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
Objectives

• 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

3
Agenda

• Latin America General Overview
• Requirements for Submission
• Stability Studies

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• 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
(USB 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 (USB)
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
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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.

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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

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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.

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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
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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

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PAHO Harmonization Efforts

• A proposal to
• harmonized
• requirements for
• Steps under discussion
• Implement instruments developed
• Train region
• Develop norms, guidelines and proposals

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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
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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
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• 2. Requirements for Submission

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CTD dossier in Latin America

• Is NOT a common dossier for all Latin America
• It does not define the content of a registration
  dossier
• Its 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

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Dossier Preparation Flow
Critical steps
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Registration Requirements (PAHO Survey)
Source Paho.Working Group on Drug Registration
in Latin America
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Registration Requirements (PAHO Survey)
Source Paho.Working Group on Drug Registration
in Latin America
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Registration Requirements (PAHO Survey)
Source Paho.Working Group on Drug Registration
in Latin America
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Registration Requirements (PAHO Survey)
Source Paho.Working Group on Drug Registration
in Latin America
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Argentina

• Language Spanish
• Population40,301,927
• 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 [phone]
• Website anmat.org.ar
• Questions can be sent to responde_at_anmat.gov.ar

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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

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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 its mandatory that the lots be
  tested locally and in presence of the authority.
  Dispositions 6877/2000

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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.
• Its 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/institucio
  nal/faleconosco/opcao2.asp
• Regulations can be found at
• http//www.anvisa.gov.br/medicamentos/registro/in
  dex.htm

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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, 2007Registration 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.

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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.

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Brazil Stability
Refer to Resolution No. 1 of July 29, 2005 for
specific guidance
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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_at_salud.
  gob.mx
• Regulations can be found at
• http//www.cofepris.gob.mx/bv/noms.htm

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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
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Chile

• Language Spanish
• Population15.116.435
• Regulatory Authority
• ISP - Instituto de Salud Pública de Chile
• Av.Marathon N 1000 Ñuñoa
• Santiago, Chile
• Telephone [phone]
• 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.

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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

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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?codigo182
• 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

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Country General Information
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Central America General Information
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• 3. Stability Studies
• in Latin America

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Drug Substance Stability Studies

• Not required across the region
• Argentina, Chile follows ICH guidelines
• Brazil follow local guidelines

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Finish Product Stability Studies
Refer to country specific stability guidelines
for additional information
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Zone Classification
The Caribbean Islands
Panama
Guyana
Venezuela
Suriname
French Guiana
Ecuador
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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 its own regulations and
  approval process THAT MUST BE TAKEN INTO
  CONSIDERATION

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• Thank you,

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