Drug Regulatory Overview Milan Smid, MD, PhD Technical Officer Quality Assurance and Safety:...

Drug Regulatory OverviewDrug Regulatory OverviewDrug Regulatory OverviewDrug Regulatory Overview

Milan Smid, MD, PhDTechnical OfficerQuality Assurance and Safety: MedicinesEssential Medicines and Pharmaceutical Policies, World Health [email protected]

2 | Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008

Principles of drug regulation

WHO regulatory support activities– Harmonization and worksharing– Assessment of regulatory functions– Trainings

Discussion


Major health technologiesMajor health technologies

Medical devicesincluding

diagnostics

Medicines and

vaccines

Herbal and traditional medicines

Functional food

Nutraceuticals

Advanced therapies

Blood componentsTransplants


Common features of health technologiesCommon 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


Protection of public healthProtection 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


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


Medicines regulationMedicines 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


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

Rationale for Government role

Consequences of weak drug regulatory capacity


Consequences of over- or improper regulation

Rationale for Government role

lack of needed medicines or delayed access increased costs of medicines due to cost of

regulatory system lack of regulatory flexibility

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Technical Briefing Seminar, WHO HQ, Geneva, Switzerland | November 2008

Regulation should

Regulatory basics

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

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Parties involved in regulatory system 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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Development of drug regulation

Quality

Safety

Efficacy

Information

Environment

Risk management and risk minimization

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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

14 |


Regulatory toolkitRegulatory 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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Incentives to develop, manufacture and supply needy medicines

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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Regulatory environment

Courts

Regulated subjects Regulatory authorities

Interested stakeholders(associations, professional bodies,

NGOs, watch dogs)

LegislationGuidelines

Appeal bodies

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Responsibilities of parties involved in regulatory system

Responsibilities of parties involved in regulatory system

LegislatedInvestigators and sponsors Manufacturers and importersWholesalers and distributors Health professionals Regulatory authorities

Non-legislated Governments and political representationsPatients Media

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DrugRegulatory

Cycle Emergency and crisis

management

Variations

Line extensions

Postregistrationcommitments

Registration

Renewals

PSUR

PSUR

PSUR

PSUR

PSURPSUR

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Principles applied in regulatory approvals 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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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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Proof of interchangeabilityProof of interchangeability

Administrative and summarizing data, including GMPAdministrative and summarizing data, including GMP

Pharmaceutical dataPharmaceutical data

Preclinical dataPreclinical data

Innovative medicineInnovative medicineExperimental data/ LiteratureExperimental data/ Literature

Generic medicineGeneric medicineMultisource interchangeableMultisource interchangeable

Clinical dataClinical data

Data required for regulatory approval

Pharmaceutical dataPharmaceutical data

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Scientific and regulatory complexity concerning medicinal products is growing

Scientific and regulatory complexity concerning medicinal products is growing

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

23 |


Capacity to make regulatory decisionsCapacity to make regulatory decisions

193 WHO Member States:

20% 50%

30% Developed

Varying

Limited

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Regulatory delays and backlogs

Lack of regulatory tools and guidelines

Lack of expertise

Lack of management skills

Regulatory pendulum

ChallengesChallenges

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Strategies used to cope with increasing demands?

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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Sharing of expertise vs. recognition of decisionSharing 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

27 |


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.

WHO approaches for considerationWHO approaches for consideration

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13th ICDRA16-19 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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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

30 |


Different initiatives to increase regulatory capacity and assemble needed scientific / inspection resources

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 StatesAustralia 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 informationPIC/S – share of standards and expertise on GMP, building confidenceRegional and subregional initiatives (ASEAN, GCC, EAC) – different extent

of co-operationNational initiatives – involvement of external experts to support NRAs,

recognition of expertise or decisions, co-operation with industry and learned societies

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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

– 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

32 |


Expertise in support of developing countries

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

33 |


Faster access to medicines through sharing of regulatory information

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.

34 |


WHO registration packageWHO 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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Different initiatives to increase regulatory capacity

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)

36 |


WHO Pilot ProjectWHO Pilot Project

Supported by European Commission;

With participation of 5 (7) countries:

Ghana, Kenya, Nigeria, South Africa, Uganda, United Republic of Tanzania and Zimbabwe

37 |



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;

38 |


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.


39 |



The same application was submitted to EMEA experts for their opinion;

In the end of the project a follow up WHO consultative meeting was conducted;

The aim was to consider:

─ the results and lessons learnt from the field-testing exercise,

─ to finalize the contents of the model technical regulatory package,

─ to provide guidance for adoption of the package by national MRAs.

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Conclusions (1)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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Conclusions (2)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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Regulatory support core functionsRegulatory 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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Developing evidence 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

44 |


Developing evidenceDeveloping evidence

44 Assessments performed on 40 Regulatory systems (with the involvement of HQ)

– 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

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Developing evidenceDeveloping evidence

2008

2007

2006

2004

2003

No

2003

46 |


Country supportCountry support

Develop and organize training opportunities– 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

47 |


Regional support 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)

48 |


Introduction to the grading modelIntroduction 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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For what purposes can it be used?For what purposes can it be used?

At country level– 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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Grading Model / MRAGrading Model / MRA

Medicines Regulatory Authority

No regulatory authority

No RA but identified service in charge of the sector

RA establishedLimited resources and capacitiesLimited documentation

RA covering all regulatory functionsAdequate resourcesQMS initiated for specific functions

RA covering all regulatory functionsVirtually unlimited resourcesQMS 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

MaturityLevel

Regulatory functions

Grade 0 Grade INotification

Grade IILimited assessment

Grade IIIFull assessment

Grade IVExpert

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Grading Model / Marketing authorizationGrading Model / Marketing authorization

Marketing authorisation

No MA system in place

Notification for all categories of products

No assessment performed

MA based on:- Information provided by DRA of other countries- WHO-type certificate- Evidence of MA in reference countries

List of products on the market

MA of generic products based on full assessment of applications



MA of new active substances (NAS) based on:

-own assessment of quality part and

- Information provided by DRA of other countries

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

Maturity level


Grade 0 Grade INotification

Grade IILimited assessment

Grade IIIFull assessment

Grade IVExpert

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Fictitious example of evaluation outcomesFictitious example of evaluation outcomes


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 PromotionPriority: To assist country A through collaboration with other countriesFollow-up: identify reasons behind country C’s low result on clinical trials and vigilance

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Contribution of PQ to capacity buildingContribution 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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0

2

4

6

8

10

12

14

2006 2007 2008 I-VIII

Trainings organized (Jan 2006 - Aug 2008)

PQ co-organized

PQ organized

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Topics of workshops in 2006 – I-VIII 2008 Topics of workshops in 2006 – I-VIII 2008

3

9

33

3

2

3 1

Prequalification advocacyPrequalification requirementsGood manufacturing practiceQuality controlBioequivalence/BCS and GCPAssessment of medicinesPharmaceutical developmentGeneral

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Focus on specific medicinesFocus on specific medicines

1

2

13

3

HIV/AIDS medicines Antimalarials

TB medicines RH products

Pediatric formulations

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0

100

200

300

400

500

600

2007 2008 I-VIII

Participants in trainings

Others

QCL staff

Regulators

Manufacturers

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Drug Regulatory Overview Milan Smid, MD, PhD Technical Officer Quality Assurance and Safety:...

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