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ICH Overview

Susan Hsu

Tel: (02) 87883182 ext. 103

Fax: (02) 87883219

E-mail: shsu@statplusinc.com

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Outline

ICH: International Conference on Harmonisation

History

Structure of ICH

ICH Steps

ICH Guidelines

MedDRA Gene Therapy

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(Phase I) (Phase II)

(Phase

III)

(Phase IV)(

(

)

2~3

3~5

3~5

2~3

IND

NDA

3~5

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Initiation of ICH

1980s, Harmonisation of regulatory requirements waspioneered by the European Community, in the 1980s, as theEC (now the European Union) moved towards the

development of a single market for pharmaceuticals. Thesuccess achieved in Europe demonstrated that harmonisationwas feasible.

At the same time there were bilateral discussions betweenEurope, Japan and the US on possibilities for harmonisation.

It was, however, at the WHO Conference of DrugRegulatory Authorities (ICDRA), in Paris, in 1989, thatspecific plans for action began to materialise.

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Initiation of ICH

Soon afterwards, the authorities approached IFPMA todiscuss a joint regulatory-industry initiative on internationalharmonisation, and ICH was conceived.

The birth of ICH took place at a meeting in April 1990,hosted by the EFPIA in Brussels. Representatives of theregulatory agencies and industry associations of Europe,Japan and the USA met, primarily, to plan an InternationalConference but the meeting also discussed the wider

implications and terms of reference of ICH. The ICH Steering Committee which was established at that

meeting has since met at least twice a year, with the locationrotating between the three regions.

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Structure of ICH

ICH Parties, directly involved in the decisionmaking process. EU: European Commission - European Union

EFPIA: European Federation of PharmaceuticalIndustries and Associations

MHLW: Ministry of Health, Labor and Welfare, Japan

JPMA: Japan Pharmaceutical Manufacturers Association

FDA: US Food and Drug Administration PhRMA:Pharmaceutical Research and Manufacturers of

America

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Structure of ICH

Observers: Since ICH was initiated, in 1990, there

have been observers to act as a link with non-ICH

countries and regions. The Observers to ICH are: WHO: The World Health Organisation

EFTA: The European Free Trade Area (EFTA)

Canada, represented at ICH by Health Canada

The Observers act as a link between the ICH and

non-ICH countries and regions.

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Structure of ICH

IFPMA has been closely associated with ICH,since its inception to ensure contact with theresearch-based industry, outside the ICH Regions.IFPMA runs the ICH Secretariat.

IFPMA: The International Federation ofPharmaceutical Manufacturers Association is aFederation of Member Associations representingthe research-based pharmaceutical industry andother manufacturers of prescription medicines in56 countries throughout the world.

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ICH Conference

ICH 1: 1991, Brussels

ICH 2: 1993, Orlando

ICH 3: 1995, Yokohama ICH 4: 1997, Brussels

ICH 5: 2000, San Diego Most up-to-date developments on the Common Technical

Documents (CTD) for registration of pharmaceuticals. ICH 6: 2003, Osaka

New Horizons and Future Challenges

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Five ICH Steps

Step 1: Development of Consensus Technical Discussions in EWG (Expert Working Group)

Step 2: Consensus text released for consultation Consensus Achieved

Step 3: Consultation outside ICH Formal Consultation

Step 4: ICH guideline finalized Finalized test

Step 5: Implementation

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ICH Topics and Guidelines

Q: Quality

Chemical and Pharmaceutical Quality Assurance

S: SafetyIn vitro and in vivo pre-clinical studies

E: Efficacy

Clinical studies in human subject

M: Multidisciplinary

Not fit uniquely into one of the above categories

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Quality Topics

Guidelines Step

Q1 Stability Testing 5

Q1A(R) Stability testing of new drug substance and products 3

Q1B Stability testing: photostability testing of new Drugsubstances and products

5

Q1C Stability testing for new dosage forms 5

Q1D Bracketing and matrixing designs for stability testingof drug substances and products

5

Q1E Evaluation of stability data 5

Q1F Stability data package for registration applications inclimatic zones III and IV

5

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Quality Topics

Guidelines Step

Q2 Analytical Validation

Q2A Text on validation of analytical procedures 5

Q2B Validation of analytical procedures: methodology 5

Q3 Impurities

Q3A(R) Impurities in new drug substances (revised) 5

Q3B(R) Impurities in new drug products (revised) 5 Q3C Impurities: guideline for residual solvents 5

Q3C(M) Impurities: guideline for residual solvents(maintenance)

5

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Quality Topics

Guidelines Step

Q4 Pharmacopoeias

Q4A Pharmacopoeial harmonisation

Q4B Regulatory acceptance of pharmacopoeialinterchangability

Q5 Quality of Biotechnological Products

Q5A Viral safety evaluation of biotechnology products

derived from cell lines of human or animal origin

5

Q5B Quality of biotechnological products: analysis of theexpression construct in cells used for production of r-DNA derived protein products

5

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Quality Topics

Guidelines Step

Q5 Quality of Biotechnological Products

Q5C Quality of biotechnological products: stability testing

of biotechnological/biological products

5

Q5D Derivation and characterisation of cell substratesused for production of biotechnological/biological

products

5

Q5E Comparability of biotechnological/biologicalproducts subject to changes in their manufacturingprocess

5

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Quality Topics

Guidelines Step

Q6 Specifications

Q6A Specifications: test procedures and acceptance criteria

for new drug substances and new drug products:chemical substances (including decision trees)

5

Q6B Specifications: test procedures and acceptance criteriafor biotechnological/biological products

5

Q7 Good Manufacturing Practice Q7A Good manufacturing practice guide for active

pharmaceutical ingredients5

Q8 Pharmaceutical development 3

Q9 Quality risk management 3

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Safety Topics

Guidelines Step

S1 Carcinogenicity studies 5

S1A Guideline on the need for carcinogenicity studies of

pharmaceuticals

5

S1B Testing for carcinogenicity of pharmaceuticals 5

S1C Dose selection for carcinogenicity studies ofpharmaceuticals

5

S1C(R) Addendum to S1C: addition of a limit dose and

related notes

5

S2 Genotoxicity Studies 5

S2A Guidance on specific aspects of regulatory tests forpharmaceuticals

5

S2B Genotoxicity: a standard battery for genotoxicitytesting for pharmaceuticals

5

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Safety Topics

Guidelines Step

S3 Toxicokinetics and Pharmacokinetics 5

S3A Note for guidance on toxicokinetics: the assessment

of systemic exposure in toxicity studies

5

S3B Pharmacokinetics: Guidance for repeated dose tissuedistribution studies

5

S4 Single dose toxicity tests 5

S4A Duration of chronic toxicity testing in animals(rodent and non-rodent toxicity testing)

5

S5A Detection of toxicity to reproduction for medicinalproducts

5

S5B(M) Addendum to the guideline on detection of toxicity toreproduction for medicinal products

5

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Safety Topics

Guidelines Step

S6 Preclinical Safety Evaluation of Biotechnology-Derived pharmaceuticals

5

S7 Pharmacology Studies 5

S7A Safety pharmacology studies for humanpharmaceuticals

5

S7B The nonclinical evaluation of the potential for

delayed ventricular repolarization (QT intervalprolongation) By human pharmaceuticals

3

S8 Immunotoxicology studies for humanpharmaceuticals

3

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Efficacy Topics

Guidelines Step

E1 The extent of population exposure to assess clinicalsafety for drugs intended for long-term treatment ofnon-life-threatening conditions

5

E2A Clinical safety data management: definitions andstandards for expedited reporting

5

E2B/

M2

Maintenance of the clinical safety data Managementincluding the maintenance of the electronic

transmission of individual case safety reportsmessage specification

5

E2C Clinical safety data management: periodic safetyupdate reports for marketed drugs

5

E2CA Addendum to E2C: periodic safety update reports for

marketed drugs

5

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Efficacy Topics

Guidelines Step

E2D Post-approval safety data management: definitionsand standards for expedited reporting

5

E2E Pharmacovigilance 5

E2D Post-approval safety data management: definitionsand standards for expedited reporting

1

E3 Structure and content of clinical study reports 5

E4 Dose-response information to support drugregistration

5

E5 Ethnic factors in the acceptability of foreign clinicaldata

5

E6 Good clinical practice: consolidated guideline 5

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Efficacy Topics

Guidelines Step

E7 Studies in support of special populations: geriatrics 5

E8 General considerations for clinical trials 5

E9 Statistical principles for clinical trials 5

E10 Choice of control group and related issues in clinicaltrials

5

E11 Clinical investigation of medicinal products in thepediatric population

5

E12A Principles for clinical evaluation of newantihypertensive drugs (consensus draft principle)

5

E14 The clinical evaluation of QT/QTc intervalprolongation and proarrhythmic potential for non-antiarrhythmic drugs

3

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Multidisciplinary Topics

M1: Medical Terminology

M2: Electronic Standards for Transmission of

Regulatory Information (ESTRI) M3: Timing of Pre-clinical Studies in Relation to

Clinical Trials

M4: The Common Technical Document (CTD)

M5: Data Elements and Standards for Drug

Dictionaries

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MedDRA

MedDRA: Medical Dictionary for Regulatory Activities

Developed under the auspices of ICH.

Particularly important in the electronic transmission ofadverse event reporting, both in the pre- and post-

marketing areas, as well as the coding of clinical trial data.

Requires to be constantly updated and maintained and it

was agreed that a Maintenance and Support Service

Organisation (MSSO) would be needed to carry out this

task and to distribute the terminology, on license, to users

in industry and regulatory agencies.

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MedDRA

In November 1998, IFPMA which was established as the

Trustee of the ICH Steering Committee for the purpose of

holding the intellectual property rights (ownership) of the

terminology, selected Northrop Grumman MissionSystems (formerly TRW Inc.) as the MSSO. Their

activities are overseen by a Management Board (MB),

composed of the 6 ICH parties, the Medicines and

Healthcare products Regulatory Agency (MHRA) of theUK, the Health Canada, The World Health Organization

and chaired by the IFPMA.

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MedDRA

The latest version of MedDRA is now available

from the MedDRA MSSO, the sole authorized

source of MedDRA subscriptions and coreservices.

MedDRA is released twice a year, 1 March and 1

September.

In 2005, we will be releasing MedDRA V 8.0 on 1

March 2005 and MedDRA V 8.1 on 1 September

2005.

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Gene Therapy Discussion Group

The objectives of the GTDG are: Monitor emerging scientific issues

Proactively set out principles that may have a beneficialimpact on harmonizing regulations of gene therapy

products

Develop new ways of communication to ensure that theoutcomes of ICH are well understood and widely

disseminated such as Public ICH gene therapy workshops

Public gene therapy press statements from the ICH SC

Establish a publicly available ICH gene therapy web page

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