module 10 - ich, ctd, actd guidelines

1

The given information is compiled from various offline online sources towards the sole

purpose of knowledge sharing

Module 10

ICH CTD ACTD guidelines

The Need to Harmonize

To have an independent evaluation of medicinal products before they were allowed on the market was reached at different times in different regions

In the US a tragic mistake in the formulation of a childrenrsquos syrup in the 1930s

In Japan government regulations requiring all medicinal products to be registered for sale started in the 1950s

In Europe the trigger was the thalidomide tragedy of the 1960s

The 1960s and 1970s saw a rapid increase in laws regulations and guidelines for reporting and evaluating the data on safety quality and efficacy of new medicinal products

Initiation of ICH

In 1989 in Paris at the WHO Conference of Drug Regulatory Authorities (ICDRA) specific plans for action began to materialize Soon afterwards the authorities approached IFPMA to discuss a joint regulatory-industry initiative on international harmonization and ICH was conceived

The birth of ICH took place at a meeting in April 1990 hosted by the EFPIA in Brussels

The Early Meetings

At the first SC meeting of ICH it was agreed that six-party Expert Working Groups (EWGs) should be set up to discuss scientific and technical aspects of each harmonization Topic Eleven such Topics were selected for discussion at the First International Conference on Harmonization

Commitment and Process

Key factors in the success of ICH have been the commitment of the parties to the objectives and outcome of ICH and the development of the ldquoICH Processrdquo for developing harmonized guidance on technical issues The commitment to ICH was set out in a Steering Committee Statement from the meeting in Tokyo October 1990

The ICH ldquoProcessrdquo was first drawn up at the Steering Committee meeting in Washington March 1992 and amended in Tokyo September 1992 The defined process with ldquodecision pointsrdquo

2



at Step 2and Step 4 has enabled the Steering Committee to monitor the progress of the topics selected for harmonization

Format of Applications

The long-term goal of developing a harmonized format has led to the creation of the ICH Guideline M4 The Common Technical Document (CTD) The CTD provides a harmonized format and content for new product applications ICH achieved Step 4 status of the CTD at the ICH5 Conference in San Diego California in November 2000 The agreed upon implementation date for the CTD in the three regions was July 2003

Global co-operation

The recent emphasis on global co-operation actions by ICH acknowledges the important role of WHO in disseminating information and providing input beyond the ICH regions The Steering Committee recognizes the need to expand its communication and dissemination of information with non-ICH parties

New ways of working together

There is a need to explore alternate approaches to the traditional ICH model of expert working groups (EWGs) particularly in areas where constantly changing scientific information has been identified

Revised ICH Terms of Reference (revised in 1997)

To maintain a forum for a constructive dialogue

To contribute to the protection of public health from an international perspective

To monitor and update harmonized technical requirements

To avoid divergent future requirements through harmonization

To facilitate the adoption of new or improved technical research and development approaches

To facilitate the dissemination and communication of information on harmonized guidelines

Structure of ICH

ICH is comprised of Six Parties that are directly involved as well as three Observers and IFPMA The Six Parties are the founder members of ICH which represent the regulatory bodies and the research-based industry in the European Union Japan and the USA These parties include the EUEFPIA MHLW JPMA FDA and PhRMA

3



The Observers are WHO EFTA and Canada (represented by Health Canada) This important group of non-voting members acts as a link between the ICH and non-ICH countries and regions

ICH is operated via the ICH Steering Committee which is supported by ICH Coordinators and the ICH Secretariat

ICH Ste er ing Co mm ittee

The ICH Steering Committee (SC) was established in April 1990 when ICH was initiated The Steering Committee working with the ICH Terms of Reference determines the policies and procedures for ICH selects topics for harmonization and monitors the progress of harmonization initiatives The Steering Committee meets at least twice a year with the location rotating between the three regions

The ICH Observers WHO Health Canada and the European Free Trade Association (EFTA) nominate non-voting participants to attend the ICH Steering Committee Meetings

ICH Coor d inator s

Fundamental to the smooth running of ICH has been the designation by each of the six co-sponsors of an ICH Coordinator to act as the main contact point with the ICH Secretariat and ensure that ICH documents are distributed to the appropriate persons within the area of their responsibility

T he ICH S ec r et ar iat

The Secretariat operates from the IFPMA offices in Geneva and is primarily concerned with preparations for and documentation of meetings of the Steering Committee as well as coordination of preparations for Working Group (EWG IWG Informal WG) and Discussion Group meetings The ICH Secretariat also provides administrative support for the GCG and MedDRA

ICH Parties

European Commission - European Union (EU)

The European Commission represents the 27 members of the EU The Commission works through harmonization of legislation and technical requirements and procedures to achieve a single market in pharmaceuticals to allow free movement of products throughout the EU

4



European Federation of Pharmaceutical Industries and Associations (EFPIA)

EFPIA is situated in Brussels and has as its members 29 national pharmaceutical industry associations and 45 leading pharmaceutical companies involved in the research development and manufacturing of medicinal products in Europe for human use

Ministry of Health Labour and Welfare Japan (MHLW)

The Ministry of Health Labour and Welfare has responsibilities for approval and administration of drugs medical devices and cosmetics in Japan

Japan Pharmaceutical Manufacturers Association (JPMA)

JPMA represents 75 members (including 20 foreign affiliates) and 14 committees Membership includes all the major research-based pharmaceutical manufacturers in Japan

US Food and Drug Administration (FDA)

The US Food and Drug Administration has a wide range of responsibilities for drugs biologicals medical devices cosmetics and radiological products The largest of the worldrsquos drug regulatory agencies FDA is responsible for the approval of all drug products used in the USA

Technical advice and experts for ICH work are drawn from the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER)

Pharmaceutical Research and Manufacturers of America (PhRMA)

The Pharmaceutical Research and Manufacturers of America - PhRMA - represents the research-based industry in the USA The Association has 67 companies in membership which are involved in the discovery development and manufacture of prescription medicines There are also 24 research affiliates which conduct biological research related to the development of drugs and vaccines

PhRMA which was previously known as the US Pharmaceutical Manufacturers Association (PMA) coordinates its technical input to ICH through its Scientific and Regulatory Section Special committees have been set up of experts from PhRMA companies to deal with ICH topics

ICH Observers

Since ICH was initiated in 1990 there have been observers to act as a link with non-ICH countries and regions The ICH Observers are

5



The World Health Organization (WHO)

The European Free Trade Association (EFTA) currently represented at ICH by Swiss medic Switzerland

Canada represented at ICH by Health Canada

IFPMA

Member companies of the International Federation of Pharmaceutical Manufacturers amp Associations (IFPMA) are research-based pharmaceutical biotech and vaccine companies IFPMA has been closely associated with ICH since its inception to ensure contact with the research-based industry outside the ICH Regions

ICH Steering Committee

ICH is administered by the ICH Steering Committee which is supported by the ICH Secretariat The ICH Steering Committee (SC) was established in April 1990 when ICH was initiated The Steering Committee working with the ICH Terms of Reference determines the policies and procedures for ICH selects topics for harmonization and monitors the progress of harmonization initiatives The Steering Committee meets at least twice a year with the location rotating between the three regions

Since the beginning each of the six co-sponsors has had two seats on the ICH Steering Committee (SC) which oversees the harmonization activities IFPMA provides the Secretariat and participates as a non-voting member of the Steering Committee


For further information on the Membership of the ICH Steering Committee see the section

ICH Coordinators


Each party has also established a Contact Network of experts within their own organisation or region in order to ensure that in the discussions they reflect the views and policies of the co-sponsor they represent The way in which this network operates differs according to the administrative structure of the party concerned

6



Due to the structural differences within the EU and MHLW ICH Technical Coordinators are also designated from the European Medicines Agency and PMDA respectively They support the ICH Coordinator and facilitate every action of the Steering Committee members in the region mainly by applying their scientific knowledge Their roles include acting as a contact point between the experts within the European Medicines Agency and PMDA and the ICH Coordinator at the main regulatory body and as a contact point with the ICH Secretariat

The ICH Secretariat


At the time of ICH Conferences the Secretariat is responsible for the technical documentation and for liaison with the speakers for the Conference Organisational aspects of the Conferences are handled by the industry and regulatory parties in the country where the Conference takes place

International amp Asian Pharmaceutical Harmonization Environment

Global Cooperation Group (GCG) bull Established March 1999 as sub-committee of ICH Steering Committee

7



bull Formed to respond to growing interest in ICH guidelines ndash Four brochures published on ICH and GCG available at ICH website wwwichorg

bull Name reflects desire to establish links with non-ICH regions bull Membership

ndash 6 ICH parties ndash 2 Observers (WHO and Health Canada) ndash ICH secretariat

Shift in Focus bull Initial focus on information-sharing bull Soon became clear that more active engagement was necessary to respond to increasing

interest in ICH and ICH guidelines bull Invited participation of regional pharmaceutical harmonization initiatives

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

8



9



CTD Guidelines

The CTD is not a ldquoGlobal Dossierrdquo

It is an agreed-upon common format for the ldquoModularrdquo presentation of summaries reports and data

Incorporates relevant ICH Guidelines

It is organized into five sections Only Modules 2-5 are CTD Module 2 ndash All summaries Overviews Module 3 ndash CMC (ldquoQualityrdquo) Module 4- Preclinical

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Module 5 ndash Clinical

11



Content of ACTD

Part I Table of Contents Administrative Data amp Product Information Section A Introduction Section B Overall ACTD ndash Table of Contents Section C Documents Required for Registration

Application Form Letter of Authorization Certification Labeling Product Information

Part II Quality Document Section A Table of Contents Section B Quality Overall Summary (QOS) Section C Body of Data

Part III Non-clinical Safety Document] Section A ToC

12



Section B Non-clinical Overview Section C Non-clinical Written amp Tabulated Summaries Section D Non-clinical Study Reports

Part IV ClinicalEfficacy Document Section A ToC Section B Clinical Overview Section C Clinical Summaries Section D Tabular Listing of All Clinical Studies Section E Clinical Study Reports Section F List of Key Literature References

ACTD Member Countries

GLOSSARY APEC Asia-Pacific Economic Cooperation and one of the Regional Harmonization Initiatives (RHIs) ASEAN Association of Southeast Asian Nations and one of the Regional Harmonization Initiatives (RHIs) Brainstorming Group Is a group that discusses the need for harmonization within specific scientific domains The outcome of Brainstorming sessions is recommendations for topics for ICH harmonization for Steering Committee consideration Business Plan After consideration of a Concept Paper the Steering Committee may request the

13



development of a Business Plan outlining the costs and benefits of harmonizing the topic proposed by the Concept Paper The Business Plan is complementary to the Concept Paper and focuses in particular on regulatory feasibility Concept Paper Describes the perceived problem and the issues to be resolved and is the trigger of all ICH activities A Concept Paper for a new harmonization activity can be submitted by any ICH party or Observer to the Steering Committee Considerations Document Are developed by discussion groups ie Gene Therapy Discussion Group (GTDG) and ICH amp Women Discussion Group These documents do not undergo the formal step sign-off approval but do require discussion and endorsement by the Steering Committee CTD Common Technical Document Discussion Group Is a group established to discuss specific scientific considerations or views ie Gene Therapy Discussion Group (GTDG) and ICH amp Women Discussion Group eCTD Electronic Common Technical Document EFPIA European Federation of Pharmaceutical Industries and Associations and one of the six ICH parties EFTA European Free Trade Association and one of the ICH Observers - currently represented by Swiss medic (Swiss Agency for Therapeutic Products) EMEA European Medicines Agency ESTRIElectronic Standards for the Transfer of Regulatory Information and Data EU European Union (EU is represented by the European Commission and EMEA and its Experts Committees) and is one of the six ICH parties EWG Expert Working Group charged with developing a harmonized guideline that meets the objectives in the Concept Paper and Business Plan FDA US Food and Drug Administration and one of the six ICH parties

GCC Gulf Cooperation Countries and one of the Regional Harmonization Initiatives (RHIs)

GCG (see ICH GCG) GTDG Gene Therapy Discussion Group Guidelines The main focus of the ICH process is the preparation of harmonized guidelines that are adopted in the three ICH regions - EU US and Japan Non-ICH countries may also use the ICH guidelines within their own countries if they so wish ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use is a joint initiative involving both regulators and research-based industry focusing on the technical requirements for medicinal products containing new drugs ICH Coordinators Are nominated by each of the six co-sponsors and are fundamental to the smooth running of the ICH An ICH Coordinator acts as the main contact point with the ICH Secretariat Due to the structural differences within the EU and MHLW ICH Technical Coordinators are also designated from the EMEA and PMDA respectively They support their respective ICH Coordinators and facilitate every action of the Steering Committee members in

14



the region mainly by applying their scientific knowledge Their roles include acting as a contact point between the experts within EMEA or PMDA and the ICH Coordinator at the main regulatory body and as a contact point with the ICH Secretariat ICH GCG Global Cooperation Group is a subgroup of the ICH Steering Committee and is composed of one representative from each of the six parties on the ICH Steering Committee plus the ICH Secretariat at IFPMA Three Observers (WHO Health Canada and EFTA) are also part of the GCG Other regional harmonization initiatives namely Asia-Pacific Economic Cooperation (APEC) Association of Southeast Asian Nations (ASEAN) Gulf Cooperation Countries (GCC) Pan American Network on Drug Regulatory Harmonization (PANDRH) and South African Development Community (SADC) have also been invited to designate permanent representatives to the GCG ICH Interested Parties Those organisations that are expected to implement or to be regulated by the outcome of ICH efforts (World Self-Medication Industry -WSMI International Generic Pharmaceutical Alliance - IGPA and other interested parties as determined by the Steering Committee over time) ICH Observers European Free Trade Association (EFTA) - currently represented by Swissmedic (Swiss Agency for Therapeutic Products) Health Canada and World Health Organization (WHO) have been associated with the ICH process from the beginning to act as a link with non-ICH countries and regions ICH Parties Are the founding members of ICH and represent the regulatory bodies and research-based industry in the EU US and Japan ICH Secretariat Operates from the IFPMA offices in Geneva Switzerland and provides administrative support to the ICH Steering Committee The Secretariat is primarily concerned with preparations for and documentation of meetings of the Steering Committee as well as coordination of preparations for Working Group (EWG IWG Informal WG) and Discussion Group meetings The ICH Secretariat also provides administrative support for the GCG and MedDRA ICH Steering Committee Is the body that governs the ICH determines the policies and procedures for ICH selects topics for harmonization and monitors the progress of harmonization initiatives Each of the six parties has two seats on the ICH Steering Committee Each of the Observers nominates non-voting participants to attend the ICH Steering Committee Meetings IFPMA also participates as a non-voting member IFPMA International Federation of Pharmaceutical Manufacturers and Associations provides the ICH Secretariat IGPA International Generic Pharmaceutical Alliance and one of the ICH Interested Parties Informal Working Group Is either an informal Expert Working Group (EWG) or Implementation Working Group (IWG) formed prior to any official ICH harmonization activity with the objectives of developingfinalizing a Concept Paper as well as developing a Business Plan IWG Implementation Working Group tasked to develop QampAs to facilitate implementation of existing guidelines JMO Japanese Maintenance Organisation (is a partner of the MSSO and is responsible for maintaining and distributing MedDRA in Japan)

15



JPMA Japan Pharmaceutical Manufacturers Association and one of the six ICH parties MedDRA Medical Dictionary for Regulatory Activities Terminology developed under the auspices of ICH and maintained by MSSO and provides an international medical dictionary applicable to all phases of drug development MedDRA Management Board Is appointed by the ICH Steering Committee to oversee the activities of the ldquoMaintenance and Support Services Organisationrdquo (MSSO) for MedDRA and ensure that the MSSO is meeting the various needs of MedDRA users The Management Board is composed of one representative from each of the six ICH Parties and one representative from MHRA and Health Canada The IFPMA acts as a non-voting observer on the Management Board and chairs the Board MedDRA Points to Consider Document (PtC) Provides a best practice approach for the use of MedDRA MedDRA Points to Consider Working Group Works to develop best practice initiatives related to the use of MedDRA and to maintain the released PtC documents in parallel with MedDRA version updates To the MedDRA Points to Consider Working Group each of the six official ICH parties nominates official representatives and unless otherwise specified by the Steering Committee the official membership is limited to two officials per party per working group and one representative per ICH Observer Representatives from the MSSO and JMO are also members of this working group Membership (As applied to EWGs IWGs Informal WGs Discussion Groups Brainstorming Groups and Pilot WG) Each of the six official ICH parties nominates official representatives and unless otherwise specified by the Steering Committee the official membership is limited to two officials per party per working group and one representative per ICH Observers and also if applicable one per interested party MHLW Ministry of Health Labour and Welfare Japan and one of the six ICH parties MHRA Medicines and Healthcare Products Regulatory Agency and a member of the MedDRA Management Board MSSO Maintenance and Support Services Organisation the repository maintainer and distributor of MedDRA Observers (see ICH Observers) Options Paper May be requested by the Steering Committee to outline the options in terms of the benefits costs and risks of outsourcing specific tasks to organisations external to the ICH process ie consideration of the use of vocabulary services for the maintenance of complex terminology or the use of SDOs (Standards Development Organisations) for the development of technical standards (M2 Message Standards) PANDRH Pan American Network on Drug Regulatory Harmonization and one of the Regional Harmonization Initiatives (RHIs) PhRMA Pharmaceutical Research and Manufacturers of America and one of the six ICH parties Pilot Working Group Is a group that works to test the initial viability of a business model or

16



idea by carrying out Pilot Testing ie the Pilot Working Group for the Maintenance of ICH Controlled Terminology Lists carried out Pilot Testing to develop Standard Operating Procedures (SOPs) for the maintenance of terminology lists PMDA Pharmaceuticals and Medical Devices Agency (Japan) POC Proof of Concept provides evidence that demonstrates ultimate feasibility ie development by the M5 M2 and E2B(R3) EWGs of POC Plan to test the viability of using M2rsquos message specifications to exchange information Determining Proof of Concept and alignment of a Guideline with the POC results is necessary for regional implementation to occur Reporter Is a representative of one of the six ICH parties who is designated by the Steering Committee when a new topic is formally adopted The Rapporteur is responsible for leading a working group (EWGIWG) and ensuring that the group keeps an up-to-date action plan and timetable with clear deliverables and deadlines The Rapporteur shall regularly present reports to the Steering Committee focusing in particular on the timelines and milestones Recommendations Document Due to the information technology (IT) nature of the M2 EWGrsquos work on Electronic Standards for the Transfer of Regulatory Information (ESTRI) some of their activities result in Recommendations These Recommendations do not undergo the ICH step process so as to allow for flexible change as both science and technologies evolve They are agreed in the EWG signed by all parties of the EWG and are approved and signed off by the ICH Steering Committee RHI Regional Harmonization Initiatives founded on the principle of harmonizing drug regulation across a defined group of non-ICH countries SADC South African Development Community and one of the Regional Harmonization Initiatives (RHIs) Steps The formal ICH procedure consists of 5 Steps Step 1 Consensus Building Step 2 Confirmation of six-party consensus Step 3 Regulatory Consultation and Discussion Step 4 Adoption of an ICH Harmonized Tripartite Guideline Step 5 Implementation Topic Leader Deputy Topic Leader Are the two officially nominated representatives that each of the six ICH parties will elect to represent their party in an EWGIWG It is the responsibility of the Topic LeaderDeputy Topic Leader to officially represent a consolidated view of their party during any ICH interaction WHO World Health Organisation and one of the ICH Observers WSMI World Self-Medication Industry and one of the ICH Interested Parties

2



at Step 2and Step 4 has enabled the Steering Committee to monitor the progress of the topics selected for harmonization

Format of Applications

The long-term goal of developing a harmonized format has led to the creation of the ICH Guideline M4 The Common Technical Document (CTD) The CTD provides a harmonized format and content for new product applications ICH achieved Step 4 status of the CTD at the ICH5 Conference in San Diego California in November 2000 The agreed upon implementation date for the CTD in the three regions was July 2003

Global co-operation

The recent emphasis on global co-operation actions by ICH acknowledges the important role of WHO in disseminating information and providing input beyond the ICH regions The Steering Committee recognizes the need to expand its communication and dissemination of information with non-ICH parties

New ways of working together

There is a need to explore alternate approaches to the traditional ICH model of expert working groups (EWGs) particularly in areas where constantly changing scientific information has been identified

Revised ICH Terms of Reference (revised in 1997)

To maintain a forum for a constructive dialogue

To contribute to the protection of public health from an international perspective

To monitor and update harmonized technical requirements

To avoid divergent future requirements through harmonization

To facilitate the adoption of new or improved technical research and development approaches

To facilitate the dissemination and communication of information on harmonized guidelines

Structure of ICH

ICH is comprised of Six Parties that are directly involved as well as three Observers and IFPMA The Six Parties are the founder members of ICH which represent the regulatory bodies and the research-based industry in the European Union Japan and the USA These parties include the EUEFPIA MHLW JPMA FDA and PhRMA

3








ICH Coor d inator s




ICH Parties



4















ICH Observers


5






IFPMA







ICH Coordinators



6




The ICH Secretariat





7













8



9



CTD Guidelines





10




11



Content of ACTD





12







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14




15




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3








ICH Coor d inator s




ICH Parties



4















ICH Observers


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IFPMA







ICH Coordinators



6




The ICH Secretariat





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8



9



CTD Guidelines





10




11



Content of ACTD





12







13






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15




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4















ICH Observers


5






IFPMA







ICH Coordinators



6




The ICH Secretariat





7













8



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CTD Guidelines





10




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Content of ACTD





12







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5






IFPMA







ICH Coordinators



6




The ICH Secretariat





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8



9



CTD Guidelines





10




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Content of ACTD





12







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6




The ICH Secretariat





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CTD Guidelines





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Content of ACTD





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CTD Guidelines





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Content of ACTD





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CTD Guidelines





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Content of ACTD





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CTD Guidelines





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Content of ACTD





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Content of ACTD





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Content of ACTD





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module 10 - ich, ctd, actd guidelines

Documents

ich process

ich regions

success of ich

outcome of ich

birth of ich

initiation of ich

sc meeting of ich

nonich parties