hereof and updated documents specified in Clause 2 of this Article with reference to guidelines of ICH, WHO and reference authorities specified in Clause 5 Article 3 of this Circular.

2. In the cases where ICH and WHO make any amendments to the GCP principles (updated documents), the Administration of Science Technology and Training shall update and publish such amendments on its website and the web portal of the Ministry of Health.

Article 5. Regulated entities of GCP principles

1. Providers of clinical trial services shall apply and comply with GCP as prescribed in the Appendix I hereof and updated documents.

2. Any provider of bioequivalence study services and bioequivalence study facility that fails to comply with GCP during the clinical trial must sign a contract or written agreement with a trial facility that complies with GCP as prescribed in the Appendix I hereof and updated documents to carry out clinical trial.

3. Trial facilities shall apply updated GCP document as prescribed in Clause 2 Article 4 of this Circular within 12 months in case of any change to infrastructure serving the trial or 06 months in case of another update, from the date on which the updated document is published on the web portal of the Ministry of Health and website of the Administration of Science Technology and Training.

Chapter III

GENERAL PROVISIONS ON INSPECTION OF GCP COMPLIANCE

Article 6. Cases of inspection of GCP compliance and maintenance thereof

1. First assessment and issuance of the certificate of eligibility for pharmacy business to providers of clinical trial services and providers of bioequivalence study services (hereinafter referred to as “providers of trial services”). Regarding the trial facility specified in Point c Clause 1 Article 2 of this Circular, first assessment shall be carried out when it conducts clinical trials.

2. Inspection of GCP compliance shall be periodically carried out every 03 years from the end of the previous inspection (except unscheduled inspections by the Ministry of Health or the Provincial Department of Health).

3. Unscheduled inspection of GCP compliance is specified in Clause 1 Article 15 of this Circular.

4. The inspection of a facility’s GCP compliance and maintenance thereof shall be carried out in accordance with laws on inspection.

Article 7. Classification of GCP compliance

The inspection of GCP compliance by a trial facility shall be carried out according to the following 03 degrees:

1. Degree 1: The trial facility complies with GCP in case no deficiencies are found.

2. Degree 2: The trial facility needs to rectify deficiencies to comply with GCP in case such deficiencies do not affect the trial quality, and safety and health of the trial subject.

3. Degree 3: The trial facility fails to comply with GCP in the following cases:

a) There are deviations from GCP. Such deviations are likely to affect the trial quality, and/or safety and health of the trial subject.

b) Data and documents are forged or falsified.

Chapter IV

FIRST ASSESSMENT OF GCP COMPLIANCE

Article 8. Applications for first assessment of GCP compliance

1. Documents used as basis for inspection of GCP compliance by a provider of trial services are those included in its application for certificate of eligibility for pharmacy business (the provider is not required to submit these documents because they have been submitted when it applies for the certificate of eligibility for pharmacy business) prescribed in Article 38 of the Law on Pharmacy and Article 32 of the Government’s Decree No. 54/2017/ND-CP dated May 08, 2017 on guidelines for the implementation of the Law on Pharmacy (hereinafter referred to as “the Decree No. 54/2017/ND-CP”). If a provider provides controlled drug trial services, it must have the documents prescribed in Article 38 of the Law on Pharmacy and Article 49 of the Decree No. 54/2017/ND-CP;

The technical documents about the provider of trial services prescribed in Article 38 of the Law on Pharmacy and Article 32 of the Government’s Decree No. 54/2017/ND-C shall be prepared in accordance with guidelines for the site master file provided in the Appendix II hereof or the site master file that is updated in the case of change of scope of operation and bear the seal of the provider of trial services.

If a provider of trial services applies for both certificate of GCP compliance and certificate of eligibility for pharmacy business, this content must be clearly specified in its application form for certificate of eligibility for pharmacy business.

2. An application used as the basis for inspection of GCP compliance by the trial facility specified in Point c Clause 1 Article 2 of this Circular include:

a) An application form for inspection of GCP compliance (Form No. 01 in the Appendix III hereof). If the trial facility applies for Certificate of GCP compliance, this content must be clearly specified in the application form;

b) Technical documents about the trial facility prepared in accordance with guidelines for the site master file provided in the Appendix II hereof and bearing the seal of the trial facility.

Article 9. Procedures for receipt of applications for inspection of GCP compliance

1. Receipt of applications:

a) The provider of clinical trial services and trial facility shall submit an application, which includes the documents specified in Article 8 herein, accompanied by the application fees in accordance with regulations of the Minister of Finance on fees for processing of applications for certification of clinical trial standards and conditions, to the Administration of Science Technology and Training - the Ministry of Health;

b) The provider of bioequivalence study services and bioequivalence study facility shall submit an application, which includes the documents specified in Article 8 herein, accompanied by the application fees in accordance with regulations of the Minister of Finance on fees for processing of applications for certification of bioequivalence study standards and conditions, to the Drug Administration of Vietnam - the Ministry of Health; The Drug Administration of Vietnam shall take charge of receiving applications and cooperate with the Administration of Science Technology and Training in inspecting GCP compliance.

2. Procedures for receiving and processing an application are specified in:

a) Clauses 2, 3, 4, 5 and 6 Article 50 of the Decree No. 54/2017/ND-CP if the applicant is a facility conducting clinical trials of narcotic drugs, psychotropic drugs, precursor drugs, pharmaceutical starting materials that are narcotic active ingredients, psychotropic active ingredients or drug precursors; combined drugs that contain narcotic active ingredients, psychotropic active ingredients or precursors;

b) Clauses 2, 3, 4 and 5 Article 51 of the Decree No. 54/2017/ND-CP if the applicant is a facility conducting clinical trials of toxic drugs, toxic medicinal ingredients; drugs and active ingredients on the list of drugs and active ingredients banned from certain fields;

c) Clauses 2, 4 and 5 Article 33 of the Decree No. 54/2017/ND-CP if the applicant is a trial facility other than the ones prescribed in Point a and Point b of this Clause.

3. Within 05 days from the date on which the satisfactory application is received, the Administration of Science Technology and Training or the Drug Administration of Vietnam (hereinafter referred to as “the receiving authority”) shall establish an inspectorate in charge of inspection of GCP compliance (hereinafter referred to as “the inspectorate”), notify the applicant of the site inspection conducted at its premise and the expected inspection date.

Within 15 days from the date of notification, the inspectorate shall conduct a site inspection at the facility as prescribed in Article 10 of this Circular.

Article 10. Process of inspection of GCP compliance

1. Inspection process:

a) Step 1. The inspectorate will declare the Decision on establishment of inspectorate, purposes and contents and plan for the site inspection at the trial facility;

b) Step 2. The applicant shall make a brief introduction of its organizational structure, personnel and implementation or application of GCP, or specific contents in conformity with the inspected contents;

c) Step 3. The inspectorate shall inspect and evaluate the application of GCP at the trial facility;

d) Step 4. The inspectorate shall have a talk with the trial facility about the degree of GCP compliance as prescribed in Article 7 of this Circular and any deficiencies found during the site inspection (if any); discuss with the trial facility in case the trial facility does not agree with the inspectorate about the inspection results.

dd) Step 5. An inspection record is prepared and signed as follows:

The inspection record shall be signed by the head of the trial facility and head of the inspectorate. The inspection record shall clearly specify members of the inspectorate, location, date and scope of the inspection and disagreements (if any) between the inspectorate and the trial facility about the inspection of GCP compliance. The record shall be made into 03 copies, among which one is kept by the trial facility and the others are kept by the receiving authority.

2. GCP inspection compliance report

a) After the site inspection, the inspectorate shall prepare a GCP inspection compliance report using the Form No. 02 in the Appendix III hereof, list and analyze the deficiencies (if any) that need to be rectified by the applicant, make a comparison of corresponding regulations specified in legal documents and assess the degree of GCP compliance as prescribed in Article 7 of this Circular;

b) In the cases where the trial facility does not agree with the inspection contents, within 30 days from the date of signing the inspection record, the trial facility shall send a written explanation to the receiving authority enclosed with evidences (such as documents, images, videos and certificates) related to such inspection contents;

c) Within 10 days from the date on which the written explanation is received, the receiving authority shall consider the GCP inspection compliance report and written explanation and consult experts in relevant fields (if any) and send a written response to the applicant. The written response shall clearly specify agreements and disagreements with the written explanation provided by the applicant. The abovementioned length of time shall not add to the time limit for inspection.

Article 11. Processing results of inspection of GCP compliance

1. If the GCP inspection compliance report indicates that the trial facility complies with GCP as prescribed in Clause 1 Article 7 of this Circular:

Within 10 working days from the date of signing the inspection record, the receiving authority shall request the Minister of Health to issue the certificate of eligibility for pharmacy business and issue the Certificate of GCP compliance according to Form No. 03 in the Appendix III hereof if the trial facility wishes to apply for the certificate of eligibility for pharmacy business. If the trial facility does not apply for issuance of the Certificate of GCP compliance, the GCP inspection compliance report that indicates the trial facility complies with GCP is valid to certify the trial facility complies with GCP and is used as the basis for requesting the Minister of Health to issue the certificate of eligibility for pharmacy business or the basis for conducting clinical trials if the trial facility is the one prescribed in Point c Clause 1 Article 2 of this Circular.

In the cases where the trial facility conducts clinical trials and trades in controlled drugs, within 20 days from the end of the site inspection at the trial facility and from the date of signing the inspection record, if the trial facility wishes to apply for the Certificate of GCP compliance, the receiving authority shall issue the Certificate of GCP compliance according to the Form No. 03 in the Appendix III hereof (and issue the certificate of eligibility for pharmacy business).

2. If the GCP inspection compliance report indicates that the trial facility is required to rectify deficiencies as prescribed in Clause 2 Article 7 of this Circular:

a) Within 05 working days from the end of the site inspection at the trial facility and from the date of signing the inspection record, the receiving authority shall submit a GCP inspection compliance report enclosed with a notification of deficiencies that need rectifying to the trial facility.

If the trial facility conducts clinical trials and trades in controlled drugs, within 15 days from the end of the site inspection at the trial facility and from the date of signing the inspection record, the receiving authority shall submit a GCP inspection compliance report enclosed with a notification of deficiencies that need rectifying to the trial facility.

b) Upon completion of deficiency rectification, the trial facility shall send a notification and documents (such as documents, images, videos and certificates) proving that all deficiencies specified in the inspection report are rectified;

c) Within 20 days from the receipt of the rectification report, the receiving authority shall consider it and conclude the degree of GCP compliance by the trial facility. To be specific:

- If results of deficiency rectification make the trial facility comply with GCP, the receiving authority shall comply with regulations specified in Clause 1 of this Article.

- If results of deficiency rectification show that the trial facility still fails to comply with GCP, the receiving authority shall request the trial facility in writing to keep rectifying deficiencies.

d) Within 06 months from the receipt of the notification of deficiencies that need rectifying, the trial facility shall submit a rectification report upon request. After the aforementioned deadline, if the trial facility fails to rectify deficiencies or the deficiency rectification documents are not satisfactory within 12 months from the first time it is submitted, the submitted application will be rejected.

3. If the GCP inspection compliance report indicates that the trial facility fails to comply with GCP as prescribed in Clause 3 Article 7 of this Circular:

Within 05 working days from the end of the site inspection at the trial facility and from the date of signing the inspection record, the receiving authority shall send a notification of failure to comply with GCP enclosed with a GCP inspection compliance report to the trial facility and shall not issue the Certificate of GCP compliance.

4. Within 05 working days from the issuance date of the certificate for eligibility for pharmacy business or the Certificate of GCP compliance, the receiving authority shall publish the following information on its website and web portal of the Ministry of Health:

a) Name and address of the trial facility that complies with GCP;

b) Full name of the person in charge, number of his/her practicing certificate;

c) Number of the certificate of eligibility for pharmacy business and Certificate of GCP compliance (if any);

d) Validity of inspection of GCP compliance and date of the next periodic inspection;

dd) The scope of operations of the trial facility.

Chapter V

INSPECTION OF GCP COMPLIANCE AND MAINTENANCE THEREOF

Article 12. Periodic inspection of GCP compliance

1. In November, every receiving authority shall publish the plan for periodic inspection of GCP compliance by trial facilities in the succeeding year on its website and send it to trial facilities that are mentioned in the plan.

2. According to the periodic inspection plan published by the receiving authority, the trial facility shall submit an application for periodic inspection as prescribed in Clause 6 of this Article, accompanied by the application fees specified by the Minister of Finance to the receiving authority at least 30 days before the estimated date of inspection specified in such plan.

3. If a trial facility fails to submit the application for periodic inspection within the time limit specified in Clause 2 of this Article, within 15 days from the date on which the trial facility is required to submit the application, the receiving authority shall request the trial facility in writing to submit the application as prescribed.

4. Within 45 days from the date on which the trial facility is requested in writing, it shall submit the application enclosed with a written explanation for its delay in submitting the application as prescribed.

5. After submitting the application for periodic inspection of GCP compliance within the prescribed time limit, the trial facility is entitled to keep operating within the scope specified in the certificate of eligibility for pharmacy business or the Certificate of GCP compliance if the trial facility is the one specified in Point c Clause 1 Article 2 of this Circular for the period from the date of submission of application for periodical inspection to the date of receipt of periodic inspection results.

6. An application for periodic inspection of GCP compliance includes:

a) An application form (Form No. 04 in the Appendix III hereof);

b) A brief report on the trial facility’s operation over the last 03 years from the date of the previous inspection (excluding unscheduled inspections by the Ministry of Health or Provincial Department of Health) to the date on which the periodic inspection is requested;

c) Technical documents indicating changes in facilities, equipment and personnel of the trial facility (if any);

7. Process of inspecting and processing of results of inspection of GCP compliance are prescribed in Articles 9, 10 and 13 of this Circular.

Article 13. Processing of results of periodic inspection of GCP compliance

1. If the GCP inspection compliance report indicates that the trial facility complies with GCP as prescribed in Clause 1 Article 7 of this Circular:

Within 10 days from the end of the site inspection at the trial facility and from the date of signing the inspection record, the receiving authority shall issue the Certificate of GCP compliance according to the Form No. 03 in the Appendix III hereof if the trial facility wishes to apply for the Certificate of GCP compliance. If the trial facility does not apply for the Certificate of GCP compliance, the GCP inspection compliance report that indicates the trial facility complies with GCP is valid to certify the trial facility complies with GCP and is used as the basis for requesting the Minister of Health to issue the certificate of eligibility for pharmacy business or the basis for the trial facility’s continuous operation.

2. If the GCP inspection compliance report indicates that the trial facility is required to rectify deficiencies as prescribed in Clause 2 Article 7 of this Circular:

a) Within 05 working days from the end of the site inspection at the trial facility and from the date of signing the inspection record, the receiving authority shall request the trial facility in writing to rectify deficiencies and send a rectification report to the receiving authority;

b) Within 45 days from the date on which the trial facility is requested in writing, the trial facility shall complete the deficiency rectification and send a notification and documents (such as documents, images, videos and certificates) proving that all necessary all deficiencies specified in the inspection report are rectified;

c) Within 20 days from the receipt of the rectification report and documentary evidences (such as documents, images, videos and certificates), the receiving authority shall assess results of deficiency rectification by the trial facility and conclude the degree of GCP compliance by the trial facility. To be specific:

- If results of deficiency rectification make the trial facility comply with GCP, the receiving authority shall issue the Certificate of GCP compliance according to the Form No. 03 in the Appendix III hereof;

- If results of deficiency rectification show that the trial facility still fails to comply with GCP, the receiving authority shall request the trial facility in writing to keep taking rectifying deficiencies and submit an additional report. The trial facility shall have 45 days from the date on which it is requested in writing to complete deficiency rectification.

d) Within 90 days from the end of the site inspection, if the trial facility fails to submit the rectification report or fails to comply with GCP after rectifying deficiencies as prescribed in Point c of this Clause, the receiving authority shall send a notification of failure to comply with GCP and impose one or some measures prescribed in Points and b Clause 3 of this Clause depending on the nature and degree of non-compliance with GCP.

3. If the GCP inspection compliance report indicates that the trial facility fails to comply with GCP as prescribed in Clause 3 Article 7 of this Circular:

Within 05 working days from the end of the site inspection at the trial facility and from the date of signing the inspection record, based on the assessment of effects of deficiencies found during the inspection on trial quality, health and safety of trial subjects, the receiving authority shall send a notification of failure to comply with GCP and impose one or some of the following measures depending on the nature and degree of non-compliance with GCP:

a) Impose penalties within its power (if any) or request a competent authority to impose administrative penalties in accordance with regulations of the Law on penalties for administrative violations;

b) Request the Minister of Health to issue a decision on revocation of the issued certificate of eligibility for pharmacy business and/or revoke the Certificate of GCP compliance (if any) as prescribed in Article 40 of the Law on Pharmacy.

4. Within 05 working days from the date of concluding that the trial facility maintains its compliance with GCP or issuing the decision on revocation of the issued certificate of eligibility for pharmacy business because of the trial facility’s failure to maintain GCP compliance, the receiving authority shall publish the degree of GCP compliance on its website as prescribed in Clause 4 Article 11 of this Circular if the trial facility complies with GCP or information about the revocation of the certificate of eligibility for pharmacy business or Certificate of GCP compliance (if any) if the trial facility fails to maintain its GCP compliance.

Article 14. Control of changes

1. During the interval between periodic inspections, the trial facility shall apply for the certificate of eligibility for pharmacy business as prescribed in Point b Clause 1 Article 36 of the Law on Pharmacy or submit an application for GCP inspection or a report on its changes using the Form No. 05 in the Appendix III hereof if:

a) having one of the changes specified in Point b Clause 1 Article 36 of the Law on Pharmacy; or

b) changing the location of the trial facility that is mentioned in Point c Clause 1 Article 2 of this Circular; or

c) changing location of one of the technical rooms serving clinical trial (examination room, treatment room, emergency room, testing room, area for phase 1 clinical trial) at the same business location/drug trial area; or

d) adding one of the technical rooms serving clinical trial (examination room, treatment room, emergency room, testing room, area for phase 1 clinical trial) to a new location at the same business location/drug trial area; or

dd) expanding one of the existing technical rooms serving clinical trial (examination room, treatment room, emergency room, testing room, area for phase 1 clinical trial); or

e) repairing or having significant changes in structure and layout of one of the existing technical rooms serving clinical trial (examination room, treatment room, emergency room, testing room, area for phase 1 clinical trial).

2. If having changes as prescribed in Point a Clause 1 of this Article, the trial facility shall apply for the certificate of eligibility for pharmacy business as prescribed in Clause 2 and Clause 4 Article 38 of the Law on Pharmacy.

Procedures for inspecting, classifying and processing the result of inspection of GCP compliance are specified in Articles 9, 10 and 11 of this Circular.

3. If the trial facility mentioned in Point c Clause 1 Article 2 of this Circular has changes as prescribed in Point b Clause 1 of this Article, it shall submit an application for GCP inspection as prescribed in Clause 2 Article 8 of this Circular.

Procedures for inspecting, classifying and processing the result of inspection of GCP compliance are specified in Articles 9, 10 and 11 of this Circular.

4. If having one of the changes prescribed in Points c and d Clause 1 of this Article, the trial facility is required to submit a report on its changes, accompanied by relevant technical documents, to the receiving authority.

a) The receiving authority shall carry out a site inspection of the trial facility. If the trial facility complies with GCP, the receiving authority shall give a written consent to its changes;

b) Procedures for inspecting, classifying and processing the result of inspection of GCP compliance by the trial facility that has changes specified in Point c Clause 1 of this Article are specified in Articles 9, 10 and 13 of this Circular.

c) Procedures for inspecting, classifying and processing the result of inspection of GCP compliance by the trial facility that has changes specified in Point d Clause 1 of this Article are specified in Articles 9, 10 and 11 of this Circular.

5. The trial facility that has one of the changes prescribed in Points dd and e Clause 1 of this Article is required to submit a report on its changes, accompanied by relevant technical documents, to the receiving authority. The receiving authority shall assess the report on changes submitted by the trial facility.

a) Within 10 days from the receipt of the report on changes, the receiving authority shall send a written consent to its changes if they meet requirements;

b) Within 10 days from the receipt of the report on changes, the receiving authority shall issue a notification of deficiencies that need rectifying to the trial facility if its changes do not comply with requirements;

b) Within 45 days from the receipt of the notification, the trial facility shall complete deficiency rectification and send a notification and documents (such as documents, images, videos and certificates) proving that all deficiencies specified in the written request are rectified;

d) Within 10 days from the receipt of the rectification report and documentary evidences (such as documents, images, videos and certificates), the receiving authority shall assess results of deficiency rectification by the trial facility and conclude the degree of GCP compliance by the trial facility. To be specific:

- If results of deficiency rectification make the trial facility comply with GCP, the receiving authority shall send a written consent to the its changes;

- If results of deficiency rectification show that the trial facility still fails to comply with GCP, the receiving authority shall carry out an unscheduled inspection and process the inspection results as prescribed in Article 15 of this Circular.

Article 15. Unscheduled inspection of GCP compliance

1. At the request of the Ministry of Health and Provincial Department of Health and according to the effects of drugs for clinical trial on health of trial subjects and degree of GCP compliance specified in Article 7 of this Circular, the receiving authority shall carry out an unscheduled inspection of GCP compliance by a trial facility in one of the following cases:

a) Results of deficiency rectification show that the trial facility still fails to comply with GCP as prescribed in Point d Clause 5 Article 14 of this Circular;

b) The trial facility that is in GCP degree 2 according to Clause 2 Article 7 of this Circular shall undergo at least 01 unscheduled inspection within 3 years from the end of the previous inspection;

c) Results of inspection by a competent authority show that the trial facility seriously violates GCP principles;

d) There is any denunciation or complaint that the trial facility seriously violates GCP principles;

dd) The trial facility fails to submit the application as prescribed in Clause 4 Article 12 of this Circular.

2. Composition of the inspectorate shall be decided by the director of the receiving authority according to the extent and purposes of the inspection.

3. Applications, process and procedures for unscheduled inspection of the trial facility are prescribed in Clauses 6 and 7 Article 12 of this Circular.

Chapter VI

INSPECTORATE CARRYING OUT INSPECTIONS OF MAINTENANCE OF GCP COMPLIANCE

Article 16. Members and standards to be satisfied by members of an inspectorate

1. The Minister of Health shall decide to establish an inspectorate, which includes:

a) the chief: a senior representative of the receiving authority;

b) 01 secretary: a specialist of the receiving authority;

c) Representatives of affiliates of the Ministry of Health (each affiliate appoints a representative only), including Medical Services Administration; Department of Legal Affairs; National Biomedical Ethics Committee; Drug Administration of Vietnam; the Administration of Science Technology and Training; Agency of Administration of Traditional Medicine if the provider of trial services conducts clinical trials of herbal drugs and traditional drugs;

d) 01 representative: a representative of the Department of Health of provinces and central-affiliated cities (hereinafter referred to as “the Department of Health”) where the trial facility’s headquarters is located if the trial facility is affiliated to the Department of Health;

dd) Members of relevant authorities and units where necessary.

2. A member of the inspectorate must satisfy the following standards:

a) He/she must obtain at least a bachelor’s degree;

b) He/she has attended training courses in GCP standards and inspection of GCP compliance;

c) He/she must be honest, objective strictly comply with regulations during the inspection and must not create any conflict of interest with the inspected provider as prescribed in Clause 3 of this Article;

d) The chief must obtain at least a bachelor’s degree in medicine or pharmacy and have at least 05 years’ experience in clinical trial management.

3. Rules for assessing the conflict of interest: A member of the inspectorate shall be deemed to involve a conflict of interest with the inspected trial facility in one of the following cases:

a) He/she has worked for the inspected provider in the past 05 years;

b) He/she has provided consulting services for the inspected trial facility in the past 05 years;

c) He/she is receiving financial benefits associated with the inspected trial facility;

d) his/her spouse, child, parent, sibling or parent-in-law is working at the inspected trial facility.

Article 17. Rights and responsibilities of an inspectorate

1. The inspectorate has the responsibility to:

a) inspect all operations of a trial facility according to corresponding GCP prescribed in Article 4 of this Circular, updated GCP documents (if any) and relevant applicable regulations; clearly record inspection contents and deficiencies found, prepare GCP inspection records and reports;

b) prepare or provide explanation for the GCP inspection compliance report if the trial facility has any disagreements with the report;

c) maintain confidentiality of information about the inspection and about clinical trials by the trial facility, unless otherwise agreed by the trial facility or at the request of a competent authority.

2. The inspectorate has the right to:

a) inspect all areas in service of clinical trials;

b) request the trial facility to provide documents concerning its operation;

c) collect documentary evidences (by copying documents, taking pictures or recording videos) of any deficiencies found during the inspection;

d) make inspection records and request the trial facility to suspend its operation if the inspectorate detects any violations which may cause adverse effects on safety and health of trial subjects or accuracy and truthfulness of trial data and request the competent official to impose penalties against such violations as prescribed.

Chapter VII

DOCUMENTATION AND PROCEDURES FOR CONDUCTING CLINICAL TRIALS

Article 18. Clinical trial procedures

A clinical trial includes phases and procedures that are specified in Articles 86 and 95 of the Law on Pharmacy. To be specific:

1. Register the clinical trial;

2. Approve the clinical trial. It is required to grant initial approval, and approval for changes during the clinical trial if the trial facility makes any change to the clinical trial outline or participant information sheet and volunteer letter of the trial subject;

3. Conduct the clinical trial;

4. Approve the clinical trial result.

Article 19. Documents about a clinical trial

Documents about a clinical trial include an application for permission for clinical trial; an application for approval for clinical trial; an application for approval for changes to clinical trial; an application for approval for clinical trial result. To be specific:

1. An application for permission for clinical trial consists of:

a) An application form (Form No. 06 in the Appendix III hereof);

b) Documents containing information about the drug (general information about the drug for clinical trial: name, ingredients, indications, physical and chemical properties, dosage form and other relevant information); pre-clinical trial documents; documents about the clinical trial in previous phases), prepared in Vietnamese or English language and accompanied by a summary made in Vietnamese language.

2. An application for approval for clinical trial consists of:

a) An application form (Form No. 07 in the Appendix III hereof);

b) Documents containing information about the drug for clinical trial:

- Drug trial documents: composition, manufacturing process, quality standard and drug test report (in the case of a modern drug, herbal drug or traditional drug, it is required to have a drug test report of the state-owned drug-testing facility that complies with GLP or provider of drug/medicinal ingredient testing services that complies with GLP within its scope of operation or of the manufacture that complies with GMP; in the case of a vaccine, it is required to have a quality test report of the National Institute for Control of Vaccine and Biologicals or Certification of analysis in the case of a batch of vaccines and biologicals);

- Documents about pre-clinical trial of the drug that needs to be tested: reports on pharmacological effects, toxicity, safety, proposed dose, administration route and directions for use;

- Documents about the clinical trial in previous phases (if the trial facility applies for permission for clinical trial in the next phases and the drug is not exempt from clinical trial in previous phases).

c) Legal documents about the drug for clinical trial:

- A copy of the written approval for registration of the clinical trial granted by the Administration of Science Technology and Training, the Ministry of Health.

- A certified true copy or a copy bearing the seal of the trial facility, produced together with the original for comparison of the application form for permission for phase 4 clinical trial submitted by the competent pharmacy authority if the drug is requested to undergo phase 4 clinical trial;

- Package insert of the drug licensed for free sale if the drug is requested to undergo phase 4 clinical trial;

- A certified true copy or a copy bearing the seal of the trial facility, produced together with the original for comparison of the trial facility’s certificate of eligibility for pharmacy business;

- A confirmation of participation provided by the trial centers if a multicenter trial is conducted in Vietnam;

- A certified true copy or a copy bearing the seal of the trial facility, produced together with the original for comparison of the written approval for participation in the trial granted by the People’s Committee of the province or central-affiliated city if a field trial is conducted;

- A clinical trial agreement between the organization/individual that has the drug for clinical trial and the provider of clinical trial services; between the organization/individual that has the drug for clinical trial and the trial assistance organization (if any).

d) A clinical trial outline and its description:

- A description of the clinical trial outline (Form No. 08 in the Appendix III hereof);

- A Case Report Form (CRF);

dd) Principal investigator’s academic résumé and copy of the certificate of completion of GCP training course which is issued by the Ministry of Health or GCP training institution;

e) Participant information sheet and volunteer letter (Form No. 09 in the Appendix III hereof);

g) A record on scientific and ethical assessment prepared by the internal Biomedical Ethics Committee;

h) Label of the drug prescribed in the Circular No. 01/2018/TT-BYT dated January 18, 2018 of the Minister of Health.

3. An application for approval for changes to clinical trial consists of:

a) An application form (Form No. 10 in the Appendix III hereof);

b) Updated versions of the documents mentioned in Clause 2 of this Article;

c) A record prepared by the internal Biomedical Ethics Committee on assessment of changes to the clinical trial that affect the health and interests of trial subjects or the trial design, process and procedures.

4. An application for approval for clinical trial result consists of:

a) An application form (Form No. 11 in the Appendix III hereof);

b) A copy of the approved clinical trial outline;

c) A copy of the decision on approval for the approved clinical trial outline;

d) A record on clinical trial assessment prepared by the internal Biomedical Ethics Committee;

dd) A full report on clinical trial result (Form No. 12 in the Appendix III hereof);

Article 20. Requirements for language, presentation and legality of documents

1. Language used in documents:

Documents about a clinical trial must be written in Vietnamese or English language. In case of failure to present documents in Vietnamese or English language, it is required to have notarized Vietnamese or English translations of such documents (including translations of contents concerning consular certification and consular legalization).

2. Document presentation:

Documents about a clinical trial shall be printed on A4 pages, firmly bound and have a table of contents. Documents shall be arranged in the order stated in the table of contents and each part shall be separated between different parts. Separated parts shall be numbered for easy reference.

3. Legality of documents:

a) The application form and application for permission for clinical trial shall bear the signature and seal of the legal representative or legally authorized person of the applicant;

b) The documents issued by a foreign authority shall be consularly legalized in accordance with regulations of law on consular legalization, except for the cases in which consular legalization is exempted by law.

Article 21. Procedures for registering a clinical trial

1. The owner of the drug for clinical trial shall submit an application for permission for clinical trial to the Administration of Science Technology and Training, the Ministry of Health, whether directly or by post.

2. The Administration of Science Technology and Training, the Ministry of Health shall verify legality of the application within 05 working days from the receipt of the application. If the application is not satisfactory, the applicant shall be instructed in writing to complete the application until it is satisfactory.

3. The applicant shall cooperate with the Administration of Science Technology and Training, the Ministry of Health in completing the application within 60 days from the date on which it is instructed in writing. After the aforementioned deadline, the application will be rejected.

4. Within 05 working days from the receipt of the satisfactory application, the Director of the Administration of Science Technology and Training, the Ministry of Health shall grant a written approval for clinical trial according to the Form No. 13 in the Appendix III hereof. If the application is rejected, it is required to respond and provide explanation in writing.

Article 22. Procedures for approving a clinical trial

1. The trial facility shall submit an application for approval for clinical trial to the Administration of Science Technology and Training, the Ministry of Health, whether directly or by post.

2. The Administration of Science Technology and Training, the Ministry of Health shall verify legality of the application within 05 working days from the receipt of the application. If the application is not satisfactory, the applicant shall be instructed in writing to complete the application until it is satisfactory.

The applicant shall cooperate with the Administration of Science Technology and Training, the Ministry of Health in completing the application within 60 days from the date on which it is instructed in writing. After the aforementioned deadline, the applicant has to re-apply for approval for clinical trial.

3. Within 25 days from the receipt of the satisfactory application, the Ministry of Health shall have a meeting with the National Biomedical Ethics Committee and a record on clinical trial outline assessment shall be made.

4. Within 05 working days from the receipt of the record prepared by the National Biomedical Ethics Committee, the Administration of Science Technology and Training shall consolidate and submit a complete application to the Minister of Health for approval. If the clinical trial outline is not approved or needs correcting, the Administration of Science Technology and Training shall respond and provide explanation in writing.

5. If the clinical trial outline needs correcting, the applicant shall cooperate with the Administration of Science Technology and Training, the Ministry of Health in completing the application within 90 days from the date on which it is provided with written response and explanation. After the aforementioned deadline, the applicant has to re-apply for approval for clinical trial.

6. Within 05 working days from the receipt of the clinical trial outline that is completed as requested, the Administration of Science Technology and Training, the Ministry of Health shall consolidate and submit a complete application to the Minister of Health for approval.

Article 23. Procedures for approving changes to a clinical trial outline

1. The trial facility shall submit an application for approval for changes to clinical trial outline to the Administration of Science Technology and Training, the Ministry of Health, whether directly or by post.

2. The Administration of Science Technology and Training, the Ministry of Health shall verify legality of the application within 05 working days from the receipt of the application. If the application is not satisfactory, the applicant shall be instructed in writing to complete the application until it is satisfactory.

The applicant shall cooperate with the Administration of Science Technology and Training, the Ministry of Health in completing the application within 60 days from the date on which it is instructed in writing. After the aforementioned deadline, the applicant has to re-apply for approval for clinical trial.

3. Within 25 days from the receipt of the satisfactory application, the Ministry of Health shall have a meeting with the National Biomedical Ethics Committee and a record on assessment of changes to the clinical trial outline shall be made.

4. Within 05 working days from the receipt of the record prepared by the National Biomedical Ethics Committee, the Administration of Science Technology and Training shall consolidate and submit a complete application to the Minister of Health for approval. If the clinical trial outline is not approved or needs correcting, the Administration of Science Technology and Training shall respond and provide explanation in writing.

5. If the clinical trial outline needs correcting, the applicant shall cooperate with the Administration of Science Technology and Training, the Ministry of Health in completing the application within 90 days from the date on which it is provided with written response and explanation. After the aforementioned deadline, the applicant has to re-apply for approval for clinical trial outline.

6. Within 05 working days from the receipt of the clinical trial outline that is completed as requested, the Administration of Science Technology and Training, the Ministry of Health shall consolidate and submit a complete application to the Minister of Health for approval.

Article 24. Conducting a clinical trial

Every trial facility shall conduct the clinical trial according to the approved clinical trial outline and GCP guidelines.

Article 25. Procedures for approving clinical trial result

1. The trial facility shall submit an application for approval for clinical trial result prepared in Vietnamese language to the Administration of Science Technology and Training, the Ministry of Health, whether directly or by post.

2. The Administration of Science Technology and Training, the Ministry of Health shall verify legality of the application within 05 working days from the receipt of the application. If the application is not satisfactory, the applicant shall be instructed in writing to complete the application until it is satisfactory.

The applicant shall cooperate with the Administration of Science Technology and Training, the Ministry of Health in completing the application within 60 days from the date on which it is instructed in writing. After the aforementioned deadline, the applicant has to re-apply for approval for clinical trial result.

3. Within 25 days from the receipt of the satisfactory application, the Ministry of Health shall have a meeting with the National Biomedical Ethics Committee and a commissioning record on clinical trial concluding that the clinical trial result is satisfactory, partially satisfactory or unsatisfactory shall be made.

4. Within 05 working days from the receipt of the National Biomedical Ethics Committee's commissioning record concluding that the clinical trial result is satisfactory in terms of safety and efficacy, the Director of the Administration of Science Technology and Training shall decide to approve the clinical trial result according to the Form No. 14 in the Appendix III hereof. If the commissioning record concludes that the clinical trial result is partially satisfactory or unsatisfactory in terms of safety and efficacy, the Administration of Science Technology and Training shall respond and provide explanation in writing.

5. If the commissioning record concludes that the clinical trial result is partially satisfactory, the applicant shall cooperate with the Administration of Science Technology and Training, the Ministry of Health in completing the application within 90 days from the date on which it is provided with written response and explanation. After the aforementioned deadline, the applicant has to re-apply for approval for clinical trial result.

6. Within 05 working days from the receipt of the application that is completed as requested, the Director of the Administration of Science Technology and Training shall decide to approve the clinical trial result.

Chapter VIII

IMPLEMENTATION CLAUSE

Article 26. Effect

1. This Circular comes into force from January 01, 2019.

2. Articles 2, 3 and 4 Chapters III, IV, V, VI, VII and VIII, Articles 39 and 40 of the Circular No. 03/2012/TT-BYT dated February 02, 2012 of the Minister of Health and the Decision No. 799/QD-BYT dated March 07, 2008 are repealed from the effective date of this Circular.

Article 27. Reference clauses

In the cases where any of the documents referred to in this Circular is amended or replaced, the newest one shall apply.

Article 28. Transition clauses

The documents about clinical trials submitted before the effective date of this Circular shall be processed in accordance with the Circular No. 03/2012/TT-BYT dated February 02, 2012 of the Minister of Health or this Circular if so requested by the applicants.

Article 29. Implementation

1. The Administration of Science Technology and Training, the Ministry of Health shall:

a) take charge of organizing the inspection of GCP compliance by providers of clinical trial services and trial facilities;

b) take charge and cooperate with relevant units in disseminating and providing guidelines for this Circular;

c) take charge and cooperate with relevant units in providing implementation guidelines to Departments of Health, health authorities and trial facilities within its jurisdiction;

d) consolidate and publish the list of providers of clinical trial services and trial facilities that have been issued with the certificate of eligibility for pharmacy business and Certificate of GCP compliance, status of such certificate, degree of GCP compliance and other information on its website according to Clause 4 Article 11 of this Circular within its jurisdiction;

dd) publish updated GCP documents on its website and the web portal of the Ministry of Health;

e) take charge or cooperate with the Inspectorate of the Ministry of Health and relevant units affiliated to the Ministry of Health in inspection of GCP compliance and maintenance thereof and impose penalties within its power;

g) receive and inspect documents about clinical trial, instruct owners of drugs for clinical trials and trial facilities to comply with regulations of this Circular and other relevant regulations of law;

h) take charge of assisting the Ministry of Health in holding meetings with the National Biomedical Ethics Committee to approve clinical trial outlines, assess changes to clinical trial outlines, commission clinical trials and approve clinical trial results;

i) carry out periodic or unscheduled supervision and inspections of clinical trial process.

2. The Drug Administration of Vietnam, the Ministry of Health shall:

a) take charge of organizing the inspection of GCP compliance by providers of bioequivalence study services and bioequivalence study facilities;

b) cooperate with relevant units in disseminating and providing guidelines for this Circular;

c) consolidate and publish the list of providers of bioequivalence study services and bioequivalence study facilities that have been issued with the certificate of eligibility for pharmacy business and Certificate of GCP compliance, status of such certificate, degree of GCP compliance and other information on its website according to Clause 4 Article 11 of this Circular within its jurisdiction;

d) take charge and cooperate with relevant units affiliated to the Ministry of Health in inspecting the GCP compliance by providers of bioequivalence study services and bioequivalence study facilities and impose penalties against violations within its power.

3. Departments of Health shall:

a) cooperate with relevant units in disseminating and providing guidelines for this Circular to units within their provinces;

b) join the inspectorate carrying out inspection of GCP compliance; supervise and impose penalties against violations of regulations on GCP compliance by trial facilities within their provinces.

4. Trial facilities shall:

a) organize the implementation of this Circular according to their current situation;

b) ensure their maintenance of GCP compliance during their operation;

c) conduct clinical trials within the licensed scope in accordance with regulations of law'

d) comply with regulations on time limit, documents and procedures for inspection of GCP compliance as prescribed in this Circular;

dd) be under unscheduled inspections of GCP compliance by competent authorities as prescribed by law.

Article 30. Responsibility for implementation

Director of Administration of Science Technology and Training, Director of Drug Administration of Vietnam, Chief of the Ministry Office, Chief Inspector, Directors and General Directors of Departments and General Departments affiliated to the Ministry of Health, heads of affiliates of the Ministry of Health and relevant organizations and individuals are responsible for the implementation of this Circular.

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

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