ICH Update: Developments and Future Directions

IV Pan American Conference on Drug Regulatory Harmonization Boca Chica, Dominican Republic 2-4 March, 2005 Mike Ward Health Canada

A Unique Approach

International Conference on Harmonisation (ICH) was created in 1990 Agreement between the EU, Japan and the USA to harmonize different regional requirements for registration of pharmaceutical drug products Unique because joint effort by regulators and associated pharmaceutical industry trade associations

ICH Objectives

Identification and elimination of the need to duplicate studies to meet different regulatory requirements More efficient use of resources in the R&D process, as a consequence Quicker access for patients to safe and effective new medicines

Working Groups
SAFETY EFFICACY

QUALITY

MULTIDISCIPLINARY

STEERING COMMITTEE
Endorses topics, guidelines and monitors progress

Retrospective
ICH a mature harmonization initiative Over 50 technical guidelines, a dictionary of medical terms, electronic standards and a common format for drug registration Six ICH conferences to date, including ICH 6 in Osaka, Japan, November 2003 Witnessing increased interest in and use of ICH guidelines globally Formation and evolution of Global Cooperation Group (GCG)

Time to Reflect
Following over a decade of significant achievements in the harmonization of quality, safety and efficacy requirements for the registration of new drugs in the three ICH regions, is the work of ICH mostly done? Will ICH become a maintenanceonly organization?

No, however
Appropriate time to evaluate the future of ICH to ensure:
Proper balance between maintenance and new activities

New topics are of high value and objectives are

achievable Most efficient use and management of resources Flexible enough to deal with evolving science and technologies More transparent

ICH Output since 3rd Pan-Am Conference, April 02 (1)

New products:

Five technical guidelines:

3 Quality: Stability (Q1E, Q1F), Biotech comparability (Q5E) 2 Efficacy: post-approval safety (E2D) and pharmacovigilance

planning (E2E)

Specifications established for electronic submissions: eCTD Four Considerations documents: 3 on gene therapy, 1 on gender and clinical trials

ICH Output since 3rd Pan-Am Conference (2)

Responding to user needs and new data: maintenance, improvement, clarification activities:
Introduction of question and answers documents (M4CTD/eCTD, E5-ethnic factors, E2B(M)-transmission of safety case reports)

Revision of Quality guidelines on stability (Q1A) and

impurities (Q3B) Maintenance of limits for residual solvents (Q3C) New addendum to periodic safety update reports (E2C); `granularity` annex to Common Technical Document (CTD) guidance

ICH Output since 3rd Pan-Am Conference (3)

MedDRA:
Continual improvement: MedDRA version 8.0

scheduled for release March 2005 Now available in 8 languages, including Spanish and Portuguese New draft Points to Consider documents on term selection and data retrieval/presentation Release of first Standardized MedDRA Queries (SMQs) collaboration with Council for International Organization of Medical Services (CIOMS)

ICH: Developments and Future Directions

`Themes`:
New topics: facilitating innovation New topics: promoting safety/public health

Regulatory communication
Maintenance/implementation Mechanics of ICH Transparency and communication

New Topics: Facilitating Innovation

Examples:
Q5E: comparability of biotech/biological products subject to

manufacturing changes Q8: pharmaceutical development Q9: risk management application to quality requirements and practices

Serve to facilitate innovation and improvement More informed, risked-based approach to regulation Consistent with FDAs GMPs for the 21st Century initiative

New Topics: Promoting Safety/Public Health

Examples:
E2E: pharmacovigilance planning (completed) E14/S7B: QT prolongation (draft)

Topics identified by regulators Considered important in contributing to drug safety and public health Potential new pharmacovigilance topics to be considered by ICH following gap analysis of current regional guidelines

New Topics: Other projects

Q4B: regulatory acceptance of (Japanese, European and US) pharmacopeial interchangeability

Process established Piloting

S8: immunotoxicology
Nonclinical test methods and decision tree for assessing

immunosuppression caused by non-biologic pharmaceuticals

Regulatory Communication (1)

ICH has sought to enhance regulatory communication through the development of:

Standardized data elements, example: E2B Controlled vocabularies, example: MedDRA Common format for drug registration: CTD Electronic specifications and standards for the transmission of such information, example:
ESTRI and eCTD

Regulatory Communication (2)

Benefits:
Speak same language: promotes

communication Quality, accuracy and consistency of information Improve timeliness of communications (electronic transmission) CTD/eCTD reduces delays and costs associated with registration of drug applications

Regulatory Communication (3)

Status of CTD/eCTD implementation:

As of July 2003 CTD mandatory in EU and

Japan, highly recommended in US and Canada Integration of CTD in existing regulatory frameworks No significant difficulties encountered New era: eCTDs now being submitted in all ICH regions

Regulatory Communication (4)

New: M5: Data elements and standards for drug dictionaries:

For use in describing medicinal products and

active ingredients Controlled vocabulary includes units, routes of administration, pharmaceutical forms Electronic message specifications to be developed

Maintenance/Implementation (1)

Critical aspects of the ICH harmonization process considering need to ensure

continued relevance and improvement of an ever-

growing number of guidelines consistent and intended use by regulators and industry

Tools/mechanisms:
Qs and As, addenda, revisions, points to consider Change control and maintenance processes: eCTD,

E2B(M) and Q3C New: maintenance of ICH controlled terminology lists

Maintenance/Implementation (2)

Tools/mechanisms:
MedDRA maintenance and support service

organization (MSSO) Creation of implementation working groups (e.g., for CTD/eCTD, E2B(M)) and implementation tool (new) Implementation standing item on ICH Steering Committee agenda General procedures and roles/responsibilities under development

Mechanics of ICH

Given costs involved in harmonization activities, it is important that effective structure and procedures are in place to ensure maximum benefit is derived Periodic reassessment of mandate, procedures within context of Future of ICH Most recent review in progress: June 03 May 2005; focus includes:

selection of new topics: business case now required streamlining of procedures clarifying roles and responsibilities means of assessing implementation of guidelines Transparency and communication

Transparency and Communication

Reviewing current practices at regional and ICH level Options to be considered to strengthen transparency and communication GCG seen as increasingly important mechanism for communication and engagement with non-ICH regions and parties

Global Cooperation Group (GCG)

Established March 1999 as sub-committee of ICH Steering Committee Formed to respond to this growing interest in ICH guidelines Name reflective of desire to establish links with non-ICH regions Membership :
6 ICH parties 2 Observers (WHO and Health Canada) ICH secretariat

Initial Mandate

Initial focus on information-sharing Soon became clear that more active engagement necessary to respond to increasing interest in ICH and ICH guidelines

Evolution In GCG Activities and Thinking

Series of joint meetings with regional representatives in preparation for ICH6 satellite session Parallel discussions within GCG on need to be more relevant through establishing closer ties with regional harmonisation initiatives

Osaka, Nov. 2003: An Important Milestone

Endorsement by ICH SC of new Mandate and Terms of Reference that call for
the ongoing participation of regional

harmonization initiatives Greater transparency

Regional Harmonization Initiatives

APEC
Asia-Pacific Economic Cooperation

ASEAN
Association of the Southeast Asian Nations

GCC
Gulf Cooperation Council

PANDRH
Pan American Network for Drug Regulatory Harmonization

SADC
Southern African Development Community

PANDRH Representation

Initial selection during PANDRH Steering Committee meeting in Madrid (February 2005):
Dr. Carlos Chiale (ANMAT)
Dr. Davi Rumel (ANVISA)

Review scheduled for next Steering Committee meeting (March 2005)

GCG Meeting 16 November 2004, Yokohama, Japan

GCG Co-chairs: Dr. Yves Juillet (European Industry) Mr. Mike Ward (Health Canada)

GCG Role and Procedures

Definition of GCG membership

Maximum of 2 permanent representatives per

regional harmonization initiative Representatives should solicit/present views of regional initiatives

Criteria for harmonization initiative to participate in GCG GCG principles: openness and transparency

GCG Reflections Paper: Mission, Activities and Operations of GCG

Issue: While new terms of reference provide authority, tools and rules (the means), they do not define the mission of the new GCG (the ends) Mission/vision necessary to guide and validate future activities

Considerations (1)

Moving beyond bounds of ICH Serve as unique forum for harmonization initiatives to discuss
Best practices, lessons learned and innovative

approaches to harmonization and regulation ICH topics of interest Technical guidelines beyond scope of ICH

Considerations (2)

Managing expectations: resources, realistic objectives

GCG not a technical body

Funding issues

Stepwise approach build on successes

Draft Mission Statement

To promote a mutual understanding of regional initiatives in order to facilitate harmonisation processes related to ICH guidelines regionally and globally; and to strengthen the capacity of drug regulatory authorities and industry to implement them.

Areas of work

ICH technical guidelines Harmonization/regulation Training and capacity building

Identified Topics of Interest

CTD implementation and e-submission GCP implementation E5 implementation Pharmacovigilance guidelines and MedDRA implementation

Interest also expressed in: - technical assistance expressed - review process and data assessment - joint GCP inspections

Regional Meetings Identified

SADC January 05: implementation of ICH guidelines, including CTD ASEAN February 05: pharmacovigilance

Next Steps: Regional Input

Comments on draft ICH guidelines (Q8, S8, then Q9) Proposals for pharmacovigilance plenary session (May 05) Identification and presentation of guideline implementation and technical difficulties (formal presentations at GCG Brussels meeting) GCG teleconference organized for April 7, 2005 Next GCG meeting May 10, 2005 in Brussels

Summary

ICH continues to balance development of important new topics with maintenance and implementation activities New procedures and business case templates meant to improve efficiency and value of ICH process Transparency, communication and engagement through GCG seen as increasingly important