ICH guideline development

A total of 45 guidelines were produced during the first phase of ICH under quality, safety, efficacy and multidisciplinary topics. It soon became clear that updating of the guidelines is an ongoing activity. A selected listing of the guidelines is set out on the following pages and complete copies are available from http://www.ifpma.org.

Harmonization initiatives that are undertaken under the auspices of ICH are guided and overseen by the ICH Steering Committee, which is composed of representatives of the six co-sponsors and observers. The Committee meets on average 2-3 times a year.

ICH Expert Working Groups (EWGs) are responsible for the drafting of individual guidelines. EWGs are made up of representatives from the six co-sponsors, according to the topic under discussion. Participation has also been extended recently to observers, the pharmacopoeial authorities, generic industry associations and representatives of the non-prescription pharmaceutical industry.

Each ICH guideline proceeds through the following stages:

Step 1: The development of a consensus among scientists working in industry and regulatory agencies who discuss the topic in Expert Working Group meetings and exchange views on successive draft documents. The drafting process is conducted by a Rapporteur.

Step 2: Is reached when the Steering Committee accepts the consensus draft and it is transmitted to the three regional regulatory agencies for formal consultation in accordance with normal internal and or external procedures.

Step 3: The draft guideline leaves the ICH process and is treated in the three ICH regions as a regulatory draft for consultation. In the European Union it is circulated as a CPMP draft guideline, in Japan it is translated and circulated internally and externally for consultation, and in the USA it is published as a consultation document in the Federal Register. Comments are collected by the regulatory agencies in the three regions and are consolidated by a Regulatory Rapporteur in order that a single, harmonized text can be adopted for implementation.

Step 4: Is reached when the final consolidated draft is accepted by the Steering Committee and "signed off" by the six co-sponsors.

Step 5: Is reached when the guideline has been adopted by the three regulatory authorities and incorporated into their appropriate administrative procedures. Simultaneous public announcements are made by regulatory authorities.

ICH documents currently available

The following summaries describe ICH Guidelines produced so far and are provided as information. An update of those Guidelines discussed during the recent International Conference on Harmonization held in November 2000 follows on page 159.

Efficacy testing guidelines

To date, the ICH has produced 11 guidelines addressing the efficacy assessment of new chemical and biological entities.

E1A The Extent of Population Exposure to Assess Clinical Safety (Adopted at Step 4 -1994)

This is a brief guideline which establishes the number of patients to be treated and minimum duration of treatment periods for the safety evaluation of drugs intended for the long-term treatment of non-life threatening diseases.

E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (Adopted at Step 4-1994)

Definitions for adverse event (or experience) terms and adverse reactions. The guideline also gives the recommended timeframe for reporting to regulatory agencies adverse drug reactions which occur during clinical development. Attachment 1 sets out the Key Data Elements for inclusion in expedited reports of serious adverse drug reactions.

E2B Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports (Adopted at Step 4 -1997)

This guideline extends E2A to give details of the data elements required for reporting individual cases of safety events (adverse drug reactions or adverse drug events) for both pre and post approval periods. The guideline covers reporting of adverse drug reactions and events from all sources and to any destinations, including reporting from authorities to the WHO Collaborating Centre for International Drug Monitoring.

E2C Periodic Safety Update Reports for Marketed Drugs (Adopted at Step 4 - 1996)

This guideline sets out the format and content for comprehensive periodic safety updates of marketed drugs for reporting to regulatory authorities. The PSUR presents the worldwide safety experience of a medicinal product at defined times (6-monthly or in multiples of 6-monthly reports) after the date of the first marketing authorization for the product granted to any company in any country in the world (international birthdate). The guideline also provides a sample model for a periodic safety update report.

E3 Structure and Content of Clinical Study Reports (Adopted at Step 4 - 1995)

This guideline sets out the structure and content of a report to allow for the compilation of a single integrated full report of any clinical study which will be acceptable to all regulatory authorities of the ICH. The report consists of the clinical and statistical description, presentations, and analysis integrated into a single report text and with appendices containing the protocol, sample case report forms, investigator related information, information related to the test drugs/investigational products including active control/comparators, technical statistical documentation, related publications, patient data listings and technical statistical details such as deviations, computations, analysis and computer output, etc. Appendices are intended to be additional information required by only some regulatory authorities and may be requested as needed.

E4 Dose Response Information to Support Drug Registration (Adopted at Step 4 -1994)

This guideline sets out the purpose, principles and study design for the determination of the relationship among dose, drug-concentration in blood, and clinical response (effectiveness and undesirable effects).

E5 Ethnic Factors in the Acceptability of Foreign Clinical Data (Adopted Step 4 -1998)

This guideline recommends a framework for evaluating the impact of ethnic factors upon a medicine's effect (its efficacy and safety at a particular dosage and dose regimen) in order to facilitate the registration of medicines among the ICH regions. Ethnic factors are defined as those factors relating to the genetic and physiological (intrinsic) and the cultural and environmental (extrinsic) characteristics of a population. The guideline also provides on outline of the properties of a compound which makes it more or less likely to be sensitive to ethnic factors. It also defines the circumstances when additional data (called bridging studies) may be needed in order to allow extrapolation of the foreign data to a new region.

E6 Good Clinical Practice: Consolidated Guideline (Adopted at Step 4 -1996)

This guideline sets out the principles and procedures to be followed when designing, conducting, recording and reporting clinical trial data that are intended to be submitted to regulatory authorities. It also provides details on the information which should be included in the Investigator's Brochure, the clinical trial protocol and the essential documentation to be collected during the course of a clinical trial.

E7 Studies in Support of Special Populations: Geriatrics (Adopted at Step 4 -1993)

This guideline sets out the principles required for the development of new drugs, new formulations and new combinations of established medicinal products which are likely to have significant use in the elderly, either because the disease intended to be treated is characteristically a disease of ageing or because the population to be treated is known to include substantial numbers of geriatric patients. The guideline defines the geriatric population and details the pharmacokinetic, pharmacodynamic (dose/response studies) and drug interaction studies which should be undertaken.

E8 General Considerations for Clinical Trials (Adopted at Step 4 - 1997)

This guideline provides an overview of the principles and practices in undertaking clinical trials for the development of new medicinal products. It illustrates the relationship between the phases of clinical development and types of study by objective and the general principles of design, conduct and analysis of trials.

E9 Statistical Principles for Clinical Trials (Adopted at Step 4 - 1998)

This guideline sets out the principles of statistical methodology to be applied to clinical trials for medicinal products being developed for marketing applications in the ICH regions.

E10 Choice of Control Group and Related Issues in Clinical Trials (Adopted at Step 4 - 2000)

The purpose of this guideline is to describe the general principles involved in choosing a control group for clinical trials intended to demonstrate the efficacy of a treatment and to discuss related trial design and conduct issues. This guideline does not address the regulatory requirements in any region, but describes what trials using each design can demonstrate.

E11 Clinical Investigation of Medicinal Products in the Paediatric Population (Adopted at Step 4 - 2000)

The goal of this guideline is to encourage and facilitate timely paediatric medicinal product development internationally. The guideline provides an outline of critical issues in paediatric drug development and approaches to the safe, efficient, and ethical study of medicinal products in the paediatric population.

Quality testing guidelines

Q1A Stability Testing of New Drug Substances and Products (Adopted at Step 4 -1993)

The scope of the guideline is confined to new molecular entities and associated drug products. Well-established active substances and associated products (generics) are not included.

Stability testing conditions:

Long-term testing: for both drug substances and drug products: 25° C ± 2° C/60% RH ± 5% for 12 months. Accelerated testing: for both drug substances and drug products: 40° C ± 2° C/75% RH ± 5% for 6 months. The long-term testing is continued for a sufficient period of time beyond 12 months to cover all appropriate re-test periods (for drug substances). Where "significant change" occurs during 6 months storage under conditions accelerated testing, additional testing at intermediate conditions of 30° C ± 2° C/60% RH ± 5% is carried out. "Significant change" at 40° C/75% RH or 30° C/60% RH is defined as failure to meet the specifications. Mutual acceptability of information generated on stability in any one of the areas has been established, provided it meets the appropriate requirements of the guideline and the labelling is in accordance with national/regional requirements.

The ICH Harmonized Tripartite Guideline on stability testing of new drug substances and products (Q1 A) notes that light testing should be an integral part of stress testing.

(Note: The WHO Stability Guideline covers the four climatic zones, whereas the ICH guideline covers only two climatic zones.

Furthermore, the WHO guidelines cover multisource products, whereas the ICH Guideline is confined to new molecular entities and associated drug products.)

Q1B Photostability Testing of New Drug Substances and Products (adopted at Step 4 - 1996)

The Guideline on Photostability Testing Q1B is an annex to guideline Q1A. The Q1B guideline addresses the generation of photostability information for submission of Registration Applications for New Molecular Entities and associated drug products. The guideline does not cover photostability of drugs after administration (i.e. under conditions of use).

A systematic approach to photostability testing is recommended in the guideline covering studies such as: (i) Tests on the drug substance; (ii) Tests on the exposed drug product outside the immediate pack; (iii) Tests on the drug product in the immediate pack (if necessary); and (iv) Tests on the drug product in the marketing pack (if necessary). A detailed Decision Flow Chart is established which describes how the extent of drug product testing can be established by assessing the change that has occurred at the end of the light exposure testing. Acceptable change is change within limits justified by the applicant. The guideline gives detailed information on light sources, procedure, presentation of samples, analysis of samples and judgement of results.

Q1C Stability Testing: Requirements for New Dosage Forms (adopted at Step 4 - 1996)

This guideline is an annex to guideline Q1A. The Q1C guideline addresses the recommendations on what should be submitted regarding stability of new dosage forms by the owner of the original application after the original submission of new drug substances and products. Stability protocols for new dosage forms should follow the Q1A guideline in principle. However, a reduced stability data base at submission time (e.g. 6 months accelerated and 6 months long-term data from ongoing studies) may be acceptable in certain cases.

Q2A Text on Validation of Analytical Procedures (adopted at Step 4 - 1994)

The guideline discusses the characteristics to be considered during the validation of analytical procedures included in the Registration Application submitted to drug regulatory authorities (DRA) in the EU, Japan and USA. The guideline contains a collection of terms and their definitions with the object of bridging the differences that often exist between various compendia and DRAs in the EU, Japan and USA. The types of analytical procedures to be validated are included in the guideline besides a tabular summation of the characteristics applicable to these different types: identification tests, control of impurities (i.e. quantitative tests for impurities content, limit tests for the control of impurities) as well as assay procedures (i.e. quantitative tests of the active moiety in samples of drug substance or drug product, or other selected components of the drug product). The validation characteristics of an analytical procedure (Accuracy, Precision, Repeatability, Intermediate Precision, Specificity, Detection Limit, Quantitation Limit, Linearity and Range) are defined in a glossary at the end of the guideline. Although robustness is not included in the table of typical validation characteristics, it is stated that it should be considered at an appropriate stage in the development of the analytical procedure. Revalidation should be carried out in case of changes in the synthesis of drug substance, in the composition of the finished product or in the analytical procedure.

Q2B Validation of Analytical Procedure - Methodology (adopted at Step 4 - 1996)

The guideline is complementary to the parent guideline Q2A on Validation of Analytical Procedures. The purpose of the guideline is to provide some guidance and recommendations on how to consider various validation characteristics for each analytical procedure. The guideline states that different approaches may be applicable for the validation, provided that they demonstrate that the procedure is suitable for its intended use. Also analytical procedures for biological and biotechnological products may be approached differently. The guideline considers the various validation characteristics in distinct sections: Specificity (identification and assay as well as impurity tests), Linearity, Range, Accuracy (assay, quantitation of impurities), Precision (repeatability, intermediate precision, reproducibility), Detection limit (based on visual evaluation, based on signal-to-noise, based on standard deviation of the response and the slope), Quantitation limit (based on visual evaluation, based on signal-to-noise, based on standard deviation of the response and the slope), Robustness, System suitability testing.

Q3A Impurities in New Drug Substances (Adopted at Step 4 -1995)

The guideline provides guidance for Registration Applications on the content and qualification of impurities in new drug substances produced by chemical synthesis. It is not intended to apply to new drug substances used in clinical trials. It does not cover biological/biotechnological peptides, oligonucleotides, radiopharmaceuticals, fermentation products, herbal products, and crude products of animal or plant origin. The guideline addresses chemistry aspects and safety aspects of impurities which are classified into the three following categories: organic impurities, inorganic impurities, residual solvents. Regarding organic impurities, the new drug substance specifications should include, where applicable, limits for: (i) Each Specified Identified Impurity; (ii) Each Specified Unidentified Impurity at or above 0.1%; (iii) Any Unspecified Impurity, with a limit of not more than 0.1%; and (iv) Total Impurities. Significant emphasis is placed on the qualification of impurities, i.e. establishing the safety of impurities at the levels specified. The applicant should provide a rationale for selecting impurity limits based on safety considerations. Qualification threshold is 0.05% in case the maximum daily dose exceeds 2g/day. The guideline includes a glossary and a decision tree for safety studies.

Q3B Impurities in New Drug Products (Adopted at Step 4 -1996)

The guideline provides guidance recommendations for registration or marketing applications on the content and qualification of impurities in new drug products produced from chemically synthesized new drug substances. The guideline is an annex to the guideline on Impurities in New Drug Substances (Q3A). The scope of the guideline is confined to degradation products of the active ingredients or reaction products of the active ingredients with an excipient and/or immediate container/closure system. The guideline does not cover impurities arising from excipients present in the drug product. The guideline does not apply during clinical research stages of development. Biological/biotechnological products, peptides, oligonucleotides, radiopharmaceuticals, fermentation products and semisynthetic products, herbal products, and crude products of animal or plant origin are not covered. Also excluded from the guideline are: extraneous contaminants which are more appropriately addressed as GMP issues, polymorphic forms, and enantiomeric impurities. Impurities present in the new drug substance need not be monitored in drug products unless they are also degradation products. The guideline deals with the analytical procedures to be used and the necessity that they are validated and the specification limits for impurities as well as the qualification of impurities. The guideline includes a glossary, thresholds for reporting, thresholds for identification and thresholds for qualification of degradation products in New Drug Products. A decision tree for safety studies is included.

Q3C Impurities: Guideline for Residual Solvents (Adopted at Step 4 -1997)

The guideline recommends acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The solvents are classified in the guideline into three classes: Class 1: solvents to be avoided; Class 2: solvents to be limited; Class 3: solvents with low toxic potential. The guideline describes two options for describing limits of class 2 solvents. Also concentration limits for solvents to be avoided are given. The guideline includes a glossary and an appendix listing solvents included in the guideline in addition to a second appendix giving additional background and a third appendix describing methods for establishing exposure limits.

Q4 Pharmacopoeial Harmonization

Already at the start of the ICH process, it was realized that the harmonization of drug quality requirements and test methods presented in pharmacopoeia monographs would not be possible through elaboration of specific guidelines, but should be treated differently, because harmonization has to affect separately each method and each individual substance. For that reason, a Pharmacopoeia Discussion Group (PDG) was established by representatives of three pharmacopoeias from the ICH group of countries: the European Pharmacopoeia, the Japanese Pharmacopoeia and the United States Pharmacopeia. The activity of PDG has proceeded in parallel to the work of ICH and in close involvement with its harmonization efforts. In the period 1992 -1999 the efforts of the PDG were directed toward harmonization of a number of general methods of drug analysis, including methods used for the analysis of biotechnology products, and towards harmonization of quality requirements contained in pharmacopoeia monographs for a considerable number of excipients and several products obtained by biotechnology. In the process of harmonization, the PDG has established a list of 45 excipients that were most widely used in preparation of dosage forms or were considered critical for their quality. By mid-1999 the PDG has achieved harmonization of some 70% of the relevant monographs between the 3 pharmacopoeias. Considerable progress has also been achieved towards harmonization of important general methods and apparatus used in quality testing of dosage forms. Further efforts in this area are continuing in connection with the work on Q6A guideline where a number of pharmacopoeial test methods which previously differed between the 3 pharmacopoeias has been now harmonized. The harmonization of pharmacopoeial requirements through the PDG activities results in practice in the elevation of quality standards through the use of more sophisticated test methods but this requires the use of highly special apparatus and costly reagents. Also the requirement to use in the tests of only official reference materials of high unit cost, which is now quite frequent in the case of testing drug impurities, tends to increase further the expenses for the testing of drug quality according to harmonized methods.

Q5A Viral Safety Evaluation of Biotechnology Products (Adopted at Step 4 -1997)

The guideline is concerned with testing and evaluation of the viral safety of biotechnology products derived from characterized cell lines of human or animal origin (i.e. mammalian, avian, insect). The term virus in this guideline excludes non-conventional transmissible agents such as those associated with Bovine Spongiform Encephalopathy (BSE) and scrapie. The scope of the guideline covers products derived from cell cultures initiated from characterized cell banks. It covers products derived from in-vitro cell culture, such as interferons, monoclonal antibodies and recombinant DNA-derived products including recombinant subunit vaccines, and also includes products derived from hybridoma cells grown in vivo as ascites. Excluded from the scope of this guideline are inactivated vaccines, all live vaccines containing self-replicating agents, and genetically engineered live vectors.

The guideline describes potential sources of virus contamination. It states that viral contamination of biotechnology products may arise from the original source of the cell line or from adventitious introduction of viruses during production processes. The guideline describes cell line qualification: Testing for viruses; Tests for Master Cell Bank (MCB), for Working Cell Bank (WCB), and cells at the limit of in vitro cell age used for production and recommended viral detection and identification assays such as: tests for retroviruses, in-vitro assays, in-vivo assays, antibody production tests. The guideline describes the acceptability of cell lines used for the manufacture of product on a risk-benefit basis. Also testing for viruses in unprocessed bulk is described. Inactivating or removing viruses is described in the guideline on the basis of viral clearance studies. The guideline includes specific precautions to be observed as well as a glossary. In summary, the guideline suggests approaches for the evaluation of the risk of viral contamination and for the removal of virus from the product, thus contributing to the production of safe biotechnology products derived from animal or human cell lines.

Q5B Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for Production of rDNA derived protein products (Adopted at Step 4 - 1995)

The guideline presents guidance for the characterization of the expression construct for the production of recombinant DNA protein products in eukaryotic and prokaryotic cells. This is important to ensure the consistent production of a recombinant DNA derived product. Nucleic acid analysis data and the evaluation of the final purified protein serve to ensure the quality of a recombinant protein product.

Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products (Adopted at Step 4 -1995)

The guideline is considered an annex to the parent guideline Q1A, "Stability Testing of New Drug Substances and Products" (1993), whose content applies to biotechnological/biological products. However, because of the distinguishing characteristics of the biotechnological/biological products, these should be given special consideration in stability testing. Being proteins and/or polypeptides, maintenance of molecular conformation is dependent on covalent and non-covalent forces. They are particularly sensitive to temperature change, oxidation, light, ionic contents and shear. Stringent storage conditions are usually necessary to ensure maintenance of biological activity. For stability studies complex analytical methodologies may be necessary. Assays for biological activity, where applicable, should be part of the stability studies. Biochemical, physicochemical and immunochemical methods for the analysis of the molecular entity and the quantitative detection of degradation products should be part of the stability studies. The scope of the guideline covers products such as cytokines (interferons, interleukins, colony stimulating factors, tumour necrosis factors), erythropoietins, plasminogen activators, blood plasma factors, growth hormones and growth factors, insulin, monoclonal antibodies and vaccines consisting of well-characterized proteins or polypeptides, i.e. well-characterized proteins and polypeptides, their derivatives and products of which they are components, and which are isolated from tissues, body fluids, cell cultures or produced using rDNA technology. The guideline does not cover antibiotics, allergenic extracts, heparins, vitamins, whole blood, or cellular components. The guideline handles selection of batches of bulk materials, intermediates and final container product as well as sample selection. Validated methods should be used to assess potency, purity and molecular characteristics. The guideline describes further storage conditions, testing frequency, specification and labelling of biotechnology products. A glossary is included.

Q5D Quality of Biotechnological Products: Derivation and Characterization of Cell Substrates used for Production of Biotechnological/Biological Products (Adopted at Step 4-1997)

The guideline provides broad guidance on standards for the derivation of human and animal cells and microbial cells to be used to prepare biotechnological/biological products and for the preparation and characterization of cell banks to be used for production. The guideline covers cell substrates having a cell banking system, i.e. microbial cells or cell lines derived from human or animal sources that possess the full potential for the generation of the desired biotechnological/biological products for human in vivo or ex vivo use. Reagents for in vitro diagnostic use are outside the scope of this guideline. Animal sources of cell lines include all those of metazoan origin. Microbial sources include bacteria, fungi, yeast, and other unicellular life forms. Biotechnological/biological products in the guideline are any products prepared from cells cultivated from cell banks with the exception of microbial metabolites, such as antibiotics, amino acids, carbohydrates, and other low molecular weight substances. Included in the guideline are cell banks used to prepare gene therapy products or vaccines. Also certain viral vaccines are prepared in primary cell cultures derived directly from animal tissues or organs. Primary cells are not banked and therefore not addressed by this guideline. However, other considerations which may apply to primary cells are discussed further in the Appendix. The guideline handles generation of cell substrates, origin, sources and history of cells, cell banking, cell banking procedures as well as principles of characterisation and testing of cell banks, such as tests of identity, tests of purity for both microbial and metazoan cells. The guideline describes further how cell substrate stability is tested. Also tests for karyology and tumourigenicity are used for characterization. A glossary is included.

Q6A Specifications for New Drug Substances and New Drug Products: Chemical Substances (Adopted at Step 4-1999)

The guideline is intended to assist in the establishment of a single set of global specifications for new drug substances and new drug products. It provides guidance on the setting and justification of acceptance criteria and the selection of test procedures for new drug substances of synthetic chemical origin and new drug products produced from them. The guideline addresses specifications, i.e. those tests, procedures and acceptance criteria used to assure the quality of the new drug substance and new drug product at release and during shelf-life. Specifications are an important component of quality assurance, but are not its only component. Other components are design, development, in-process controls, GMP controls, and process validation. Guidance is provided with regard to universal acceptance criteria, which should be established for all new substances and drug products and those which are considered specific to individual drug substances and/or dosage forms. The guideline gives a definition for general concepts which are important in setting harmonized specifications. These concepts are not universal, but can be considered in particular circumstances. They include: periodic/skip testing, release vs. shelf-life acceptance criteria, in-process tests, design and development considerations, limited data available at filing, parametric release, alternative procedures, pharmacopoeial tests and acceptance criteria, evolving technologies, impact of drug substance on drug product specifications, reference standards.

The guideline does not address drug substances or drug products during clinical research stages of drug development. Biological/biotechnological products, high molecular weight peptides, oligonucleotides, fermentation products, radiopharmaceuticals, herbal products, and crude products of animal or plant origin are not covered by the guideline. The full utility of this guideline is dependent on the successful completion of harmonization of pharmacopoeial procedures for several attributes commonly considered in the specifications for new drug substances or new drug products.

Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (Adopted at Step 4 -1999)

The guideline contains the requirements for the testing of products obtained by biotechnology. The guideline provides general principles on the setting and justification of a uniform set of international specifications for biotechnological and biological products to support marketing applications. The scope of the guideline covers proteins and polypeptides, their derivatives, and products of which they are components, e.g. conjugates. These proteins and polypeptides are produced from recombinant or nonrecombinant cell-culture expression systems and can be highly purified and characterised using an appropriate set of analytical procedures. The principles outlined in this guideline apply also to proteins and polypeptides isolated from tissues and body fluids. The following are not covered: antibiotics, synthetic peptides and polypeptides, heparins, vitamins, cell metabolites, DNA products, allergenic extracts, conventional vaccines, cells, whole blood and cellular blood components. The principles to be considered in setting specifications are described in detail as:

• characterization (physicochemical properties, biological activity, immunochemical properties, purity, quantity)

• analytical considerations: (reference standards and reference materials, validation of analytical procedures)

• process control (process-related considerations, in-process acceptance criteria and action limits, raw materials and excipient specifications)

• pharmacopoeial specifications

• release limits versus shelf-life limits

• statistical concepts.

A justification of the specifications is handled in detail. A glossary is included in the guideline.

Safety testing guidelines

S1A Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals (Adopted Step 4-1995)

This guideline sets out the definitions of 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.

S1B Testing for Carcinogenicity of Pharmaceuticals (Adopted Step 4 - 1997)

This guideline outlines the scientific approach to testing pharmaceuticals for carcinogenicity in both mice and rats, and provides guidance on alternative testing procedures which may be applied without jeopardizing safety.

S1C Dose Selection for Carcinogenicity Studies of Pharmaceuticals (Adopted Step 4 -1995)

This guideline sets out the criteria for the selection of the high dose to be used in carcinogenicity studies for new therapeutic agents.

S2A Genotoxicity: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals (Adopted Step 4 -1995)

This guideline gives specific guidance and recommendations for in vitro and in vivo tests and on the evaluation of test results. It also includes a glossary of terms related to genotoxicity tests.

S2B Genotoxicity - A Standard Battery for Standard Genotoxicity Testing of Pharmaceuticals (Adopted Step 4-1997)

This guideline sets out a standard set of assays to be conducted for registration of new medicinal products and the extent of confirmatory experimentation in any particular genotoxicity assay in the standard battery.

S3A Note for Guidance on Toxicokinetics: the Assessment of Systemic Exposure in Toxicity Studies (Adopted Step 4 -1994)

This guideline gives guidance on developing test strategies in toxicokinetics and the need to integrate pharmacokinetics into toxicity tests in order to aid in the interpretation of the toxicity findings and promote rational study design development.

S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies (Adopted Step 4-1994)

This guideline gives guidance on the circumstances when repeated dose tissue distribution studies should be considered (i.e. when appropriate data cannot be derived from other sources). It also gives recommendations on the conduct of such studies.

S4 Single Dose Toxicity Tests (Adopted at ICH-1, 1991)

Agreement was made in 1991 that the LD₅₀ determination should be abandoned on pharmaceuticals.

S4 Duration of Chronic Toxicity Testing in Animals (Rodent and Non-Rodent Toxicity Testing) (Adopted Step 4-1998)

Sets out guidance for repeated dose toxicity tests.

S5A Detection of Toxicity to Reproduction for Medicinal Products (Adopted Step 4 -1993)

This guideline gives guidance on the tests required 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 of risk.

S5B Reproductive Toxicology: Male Fertility Studies (an Addendum to S5A) (Adopted Step 4-1995)

This guideline is an Addendum to S5A to 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 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (Adopted at Step 4 -1997)

This guideline gives guidance on the preclinical safety testing requirements for biotechnology products, It 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 the duration of toxicology studies.

Multidisciplinary guidelines

In this group of guidelines only guideline M3 has reached the implementation stage although M1, M2 and M3, discussed on page 159, are nearing implementation.

M3 Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (Adopted at Step 4 -1997)

The guideline addresses the principles of developing pre-clinical strategies on the timing of toxicity studies in relation to the conduct of clinical trials. It covers the timing of single dose and repeated dose toxicity studies, reproduction toxicity studies, genotoxicity studies, local tolerance studies and carcinogenicity studies as well as studies for safety pharmacology and pharmacokinetic studies in relation to different phases of human clinical trials.

ICH documents currently under discussion (2000)

The main ICH documents that are at present at the development stage include the M4 guideline on Common Technical Document and the Q7A guideline on GMP for Active Pharmaceutical Ingredients. Other guidelines that are still under development include guidelines in the drug efficacy and drug safety areas as well as a revision of several quality guidelines. At the International Conference on Harmonization held in November 2000 further progress in preparation of the guidelines was achieved and several other guidelines proposed for development.

Efficacy Guidelines

Guidelines that are under development include:

• E2B(M) - Data Elements for Transmission of Individual Case Safety Reports.

• E12A - Principles for Clinical Evaluation of New Antihypertensive Drugs. It is intended that this guideline should serve as an example for a whole series of guidelines on clinical trials of specific groups of drugs.

Quality guidelines

Several important guidelines related to this area are still at various stages of development including:

• Q1Ar- Guideline on Stability Testing of New Drug Substances and Products.

• Q3Ar - Guideline on Impurities in New Drug Substances.

• Q3Br - Guideline on Impurities in New Drug Products.

• Q3C(_M) - Impurities: Residual Solvents - (PDE for tetrahydrofuran) (PDE for N-methylpyrrolidone).

• Q7A - Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. The guideline is intended to produce a common text for good practices in the manufacture of pharmaceutical substances used as active ingredients. It will describe all elements of control required in process during production of active pharmaceutical ingredients, as well as requirements for all wholesalers (agents, brokers, distributors, etc.) trading in these products.

Safety Guidelines

• S7 - Safety Pharmacology Studies for Human Pharmaceuticals. The guideline will describe the core battery of safety pharmacology studies, the necessity of such studies and the application of Good Laboratory Practices to safety pharmacology.

Multidisciplinary Guidelines

• M1 Medical Terminology

The guideline will describe a single medical terminology for drug regulatory purposes, including adverse drug reaction reporting. After discussing medical terminologies that currently exist and are in extensive use it was decided to select the MEDDRA terminology developed by the Medicines Control Agency in UK as suitable for the needs of the electronic transfer of data. The MEDDRA dictionary has taken into consideration the terms of several widely used terminologies, including WHOART (WHO Adverse Reaction Terminology), COSTART (used by US FDA) and ICD 9. Future modifications may include additional terms, such as those in the ICD 10.

• M2 Electronic Standards for the Transfer of Information and Data

The guideline will define electronic communication standards for direct communication of applications for drug registration, and drug safety data in a way that ensures the integrity of information. It should facilitate the exchange of data between pharmaceutical companies and drug regulatory authorities.

• M4 Common Technical Document

The Common technical document should serve as a standard document for submission of applications to drug regulatory authorities for registration of a new product. The document would consist of a general part (M4) and 3 specialized parts for sub-topics M4Q, M4S and M4E. The latter deal with the elements related to quality, safety and efficacy issues. Various parts of the document have now been completed and it was finalized during the International Conference on Harmonization in November 2000.