PRESENTATION

ON COMPARATIVE STUDY OF DOSSIER COMPILATION & SUBMISSION PROCESS OF DRUG PRODUCT IN USA, EUROPE & INDIA

PRESENTED BY

Devesh Sharma
M.Pharm-DRA
devesh.m.pharmdra@gmail.com

CONTENTS
          Aim & Objective of work Introduction Literature review Regulatory guidelines for dossier submission in USA Regulatory guidelines for dossier submission in Europe Difference b/w EU & FDA Drug product approval process in India Comparative study of dossier submission process of drug product in USA, EU & India Summary & conclusion References

AIM & OBJECTIVE

Comparative study of dossier compilation &

submission process in USA, Europe & India

To understand the regulatory guidelines

in

drug approval procedure

To

understand the importance of regulatory guidelines of

Comparative study of regulatory guidelines

FDA, EMEA & MHFW

INTRODUCTION
Dossier is a file document submitted for the approval of drug product. It is submitted in form of CTD. CTD is a harmonized format (template) for presenting data in the ICH regions Generic drug product is comparable to an innovator drug product In dosage form  Strength  Route of administration  Quality  Use etc

Generic drug approved under ANDA submission (USA)  MAA submission (EU) Generic drug applications are termed as Abbreviated RLD- An approved drug product to which new generic versions are compared to show that they are bioequivalent.

Orange book-Approved drug product with booktherapeutic equivalence evaluations , published by the FDA (CDER) HatchHatch-Waxman act 1984 eliminates the costly clinical trial for approval of generic drugs. CDSCO is regulatory authority for the approval of new drugs proposed to be imported. (India)

REVIEW OF LITERATURE
Martin s. lipsky, in 2001, The drug approval process Food and Drug Administration (FDA) is responsible for assuring that foods and cosmetics are safe and that medicines and medical devices are both safe and effective. Welage L.S., in 2001, Understanding scientific issues embedded in the generic drug approval process Regulations regarding bioequivalence have been in place for more than 20 years, controversies over bioequivalence continue to arise. Lionberger RA., in 2008, Opportunities for generic drug development FDA's critical path initiative documents have focused on the challenges involved in the development of generic drugs. Peters JR., in 2009, Generic drugs-safe, effective and affordable dermotol The history and evolution of the process for generic drug evaluation and approval in the United States, with emphasis on locally acting dermatologic products.

Jaime R hornecker,in 2009, Generic drugs: history, approval process and current challenges According to the FDA, a generic drug is a product that compares to the pioneer, or reference, drug product (usually a branded drug) in dosage form, route of administration, strength, quality, safety, and performance characteristics. Filiz hinchal,in 2009, An introduction to safety issues in biosimilars/follow-on biopharmaceuticals Biopharmaceuticals are emerging global healthcare tools, which promise to provide effective treatment of many serious and lifethreatening illnesses with their high specificity and activity; they are considered the future of drug therapy. Holmes CB,2010, Use of generic antiretroviral agents and cost savings in PEPFAR treatment programmes. One of the biggest hurdles to the rapid scale-up of antiretroviral therapy in the developing world was the price of antiretroviral drugs (ARVs).

Chow sc, 2010, Statistical assessment of biosimilar products Biological products or medicines are therapeutic agents that are produced using a living system or organism. Access to these lifesaving biological products is limited because of their expensive costs. Howland RH, 2010, Evaluating the bioavailability and bioequivalence of generic medications The U.S. Food and Drug Administration (FDA) is permitted to approve generic versions of brand-name medications without necessarily requiring that research be conducted to prove them safe and effective, provided that a number of criteria are met. The most important criterion is bioequivalence. Bioavailability refers to the rate and extent to which the active ingredient is absorbed from a drug product. Bioequivalence means that there is an equivalent rate and extent of absorption of the same active ingredient from two or more drug products.

REGULATORY GUIDELINES FOR DOSSIER SUBMISSION IN USA

Dossier is submitted in CTD format.

CTD FORMAT Aim To harmonize the structure and format of registration documentation. Benefits Complete, well-organized submissions Facilitates electronic submissions Easier analysis across applications etc.

Not Part of CTD Regional Admin Information

Module-1
Nonclinical overview Nonclinical summary Nonclinical Studies Reports Clinical overview Clinical Summary Clinical Study Reports Module-2

The CTD

Quality overall summary

Quality

Module-3

Module-4

Module-5

The CTD Triangle

The CTD is organized into five modules: Module 1 is region specific. Modules 2, 3, 4, and 5 are intended to be common for all regions. Module 1. Administrative Information Should contain documents specific to each region; e.g. application forms or the proposed label for use in the region.

1.1 Table of Contents of the Submission 1.2 Documents Specific to Each Region (for example, application forms,prescribing information,)

Module 2. CTD Summaries Begin with a general introduction to the pharmaceutical (its pharmacological class, mode of action, proposed clinical use. It contain 7 sections in the following order: 2.1 Common Technical Document Table of Contents (Modules 2-5) 2.2 CTD Introduction 2.3 Quality Overall Summary

2.4 Non-clinical Overview 2.5 Clinical Overview 2.6 Non-clinical Written and Tabulated Summaries 2.7 Clinical Summary Module 3. Quality 3.1 Table of Contents of Module 3 3.2 Body of Data [Drug Substance, Drug Product & Regional information] 3.3 Literature References

Module 5. Clinical Study Reports

5.1 Table of Contents of Module 5 5.2 Tabular Listing of All Clinical Studies 5.3 Clinical Study Reports (BA/BE) 5.4 Literature References

REGULATORY GUIDELINES FOR DOSSIER SUBMISSION IN EUROPE

Pharmaceutical companies of EU are use three approval procedures to market their pharmaceuticals A centralized or A decentralized or Mutual recognition

CENTRALIZED PROCEDURE Allows a pharmaceutical company to market its

pharmaceutical product in all 25 member states  Without having to obtain separate approvals from each member state

Draft decision of the commission

DECENTRALIZED PROCEDUREAn applicant can go directly to a national marketing authority to obtain permission to market its product in that member state and Then seek to have other member states accept the marketing approval of the first member state.

MUTUAL RECOGNITION PROCEDURE (MRP)Used in order to obtain marketing authorizations in several Member States where the medicinal product in question has received a marketing authorization in at least one Member State at the time of application.

DIFFERENCE B/W EU & FDA

EU Multiple agencies European Medicines Evaluation Agency (EMEA) administrative organization Committee for Medicinal Products for Human Use (CHMP) of the EMEA scientific input National Health Agencies FDA One agency

EU Multiple registration procedures Centralized European Community Decentralized/Mutual Recognition At least 2 Member States National 1 Member State FDA One registration procedure

EU TSE /BSE study data is required Braille code is required on labeling FDA TSE /BSE study data is not required Braille code is not required on labeling

REGULATORY GUIDELINES FOR DOSSIER SUBMISSION IN INDIA

Drug & Cosmetic Act 1940 & Rules 1945

Regulates the import, manufacture, distribution & sale of drugs & cosmetics.

Schedule Y
 Provides guidelines & requirements for clinical trials

CDSCO A licensing authority for approval of new drug proposed to be imported Head office located in New Delhi & functioning under the control of directorate general of Health services, MHFW, Govt of India. DCGI Responsible for approval of new drug & Clinical trials to be conducted in India Appointed by Central Govt of India

COMPARATIVE STUDY OF DOSSIER SUBMISSION PROCESS OF DRUG PRODUCT IN USA, EU, INDIA

S.NO. A. 1. 2. 3 4 5 6 B. 1.

REQUIREMENTS ADMINISTRATIVE Application Debarment Certification No. of copies Approval time line Fees Presentation FINISHED PRODUCT CONTROL Justification

USA

EU

INDIA

ANDA Required 3 18 Month No Fees eCTD & Paper

MAA NA 1 12 Month 10-20 Lakh eCTD

MAA NA 1 12 Month 50,000 Paper

ICHQ6A

ICHQ6A

ICHQ6A

S.NO. 2. 3. 4. 5. C. 1. 2. 3.

REQUIREMENT Assay Disintegration Color Identification Water content MANUFACTURING & CONTROL No. of batches Packaging Process validation

USA 90-100% Not required Not required Required

EU 95-105% Required Required Not Required

INDIA 90-110% Required Required Required

01 A min of 1,00,000 Units

03 Not Required

1 Required

Not required at Required the time of submission

4.

Batch size

Min of 1,00,000 Min of 1,00,000 Not Specified Units Units

S.No. D. 1. 2. 3.

Requirement STABILITY No. of batches Condition Date & Time of submission

USA

EU

India

01 25/60: 40/75 3 Month Accelerate & 3 Month Long term Inverted & Upright 21CFR Part 210 & 211

02 25/60: 40/75 6 Month Accelerate & 6 Month Long term

01 30/35; 30/70 6 Month accelerated & 3 Month Long term

4. 5.

Container orientation Clause

Do not address Do not address Volume4, EU guidelines for medicinal product Required ICHQ1F

6.

QP Certification

Not Required

Required

S.NO. E.

REQUIREMENT BIOEQUIVALENCE

USA

EU

INDIA

CRO

Audited by FDA

Audited by MHRA No such requirement NO such requirement

CDSCO

2.

Reserve sample

5 Times the sample required for analysis Must be as per OGD recommendation

3.

Fasted/Fed

As CDSCO recommendation

4.

Retention of samples 5 Year from the date of filing the application

No such requirement but usually followed

3 years from date of filing the application

SUMMARY
In this presentation we did individually study about the rule & regulations which are followed for drug approval process in USA, Europe & India. Data in the dossier gives the answer of following questions: What is the product?  Is the quality presented acceptable on grounds of safety and efficacy?  Is the quality presented reproducible?  How long can the quality be maintained? Quality must ensure consistency of safety and efficacy during the shelf life of all batches produced.

And in last we did the comparative study. This comparative study of dossier compilation given a brief idea about the difference in regulatory requirements for drug approval process among USA, EU & India.

CONCLUSION
Significantly reduces the time and resources needed to compile applications for registration of human pharmaceuticals Eases the preparation of electronic submissions Facilitates regulatory reviews and communication with the applicant by a standard document of common elements Simplifies exchange of regulatory information between Regulatory Authorities

Provide for a scientifically sound means of establishing the quality, safety and efficacy of therapeutic products Improve the transparency, predictability and efficiency of the regulatory process Contribute to reducing unnecessary regulatory burden and promoting industry compliance Promote bilateral and multilateral regulatory communication and cooperation common regulatory platform Level playing field good for export market

REFERENCE
1. Generic drug. drugs, websitewww.wikipedia.org/wiki/generic2. CTD Guidelines map (ICH,EMEA AND FDA), website www.reg- info.com/ctd-guidelines 3. Drug price compitition & patent term restoration act of 1984, website-http://www.cptech.org/ip/health/generic/hw.html 4.180-day generic exclusivity, websiteww.fda.gov/downloads/Drugs/.../Guidances/ucm079342.pdf 5. Bioequivalence and Generic Medicines Introduction, websitewww.egagenerics.com/doc/zanen-biogenerics.pdf 6. Introduction - European Agency for the Evaluation of Medicinal products, websitewww.emea.europa.eu/docs/en_GB/...library/.../WC500074880. pdf

7. EMEA and Overview of the Centralised Procedure, websitewww.who.int/entity/vaccine_research/diseases/influenza/Celis.p df 8. Matin s.lipsky,lisa k. sharp, The drug approval process, Jabfp, sep-oct 2001,vol 14(5) 9. Welage LS kinking dm,ascione FJ, gaither CA. Understanding scientific issues embedded in the generic drug approval process,2001.feb- may04(5);114-30. 10. Lionberger RA., FDA critical path- initiatives, Opportunities for generic drug development.AAPS J.2008, 10(1): 103-9, Epub2008 feb20. 11. Peters JR,hixon DR, conner DP, davit BM, catterson DM, parise CM generic drugs-safe, effective and affordable dermotol ther.2009 may-jun,22(3);229-40 12. Jaime R hornecker, Generic drugs: history, approval process and current challenges, US pharm2009,34(6),26-30

13. Filiz hinchal, An introduction to safety issues in biosimilars/follow-on biopharmaceuticals, Jmed cbr 7,1 sept. 2009 14. Holmes CB, coggin W,jamiesn D mihm H,rrancn R,savio P,Hope M,ryan C,moloney-kitts M,goosby EP, dybul M, use of generic antiretroviral agents and cost savings in PEPFAR treatment programmes. JAMA 2010 jul21,304(3) 313-20. 15. Chow sc lio.jp, Statistical assessment of biosimilar products. J.bio pharm stat2010 Jan, 20(1); 10-30. 16. Howland RH, Evaluating the bioavailability and bioequivalence of generic medications, J. psychosocial nursing and mental health serv.2010jan, 48(1) 17. Submitting Marketing Applications According to the ICH-CTD Format - General Considerations, websitehttp://www.fda.gov/RegulatoryInformation/Guidances/ucm1297 03.htm

18.Revision History Module 1 Administrative informationwebsitewww.fda.gov/downloads/Drugs/.../UCM163175.pdf 19.FDA Debarment List (Drug Product Applications), websitewww.fda.gov/ICECI/.../FDADebarmentList/default.htm 20. Guidance for Industry - FDA, www.fda.gov/.../Drugs/.../FormsSubmissionRequirements/Electro nicSubmissions/UM163188.pdf 21. ICH Guideline: The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality M4Q; Quality Overall Summary of Module 2, Module 3: Quality,:http://www.ich.org

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