CIRCULAR

On phamarceutical products for which in vivo bioequivalence studies are required and requirements for documentation of bioequivalence study reporting during application for marketing authorization of these drugs in Vietnam

Pursuant to the Law on Pharmacy dated April 06, 2016;

Pursuant to Decree No. 54/2017/ND-CP dated May 08, 2017 of the Government of Vietnam providing detailed regulations on some Articles and  measures for implementation of the Law on Pharmacy;

Pursuant to Decree No. 75/2017/ND-CP dated June 20, 2017 of the Government on function, tasks, powers and organizational structures of the Ministry of Health of Vietnam;

At the request of the Director General of Drug Administration of Vietnam,

The Minister of Health promulgates a Circular on pharmaceutical products for which in vivo bioequivalence studies are required and requirements for documentation of bioequivalence study reporting during application for marketing authorization of these pharmaceutical products in Vietnam.

Chapter I

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Article 1. Scope

1. This Circular provides for:

a) Generic drugs whose active pharmaceutical ingredients (APIs) or dosage forms are subject to bioequivalence study reporting during application for marketing authorization in Vietnam;

b) Documentation of bioequivalence study reporting of generic drugs.

2. This Circular applies to generic drugs which have systemic actions after these drugs are absorbed into the general circulation.

Article 2. Definitions

For the purposes of this Circular, the terms below shall be construed as follows:

1. “reagent" is a generic drug which is used for proving that it is therapeutically equivalent (with respect to both efficacy and safety of the drug) to a comparator product when being administered to patients in the same dose by the same route under the specific conditions specified in the labeling (if any) via data of in vivo bioequivalence studies or in vitro bioequivalence studies.

2. “comparator product/reference product” is a pharmaceutical product with which the generic drug is intended to be interchangeable in clinical practice. The comparator products will normally be innovator pharmaceutical products or products granted marketing authorizations for which efficacy, safety and quality have been established.

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4. “pharmaceutical equivalence” means products containing the same molar amount of the same API (for single ingredient drugs) or the same APIs (for multi-ingredient drugs) in the same dosage form, having the same drug release mechanism, the same route of administration and the equivalent quality standards.

5. “Pharmaceutical alternatives” are products which contain the same active pharmaceutical moiety or moieties but differ in chemical form (e.g. different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives) of each API or differ in drug content or dosage form.

6. “drug under consideration" is a generic drug for which a marketing authorisation application which includes documentation of bioequivalence study reporting has been submitted.   

7. “In vivo bioequivalence study” means a clinical study undertaken on a volunteer and designed to compare the bioavailability of a generic drug with a comparator product with the aim of demonstrating the interchangeability of generic drugs to replace comparator products.

8. “equivalence dissolution” means a study that includes comparison of dissolution profile between drugs/pharmaceutical products in different dissolution media. Equivalence dissolution is also known as an in vitro equivalence study.

9. “In vitro - in vivo correlation” means a predictive mathematical model describing the relationship between the in vitro property (drug dissolution or release) and relevant in vivo response (drug concentration or amount absorbed in biological fluids) of a drug/pharmaceutical product.

10. “research facility” is an organization partly or wholly participating in the in vivo bioequivalence study or in vitro equivalence study of the drug under consideration.

11. “immediate release dosage form” means a dosage form using classic excipients and preparation techniques, without intentionally changing the drug release rate from the dosage form- including conventional dosage forms such as tablets, capsules, suspensions, solutions for oral administration, solutions, suspensions, emulsions for injection and unconventional dosage forms which are also known as special dosage forms such as solid dispersion systems, lozenges, chewable tablets, oral dispersible tablets and sublingual tablets.

12. “Modified release dosage form” means a dosage form using some excipients and/or preparation techniques different from those of the immediate release dosage form in order to produce a rate and/or site of drug release different than those of the immediate release dosage form when being administered by the same route. The most common modified release dosage forms include delayed release, prolonged release, multiphasic release, drug, intramuscular/subcutaneous depot and transdermal drug delivery system.

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14. “Biopharmaceutics classification system (BCS)” means a system of classifying APIs based upon their aqueous solubility and intestinal permeability.

15. “bio-waiver” means the approval for a generic drug, based on evidence of equivalence between the generic drug and its comparator product other than in vivo bioequivalence study reporting.

16. “study under fasted condition” is a bioequivalence study that a volunteer participating in the study did not eat and drink alcohol or xanthine for at least 8 hours before taking the drug.

17. “study under fed condition” is a bioequivalence study that a volunteer participating in the study takes the drug immediately after eating or according to the instructions on time for taking the drug compared to the time for eating as mentioned in the drug property summary.

18. “single-dose study” means a bioequivalence study that biological samples used for analysis are collected after taking a single dose of drug at each study period.

19. “multi-dose study” means a bioequivalence study that biological samples used for analysis are collected after taking multiple doses of a drug to achieve a stable drug concentration in the blood.

20. “Polarized approach” means the analysis and selection of 02 strengths in many different strengths of the same drug (with the same dosage form, manufactured by the same manufacturer) that are determined as having the most significant differences so that any difference between the remaining strengths is within the difference of these two selected strengths to conduct a research and extrapolate the research results to the remaining strengths.

21. “ASEAN" is an abbreviation of the English phrase “Association of Southeast Asian Nations”, translated into Vietnamese as “Hiệp hội các nước Đông Nam Á”.

22. “ICH” is an abbreviation of the English phrase “International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use”, translated into Vietnamese as “Hội nghị quốc tế về hài hòa các thủ tục đăng ký dược phẩm sử dụng cho con người”.

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24. “Form of ICH bioequivalence study reports" means a reporting form according to the Guideline on the Structure and Content of Clinical Study Reports (E3 Guideline) of ICH.

Chapter II

REGULATORY REQUIREMENTS OF BIOEQUIVALENCE STUDY REPORTS FOR GENERIC DRUGS CONTAINING APIS OR THOSE IN DOSAGE FORM

Article 3. Regulatory requirements of bioequivalence study reports for generic drugs containing APIs upon applying for marketing authorization

1. Criteria for selection of an API contained in a generic drug subject to a bioequivalence study report upon applying for marketing authorization are sorted according to the following priority:

a) Possessing a narrow therapeutic index;

b) Having a bioavailability that is low and/or very different between individuals;

c) Being presented in prescription drugs, belonging to one of the drug classes including cardiovascular drugs, hypoglycemic drugs, antibiotics, antipsychotic/antiepileptic drugs, antivirals;

d) Being contained in drugs in the list of drugs used in National Programs, including: HIV-AIDS prevention project; Community mental health protection project; Tuberculosis prevention project; Malaria Prevention Project.

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Article 4. Regulatory requirements of bioequivalence study reports for generic drugs in dosage form upon applying for marketing authorization

Generic drugs in dosage form for which reports on bioequivalence study data are required upon applying for marketing authorization include:

1. Immediate release pharmaceutical products with systemic action, which contain APIs specified in Clause 2, Article 3 of this Circular and do not fall into the cases specified in Article 5 of this Circular.

2. Modified release pharmaceutical products with systemic action, except for cases specified in Article 5 of this Circular.

Article 5. Generic drugs for which in vivo bioequivalence studies are waived due to the available bioequivalence between these drugs and comparator products

Generic drugs for which in vivo bioequivalence studies are waived due to the available bioequivalence between these drugs and comparator products include:

1. Generic drugs which are used for intravenous (IV) injection in the form of aqueous solutions, contain the same APIs at the same molar concentrations when being used as comparator drugs and do not contain excipients that interact with APIs or have the same effect on the distribution of the APIs as that of the comparator products. In case these excipients must be used in the formulation, these excipients and excipients contained in the comparator products must have the same qualitative and quantitative composition or if there is a difference in quantity, it must be demonstrated that this difference does not affect the pharmacokinetics of the APIs.

2. Generic drugs which are used for other routes of administration other than IV injection in the form of aqueous or oil-based solutions, contain the same APIs at the same molar concentrations and contain the same excipients with the similar concentrations when being compared with their comparator products. For an injecting drug which is an aqueous solution, excipients in the formulation may be different but they must have the same class (same effect) and concentration as those contained in the comparator product and different excipients must not affect the viscosity of the aqueous solution according to evidence.

3. Generic drugs which are oral solutions (including solid dosage-form drugs with instructions for dissolving into oral solutions before use), are equivalent in pharmaceutical formulation to their comparator products and both generic drugs and comparator products do not contain excipients which may affect the in vivo delivery, absorption or stability of APIs as those in their comparator products.  In case there must have excipients that may affect the in vivo delivery, absorption or stability of APIs in the pharmaceutical formulation of the generic drugs, categories and quantities of these excipients of the generic drugs must be equivalent to those of their comparator products.

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Chapter III

REQUIREMENTS FOR COMPARATOR PRODUCTS AND IN VIVO BIOEQUIVALENCE STUDIES

Article 6. Comparator products used in in vivo bioequivalence studies

1. Criteria for selection of a comparator product for an in vivo bioequivalence study serving the application for marketing authorisation are prescribed in the priority as follows:

a) Being a drug/pharmaceutical product on the list of proprietary drugs published by the Ministry of Health or a pharmaceutical product granted a marketing authorization with adequate data on clinical efficacy, safety and quality;

b) Being an innovator pharmaceutical product which is not granted a Marketing Authorization Approval certificate in Vietnam but is approved and marketed in a country by a stringent pharmaceutical regulatory authority prescribed in clause 10 Article 2 of Circular No. 32/2018/TT-BYT of the country;

c) In case it is unable to determine any comparator product meeting regulations in point a and point b of this clause, the comparator product will be selected in the priority as follows:

- Being a pharmaceutical product which is approved and marketed in a country by a stringent pharmaceutical regulatory authority prescribed in clause 10 Article2 of Circular No. 32/2018/TT-BYT of the country.

- Being a pharmaceutical product which has been prequalified by the World Health Organization (WHO).

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2. In addition to the requirements mentioned in clause 1 of this Article, if the comparator product used in the in vivo bioequivalence study is a an immediate release pharmaceutical product, modified release pharmaceutical product or fixed-dose combination finished pharmaceutical product, it must meet the following requirements as well:

a) In case a pharmaceutical product which is under consideration is a single ingredient drug in immediate release dosage form, the comparator product must be a single ingredient drug in immediate release dosage form as well;

b) In case the pharmaceutical product which is under consideration is a modified release pharmaceutical product, the comparator product must also be a modified release product with the same drug release mechanism as the pharmaceutical product;

c) For a fixed-dose combination finished pharmaceutical product:

- In case the pharmaceutical product is under consideration to intendedly replace a fixed-dose combination finished pharmaceutical product approved with complete documentation of safety and efficacy in clinical practice (which is a proprietary drug or an innovator pharmaceutical product), the fixed-dose combination finished pharmaceutical product will be selected to be the comparator product.

- In case the pharmaceutical product which is under consideration is developed for the purpose of replacing the fixed-dose combination of single ingredient drugs with complete documentation of safety and efficacy in clinical practice, the comparator product will be a corresponding single-ingredient drug.

3. The comparator product used in the in vivo bioequivalence study must have clear origin. Documentary evidence of origin of the comparator product is prescribed in point c clause 1 Article 8 hereof.

4. On the basis of criteria for selection of comparator products prescribed in clause 1 of this Article, other requirements for them prescribed in clause 2 and clause 3 of this Article and actual conditions, the Drug Administration of Vietnam shall make a list of comparator products and ask the Consulting Council for issuance of marketing authorizations of pharmaceutical products and medicinal ingredients for promulgation of a Decision on issuing the List of comparator products used in in vivo bioequivalence studies. The List of comparator products used in in vivo bioequivalence studies is published on the website of the Drug Administration of Vietnam at https://dav.gov.vn/.

Article 7. Regulations for bioequivalence studies in the documentation of bioequivalence study reporting

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a) must be designed and conducted according to the Guideline on conducting ASEAN bioequivalence studies or reference guidelines of other organizations prescribed in Appendix VI enclosed herewith.

b) For oral, modified release pharmaceutical products with systemic action, must conduct the study under fasted condition and fed condition;

c) For immediate release pharmaceutical products with systemic action, except for cases specified in Article 5 of this Circular, must conduct the study under fasted condition. On the basis of pharmacokinetics of the comparator product, it is known that food can affect bioavailability or the comparator product must be used after meal as specified in instructions for use, may conduct the study under fed condition instead of fasted condition;

d) For a fixed-dose combination finished pharmaceutical product, must conduct the study on bioequivalence evaluation of active pharmaceutical moieties contained in the product;

dd) Apply in vivo bioequivalence study design for each pharmaceutical product according to recommendations of US Food and Drug Administration (US FDA) or European Medicines Agency (EMA).

2. The study must be conducted at testing centers that are evaluated and approved by competent authorities in the hosting country and must comply with regulations on good clinical practice (GCP) as prescribed in clause 1 Article 4 of Circular No. 29/2018/TT-BYT dated October 29, 2018 of the Ministry of Health on clinical trials and good laboratory practice (GLP) as prescribed in clause 1 Article 3 of Circular No. 04/2018/TT-BYT dated February 09, 2018 of the Ministry of Health on Good Laboratory Practice.

3. In case a bioequivalence study of a pharmaceutical product which is under consideration uses a comparator product which is an innovator pharmaceutical product but is not produced in the same manufacturer as the innovator pharmaceutical product granted a marketing authorization in Vietnam of the product, the applying facility needs to prove the mutual interchangeability between the comparator product used in the study and the innovator product granted the marketing authorization in Vietnam of the product according to the ASEAN Guideline for the conduct of Bioavailability/Bioequivalence studies.

4. Form of documentation of bioequivalence study reporting of pharmaceutical products is prescribed in point a clause 1 Article 8 hereof.  Specific requirements for the documentation of bioequivalence study reporting of pharmaceutical products under consideration are prescribed in Appendix III enclosed herewith.

5. Bio-waiver is claimed for pharmaceutical products under consideration if they meet the following requirements:

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b) Pharmaceutical products under consideration which have the same dosage form, pharmaceutical formulation and manufacturing process as reagents in the bioequivalence studies but differ in strengths of APIs meet regulations in section II Appendix II enclosed herewith;

c) Oral, solid and immediate-release pharmaceutical products under consideration which have pharmaceutical equivalence upon being compare with comparator products and APIs classified into the class of high solubility and high permeability according to the biopharmaceutics classification system meet regulations in section III Appendix II enclosed herewith;

d) Pharmaceutical products under consideration which are manufactured a manufacturing site different from it of reagents in a bioequivalence study meet requirements in section IV Appendix II enclosed herewith.

Chapter IV

DOCUMENTATION OF BIOEQUIVALENCE STUDY REPORTING

Article 8. Documentation of bioequivalence study reporting of pharmaceutical products under consideration and comparator products.

1. The documentation shall include:

a) A report on in vivo bioequivalence study data based on the current form of ASEAN bioequivalence study reports or form of ICH bioequivalence study reports, from which a written commitment on the equivalence between the reagent in the study and the pharmaceutical product under consideration must be prepared according to Schedule 01/BE prescribed in Appendix VII enclosed herewith;

b) Documents and information of the research facility as prescribed in Article 12 hereof;

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- A copy of an invoice of comparator product with clear name and address of the manufacturer;

- A copy of the product label with confirmation of the applying facility/manufacturer with full and clear information about name of the comparator product, name and address of the manufacturer, batch number and expiry date;

- The written commitment with signature of the Director of the applying facility/manufacturer on the purchase of the comparator product from the right country where the product is granted its marketing authorisation approval certificate and preservation under the reasonable condition labeled from the time of purchase to the time of beginning conducting the study in order to confirm the authentication of the documents provided above.

2. In case a volunteer takes the pharmaceutical product under consideration in different conditions (fed, fasted, single-dose or multi-dose), the documentation of bioequivalence study reporting including various reports on bioequivalence studies and each of them will specify each condition of taking the product must be adequate or documented to have adequate documents prescribed in clause 1 hereof.

Article 9. Documentation of bioequivalence study reporting of pharmaceutical products under consideration prescribed in point a point b clause 5 Article 7 hereof

The documentation of bioequivalence study reporting of a pharmaceutical product under consideration prescribed in point a point b clause 5 Article 7 hereof includes:

1. A petition for bio-waiver for the pharmaceutical product under consideration according to Schedule 02/BE prescribed in Appendix VII enclosed herewith.

2. A dossier on bioequivalence of a strength or strengths selected to conduct an in vivo bioequivalence study for the comparator product meeting regulations in Article 8 hereof.

4. A comparison table for pharmaceutical formulation with strengths for which the bio-waiver is applied, including strength of the pharmaceutical product under consideration and that of strengths of which there are bioequivalence study reports.

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6. An in vitro bioequivalence study report between strengths for which the bio-waiver is applied, including strength of the pharmaceutical product under consideration and strengths of which there are reports on bioequivalence study data. Requirements for the in vitro bioequivalence study report are prescribed specifically in Appendix IV enclosed with this Circular.

7. A commitment to the equivalence between the pharmaceutical product under consideration and the reagent used in in vitro bioequivalence study according to schedule 01/BE prescribed in Appendix VII enclosed herewith.

8. Information about linear pharmacokinetics of the pharmaceutical product under consideration (if applicable).

Article 10. Documentation of bioequivalence study reporting of the pharmaceutical products under consideration prescribed in point c clause 5 Article 7 hereof

The documentation of bioequivalence study reporting of a pharmaceutical product under consideration prescribed in point c clause 5 Article 7 hereof shall include:

1. A written petition for bio-waiver for the pharmaceutical product under consideration according to schedule 02/BE prescribed in Appendix VII enclosed herewith.

2. Documents of the research facility prescribed in Article 12 hereof.

3. Documentary evidence of the good solubility and permeability of the API/APIs contained in the product under consideration according to the guideline in Appendix III. The bio-waiver is based on the BCS of the ASEAN Guideline on conduct of bioequivalence studies issued together with Circular No. 32/2018/TT-BYT.

4. Data proving that the product under consideration contains excipients meeting requirements for being taken into consideration for bio-waiver includes:

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Some official approved reference sources include: the approved Guideline on use of pharmaceutical products by the Drug Administration of Vietnam, overview of properties of authorized pharmaceutical products or report on evaluation of pharmaceutical products posted on the website of the European Medicines Agencies (EMA) and the stringent regulatory authority (SRA) prescribed in clause 10 Article 2 of Circular No. 32/2018/TT-BYT or on official sites for drug and medication information such as eMC (electronic Medicines Compendium). In case information on the excipients used in the formulation of the comparator product or reference product can not be found, qualitative results of the excipients in the formulation of the comparator product or the reference product must be provided to demonstrate that the product under consideration has the same excipients in the formulation as one of these products;

b) In case excipients used in the formulation of the product under consideration affect bioavailability of it, qualitative and quantities results of the excipients used in the formulation of the product under consideration and that of the comparator product must be provided to demonstrate that the product under consideration has the same excipients as the comparator product;

c) A report on validation of qualitative and quantitative analytical procedures used in the above-mentioned studies.

5. A report on evaluation of the solubility of the product under consideration (for products with the very rapid solubility) or a report on in vitro bioequivalence study between the product under consideration and the comparator product (for products with the rapid solubility). Requirements for the report on in vitro bioequivalence study are prescribed specifically in Appendix IV enclosed with this Circular.

6. A commitment of the equivalence between the product under consideration and the reagent used in the in vitro study or in vitro bioequivalence study according to schedule 01/BE prescribed in Appendix VII enclosed herewith.

7. Related documents concerning the comparator product in accordance with regulations in point c clause 1 Article 8 hereof.

Article 11. Documentation of bioequivalence study reporting of pharmaceutical products under consideration prescribed in point d clause 5 Article 7 hereof

The documentation of bioequivalence study reporting of a pharmaceutical product under consideration prescribed in point d clause 5 Article 7 hereof includes:

1. A written petition for bio-waiver for the pharmaceutical product under consideration according to Schedule 02/BE prescribed in Appendix VII enclosed herewith.

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3. In case of change of manufacturing site due to the change between different manufacturers of the same product owner or between different manufacturing sites of the same manufacturer: a written explanation of the product owner or applying facility of reasons for the change of manufacturing site.

4. A document about quality of the reagent used in the bioequivalence study includes:

- Part S. APIs:  an overview of API integration process attached to a process mapping; Solvents used in the process; API properties; Impurity properties; Quality standards of APIs; Analytical data on batches of APIs;

- Part P. Finished pharmaceutical products (FPPs): Pharmaceutical formulation; Manufacturing process; Quality standards of excipients; Quality standards and analytical procedures for FPPs; Analytical data on at least 03 pilot-scale batches of FPPs as specified in Appendix V hereof - including batches used in in vivo bioequivalence study; Stability of FPPs (in case there is not enough data on the long-term stability of the product under consideration until its registered expiry date); Bioequivalence dossiers satisfying the regulations in Article 8 hereof.

5. Documents prescribed in clauses 3, 4, 5, 6, 7, and 8 Article 9 hereof in case the product under consideration has been manufactured according to regulations in point a or b clause 5 Article 7 hereof at the old manufacturing site.

6. A table listing changes related to the pharmaceutical formulation, production batch size, manufacturing process, manufacturer of APIs during marketing (if any) of the pharmaceutical product under consideration manufactured at the old manufacturing site.

7. A written approval for these changes of the pharmacy authority of the host country.

8. A dossier on changes and addition to each listed change meeting regulations in Appendix II enclosed with Circular No. 32/2018/TT-BYT, except for administrative documents.

9. The documentation of scientific bases attached to experimental data proving that the reagent used in the bioequivalence study are still representative of the product under consideration. The documentation of scientific bases must include the following contents at the minimum:

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b) The equivalence of quality standards of APIs including API properties known as having effects on bioavailability of FPPs, quality standards of excipients, manufacturing process and standard operating procedures, equipment used in manufacture and environmental control in the manufacturing process, quality standards of FPPs;

c) Properties of excipients effecting bioavailability of APIs used in the formulation;

d) Comparison of analytical data of at least 03 pilot-scale batches as prescribed in Appendix V hereof including batches of reagents used in the bioequivalence study and batches of products under consideration.

10. The documentation of in vitro bioequivalence between the pharmaceutical product manufactured at the old manufacturing site and the product under consideration. Requirements for the report on in vitro bioequivalence study are prescribed specifically in Appendix IV enclosed with this Circular. This documentation is not required if the change of manufacturing site only relates to one or a number of stages including primary packaging without dosing, quality control, batch release and secondary packaging.

11. The data documentation of in vitro - in vivo correlation which has been established in case of modified release pharmaceutical products. In case the change of manufacturing site only affects one or a number of stages including primary packaging after dosing, quality control, batch release and secondary packaging, this documentation is not required.

12. In case manufacturing site changes due to the change of the manufacturer and the product manufactured at the old manufacturing site which has been granted the marketing authorization in Vietnam according to ASEAN common technical dossier (ACTD) but has not been released as a documented bioequivalent product: the documentation of bioequivalence study reporting of the product manufactured at the old manufacturing site which must meet regulations in Article 8 and the documentation of bioequivalence study reporting of the product under consideration which must meet regulations in clauses 1, 2, 3, 5, 6, 7, 8, 9, 10 and 11 of this Article.

13. In case manufacturing site changes due to the change of the manufacturer and the product manufactured at the old manufacturing site which has been released as a documented bioequivalent product: the documentation of bioequivalence study reporting of the product under consideration which must meet regulations in clauses 1, 2, 3, 5, 6, 7, 8, 9, 10 and 11 of this Article.

14. In case there is a change in different manufacturing sites of the same manufacturer and product manufactured at the old manufacturing site which has been granted the marketing authorisation in Vietnam: based on the changes and addition of pharmaco-chemical products already granted marketing authorizations specified in Appendix II issued with Circular No. 32/2018/TT-BYT.

Article 12. Documents and information of research facilities

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2. Documentation for a research facility certified by the World Health Organization and published on the list of prequalified laboratories allowed to conduct in vivo bioequivalence studies or a facility assessed and certified as being allowed to conduct in vivo bioequivalence studies by one of pharmaceutical regulatory authorities prescribed in clause 10 Article 2 of Circular No. 32/2018/TT-BYT or a facility certified by a competent regulatory authority of one of the countries of the ICH to conduct in vivo bioequivalence study or a facility named in the list of facilities performing bioequivalence studies approved under the ASEAN mutual recognition arrangements (MRAs) for bioequivalence study reports of pharmaceutical products (posted on the ASEAN website) and other facilities belonging to countries with which Vietnam has a recognition arrangement is one of the following two types of:

a) An original or a copy of a certificate of a facility meeting GCP and GLP or ISO/IEC 17025 or a license/certificate/confirmation/notification granted to a facility performing in vivo bioequivalence study by a competent authority of the host country or a certificate/confirmation/notification of approval for conducting in vivo bioequivalence study by a facility from a competent authority of the host country;

b) A result after self-searching a legal document prescribed in point a of this clause from the English website of the agency granting the legal document attached to a document providing information on reference links to the Drug Administration of Vietnam in case of an electronic legal document, or lack of signature, name of signatory or certificate seal of a competent state regulatory authority of the country granting the legal document.

3. Documentation which must be submitted of a research facility which is not prescribed in clause 1 and clause 2 of this Article is one of the following documents:

a) An original or a copy of a license/certificate/confirmation/notification granted to a facility performing in vivo bioequivalence study by a competent authority of the host country or a certificate/confirmation/notification of approval for trial conduct of in vivo bioequivalence study of a pharmaceutical product under consideration by a facility from a competent authority of the host country;

b) An original or a copy of a certificate of meeting GLP or certificate of meeting ISO/IEC 17025 to perform an analysis of biological fluids granted to a facility participating in the analytical stage by a regulatory authority of the host country and a certificate of meeting GCP granted to a facility participating in the clinical stage by a regulatory authority of the host country;

c) In case a research facility cannot provide documents prescribed in point a or b of this clause due to law of the host country which not provides for issuing these documents to the research facility, the unit which applies for marketing authorization of the product under consideration is required to provide documentary evidence of the compliance with GCP and/or GLP including:

- Documentary evidence of the compliance with GLP:

+ A quality manual or an overall profile of the bioequivalence research facility. These documents must address capacity and scope of conducting the study;

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+ A list of inspections by regulatory authorities or accreditation bodies over the last 3 years and the most recent inspection report of the local regulatory authority.

- Documentary evidence of the compliance with GCP:

+ An overall profile of a center for bioequivalence studies and clinical research (CBSCR) demonstrating full testing capacity for conducting bioequivalence studies of pharmaceutical products;

+ An original or a copy of a contract between the bioequivalence research facility and its donor and subcontractors;

+ An original or a copy of an inspection report of a national pharmaceutical regulatory authority or WHO which has been made within 3 years;

+ An original or a copy of a research supervision report by a donor or research organization for studies under consideration.

4. Documents prescribed in clause 2, points a and b clause 3 of this Article must satisfy the following requirements: 

a) Documents must be valid during the study period.  A document shall be effective for 03 years from the date on which it is issued if the effective period is not clarified on the document;

b) In case the certificate of meeting GLP and the certificate of meeting GCP do not satisfy the regulations in point a of this clause, conclusion of GLP/GCP assessment in the inspection report of the competent regulatory authority of the latest inspection in 03 years after the date on which the assessment is carried out.

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Chapter V

IMPLEMENTATION CLAUSES

Article 13. Effect

1. This Circular comes into force from November 01, 2022.

2. Circular No. 08/2010/TT-BYT dated April 26, 2010 of the Minister of Health providing for Guideline on reports on bioavailability/bioequivalence study data in applying for marketing authorisation of pharmaceutical products is null and void from the date on which this Circular comes into force.

Article 14. Application route

1. From the date on which this Circular comes into force, each facility applying for marketing authorization of the following pharmaceutical products must submit the documentation of bioequivalence study reporting when the facility submits an application for issuance of marketing authorization of the pharmaceutical products including:

a) Generic drugs which are prepared in the immediate release dosage form and delayed release dosage form, are single active ingredient or fixed-dose combination drugs, contain APIs on the List of APIs in the formulation for which bioequivalence study reports are required when applying for marketing authorization of these drugs;

b) Generic drugs which are prepared in the modified release dosage form, except for delayed release drugs which are not prescribed in point a of this clause;

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3. After 48 months from the date on which this Circular comes into force, each applying facility granted marketing authorization of pharmaceutical products containing APIs or being in dosage forms required of in vivo bioequivalence studies according to regulations herein must be certified publically to have pharmaceutical products which are bioequivalent after being documented. Procedures for public certification of pharmaceutical products which are bioequivalent after being documented are prescribed in the Circular on the application for marketing authorization of drugs and medicinal materials.

Article 15. Transitional regulations

1. Bioequivalence study reports in applications for issuance, change or addition of marketing authorizations submitted before the date on which this Circular comes into force shall continuously comply with regulations in Circular No. 08/2010/TT-BYT dated April 26, 2010 of the Minister of Health providing for guideline on reports on bioavailability/bioequivalence study data in applying for marketing authorization of pharmaceutical products, except for the case that facilities voluntarily comply with regulations herein.

2. For pharmaceutical products of which marketing authorization applications are submitted before the date on which this Circular comes into force: bioequivalence study reports are not required of additional submission before the dates on which marketing authorizations are granted; facilities applying for marketing authorization must comply with regulations in clause 3 Article 14 after marketing authorizations of pharmaceutical products are granted.

3. In case in vivo bioequivalence studies or in vitro bioequivalence studies are conducted before the date on which this Circlular comes into force, commitments of enterprises to origins of comparator products used in these studies shall be approved according to schedule 03/BE prescribed in Appendix VII enclosed herewith if documentary evidence of origins of these comparator products cannot be provided according to regulations in point c clause 1 Article 8 hereof.

4. In case in vivo bioequivalence studies are conducted before the date on which this Circular comes into force, research facilities, comparator products and study designs shall be approved if pharmaceutical products under consideration have been approved and marketed in countries by their stringent regulatory authorities prescribed in clause 10 Article 2 of Circular No. 32/2018/TT-BYT. 

5. In case in vivo bioequivalence studies are conducted before the date on which this Circular comes into force, except for cases prescribed in clause 3 of this Article, comparator products that are selected in these studies shall be approved in one of the following cases:

a) Comparator products are prescribed in the lists of proprietary drugs issued by the Ministry of Health in the study periods;

b) Comparator products are approved in writing by the Drug Administration of Vietnam of the Ministry of Health;

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Article 16. Reference regulations

In case legislative documents and regulations cited in this Circular are changed, added or replaced, new legislative documents or cited regulations shall be applied.

Reference technical guidelines prescribed in Appendix VI enclosed herewith shall be applied as bases for consideration and assessment of dossiers on in vivo bioequivalence studies. In case these guidelines have changes or updates, research facilities are permitted to apply new versions of them.

Article 17. Responsibility for implementation

1. Drug Administration of Vietnam is responsible for:

a) organizing guidance and implementing regulations herein;

b) updating and publishing the List of comparator products used in in vivo bioequivalence studies issued by the Ministry of Health;

c) updating and publishing the list of facilities conducting bioequivalence studies assessed and approved by the Ministry of Health of Vietnam;

2. Chief of the Ministry Office, Director General of the Drug Administration of Vietnam, Chief Inspector of the Ministry,  Heads of units affiliated to the Ministry of Health, Directors of Departments of Health of provinces or central-affiliated cities; Heads of healthcare facilities of health sectors, directors of facilities conducting in vivo bioequivalence studies of pharmaceutical products; organizations and individuals operating in the field of marketing authorization of pharmaceutical products are responsible for implementation of this Circular.

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PP. MINISTER
DEPUTY MINISTER




Do Xuan Tuyen