My slides for the Regulatory Affairs in Emerging Markets Informa Conference in Berlin, October 2012

1. CASE STUDY
ASSESING THE
REGULATORY
ENVIRONMENT IN
MEXICO
María Inés Guaia
October 2012 - Berlin

2. Mexico: an emerging economy
$1.231 trillion GDP Services 70%
#14 World
#2 Latin America
Industry 26%
3,9% annual growth rate Agriculture 4%
112 million people
44% below poverty line

3. Mexico and the pharma business
Mexican pharmaceutical market
• Epidemiological
transition
worth around
• Strong brand loyalty $13 billion
• Black market, low-cost
#10 World
medicines #2 Latin America
• 2/3 of the population
under the social Public sector
security system (generic drugs – Private sector
tender)
Aim: universal % Value 20 80
healthcare % Volume 80 20

4. The drug agency in Mexico
Comisión Federal para la Protección contra
Riesgos Sanitarios
July 2012: PAHO/WHO designated
Federal Commission for COFEPRIS National
Protection against Sanitary Regulatory Authority of
Risks Regional Reference
New Molecules Committee Support in evaluation
of quality, efficacy and
• New drug substances (new in the world or new for Mexico) security information
• New combinations of drug substances
• New indications
REPORT registration
• Other special cases (e.g. similar biotherapeutic products)
process

5. Understanding
pharmaceutical
registration in Mexico
General Panorama

6. Drug registration in Mexico
Timeline to approval NEW 2012! Authorized
official: 6 months
third parties review dossiers
real: very variable 12 – 24 months
(cost) and generate report –
Registration period: 5 years include in submission –
Renewal submission: at least 6 months COFEPRIS response in 30
before registration expiry days! (no experience yet)
local manufacturing
new entity
small import
molecules local manufacturing
generic
Registration import
local manufacturing
cases new entity
import
biotechs
local manufacturing
biocomparable
import

7. Small molecules, new entities
Before submission for registration New molecule Committee
• Form
If not manufactured in
• Stability studies
Mexico
• Efficacy and safety information (publications, Additionally:
studies) • CPP of origin
• Labeling texts • DS+DP GMP certification
of origin by a recognized
• Patent or licensing documents country
• Origin identification and GMP certificate for (apostilled/legalized)
• Authenticated
DS+DP representation letter, if
• Technical information for raw materials. solicitor is not affiliate or
headquarter of
• Technical information for finished product. manufacturing company
• Technical information for packaging materials.

8. Small molecules, generic
• Form
If not manufactured in
• Stability studies Mexico
• Interchangeability evidence Additionally:
• DS+DP GMP certification
• Labeling texts
of origin by a recognized
• Patent or licensing documents country
(apostilled/legalized)
• Origin identification and GMP certificate for • Authenticated
DS+DP representation letter, if
• Technical information for raw materials. solicitor is not affiliate or
headquarter of
• Technical information for finished product. manufacturing company
• Technical information for packaging materials.

9. Biotechs, new entity
Before submission for registration New molecule Committee
Biotech Products Evaluation
• Form Subcommittee
• Patent or licensing documents
• Labeling texts If not manufactured in
• Risk management plan Mexico
Additionally:
• Clinical studies • CPP of origin
• Origin identification and GMP certificate for DS+DP+diluent • DS+DP+diluent GMP
• Copy of sanitary license and technical responsible designation for certification of origin by a
solicitor, manufacturing, packaging, storage and distribution sites recognized country
(apostilled/legalized)
• Drug substance: technical documents, manufacturing • Authenticated
information, origin and history of biologic raw materials. representation letter, if
solicitor is not affiliate or
• Additives/excipients: technical documents. headquarter of
• Drug product: technical documents, manufacturing information. •
manufacturing company
Document accrediting a
• Diluent: technical documents. legal representative as
resident in Mexico.
• Packaging: technical documents.

10. Biotechs, biocomparable
• Form
• Patent or licensing documents If not manufactured in
• Labeling texts Mexico
• Risk management plan Additionally:
• CPP of origin
• Biocomparability studies • DS+DP+diluent GMP
• Origin identification and GMP certificate for DS+DP+diluent certification of origin by a
• Copy of sanitary license and technical responsible designation recognized country
(apostilled/legalized)
for solicitor, manufacturing, packaging, storage and distribution
• Authenticated
sites representation letter, if
• Drug substance: technical documents, manufacturing solicitor is not affiliate or
headquarter of
information, origin and history of biologic raw materials. manufacturing company
• Additives/excipients: technical documents. • Document accrediting a
legal representative as
• Drug product: technical documents, manufacturing resident in Mexico.
information.
• Diluent: technical documents.
• Packaging: technical documents.

11. Overview of the
local clinical trials
requirement

12. Local Clinical Trials in Mexico
• Why?
Pharmacogenomic studies have shown that drug
• How?
metabolism in Mexican-Hispanic population can
When clinical studies are
be influenced by its genetic makeup.
multicentric, Mexican population must be
included.
• In which cases?
Local clinical studies are required by COFEPRIS Sample size: not specified in regulations;
for: to be calculated based on incidence of
• New molecules disease.
• Biotech and biocomparable products
• Generic drugs that are not commercialized If Mexican patients are not included in the
anywhere else in the world. clinical trials: New Molecule Committee
• Other cases upon authority request will request pharmacokinetic studies to
evidence not significant differences in
• When? safety or efficacy in Mexicans.
• Previous submission and approval of clinical
• Good Clinical Practices guidelines
protocol – Have results before submission for
registration.

13. New regulation for
biotech products
Critical update

14. The need for updated regulations
Chronic and
Mexico degenerative
Epidemiological
Infectious transition diseases
diseases • Cancer
• Diabetes Biotech drug
• Rheumatoid
Arthritis products
Structural and functional
complexity
Innovative Novel small ‘The product is the
New biotech products
drugs molecules
process’
Similar
Subsequent Generic drugs
entry drugs (bioequivalent) Biotherapeutic New challenges
Product (SBP)
for evaluation
and regulation!

15. Biotech regulations: Mexico at the vanguard
Late ‘90s 1997 1998 2004 2005
Some legal Modification of Inclusion of some USA – EU started EU: First specific
adaptations to General Health Law – concepts and discussions on guidelines
include innovative all biotech products guidelines in Health regulations for SBP
biotech drug Supplies Regulation
products
+170 biotech drug products approved
Development of specific,
detailed regulation Oct 2011
2007 2009 Apr 2012
COFEPRIS, industry,
Starts congress Modification to other actors New biotech
discussion in Mexico Health General Regulation
Law – general regulation
principles for
became
SBP effective

16. Summary of new regulations
• Definition of biocomparability • Local clinical studies (innovative or
biocomparable) might be requested
• Preclinical and clinical studies to evidence
comparability • Inmunogenigity studies and adverse
effects reports – in the case of
• 12 years from submission of patent of biocomparables, to evidence comparability
reference - request authorization to start
studies and tests • For biocomparable products: toxicology
tests in animals, characteristics of
• New Drug Committee: Biotech Products pharmacodynamic studies and minimum
Evaluation Subcommittee requisites of comparative clinical studies
are detailed
• Labeling: MB (Medicamento Biotecnológico)
or MBB. (Medicamento Biotecnológico • Specific requirements set on a ‘case by
Biocomparable) + INN case’ basis, and then defined for INN
• Prescriptions: INN mandatory, proprietary • The better characterization and physic-
name optional chemical comparability evidence, the less
clinical evidence will be required
• Pharmacovigilance

17. Assessing the GMP
inspection process by
COFEPRIS
Regulatory aspects

18. GMP verification by COFEPRIS
When? GMP Certificates issued by FDA (USA),
ANVISA (Brazil), Health Canada
• For new registration and manufacturing changes
of biologic, biotech and hemoderivate products. (Canada), EMA (EU), Pharmaceutical
and Food Safety Bureau (Japan), and
• For new registration or renewal of drug products Therapeutic Goods Administration
or drug substances of any kind manufactured in
(Australia) are accepted.
countries not considered as high sanitary
surveillance by COFEPRIS.
Request for inspection
Inspection is required prior
• Submit form and required documents
to submission
the certificate is an important document to be annexed to • Propose two inspection dates (production of
the submission dossier DS/DP) and inspection schedule
• Propose hotel and flight options. Cost of visit
What? + travel expenses: company
Manufacturing sites of drug substance and • Arrange a Spanish translator
drug product – DP/DS specific • Timeline to get an inspection: about 3
months

19. Required information and documents
• Name and general data of the applying company, authorization
• Name of DP/DS – use, action, indication All documents in
• Name and address of all sites involved in manufacturing Spanish, or English
process, description of process stages with Spanish
translation, verified
• Manufacturing process – list and description of other DS/DP
and signed by technical
manufactured in same line
responsible
• Person designated by the applicant to be in charge
• Technical documents: Documents issued by
 Organization charts foreign authorities:
 Architectural drawings apostilled or
 Flowchart of manufacturing process
 General summary of quality system legalized and
 Validation master plan translated by certified
 Two last annual product reports translator
• Payment

20. Thank you! Gracias!
• Erika Aguilar
• Luis Joaquín Serrano
• Esther Domínguez
• Omar Cruz
• María del Carmen García Floriano
• Austin Keeble
• former Bayer colleagues
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