Transcript Drug Regulatory Overview Milan Smid, MD, PhD Technical Officer Quality Assurance and Safety: Medicines Essential Medicines and Pharmaceutical Policies, World Health Organization [email protected].

Drug Regulatory Overview
Milan Smid, MD, PhD
Technical Officer
Quality Assurance and Safety: Medicines
Essential Medicines and Pharmaceutical
Policies,
World Health Organization
[email protected]
 Principles of drug regulation
 WHO regulatory support activities
– Harmonization and worksharing
– Assessment of regulatory functions
– Trainings
 Discussion
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Major health technologies
Medicines
and
vaccines
Blood components
Transplants
Herbal and
traditional
medicines
Functional food
Nutraceuticals
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Medical devices
including
diagnostics
Advanced
therapies
Common features of health technologies
 Used to prevent, diagnose or treat disease
 Benefits from use must overweight the risks in
order to improve health
 To evaluate risk-benefit is frequently highly
scientifically demanding
 Not all health technologies bear comparable risks
 Health technologies are subject of commerce and
profit oriented behaviour
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Protection of public health
 To achieve acceptable level of risk related to use of health
technologies and maximize their benefit, governments have to
intervene
 Governmental interventions interfere with rights of persons and
companies and with business practices
 Regulatory systems and scope of regulation differ worldwide
 Health products are split into different categories
 Regulation of medicines is currently one of most sophisticated
and complicated regulatory functions globally
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Medicines regulation
 Medicines regulation is the totality of all
measures - legal, administrative and technical which governments take to ensure the safety,
efficacy and quality of medicines, as well as the
relevance and accuracy of product information
 Medicines are special goods for which also prices
are frequently regulated by governments to
achieve affordability for patients
 Medicines are needed and different government
incentives are used to develop and produce them
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Medicines regulation
Models for regulation of medicines are determined by:
 Public health needs
 Organization of the state and state administration
 Size of the pharmaceutical market
 Presence and type of pharmaceutical industry
 Availability of resources (human, scientific, financial)
 Maturity of stakeholders
 Participation in regulatory networks
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Rationale for Government role
Consequences of weak drug regulatory capacity
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substandard, counterfeit, harmful, useless
medicines on the market
biased information about medicines circulates
substandard practices in clinical testing,
manufacture and supply of medicines
irrational prescription and consumption
Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Rationale for Government role
Consequences of over- or improper regulation
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lack of needed medicines or delayed access
increased costs of medicines due to cost of
regulatory system
lack of regulatory flexibility
Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Regulatory basics
Regulation should
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Keep patient in its centre
Be evidence based
Be risk oriented
Bring added value
Respect interests of stakeholders and real
possibilities
Be transparent but respect confidentiality
Be effective and flexible
Be part of broader drug policy
Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Parties involved in regulatory system
 Regulated subjects
–
–
–
–
Investigators and sponsors, members of ethics commitees
Manufacturers and importers
Wholesalers and distributors
Health professionals
 Regulators
– Regulatory authorities
– Governments and political representations
 Interested parties
– General public and patients groups
– Academia
– Media
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Development of drug regulation
 Quality
 Safety
 Efficacy
 Information
 Environment
 Risk management and risk minimization
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Essential regulatory activities
 R&D – data quality and ethics (GLP, GCP, bioethics)
 Manufacture, import and supply – quality (GMP, GDP)
 Market entry and existence on the market – Q, S, E, I, Env
authorization/registration, maintenance, renewals
 Special access schemes
 Dispensation – safe and indicated use (GPhP)
 Use – pharmacovigilance (GPhVP)
 Promotion – unbiased, valid and understandable information
(Conduct codes)
 Environment – premarket review and environment monitoring
 Regulatory and scientific advice
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Regulatory toolkit
 Legislation
 Standards (GXPs, Pharmacopoeias, Q,S,E guidelines)
 Data assessment
– Submitted data
– Collected data
 Inspections
 Licensing (authorizations / registrations, products and
operations)
 Certification
 Laboratory control
 Provision of information
 Regulatory intelligence and co-operation
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Incentives to develop, manufacture and
supply needy medicines
 Patents and supplementary patent protection
 Data exclusivities
 Market exclusivities
 Limited data requirements
 Regulatory advice
 Regulatory fast tracks
 Waivers of regulatory fees
 Public-private partnership, stimulating price, guaranteed
demand
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Regulatory environment
Courts
Legislation
Guidelines
Appeal bodies
Regulated subjects
Regulatory authorities
Interested stakeholders
(associations, professional bodies,
NGOs, watch dogs)
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Responsibilities of parties involved in
regulatory system
Legislated
 Investigators and sponsors
 Manufacturers and importers
 Wholesalers and distributors
 Health professionals
 Regulatory authorities
Non-legislated
 Governments and political representations
 Patients
 Media
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Registration
Line
extensions
PSUR
Variations
Renewals
PSUR
Drug
Regulatory
Cycle
PSUR
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Postregistration
commitments
Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
PSUR
PSUR
PSUR
Emergency
and crisis
management
Principles applied in regulatory approvals
 Benefits prevail the risks at a time of regulatory
approval and nothing indicates that benefits will not
prevail also during use of product in normal medical
practice
– Available data about quality (Dossier)
– Available data about efficacy and safety or interchangeability (Dossier)
– Available data are credible and were eticaly obtained
• Good practices (GLP, GCP, GPhVP, …)
– Existing reassurance about production in stable quality and quality
assurance mechanisms
• GMP
– Way of use of medicine characterized for physicians and patients
• Data sheets, SPCs, PILs, package labeling
– Lack of knowledge is properly managed
• Pharmacovigilance, risk management programmes, commitments
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Regulation of innovatory products and generics
 For innovator products proof of QUALITY,
SAFETY and EFFICACY is needed. Newly also
plan of prospective risk-management.
 For multisource products QUALITY, safety and
efficacy data is referred to the originator,
providing only evidence of
INTERCHANGEABILITY (bioequivalence, clinical
testing, in certain cases dissolution data).
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Innovative medicine
Experimental data/ Literature
Data required for
regulatory approval
Clinical data
Generic medicine
Multisource interchangeable
Preclinical data
Pharmaceutical data
Proof of interchangeability
Pharmaceutical data
Administrative and summarizing data, including GMP
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Scientific and regulatory complexity
concerning medicinal products is growing
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New technologies
New therapeutic approaches
Evidence based medicine
Globalisation of commerce
Telematic instruments
Information and transparency
requirements
 Risk aversion in society
 New tasks
 Speed of change
 Regulatory resources rarely
reflect expectations of society
and regulators themselves
Paradigms of drug regulation are
evolving
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Capacity to make regulatory decisions
193 WHO Member States:
50%
20%
30%
Developed
Varying
Limited
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Challenges
 Regulatory delays and backlogs
 Lack of regulatory tools and guidelines
 Lack of expertise
 Lack of management skills
 Regulatory pendulum
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Strategies used to cope with increasing
demands?
 Concentration on priority issues most relevant
for public health
 Co-operation with partners in order to increase
regulatory capacity by elimination of duplicated
activities
– Facilitated by comparable standards and
administrative requirements
 Increased effectivity of internal operations
– Quality systems, international benchmarking
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Sharing of expertise vs. recognition of decision
 Acceptance of expertise is not equal to acceptance
of decision
 Acceptance of decision
– is formal legal act, frequently requiring international treaties
– may modify liabilities of involved parties and requires legal
specification of acceptance and non-acceptance
 Acceptance of expertise
– is sovereign and complex regulatory decision of NRA based on
scientific arguments and confidence
– may be applied case to case
– is followed by formal independent decision according to national
legislation and mandate of NRA
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
WHO approaches for consideration
 Stimulating / initiating collaboration between regulators
from various developing countries on various regulatory
activities;
 Employing internationally accepted guidelines adapted to
suit local needs/circumstances;
 Facilitating joint assessments between regulators through
sub-regional approaches.
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
13th ICDRA
16-19 September 2008, Bern
 Concentration on priority issues most
relevant for public health
– Risk-based approaches: regulation of clinical
trials, GMP, product licensing, safety monitoring,
market oversight
 Increased effectivity and efficiency of internal
operations
– assessment of practices and performance by
common toolkits
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
13th ICDRA
16-19 September 2008, Bern
 Co-operation with partners in order to increase
regulatory capacity by elimination of duplicated work
investments and optimising use of experts
– Harmonization: standards: terminology, guidelines, good
practices, pharmacopoeias, format and data content of
applications, safety monitoring practices,
– Collaboration and networking: inspections, market
surveillance, counterfeits,
– Information sharing and common data sets, information
availability: trial registries, inspection outcomes and
assessment reports, licensing outcomes,
pharmacovigilance
– Building mutual trust
– New phenomenon: Major regulatory authorities (FDA, EMEA)
recognize need of collaboration with NRA in exporting countries
concerning oversight of manufacturers and information exchange
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Different initiatives to increase regulatory capacity
and assemble needed scientific / inspection resources
WHO – standards, international expert teams, pharmacovigilance UMC
ICH – common standards for developed markets, involvement of regulators
as well as industry experts
EMEA - co-ordination of expertise available to EU/EEA Member States
Australia and New Zealand – merger of NRAs (currently frozen)
Monaco, Liechtenstein – recognition of regulatory decisions of France resp.
Switzerland
Canada, Switzerland, Japan, EU, Australia etc. – MRA on mutual acceptance
of GMP standards
FDA, EMEA, WHO, TGA … etc. – MoU on sharing of information
PIC/S – share of standards and expertise on GMP, building confidence
Regional and subregional initiatives (ASEAN, GCC, EAC) – different extent
of co-operation
National initiatives – involvement of external experts to support NRAs,
recognition of expertise or decisions, co-operation with industry and
learned societies
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
 Not to share expertise - If trustful expertise is available, not to
consider it may be unjustified waste of resources needed elsewhere
 Accepting the expertise of other regulators is complex regulatory
and scientific decision, depending on
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legislation, mandate
capacities and competence available for given issue
scientific arguments related to benefit/risk for public health
priorities for protection of public health
 Understanding to limitations of transfer of expertise and its proper
management are needed when considering expertise of others
 Targeted, risk-based approach may be appropriate in some
situations
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Expertise in support of developing
countries
 WHO PQP - HIV/AIDS, TB, malaria, RH, paediatric
therapy
 US PEPFAR - HIV/AIDS
 EU Article 58 – assessment of products for non-EU
teritories
 Canada's Access to Medicines Regime – assessment
of products according to WHO Model List of Essential
Medicines
 Other - orphans, paediatric therapy
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Faster access to medicines through
sharing of regulatory information
 WHO is working with regulators to find out how best to
build confidence in regulatory decisions taken by other
regulators, including
-- how to facilitate exchange
of consolidated information
about assessments.
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
WHO registration package
Purpose:
 For less-resourced agencies – in decision making
process, to benefit from technical information developed
by well-resourced ("mature") regulatory authorities;
 To facilitate the "transfer of expertise";
 To create a format for exchange of regulatory
information.
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Different initiatives to increase
regulatory capacity
WHO proposed a framework based on what is
publicly available:
– Summary Basis for Decision (Health Canada)
– European Public Assessment Report (EMEA and EC)
– Common Technical Document (US FDA)
– WHO Public Assessment Report (WHOPAR) and
Public Inspection Report (WHOPIR)
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
WHO Pilot Project
 Supported by European Commission;
 With participation of 5 (7) countries:
Ghana, Kenya, Nigeria, South Africa, Uganda,
United Republic of Tanzania and Zimbabwe
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
WHO Pilot Project
Purpose:
 To field-test a model technical registration
package;
 To finalize the content of the package and the
guidance for its effective implementation in
countries;
 To ensure that the package is developed and
implemented through a wide consultation with
existing and potential stakeholders;
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
WHO Pilot Project
Field testing exercise
 In order to have a maximum benefit from the field-test
exercise, it was decided to provide all participating
DRAs with the same drug application;
 To ask them to develop their own registration package,
based on the provided draft template;
 One of the recently developed pharmaceutical products
has served as a model application for the field-testing
of the WHO model registration package.
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
WHO Pilot Project
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The same application was submitted to EMEA experts
for their opinion;
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In the end of the project a follow up WHO consultative
meeting was conducted;
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The aim was to consider:
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the results and lessons learnt from the field-testing exercise,
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to finalize the contents of the model technical regulatory package,
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to provide guidance for adoption of the package by national MRAs.
Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Conclusions (1)
 The main objective for DRAs should be to get the
relevant information for the country, while avoiding
collection of large amounts of the country-specific data
that does not add value;
 Sharing of information can help with best use of
available resources, reduce workload and improve
overall regulatory performance;
 Available tools can be packaged for ease of reference
and information exchange;
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Conclusions (2)
 Procedures can be streamlined and processes can be
improved (e.g., Fast Track or Priority Review for those
products that address unmet medical needs);
 Expert knowledge can be pooled and resources
directed to functions that can improve public health and
facilitate access to essential medicines.
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Regulatory support core functions
 Developing evidence on the situation of Medicines
Regulatory Systems worldwide
 Providing Country support for strengthening
medicines regulation
 Providing Regional support for strengthening
medicines regulation
 Facilitate communication and promote
harmonization among medicines regulatory authorities
 Develop and continuously improve internal supporting
tools, mechanism and capacities
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Developing evidence
 To develop and maintain a comprehensive database on DRAs
 To assess of medicine regulatory systems
– Perform assessment to identify needs
– Provide evidence for various supporting activities (Financial,
Training, Consultancy,Equipment)
– Develop institutional plan
 To promote self-assessment as a tool for analysis and continuous
improvement
– Two training events performed for DRAs
 Tool for harmonization purposes
– 5 Pacific Island Countries / WPRO
– 3 EAC Countries / AFRO
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Developing evidence
 44 Assessments performed on 40 Regulatory
systems (with the involvement of HQ)
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–
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AFRO - 21 COUNTRIES / 24 ASSESSMENTS
EURO - 2 COUNTRIES / 2 ASSESSMENTS
EMRO - 4 COUNTRIES / 5 ASSESSMENTS
SEARO - 4 COUNTRIES / 4 ASSESSMENTS
WPRO - 7 COUNTRIES / 7 ASSESSMENTS
PAHO - 2 COUNTRIES / 2 ASSESSMENTS
Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Developing evidence
2008
2007
2006
2004
2003
2003
No
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Country support
 Develop and organize training opportunities
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Strengthen information management capacity - SIAMED
Strengthen inspection capacity
Strengthen QC laboratory capacity
Strengthen marketing authorization capacities
 Promoting good regulatory practices by providing guidelines, tools
and technical assistance
 In close collaboration with capacity building team within the PQ
Program
 In cooperation with IVB Vaccines on clinical trials
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Regional support
 Provision of technical assistance to harmonization
initiative and supporting participation of regulators
– SADC, EAC, PIC, CARICOM,…
 Financial support for technical secretariat (EAC, SADC
and UEMOA)
 WHO/EAC joined assessment of DRAs
 Promoting and facilitating networking
– Network of DRAS (EAC, SADC)
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Introduction to the grading model
 Preliminary work made by Eshetu Wondemagegnehu
– Possible approaches to developing drug regulation in:
Effective Drug Regulation: what can countries do?
 Based on Capability Maturity Model (CMM)
– first described by W. Humphrey in Managing the Software Process
 Maturity model for quality management system
– introduced by P. Crosby in his book 'Quality is Free'.
Generic approach of maturity of organization as a
learning curve applied to medicines regulatory
processes
Not to give a mark
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
For what purposes can it be used?
 At country level
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–
–
–
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To build a strategy
To visualize the stage of development/maturity
To visualize and demonstrate progress
To assist process of harmonization
To identify areas of priority support
 At sub-regional level
– To organize sharing and exchange of expertise
– To develop process of harmonization, cooperation or collaboration
 At international level
– To map regulatory systems
– To build strategy/approach
– To document results and planned activities
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Grading Model / MRA
Maturity
Level
Grade 0
Grade I
Notification
Grade II
Limited
assessment
Grade III
Full assessment
Grade IV
Expert
No regulatory
authority
No RA but
identified service
in charge of the
sector
RA established
Limited resources
and capacities
Limited
documentation
RA covering all
regulatory
functions
Adequate
resources
QMS initiated for
specific functions
RA covering all
regulatory
functions
Virtually
unlimited
resources
QMS in place
and fully
operational
No information
management
system (IMS)
IMS limited to
basic
information on
establishments
and products
Simple IMS for
storing
information about
licensed
establishments
and products
IMS with
information about
licensed
establishments
and products, CT,
vigilance with
adequate
query/retrieval
capacity
Fully
developed
global IMS for
all activities
with features
to design
sophisticated
queries and
remote access
Regulatory
functions
Medicines
Regulatory
Authority
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Grading Model / Marketing authorization
Maturity
level
Grade 0
Grade I
Notification
Grade II
Limited
assessment
Grade III
Full assessment
Grade IV
Expert
No MA system in
place
Notification for all
categories of
products
MA of generic
products based on
full assessment of
applications
MA of generic
products based
on full
assessment of
applications
MA of generic
products
based on full
assessment of
applications
MA of new active
substances (NAS)
based on:
Registration of
NAS based on
full assessment
of application
Registration of
new products
based on full
assessment of
application
MA of biological
& complex
products (e.g.
biotech) based
on information
provided by
other DRA
MA of
biological &
complex
products (e.g.
biotech) based
on full
assessment of
applications
Regulatory
functions
Marketing
authorisation
No assessment
performed
MA based on:
- Information
provided by DRA
of other countries
- WHO-type
certificate
- Evidence of MA
in reference
countries
-own assessment
of quality part and
- Information
provided by DRA
of other countries
List of products on
the market
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Fictitious example of evaluation outcomes
Regulatory
functions
Country A
Country B
Country C
Country D
Country E
Licensing
Level 3
Level 3
Level 3
Level 4
Level 3
Registration
Level 2
Level 3
Level 3
Level 4
Level 3
Inspections
Level 2
Level 3
Level 3
Level 4
Level 3
QC Laboratory
Level 2
Level 3
Level 3
Level 4
Level 3
Vigilance
Level 2
Level 2
Level 1
Level 3
Level 2
Clinical Trials
Level 3
Level 3
Level 1
Level 4
Level 3
Drug Promotion
Level 3
Level 3
Level 3
Level 4
Level 3
Harmonisation : easier to achieve for Licensing & Control of Promotion
Priority: To assist country A through collaboration with other countries
Follow-up: identify reasons behind country C’s low result on clinical trials and vigilance
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Contribution of PQ to capacity building
 Organization of trainings
– general and problem specific (HIV/AIDS, TB and antimalarial
products, pediatric dosage forms, BE, BE/BCS)
– Trainings of NRA staff and manufacturers frequently combined
 Involvement of assessors from NRAs into PQ assessment
 Involvement of inspectors from NRAs into PQ inspections
 3 months rotations of experts from NRAs in WHO HQ –
PQT
 Technical Briefing Seminars
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Trainings organized (Jan 2006 - Aug 2008)
14
12
10
PQ co-organized
8
PQ organized
6
4
2
0
2006
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2007
2008 I-VIII
Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Topics of workshops in 2006 – I-VIII 2008
3
1
3
2
3
9
3
3
Prequalification advocacy
Prequalification requirements
Good manufacturing practice
Quality control
Bioequivalence/BCS and GCP
Assessment of medicines
Pharmaceutical development
General
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Focus on specific medicines
1
3
2
1
3
HIV/AIDS medicines
TB medicines
Pediatric formulations
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Antimalarials
RH products
Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Participants in trainings
600
500
Others
400
QCL staff
Regulators
300
Manufacturers
200
100
0
2007
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2008 I-VIII
Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008
Thank you for the attention
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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008