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© 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).
© PharmOut 20165
“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)
© PharmOut 20166
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
© PharmOut 20167
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.
© PharmOut 201614
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.
© PharmOut 201615
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.
© PharmOut 201616
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:
© PharmOut 201619
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
© PharmOut 201620
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.
© PharmOut 201621
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?
© PharmOut 201622
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
© PharmOut 201623
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
© PharmOut 201624
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)
© PharmOut 201625
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
© PharmOut 201627
• 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
© PharmOut 201628
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”.
© PharmOut 201629
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?