Ppt 1 overview of regulatory affairs and diff bodies_august2016_final

Overview of Regulatory Affairs
and Worldwide Regulatory
bodies
Rajashri Survase-Ojha
(Founder & Director, Raaj GPRAC)
www.raajpharmaelearning.com
rajashrio@gmail.com
raajgprac@gmail.com

Disclaimer
 Contents of this presentation are the
presenters personal views and do not
necessarily represent any companies
policies and position.
 Some images are taken – freely available
from the internet for a diagrammatic
representation of the content and the
source is acknowledged.
2

What is RA?
 Regulatory Affairs (RA) is a profession within the health care industry
namely, Pharmaceutical, Medical Device, Biologics, & Functional Food.
 Regulatory Affairs is a profession which has developed from the desire of
governments to protect public health, by controlling the safety and efficacy
of products in areas including pharmaceuticals, veterinary medicines,
medical devices, pesticides, agrochemicals, cosmetics and complementary
medicines.
 RA profession at its heart is all about Collecting, Analyzing and
Communicating the Risks and Benefits of health care products to
regulatory agencies and public all over the world.
RA can be defined as :
 It means government affairs 3

Role of RA Professionals
 RA as profession is broader than registration of products, they advise companies
both strategically and technically at the highest level. Their role begins right from
development of a product to making, marketing and post marketing.
 They advice at all stages both in terms of legal and technical requirements and
restrains help companies save a lot of time and money in developing the product
and marketing the same.
 They have a major contribution in company’s success both commercially and
scientifically.
 Their main role is to comply with Safety & Efficacy of the products as per
regulation laid down by the government.
4

Role of RA Professionals cont..
 In an organization their prime responsibilities involves
preparation and presentation of registration documents to
regulatory agencies and carry out all following discussion
to obtain and maintain marketing authorization (MA) for
the products concerned.
 They need to keep a track on ever changing legislation in
all countries where the companies is looking to market
their product.
 They are responsible for the presentation of registration
documents to regulatory agencies in India and importing
countries and carry out all the subsequent negotiations
necessary to obtain and maintain marketing authorization
for the products concerned in country of origin as well as
importing countries
5
5

Why RA??
 The Pharmaceutical sector has been ever growing and with
globalization the race to lead to be first is no more restricted by
boundaries, companies need to dominate on a global level to
stay on top. As a result of this competitiveness companies
success lies in the “time taken” by the product to reach the
market.
 The companies responsible for the discovery, testing,
manufacture and marketing of these products also want to
ensure that they supply products that are safe and make a
worthwhile contribution to public health and welfare. Most
companies, whether they are major multinational
pharmaceutical corporations or small, innovative biotechnology
companies, have special departments of Regulatory Affairs
professionals
6

Why RA??
 On an average it takes 15-20 years for a
new drug development, and it cost around
$800-1000 million. With such an
expensive and time consuming activity
 Companies cannot afford a single day
delay in getting the product to the market.
RA Professional play the very important
role in getting the product to market,
improper data reporting can delay
evaluation of a positive marketing
authorization.
7

 FDA is the federal agency responsible for ensuring that foods are
safe, wholesome and sanitary; human and veterinary drugs,
biological products, and medical devices are safe and effective;
cosmetics are safe; and electronic products that emit radiation
are safe.
 FDA also ensures that these products are honestly, accurately
and informatively represented to the public.
• Biologics
 Cosmetics
 Drugs
 Foods
 Medical devices
 Radiation Emitting Electronic products
 Veterinary Products
What is FDA?
What does FDA regulate?

• Advertising
 The Federal Trade Commission is the federal agency which regulates all
advertising, excluding prescription drugs and medical devices. FTC ensures that
advertisements are truthful and not misleading for consumers.
• Alcohol
 The labeling and quality of alcoholic beverages are regulated by the Treasury
Department's Bureau of Alcohol, Tobacco, and Firearms (ATFs).
• Consumer Products
 While FDA regulates a large portion of the products that consumers purchase,
the agency has no jurisdiction over many household goods. The Consumer
Product Safety Commission (CPSC) is responsible for ensuring the safety of
consumer goods such as household appliances (excluding those that emit
radiation), paint, child-resistant packages, and baby toys.
• Drugs of Abuse
 Illegal drugs with no approved medical use--such as heroin and marijuana--are
under the jurisdiction of the Drug Enforcement Administration.
• Health Insurance
• FDA does not regulate health insurance, the cost of health care products or
procedures, or reimbursement for health and medical expenses. Questions about
Medicare should be directed to the Centers for Medicare and Medicaid Services.
What FDA does not regulate?

What FDA does not regulate?
Contd…
 Meat and Poultry
 The U.S. Department of Agriculture's Food Safety and Inspection Service is
responsible for the safety and labeling of traditional meats and poultry. (FDA
regulates game meats, such as venison, ostrich and snake.)
• Pesticides
 FDA, USDA, and the Environmental Protection Agency share the responsibility
for regulating pesticides. EPA determines the safety and effectiveness of the
chemicals and establishes tolerance levels for residues on feed crops, as well as
for raw and processed foods.
• Restaurants and Grocery Stores
 Inspections and licensing of restaurants and grocery stores are typically handled
by local county health departments.
• Water
 The regulation of water is divided between the Environmental Protection Agency
and FDA. EPA has the responsibility for developing national standards for
drinking water from municipal water supplies. FDA regulates the labeling and
safety of bottled water.

The US Regulatory Environment (1)
The US Food and Drug Administration (FDA)
 FDA’s Role and Responsibilities:
– FDA is regulating drugs, foods, cosmetics, biologics, medical
devices
– FDA is responsible for administration, enforcement,
interpretation of US drug law and has power to establish
regulations which have the force and effect of law
– FDA has developed policies, procedures and regulations to
implement its Reglatory initiatives, some going beyond the
intent of the original laws
Drug Registration in the US = one of the most
rigorous systems in the world

 Overview of FDA Organization – top level
 Office of the Commissioner (OC)
 Office of Regulatory Affairs (ORA)
 Centers for Product Jurisdiction
 CDER (Center for Drug Evaluation and Research)
 CBER (Center for Biologics Evaluation and Research)
 CDRH (Center for Devices and Radiological Health)
 CVM (Center for Veterinary Medicine)
 CFSAN (Center for Food Safety and Applied Nutrition)
 NCTR (National Center for Toxicological Research)
The US Regulatory Environment (2)

EU Regulatory
Environment [EMA]

Evolution of the European Regulatory Environment
since 1995…
1995 2000 2003 2004 2005 2006 2007
EMEA
Centralised
Procedure
Mutual
Recognitio
n
Procedure
Orphan
Drugs
Regulation
Annex I
(to Directive
2001/83/EC)
(CTD)
New
Legisl.
Title IV of
Reg.
726/04
immediate
New
Legisl.
fully into
force
Paediatric
Regulatio
n
Legisl.
on
Advance
d
Therapy
Enlargeme
nt
(to 15 MS)
Enlargemen
t to 25 MS
(CY, CZ, EE,
HU, LT, LV,
MT, PL, SI,
SK)
Enlargemen
t to 27 MS
(BG & RO)
Birth of theBirth of the
EMEAEMEA
2008
Enlarged
Scope
of CP
2010
New
Variation
Regulation
New
Pharmacov
igilance
legislation
Future…
Accession of
Croatia
2012
Implem.
of New
PV
Legisl.
PRAC
(July
2012)

 Austria (1995)
 Belgium (1952)
 Bulgaria (2007)
 Cyprus (2004)
 Czech Republic (2004)
 Denmark (1973)
 Estonia (2004)
 Finland (1995)
 France (1952)
 Germany (1952)
 Greece (1981)
 Hungary (2004)
 Ireland (1973)
 Croatia (2013)
 Italy (1952)
 Latvia (2004)
 Lithuania (2004)
 Luxembourg (1952)
 Malta (2004)
 Netherlands (1952)
 Poland (2004)
 Portugal (1986)
 Romania (2007)
 Slovakia (2004)
 Slovenia (2004)
 Spain (1986)
 Sweden (1995)
 United Kingdom (1973)
20
Member states of the European Union
08/25/16

COMP
Committee
on Orphan
Medicinal
Products
COMP
Committee
on Orphan
Medicinal
Products
CHMP
Committee for
Medicinal
Products for
Human Use
CHMP
Committee for
Medicinal
Products for
Human Use
HMPC
Committee
on Herbal
Medicinal
Products
HMPC
Committee
on Herbal
Medicinal
Products
NATIONAL COMPETENT AUTHORITIES ( > 3 500 EUROPEAN EXPERTS )
Structure of the European Medicines Agency
(EMA)
PRAC
Pharmacovig.
and Risk
Assessment
Committee
PRAC
Pharmacovig.
and Risk
Assessment
Committee
CVMP
Committee for
Medicinal
Products for
veterinary use
CVMP
Committee for
Medicinal
Products for
veterinary use
xpertsappointedbyNCA
EXECUTIVE
DIRECTOR
Guido Rasi
COMMUNICATIONS
AND NETWORKING
ADMINISTRATIONVETERINARY
MEDICINES
AND
INSPECTIONS
VETERINARY
MEDICINES
AND
INSPECTIONS
PATIENT HEALTH
PROTECTION
PATIENT HEALTH
PROTECTION
HUMAN
MEDICINES
DEVELOPMENT
AND EVALUATION
HUMAN
MEDICINES
DEVELOPMENT
AND EVALUATION
EMAPermanentStaff
PDCO
Paediatric
Committee
PDCO
Paediatric
Committee
CAT
Committee
for
Advanced
Therapies
CAT
Committee
for
Advanced
Therapies

• 27 MSs + NO/IS (EEA Countries) - 22 Languages (Working Language EN)
• 1 scientific expert member nominated by each MS and 1 alternate
• 1 scientific expert member from NO and IS and 1 alternate (observers)
• 5 co-opted members as appointed by Management Board
• 3 years Mandate renewable
Composition
Chairman (Dr. T. Salmonson; SE)
&
Vice-Chairman (Dr. I. Hudson; UK)
CHMP (Committee for Human Medicinal Products)

 Delivering opinions to the European Commission
 on new medicinal products/variation/renewal/line extension
 on arbitration/referral procedures
• Advising on general EU guidelines/policies
• Scientific Advice & guidelines to companies
• Opinions on Compassionate Use to MSs
• Contribution to ICH process
• Establish Working Parties, SAGs & Expert Groups
• Delivering opinions to WHO
CHMP main tasks & responsibilities

Working Party Constellation
CHMP
QWP*
SWP*
BWP*Sci Adv
PhVig*
Patients &
Consumers
Biosimilars tWP
Biostatistics tWP
Blood Prod. tWP
Cardiovascular
tWP
CNS tWP
Rheumatology
Immunology
tWP
Infectious
Diseases tWP
Oncology tWP
Pharmacokinetics
tWP
Pharmacogenomic
s tWP
Vaccines
tWP
Gastroenterology DG
Respiratory DG
Urology DG
Radiopharmaceuticals DG
QSE
standards
Evaluation of
Medicines
* 1 / MS representation
SAG
diagnostics
SAG
CVS
SAG
Neurology
SAG
Psychiatry
SAG
Diabetes
SAG
HIV / Antiviral
SAG
Anti-Infectives
SAG
Oncology
DG = drafting
groups
tWP = temporary
working party
SAG
Vaccines

CompositionComposition
Chair and Vice Chair
+
1 member/MS
+
3 reps patient organizations
+
3 EMA reps
+ 3 patient organisations
+ 3 EMA
COMP (Committee for Orphan Medicinal
Products)
Dr. Westermark

26
Composition:
Chair and Vice Chair
+
5 CHMP members
+
1 member/MS
(not yet represented by member appointed
by CHMP)
+
3 reps patient organizations
+
3 reps healthcare
professionals
+ 3 patient organisations
+ 3 healthcare
prof.
Dr. D. Brasseur
PDCO (Paediatric Committee)

27
Registration in Europe Post Nov 2005 :
 Three European Systems
Centralised
Procedure
(via EMA)
Mutual
Recognition
procedure
Decentralised
Procedure

EU Centralised Procedure
 Legal Basis: Regul. (EC) No 726/2004 (also establishing “EMA” European Medicines
Agency)
 Principle: single application / evaluation  single authorisation
 direct access to all EU(27MSs) + Norway, Iceland and Liechtenstein
 Scope:
 Compulsory for:
 Biotech (recombinant DNA, gene expressed proteins, hybridoma &
monoclonal antibodies)
 New Active Substances in Specific Therapy Areas: AIDS, Cancer,
Neuro-degenerative disorder, Diabetes, Auto-immune disease, other
immune deficiencies, Viral diseases
 Orphan Drugs
 Optional for:
 Any Other New Active Substance
 significant innovation (therapeutic, scientific or technical)
 in the interests of patients at community level
 Generic of Centralised reference prod. (may use CP or MRP/DCP)

Project management and
co-ordination
Industry
•Rapporteur/Co-rapporteur
•Scientific evaluation - experts
•Opinion and assessment report
•Working parties
EMA
CHMP
EU
Commissio
nDriving & adoption
of the decision
(EU license)
Members
states1 per MS + 5 Co-opted
members. Each MS has an
Alternative.
Applicant
MAH

Procedures for evaluating medicinal products and
granting marketing authorization
 The European system for the authorisation of
medicinal products for human and animal use was
introduced in January 1995 with the objective of
ensuring that safe, effective and high quality
medicines could quickly be made available to citizens
across the European Union.
 The European system offers several routes for the
authorisation of medicinal products:
30
'©"RaajGPRAC,Mumbai2010-2016.Allrightsreserved.''

Centralised procedure
 The centralised procedure, which is compulsory for products
derived from biotechnology, for orphan medicinal products
and for medicinal products for human use which contain an
active substance authorised in the Community after 20 May
2004 (date of entry into force of Regulation (EC) No 726/2004)
and which are intended for the treatment of AIDS, cancer,
neurodegenerative disorders or diabetes. The centralised
procedure is also mandatory for veterinary medicinal products
intended primarily for use as performance enhancers in order
to promote growth or to increase yields from treated animals.
Applications for the centralised procedure are made directly
to the European Medicines Agency (EMA) and lead to the
granting of a European marketing authorisation by the
Commission which is binding in all Member States.
31

MRP & DCP
 The mutual recognition procedure, which is applicable to the
majority of conventional medicinal products, is based on the
principle of recognition of an already existing national
marketing authorisation by one or more Member States.
 The decentralised procedure, which was introduced with the
legislative review of 2004, is also applicable to the majority of
conventional medicinal products. Through this procedure an
application for the marketing authorisation of a medicinal
product is submitted simultaneously in several Member
States, one of them being chosen as the "Reference Member
State". At the end of the procedure national marketing
authorisations are granted in the reference and in the
concerned Member States. 32

The 3 steps of the Centralised Procedure
Step I
Pre-submission to application
• Early advice
• Rapporteur/C-rapporteur appoinmt
• Assessment team
• Application
• Validation
Step II
Scientific evaluation
• Assessment Reports
• List of Questions (+ clock stop)
• CHMP Opinion
• Possibility to appeal
• Transfer to EU Commission
Step III
Decision Making Process
-120 days
210 days
67 days
Notify the EMA
Request Rapporteur/co-Rapporteur
Submit the MAA
CHMP Opinion
Draft EC Decision
EC Decision
Community Licence
favourable
Answer to questions
Oral hearing
Clock stop for
answer to questions

Two options
Mutual Recognition Procedure
 Art. 28 para. 2 of Dir. 2001/83/EC
 For products with an existing MA
Decentralised Procedure
 Art. 28 para. 3 of Dir. 2001/83/EC
 Only possible, if no authorisation has already been
granted
 Most significant difference with MRP = consultation
between MS‘s before 1st MA issued
&:

MRP & DCP: key authority stakeholders
 CMDh ("Coordination group for mutual recognition and decentralised procedure for
human medicinal products"):
 Mixed responsibilities: procedural, regulatory and scientific
 One representative from each MS, appointed for 3 years (renewable)
+ observer from EMA and Commission
 CMD(h) Chair appointed for 3 years
+ Vice-chair representative of MS that has presidency of Council
 RMS ("Reference Member State")
 Selected by the applicant
 Has to prepare the assessment report (AR)
 Acts as central point between MS and MAH
 CMS ("Concerned Member State(s)")
 All other MS‘s where the Company has submitted the dossier

Overview of the MRP
Application to Reference Member State (RMS)
RMS Approval (Day 210)
Submit MR application to Member States
National
Submission
210 days
Mutual
Recognition
90 days
Closure of procedure
(AR, SPC, labelling, PIL)
Arbitration by CHMP (Art.32, 33, 34)
60 days (CHMP opinion) + 30 days (Commission decision)
National
licences
granted within
MSs
Approval
Arbitration
By CMDh
(60 days)
CMDh
National Step
(30 days)
Serious objections
Referral to CMDh
ApprovalSerious objections
Referral to CHMP

Overview of the DCP
Submission of dossier to Reference Member State (RMS)
and Concerned Member States (CMSs)
RMS starts evaluation, and issues preliminary
Assessment Report (AR) for comments by CMSs
RMS sends consolidated list of questions to Applicant
RMS prepares draft AR, draft SPC and
draft labelling/package leaflet
Submit MR application to Member
States
Closure of procedure
(AR, SPC, labelling, PIL)
Arbitration by CHMP (Art.32, 33, 34)
60 days (CHMP opinion) + 30 days (Commission decision)
National
licences
granted within
MSs
Approval
DCP Step1
120 days
DCP Step 2
90 days
Arbitration
By CMDh
(60 days)
CMDh
Clock stop
National Step
(30 days)
Serious objections
Referral to CMDh
ApprovalSerious objections
Referral to CHMP
(recommended 3 mths)

The “Pharmacovigilance and Risk Assessment
Committee” (PRAC)
 Replacing Pharmacovigilance Working Party (PhV WP)
 Mandate: Risk detection, Benefit-Risk Assessment, Communication of risk and
benefit/risk, Risk Minimisation and Analysis Impact, Design and Evaluation of PASS
 CHMP & CMDh to “rely upon” recommendations from PRAC but retain responsibility
for benefit-risk assessments
 PRAC started in July 2012
 Membership:
 1 member (& 1 alternate) from each MS
 Chair: June M. Raine (UK – MHRA)
 Vice-Chair: Almath Spooner (Ireland – IMB)
 Interaction between PRAC & CHMP:
 About 30% of CHMP agenda would go to PRAC
 Aiming that PRAC Rapporteur could come from same MS as CHMP Rapporteur
 Chalenge with timing of PRAC opinions: i.e. trying to fit the PRAC 60 day review
timeframe into overall timelines and still allow CHMP time to consider PRAC
input before adopting their opinion

New requirements for the Marketing Authorisation
Application (MAA)
 Pharmacovigilance System Master File (PSMF)
 MAH must prepare and maintain “Pharmacovigilance system master
file” (PSMF): replaces former “Detailed Description of Pharmacovigilance
System” (DDPS), and must be held at MAH site
 Summary of the Pharmacovigilance System must be included in the MAA
dossier
 Full PSMF to be provided within 7 days of request from a competent
authority
 Risk Management Plan (RMP)
 ‘detailed description of risk management system’
 RMPs to be included in MAAs for all new products
 N.B. Authorities can impose need for Risk Management System on already
authorised products if concerns about Benefit/Risk balance
 Format and content of RMPs addressed in Commission’s implementing
measures

Overview of the Regulation-EU
EU Regulatory system
Assessment on MAA
(Agencies-EMEA)
[www.eudra.org/emea]
EDQM/Ph.Eur
(Council of Europe)
[www.pheur.org]
Volume 1: Pharmaceutical Legislation for Medicinal
Products for Human use
Volume 2: Notice to Applicants for MP for Human use
2A Procedures for marketing Authorization
2B Presentation and format of the dossier(CTD)
Volume 3: Guidelines
3A Quality and Biotechnology
3B Safety, environment and information
3C Efficacy
Volume 4: Good Manufacturing Practices
Volume 5: Pharmaceutical Legislation for Medicinal
Products for Veterinary use
Volume 6: Notice to Applicants for MP for Veterinary
use
Volume 7: Scientific guidelines for MP for Veterinary
use
Volume 8: Maximum residue limits
Volume 9: Guidelines for PV for MP for Human and
Veterinary use
Volume 10: Guidelines for Clinical Trial
Laws, Directives, regulations (EU institutions)
[http://pharmacos.eudra.org]
Relevant EU legislation/ Guidelines

Maintenance of Marketing Authorizations
(Variations, Renewals)
 EU Variations
 Commission Guideline on Dossier Requirements for Type IA & IB
Notifications, July 2006
 Categories of Variations
Minor Changes
Type IAIN variation and Type IA
Type IB variation (Notify, wait for 30 days )
Type II variation (Needs prior approval, 60
days evaluation time period)
Major Changes
Differences between the categories
• Approval time
• Documentation to be submitted
• Money(Fees)

 The Medicines Control Council (MCC) is a statutory
body that was established in terms of the Medicines
and Related Substances Control Act, 101 of 1965, to
oversee the regulation of medicines in South Africa.
 It is appointed by the Minister of Health and its main
purpose is to safeguard and protect the public
through ensuring that all medicines that are sold and
used in South Africa are safe, therapeutically
effective and consistently meet acceptable standards
of quality.

South Africa : MEDICINES CONTROL
COUNCIL(MCC)

 MCC Structure
A F R IC A N T R A D I T IO N A L M E D I C I N E S C O M M IT T E E
C h a i r p e r s o n
V i c e - C h a i r p e r s o n
C O M P L E M E N T A R Y M E D I C I N E S C O M M I T T E E
V E T E R I N A R Y C L I N I C A L C O M M I T T E E
A N A L Y T I C A L C O M M I T T E E
B I O L O G IC A L C O M M IT T E E
C L I N I C A L C O M M I T T E E
C L I N I C A L T R I A L S C O M M I T T E E
P H A R M A C E U T I C A L / B I O A V A I L A B IL I T Y C O M M I T T E E
P H A R M A C O V I G I L A N C E C O M M I T T E
S C H E D U L IN G C O M M I T T E E
M E D I C I N E S C O N T R O L C O U N C IL
South Africa : MEDICINES CONTROL
COUNCIL(MCC)

UK-MHRA: Medicines and Healthcare
products Regulatory Agency
The MHRA regulates a wide range of materials like;
 Medicines
 Devices
 Tissue Engineering
 Nanotechnology
 Blood
The term “medicines” embraces both pharmaceutical and
biological medicines, and vaccines.
The term “medical devices” includes medical equipment.
 Medical devices are all products, except medicines, used in
healthcare for the diagnosis, prevention, monitoring or
treatment of illness or disability. Examples include X-ray and
other imaging equipment, pacemakers, artificial joints,
anaesthetic equipment, pregnancy test kits, infusion
equipment, beds, wheelchairs, condoms and surgical dressings.

WHO: World Health Organization
 WHO is the directing and coordinating authority for health
within the United Nations system.
 It is responsible for providing leadership on global health
matters, shaping the health research agenda, setting norms and
standards, articulating evidence-based policy options, providing
technical support to countries and monitoring and assessing
health trends.
 WHO is Geneva based.
 Many countries follow the guidelines provided by WHO.
 Food and Drugs Control Authority India follows WHO guidelines.
 WHO GMP certification is a requirement and well accepted in
most of the countries across Asia, Africa, CIS and Latin America.

How does WHO work and for whom?
WHO’s main functions:
- To act as the directing and
coordinating authority on international
health work
- To encourage technical cooperation for
health with Member States
- Has constitutional mandate to develop
norms and standards

Countries
 All countries which are Members of the United Nations may
become members of WHO by accepting its Constitution. Other
countries may be admitted as members when their application
has been approved by a simple majority vote of the World
Health Assembly.
 Territories which are not responsible for the conduct of their
international relations may be admitted as Associate Members
upon application made on their behalf by the Member or other
authority responsible for their international relations. Members
of WHO are grouped according to regional distribution (193
Member States).
WHO: World Health Organization

Japanese Regulatory
Environment

Japanese law and relevant authorities
for medicines registration
 Pharmaceutical Affairs Law (PAL) – April 2005
 MHLW (Ministry of Health, Labour and Welfare)
– Responsibility for approvals and licensing
– http://www.mhlw.go.jp/english/index.html
 PMDA (Pharmaceuticals and Medical Devices
Agency)
– Responsibility for scientific review (incl. audit for GMP, GLP,
GCP)
– Branch under MHLW, created in 2004
– http://www.pmda.go.jp/english/index.html
 NIID (National Institute of Infectious Diseases)
– Responsibility for national testing
– http://www.nih.go.jp/niid/index-e.html

Relationship between MHLW and PMDA
Applicant MHLW Advisory
Committee
Consultation
AdviceApproval
Pharmaceuticals and Medical
Devices Agency (PMDA)
Consultation and Review
(Single Review Team) External Experts
Compliance
Review etc
Questions
and
Responses
Consultation
and NDA
Review
Report
Instruction
Expert
Discussion

INTERNATIONAL
REGULATORY
ENVIRONMENT

Scope
192 countries
23 time zones
Between 4000 and 6000 languages
More than 150 monetary currencies
More than 70% of the world’s
population are:
Asia Pacific and Emerging Markets
(APEM )

International & Emerging Regions
 Asia Pacific:
 India, Philippines, South Korea, Taiwan
 China / Hong Kong / Macau:
 China
 Latin America :
 Argentina, Brazil, Chile, Mexico
 Middle East and North Africa (MENA):
 Egypt, Pakistan, Saudi Arabia, Turkey
 Sub Saharan Africa (SSA):
 South Africa
 Eastern Europe:
Key markets

Models for drug regulatory assessment
Countries can be categorised in 2 licensing models:
 model of licensing system based upon submission of evidence of
registration in reference countries
 model of licensing system based upon a full assessment of new drug
applications (including biological products)

RoW = Rest of the World
 What are the RoW countries?
 World regions excluding US, CA, EU, CH, Au,
and Nz.
 What are the regions and sub-regions?
 AMEA – Asia Middle East and English-speaking
Africa
 LATAM – Latin America
 RIC+ - Russia & Former Soviet States, Greater
China, Greater India, Israel, French-speaking
Africa, South-east Europe

Regions and Sub-regions
- definitions
 AMEA
 ASIA
 ASEAN (Association of South East Asian Nations)
 Korea, Australasia (AUS, NZ), Japan
 MIDDLE EAST
 Arabian Peninsula (Saudi Arabia)
 Gulf (Bahrain, Kuwait, Qatar, UAE, Oman, Yemen)
 Near East (Egypt, Jordan, Lebanon, Syria, Irak, Iran,
Afghanistan, Pakistan)
 AFRICA
 English-speaking Africa

Region ASEA – definition
 ASEAN (Association of South East Asian Nations)
 Singapore, Malaysia, Thailand, Philippines, Indonesia, Laos, Cambodia,
Vietnam , Brunei Darussalam, Myanmar

 ASEAN
 Association of Southeast Asian Nations
 10 member states : Indonesia, Malaysia, Philippines,
Singapore, Thailand, Brunei, Vietnam, Laos, Myanmar,
Cambodia
 Population of about 560 million, a total area of 4.5
million square kilometers, a combined GDP of US$ 1,100
billion, and a total trade of about US$ 1,400 billion
 Objectives : To accelerate economic growth, social
progress and cultural development in the region and to
promote regional peace and stability

ASEAN: 2 main areas of
Harmonisation
 ACTD (ASEAN Common Technical
Dossier) : > Harmonize format
 ACTR (ASEAN Common Technical
Requirement) :> Harmonize technical
content
Developed based on international guidelines such
as ICH, EMEA, FDA, WHO

ASEAN: Organization of Application Dossier
(ACTD)
* Upon RequestPart I
Administrative Data &
Product Information
Part II
Quality
Overall Summary
& Reports
Part III
Non-clinical
Overview,
Summary
& Study Reports*
Part IV
Clinical
Overview,
Summary
& Study Reports*

Region AMEA – definition
 ENGLISH-SPEAKING AFRICA
 Angola, Ethiopia, Ghana, Kenya, Malawi, Mozambique, Namibia,
Nigeria, Sierra Leone, Somalia, South Africa,Tanzania, Uganda,
Zambia, Zimbabwe

Region RIC+
 RIC+
 RUSSIA AND FORMER SOVIET UNION COUNTRIES
 Russia
 Ukraine
 OFSUs (Armenia, Azerbaijan, Belarus, Georgia,
Kazakhstan, Kirghistan, Moldova, Tajikistan,
Turkmenistan, Uzbekistan)
 GREATER INDIA (India, Sri Lanka, Bangladesh)
 GREATER CHINA (China, Hong Kong, Taiwan)
 ISRAEL
 FRENCH-SPEAKING AFRICA
 SOUTH-EAST EUROPE (Albania, Bosnia-Herzegovina,
Kosovo, Macedonia, Montenegro, Serbia, Srpska)

Region RIC+
1. Armenia 2. Azerbaijan 3. Belarus 5. Georgia 6. Kazakhstan 7.
Kirghistan 10. Moldova 11. Russia 12. Tajikistan 13. Turkmenistan 14.
Ukraine 15. Uzbekistan
 RUSSIA AND FSU COUNTRIES

Region RIC+
 FRENCH-SPEAKING AFRICA
Algeria, Benin, Burkina Faso, Cameroon, Chad, Congo Brazzaville,
Congo Kinshasa, Ethiopia, Gabon, Guinea, Ivory Coast, Madagascar,
Mali, Mauretania, Mauritius, Morocco, Rep. Central Africa, Senegal,
Togo, Tunisia (Arabic-speaking Africa : Libya, Sudan )

General Overview of specific
regional requirements
 Regions, but all are national registrations
 Enormous diversity of regulatory requirements
 However, some harmonisation on some clusters e.g. ASEAN,
Gulf
 Currently, the registration documentation can be either
 EU-based files, complemented with additional HA’s
requirements, OR
 CTD files specifically prepared for geographical expansion
in AMEA, LATAM, RIC+
 CTD format is not accepted in all RoW countries but dossier
must be submitted as per respective HA guidelines.

General Overview of specific
regional requirements
 When a standard file is sent to RoW countries for submission,
Regulatory dept. often receives a list of additional documents
needed before the file can be submitted to the HA. Collecting
these documents can take weeks/months and further delay
the submission.
 Many countries insist on additional specific documentation for
product registration, variations, site changes, etc.
 Mostly, the additional requirements are of a CMC nature,
although there are requests for extra certificates, statements,
CPPs, etc

GCC-Middle East Countries
Armenia Israel Syria
Azerbaijan Jordan Turkey
Bahrain Kuwait Turkmenistan
Egypt Lebanon United Arab Emirates
Georgia Oman Yemen
Iran Qatar
Iraq Saudi Arabia

 Middle East 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.)
Background:

69
REGULATORY
SUBMISSIONS IN INDIA

Local (Domestic market)
 Registration of products in our own
country India for selling to Local market
 Regulatory Authority :Food and Drug
Administration (FDA)
 Reference : Drugs and cosmetic Act 1940,
Rules 1945
70

Regulatory Bodies Governing & Controlling Clinical
Trials
Regulatory
Body
Ministry Location
Drugs
Controller
General
(India)
(DCGI),
Directorate
General of
Health
Services
(DGHS)
Ministry
of
Health
and
Family
Welfare
Central
Body
(Delhi)

Local (Domestic market) New
Molecule
 Registration of new products in our own
country -India for selling to Local market
 Regulatory Authority :Drug Control General
(DCGI),Delhi
 Reference : Drugs and cosmetic Act 1940.
Rules 1945.
72

Global Harmonisation
Initiatives

What is ICH?
“International Council on Harmonization of
Technical Requirements for Registration of
Pharmaceuticals for Human Use”.
ICH is a joint initiative involving both regulators and
research-based industry representatives of the
EU, Japan and the US in scientific and technical
discussions of the testing procedures required to
assess and ensure the safety, quality and efficacy
of medicines.

ICH Structure / Organisation
 6 official parties (co-sponsors) directly involved :
Authorities and research based industry from
 EU:- European Commission + EMA and CHMP
- EFPIA (Eur.Feder.Pharmac.Industries&Associations)
 Japan:- MHLW (Ministry of Health and Welfare)
- JPMA (Japanese Pharmaceutical Manuf. Association)
 USA:- FDA (US Food and Drug Administration)
- PhRMA (Pharmaceut. Research and Manuf. of America)
 Official "Observers"
 World Health Organisation (WHO)
 European Free Trade Area (EFTA)
 Canada (Health Protection Branch)
 "Interested Parties" also involved
 Pharmacopoeias (Eur.Ph., J.P., U.S.P.)
 other industry sectors (OTC and Generics)

What is the purpose of ICH?
 The objective of ICH is to increase
international harmonization of technical
requirements to ensure that safe, effective,
and high quality medicines are developed
and registered in the most efficient and cost
effective manner.

ICH Guidelines
The ICH Topics are divided into four major categories and
ICH Topic Codes are assigned according to these categories.
Q S E M
"Quality" Topics,
i.e., those relating
to chemical and
pharmaceutical
Quality
Assurance
(Stability Testing,
Impurity Testing,
etc.)
"Safety" Topics,
i.e., those relating
to in vitro and in
vivo pre-clinical
studies
(Carcinogenicity
Testing,
Genotoxicity
Testing, etc.)
"Efficacy"
Topics, i.e.,
those relating to
clinical studies in
human subject
(Dose Response
Studies, Good
Clinical Practices,
etc.)
"Multidisciplinar
y" Topics, i.e.,
cross-cutting
Topics which do
not fit uniquely
into one of the
above categories
(MedDRA,
ESTRI, M3, CTD,
M5)

 Stability - Q1A – Q1F
 Analytical Validation – Q2
 Impurities – Q3A - Q3C (Q3D – concept paper)
 Pharmacopoeias – Q4A - Q4B (and annexes)
 Quality of Biotechnological Products – Q5A – Q5E
 Specifications – Q6A – Q6B
 Good Manufacturing Practice – Q7
 Pharmaceutical Development – Q8
 Quality Risk Management - Q9
 Pharmaceutical Quality System – Q10
 Development and Manufacturing of Drug Substances – Q11
"Quality" Topics

Efficacy Topics
E1: The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-
Term Treatment of Non-Life-Threatening Conditions
E2A: Clinical Safety Data Management : Definitions and Standards for Expedited ReportingE3:
Structure and Content of Clinical Study Reports
E3: Structure and Content of Clinical Study Reports
E4: Dose-Response Information to Support Drug Registration
E5(R1): Ethnic Factors in the Acceptability of Foreign Clinical Data
E6: Good Clinical Practice : Consolidated Guideline
E7: Studies in Support of Special Populations : Geriatrics
E8: General Considerations for Clinical Trials
E9: Statistical Principles for Clinical Trials
E10: Choice of Control Group and Related Issues in Clinical Trials
E11: Clinical Investigation of Medicinal Products in the Pediatric Population
E12: Principles for Clinical Evaluation of New Antihypertensive Drugs
E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for
Non-Antiarrhythmic Drugs
E15: Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic
Data and Sample Coding Categories
E16: Genomic Biomarkers Related to Drug Response: Context, Structure and Format of
Qualification Submissions

Multidisciplinary Guidelines
 M1 MedDRA
Medical Terminology
 M2 ESTRI
Electronic Standards for the Transfer of Regulatory Information
 M3M3(R2)
Nonclinical Safety Studies for the Conduct of Human Clinical Trials
and Marketing Authorization for Pharmaceuticals
 M4CTD
The Common Technical Document
 M5M5
Data Elements and Standards for Drug Dictionaries

ICH Now and in the Future
 New areas to develop ICH guidelines:
 Post-marketing pharmacovigilance
 Pharmacogenomics
 Biomarkers
 Gene Therapy
 Continued Harmonisation: prevention of new
interregional disharmony
 Avoid unilateral development of requirements in specific areas

…Globalising ICH
 ICH Global Cooperation Group (GCG)
 Representatives from other Regional Harmonisation initiatives
 APEC (Asia-Pacific Economic Cooperation)
 ASEAN (Association of the Southeast Asian Nations)
 GCC (Gulf Cooperation Council)
 PANDRH (Pan American Network for Drug Regulatory Harmonization)
 SADC (Southern African Development Community)
 Evolution in ICH and understanding that some non-ICH countries are
now major contributors/consumers to the global pharmaceutical market
 Regulators Forum - started in 2008
 Including representatives from Australia, Brazil, China, Taiwan,
India, Russia, Singapore and South Korea most of which are not
part of Harmonisation Initiatives already
 Key areas of focus: API GMP; clinical trials; pharmacovigilance

 USA : UNITED STATES FOOD AND DRUG ADMINISTRATION
 http://www.fda.gov/
 Europe : THE EUROPEAN AGENCY FOR THE EVALUATION OF
THE MEDICINAL PRODUCTS (EMEA)
 http://www.emea.europa.eu/
 Health Canada:
 http://www.hc-sc.gc.ca/dhp-mps/index-eng.php
 South Africa : MEDICINES CONTROL COUNCIL (MCC)
 http://www.mccza.com/
 United Kingdom : MEDICINES AND HEALTHCARE PRODUCTS
REGULATORY AGENCY (MHRA)
 http://www.mhra.gov.uk/

Various links

 New Zealand : NEW ZEALAND MEDICINES AND
MEDICAL DEVICES SAFETY AUTHORITY (MEDSAFE)
 http://www.medsafe.govt.nz/
 Australia : THERAPEUTIC GOODS ADMINISTRATION
(TGA)
 http://www.tga.gov.au/
 Brazil: ANVISA
http://www.anvisa.gov.br/eng/legis/index.htm#6
Various links

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