Dr Vijay D Wagh

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Drug Regulatory Affairs in India

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Regulatory Process for Drug Approval in India :

Prof. Dr. Vijay D. Wagh Professor Department of Pharmaceutics Gokhale education society’s Sir dr. M. S. gosavi college of pharmaceutical education and research, NASHIK 06-Mar-19 1 Regulatory Process for Drug Approval in India

FDA:

FDA 06-Mar-19 2 The mission of FDA's Center for Drug Evaluation and Research (CDER) is to ensure that drugs marketed in this country are safe and effective . CDER does not test drugs, although the Center's Office of Testing and Research does conduct limited research in the areas of drug quality, safety, and effectiveness . It has responsibility for both prescription and nonprescription or over-the-counter (OTC) drugs.

Drug Approval Process:

Drug Approval Process 06-Mar-19 3 A regulatory process, by which a person/organization/sponsor/innovator gets authorization to launch a drug in the market, is known as drug approval process. In general, a drug approval process comprises of various stages Application to conduct clinical trials , Conducting clinical trials, Application to marketing authorization of drug and post-marketing studies. Every country has its own regulatory authority, which is responsible to enforce the rules and regulations and issue the guidelines to regulate the marketing of the drugs.

Comparison of Drug approval process:

Comparison of Drug approval process 06-Mar-19 4 Country Time for Regulatory Approval of CTA/IND Application Time for Evaluation of Marketing Authorisation Application (MAA) MAA Fee Australia 120 day 50 days $192,400 China 50 days 180 days DNA India 126 days 84 days 50,000 INR UK 35 days 210 days £254100 USA 30 days 180 days $217,787 IND-Investigational New Drug, CTA-Clinical Trial Authorization, DNA-Data Not Available.

Drug Approval Process in India:

Drug Approval Process in India 06-Mar-19 5 1 ) Investigation of New D rug in India During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans , and if the compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited , early-stage clinical studies.

IND application must contain :

IND application must contain 06-Mar-19 6 1.Animal Pharmacology and Toxicology Studies – Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.  Also included are any previous experience with the drug in humans (often foreign use ). 2. Manufacturing Information -  Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product.  This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.

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06-Mar-19 7 3.Clinical Protocols and Investigator Information – Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks .  Also , information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties.  Finally , commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB) , and to adhere to the investigational new drug regulations .

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06-Mar-19 8

New Drug Registration Procedure of India:

New Drug Registration Procedure of Indi a 06-Mar-19 9 IND-Investigational New Drug, DCGI-Drug Controller General of India, CDSCO-Centre for Drug Standards Control Organization

What's in India:

What's in India 06-Mar-19 10 The drug approval process varies from one country to another. In some countries, only a single body regulates the drugs and responsible for all regulatory task such as approval of new drugs, providing license for manufacturing and inspection of manufacturing plants e.g. in USA, FDA performs all the functions. However in some counties all tasks are not performed by a single regulatory authority, such as in India, this responsibility is divided on Centralised and State authorities . Other issues where the difference appears are, time taken for the approval of a CTA (Clinical Trial Authorisation) application , time taken in evaluation of marketing authorization application , registration fee, registration process and marketing exclusivity. Some counties have two review processes as normal review process and accelerated review process as in USA, China etc. and some countries have only a single review process as in India.

How to go ahead for approval:

How to go ahead for approval COMMON TECHNICAL DOCUMENTS (CTD) guidelines This guideline applies to import / manufacture and marketing approval of new drugs including New Chemical E ntity , New I ndication , New Dosage F orms , Modified R elease F orm , New R oute of Administration etc. Under the definition of new drug under Rule 122E of Drugs & Cosmetics rules as a finished pharmaceutical product. 11

What is CTD?:

What is CTD? 12 The CTD is only a format for submission of information to CDSCO ( Centre for Drug Standards Control Organization). It does not define the content. Difference in organization of data in each application has made reviewing more difficult and can also lead to omission of critical data or analysis so unnecessary delay in approval. Thus common format of submission will help. Through the ICH process, CTD guidance developed for Japan, EU & US. We in India (CDSCO ) also adopted the CTD .  

CTD: Over view Module 1: General Information :

CTD: Over view Module 1: General Information This module should contain documents specific to India; for example, Form 44, Treasury challan fee or the proposed label for  use in India. 1 )      Covering letters & comprehensive table of contents ( module 1 to 5 ) 2)      Administrative information Brief introduction about the applicant company Duly filled and signed application form 44 and treasury challan Legal and critical documents Coordinates related to the application General information of the drug product Summary of the testing protocol(s) for quality control testing Regulatory status in other countries Domestic price of the drug followed in the countries of origin Brief profile of manufacturer’s company & business activity Information regarding  involvement of expert if any Samples of drug product Promotional material. 13

Module 2: CTD Summaries:

This module should begin with a general introduction to the pharmaceutical, including its pharmacologic class, mode of action, and proposed clinical use , not exceeding one page . 1)   CTD table of contents 2)   CTD introduction 3)   Quality overall summary 4)   Nonclinical overview 5)   Clinical overview 6)   Nonclinical written and tabulated summaries 7)   Clinical summary   In this module following information is required 1) Table of content of module 2) Introduction 3) Quality overall summary In this section not provide the entire information it is presented in module 3. It is not more than 40 pages. 4) Summary of drug substance & drug product 5) Nonclinical overview 6) Clinical over view 14 Module 2: CTD Summaries

MODULE: 3 Quality:

In this module following information is required 1) Table of contents of module 3 2) Drug substances 3) Manufacture of drug substances 4) Characterization of drug substances 5) Quality control of drug substances 6) Reference standards and material 7) Container closer system 8) Stability of drug substance 9) Drug product and manufacture of drug product 10) Control of drug product and excipient 15 MODULE: 3 Quality

MODULE:4 Non Clinical Study Report:

Table of contents in this module should be provided that lists all of the nonclinical study reports and gives the location of the each study reports in CTD. It contains following data 1)      Study reports Pharmacology Pharmacokinetic Toxicology 2)      Literature references 16 MODULE:4 Non Clinical Study Report

MODULE:5 Clinical Study Report:

It contains tabular listing of all clinical studies . 1)      Clinical S tudy R eport Reports of biopharmaceutical studies Reports of studies pertinent to pharmacokinetic using human biomaterials. Reports of human pharmacokinetic studies Reports of human pharmacodynamic studies Reports of efficacy and safety study Reports of post marketing experience Case report form and individual patient listing Literature references [CDSCO Guideline] 17 MODULE:5 C linical S tudy R eport

DOCUMENTS TO BE SUBMITTED FOR GRANT OF PERMISSION TO CONDUCT BIOEQUIVALENCE STUDIES FOR EXPORT PURPOSE:

DOCUMENTS TO BE SUBMITTED FOR GRANT OF PERMISSION TO CONDUCT BIOEQUIVALENCE STUDIES FOR EXPORT PURPOSE A large number of applications are being filed to the office of DCG (I) at CDSCO (HQ) by Pharmaceutical companies, both manufacturers and importers as well as CRO’s on behalf of them,  requesting for the approval to carry out BE studies with various pharmaceutical dosage formulations  on Indian subjects . In light of the above, for easy processing of such applications and to bring uniformity in decision making all stake holders of the afore mentioned activities are hereby advised to submit their applications with necessary documents . 18

New Drugs – developed in India as an IND and not marketed anywhere in world:

New Drugs – developed in India as an IND and not marketed anywhere in world 1 . Form 44. 2. Treasury Challan of INR 50,000. 3. Source of bulk drugs /raw materials.  19

Requirements for BE study of a new molecule not approved in India but approved in the other countries:

Requirements for BE study of a new molecule not approved in India but approved in the other countries Application in Form-44 duly signed , by the competent authority with name and designation. Treasury Challan of Rs. 50,000 /- as per Drugs & Cosmetic Rules. Undertaking by the Principal Investigator (PI) as per appendix VII of schedule “Y” of Drugs and Cosmetic Rules. A copy of the approval granted to the BE study centre by CDSCO. Sponsor’s Authorization letter duly signed by the competent authority on their letterhead. The study protocols. The study synopsis Pre-clinical single dose data and repeated dose toxicity data. 20

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Clinical study data and published report of pharmacokinetic and pharmacodynamic study carried out in healthy volunteers/patients data published in reputed journals. Regulatory status of the drug. Names of the countries where the drug is currently being marketed (to be mentioned in the covering letter also). Package literature on  the international product. Complete Certificate of Analysis of same batches (both test & reference formulations) to be used in the BE study. In the case of multiple dose BE study adequate supporting safety data should be submitted. In the case of Injectable preparation the sub-acute toxicity should be submitted on the product of the sponsor, generated in two species for adequate duration. Depending on the nature of the drug like cytotoxic agent, hormonal preparations etc.  Proper justification for conducting studies on healthy volunteers/patients or male/ female should be submitted. 21

New Drugs approved in India within period of 1 year:

New Drugs approved in India within period of 1 year Application in Form-44 duly signed, by the competent authority with name and designation Treasury Challan of Rs. 25,000 /- as per Drugs & Cosmetic Rules. Undertaking by the Principal Investigator (PI) as per appendix VII of schedule “Y” of Drugs and Cosmetic Rules. A copy of the approval of the BE study centre from CDSCO. Sponsor’s Authorization letter duly signed by the competent authority on their letterhead. The study protocols. Clinical study data and published report of pharmacokinetic and pharmacodynamic study carried out in healthy volunteers data published in reputed journals. Package literature on the international product. Complete Certificate of Analysis of same batches (both test & reference formulations) to be used in the BE study. In the case of multiple dose BE study adequate supporting safety data should be submitted. In the case of Injectable preparation the sub-acute toxicity should be submitted on the product of the sponsor, generated in two species for adequate duration. Proper justification for conducting studies on healthy volunteers/patients or male/ female should be submitted . 22

New Drugs approved within period of more than 1 year & less than 4 years:

New Drugs approved within period of more than 1 year & less than 4 years Application in Form-44 duly signed, by the competent authority with name and designation Treasury Challan of Rs. 15,000 /- as per Drugs & Cosmetic Rules. Undertaking by the Principal Investigator (PI) as per appendix VII of schedule “Y” of Drugs and Cosmetic Rules. A copy of the approval of the BE study centre from CDSCO. Sponsor’s Authorization letter duly signed on their letterhead by the competent authority. The study protocols. Complete Certificate of Analysis of same batches (both test & reference formulations) to be used in the BE study. In the case of multiple dose BE study adequate supporting safety data should be submitted. In the case of Injectable preparation the sub-acute toxicity should be submitted on the product of the sponsor, generated in two species for adequate duration. Proper justification for conducting studies on healthy volunteers/patients or male/ female should be submitted . 23

BE NOC for all the drug products in modified release form irrespective of their approval status:

BE NOC for all the drug products in modified release form irrespective of their approval status Application in Form-44 duly signed, by the competent authority with name and designation. Treasury Challan of Rs. 15000 /- as per Drugs & Cosmetic Rules. Undertaking by the Principal Investigator (PI) as per appendix VII of schedule “Y” of Drugs and Cosmetic Rules. A copy of the approval of the BE study centre from CDSCO. Sponsor’s Authorization letter duly signed on their letterhead by the competent authority. The study protocols. Complete Certificate of Analysis of same batches (both test & reference formulations) to be used in the BE study. In the case of multiple dose BE study adequate supporting safety data should be submitted. In the case of Injectable preparation the sub-acute toxicity should be submitted on the product of the sponsor, generated in two species for adequate duration. Depending on the nature of the drug like cytoxic agent, hormonal preparations etc.  Proper justification for conducting studies on healthy volunteers/patients or male/ female should be submitted. 24

APPLICATION FORM FORMAT:

APPLICATION FORM FORMAT Form 44(INDIA ) (See rules 122 A, 122 B, 122 D, and 122 DA) Application for grant of permission to import or manufacture a New Drug or to undertake clinical trial . ***** I/we ____________________________________________ of M/s. _____________________________________( address) hereby apply for grant of permission for import of and/or clinical trial or for approval to manufacture a new drug or fixed dose combination or subsequent permission for already approved new drug. The necessary information / data is given below: 1.Particulars of New Drug : (1) Name of the drug: (2) Dosage Form: (3) Composition of the formulation: (4) Test specification: ( i ) active ingredients: ( ii) inactive ingredients: (5) Pharmacological classification of the drug: (6) Indications for which proposed to be used: (7) Manufacturer of the raw material (bulk drug substances): (8) Patent status of the drug: 25

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2. Data submitted along with the application ( as per Schedule Y with indexing and page nos .) Permission to market a new drug (1) Chemical and Pharmaceutical information (2) Animal Pharmacology (3) Animal Toxicology (4) Human/Clinical Pharmacology ( Phase I ) (5) Exploratory Clinical Trials ( Phase II ) (6) Confirmatory Clinical Trials ( Phase III ) (including published review articles) (7)  Bio-availability, dissolution and stability study Data (8) Regulatory status in other countries (9)  Marketing information : ( a) Proposed product monograph ( b) Drafts of labels and cartons (10) Application for test license 26

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B. Subsequent approval / permission for manufacture of already approved new drug ( a) Formulation : ( 1) Bio-availability/ bio-equivalence protocol ( 2) Name of the investigator/ center ( 3) Source of raw material (bulk drug substances) and stability study data. ( b) Raw material (bulk drug substances ) ( 1) Manufacturing method ( 2) Quality control parameters and/or analytical specification , stability report. ( 3) Animal toxicity data 27

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C. Approval / Permission for fixed dose combination : (1)  Therapeutic Justification (authentic literature in pre- reviewed journals/text books) (2) Data on pharmacokinetics/ pharmacodynamics combination (3) Any other data generated by the applicant on the safety and efficacy of the combination. D. Subsequent Approval or approval for new indication – New Dosage Form : (1) Number and date of Approval/permission already granted. (2) Therapeutic Justification for new claim / modified dosage form . (3) Data generated on safety, efficacy and quality parameters. 28

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A total fee of rupees_________(in words)_________) has been credited to the Government under the Head of Account_________( Photocopy of receipt is enclosed ). Dated _____ Signature __________________ Designation ________________ Note- Delete, whichever is not applicable (Form 44 ends here) 29

CONCLUSION:

CONCLUSION 30 Generally, the drug approval process comprised mainly the two steps , application to conduct clinical trial and application to the regulatory authority for marketing authorization of drug . In most of the counties, sponsor firstly files an application to conduct clinical trial, and only after the approval by the regulatory authority, the applicant conducts the clinical studies and further submits an application to the regulatory authority for marketing authorization of drug . In all countries, information submitted to regulatory authorities regarding the quality, safety and efficacy of drug is similar ; however, the time, fee and review process of clinical trials and marketing authorization application differs .

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06-Mar-19 31 For the purpose of harmonization, the International Conference on Harmonization (ICH) has taken major steps for recommendations in the uniform interpretation and application of technical guidelines and requirements. This step will ultimately reduce the need to duplicate work carried out during the research and development of new drugs. Therefore, finally we can conclude that harmonization of drug approval processes either by ICH or WHO may be initiated at global level.

BIBLIOGRAPHY:

BIBLIOGRAPHY 32 Central drugs standard control organization directorate general of health services ministry of health & family welfare govt. Of india , 24thaugust 2011. Form 44 format at URL Form%2044.htm accessed on 15/7/2011. Guarino , R.A. New drug approval process. Third edition. Marcel Dekker publication. New York. Pg.no-69-70 Investigation of new drug by U.S. Food and drug administration at URL Investigational%20New%20Drug%20(IND)%20Application.htm  accessed on 15/7/2011. New drug approval process in india by Dr. Harish Dureja at URL New%20Drug%20Approval%20Process%20%20Regulatory%20View%20%20%20Pharmainfo.net.htm accessed on 21/7/2011. Schedule y at URL Schedule%20Y(ammended%20version)%20-%20CDSCO.htm accessed on 15/7/2011. Vyawahare , N.S. Itakar , S.C. Drug regulatory affairs. Published by Nirali Prakashan . Pg.no-4.1, 16.

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06-Mar-19 33 THANK YOU ……

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