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ICH Topics and Guidelines


A brief guide to the ICH Topics follows. Where Guidelines have reached Step 2 or Step 4/5 of the ICH Process, the documents are presented as Adobe Acrobat (PDF) files. Your browser will have to be configured either to read pdf files directly or save them to disk for viewing with Acrobat Reader.

Problems have occured when downloading some of the PDFs from some of the PharmWeb mirror sites. While we resolve this, the PDF files will be served up from the main PharmWeb server.

This Page has been updated to give information on the Guidelines adopted at the ICH Steering Committee 6-7 November 1996 (<NEW>).

See also: ICH News

For information on the Steps in the development of a guideline, see <ICH Process>

Topics are listed by category: Safety, Efficacy, Quality, and Regulatory Communications.

Safety Topics

S1: CARCINOGENICITY STUDIES
IFPMA S1A Guideline on the need for Carcinogenicity Studies of Pharmaceuticals Step 5

This guideline was finalised at ICH 3 and has been recommended for implementation by the regulatory parties in the EU, Japan and the USA. The objective is to provide consistency in defining the circumstances under which it is necessary to undertake carcinogenicity studies on new drugs, taking account of known risk factors and the intended indications and duration of exposure. This will eliminate the need to carry out unnecessary studies.

IFPMA S1B Testing for Carcinogenicity in Pharmaceuticals Step 2

The scientific approach to testing pharmaceuticals for carcinogenicity has been intensely reviewed, especially in respect of the need to carry out carcinogenicity studies in both the mouse and the rat, or whether reduced testing procedures can be accepted without jeopardising safety. Consensus was reached in May 1996 on a draft guideline which allows for alternative testing methods. This draft has been released for consultation under Step 2 of the ICH Process.

IFPMA S1C Dose Selection for Carcinogenicity Studies of Pharmaceuticals Step 5

A harmonised tripartite guideline was adopted in October 1994, which gives criteria for the selection of the high dose which is to be used in carcinogenicity studies on new therapeutic agents, in order to harmonise current practices and improve the design of studies. This has been implemented by the regulatory parties in the three ICH regions.
S1C (R) - Review of the Guideline
IFPMA S1C (R)
<New> The recommendations for selecting the upper dose limit for carcinogenicity studies have been reviewed in the light of current scientific knowledge and practices. Consensus has been reached on a draft revision to the guideline and the amendment was released for consultation under Step 2 of the ICH Process, on 7 November 1996.

S2: GENOTOXICITY STUDIES

IFPMA S2A Genotoxicity: Specific Aspects of Regulatory Tests Step 5

A harmonised tripartite guideline was adopted in July 1995, which gives specific guidance and recommendations for in vitro and in vivo tests, on the evaluation of test results. It also includes a glossary of terms related to genotoxicity tests, to improve consistency in applications. The guideline is in the process of implementation by the regulatory parties in the three ICH regions.

IFPMA S2B Genotoxicity: Standard Battery Tests Step 3

Consensus was reached, by postal "sign-off" in October 1996, on a guideline which complements the one described above and addresses two fundamental areas of genotoxicity testing: the identification of a standard set of assays to be conducted for registration, and the extent of confirmatory experimentation in any particular genotoxicity assay in the standard battery. The draft guideline has been released for regulatory consultation under Step 2 of the ICH Process.

S3: TOXICOKINETICS AND PHARMACOKINETICS

IFPMA S3A Toxicokinetics: Guidance on the Assessment of Systemic Exposure in Toxicity Studies Step 5

A harmonised tripartite guideline was adopted in October 1994 which provides guidance on developing test strategies in toxicokinetics and the need to integrate pharmacokinetics into toxicity testing, in order to aid in the interpretation of the toxicology findings and promote rational study design development. This has been implemented by the regulatory parties in the three ICH regions.

IFPMA S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies Step 5

A harmonised tripartite guideline was adopted in October 1994 which gives guidance on circumstances when repeated dose tissue distribution studies should be considered, that is, when appropriate data cannot be derived from other sources. It also gives recommendations on the conduct of such studies. This has been implemented by the regulatory parties in the three ICH regions.

S4: TOXICITY TESTING

S4 Single Dose and Repeat Dose Toxicity Tests Step 5

At the time of ICH 1, agreement was reached on the reduction of the duration of repeat dose toxicity studies in the rat from 12 to 6 months in all three regions and that the LD50 determination should be abandoned for pharmaceuticals.

S4A Repeat Dose Toxicity Tests in Non-Rodents Step 1

At the time of ICH 1, it was also proposed that the duration of repeat dose studies in non-rodents could be reduced from 12 to 6 months. This recommendation is still under discussion and a study is underway of comparative data on different compounds.

S5: REPRODUCTIVE TOXICOLOGY

IFPMA S5A Detection of Toxicity to Reproduction for Medicinal Products Step 5

A harmonised tripartite guideline was adopted in June 1993 which gives guidance on tests for reproductive toxicity, in which animals are treated during defined stages of reproduction, in order to better reflect human exposure to medicinal products and allow more specific identification of stages at risk. The guideline has been implemented and is being widely utilised with the effect that only a single study design is needed for these studies, and duplication of testing is avoided.

IFPMA S5B Reproductive Toxicology: Male Fertility Studies Step 5

An addendum to the main guideline (above) with respect to male fertility studies was agreed at the time of ICH 3. The amendments provide a better description of the testing concept and recommendations, for male fertility studies, especially those addressing flexibility, pre-mating treatment duration, and observations.

S6: BIOTECHNOLOGICAL PRODUCTS

IFPMA S6 Pre-Clinical Studies for Biotechnological Products Step 2

<New> Consensus was reached, at the November meetings, on a draft guideline on the Pre-clinical Safety Testing Requirements for Biotechnological Products. This covers the use of animal models of disease, determination of when genotoxicity assays and carcinogenicity studies should be performed, and the impact of antibody formation on duration of toxicology studies. The draft was released for consultation, under Step 2 of the ICH Process, 7 November 1996.

JOINT SAFETY/EFFICACY (MULTIDISCIPLINARY) TOPIC

IFPMA M3 Timing of Pre-clinical Studies in Relation to Clinical Trials Step 2

<New> Consensus has been reached on a draft guideline on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals which addresses principles for the development of non-clinical strategies on the timing of toxicity studies in relation to the conduct of clinical trials. The draft text represents an important step forward on requirements for the different phases of clinical development but it is recognised that there remain some further important issues to be resolved, within this topic.

Efficacy

IFPMA E1 The Extent of Population Exposure to Assess Clinical Safety Step 5

A harmonised tripartite guideline was adopted in October 1994 which gives recommendations on the numbers of patients and duration of exposure for the safety evaluation of drugs intended for the long-term treatment of non-life-threatening conditions. This has been implemented by the regulatory parties in the three ICH regions.

E2: CLINICAL SAFETY DATA MANAGEMENT

IFPMA E2A Definitions and Standards for Expedited Reporting Step 5

A harmonised tripartite guideline was adopted in October 1994 which gives standard definitions and terminology for key aspects of clinical safety reporting. It also gives guidance on mechanisms for handling expedited (rapid) reporting of adverse drug reactions in the investigational phase of drug development. This has been implemented by the regulatory parties in the three ICH regions.

IFPMA E2B Data Elements for Transmission of ADR Reports Step 2

Consensus was reached in May 1996 on an extension of the above guidelines to standardise the data elements for the transmission of all types of individual case safety reports, regardless of source and destination. The draft guideline has been released for regulatory consultation under Step 2 of the ICH Process.

IFPMA E2C Clinical Safety Data Management: Periodic Safety Update Reports Step 2

<New> A tripartite harmonised ICH guideline has been agreed on the format and content of safety updates, which need to be provided to regulatory authorities, at intervals, after products have been marketed. This has been released at Step 4 of the ICH Process and recommended for regulatory implementation in the three ICH regions.

E3: CLINICAL STUDY REPORTS

IFPMA E3 Clinical Study Reports: Structure and Content Step 5

A harmonised tripartite guideline was agreed, at the time of ICH 3, which will allow a single compilation of world-wide core clinical study reports, for inclusion in regulatory applications. This will ensure more efficient generation of data and submission to the regulatory authorities.

E4: DOSE RESPONSE STUDIES

IFPMA E4 Dose-Response Information to Support Drug Registration Step 5

A harmonised tripartite guideline was adopted in March 1994 which gives recommendations on the design and conduct of studies to assess the relationship between dose, blood levels and clinical response in the early stages of the clinical development of a new drug. These trials are pivotal to the clinical development of a new drug and harmonisation means that they only need to be carried out once, to meet regulatory requirements. This guideline has been implemented by the regulatory parties in the three ICH regions.

E5: ETHNIC FACTORS

E5: Ethnic Factors in the Acceptability of Foreign Clinical Data Step 1

A guideline is under development which addresses the intrinsic characteristics of the drug recipient and extrinsic characteristics associated with environment and culture, which are likely to impact on the results of clinical studies carried out in different ethnic groups. It is anticipated that the guideline will reach Step 2 of the ICH Process in March 1997.

E6: GOOD CLINICAL PRACTICE

IFPMA E6 GCP: Consolidated Guideline Step 4

An ICH harmonised tripartite guideline on Good Clinical Practice (GCP) for the conduct of clinical studies was finalised and adopted by the Steering Committee in May 1996. This is a consolidated document setting out a tripartite standard for the conduct of clinical trials covering aspects of preparation, monitoring, reporting, and archiving of clinical trials and incorporating addenda on the Essential Documents and on the Investigator's Brochure which had been agreed through the ICH process (see below).

E6A: GCP: Addendum on Investigator's Brochure

A harmonised tripartite guideline was finalised in March 1995, which gives recommendations on the clinical and non-clinical information to be included in the brochure provided to investigators and others involved in a clinical trial. This has been incorporated in the ICH consolidated GCP.

E6B: GCP: Addendum on Essential Documents

A harmonised tripartite guideline was finalised in October 1994, which identifies the documentation which must be generated to permit evaluation of the conduct of a trial and the quality of the data produced. This has been incorporated in the ICH consolidated GCP.

E7: CLINICAL TRIALS IN SPECIAL POPULATIONS

IFPMA E7 Clinical Trials in Special Populations: Geriatrics Step 5

A harmonised tripartite guideline was finalised in June 1993, which gives recommendations on the special considerations which apply in the design and conduct of clinical trials on medicines that are likely to have significant use in the elderly. The guideline has been adopted by the regulatory authorities in the three ICH regions.

CLINICAL TRIAL DESIGN

IFPMA E8 General Considerations for Clinical Trials Step 2

<New> Consensus has been reached on a draft guideline which sets out the general scientific principles for the conduct, performance and control of clinical trials. The guideline, which addresses the design and execution of clinical trials and the evaluation of the scientific validity of protocols, was released for regulatory consultation under Step 2 of the ICH Process, on 7 November 1996.

E9 Statistical Considerations in the Design of Clinical Trials Step 1

An ICH guideline is under development using as the core document the EU guideline Biostatistical Methodology in Clinical Trials in Applications for Marketing Authorisations of Medicinal Products, adopted by the CPMP in December 1994, to which additional concepts will be added in response to feedback from each of the regions.
Existing biostatistical documents in each region have different levels of detail which can be an obstacle to the general acceptance of analyses and conslusions from clinical trials, and extrapolation of confirmatory Phase III clinical trials to other regions.

E10 Choice of Control Group in Clinical Trials

Step 1

An ICH guideline is under development on the choice of control groups in clinical trials needed for an approval of a dossier with respect to efficacy and safety.
At present there are major differences in practice and attitudes towards the need for placebo controlled trials (or other trials in which a difference between treatments is shown) and the acceptability of active control equivalance trials as evidence of efficacy and safety. This difference applies both to determinations of intrinsic efficacy and to the need for comparison with other drugs.

Quality

Q1: STABILITY TESTING

IFPMA Q1A Stability Testing of New Drugs and Products Step 5

A harmonised tripartite guideline was adopted in October 1993, which gives recommendations on the stability testing protocols which should be followed to assess the stability of new drug substances and products. Recommendations are given on temperature and humidity levels as well as the duration of trials. The guideline has been adopted by the regulatory agencies in the three ICH regions and is being followed by a majority of companies involved in new drug development. It allows a single protocol for stability testing to be followed, eliminating the need to duplicate studies.

IFPMA Q1B Photo-stability Testing Step 4

<New> A tripartite harmonised ICH guideline was agreed in November 1996 which will form an annex to the main stability guideline, and give guidance on the basic testing protocol required to evaluate the light sensitivity and stability of new drugs and products. This reached Step 4 of the ICH Process on 7 November 1996 and has been recommended for regulatory implementation in the three ICH regions.

IFPMA Q1C Stability Testing: New Formulations Step 4

<New> An extension of the main stability guideline has been agreed which defines the circumstances under which reduced stability data can be accepted, at the time of filing an application, in the case of new formulations of already approved medicines. This reached Step 4 of the ICH Process on 7 November 1996 and has been recommended for regulatory implementation in the three ICH regions.

Q2: VALIDATION OF ANALYTICAL PROCEDURES

IFPMA Q2A Definitions and Terminology Step 5

A harmonised tripartite text was adopted in October 1994, which identifies the validation parameters needed for a variety of analytical methods. It also discusses the characteristics that must be considered during the validation of the analytical procedures which are included as part of registration applications. The text has been incorporated into the regulatory requirements in the three ICH regions.

IFPMA Q2B Methodology Step 4

<New> An extension to the above text has been agreed which describes the actual experimental data required, along with the statistical interpretation, for the validation of analytical procedures. This reached Step 4 of the ICH Process on 7 November 1996 and has been recommended for regulatory implementation in the three ICH regions.

Q3: IMPURITY TESTING

IFPMA Q3A Impurities in New Drug Substances Step 5

A harmonised tripartite guideline was adopted in March 1995, which provides guidance on limits and qualification of impurities in new drug substances, produced by chemical synthesis. The guideline has been implemented by the regulatory parties in the three ICH regions and is being widely followed by companies involved in new drug development, to ensure that a single drug substance specification is developed which is acceptable in all three regions.

IFPMA Q3B Impurities in Dosage Forms Step 4

<New> Agreement has been reached on an extension to the main guideline on impurities in new drug substances. This makes recommendations on the content and qualification of impurities that may arise in the drug products due to degradation of the active ingredient or interaction with other components. This reached Step 4 of the ICH Process on 7 November 1996 and has been recommended for regulatory implementation in the three ICH regions.

IFPMA Q3C Impurities: Residual Solvents Step 2

<New> Consensus has been reached on a draft guideline which recommends the use of less toxic solvents in the manufacture of drug substances and dosage forms, and sets pharmaceutically acceptable limits for residual solvents (organic volatile impurities) in drug products. The guideline was released for regulatory consultation, under Step 2 of the ICH Process on 7 November 1996.

Q4 Pharmacopoeial Harmonisation

The Pharmacopoeial authorities have been closely involved with the work of ICH since the outset and harmonisation between the major Pharmacopoeias, which started before ICH, has proceeded in parallel. The ICH Steering Committee receives regular reports on pharmacopoeial harmonisation at its meetings.

Q5: QUALITY OF BIOTECHNOLOGICAL PRODUCTS

IFPMA Q5A Viral Safety Evaluation Step 2

Scientific consensus was reached, at the time of ICH 3, on a draft guideline entitled Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. This is concerned with testing and evaluation of the viral safety of biotechnology products derived from characterised cell lines of human or animal origin. The purpose is to provide a general framework for virus testing, experiments for the evaluation of virus clearance and the design of viral tests and clearance evaluation studies. It has been released for regulatory consultation in the three ICH regions, under Step 2 of the ICH Process.

IFPMA Q5B Quality of Biotechnological Products: Genetic Stability Step 5

A harmonised tripartite guideline was adopted, at the time of ICH 3, entitled Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products. It advises on the types of information that are considered valuable in assessing the structure of the expression construct used to produce recombinant DNA derived proteins.

IFPMA Q5C Quality of Biotechnological Products: Stability of Products Step 5

A harmonised tripartite guideline was adopted, at the time of ICH 3, which forms an annex to the main ICH Stability Guideline (Q1A above) and deals with the particular aspects of stability test procedures needed to take account of the special characteristics of products, in which the active components are typically proteins and/or polypeptides.

Q5D: Quality of Biotechnological Products: Cell Substrates Step 1

A guideline is under development which will provide broad guidance on appropriate standards for the derivation of human and animal cell lines and microbes used to prepare biotechnological/biological products and for the preparation and characterisation of cell banks to be used for production. It is anticipated that regulatory consultation on the issues will be possible in 1996.Q6:

Q6: SPECIFICATIONS FOR NEW DRUG SUBSTANCES AND PRODUCTS

Bulk drug substance and final product specifications are key parts of the core documentation for world-wide product license applications. However, little if any guidance has been provided on how to set such specifications in a meaningful manner. Thus regulators and manufacturers often find themselves setting or agreeing to conflicting standards for the same product as part of the registration in different regions, leading to increased expenses and opportunities for error, as well as a potential cause for interruption of product supply. The Topic is divided into two parts:

Q6A Chemical Substances Step 1

An ICH guideline will be developed on setting specifications for new chemical drug substances and dosage forms. This will address the process of selecting tests and methods and setting specifications for the testing of drug substances and dosage forms. Account will be taken of the considerable guidance and background information that is present is existing regional documents.

Q6B Biotechnological Substances Step 1

The scope of this part of the Topic will initially be limited to well characterised biotechnological products, although the concepts may be applicable to other biologicals which are not well characterised. In view of the nature of the products, the topic of specifications will include in-process controls, bulk drug, final product, and stability specifications, and will give guidance for a harmonised approach to determining appropriate specifications based on safety, process consistency, purity, analytical methodology, product administration, and clinical data considerations.

Regulatory Communications

In October 1994, the ICH Steering Committee announced a "new direction" in the harmonisation work coming within the purview of ICH. In response to developments in communications technology and the need to avoid divergence in the three regions, which could affect the efficiency of the regulatory process, it was agreed that certain aspects on Regulatory Communications should be included in the ICH Programme.

Regulatory Communication, in this context, involves exchanges:

Two specific aspects are being addressed by ICH: the development of an international Medical Terminology and agreement on Electronic Standards for the Transfer of Information and Data.

M1:

Medical Terminology

Different terminologies for recording drug-related information have been developed at national and international level, especially in the field of adverse drug reaction reporting. It has been agreed that ICH should take up the development of a single medical terminology for regulatory purposes, which could also be used at global level.

Having reviewed existing terminologies, it was agreed that the International Terminology should be developed from the European Union system, MEDDRA (Medical Dictionary for Drug Regulatory Affairs).

A three-stage process was agreed:

Stage 1: Testing of MEDDRA Version 1 by a wide range of potential users, within and outside ICH.

Stage 2: Development of "MEDDRA Version 1.5", by an ICH Expert Working Group, with the objective of it being adopted as an International Terminology.

Stage 3: Globalisation and maintenance of the International Terminology - Version 2.0. At ICH 3 significant progress towards finalisation of MEDDRA Version 2.0 was announced. This will be implemented in a phased manner in the three ICH regions. MEDDRA Version 2.0 will provide significant improvement over current terminologies in comprehensiveness, specificity and as a data retrieval tool, so facilitating and simplifying regulatory processes.

M2:

Electronic Standards for the Transfer of Regulatory Information and Data

A test project is underway to define logical electronic communication standards to ensure the integrity of information and data exchange between pharmaceutical companies and authorities and between authorities. This involves defining those international standards essential for the direct communication of all information associated with applications and product licences as part of the regulatory process.

A test was conducted which involved transferring encrypted and non-encrypted files between a limited number of international centres. Transfer of encrypted files internationally is feasible and a series of structured and unstructured messages were exchanged successfully.

At the time of ICH 3, it was agreed that work on this project should continue and should include the verification of procedures for consistent, accurate transfer of information; the evaluation of encryption technologies and key certification procedures; the development of collaborative projects with other ICH Expert Working Groups; and the consideration of the role of a standards coordination and maintenance group.


Printed Copies of the Guidelines

Printed copies of the ICH guidelines that have reached Step 2 (regulatory consultation) and Step 4 (finalised) may be obtained from the ICH Secretariat and copies are also available on Diskette (MS Word 6). A charge is made to cover the cost of printing, postage and packaging, but single sets can be provided free of charge to governmental and academic institutions and organisations in developing countries.

Contact: ICH Secretariat at ich@ifpma.org giving a fax number, to receive details for ordering.


We hope that you will find this site helpful. Date of current revision: 13 November 1996


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