International Regulatory Convergence

Transcription

1 International Regulatory Convergence - Is Enough Being Done? Bob Tribe, 11 July

2 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. 2

3 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. 3

4 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). 4

5 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) 5

6 Levels of Regulatory Cooperation Recognition Treaty Based on treaties & MRAs. However, partial loss of sovereignty in decisionmaking. Sharing of workloads, but independent decisions Reliance/Work Sharing Trust Confidence Building Equivalence of requirements Harmonization/Convergence Information Sharing 6

7 History of GMP Controls in Australia (As a case study in Regulatory Convergence) : Joint Commonwealth/State inspections of manufacturers of therapeutic goods. 1971: 1st edition of Australian Code of GMP for Medicines. 17 pages only 3 rd GMP in the world 7

8 History of GMP Controls in Australia (As a case study in regulatory convergence) : Joint Commonwealth/State inspections of manufacturers of therapeutic goods. 1971: 1st edition of Australian Code of GMP for Medicines. Poor GMP in Australia (1982) 8

9 History of GMP Controls in Australia (As a case study in regulatory convergence) : Joint Commonwealth/State inspections of manufacturers of therapeutic goods. 1971: 1st edition of Australian Code of GMP for Medicines. Poor GMP in Australia (1983) 9

10 History of GMP Controls in Australia (Case study of regulatory convergence) : 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 10

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

12 Some examples of international regulatory cooperation initiatives Recognition MRA - EC/Australia ASEAN MRA on GMP Inspections Reliance/ Work Sharing ACSS Consortium (TGA, HSA, Health Canada, Swissmedic) Mutual Reliance Initiative FDA and EU Confidence Building Harmonisation/ Convergence Information Sharing PIC/S; ICH; ICMRA; IPRF; IGDRP; IMDRF WHO trainings and networks; ICDRA

13 Initiatives involving Convergence/Harmonization (different forums involving regulators) Organization Main objective(s)/areas of work ICMRA PIC/S ICH IPRF IGDRP ICDRA ACSS IMDRF International Coalition of Medicines Regulatory Authorities Pharmaceutical Inspection Cooperation Scheme International Conference on Harmonization International Pharmaceutical Regulators Forum International Generic Drug Regulators Programme International Conference of Drug Regulatory Authorities Australia Canada Singapore Switzerland Consortium International Medical Devices Regulators Forum Regulatory convergence, alignment and standards development; regulatory cooperation and work-sharing; capacity and competence building/technical assistance; regulatory systems comparability criteria and assessment criteria. Developing and promoting harmonized GMP standards, guidance documents, inspection practices & training of inspectors. Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Support implementation of ICH and other internationally harmonized technical guidelines; identification of need for harmonization or convergence in specific areas; Promote collaboration and convergence in generic drug regulatory programs, including sharing of assessment reports related to new generic drug applications. A WHO initiative to provide WHO member states with a forum to meet & discuss ways to strengthen collaboration. Collaborative projects involving medicines & medical devices. Accelerated international medical device regulatory harmonization & convergence.

14 ICMRA Main Features (International Coalition of Medicines Regulatory Agencies) 14 Formed in December 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.

15 ICMRA Current Initiatives 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. 15

16 PIC/S Main Features Commenced operating in November 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. 16

17 48 PIC/S member authorities (July 2016) Canada Iceland Norway EUROPEAN UNION Member States Agencies (29) USA Ukraine Croatia South Korea Japan Switzerland Liechtenstein Israel Hong Kong Malaysia Singapore Indonesia Taiwan Argentina Australia 4 Partners EDQM EMA UNICEF WHO South Africa New Zealand

18 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 Regulatory authorities of the following countries: Pre Applicants (gap analysis by PIC/S) 1. Belarus 2. Kazakhstan Armenia, Uganda & Chile (have completed this procedure & will soon make a full application) Interested 1. Bulgaria 2. Hungary (vet) 3. Russia 4. Nigeria 5. China (CFDA) 6. India (CDSCO) 7. Saudi Arabia 8. Vietnam NOTE Americas Europe Asia Africa

19 PIC/S Seminar for GMP Inspectors Theme: 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

20 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. 20

21 PIC/S & Regulatory Convergence 21 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?

22 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 Melamine Chromium in hard shell capsules

23 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 23

24 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) 24

25 Impediments to Regulatory Convergence 25 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.

26 Foreign Inspections A Need for Regulatory Convergence & Work Sharing 2014 GMP Inspection Data (EFPIA member survey) Number of Foreign Inspections in 2014 undertaken by different regulatory authorities > 30 inspections Australi a 10 to 30 inspections < 10 inspections

27 Recent Pilot Programs Promoting Regulatory Convergence 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 3 rd party Auditing Organisations. Outcome: this pilot is still underway. 27

28 TGA Commitments to Promoting Regulatory Convergence Some Key Quotes from TGA Business Plan for : 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. 28

29 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 29

30 ANY QUESTIONS? 30