Thông tư 08/2010/TT-BYT về báo cáo số liệu nghiên cứu sinh khả dụng

CIRCULAR

GUIDING REPORT OF BIOAVAILABILITY/BIOEQUIVALENCE STUDY DATA WHEN REGISTERING DRUGS

Pursuant to the Law on Pharmacy dated 14/6/2005;

Pursuant to the Decree No.188/2007/ND-CP dated 27/12/2007 of the Government stipulating the function, tasks, powers and organizational structure of the Ministry of Health;

Pursuant to the Decree No.79/2006/ND-CP dated 9/8/2006 of the Government detailing the implementation of a number of Articles of the Pharmacy Law;

To participate in the integration process in ASEAN on drug registration, the Ministry of Health guidelines for the report of bioavailability/bioequivalence study datain drug registration as follows:

Chapter I

GENERAL PROVISIONS

Article 1.Scope of governing

This Circular guides the report of bioavailability/bioequivalence study data in drugs circulation registrationin Vietnam.

Article 2. Subjects of application

This Circular applies to domestic and foreign agencies, organizations, and individuals whose activities are related to the circulation registration of drugs in Vietnam.

Article 3. Interpretation of terms

1.Invention drug (Innovator pharmaceutical product)means the drug licensed for the first circulation, on the basis of full data on quality, safety, and efficiency.

2.Generic drug (generic product)means a finished drug in order to replace an invention drug produced without concession license of the invention company and marketed after the patent and the monopolies have expired their term.

3.Control drug (Comparator product)means drug that generic drug will be used to replace it in therapy. Normally, the control drug is an invention drug with data on effectiveness, safety, and quality which have been established.

4.Dosage equivalence (Pharmaceutical equivalence): the drugs are considered as dosage equivalence if they contain the same pharmaceutical substance with the same content in the same dosage form, same usage and reaching the same level of quality standards.

5.The made substitutes (Pharmaceutical alternatives): The drugs are considered as made substitutes if they contain the same type of pharmaceutical substance but different from chemical forms of the pharmaceutical substance (base, salt or ester ...) or different from content or dosage forms.

6.Bioavailabilitymeans the characteristic indicates the speed and extent of absorption of a pharmaceutical substance or group of substances with effects on general circulation and is available in place of impact. It is also possible to understand that the bioavailability indicates the extent and speed of the pharmaceutical substance or substance that are released from the dosage form and is available in general circulation.

7.Bioequivalence (Bioequivalence): Two drugs are considered as bioequivalence if they are pharmaceutical equivalence drug or pharmaceutical alternatives, and their bioavailability after taking the same dose in the same conditions of test is similar so their treatment effect is considered to be basically equivalent to each other.

8.Conventional dosage forms: a dosage form using exipients and classical preparation technique, without intention to change the release speed of pharmaceutical substance out of dosage forms.

9.Modified release dosage forms (Modified release dosage form): means the dosage form to use some excipients and/or preparation techniques different from conventional dosage forms to create pharmaceutical substance release speed different from the form conventional dosage. It includes accelerated, rhythm, stretching, delayed release dosage form...

10.Extended-release dosage form (extended release, sustained release dosage form): means a form of modified release dosage with a speed of pharmaceutical substance release which is changed by the direction of the prolonged effects of the drug to reduce the frequency of use of drugs compared with conventional dosage forms of the same pharmaceutical substance.

11. Delayed release dosage forms (Delayed release dosage form): means a modified release dosage forms that pharmaceutical substance is delayed for a certain period of time after treatment and then released as normal in conventional dosage forms. Package dosage form dissolved in the intestine is of this type.

12. Approved drugs: Within the scope of this Circular, the drugs which have been approved means invention drug or generic drug with sufficient data of bioavailability/bioequivalence study meeting requirements and granted circulation registration numbers.

Article 4. Regulations for the study of bioavailability/bioequivalence

1. The study must be designed and implemented in accordance with provisions in the guideline to study bioavailability/bioequivalence of ASEAN or the equivalent guidance of the other organizations (such as the World Health organization (WHO) , international Conference on harmony (ICH), the U.S. Food Drug Administration (U.S. FDA)). For the studies conducted in Vietnam, before the study, research scheme must be evaluated and approved by specialized technical agencies authorized by the Ministry of Health.

2. The study must be conducted at the unit of testing that has been assessed and accredited by a competent agency in the home country, and must be done in accordance with the principles of good clinical practice (GCP) and good laboratory practice (GLP) according to regulations of Vietnam or other similar regulations. The registered establishments shall have to provide valid sufficient evidence on the study which was conducted to meet the above requirements.

3. The report of bioavailability/bioequivalence study data must include the full contents specified in the form of report –of bioavailability/bioequivalence study guidance of ASEAN.

Article 5. Regulations for the use of control drugs in the study of compared bioequivalence / bioavailability for drug registration

1. For generic drugs in conventional dosage forms which effect the whole body, containing the pharmaceutical substance on the list of drugs required to report bioequivalence study data as registering drug (Annex 2): control drug used in the study is prescribed together with the list.

In case the studies used control drug as invention drug but not invention drug being circulated in Vietnam is specified in the list, the registration establishments required to provide the data demonstrated the ability to replace each other (solubility equivalence or bioequivalence) between the invention drug which has been used in research and invention drug which are being circulated in Vietnam.

2. For generic drugs with a combination of some pharmaceutical substances including the pharmaceutical substance on the list of the pharmaceutical substance required to report bioequivalence study data as registering drug (Annex 2): Control drug used in the study must be the invention drug with a similar coordination on ingredients of pharmaceutical substance and proportion of coordination between the ingredients or corresponding single ingredient control drug prescribed together in the list.

3. For generic drugs in the form of modified release dosage: Drug control used in the study must be selected according to the principles set out in Annex 1 of this Circular.

4. The drug registration establishments shall have to prove control drug which is selected by them for testing meeting the principles as prescribed, to provide accurate, adequate information on the country of origin as well as the production lot number and expiry date of the control drugs used in research.

Article 6. Principles of selection of pharmaceutical substance included in the list of pharmaceutical substance required to report bioequivalence study data as registering drug

The pharmaceutical substance selected for inclusion in the list must meet one or more of the following principles of priority:

1. Being in the drugs on the list of treatment medications primarily used in the medical facilities issued by the Ministry of Health together with the Decision No.05/2008/QD-BYT on 01/02/2008 and to be of one of the pharmacological effects groups of priority as follows:

a) The heart and blood pressure drugs;

b) The anticonvulsant, antiepileptic drugs;

c) The blood glucose lowering drugs;

d) The antibiotics;

đ) The drugs that effect on the gastrointestinal tract to reduce gastric acid secretion;

e) The anti-psychiatric disorder drugs;

f) The anti-inflammatory drugs (non-steroid and steroid);

g) The antiviral drugs.

2. Being in the drugs on the list of drugs used in the national program (tuberculosis drugs, antimalarials, anti-HIV medicines, birth control pills ...).

3. Having some narrow therapy and/or bioavailability problem.

Chapter II

PROVISIONS FOR STUDY DATA REPORT OF BIOAVAILABILITY/BIOEQUIVALENCE IN DRUG REGISTRATION

Article 7. The generic drugs in conventional dosage forms effecting the whole body

1. The drugs falling into one of the following cases are exempted from reporting bioequivalence study data as registering drug:

a) Intravenous injection drug with the same type of use as injected is the solution in water, with the same pharmaceutical substance and the same concentration with the drug which has been approved;

b) Drug using way of injection different from by intravenous injection with the same using form as injected is the solution in water or in oil, with the same pharmaceutical substance and the same pharmaceutical substance concentration, the same exipient or the type of exipient equivalent to drug which has been approved;

c) The drug is used under the form of solution in water as drinking, with the same pharmaceutical substance and the same pharmaceutical substance concentration with approved drugs with a condition that the excipients contained in drug do not affect the transport of drugs through digestion, absorption, and stability of the pharmaceutical substance in the body.

d) Drug used in aerosol form.

2. The drugs do not fall into the cases prescribed in clause 1 of this Article, containing pharmaceutical substance on the list of pharmaceutical substances required to report bioequivalence study data as registering drug (Annex 2) must report bioequivalence study data as registering.

3. The drug that its formula has a combination of several pharmaceutical substances, including pharmaceutical substances on the list of pharmaceutical substances required to report bioequivalence study data as registering drug (Annex 2), must report bioequivalence study data for such pharmaceutical substances.

4. For different contents of oral use of the same pharmaceutical substance (or the same combination of pharmaceutical substances), the same dosage forms of the same manufacturer, made in the same location, the report of bioequivalence study data of a content can be considered to accept for the remaining contents (usually the contents shall be lower except for the bioequivalence study for higher contents cannot make because of safety reasons) when meeting the following conditions:

a) The being considered contents have the same production process with the content used in bioequivalence study;

b) Formula of dosage of the being considered contents must be the same on composition (excipients and pharmaceutical substance) and the same rate of combination between the compositions or, in the case of pharmaceutical substance account for less than 5% in the formula, the rate of coordination among the remaining compositions in the formula must be similar as compared with the dosage formula of the content used in bioequivalence study;

c) Having a linear relationship between pharmaceutical substance content and absorption ability of pharmaceutical substance into the body in the considered dose (or treatment dose);

d) For the solid oral drugs: In the same conditions of testing the solubility, dissolution diagram of the being considered content must be similar to the contents used in bioequivalence study (based on percentage of pharmaceutical substance released by time). The method of setting, comparisons of dissolution diagram and acceptable limits specified in Annex II- bioavailability/bioequivalence study guideline of ASEAN.

Article 8. The generic drugs in modified release dosage form with full body effects

1. The drugs under package dosage form dissolved in the intestine: applied as for the drug in conventional dosage forms in accordance with provisions in Article 7.

2. The drug containing any pharmaceutical substance in the modified release dosage form not dissolved in the intestine must report bioavailability or bioequivalence study data and/or report appropriate clinical trials the case by case basic as follows:

a) Drug in the modified release dosage form is marketed for the first time intended to replace a drug in the conventional dosage form or the modified release dosage form of different style which has been approved of the same pharmaceutical substance:

- If it has data on a correlation between clinical response (including response to therapy and adverse reactions) and drug concentrations or active metabolites (from pharmaceutical substance for trying) in plasma, required to report bioavailability study data comparing between the drugs need to be tried with respective control drug in conventional dosage form. This obtained comparison bioavailability study data will be used to evaluate the safety and efficacy of drugs in being considered modified release dosage forms. If the obtained pharmacokinetic data in the study is not sufficient to prove the safety and efficacy of being considered drugs, it needs to conduct a proper clinical trial to supplement;

- If it has no available data on a correlation as mentioned above, it must conduct an appropriate clinical trial to determine at the same time the parameters of pharmacokinetics and pharmacodynamics of drugs.

b) Drug in the modified release dosage form intended to be equivalent to a drug in modified release dosage form of the same type which has been approved: required to report bioequivalence study data of drugs compared with corresponding control drug which are considered for the equivalent design.

3. The generic drugs in extended-release dosage form of oral use:

a) Apart from the provisions applied generally to the drug in modified release dosage form not dissolved in the intestine mentioned in clause 2 of this Article, required to supplement the report of research data on the effects of food to bioavailability of the drug.

b) For the drugs have different contents of the same pharmaceutical substance (or the same combination of pharmaceutical substances) in this dosage form, may be considered acceptable bioequivalence study report data of the high content for the lower content in the case satisfying the following conditions:

- As the capsule form containing the same type of particle that difference on the contents of pharmaceutical substance in the capsule obtained by adjusting the amount (or volume) of particles in the capsule or:

As the tablet form of the same pharmaceutical substance -release mechanism, with the dosage formula similar to the ingredients (excipients and pharmaceutical substance) and with the same rate of combination of these ingredients in the formula;

- The being considered contents are of the same manufacturer, made in the same location and same process of preparation with a content used in bioequivalence study;

- Having a linear relationship between pharmaceutical substance content and absorption ability of pharmaceutical substance into the body in the considered dose (or treatment dose);

- In the same conditions of testing the solubility, the dissolution diagram of the being considered content must be similar to the content used in the bioequivalence study (based on the percentage of pharmaceutical substance released by time ). The methods of setting, comparison of the dissolution diagram and acceptable limits specified in Annex II- bioavailability/bioequivalence study guideline of ASEAN.

Article 9. The changes for drugs approved

1. Changes in recipe or dosage processes that affect the bioavailability of the drug:

a) For invention drug: requirements to report bioequivalence study data of drugs have changed compared with the control drug as invention drugs with the formula and process of dosage which has been approved;

b) For generic drugs: requirements to report bioequivalence study data of drugs have changed compared with the control drug used in bioequivalence studies of drugs which has been approved.

2. Relocation of production (unchanged preparation recipe and process of preparation) requirements to report similar data of solubility of the drug is produced at the new location compared to manufactured drugs at the former place approved. Similar evaluation method of solubility and acceptable limits is specified in Annex II- study guidance of bioavailability/bioequivalence of ASEAN.

Article 10. The process and procedures for receiving records

Report of bioavailability/bioequivalence study data is part of drug registration dossier, which was received at the Drug Administration of Vietnam under the provisions of Circular No.22/2009/TT-BYT dated 24/11/2009 of the Health Ministry provided for medicine registration.

Chapter III

IMPLEMENTATION ORGANIZATION

Article 11. Effect

This Circular takes effect after 06 months from the date of signing. The Ministry of Health encourages the drug registration facilities to submit report of bioavailability/bioequivalence study data as registering drug as prescribed in this Circular before the effective date of this Circular.

2. From the effective date of this Circular, to the drugs specified in the clauses 2 and 3 of Article 7 and clauses 1, 2, 3 of Article 8:

a) It must submit report of bioavailability/bioequivalence study data of drugs when they are registered for the first time or re-registered but the previous registrations have not been reported bioavailability/bioequivalence study data in the profile.

b) It is encouraged to submit additional bioavailability/bioequivalence study data report of drugs for the drugs that have the valid registration numbers.

Article 12. Responsibility for implementation

Mr., Ms. Chiefs of the Ministry Office, Chief Inspector of the Ministry, General Director of Drug Administration of Vietnam, heads of units under the Ministry, the Directors of Health Services of provinces and cities directly under the Central Government, heads of health agencies, directors of facilities producing drugs, drug registration re responsible for the implementation of this Circular./.

ANNEX 1:

PRINCIPLES OF SELECTION OF CONTROL DRUGS USED IN BIOEQUIVALENCE STUDY FOR DRUGS REGISTRATION
(Issuing together with the Circular No.08/2010/TT-BYT dated 26/4/2010)

Control drug used in bioequivalence studies for drug registration are selected according to the following priority order:

1. Control drug is the invention drug with complete data on quality, safety, and efficiency which has been licensed and is being circulated in Vietnam.

2. Control drug to be of the list of the control drugs of the World Health Organization (WHO comparator list), are the drugs were licensed in circulation based on data on quality, safety and efficacy of drugs. The information on manufacturers and country where the drug was first produced provided together with the list. Control drugs used in research must be purchased at the first producing country.

3. Drug control is the invention drug has been licensed and is being circulated in one of the member countries of international Conference on harmony (ICH-including the countries of the EU, U.S., Japan) or in Canada, Australia, Switzerland. Control drugs used in research must be purchased at one of the countries where the drug is licensed for circulation above.

4. In case of unable to identify the invention drug, criteria for selection of control drug is arranged by the following order of priority:

a) Drugs have been licensed and are being circulated in one of the member countries of the International Conference on harmony mentioned above or in Canada, Australia, and Switzerland.

b) Drug was assessed quality (prequalified) by the World Health Organization. In both above cases, the drug must meet the standards of the Pharmacopoeia, if these standards exist.

ANNEX 2:

LIST OF PHARMACEUTICAL SUBSTANCE REQUIRED TO REPORT BIOEQUIVALENCE STUDY DATA WHEN REGISTERING DRUGS

(First Issuance)

(Issuing together the Circular No.08/2010/TT-BYT dated 26/4/2010)

1. The purpose of the list promulgation

The Ministry of Health promulgates the list of pharmaceutical substances required to report bioequivalence study data when registering drugs in order to gradually improve the quality of generic drugs being circulated on the market and meet the requirements of harmony in field of drug registration among the ASEAN countries.

This list is updated annually or upon the request of management need to respond immediately to ensure the safety and efficacy of drugs circulated.

2. The list of pharmaceutical substances and respective control drugs

* The invention drugs have not been circulated in Vietnam now. Drugs are purchased in the producing countries by information in the list.

** The invention drugs have not been circulated in Vietnam now. Drugs are purchased in countries where drugs are licensed for circulation according to information in the list.

1.2 Information on manufacturers, producing countries/countries licensing for circulation for the control drugs prescribed in the list will be updated according to their actual production and circulation.