“Development of a Harmonized Dossier for use Across Latin America”

1. “Development of a Harmonized Dossier for use Across Latin America” Maritza Moncayo Manager, Regulatory Affairs, Astellas Pharma CPDG Symposium, April 11, 2008

2. Promote a brief understanding of the local requirements in the Latin American region Help in the understanding of the development of a harmonized dossier that can be used across Latin America Objectives

3. Agenda: • Latin America General Overview • Requirements for Submission • Stability Studies

4. Latin America General Overview

5. Latin America Overview Language: Primarily Spanish, Portuguese some islands French and English Population: 561,326,261 Economic performance: a economic growth rate of 5.3% was estimated in 2006, equivalent to a per capita increase of 3.8% Total Area: 18,376,0202 km Central America – 7 countries The Caribbean – 26 countries and territorries South America – 15 countries

6. Largest Pharmaceutical Markets Worldwide (US$B – 2006) US $B (2006) 254 30 20 40 60 10 50 254 Figures for 2006 Source: IMS Health

7. Latin America Market is Worth Over US$ 35B LA Markets in 2006 (US$B) * Rank position in Worldwide Sales by Country Figures for 2006 Source: IMS Health

8. Latin America Overview Background: • Latin America countries developed legislations for drug registrations, inspection, drug control and life cycle. • Legislation and review process varies from country to country • Classification of the products varies to the degree of development (new chemical entities, generic, similar etc.) Source: Paho.Working Group on Drug Registration in Latin America

9. Latin America Definition Reference Drug also referred to as a New Molecule Entity (Innovator), is a unique compound that has been approved by the FDA or any major Market (EMEA, JP, CANADA) and has patent protection and the efficacy, Safety and quality has been proven. Generic drug must contain the same active ingredients as the original Formulation (innovator). They are assumed to be identical in dose, strength, route of administration, safety, efficacy, and intended use. In most cases, generic products are not available until the Patent protection of the original developer expired. Similar Drug: Is structurally similar to already known drug which contains the same API, same concentration, form, administration, dosing and therapeutic, preventive or diagnostic indication as the reference product that has already been registered.

10. Latin America Overview Approval conditioned on: • Presentation and evaluation of a dossier per local country regulation and requirements • Product approval in one of the reference countries or in a country of high development (Japan, Canada, EMEA, USA) presentation of a CPP per WHO (World Health Organization) guideline • Approval Time: Varies between 2 to 24 months

11. Latin America Overview General Requirements: • Legal Documents (POA, LOA, CPP etc.) • Information on Drug Substance • Information on Finish Product • Clinical Data • Packaging Materials (primary & secondary) • Package Insert or SPC • The difference in requirements in the Americas generated initiatives from international agencies to find mechanisms to harmonize the requirements for drug registration. No specific agreement has been yet finalized.

12. Harmonization Efforts Groups working on harmonization initiatives: • NAFTA – The North American Free Trade Agreement, limited to the exchange of information as an instrument for promoting harmonization. (Canada, Mexico and USA) • MERCOSUR - Southern cone Common Market (Brazil, Argentina, Paraguay and Uruguay, Chile and Bolivia participate as observers) • CAIS – Central American Integration System (Costa Rica, El Salvador, Honduras, Guatemala and Nicaragua), recently approved mutual recognition of drug registration among Guatemala, El Salvador and Honduras for product manufactured locally. • CAN – Andean Community of National (Bolivia, Colombia, Ecuador, Peru and Venezuela) • CARICOM – Caribbean Community • PAHO/WHO – Pan American Health Organization/World Health Organization Source: Paho.org

13. LATIN AMERICA HARMONIZATION EFFORTS • International Conference of Harmonization ICH and Global Cooperation Group (GCC) – Achieve harmonization initiatives in different parts of the world. • Pan American Health Organizacion (PAHO) created a work team to create a proposal for Latin America harmonization on Common Requirements for Drug Registration for Latin America. http://www.paho.org/search/DbSReturn.asp

14. PAHO Harmonization Efforts A proposal to harmonized requirements for: Steps under discussion: • Implement instruments developed • Train region • Develop norms, guidelines and proposals

15. Harmonization Initiatives • PAHO working team prepared a survey on LA requirements for drug registration and identified gaps • With the survey information a proposal was prepared recommending the countries the necessary and sufficient requirements of a drug product that can be a guarantee to the public health on the safety, efficacy and drug quality as well as the harmonization of the labeling requirements in the region (draft) Source: Paho.org

16. Latin America Overview Bioequivalence Studies: • Is required for most oral generic drug products seeking a marketing authorization in Latin America to prove the product is therapeutically equivalent to the innovator. (Efficacy, Safety and Quality) • It may be waived when a product is administered parenterally (IV, IM, SC) or for solutions for oral use: otic or ophthalmic, topical products inhalators or nasal spray products. Clinical trials: • All countries subscribe to the principle of the Declaration of Helsinki and county specific regulations • In an effort to avoid duplication of work and acceptance of data from clinical trials from other countries led different regions to harmonize standards for good practice in clinical research. • ICH, EMEA, US, Japan, Canada and the World Health Organization, among others, produced guidelines standardizing criteria • Within the framework of the ICH there emerged Guidelines for GCP, which set forth a series of guidelines for the design, implementation, auditing, completion, analysis, and reporting of clinical trials in order to ensure their reliability. Source: Paho.org

17. 2. Requirements for Submission

18. CTD dossier in Latin America • Is NOT a common dossier for all Latin America • It does not define the contentof a registration dossier • It’s not a road towards common review practices across the region It is…. • A tool to ease the location of the information needed in each country

19. Sections Edited reduce EU, CA, US, JP Dossier Translate Local Language (Spanish- Portuguese) Country Affiliate Agent Legal Docs Local Format Country HA Review HA Approval Questions Feedback Dossier Preparation Flow Critical steps

20. Registration Requirements (PAHO Survey) Source: Paho.Working Group on Drug Registration in Latin America

21. Registration Requirements (PAHO Survey) Source: Paho.Working Group on Drug Registration in Latin America

22. Registration Requirements (PAHO Survey) Source: Paho.Working Group on Drug Registration in Latin America

23. Registration Requirements (PAHO Survey) Source: Paho.Working Group on Drug Registration in Latin America

24. Argentina • Language: Spanish • Population:40,301,927 • Regulatory Authority: under the supervision of Ministry of Health (Minsa). ANMAT - set in 1992 Argentine National Administration of Drugs, Food & Medical Technology (equivalent to the FDA) Avenida de Mayo 869 (C1084AAD) Ciudad Autónoma de Buenos Aires - Argentina – Tel: 54-11-4340-0800 / 54-11-5252-8200 • Website: anmat.org.ar • Questions can be sent to: responde@anmat.gov.ar

25. Argentina Regulatory Legal Framework for Imported Product: Pharmaceutical Law 16.463, ( 04/08/1964), establishes the scientific and sanitary criteria of approval and authorization of pharmaceutical products. (API, quality, efficacy, safety, therapeutic advantages) • Decree 150: New Product Registrations implemented in 1992 with updates 1890/92, and 177/93. • Controlled Drugs - SEDRONAR - Secretariat of Planning for the Prevention of Drug Addiction and Fight Against Narcotrafficking • Time of approval: 90-120 days • Product renewal: Every 5 years * The importer must have a local laboratory facility, quality control release product, be registered with ANMAT, have a Technical Director

26. Argentina • Products that have been approved and are marketed in the countries indicated in Annex I & II DO NOT require local clinical trials to demonstrate the efficacy and safety of the product. • NME that are being developed in Argentina or that will be imported from a country that is not included in Annex I or II MUST provide local Clinical Pharmacological investigation of Phases O, I, II, III (Disposition 5330 GCP, ICH). • Annex 1: United States, Japan, Sweden, Israel, Canada, Austria, Germany, France, United Kingdom, Netherlands Belgium, Denmark Spain, Italy. • Annex 2: Australia, Mexico, Brazil, Cuba, Chile, Finland, Hungary, Ireland, China, Luxembourg, Norway, New Zealand. • After approval and previous to the marketing of the product it’s mandatory that the lots be tested locally and in presence of the authority. Dispositions: 6877/2000

27. Brazil Language: Portuguese Population: 190,010,647 Regulatory Authority: ANVISA (National Health Surveillance Agency) established in January 1999 - under the auspices of the Ministry of Health The Agency is autonomous operating under a special regime. It’s main purpose is to foster protection of the health of the population by exercising sanitary control over production and marketing of products. • Website: www.anvisa.gov.br • Questions to: https://www.anvisa.gov.br/institucional/faleconosco/opcao2.asp# • Regulations can be found at: http://www.anvisa.gov.br/medicamentos/registro/index.htm

28. Brazil Regulatory Legal Framework: • Law No. 6360/76 which has been updated on several occasions since its introduction. • Resolution No. 136 of 29 May 2003 - This Regulation applies to all new or innovative medicaments except those, which are governed by specific legislation (similar) • Resolution No.17 of March 2, 2007–Registration of Similar Product • Resolution No. 16 of Marc 2, 2007 – Registration of Generic • Resolution No. 1 of July 29, 2005 – Guide for stability studies • Time of approval: 6 to 24 months • Product renewal: Every 5 years • All material included in the product dossier, such as production and quality control reports, information contained in the labels, inserts, and packaging, shall be in Portuguese. • Any official documents in a foreign language used for registration, issued by the health authorities shall be accompanied with a certified sworn translation.

29. Brazil Requirements: Resolution No. 136 of 29 May 2003 • Technical information of the API • Pharmacodynamics; Pharmacokinetics • Transmissible Spongiform Encephalopathy (TSE)/BSE certificate if applicable • Quality control of all raw materials used • Quality control of finished product • All documents shall be addressed in hard copy signed on the final page and initialed on every page by the technician responsible for the company. Add a copy of all technical reports recorded on diskettes or CD-ROM in doc extension files or in any extension acceptable to ANVISA. • Transfer of methodology to execute local product release • GMP certificate issued by ANVISA or a copy of the application voucher requesting the inspection by ANVISA of the manufacturing site. • Price certificate of the countries where the product is marketed must be submitted in order to obtain final approval, if product is not yet marketed submit a proposed price.

30. Brazil Stability Refer to Resolution No. 1 of July 29, 2005 for specific guidance

31. Mexico • Language: Spanish • Population: 108,700,891 • Regulatory Authority: Is a decentralized organ of the Department of Health with technical, administrative and operational autonomy COFEPRIS - Comisión Federal para la Protección contra Riesgos Sanitarios Monterrey No. 33, Col. Roma, Delegación Cuauhtémoc, C.P. 06700, México, D.F. Tel: 5080 5200 • Website: http://www.cofepris.gob.mx/index.htm • Questions can be sent to: contacto_cofepris@salud.gob.mx • Regulations can be found at: http://www.cofepris.gob.mx/bv/noms.htm

32. General changes in Mexico regulations • For new registration Mexico could submit: • Clinical trials done in Mexico (finished) • 2 types of drugs (reference and generics) • Longer times for resolutions/approvals • New products registered and sold in the country of origin - 240 working days (in some cases might need a meeting with the new molecules committee of the Health Authority) • Generics 180 working days • Prior approval variations 180 working days • Free sale certificate, GMPc 60 working days • In order to register a product in Mexico you must have a “Licencia Sanitaria” authorization of the operation of a manufacturing plant that must conduct ALL the production process REGULATIONS STABILITY

33. Chile • Language: Spanish • Population:15.116.435 • Regulatory Authority: ISP - Instituto de Salud Pública de Chile Av.Marathon N° 1000 Ñuñoa Santiago, Chile Telephone: 56-2- 3507477 • Website: http://www.ispch.cl/ • Regulation and Questions can be found and sent to: http://www.ispch.cl/oirs/ • Time of approval: 9-12 months • Product renewal: Every 5 years • Legal Framework: Reglamento del Sístema Nacional de Control de Productos Farmacéuticos, Decreto Supremo 1.876 de 1.995.

34. Chile CHEMICAL AND PHARMACEUTICAL DOCUMENTS • Formula • Manufacture method • Control tests of the raw materials, intermediate products and finished product • Stability test of pharmaceutical product (on 3 batches, accelerated and long term) • Stability test of drug (*) • Pharmacological animal studies (*) • Toxicological animal studies (*) • Physical-chemical data (*) • Pharmacokinetic studies (*) • Dissolution test (*) • Complete clinical trials (complete papers and summary sheet) (*) • Expert reports (*) • Samples of finished products: 15 • Working standard • Origin / Manufacturer of drug (raw material) and standard • IR, UV, HPLC spectrum or other, of drug (raw material) and standard • Storage conditions of finish product, raw material, and standard • COA of drug (raw material) and standard • Validation (analytical methods and manufacture) • (*): If the pharmaceutical product is new in Chile

35. Colombia • Language: Spanish • Population: 44,379,598 • Regulatory Authority: • INVIMA – Instituto Nacional de Vigilancia de Medicamentos y Alimentos Carrera 68 D No. 17 - 11 / 21Bogotá D.C. - ColombiaTelephone: (57)(1) 294 8700 • Website: http://www.invima.gov.co/Invima/index.jsp • Regulation and Questions can be found and sent to: http://www.invima.gov.co/Invima//normatividad/medicamentos.jsp?codigo=182 • Time of approval: 9-12 months • Product renewal: Every 10 years • Legal Framework: Decree 2092 of 1986 and Decree 677 of 1995 (additional amendments) • Colombian product registrations last ten years, but all medicines with an 'expired' period of data exclusivity are exempt • Does not require Good Manufacturing Practice (GMP) compliance for raw materials, nor studies proving bioequivalence for generics

36. Country General Information

37. Central America General Information

38. 3. Stability Studies in Latin America

39. Drug Substance Stability Studies • Not required across the region • Argentina, Chile follows ICH guidelines • Brazil – follow local guidelines

40. Finish Product Stability Studies Refer to country specific stability guidelines for additional information

41. Mexico Belize Guatemala Honduras El Salvador Nicaragua Costa Rica Colombia Peru Brazil Bolivia Zone II - 25°C±2°C/60%±5%RH Paraguay Chile Argentina Uruguay Zone IVa - Hot and Dry 30°C±2°C/65%±5%RH Zone IVb - Hot and Humid 30°C±2°C/75%±5%RH Zone Classification The Caribbean Islands Panama Guyana Venezuela Suriname French Guiana Ecuador

42. Conclusion • When you start investigating a new molecular entity, think it will be registered around the world and will provide a cure to a specific disease, then the main concern is to ensure the finished product reaches the population with approved criteria for QUALITY, EFFICACY and SAFETY • Every country has it’s own regulations and approval process THAT MUST BE TAKEN INTO CONSIDERATION

43. Thank you, ?