Regulatory Strategy In Emerging Markets

© 2017 PAREXEL INTERNATIONAL CORP.
REGULATORY
STRATEGY IN
EMERGING
MARKETS
Angela McGillivary
Principal Consultant

© 2017 PAREXEL INTERNATIONAL CORP. / 2
INTRODUCTION TO EMERGING
MARKETS
STRATEGY CONSIDERATIONS FOR
ENTERING EMERGING MARKETS
oCommercial Considerations
oClinical Development
oRegulatory Requirements
oSubmission Strategy
oPost Approval
CONCLUSION
CASE STUDIES
AGENDA

INTRODUCTION TO EMERGING MARKETS
EMERGING MARKET DEFINITIONS
BRIC MIST
• Brazil
• Russia
• India
• China
• Mexico
• Indonesia
• South Korea
• Turkey
Tier 1
• China
Tier 2
• Brazil
• India
• Russia
Tier 3
• Poland,
Argentina,
Turkey,
Mexico,
Venezuela,
Romania,
Saudi Arabia
and
Colombia
• Vietnam,
South Africa,
Algeria,
Thailand,
Indonesia,
Egypt,
Pakistan,
Nigeria and
Ukraine
Pharmerging1
1IMS definition - countries with >$1 billion absolute spending growth over 2014-18 and which have GDP per capita of
less than $30,000

EMERGING MARKET REGIONS
LATIN
AMERICA
~648 million
MIDDLE EAST
&
AFRICA
~1,247 million
ASIA PACIFIC
~4 billion
Russia & CIS
~292 million

Complex Environment
Agencies becoming more sophisticated demanding more
information
A number of markets moving towards or recognising ICH
Cultural and political considerations for interactions with local
authorities and KOLs
r
Some harmonization GCC, ASEAN
Diverse regions with different regulatory authorities
Companies need to have a local presence in the country either an
affiliate office or partner with distributor

INTRODUCTION TO EMERGING MARKETS:
WHY CHOOSE EMERGING MARKETS?
• Growth in developed markets is slowing
• Emerging Markets are seeing1
• Governments increase spend on healthcare
o e.g. Russia, Saudi Arabia, South Africa, Indonesia
• Growing middle class
• Large population with Increase in aging population
o e.g. China
• High rates of Western type diseases e.g. diabetes, cancer, cardiovascular and mental
health issues
• Increasing awareness of available therapies through internet and social media
• Emerging Markets represents significant opportunity for biopharmaceutical
companies
1 IMS “Global Medicine Use in 2020 Outlook and Implications” IMS Institute Healthcare Informatics, 2015

INTRODUCTION TO
EMERGING MARKETS • Enter market quickly avoid the
lag behind EU and US approvals
• Include EM strategy into your
Integrated Product Development
• Decisions taken during early
product development will impact
success in EM

CHINA NEW REFORMS
New CFDA reform guidance by the central government released on October 8, 2017
Multinational Trials
• There is no longer the requirements that a drug has to be registered or already in phase II/ III to start simultaneous
multiregional phase I trials
• Priority Review
• Accelerate NDA approval for life threatening drugs and medical devices, drugs for un-met medical need and orphan
drugs
• Conditional (PMS commitment) Waive of phase III clinical trial data if certain criteria are met
• Change to NDA/MAA process
• No longer requirement for NDA to be approved in a foreign country like EU or US before submission in China i.e. no
need for CPP
• Submission for clinical trial waiver for MAA submission not required
• Possibility to submit in parallel with EU / US, with the aim to implement comparable approval timeline (7 -13 months
excluding clock stop)
Data Protection
• Data exclusivity offered if NDA before any other country approval 6 years for NDA, 10 years for rare diseases
paediatrics and new biologics

DUBLIN, IRELAND
STRATEGY
CONSIDERATIONS

DEVELOPMENT STRATEGY
EM Product
Development
Strategy

COMMERCIAL CONSIDERATIONS
Commercial Strategy Extremely Important to have successful business in EM.
Epidemiology and Unmet Medical Need
• Prevalence of diseases in certain regions e.g. high incidents of lung head and neck liver and gastric cancers in Asia
compared to the West
Label
• Label claim can influence reimbursement if there are competitors with similar or better label
• Regulators consider label approved by Tier 1 authorities
• Essential that research is done at the start of clinical trials
IP Risks
• Threat of generics due to poor IP protection
• Compulsory Licence – there have been several cases where governments have given permission to generic companies to
produce patented products or use processes without the consent of the patent owner
Reimbursement
• Local manufacturers preferred by many governments e.g. Russia, Brazil
• Pharma should work with local governments on patient access incentives donations programs flexible pricing
Tenders
• Maintaining awareness of tendering process and cycles
• Being able to service tender applications promptly and thoroughly

CLINICAL DEVELOPMENT
EM Product
Development
Strategy

CLINICAL DEVELOPMENT
As patient recruitment becomes more challenging, there has been an
increase in clinical trials conducted outside of EU and US e.g. Asia, Latin
America, Middle East.
• A number of markets require local clinical data at time of NDA submission e.g.
Russia, South Korea, Taiwan, China, Vietnam (if product on the market for less
than 5 years), Nigeria, Mexico (not mandatory but could be requested)
• Important that clinical development plan includes EM considerations as early as
phase II e.g.
o Korea will only accept data generated in Korean patients in Korea
• If considering entering any of these markets careful consideration should be
made to include them in your global Phase III program or develop a regional
strategy e.g. Asia development strategy including Japan, Korea, Taiwan, and
China
• This will avoid having to perform additional studies and delays in registration
and consequently lost revenue

CLINICAL DEVELOPMENT:
KOREA
Two Options
1. Bridging Waiver
• Orphan drug life-threatening
diseases HIV, Oncology (no
available treatment or available
treatment fails) diagnostics no
systemic effect proven ethnic
insensitivity
2. Bridging Data Package
• If NCE not applicable for waiver
then Korean clinical data will be
required
• Ideal scenario Korea take part in
phase III program makes
comparability to Western
population easier

CLINICAL DEVELOPMENT: TAIWAN
Clinical Trial Waiver
• Certain therapeutics categories mean no Asian data required
• Similar to Korea with additional therapy areas organ transplantation laxatives
nutritional supplements
Bridging Study Evaluation
• If NCE not applicable for waiver, then Asian clinical data required
• Ideal scenario Asian countries take part in phase III program, makes
comparability to Western population easier (PK, Safety & Efficacy).
• If BSE fails a local clinical trial addressing the deficiencies becomes
necessary
• If Taiwan participates in a PhIIa or earlier clinical study and the data is
presented in the BSE probability of regulatory success is increased

CLINICAL DEVELOPMENT: RUSSIA
• Federal law came into place in 2010 making it mandatory to have clinical data in the local
population
• Typically 50-100 patients are required (however no guidance given by Russian MoH on numbers)
• Mandatory requirement to submit your Russian CT data (ideally as part of a global Phase III
study) either before or with your MAA
• MAA registration with local Russian data (12 – 18 Months Approval)
1. MoH review dossier and forwards to experts
2. Experts conduct evaluation and issues expert conclusion
3. MoH reviews expert conclusion and makes registration decision
4. MoH issues Registration Certificate to Applicant
• MAA registration without local Russian data (additional 1 - 2+ years)
1. Applicant submits CTA to MoH
2. MoH evaluates the dossier and approves CT
3. Applicant conducts CT
4. Submission of MAA

QUALITY STRATEGY
EM Product
Development
Strategy

QUALITY REQUIREMENTS
CMC
• Majority of markets will have their own format for the registration dossier, although CTD
for Modules 2 – 5 is becoming acceptable in an increasing number of markets
• Some markets have harmonised procedures e.g. ASEAN CTD (ACTD)
• Variety of additional Module 1 and CMC documents not usually submitted in the EU or
US some of which will require market specific authentication and legalisation
Manufacturing & Supply Chain
• The majority of markets can only register and receive supply from the manufacturing
sites listed on the CPP
• Indonesia require you to have a local manufacturing plant or expect you to partner with
a local manufacturer
• Some markets will only allow one manufacturing site/ supply chain site per licence,
additional manufacturing sites will mean additional licenses
• Local labelling requirements will need to be considered and may require the
development of market-specific or regional packs

Stability
• A number of markets in Latin America, Asia and Middle East will require Zone IV stability
data for NCE’s 30°C/75%RH.
• Stability data at least 2 commercial scale batches may be required from each
Manufacturing site that you intend to register
• Long term stability required i.e. for a 36 months shelf life 36 months real time stability
on 3 batches is required at time of submission extrapolation not accepted e.g. Middle
East.
Formulation
• Consideration needs to be made for Middle East and some Asia markets, porcine
excipients not allowed
• Halal Certificate may be required
• Certain colours/ flavouring which contain alcohol (via fermentation) additives not
permitted e.g. Egypt does not permit ethanol
• Many markets in the Middle East will not permit raw materials to be sourced from any
companies with interests in Israel

CERTIFICATE OF PHARMACEUTICAL PRODUCT CPP
What is a CPP?
• Issued by a competent authority e.g. EU, US FDA, Swiss Medic, Health Canada, TGA
• Intended for use in countries with limited regulatory capacity
• A tool to assist rapid assessment and patient access to safe and effective medicines
CPP Demonstrates
• Positive quality, safety and efficacy review of the pharmaceutical product
• GMP compliance
CPP Requirements
• Markets require CPP either at submission or during review or for tender submissions
• A number of markets require that the CPP is available from the country that will supply the product i.e. they cannot
accept a US CPP if the supply is coming from the EU e.g. Latin America
• Some markets require more than one CPP e.g. Hong Kong
• Important that supply chain is determined early on in development
• CPP needs to be Apostilled, Notarised and or Embassy Legalised
• Markets will also reference the label

SUBMISSION STRATEGY
EM Product
Development
Strategy

SUBMISSION STRATEGY
Activities Prior to Submission
• Gap analysis of data package for nominated markets/regions
• Pre-Submission Agency Meetings
• GMP Applications
Filing Priorities
• Combination of commercial priority and regulatory requirements
Dossier Management and Publishing
Post Submission Activities e.g. response to questions

AGENCY MEETINGS • It is not mandatory to have a meeting
with MoH prior to product
registration in the majority of
countries except Mexico
• Advisable to have meetings were
possible to speed up to registration
process
• Meetings can be requested if you
have a novel approach e.g. limited
clinical data
• Mexico requires that you have a pre-
submission meeting with the agency
COFEPRIS called “New Molecule
Committee Meeting (NMC)”
• Required for NCE, New Indications,
Line extensions and Biologics (2
meetings required NMC and Biologics
Committee)

GMP APPLICATIONS & COMPANY /MANUFACTURING
SITE REGISTRATION
GMP Inspections
• The MoH will inspect the API and DP manufacturing sites over a number of days
• GMP Inspection required in Brazil, Turkey, Argentina, China, Russia, Korea and GCC
markets
• Need to build these into submission plan as they are required before submission of
the product application e.g.
o Brazil – Request application 6 – 9 months before inspection
o Turkey – request application 12 – 18 months before product application
Site and Company Registration
• Required in a number of Middle East markets
• This is a separate process in some markets e.g. GCC and is required before product
registration

FILING PRIORITIES
How do you determine your Submission Strategy?
Wave 1
• Non CPP
dependant
Markets e.g.
South Africa
Wave 2
• CPP required
during
submission e.g.
Brazil
Wave 3
• CPP required at
time of
Submission
Wave 4
•Markets requiring
local data but not
included in global
clinical plan e.g.
Korea, Russia,
Taiwan
EU Day 180 response CHMP Positive Opinion Legalized CPP After completion of local study
EU Final Approval
Submission Waves

SUBMISSION DOSSIER
Redacted
EU /US
CTD
ASEAN
CTD
e.g. Thailand
Vietnam
Singapore
Country
Specific
CTD
e.g. South
Africa
Global EM
Dossier
ICH Format
e.g. Turkey
Israel
Publishing
requirements
e.g. Paper copies/
CD
Electronic
submission
Local Language
Module 1
Documents
Application
Forms
Fees
CPP
Samples
GMP Certificates
CoAs
Chromatograms
and calculations
Batch records
Price certificates
Preparation of EM submission dossier will usually start with a redacted version of the
EU or US CTD
• The majority of markets will use their own format although some are moving towards CTD e.g. Brazil
• Where possible use a global EM Dossier

POST SUBMISSION
MANAGING REPONSES TO AGENCY QUESTIONS
Will require consolidated plan to managing response to questions
• Approval timelines can vary from 6 months to 3+ years
• Majority of review procedures do not have clock stops
• Questions can come at any time with some markets concentrating on CMC type
questions while other focus on clinical and safety
• Response times can also vary e.g. INVIMA (Chile) 5 days
• Extensive multiple rounds of questions e.g. TFDA (Taiwan)
Ensure that team have system for tracking questions and that there is
enough manpower to manage volume of questions
Also ensure the manufacturer(s) are on board to respond in a timely manner

LIFECYCLE MANAGEMENT
EM Product
Development
Strategy

POST APPROVAL - LIFE CYCLE MAINTENANCE
CMC
Variations
Tenders

LIFE CYCLE MAINTENANCE
It is also important to consider that the once your product is approved you will need
to maintain the licence.
Licence Renewals
• For majority of markets the licence has to be renewed every 5 years with the application for renewal submitted at
least 6 months before the licence expires
• Variations can not be submitted during the renewal in Russia
• Additional data will need to be generated e.g. Stability
• Requirements for local manufacturer to be established during the licence period e.g. Indonesia
Labelling and CMC Variations
• CMC changes in some markets have extensive review periods and restrictions on submission
o Brazil and South Africa review period for CMC variations is typically 2 years
o In Mexico can not submit variations while others are under review
o South Africa – can not submit new variation that affects the same CTD section of a previous variation under review
need to wait for approval
o Addition of new manufacturing sites can initiate inspections e.g. Brazil, Russia
Need to set out plan for variations and manufacturing changes so that your product remains in compliance
Introduction of Additional Strengths / New Presentations
• Additional presentations or strengths may be classed as new products with separate licences ( more licences to
manage, artwork updates etc.)
• New presentation may require BE data

CONCLUSION
EM Product
Development
Strategy

CONCLUSION
To build successful strategy for entry into Emerging Markets:
• Assess the commercial benefit of your product
• Emerging Market requirements are very diverse – need to have good knowledge
of the regulatory requirements and environment
• Involve your EM staff early on in the Development Plan to avoid lag behind your
EU and US submissions
• Your global clinical development plan should include markets that will need local
data to register to avoid delays in registration. Consider regional trials
• Plan your submission strategy – there may be many markets so you will need to
plan which markets to file in first
• Post Approval - ensure that you work with manufacturing and labelling team to
keep your licence compliant

BOSTON, MASSACHUSETTS
CASE STUDIES

• To submit Biosimilar MAA applications within a number of markets; including Russia,
Brazil and Mexico’
• Intelligence / gap phase identified that a few target countries were not feasible at this
time
• Client did not have affiliates / partners in all countries
• PAREXEL developed a submission plan for all countries
• PAREXEL managed CTD preparation of MAAs and successful submission in all
target countries
• PAREXEL developed a submission plan that prioritised the feasible markets
• PAREXEL assisted client with identifying local distributors/partners who could act as
local MAH
• Russia: PAREXEL supported in negotiations with Agency regarding new trial data
(during transition phase)
SITUATION AND CHALLENGE
CASE STUDY: MAAS IN EMERGING MARKETS
BENEFIT
SOLUTION

• Large pharmaceutical and device company who is in the process of reorganising and
realigning their emerging markets group
• All submissions and regulatory strategy need to be carried forward amid transitioning
staff
• Client has a number of products registered in a various Middle East and African
countries; there were a number of submissions to take over and two new products to
be filed in over 15 markets by the end of the year. Client did not have
affiliates/partners in all countries
• PAREXEL has ensured a smooth transition which has resulted in no impact to the on-
going submission
• Client is in position to submit in all targeted markets by the end of the year
• PAREXEL has partnered with the company offices in each of the markets, compiling
submission and tracking tables, validating country requirements, and pulling together
all documents required for submission
SITUATION AND CHALLENGE
CASE STUDY: EMERGING MARKET MAINTENANCE
SUPPORT
BENEFIT
SOLUTION

THANK YOU

Regulatory Strategy In Emerging Markets

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