✦ Smart summary
Circular No. 08/2010/TT-BYT guides the reporting of bioequivalence/bioavailability research data in drug registration in Vietnam, applicable to agencies, organizations, and individuals involved in drug registration activities. This circular specifies the method, content, and submission deadlines for reporting research data.
Scope of application
Agencies, organizations, and individuals both within and outside Vietnam engaged in drug circulation registration activities.
Key points
- Agencies, organizations, and individuals must report bioequivalence/bioavailability research data for drugs as prescribed (Article 4-9).
- Research must be designed and conducted according to international guidelines or those of WHO, ICH, US FDA (Article 4.1).
- The comparator drug used in bioequivalence/bioavailability comparative studies for drug registration must meet specific requirements (Article 5).
- Generic drugs in conventional dosage forms with systemic effects need to report bioequivalence research data when registering, except for certain exempted cases (Article 7).
- Modified-release generic drugs must comply with specific regulations regarding the reporting of bioequivalence/bioavailability research data (Article 8).
🌐 Social impact of this document
- Positive impact: Enhances the quality and safety of drugs on the market, helping the public access more effective medications.
- Negative impact: May increase registration costs for pharmaceutical manufacturing enterprises, requiring significant resources to conduct research.
❓ Frequently asked questions
Which agencies and organizations must comply with this Circular?
This Circular applies to agencies, organizations, and individuals both within and outside Vietnam engaged in drug circulation registration activities.
What regulations must bioequivalence/bioavailability research follow?
Research must be designed and conducted according to international guidelines or those of WHO, ICH, US FDA (Article 4.1).
Must generic drugs in conventional dosage forms with systemic effects report bioequivalence research data when registering?
Except for certain exempted cases, generic drugs in conventional dosage forms with systemic effects must report bioequivalence research data when registering (Article 7).
What requirements must the comparator drug used in bioequivalence/bioavailability comparative studies for drug registration meet?
The comparator drug used in research must be an original drug or a single-component comparator drug as specified (Article 5).
What requirements apply to modified-release generic drugs?
Modified-release generic drugs must report bioequivalence/bioavailability research data according to specific regulations (Article 8).
Full text
CIRCULAR
Guidelines for reporting bioavailability/bioequivalence study data in drug registration
Pursuant to the Drug Law No. 34/2005/QH11 dated June 14, 2005;
Pursuant to Decree No. 188/2007/NĐ-CP dated December 27, 2007 of the Government on the functions, tasks, powers, and organizational structure of the Ministry of Health;
Pursuant to the Government's Decree No. 79/2006/NĐ-CP dated August 9, 2006 detailing the implementation of certain provisions of the Drug Law;
To participate in the harmonization process within the ASEAN bloc regarding drug registration, the Ministry of Health provides guidelines for reporting bioavailability/bioequivalence study data in drug registration as follows:
PART I
GENERAL PROVISIONS
Article 1. Scope of Regulation
These Circulars provide guidelines for reporting bioavailability/bioequivalence study data in drug circulation registration in Vietnam.
Article 2. Applicability
These Circulars apply to domestic and foreign agencies, organizations, and individuals involved in drug circulation registration activities in Vietnam.
Article 3. Explanation of Terms
1. (Innovator pharmaceutical product): Is the first drug approved for circulation worldwide based on complete data on quality, safety, and efficacy, including drugs approved or not yet approved for circulation in Vietnam. (Innovator pharmaceutical product): is a drug that is first licensed for circulation based on complete data on quality, safety, and efficacy.
2. Generic drug (Generic product): is a finished drug intended to replace an innovator drug produced without a license from the innovator company and marketed after the expiration of the patent and other exclusive rights.
3. (Comparator product/Reference product): Is the drug that the generic drug will replace in treatment. Typically, the reference drug is an innovator drug or a drug that has been registered for circulation with established data on efficacy, safety, and quality. (Comparator product): is the drug that the generic drug will be used to replace in treatment. Typically, the comparator drug is an innovator drug with established data on efficacy, safety, and quality.
4. (Pharmaceutical equivalence): Are drugs containing the same active ingredient (for single-ingredient drugs) or the same set of active ingredients (for multi-ingredient drugs), where the active ingredients in the drugs are identical and have the same molar concentration, while the drugs have the same dosage form, drug release mechanism, the same route of administration, and equivalent quality standards. (Pharmaceutical equivalence): drugs are considered pharmaceutically equivalent if they contain the same active ingredient at the same strength in the same dosage form, have the same route of administration, and meet the same quality standards.
5. (Pharmaceutical alternatives): Are drugs containing the same active ingredient but differing in chemical form (salts, esters, ethers, isomers, mixtures of isomers, complexes, or derivatives) of each active ingredient or in active ingredient concentration or dosage form. (Pharmaceutical alternatives): drugs are considered pharmaceutically alternative if they contain the same active ingredient but differ in the chemical form of the active ingredient (base, salt, or ester...) or in strength or dosage form.
6. Bioavailability (Bioavailability): is the characteristic indicating the rate and extent of absorption of an active substance or group of substances into the systemic circulation and availability at the site of action. Bioavailability can also be understood as the extent and rate of the active substance or substance of effect being released from the dosage form and available in the systemic circulation.
7. Bioequivalence (Bioequivalence): two drugs are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutically alternative, and their bioavailability after administration of the same dose under the same test conditions is similar, leading to their therapeutic effects being essentially considered equivalent.
8. Conventional dosage form (Conventional dosage form): is a dosage form using traditional excipients and manufacturing techniques without the intention of changing the rate of release of the active substance from the dosage form.
9. Modified release dosage form (Modified release dosage form): is a dosage form using different excipients and/or manufacturing techniques compared to conventional dosage forms to create a different rate of release of the active substance than conventional dosage forms. It includes delayed-release, extended-release, pulsatile-release, and fast-release forms.
10. Extended-release dosage form (Extended-release, Sustained-release dosage form): is a modified-release dosage form with a modified release rate of the active substance designed to extend the duration of drug action to reduce the frequency of use compared to the conventional dosage form of the same active substance.
11. Delayed-release dosage form (Delayed-release dosage form): is a modified-release dosage form where the release of the active substance is delayed for a specific period after administration and then releases normally as in a conventional dosage form. Enteric-coated forms belong to this category.
12. Approved drug: Within the scope of these Circulars, an approved drug refers to an innovator drug or generic drug with complete bioavailability/bioequivalence study data meeting requirements and having been granted a registration number for circulation.
Article 4. Provisions for bioequivalent/bioavailability research subjects
1. Research must be designed and conducted in accordance with the ASEAN Bioequivalent/Bioavailability Research Guidelines or equivalent guidelines from other organizations (such as the World Health Organization (WHO), International Conference on Harmonization (ICH), United States Food and Drug Administration (US FDA)). For research conducted in Vietnam, before commencing the research, the research outline must be reviewed and approved by the specialized technical agency authorized by the Ministry of Health.
2. Research must be carried out at testing units that have been evaluated and recognized by the competent authority of the host country, and must be conducted in compliance with Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) principles as prescribed in Vietnam or equivalent regulations. The registration entity shall be responsible for providing complete and legally valid evidence that the research has been conducted in accordance with the requirements mentioned above.
3. Reports on bioequivalent/bioavailability research data must include all contents specified in the Reporting Form - ASEAN Bioequivalent/Bioavailability Research Guidelines.
Article 5. Provisions for the use of control drugs in comparative bioequivalent/bioavailability studies for drug registration
1. For generic drugs in conventional dosage forms with systemic effects containing active substances listed in the Active Substances List requiring bioequivalent/bioavailability study data when registering drugs (Annex 2): The control drug used in the study is specified in the List.
In cases where the study uses a control drug that is an innovator drug but not an innovator drug currently circulating in Vietnam as specified in the List, the registration entity must provide data proving the interchangeability (bioequivalence or bioavailability equivalence) between the innovator drug used in the study and the innovator drug currently circulating in Vietnam.
2. For generic drugs combining several active substances including those listed in the Active Substances List requiring bioequivalent/bioavailability study data when registering drugs (Annex 2): The control drug used in the study must be an innovator drug with a similar composition of active substances and ratio of components, or a corresponding single-component control drug specified in the List.
3. For generic drugs in modified release dosage forms: The control drug used in the study must be selected according to the principles set forth in Appendix 1 of this Circular.
4. The drug registration entity must be responsible for proving that the control drug chosen for testing meets the prescribed principles, and must provide full and accurate information about the country of origin as well as the batch number and expiration date of the control drug used in the study.
Article 6. Principles for selecting active substances to be included in the Active Substances List requiring bioequivalent/bioavailability study data when registering drugs
Active substances selected for inclusion in the List must meet one or more of the following priority principles:
1. Included in the list of essential medicines used in healthcare facilities as issued by the Ministry of Health under Decision No. 05/2008/QD-BYT dated February 1, 2008, and belong to one of the following prioritized pharmacological groups:
a) Cardiovascular-hypotensive drugs;
b) Anticonvulsant and antiepileptic drugs;
c) Hypoglycemic drugs;
d) Antibiotics;
đ) Drugs acting on the digestive tract to reduce gastric acid secretion;
e) Psychotropic drugs;
f) Anti-inflammatory drugs (non-steroidal and steroidal);
g) Antiviral drugs.
2. Included in the list of drugs used in national programs (tuberculosis drugs, malaria drugs, HIV drugs, contraceptive drugs...).
3. Have a narrow therapeutic range and/or issues related to bioavailability.
Chapter II
PROVISIONS FOR REPORTING BIOEQUIVALENT/BIOAVAILABILITY RESEARCH DATA IN DRUG REGISTRATION
Article 7. Generic drugs in conventional dosage forms with systemic effects
1. Drugs falling under any of the following cases shall be exempted from reporting bioequivalence study data when registering the drug:
a) Intravenous injection drugs, having the same form of use at the time of injection as a water solution, the same active ingredient and the same concentration as the approved drug;
b) Injection drugs other than intravenous injection, having the same form of use at the time of injection as a water solution or oil solution, the same active ingredient and concentration of active ingredient, and the same excipient or equivalent excipient to the approved drug;
c) Drugs used in the form of a water solution for oral administration, having the same active ingredient and concentration of active ingredient as the approved drug, provided that the excipients in the drug formulation do not affect the transport of the drug through the digestive tract, absorption, and stability of the active ingredient in the body;
d) Drugs used in the form of inhalation aerosol.
2. Drugs not falling under the cases stipulated in Clause 1 of this Article, containing active ingredients listed in the List of Active Ingredients Requiring Reporting Bioequivalence Study Data When Registering Drugs (Annex 2) must report bioequivalence study data when registering.
3. Drugs in formulations combining several active ingredients, including active ingredients listed in the List of Active Ingredients Requiring Reporting Bioequivalence Study Data When Registering Drugs (Annex 2), must report bioequivalence study data for such active ingredient.
4. For different strengths of the same active ingredient (or the same combination of active ingredients) used orally, produced by the same manufacturer at the same location, the bioequivalence study data of one strength may be considered acceptable for the remaining strengths (usually lower strengths, except in cases where bioequivalence studies for higher strengths cannot be conducted due to safety reasons) if the following conditions are fully met:
a) The strengths under consideration have the same production process as the strength used in the bioequivalence study;
b) The formulation of the strengths under consideration must be identical in composition (excipients and active ingredient) and have the same ratio of components, or, in the case where the active ingredient constitutes less than 5% of the formulation, the ratio of the remaining components in the formulation must be similar compared to the formulation of the strength used in the bioequivalence study;
c) There is a linear correlation between the strength of the active ingredient and its absorption capacity into the body within the dose range (or therapeutic dose);
d) For solid oral dosage forms: Under the same dissolution testing conditions, the dissolution profile of the strength under consideration must be similar to the strength used in the bioequivalence study (based on the percentage of active ingredient released over time). The method for establishing, comparing dissolution profiles and the acceptable limits are specified in Annex II - Guidelines for Bioavailability/Bioequivalence Studies of ASEAN.
Article 8. Generic drugs in modified release formulations with systemic effects
1. Drugs in enteric-coated formulations: Apply as for conventional dosage forms as stipulated in Article 7.
2. Drugs containing any active substance in modified release formulations other than enteric-coated formulations must report bioavailability or bioequivalence study data and/or appropriate clinical trial reports as follows:
a) Drugs in modified release formulations being introduced to the market for the first time intended to replace a conventional dosage form or another type of modified release formulation of the same active substance that has been approved:
- If there is data on a correlation between clinical response (including therapeutic response and adverse reactions) and drug or active metabolite concentrations in plasma, comparative bioavailability study data between the test drug and the corresponding reference conventional dosage form must be reported. These comparative bioavailability study data will be used to assess the safety and efficacy of the modified release formulation under consideration. If pharmacokinetic data obtained from the study are insufficient to demonstrate the safety and efficacy of the drug under consideration, an appropriate clinical trial should be conducted to supplement this information;
- If such correlation data are not available, a suitable clinical trial must be conducted to simultaneously determine pharmacokinetic and pharmacodynamic parameters of the drug.
b) Drugs in modified release formulations intended to be equivalent to a previously approved modified release formulation of the same type: Bioequivalence study data of the drug compared to the corresponding reference drug which the drug under consideration is designed to be equivalent to must be reported.
3. Oral extended-release generic drugs:
a) In addition to the general requirements applicable to non-enteric-coated modified release formulations as specified in Clause 2 of this Article, additional reporting of food effect bioavailability study data is required.
b) For drugs with different strengths of the same active substance (or the same combination of active substances) in this formulation, if the following conditions are met, bioequivalence study data of the higher strength may be accepted for lower strengths:
- Are capsules containing the same type of pellets where the difference in active substance strength is achieved by adjusting the number (or weight) of pellets within the capsule or:
- Are tablets with the same drug release mechanism, having similar formula compositions regarding ingredients (excipients and active substances) and the same ratio of these components in the formula;
- The strengths under consideration are produced by the same manufacturer at the same location and using the same manufacturing process as the strength used in the bioequivalence study;
- There is a linear relationship between the active substance strength and its absorption capacity into the body within the dose range (or therapeutic dose);
- Under the same dissolution testing conditions, the dissolution profile of the strength under consideration must be similar to the strength used in the bioequivalence study (based on the percentage of active substance released over time). The method for establishing, comparing dissolution profiles and acceptable limits are specified in Appendix II - Guidelines for Bioavailability/Bioequivalence Studies of the ASEAN.
Article 9. Changes to approved drugs
1. Changes in formula or manufacturing process that affect drug bioavailability:
a) For innovative drugs: A requirement to submit data from bioequivalence studies of the changed drug compared to the reference innovative drug with the approved formula and manufacturing process;
b) For generic drugs: A requirement to submit data from bioequivalence studies of the changed drug compared to the reference drug used in the bioequivalence study of the approved drug.
2. Change in place of manufacture (formula and manufacturing process unchanged): A requirement to submit data comparing the solubility equivalence of the drug produced at the new location with the drug produced at the previously approved location. The evaluation method for solubility equivalence and acceptable limits are specified in Appendix II - Guidelines for Bioavailability/Bioequivalence Studies of ASEAN.
Article 10. Procedures and processes for receiving applications
Data reports on bioavailability/bioequivalence studies are part of the drug registration dossier, received at the Drug Administration according to Circular No. 22/2009/TT-BYT dated November 24, 2009 of the Ministry of Health on drug registration procedures.
Chapter III
IMPLEMENTATION
Article 11. Effective Date
This Circular takes effect six months from the date of issuance. The Ministry of Health encourages drug registration entities to submit data reports on bioavailability/bioequivalence studies when registering drugs in accordance with this Circular before its effective date.
2. From the date this Circular takes effect, for drugs stipulated in Clauses 2, 3 of Article 7 and Clauses 1, 2, 3 of Article 8:
a) Must submit data reports on bioavailability/bioequivalence studies of the drug when registering for the first time or re-registering without previous data reports on bioavailability/bioequivalence studies in the dossier.
b) Encouraged to submit additional data reports on bioavailability/bioequivalence studies of the drug for drugs with valid registration numbers.
Article 12. Responsibility for Implementation
Heads of the Ministry's Office, Inspectorate, Drug Administration, heads of subordinate units of the Ministry, Directors of Provincial Health Departments, health sector heads, directors of drug production and registration entities are responsible for implementing this Circular./.
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