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Information on the History of ICH was included in the background information for paticipants at the Fourth International Conference on Harmonisation, Brussels, July 1997 and a statement by the ICH Steering Committee, on the Future of ICH was also published at that time. Both are given here.


A Brief History of ICH

The Need to Harmonise

The history of medicinal product registration, in much of the industrialised world, has followed a similar pattern which could be described as: Initiation, Acceleration, Rationalisation and Harmonisation.

The realisation that it was important to have an independent evaluation of medicinal products before they are allowed on the market was reached at different times in different regions. In the United States a tragic mistake in the formulation of a children's syrup in the 1930s was the trigger for setting up the product authorisation system under the Food and Drug Administration. In Japan, government regulations requiring all medicinal products to be registered for sale started in the 1950s. In many countries in Europe the trigger was the thalidomide tragedy of the 1960s, which revealed that the new generation of synthetic drugs, which were revolutionising medicine at the time, had the potential to harm as well as heal.

For most countries, whether or not they had initiated product registration controls earlier, 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. The industry, at the time, was becoming more international and seeking new global markets, but the registration of medicines remained a national responsibility. Although different regulatory systems were based on the same fundamental obligations to evaluate the quality, safety and efficacy, the detailed technical requirements had diverged over time to such an extent that industry found it necessary to duplicate many time-consuming and expensive test procedures, in order to market new products, internationally.

The urgent need to rationalise and harmonise regulation was impelled by concerns over rising costs of health care, escalation of the cost of R&D and the need to meet the public expectation that there should be a minimum of delay in making safe and efficacious new treatments available to patients in need.

Initiation of ICH

Harmonisation of regulatory requirements was pioneered by the European Community, in the 1980s, as the EC (now the European Union) moved towards the development of a single market for pharmaceuticals. The success achieved in Europe demonstrated that harmonisation was feasible. At the same time there were bilateral discussions between Europe, Japan and the US on possibilities for harmonisation. It was, however, at the WHO Conference of Drug Regulatory Authorities (ICDRA), in Paris, in 1989, that specific plans for action began to materialise. Soon afterwards, the authorities approached IFPMA to discuss a joint regulatory-industry initiative on international harmonisation, and ICH was conceived.

The birth of ICH took place at a meeting in April 1990, hosted by the EFPIA in Brussels. Representatives of the regulatory agencies and industry associations of Europe, Japan and the USA met, primarily, to plan an International Conference 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 location rotating between the three regions.

The Early Meetings

At the first SC meeting of ICH the Terms of Reference were agreed and it was decided that the Topics selected for harmonisation would be divided into Safety, Quality and Efficacy to reflect the three criteria which are the basis for approving and authorising new medicinal products. It was also agreed that six-party Expert Working Groups (EWGs) should be set up to discuss scientific and technical aspects of each harmonisation Topic. Eleven such Topics were selected for discussion at the First International Conference on Harmonisation.

The "pattern" of ICH work was also established in those early Steering Committee meetings, that is, that the EWGs meet in the same week as the Steering Committee and report on their progress to the Committee.

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 "ICH Process" for developing harmonised 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 "Process" was first drawn up at the Steering Committee meeting in Washington, March 1992 and amended in Tokyo, September 1992. The defined process with "decision points" at Step 2 and Step 4 has enabled the Steering Committee to monitor the progress of the topics selected for harmonisation.

STATEMENT BY THE ICH STEERING COMMITTEE TOKYO, OCTOBER 1990

  • The Parties cosponsoring this Conference, represented at the 2nd Steering Committee Meeting in Tokyo, 23-24 October 1990 re-affirmed their commitment to increased international harmonisation, aimed at ensuring that good quality, safe and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimise the use of animal testing without compromising the regulatory obligations of safety and effectiveness.
  • This Conference will provide a unique opportunity for regulators and industry to reach consensus on the steps needed to achieve this objective through greater harmonisation of technical requirements and to set out practical and realistic targets for harmonising requirements where significant obstacles to drug development and the regulatory process have been identified.
  • Recognising the substantial progress which has already been made in achieving harmonisation within Europe and through bilateral contacts between Europe, Japan, USA and other regions, the Conference will seek to make further progress through a trilateral approach, with clearly defined priorities, methods of work and recommendations to both industry and regulatory authorities.
  • Whilst the Conference will be an important step forward, it is not seen as an end in itself, but as a stage in a developing process, at a high level, between regulators and industry.
  • The Conference, its preparations and follow-up activities will be conducted in an open and transparent manner and the presence of observers from other regulatory authorities and WHO is welcomed as a means of ensuring that the benefits of progress towards harmonisation can be utilised world-wide.
  • The Conference will not only look at existing issues but will, based on past experience, seek to minimise future divergence of new registration requirements, as a consequence of technical progress.

Topics and Conferences

The Topics selected for discussion in the three Workshops at ICH 1, particularly those for Quality and Safety were very broad in their scope. Whilst ICH 1 was clearly a successful Conference, it was evident that the harmonisation Topics would need to be more focused, with a clearly defined, and realistic objective. Thus most of the eleven ICH 1 Topics (identified simply as "Quality T1-T3", "Safety T1-T4 and "Efficacy T1-T4") were subsequently sub-divided and given the ICH Codes which are more familiar today.

At least one Topic has come "full circle" since ICH 1. The single Quality Topic Specifications was divided into topics on Analytical Validation (Q2) and Impurities (Q3) and these were further sub-divided and developed into harmonised guidelines. Once these tasks were substantially complete, it was agreed, at ICH 3, that work should re-commence on a consolidated guidance for setting specifications for new drugs and products (Q6).

The broad Safety Topic from the first Conference, Toxicity Testing Programme was also broken down into more manageable elements which have resulted in harmonised guidelines. Other Topics were put "on hold" but have since been re-visited, such as Safety Testing for Biotechnology Products and the Timing of Toxicity Studies in Relation to Clinical Trials.

Format of Applications

When the selection of harmonisation Topics was first discussed by the Steering Committee, the subject was raised of harmonising the format for reporting data, particularly the sections on quality data. It was felt, however, that this was premature and that priority should be given to harmonising the technical content of those sections of the data where significant differences had been identified between regulatory requirements.

The subject of the Content and Format of Clinical Study Reports (E3) was, however, undertaken and the outcome was successful, with agreement on a single format for reporting the core clinical studies which make up the Clinical Section of a registration dossier.

A target for the first phase of ICH activities was to remove redundancy and duplication in the development and review process, such that a single set of data could be generated to demonstrate the quality, safety and efficacy of a new medicinal product. As ICH is approaching this target of a single set of data for a new product, discussions are once again focused on the feasibility of developing a Common Technical Document for reporting this data to the regulatory authorities.


The Numbers Game

The progress of harmonisation cannot be measured merely by counting guidelines but, nonetheless, the numbers shown below illustrate the scale of the work that has been undertaken by ICH in its first phase of activities.

Conference

Consensus Building

Reg. Consultation

Total "Active"1

Total Finalised

 

Step 1

Step 2/3

 

Step 4/5

ICH 2 (end)

13

9

23

4

ICH 3 (end)

12

7

22

20

ICH 4 (end)

3

3

9

36

     

Total Topics: 45

1The count of Active Topics includes Q4 Pharmacopoeias, and (for ICH 3 and 4) M1 Medical Terminology and M2 Electronic Standards for the Transfer of Regulatory Information. These are counted as harmonisation topics, but the Step-wise "ICH Process" does not apply, as expected outcome is not a tripartite harmonised "guideline".


See ICH Topics for a full listing of ICH Guidelines and their Status.

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Future of ICH

Statement by the ICH Steering Committee on the occasion of the Fourth International Conference on Harmonisation
16-18 July 1997, Brussels

 The International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 as a joint regulatory/industry project to improve, through harmonisation, the efficiency of the process for developing and registering new medicinal products in Europe, Japan and the United States, in order to make these products available to patients with a minimum of delay.

The six parties to ICH represent the regulatory bodies and research-based industry in the three regions, Europe, Japan and the USA, where the vast majority of new medicines are currently developed.

The ICH process has achieved success because it is based on scientific consensus developed between industry and regulatory experts and because of the commitment of the regulatory parties to implement the ICH tripartite, harmonised guidelines and recommendations.

The Fourth International Conference on Harmonisation (ICH 4) Brussels, 16-18 July 1997, marks the completion of the first phase of ICH activities in which significant progress has been made towards the goal of reducing duplication in the process for developing new medicinal products and submitting technical data for registration.

Continuation of Harmonisation Activities

The six-party structure will continue as the operational basis for harmonising technical requirements for new medicine development and registration of products containing new drug substances.

The six founder members of ICH have agreed that a second phase of harmonisation activities should continue after ICH 4 in order to ensure that:

 Scientific Consensus

It is recognised that some of the topics selected for harmonisation have implications for regulatory agencies and sectors of industry not represented by the six parties to ICH.  Since it first started, the ICH Steering Committee has included observers from WHO and regulatory authorities in EFTA and Canada and participation in the Expert Working Groups has been extended, according to the sub-jects discussed, to Pharmacopoeial authorities, generic industry associations and representatives of the non-prescription pharmaceutical industry.

This wider participation in the expert working groups will continue and may be extended on a topic-by-topic basis.  This will apply to Expert Working Groups which are convened to discuss new topics or the updating or extension of current ICH guidelines, especially where the topics have implications beyond the registration of new drug products in the three ICH regions.

Notwithstanding the wider participation in technical discussions, the adoption and implementation of new, updated or extended harmonised ICH guidelines will continue to be the responsibility of the regulatory parties in the three ICH regions, taking into account the results of the regulatory consultative process, within each region.

Conferences and Workshops

The biennial International Conferences on Harmonisation (Brussels, 1991; Orlando, Florida, 1993; Yokohama, Japan, 1995; and Brussels, 1997) have been important for disseminating information on ICH and for ensuring that harmonisation is conducted in an open and transparent manner. Periodic Conferences and Workshops will continue to be organised by ICH as a vehicle for communication and discussion of harmonisation issues.

Globalisation of the Benefits of Harmonisation

The success of the ICH initiative and its first phase of activities has resulted in considerable interest from regulatory and industry bodies outside the three ICH regions.

With the successful completion of the first phase of international harmonisation, it will be increasingly important to ensure that the objectives and outcome of ICH are well understood and widely disseminated.  This challenge will be taken up by the six parties to ICH, WHO and through the International Federation of Pharmaceutical Manufacturers Associations (IFPMA), in conjunction with other interested parties.

The important role of WHO, both in actively disseminating the guidelines and encouraging the wide-spread adoption and use of ICH guidelines is warmly welcomed and is essential if the long-term benefit of international harmonisation, in terms of quicker access to effective new medicines, is to be available to patients throughout the world.

Second Phase of International Harmonisation

ICH activities will move into a second phase with a continuing commitment to increased international harmonisation, aimed at ensuring that good quality, safe and effective medicines are developed in the most expeditious and cost effective manner.  These activities are pursued in the interest of the patient, consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimise the use of animal testing without compromising the regulatory obligations of safety and effectiveness.
 

Revised ICH Terms of Reference


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