Công văn 7616/QLD-CL của Cục Quản lý Dược về việc chuẩn bị hồ sơ đề nghị công bố thuốc có chứng minh tương đương sinh học

THE MINISTRY OF HEALTH
DRUG ADMINISTRATION OF VIETNAM

Official Dispatch No. 7616/QLD-CL dated May 21, 2013 of the Drug Administration of Vietnam preparing dossier to request for the announcement of drugs with documents proving bioequivalence

Following the Decision No. 2962/QD-BYT dated 22/8/2012 of the Minister of Health, on promulgating temporary regulation on documents need supply in order to announce lists of original proprietary medicines, medicines used for treatment similar with original proprietary medicines, medicines with documents proving bioequivalence,

Pursuant to provisions in the Circular No. 08/2010/TT-BYT dated 26/4/2010 of the Ministry of Health, guiding report of bioavailability/bioequivalence study data when registering drugs, the Joint Circular No. 01/2012/TTLT-BYT-BTC dated 19/01/2012 of the Ministry of Health and the Ministry of Finance guiding bidding of drugs procurement in the medical facilities; the Circular No. 11/2012/TT-BYT dated  28/6/2012 of the Ministry of Health providing guidance on preparation of tender invitation documents for drug purchase in medical facilities,

Drug Administration of Vietnam specifies dossiers to request for the announcement of drugs with documents proving bioequivalence, including dossier to report on bioequivalence study data enclosed with dossier of drug registration as follows:

I. Dossier to request for the announcement of drugs with documents proving bioequivalence

Establishments requesting for the announcement of drugs with documents proving bioequivalence should supply dossier in Vietnamese or English as follows:

1. Written request for the announcement of drugs with documents proving bioequivalence: made according to Form in the Annex 3 of Decision No. 2962/QD-BYT dated 22/8/2012 (this content does not apply to parts of dossier to report on bioequivalence study data enclosed with dossier of drug registration). 

2. Dossier to prove the legality of establishments studying bioequivalence: Establishments requesting for the announcement must supply one of following valid legal papers (original already consular legalized or copy from the original already consular legalized and authenticated lawfully):

2.1. Permit or certificate of establishments participating in study for eligibility to conduct bioavailability/bioequivalence study that is issued by the Ministry of Health or the Drug Management Authority of host country. In case of failing to supply permits or certificates above, establishments may supply information and evidences on the establishments participating in study having their names in list of study establishments recognized by the Ministry of Health or the Drug Management Authority of their host countries.

2.2. GCP and GLP Certificates (in accordance with regulations of host countries) that are issued by competent agencies or the recognized organizations of quality certification to the bioavailability/bioequivalence study establishments

2.3. If in study, clinical phases and analysis phases are performed at 02 separate establishments, dossier must supply one of two kinds of legal papers that is issued for each establishments specified in point 2.1 or point 2.2 of this item (certificate of eligible establishments for study or GCP/GLP respective certificate of each establishments).

2.4. Certificates of bioavailability/bioequivalence study already been inspected and met the GCP and GLP principles (in accordance with regulations of host countries), issued by the Ministry of Health or Drug Management Authorities of host countries or competent agencies of one of countries as England, France, German, United States, Japan, Australia, Canada or agencies for medical appraisal and assessment of Europe – EMA.

3. Report on bioequivalence study date: content and form of presentation must comply with the forms of report on bioequivalence study according to ASEAN or ICH E3 in Annex enclosed with this official dispatch.

II. Requirement for comparator product in bioequivalence study

1. For drugs that are required to submit report on bioequivalence study data when registering drugs specified in Circular No. 08/2010/TT-BYT dated 26/4/2010 of the Ministry of Health, comparator products in study must meet provisions in Article 5 of the Circular No. 08/2010/TT-BYT.

2. For generic drugs in the conventional dosage form which effect whole not in cases specified in clause 1 Article 7 of the Circular No. 08/2010/TT-BYT dated 26/4/2010 of the Ministry of Health, containing pharmaceutical substances not in list of pharmaceutical substances required to report on bioequivalence study data when registering drugs specified in Annex 2 of the Circular No. 08/2010/TT-BYT, comparator products in study must be selected according to principles stated in Annex 1 of the Circular No. 08/2010/TT-BYT.

3. Comparator products in list of comparator products that are promulgated by management agencies of countries belonging to ICH and linkage countries (Canada, Australia, Switzerland) are recognized as have satisfied principles on selecting comparator products specified in Annex 1 of the Circular No. 08/2010/TT-BYT dated 26/4/2010 of the Ministry of Health. Establishments requesting for the announcement of drugs with documents proving bioequivalence must supply List of comparator products that are promulgated officially by the management agencies of countries belonging to ICH and linkage countries (documents or links of websites publishing list).

4. Establishments requesting for drug announcement with documents proving bioequivalence must prove that comparator products selected for test meet principles as prescribed, must supply sufficient and accurate information about origin countries as well as about number of production batch and expiry day of comparator product already been used in study.

Drug Administration of Vietnam notifies the Departments of Health of central-affiliated cities and provinces, drug manufacturers and traders for information and implementation. In the course of implementation, any arising problems should be reported to the Drug Administration of Vietnam for consideration.

For the Director of Drug Administration of Vietnam

Deputy Director

Nguyen Viet Hung

ANNEX

FORM OF REPORT ON BIOEQUIVALENCE STUDY

I. FORM OF REPORT ACCORDING TO ASEAN

1. Title page

1.1. Study name

1.2. Name and address of donors

1.3. Name, competent persons and address of study unit

1.4. Name and address of principal researcher

1.5. Name of clinical researcher / medical officers

1.6. Name, the responsible person and address of establishments implementing clinical study

1.7. Name, the responsible person and address of establishments implementing analysis

1.8. Name, the responsible person and address of establishments analyzing statistics, processing data, counting pharmacokinetics

1.9. Name and address of other researchers and persons participating in study

1.10. Day of beginning and ending phases of taking samples, analyzing

1.11. Signatures, day of signing of researchers (medical administrative officers, person in charge of QA, if apply)

2. Study summary

3. Index

4. Explanation of terms and abbreviated words

5. Introduction

5.1 Pharmacology

5.2 Pharmacokinetics

5.3 Disadvantage events

6. Study objectives

7. Information of product

7.1. Information of reagent (study drug)

- Trade name

- Name of pharmaceutical substance, content, use method

- Number of batch, day of manufacture, expiry date

- The conformity of batch size (may be supplied by donors)

- Formula of medicine preparation (may be supplied by donors)

- Quality standards of finished products (may be supplied by donors)

- Name and address of manufacturers

7.2. Information of comparator product

- Trade name

- Name of pharmaceutical substance, content, use method

- Number of batch, day of manufacture, expiry date

- Name and address of manufacturers

- Name and address of importer or competent person

7.3. Data on equivalent medicine preparation

- Comparison of content of pharmaceutical substance / treatment ability (between sample of reagent and comparator product)

- Uniform extent of dosage unit

7.4. Comparison of soluble process (may be supplied by donors)

7.5. The official dispatch / letter of the register / donor affirming that the sample of reagent used in study and product that is registered for circulation license are alike

8. Study plan

8.1. The clinical study design

- Study design (diagonal, parallel)

- Test in condition of hunger / fullness

- Standards for acceptance, exclusion, limit (for volunteers)

- Standardization of study conditions

- Method of medicine use

- Type of volunteers’ data without assessment 

- Health examination

- Data of volunteers, quantity, discrepancy in comparison with outline

- Plan / schedule of taking samples, preparation / handling of samples, preservation, and discrepancy in comparison with outline

- Volume of the taken blood

- Supervision for volunteers

- Genetic element (if apply)

8.2. Study drawing

- Select of dosage - single-dose and multi-dose

- Identity of study drugs, the use dose

- Randomization

- Blinding

- Rest time between phases (elution)

- Volume of water used for drug

8.3. Safety and clinical report

- Disadvantage events

- Disadvantage reaction relating to drugs

8.4 Pharmacokinetic parameters

- Definition and calculation method

8.5. Analyzing statistics

- The analyzing data transferred lariat (AUC, Cmax)

- Adjustment according to time of taking sample

- t max,

- t ½

- Standards for bioequivalence acceptance

- ANOVA data

- Reliability (Power)

8.6. Method of analyzing and appraisal

- Description of quantitative method

- Method of detecting

- Process of appraisal and result summary

-      Specific extent;

-      Rightness

-      Correctness;

-      Recovery ability (efficiency);

-      Stability;

-      Limitation of quantitative method

-      Linearity

8.7. Data of quality assurance

9. Result and discussion

9.1. The clinical study result

- General information (demographic characteristics) of volunteers.

- Detail description of phase of taking sample.

- Differences in comparison with outline, if any.

- Data of medicine use, smoking, drinking alcohol, decrease record and health examination, vital signs and the testing results of volunteers.

- Reports on incidents, disadvantage reactions that happen with reagent and the comparator product.

9.2. Summary of the analyzing result

9.3 Analyzing pharmacokinetics

- Concentration of drug at each time point of taking sample, data of statistics

- Table of pharmacokinetic parameters of each volunteer,

- Line showing changes according to time of the average concentration of drug in plasma or urine

- Line showing changes according to time of concentration of drug in plasma or urine of each volunteer.

9.4. Analyzing statistics

- Calculating statistics

- Points used for calculate Kel, t1/2

- Summary of statistics for pharmacokinetic parameters: AUCt, % AUC extrapolation, AUCinf, Cmax, tmax, t1/2

- Summary of meaning in making statistics of AUC and Cmax (Confidence interval of 90% of the geometric mean of test/reference drug, calculated on data transferred logarithm) and tmax (according to the P value calculated on data did not transfer logarithm).

- Data counted similarly for sample of urine: Ae and dAe/dt (Ae corresponding to AUC, (dAe/dt)max corresponding to Cmax).

- Oscillations among arganisms

- Meaning of study (Power)

- Assessment on influences of processes, phases and the trial drawings

- The ANOVA table (analysis of variances), the average of minimum squares for each pharmacokinetic parameter.

- Table of calculating confidence interval of 90% of ratio of pharmacokinetic parameters should be considered on data transferred logarithm

10. Conclusion

11. Annex

11.1. Outline and approval

- Written approval/ acceptance of the Drug management agencies (if apply)

- Study outline and documents of supplementations, approvals of the Ethic Council / Science Council at grassroots

- Volunteers’ written acceptance of participating in study

- Contents different with outline

- Total disadvantage events

- Quality standards and test certificates

11.2. Report on appraising the analysis method (including 20% of the analyzing chromatogram)

11.3. Report on analysis (including 20% of chromatogram) 

11.4. Certificate of clinical establishments (taking samples), the clinical test rooms, analyzing and experiment rooms (if any)

11.5. Comparison of the soluble process at the ratio among various contents (if the BE study is conducted only on a content, but register for some various contents (be supplied by donors).

II. FORM OF REPORT ACCORDING TO E3

1. Title page

- Study name

- Name of reagent and comparator product

- Study objectives (indication studied)

- Description on study design summary

- Name of donors

- Code of study outline

- Study phase

- Day of beginning study

- Day of completion

- The principal researcher:  Name, qualification, address

- Representative of donors: Name, address, telephone number

- Announcement on the GCP compliance

- Day of report

2. Study summary

-      Title, researcher, Study center.

-      Study duration

-      Objective

-      Method: Total volunteers, test dose, taking blood sample, rest duration

-      Quantity of volunteers (plan and analysis)

-      Standards for acceptance

-      Reagent, dose, drug usage way, number of batch

-      Comparator product, dose, drug usage way, number of batch

-      Duration: Detailing phase I, II, travel.

-      Criteria for evaluation: Confidence interval (CI) at 90% of Cmax, AUC

-      Method of analysis

-      Pharmacokinetic calculation software

-      Statistical method

-      Summary: Result of reagent and comparator product, ratio

-      Study result: Equivalent or not equivalent

-      Consideration on safety

-      Day of report

3. Index

-      Name of item, page number

-      List of table

-      Drawings and graphs

-      List of annexes, records of volunteers

-      Page for signature and approval

4. Explanation of terms and abbreviated words

List for both of clinical and analysis parts

5. Ethic

-      To be considered by the Ethic Council (IEC) enclosed with list of chairman of council and members in Annex

-      To conduct ethical assurances: According to GCP of ICH, Declaration of Helsinki and other approvals as prescribed.

-      Information of Volunteers and their written acceptance of participating in study: Activities related to recruitment and selection including forms in Annex

6. The researchers and administrative officers

-      Principal researcher and clinical researcher

-      Study director

-      The person making analysis and statistics

-      The person making reports

-      Address of establishments conducting clinical activities, analysis, report, statistics, testing center, X-ray, ethical council

-      Explanation in summary for reason of this study: For approval of a generic preparation for study on comparison of speed and extent of absorption between test – reference drugs; for examining the bioavailability of a new drug.

8. Study objectives

-      Description of the overall objectives in study

-      ● Detailed targets under the outline

9. Study plan

9.1 Design of overall study and plan: Summary but having to be clear, example diagonal, parallel design

-      Outline for implementation - 16.1.1

-      Quantity of volunteers

-      Blinding / Randomization for dividing group using drug.

-      Study process and duration:  Using diagram:  Annexes IIIa, IIIb

-      Detailing meal: Type of food, duration of meal, test regime upon being hungry, full

-      The staying duration of volunteers, rest duration between phases (elution), travel time, phases I, II

-      9.2 Discussion on study design, including the selection of reference group:

-      Explanation on selecting test dose, period for each dose, period of testing samples in comparison with duration of semi-discharge (number of times), selection of elution time in diagonal study.

-      Study in condition of hunger / fullness

-      Way to ensure objectivity (restraining the partiality,   determining the result based on emotion): through random samples or blinding with analyzed person.

-      Special study design

9.3 To select volunteers for study

9.3.1 Standards for acceptance: Way of selection, height, weight, BMI, special tests,  selection value, written agreement.

9.3.2 Standards for exclusion: Matters related to cardiovascular, alcoholism, selection value fails to meet standards, suffering other diseases

9.3.3 To exclude volunteers from study data: Details if any volunteer leaves from study.

9.4 Use of study drug (interventions / trial guidelines)

9.4.1. Study drug: Usage way, dose

9.4.2. To identify study drug: Details of content, number of batch, day of manufacture, expiry day of reagent and comparator product.

Dossiers of delivery and receipt, distribution and preservation

9.4.3 Method of dividing volunteer groups in groups using drug is random

9.4.4 Selection of test dose for study: basis of selection

9.4.5 To determine duration of medicine usage for each volunteer: clear description of using medicine of single dose, drink with …, eating after …, or study in condition of fullness, time of elution, date and time of medicine usage for each volunteer

9.4.6 Blinding

9.4.7 Being treated before or concurrently: the used medicine, whether they influence to the study or not, time of use, reason of use

9.4.8 The compliance of medicine usage

9.5Changes on efficiency and safety

9.5.1 Discussion on pharmacokinetics and safe assessment, graphs, table of pharmacokinetic parameters for each volunteer and the used software 

Examinations of safety extent already conducted, stated in details.

9.5.2 The conformity of the measured values …

Time of taking sample selected for defining tmax, time of semi-discharge. 

9.5.3 Preliminary / variability efficiency of PK pharmacokinetics – defining BE based on Cmax, AUC

9.5.4 To determine the medicine concentration:  The taken samples, description of the used method for analyzing, detecting the appraisal result

9.6. Data of quality assurance

-      Details of the external / independent supervisor, donors, report

-      Internal examination to affirm the compliance of GCP, GLP, SOP

-      Certification of QA

9.7 Statistical method inscribed in outline and defining size of sample

9.7.1 Plan on analyzing and making statistics

The used software, calculation examination ...

Using ANOVA for calculating 90% confidence interval …

9.7.2 To define size of sample:

9.8 Changes during the study: Any supplementation If there is no supplementation, writing similar.

10. Volunteers

10.1 Volunteers: Quantity of persons participated in study, quantity of persons participated fully, quantity of persons gave up, details of number of volunteers who used medicine in each phase

10.2 Contents different to outline: To describe the important differences during the course of study implementation

11. Assessment on efficiency

11.1 The analyzed data: Total volunteers participated in study, quantity of volunteer used for calculating pharmacokinetics and making statistics

11.2 Demographics and other fundamental characteristics: human races, age, height, weight, acceptance, exclusion. Making a detailed table

11.3 The value measured for each drug, clinical, concentration of medicine of each volunteer

11.4 Table of result data and efficiency of each volunteer

11.4.1 To analyze efficiency

Details of pharmacokinetic parameters (analyze efficiency), to define for each parameter, handle data of volunteers, samples are lost, samples are lower than value of quantitative method under (BLQ) and result.

11.4.2 Analysis and statistics

To describe software, calculation, result

11.4.2.3 To analyze preliminary and supervision data

11.4.2.4 to 11.4.2.8:      Not apply to BE

11.4.3 The data table for each volunteer: Details in the Annex 16.2.5

11.4.4 - 11.4.5 Not apply to BE

11.4.6 To present according to volunteers: The curve of medicine concentration -  time.

The curve of each volunteer may be put into annex

11.4.7 Conclusion of efficiency (analyze efficiency )

Result of comparison between Test and Reference

12. Assessment on safety

12.1 Exposure extent: single dose / multiple dose

12.2 Disadvantage events: Make summary and display of disadvantage events (presented under table form) and analysis disadvantage events

13. Discussion and general conclusion

-      Principal objective

-      Design

-      Process of analyzing

-      Pharmacokinetic analyzing (analyze efficiency)

-      Analysis and statistics

-      Conclusion

14 Tables mentioned but not in report

-      Demographic data

-      The pharmacokinetic data table (analyze efficiency) of each volunteer:

-      Data of disadvantage events (AE)

-      Other tables

15. References

16. Annex:  According to form E3, report on appraising the method of analysis, report on analysis, 20% chromatogram of volunteer, test certificates of the used standard substances, the used important SOP.