Pharma Regulatory Affairs in Mexico

Pharma Regulatory Affairs in

MexicoMaria Ines Guaia - Informa Conference: Regulatory Affairs in Emerging Markets - Prague, October 2013

Disclaimer

• For educational purposes, some tables and graphs have been borrowed from an informative COFEPRIS presentation. You can find the complete original presentation in the following link: http://www.deloitte.com/assets/Dcom-Mexico/Local%20Assets/Documents/mx(es-mx)PanoramaMexico_IndustriaCofepris.pdf

http://www.deloitte.com/assets/Dcom-Mexico/Local%20Assets/Documents/mx(es-mx)PanoramaMexico_IndustriaCofepris.pdf



Mexico: an emerging economy

120 million people (est. 2012)

46% below poverty line

Services 70%

Industry 26%

Agriculture 4%

$1.177 trillion GDP#14 World#2 Latin America

Annual growth rate:3.9 (2012)3.5 (exp. 2013)

Mexican GDP growth

Source: COFEPRIS

Mexican GDP growthrelative to US GDP growth

Source: COFEPRIS

Mexican balance of paymentsAccounting record of all monetary transactions between a country and the rest

of the world. Indicator of a country's position in the global economy.

Source: COFEPRIS / Data: 2010

Mexican fiscal deficitDifference between public expenditure and income. Indicator of a government’s

budget and dependence on credit.

Source: COFEPRIS / Data: 2011

Direct foreign investment in Mexico

Source: COFEPRIS

Public expenditure in drug products

Source: COFEPRIS

Public expenditure in drug products - global comparison

Source: COFEPRIS

Out-of-pocket health expenditure

as a percentage of total health expenditure

Source: COFEPRIS

The pharma industry in Mexico

Source: COFEPRIS

% of GDP 1.2

% of manufacturing GDP 6.9

Annual exports (millions of USD) 2,200

Total pharma market (billions of dollars)

13

Direct employment 78,500

Indirect employment 330,000

2nd biggest in LatAm11th biggest worldwide

Steady annual growthrate2005-2011: average of 4.8%

The pharma industry in Mexico

Source: COFEPRIS

Mainly internal consumption (exports only 14% of production)

COFEPRIS: the Mexican Health Authority

Regulates:• Food and beverages• Tobacco products• Healthcare supplies

(including drugs, medical devices, vaccines, blood and tissues, etc.)

• Healthcare services• Other consumer goods

(cosmetics)• Pesticides, plant nutrients

and toxic substances• Emergencies• Occupational health• Environmental risks

Through all the supply chain• Production• Distribution• Commercialization• Imports• Exports• Advertisement• Sales and supply

92 billion $ market! (around 10% of GDP)

COFEPRIS: the Mexican Health Authority

July 2012: COFEPRIS recognized as Health Authority of Regional Reference

Other ARRs: ANVISA (Brazil), ANMAT (Argentina), INVIMA (Colombia), CECMED (Cuba)

Photo: PAHO

COFEPRISCommisionate: Mikel Arriola

Drug product Registration in MexicoGeneral overview

Drug registration in Mexico

Small moleculesnew entity

generic

Biotechsnew entity

biocomparable

Vaccines

Orphan drugs

Timeline to approval officially: 6 months In reality: very variable and changing 12 – 24 months

Registration period: 5 yearsSubmission for registration renewal: at least 6 months before registration expiry

Registration cases

Before submission: Committee of New Molecules

Dossier structurefor the different registration cases

New Molecules

• Module I. Legal/Administrative information

• Module II. Quality information• Module III. Preclinical studies• Module IV. Clinical studies

Generic drugs


• Module II. Quality information• Module III. Bioavailability and/or

bioequivalence

Vaccines


• Module II. Quality information• Module III. Preclinical studies• Module IV. Clinical studies

Orphan drugs


• Module II. Quality information• Module III. Justification of ‘orphan drug’

status• Module IV. Preclinical studies• Module V. Clinical studies

Dossier structurecontent of the modules

Module I. Legal/Administrative information

1. Form.

2. Proof of payment of fee.

3. Sanitary authorization. (licencia sanitaria) For foreign manufacturing site provide licence, certificate or other document authorizing the site to manufacture the pharmaceutical products of interest, issued by country of origin, legalized or apostilled, translated to Spanish by an official translator (perito traductor).

4. ‘Responsible sanitario’ notice.

5. Labeling texts (if applicable).

6. Complete and summarized prescription information.

7. GMP certificate for manufacturing site of API.

8. GMP certificate for manufacturing site of finished product.

9. GMP certificate for manufacturing site of diluent (if applicable).

10. For drug products manufactured outside of Mexico: Certificate of Pharmaceutical Product (CPP) of origin, apostilled or legalized, with official translation (perito traductor). Representation letter, assigning the legal representative of the foreign company in Mexico. (Reccomended: broad power of representation letter, minimum validity time of 5 years.

11. Commercial name.

12. Intellectual property information.

13. Information on the waiver for the local manufacturing facility requirement.


Module II. Quality information

1. API

1.1. Manufacturing information

1.2. General information

1.3. Quality control

1.3.1. Literature/Pharmacopoeial references. Specifications. Analytical methods. Validation reports. Certificates of analysis (CoAs).

2. Excipients and additives

2.1. For new additives, usage safety information


2.2.1. Literature/Pharmacopoeial references. Specifications. Analytical methods. Validation reports. Certificates of analysis (CoAs).


Module II. Quality information (cont.)

3. Finished product

3.1. Pharmaceutical development

3.2. Formula

3.3. Manufacturing information

3.3.1. Manufacturing/packaging order, in-process controls.


3.4.1. Monograph

3.4.2. Specifications

3.4.3. Analytical methods and validation reports (if applicable)

3.4.4 Certificates of analysis (CoAs).

3.5 Stability

3.5.1 Stability protocol

3.5.2. Tabulated stability data

3.5.3 Analytical evidence for first and final testing points.

3.5.4 Conclusions


Module II. Quality information (cont.)

4. Packaging materials

4.1. Description and capacity of primary packaging materials.

4.2. Description and capacity of secondary packaging materials.

4.3. Description, capacity and information of any additional materials or devices.


Module III. Preclinical studies (for new molecules, vaccines, orphan drugs).

1. Preclinical studies

1.1. Pharmacodynamics' studies

1.2. Pharmacokinetic studies

1.3. Toxicology

Module IV. Clinical studies (for new molecules, vaccines, orphan drugs).

1. Clinical studies

1.1. Phase I studies

1.2. Phase II studies

1.3. Phase III studies

1.4. Phase IV studies (if applicable)

1.5. For combination of two or more drugs: risk-benefit assessment.


Module III. Bioavailability and/or bioequivalence (for generic drug products)

1. Type of test

1.1. A

1.2. A (3)

1.3. B

1.4. C

Sep 2012

Operative guidelines became effective

Late ‘90s

Some legal adaptations to

include innovative

biotech drug products

1997

Modification of General Health

Law – all biotech products

1998

Inclusion of some concepts and

guidelines in Health Supplies Regulation

+170 biotech drug products approved

2004

USA – EU started

discussions on regulations for

SBP

2005

EU: First specific guidelines

2007

Starts congress discussion in

Mexico

2009

Modification to Health

General Law – general

principles for SBP

Development of specific, detailed regulationCOFEPRIS, industry, other actors

Biotech regulations: Mexico at the vanguard

Oct 2011 – April 2012

Modification of General Health

Law

Drug registration in Mexicoforeign manufacturers

Until August 2008: local manufacturing site requirementthe solicitor of a registration had to own a manufacturing facility in Mexico

Currently: Solicitor must hold license, permit or similar document issued by the country of origin authorizing the manufacturing of medical products

Foreign manufacturer Legal representative

Importer (Mexican company)

Warehouse (storage and distribution)• License to

manufacture medical products

• GMP certificate

Lab of Analysis (Authorized Third Parties)

Unit of pharmacovigilanceSanitary responsible

New Molecule CommitteeFor registration of novel compounds

Presentation at the New Molecule Committee

Cases in which a drug is considered a “New Molecule”• New drug substances (new in the world or new for Mexico)• New combinations of drug substances (for Mexico)• New indications• Other special cases (e.g. similar biotherapeutic products)

1- Request meeting with the New Molecule Committe. (before dossier submission)

2- Presentation by company on the product, followed by questions by the members of the committee.

3- After the meeting, the committee will issue a report thet will be attached to the dossier for submission.

Pre-revision of submission dossiers by Authorized Third Parties

A solution for eternal approval timelines

Pre-revision of dossierStarting in 2012, the possibility of having submission dossiers pre-revised by private parties especially authorized by COFEPRIS was introduced.

How does it work? After all the necessary meetings and exchange of information, the ATP will issue a technical report. If this final report is positive, it can be attached to the submission package for registration. This submission package will enter the COFEPRIS through a special fast-track channel and will be revised in a much shorter time than applications going through the conventional channel.This option is available for new drug applications, renewal of registration certificate and variations.

COFEPRIS doesn’t have any inference in the relations and terms of agreement between clients and ATP.

Main benefits of this new option• Cut current revision times.

• Avoid unnecessary deficiency letters.

The technical report that the ATP issues does not replace the evaluation and decision by COFEPRIS.

Significant reduction in processing times!

Source: COFEPRIS

NEW August 2013: expansion of the Third Authorized Parties’ pre-revision scheme to include biotech products

GMP verification and certification

GMP verification by COFEPRIS

When?

• For new registration and manufacturing changes of biologic, biotech and hemoderivate products.

• For new registration or renewal of drug products or drug substances of any kind manufactured in countries not considered as high sanitary surveillance by COFEPRIS.

Inspection is required prior to submission

the certificate is an important document to be annexed to the submission dossier

What?

Manufacturing sites of drug substance and drug product – DP/DS specific

GMP Certificates issued by FDA (USA),

ANVISA (Brazil), Health Canada

(Canada), EMA (EU), Pharmaceutical and

Food Safety Bureau (Japan), and Therapeutic

Goods Administration (Australia) are accepted.

Request for inspection

• Submit form and required documents

• Propose two inspection dates (production of DS/DP) and inspection schedule

• Propose hotel and flight options. Cost of visit + travel expenses: company

• Arrange a Spanish translator

• Timeline to get an inspection: about 3 months

Cooperation within the Pacific Alliance bloc and with other Sanitary Authorities of Regional Reference

Required info and documents• Name and general data of the applying company,

authorization

• Name of DP/DS – use, action, indication

• Name and address of all sites involved in manufacturing process, description of process stages

• Manufacturing process – list and description of other DS/DP manufactured in same line

• Person designated by the applicant to be in charge

• Technical documents: Organization charts Architectural drawings Flowchart of manufacturing process General summary of quality system Validation master plan Two last annual product reports

• Payment

All documents in

Spanish, or English with Spanish

translation, verified and signed by technical responsible

Documents issued by foreign authorities:

apostilled or legalized and translated by certified translator

NEW! AUGUST 2013: Open call to private parties to enroll as inspectors for DS and DP facilities (Authorized Third Parties)

Clinical trials in Mexican population

Local Clinical Trials in Mexico•Why?

Pharmacogenomic studies have shown that

drug metabolism in Mexican-Hispanic

population can be influenced by its genetic

makeup.

•In which cases?

Local clinical studies are required by COFEPRIS

for: •New molecules •Biotech and biocomparable products•Generic drugs that are not commercialized

anywhere else in the world.•Other cases upon authority request

•When? •Previous submission and approval of clinical

protocol – Have results before submission for

registration.

•How? When clinical studies are multicentric,

Mexican population must be included.

Sample size: not specified in regulations;

to be calculated based on incidence of

disease.

If Mexican patients are not included in the

clinical trials: New Molecule Committee

will request pharmacokinetic studies to

evidence not significant differences in

safety or efficacy in Mexicans.

•Good Clinical Practices guidelines

Agreement for innovationOctober 2012

Agreement for InnovationThree main tenants

1. Give strong support for innovation projects proposed by the national sector: expedition of approval of clinical protocols to be carried out in Mexican clinical centers, follow-up on the execution of the studies, and expedition of registration approval timelines for drug products manufactured in Mexico, from the current average of 240 working days to 60.

2. Strengthen the import of innovative drugs to the Mexican market: recognition of product registrations in the USA, Canada, Switzerland, Australia and the EU and expedition in registration approval timeline for drug products being marketed in any of these countries from a current average of 360 working days to 60.

3. Make Mexico the first country of commercialization of new innovative drug products: modification of the Regulations for Healthcare Supplies: the previously compulsory requirement of providing a CPP of origin offers now the alternative of being waived if a report of clinical trials on Mexican population is submitted.

Agreement for InnovationResults: reduction in dossier revision times

Source: COFEPRIS

Agreement for InnovationConcrete results

• 88 new innovative drug products have entered the Mexican market, most of them through the expedited revision process for registration of innovative imported drugs registered in high-sanitary-surveillance countries, and including five orphan drugs. Most of the newly approved drugs target cardiovascular, oncologic or cerebrovascular conditions.

• Increase of 20% from 2011 to 2013 in applications for clinical trials in Mexico (current figure: 388 applications), and COFEPRIS is implementing measures to decentralize the revision of clinical protocols to the National Institutes of Health in order to reduce evaluation times, from 90 to 30 days.

• In January 2013, one new drug was approved in Mexico before any other country in the world, making Mexico a worldwide pioneer for an innovative drug product for the first time: Lixisenatide (Sanofi Pasteur), trade name Lyxumia, the latest pharmaceutical innovation to treat Type 2 Diabetes, a once-daily injectable GLP-1 receptor agonist.

Coming soon:Regulations on personalized medicine/pharmacogenomics

Regulations on personalized medicine

Guidelines coming soon

• Guidelines to guarantee safety and effectiveness of personalized therapies based on pharmacogenomics approach

• Define specific GMP requirements for pharmacogenomics-based products.

• Make Mexico a pioneer in regulation for this kind of product in Latin America.

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Health & Medicine

Pharma Regulatory Affairs in Mexico