© PharmOut 20161

Bob Tribe, 11 July 2016

International Regulatory

Convergence

- Is Enough Being Done?

© PharmOut 20162

Why Improve Regulatory Convergence?

• Many different efforts promoting regulatory convergence.

• These efforts are fragmented & uncoordinated.

• This is costly to the pharmaceutical industry:

• Duplication of GMP inspections.

• Many different GMP requirements.

• Many different pharmacopoeias.

• Industry should lobby ICMRA to coordinate and lead regulatory convergence internationally.

© PharmOut 20163

Overview

• What is Regulatory Convergence?

• History of GMP Controls in Australia as a case study.

• Examples of regulatory convergence internationally.

• Roles of ICMRA and PIC/S in regulatory convergence.

• Impediments to regulatory convergence.

• Conclusion.

© PharmOut 20164

“Convergence” & “Harmonization”

Typical Definition for “Regulatory Convergence”

Represents a process whereby regulatory requirements across economies become more similar or aligned over time as a result of the gradual adoption of internationally recognized technical guidance documents and standards. (APEC)

Typical Definitions for “Regulatory Harmonization”

The process by which the interpretation and/or application of technical guidelines can be made uniform or mutually compatible.(US-FDA).

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“Reliance” & “Work-Sharing”

Typical Definition for “Reliance”

The state of being dependent upon or confident in something or someone; having trust. (The Business Dictionary).

Typical Definition for “Work sharing”

Reliance on or consideration of work already performed by other agencies. “Real-time” work sharing for simultaneous activities (e.g. “joint assessments”). (ACSS Consortium)

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Levels of Regulatory Cooperation

Recognition

Reliance/Work Sharing

Confidence Building

Harmonization/Convergence

Information Sharing

Treaty

Trust

Based on treaties & MRAs.However, partial loss of sovereignty in decision-making.

Sharing of workloads, but independent decisions

Equivalence of requirements

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History of GMP Controls in Australia(As a case study in Regulatory Convergence)

1969-91: Joint Commonwealth/State inspections of manufacturers of therapeutic goods.

1971: 1st edition of Australian Code of GMP for Medicines.

• 17 pages only

• 3rd GMP in the world

© PharmOut 20168

History of GMP Controls in Australia(As a case study in regulatory convergence)

1969-91: Joint Commonwealth/State inspections of manufacturers of therapeutic goods.

1971: 1st edition of Australian Code of GMP for Medicines.

Poor GMP in Australia (1982)

© PharmOut 20169

History of GMP Controls in Australia(As a case study in regulatory convergence)

1969-91: Joint Commonwealth/State inspections of manufacturers of therapeutic goods.

1971: 1st edition of Australian Code of GMP for Medicines.

Poor GMP in Australia (1983)

© PharmOut 201610

History of GMP Controls in Australia(Case study of regulatory convergence)

1969-91: Joint Commonwealth/State inspections of manufacturers of therapeutic goods.

1970: 1st edition of Australian Code of GMP for Medicines.

1987: TGA applied to join PIC (Pharmaceutical Inspection Convention).

1990: 5th edition of Australian Code of GMP – “The Blue Code”

• 80 pages

• The last unique Australian Code of GMP

• Based on PIC GMPs of that time

© PharmOut 201611

History of GMP Controls in Australia(Case study of regulatory convergence)

1969-91: Joint Commonwealth/State inspections of manufacturers of

therapeutic goods.

1970: 1st edition of Australian Code of GMP for Medicines.

1987: TGA applied to join PIC (Pharmaceutical Inspection Convention).

1990: 5th edition of Australian Code of GMP – “The Blue Code”.

1991: Therapeutic Goods Act 1989 commenced operating -

Commonwealth inspections only (by TGA).

1993: TGA Became a member of PIC (PIC changed name to PIC/S in 1995).

1999: MRA between EC & Australia (medicines for human use)

2000: Adoption of Annex 1 of PIC/S GMP Guide.

2001: Adoption of the ICH Q7 - GMP Guide for APIs

2002: Adoption of entire PIC/S GMP Guide (285 Pages).

(but version 8 of Jan’09 is currently the legal requirement in Australia;

latest version issued by PIC/S is version 12 of Oct’15).

Some examples of international regulatory cooperation initiatives

• MRA - EC/Australia

• ASEAN MRA on GMP InspectionsRecognition

• ACSS Consortium (TGA, HSA, Health Canada, Swissmedic)

• Mutual Reliance Initiative – FDA and EUReliance/

Work Sharing

• PIC/S; ICH; ICMRA; IPRF; IGDRP; IMDRF

• WHO trainings and networks; ICDRA

Confidence Building

Harmonisation/Convergence

Information Sharing

Initiatives involving Convergence/Harmonization(different forums involving regulators)

Organization Main objective(s)/areas of work

ICMRA International Coalition of Medicines Regulatory Authorities

Regulatory convergence, alignment and standards development; regulatory cooperation and work-sharing; capacity and competence building/technical assistance; regulatory systems comparability criteria and assessment criteria.

PIC/S Pharmaceutical Inspection Cooperation Scheme

Developing and promoting harmonized GMP standards, guidance documents, inspection practices & training of inspectors.

ICH International Conference on

Harmonization

Harmonisation of Technical Requirements for Pharmaceuticals for

Human Use.

IPRF International Pharmaceutical Regulators Forum

Support implementation of ICH and other internationally

harmonized technical guidelines; identification of need for

harmonization or convergence in specific areas; …

IGDRP International Generic Drug Regulators Programme

Promote collaboration and convergence in generic drug regulatory

programs, including sharing of assessment reports related to new

generic drug applications.

ICDRA International Conference of Drug

Regulatory Authorities

A WHO initiative to provide WHO member states with a forum to meet & discuss ways to strengthen collaboration.

ACSS Australia Canada Singapore Switzerland Consortium

Collaborative projects involving medicines & medical devices.

IMDRF International Medical Devices Regulators’ Forum

Accelerated international medical device regulatory harmonization & convergence.

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ICMRA – Main Features(International Coalition of Medicines Regulatory Agencies)

• Formed in December 2013.

• First regulatory coalition at agency head level.

– Heads of Agency of 23 countries + EMA, EU & WHO.

• Provides strategic, high-level advocacy and leadership.

• Leverages existing efforts to maximise global impact.

• Initial priorities:

– Better information sharing mechanisms between regulators

– GMP inspection work sharing

– Generic medicines convergence and work-sharing

– Capacity building of emerging regulators

• Probably the best organisation to drive/coordinate regulatory

convergence activities.

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ICMRA – Current Initiativeswww.icmra.info

• Various work streams, including:• GMP harmonisation

• Supply chain integrity

• Pharmacovigilance

• Crisis management

• MHRA is leading an ICMRA work stream on GMP harmonisation.

• Reliance on information in inspection reports of other countries, i.e. desk top assessments.

• Ultimate goal is to reduce duplication of inspections globally.

• Limited information available publicly (at present).

• Good communication between ICMRA and PIC/S.

• Industry needs to lobby ICMRA & its participants to support this work and advocate similar projects that promote regulatory convergence internationally.

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PIC/S – Main Features

• Commenced operating in November 1995.

Previously existed as “PIC” (Pharmaceutical Inspection Convention) from 1971 as a legal treaty between 10 countries.

• Is an informal “Cooperative Arrangement” between GMP regulatory authorities; i.e. not a legal treaty.

• A forum for:

networking and confidence building

Exchange of information and experience on GMP

Focus on Quality Systems for Inspectorates

Focus on training of GMP inspectors

International harmonisation of GMP

• No obligation for member authorities to accept inspection reports of other members.

• PIC/S meetings & seminars not open to industry.

New Zealand

48 PIC/S member authorities (July 2016)

Iceland

Canada

USA

Argentina

South Africa

Australia

Malaysia

Taiwan

Switzerland

Norway

Indonesia

Ukraine

Singapore

Israel

Liechtenstein

EUROPEAN UNION Member States Agencies (29)

Japan

South Korea

4 Partners

EDQMEMA

UNICEFWHO

Croatia

Hong Kong

Candidates for PIC/S Membership(at July 2016)

Applicants(Up to 6 years)

1. Brazil*2. Mexico*3. Turkey*4. Philippines*5. Iran*6. Thailand*

*on-site visit due in 2016*on-site visit has occured

Pre–Applicants(gap analysis by PIC/S)

1. Belarus2. Kazakhstan

Armenia, Uganda & Chile (have completed this procedure & will soon make a full application)

Interested

1. Bulgaria2. Hungary (vet)3. Russia4. Nigeria5. China (CFDA)

6. India (CDSCO)

7. Saudi Arabia8. Vietnam

Asia AfricaAmericas Europe

NOTE

Regulatory authorities of the following countries:

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2016 PIC/S Seminar for GMP InspectorsTheme: “Inspectorates of the Future”(Manchester, UK. 5-7 July 2016)

Day 1:Inspection Trends & future development

– GMP trends & GMP deficiencies

– GMP Evolution - Data Integrity inspections in the modern supply chain

– Industry Developments – Future Direction of Manufacturing

Day 2:Inspectorates of the Future

– Working Together – PIC/S, ICMRA, etc. Reliance frameworks

– Risk Based Inspections

– Compliance Management – Increase Patient Safety & Security of Supply

– Shortages and complex supply chain

Day 3:

A New Dawn:

– Pharmaceutical Inspectorates’ Academy

– PIC/S Highlights and Vision for 2020

David Churchward (MHRA)

& Noel Fraser (TGA)

Harry Rothenfluh (TGA)

However, this agenda could

change to discuss the

implications of Brexit

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PIC/S Working Groups(an indication of the future directions of PIC/S)

• Harmonisation of Classification of GMP Deficiencies (TGA = Chair)

• EMA-PIC/S Joint drafting Group on revision of Annex 1 (EMA = Chair)

• Steering Committee for the PIC/S Inspectors’ Academy (PIA)

• Good Clinical Practices (GCP) & Good Pharmacovigilance Practices (GVP)

• Controlling Cross-contamination in Shared Facilities

• Data Integrity (TGA & MHRA = joint Chairs)

• Advance Therapy Medicinal Products (ATMPs)

• Strategic development (share lists of planned foreign inspections & promote joint inspections. Aim is to avoid duplicate inspections).

• Strengthen cooperation with ICMRA.

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PIC/S & Regulatory Convergence

PIC/S plays an important role in facilitating regulatory convergence,

particularly for:

• Preparing harmonized GMP requirements & guidance documents.

• Facilitating joint inspections & sharing of results of inspections.

• Training of inspectors in uniform approaches to inspections.

However, difficulty in applying uniform assessments of new applicants

to ensure equivalence.

• Some Agencies are complex, with inspections decentralised to different

layers of government – resulting in inconsistencies.

• Determining equivalence of GMP requirements is easy;

determining equivalence of implementation of the GMP is not easy.

• Limited PIC/S resources for new applicant assessments, with workload not

evenly spread across all members.

• Lack of transparency about the outcomes of PIC/S membership

assessments.

• How will the applications from CFDA (China) & CDSCO (India) be handled?

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China – Examples of Manufacturing Problems

Recent EU inspection of Chinese API

manufacturer:

“The manufacturing site and its equipment was found to be in a

devastated state. Huge layers of dust and product indicated that no

cleaning was applied to either the facility or the equipment, leading to an

extreme risk of cross contamination. No batch manufacturing

documentation could be seen. Etc. etc.”.

Contamination Scares:

• Heparin - 2008

• Melamine - 2008

• Chromium in hard shell capsules - 2012

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India – Examples of Manufacturing Problems

Data Integrity:Data integrity breaches by pharmaceutical manufacturers is a major problem in India, with many manufacturers forced to halt supply of their products to foreign countries.

Manufacture of counterfeit/falsified medicines:

“One in five drugs made in India are fake” (WHO Feb’14).

“75% of global cases of counterfeit drugs originated from India” (Eur. Commission Mar’12)

Indian manufacturer of Counterfeit Viagra tablets

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Impediments to Regulatory Convergence

Too many organisations working in isolation of each other, without hierarchical coordination/leadership. For example:

• Too many different GMPs.

– Why does USA, Canada, WHO, etc., need to have own GMPs?

– Could the ICH Q7 API model be adopted for medicines?(TGA initiated work to prepare Q7 at conference in Canberra in 1996)

• Too many different GMP guidance documents.

– Many different guidance's for the same topic, e.g. data integrity, etc.

• Some guidance exceed minimum GMP requirements.

– e.g. WHO guidance for HVAC is excessive for non-sterile dosage forms.

• Too many different pharmacopoeias

– Estimated to be 42 (WHO index of pharmacopoeias)

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Impediments to Regulatory Convergence

• Not enough work sharing between Agencies.

– e.g. inspection schedules, joint inspections, etc.

– However, PIC/S is actively working on this.

• Not enough shared access to Agency databases.

– To provide info on manufacturers licensed, suspended, revoked.

– To provide info on inspection findings.

– However, the EudraGMDP is the exception.

• Not enough sharing of assessment reports for new drugs

– However, IGDRP (& ACSS Consortium) proposes sharing of assessment reports related to new generic drug applications.

• Minimal sharing of post-market vigilance.

– Important because medicines increasingly global commodities.

– However, WHO has online ADR database (vigiaccess.com) – but this has limitations.

2014 GMP Inspection Data (EFPIA member survey)

Number of Foreign Inspections in 2014 undertaken by different regulatory authorities

> 30 inspections

10 to 30 inspections

< 10 inspections

Australia

Foreign Inspections – A Need for Regulatory Convergence & Work Sharing

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• International API Inspection Pilot – 2008 to 2010:

– Involved TGA, US FDA and EU Inspectorates.

– Exchange of inspection reports of past inspections & compare inspection results.

– Joint inspections.

Outcome: Recommendation to continue & extend to new partners, including WHO.

• Medical Device Single Audit Program – 2014:

– An initiative of IMDRF (International Medical Devices Regulators’ Forum).

– Involved TGA, US FDA, Japan PMDA, Health Canada & Brazil ANVS

– Single audit of a medical device manufacturer by recognised 3rd

party “Auditing Organisations”.

Outcome: this pilot is still underway.

Recent Pilot Programs Promoting Regulatory Convergence

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TGA Commitments to Promoting Regulatory Convergence

Some Key Quotes from TGA Business Plan for 2015-16:

“Provide secretariat and strategic support to TGA’s participation in the ICMRA Management Committee and ACSS Consortium”.

“Influence the international regulatory harmonisation agenda through membership of the Management Committee of ICRMA, and lead ICMRA projects on generic medicines, on pharmacovigilance and GMP equivalency”.

“Negate the requirement for inspecting overseas manufacturers that have already been approved by a recognised regulatory agency”.

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Conclusion• Many different efforts promoting regulatory convergence.

• However, these efforts are fragmented and not coordinated in a hierarchical manner.

• Better coordination needed with one organisation taking lead role.

• In my opinion, ICMRA seems the best organisation for this leading role, with PIC/S, ICH, etc. doing the technical work.

– Heads of Agencies has the power/authority to lead & direct.

• Industry should lobby ICMRA to coordinate and lead regulatory convergence internationally.

• Likely Results:

– Leadership for regulatory convergence

– Coordination of existing efforts to maximise global impact

– Duplication of effort avoided

– Cost savings for industry

– Better public health outcomes worldwide

© PharmOut 201630

ANY QUESTIONS?