Guide to the investigational medicinal product dossier

Guide to the investigational medicinal product dossier Item type Authors Publisher Other Irish Medicines Board (IMB) Irish Medicines Board (IMB) Downloaded 1-May-2018 07:31:12 Link to item http://hdl.handle.net/10147/96980 Find this and similar works at - http://www.lenus.ie/hse

IRISH MEDICINES BOARD GUIDE TO THE INVESTIGATIONAL MEDICINAL PRODUCT DOSSIER AUT-G0004.01 NOVEMBER 2006 This guide does not purport to be an interpretation of the law and/or regulations relating to the authorisation and is for guidance purposes only.

IMB Guide to investigational Medicinal Product Dossier CONTENTS SCOPE 1 INTRODUCTION 1 2.1 INVESTIGATIONAL QUALITY DATA 3 SECTION 2.1S - DRUG SUBSTANCE 3 SECTION 2.1P - TEST PRODUCT 9 SECTION 2.1P - PLACEBOS 14 SECTION 2.1P - COMPARATOR PRODUCTS 16 SECTION 2.1A - APPENDICES 18 2.2 PRE-CLINICAL (PHARMACOLOGY AND TOXICOLOGY) DATA 19 2.3 CLINICAL TRIAL AND PREVIOUS HUMAN EXPERIENCE DATA 27 AUT-G0004.01

SCOPE The guidance in this document applies to the Investigational Medicinal Product Dossier (IMPD) submitted with clinical trial applications for medicinal products for human use. INTRODUCTION The IMPD (full or simplified) provides information on the quality of test products, processed comparators and placebos to be used in the clinical trial and data from nonclinical and clinical studies. The following guide outlines the relevant sections that should be detailed in an IMPD. All the headings may not applicable to all applications nor may information under all the headings be available at the time of submission. The applicant may cross-refer to the Investigator s Brochure for pre-clinical and clinical parts of the dossier. Where this is done, it must be clearly stated in the relevant section of the IMPD that a cross-reference has been made. In general a full IMPD should be submitted however a simplified IMPD is acceptable in certain situations. For guidance, please see the table on the next page. If the medicinal product is licensed within the EU and is being for the licensed indication, then a current version of the Summary of Product Characteristics (SPC) may be submitted in place of the IMPD for that product. This guidance document indicates the headings of the IMPD and gives advice on the documentation to be supplied. Please note that the sections are numbered from 2.1 to 2.3, as section 1 of the application comprises the application form and its appended documents. AUT-G0004.01 1/29

Table 1: Reduced information requirements for IMPs known to the IMB A: appendices of the IMPD CTA: clinical trial application P: drug product data S: drug substance data SPC: Summary of Product Characteristics Types of previous assessment Quality data Non-clinical data The IMP has a MA in any EU Member State and is used in the study: within the conditions of the SPC outside the conditions of the SPC with a change to the drug substance manufacture or manufacturer Another pharmaceutical form or strength of the IMP has a MA in any EU Member State and the IMP is supplied by the MAH The IMP has no MA in any EU Member State but is authorised in a MS and: is supplied from the same manufacturer is supplied from another manufacturer The IMP has a previous CTA in the Member State(s) concerned: no new data available since CTA new data available since CTA SPC SPC S+P+A SPC If appropriate No 1 P+A Yes Yes P+A S+P+A No New data Yes Yes No New data The IMP is a placebo P+A No No Clinical data SPC If appropriate No Yes Yes No New data 1 Where the change to drug substance manufacture produces a new potentially toxic substance such as a new impurity or degradation product or introduces a new material in the production of a biological product, additional non-clinical information may be required. AUT-G0004.01 2/29

2.1 INVESTIGATIONAL QUALITY DATA SECTION 2.1S - DRUG SUBSTANCE 2.1.S.1 General Information 2.1.S.1.1 Nomenclature - INN - Chemical name - Other name - Laboratory name Additional, for products of biotechnology - Schematic amino acid sequence - Glycosylation pattern - Other post-translational modifications 2.1.S.1.2 Description - Physical form - Structural formula (including conformational data for macromolecules) - Molecular formula - Relative molecular mass - Chirality 2.1.S.1.3 General Properties Physico-chemical and other relevant properties of the drug substance. 2.1.S.2 Manufacture Data are required for non-pharmacopoeial active substances or for active substances which are monographed in a well-known pharmacopoeia but which are synthesised by a method liable to leave impurities not covered by the monograph. Where the data have been previously supplied in any CT, PA or EU application, they should not be included again but a cross-reference to the application should be given. 2.1.S.2.1 Manufacturer(s) Name(s) and address(es) of the manufacturing site(s) AUT-G0004.01 3/29

2.1.S.2.2 Description of Manufacturing Process and Process Controls - Synthetic route (including flow chart for the process) - Brief description of process including in-process controls - Catalysts, solvents, reagents and any other materials - Purification stage including reprocessing criteria for purification stage, if appropriate For products of biotechnology Details of the manufacturing process, typically starting with a vial from a cell bank through, culture, harvest and purification Explanation of batch numbering system Details of any pooling to be carried out Batch size or scale Cell culture and harvest Flow diagram of the process Detailed explanation of each process step in the diagram Major equipment Process controls with acceptance criteria where available Details of pilot scale fermentation where different from production side Purification and downstream processing Flow diagram of the purification steps up to the step preceding filling Description of each process step in the flow diagram Identification of critical steps Use and re-use of membranes and columns In process controls with acceptance criteria where available Filling, storage, transportation Description of filling procedure for the drug substance Transfer, storage and shipping conditions where appropriate 2.1.S.2.3 Control of Materials Specifications should be given for the following: - Starting materials, i.e., compounds contributing to the final structure of the active substance - Solvents used in purification of the active substance - Reagents for which the correct structure is critical for synthesis, e.g., chirally-active compounds AUT-G0004.01 4/29

For products of biotechnology: Summaries of studies demonstrating freedom from transmissive agents Cell Substrate Information on the source and history of the cell substrate Analysis of the expression construct Cell banking system Details of master and working cell bank Quality control and storage arrangements Stability of the cell line 2.1.S.2.4 Controls of Critical Steps and Intermediate - Intermediates isolated during synthesis - In-process tests, including controls on isomerism during synthesis 2.1.S.2.5 Process Validation and/or Evaluation Brief details should be provided, where relevant. For products of biotechnology Studies demonstrating that the manufacturing process is suitable for its intended purpose. Summary evaluation of those steps designed to remove or inactivate viral contamination. 2.1.S.2 Manufacturing Process Development Brief details should be provided, where relevant. 2.1.S.3 Characterisation Data are required for non-pharmacopoeial active substances or for active substances which are monographed in a well-known pharmacopoeia but which are synthesised by a method liable to leave impurities not covered by the monograph. Where the data have been previously supplied in any CT, PA or EU application, they should not be included again but a cross-reference to the application should be given. AUT-G0004.01 5/29

2.1.S.3.1 Elucidation of Structure and Other Characteristics Evidence of chemical structure from synthetic route, intermediates, elemental analysis, MS, 1H-NMR, 13C-NMR, IR, UV, etc. Spectra should be legible and clear, and assignments should be indicated. Potential isomerism. If appropriate, evidence to support the claimed stereochemistry. Physico-chemical characteristics (solubility, physical characteristics, polymorphism, pka and ph values, other). 2.1.S.3.2 Impurities Potential impurities arising from the route of synthesis, e.g., starting materials, byproducts, intermediates, catalysts, etc. Potential degradants and possible routes of degradation if known. Discussion of suitability of routine analytical methods to detect potential impurities and degradants. Information on impurities and degradants found in batches of active substance to date, including batches used in toxicological and clinical studies. The impurity profile of batches should include the identity of each impurity (by name, HPLC retention time, TLC Rf value, as appropriate) and the levels of each impurity found. The use of each batch should be indicated. The impurity profile of batches of active substance used to manufacture test product for the study should be shown to be adequately qualified by batches used in toxicity studies. 2.1.S.4 Control of Drug Substance 2.1.S.4.1 Specification Active substance described in a pharmacopoeia: For active substances monographed in the current edition of the BP or Ph. Eur. or a well-known pharmacopoeia such as the USP or JP, it is sufficient to state that the material used complies with the monograph. Where the active substance is monographed in a less well-known pharmacopoeia or in an earlier edition of a well-known pharmacopoeia, the full specification should be provided, translated into English if necessary. AUT-G0004.01 6/29

For active substances of animal origin or where a material or reagent of animal origin is used in production, a statement is required regarding compliance of the active substance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products. Active substance not described in a pharmacopoeia For active substances not described in a pharmacopoeia, the in-house specification should be provided. Where the active substance is a herbal drug, the specification of the plant material should include limits on potential pesticides, heavy metals and microbial contamination as appropriate. The tests and limits proposed must be justified in relation to batch and stability data of the active substance and to the impurity profile of batches of the active substance used in toxicity studies. Test limits which are not justified will not be accepted, though approval for the use of particular batches to manufacture test product for the study may be given on a batch-by-batch basis. If any CT, PA or EU application has been submitted previously for the same active substance, confirm that the specification is the same or indicate otherwise For active substances of animal origin or where a material or reagent of animal origin is used in production, a statement is required regarding compliance of the active substance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products 2.1.S.4.2 Analytical Procedures Brief details of test methods should be given. 2.1.S.4.3 Validation of Analytical Procedures Analytical validation for non-pharmacopoeial methods, as summarised data for each parameter validated. 2.1.S.4.4 Batch Analyses Batches tested (batch number, batch size, date of manufacture and use of each batch). Results of tests, including the impurity profiles Certificate(s) of analysis for the batch(es) of active substance used to manufacture test product for the study. AUT-G0004.01 7/29

2.1.S.4.5 Justification of specification A summarised justification of the tests and limits should be given. 2.1.S.5 Reference Standards or Materials Characterisation of the primary reference standard. Information on the reference standard, its characterisation, specification and test results. 2.1.S.6 Container Closure System Brief details of the container and closure used to store the active substance. 2.1.S.7 Stability No stability data are required for active substances monographed in a pharmacopoeia (see 2.1.S.4.1) or active substances with an established use. Data are required for all other active substances (principally new chemical entities). The following information should be submitted: - Details of batches tested. - Storage conditions. - Test methods and validation (or a reference to 2.1.S.4.2 if the methods are the same). The methods used should be shown to be capable of detecting degradation products. - Stability results, including results for degradation products. - Proposed re-test period, which must be supported by the data provided. AUT-G0004.01 8/29

SECTION 2.1P TEST PRODUCT 2.1.P.1 Description and Composition of the Medicinal Product The full qualitative and quantitative composition should be given per unit dose or per unit volume or weight or percentage, as appropriate. The ingredients in capsule shells, tablets coatings, polishes, excipient mixtures, etc., should be included. 2.1.P.2 Pharmaceutical Development 2.1.P.2.1 Components of the Medicinal Product 2.1.P.2.1.1 Drug Substance Brief details should be provided, where relevant. 2.1.P.2.1.2 Excipients Brief details should be provided, where relevant. 2.1.P.2.2 Medicinal Product 2.1.P.2.2.1 Formulation Development Brief details of any pharmaceutical development work carried out should be provided. Formulations of the product used in any previous clinical trials reported in support of this application; the formulations and corresponding clinical trials should be clearly indicated. 2.1.P.2.2.2 Overages Any overage should be indicated, and justified. 2.1.P.2.2.3 Physicochemical and Biological Properties For modified-release products, the dissolution specification should be discussed in terms of the proposed dosage regimen and patient safety, and in-vitro/in vivo results previously obtained. If the test product is a marketed product which is blinded for the purposes of the trial, data are required to show that blinding does not significantly affect dissolution. Comparative dissolution data should be provided on product pre and post-blinding or AUT-G0004.01 9/29

at a minimum, on blinded product only. Any differences considered by the applicant to have a significant effect on in vivo/clinical performance should be discussed. 2.1. P.2.3 Manufacturing Process Development Brief details, where relevant. 2.1.P.2.4 Container Closure System A brief description of the containers should be provided 2.1.P.2.5 Microbiological Attributes Results of preservative efficacy testing should be provided where appropriate for liquid or semi-solid dosage forms. Justification is required for the method of manufacture of sterile products where the product is not subject to a terminal sterilisation procedure. 2.1.P.2.6 Compatibility Compatibility of the active and excipients, where relevant. 2.1.P.3 Manufacture 2.1.P.3.1 Manufacturer(s) Name(s) and address(es) of manufacturer(s). 2.1.P.3.2 Batch Formula The manufacturing formula should be given, including any ingredients which are removed during manufacture. 2.1.P.3.3 Description of Manufacturing Process and Process Controls A brief description of the manufacturing process should be provided. Full details of any sterilisation process should be given. The inclusion of flow diagrams may be useful. 2.1.P.3.4 Controls of Critical Steps and Intermediates A brief description should be provided of in-process controls (tests and limits). For an aseptically filled sterile product, it is expected that bioburden limits of less than 10 cfu/100 ml will be specified for the bulk solution. AUT-G0004.01 10/29

2.1.P.3.5 Process Validation and/or Evaluation Brief details of any process validation results should be provided, particularly for critical manufacturing steps. For standard production methods, no information would generally be required. 2.1.P.4 Control of Excipients 2.1.P.4.1 Specifications Excipient(s) described in a pharmacopoeia: For excipients monographed in the BP or Ph. Eur. or a well-known pharmacopoeia such as the USP or JP, it is sufficient to state that the material used complies with the current monograph. Excipient(s) not described in a pharmacopoeia: For excipients not described in a well-known pharmacopoeia, the in-house specification should be provided. The specification should include identification, purity and content tests as appropriate. Any flavouring agent should be confirmed as complying with Directive 88/388/EEC and all ingredients should be confirmed as being generally recognised as safe. 2.1.P.4.2 Analytical Procedures Brief details of test methods should be given. 2.1.P.4.3 Validation of Analytical Procedures Summarised validation data for any non-pharmacopoeial analytical methods. 2.1.P.4.4 Justification of Specifications A summarised justification of the tests and limits should be given. 2.1.P.4.5 Excipients of Human or Animal Origin For excipients of animal origin or where a material or reagent of animal origin is used in production, a statement is required regarding compliance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products. AUT-G0004.01 11/29

2.1.P.4.6 Novel Excipients Where a new excipient is proposed, evidence is required that the substance is safe for its intended use in the test product. 2.1.P.5 Control of Medicinal Product 2.1.P.5.1 Specification(s) Release and shelf-life specifications should be provided. If the test product is over-encapsulated, specifications should be provided both for the test product and for the over-encapsulated product. 2.1.P.5.2 Analytical Procedures Brief details of the test procedures used. If methods of the BP, Ph. Eur. or another well-known pharmacopoeia are used, a reference to the test method is sufficient. 2.1.P.5.3 Validation of Analytical Procedures Summarised validation data for any non-pharmacopoeial analytical methods. 2.1.P.5.4 Batch analysis Results of batch analytical testing, including batch numbers, batch size and dates of manufacture. Certificates of analysis (signed) should be provided where deemed necessary by the IMB for batches of test product (and for over-encapsulated product, if relevant) to be used in the study. If not available at the time of submission, they may be provided before commencement of the study. If further batches are required for the study, certificates of analysis should be provided and written approval of the IMB obtained before use. 2.1.P.5.5 Characterisation of Impurities Brief details should be provided. 2.1.P.5.6 Justification of Specification(s) A summarised justification of the tests and limits should be given. Where impurities limits are not supported by the impurity profiles of batches used in non-clinical or clinical studies, the specification limits will not be approved. Batches for use in the study will, however, be accepted on a batch-by-batch basis, provided that levels of related substances are deemed acceptable. In AUT-G0004.01 12/29

these cases, the certificate of analysis of each batch should be submitted to the IMB before they are used in the study. 2.1.P.6 Reference Standards or Materials Information on the reference standard used in the analytical methods. 2.1.P.7 Container Closure System - Type of material - Construction - Quality specification (routine tests) and test procedures The above data are only required for non-standard immediate packaging material. 2.1.P.8 Stability At the time of submission, data on the formulation for the study may be limited. The proposed shelf life may therefore be supported by data on related formulations. The following information should be provided: - Shelf-life specification if different from the release specification. - Details of batches tested and of packaging. - Storage conditions. - Test methods and validation. The methods used should be shown to be capable of detecting degradation products. - Stability results, including results for degradation products. - Proposed shelf life and storage conditions, which must be supported by the data package provided. When sufficient data in the proposed formulation are not available to support the intended shelf life, stability data on related formulations may be acceptable provided that results on the study formulation are provided on an on-going basis. AUT-G0004.01 13/29

SECTION 2.1P PLACEBOS 2.1.P.1 Description and Composition of the Placebo Product The full qualitative and quantitative composition should be given per unit dose or per unit volume or weight or percentage, as appropriate. The ingredients in capsule shells, tablets coatings, polishes, excipient mixtures, etc., should be included. 2.1.P.3 Manufacture This section should be completed for sterile placebos only. 2.1.P.3.1 Manufacturer(s) State the name and address of the manufacturer(s). 2.1.P.3.2 Batch Formula The manufacturing formula should be given, including any ingredients which are removed during manufacture. 2.1.P.3.3 Description of Manufacturing Process and Process Controls A brief description of the manufacturing process should be provided. Full details of any sterilisation process should be given. The inclusion of flow diagrams may be useful. 2.1.P.3.4 Controls of Critical Steps and Intermediates A brief description should be provided of in-process controls (tests and limits). For an aseptically filled sterile product, it is expected that bioburden limits of less than 10 cfu/100 ml will be specified for the bulk solution. 2.1.P.4 Control of Excipients 2.1.P.4.1 Specifications Excipient(s) described in a pharmacopoeia For excipients monographed in the BP or Ph. Eur. or a well-known pharmacopoeia such as the USP or JP, it is sufficient to state that the material used complies with the current monograph. AUT-G0004.01 14/29

Excipient(s) not described in a pharmacopoeia For excipients not described in a well-known pharmacopoeia, the in-house specification should be provided. The specification should include identification, purity and content tests as appropriate. Any flavouring agent should be confirmed as complying with Directive 88/388/EEC and all ingredients should be confirmed as being generally recognised as safe. 2.1.P.4.5 Excipients of Human or Animal Origin For excipients of animal origin or where a material or reagent of animal origin is used in production, a statement is required regarding compliance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products. 2.1.P.4.6 Novel Excipients Where a new excipient is proposed, evidence is required that the substance is safe for its intended use in the test product. 2.1.P.5 Control of Placebo 2.1.P.5.1 Specification(s) Release and shelf-life specifications should be provided, which will include a test for the absence of the active substance. If the placebo is over-encapsulated, specifications should be provided both for the placebo and for the over-encapsulated placebo. 2.1.P.5.4 Batch analyses Certificates of analysis are not routinely required for batches of placebo to be used in the study, where these have been manufactured under conditions of GMP and released by a Qualified Person in accordance with the provisions of Article 13 of Directive 2001/20/EC and to a specification which ensures the absence of active substance. The IMB reserves the right to request certificates of analysis for placebo in certain situations. AUT-G0004.01 15/29

SECTION 2.1P COMPARATOR PRODUCTS Where an authorised comparator product containing an established active substance is used in a study without further processing or re-packaging, no pharmaceutical information need be supplied. 2.1.P.1 Description and Composition of Comparator Product For comparator products which are over-encapsulated or subject to any processing, details are required of the names and quantities of ay additional ingredients. 2.1.P.2.2.1 Formulation Development Data are required to show that blinding of comparator does not significantly affect dissolution. Comparative dissolution profiles should be provided for product pre- and post-blinding. Any differences considered by the applicant to have a significant effect on in vivo/clinical performance should be discussed. 2.1.P.3 Manufacture This section should be completed for comparator products which are overencapsulated or subject to any processing. 2.1.P.3.1 Manufacturer(s) State the name and address of the manufacturer(s). 2.1.P.3.2 Batch Formula The manufacturing formula should be given, including any ingredients which are removed during manufacture. 2.1.P.3.3 Description of Manufacturing Process and Process Controls A brief description of the manufacturing process should be provided. Full details of any sterilisation process should be given. The inclusion of flow diagrams may be useful. 2.1.P.3.4 Controls of Critical Steps and Intermediates A brief description should be provided of in-process controls (tests and limits). For an aseptically filled sterile product, it is expected that bio burden limits of less than 10 cfu/100 ml will be specified for the bulk solution. AUT-G0004.01 16/29

2.1.P.4 Control of Excipients This section should be completed for comparator products which are overencapsulated or subject to any processing. 2.1.P.4.1 Specifications Excipient(s) described in a pharmacopoeia: For excipients monographed in the BP or Ph. Eur. or a well-known pharmacopoeia such as the USP or JP, it is sufficient to state that the material used complies with the current monograph. Excipient(s) not described in a pharmacopoeia: For excipients not described in a well-known pharmacopoeia, the in-house specification should be provided. The specification should include identification, purity and content tests as appropriate. Any flavouring agent should be confirmed as complying with Directive 88/388/EEC and all ingredients should be confirmed as being generally recognised as safe. 2.1.P.4.5 Excipients of Human or Animal Origin For excipients of animal origin or where a material or reagent of animal origin is used in production, a statement is required regarding compliance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products. 2.1.P.4.6 Novel Excipients Where a new excipient is proposed, evidence is required that the substance is safe for its intended use in the test product. 2.1.P.5 Control of Comparator Product 2.1.P.5.1 Specification(s) Release and shelf-life specifications should be provided for over-encapsulated or processed comparators. 2.1.P.5.4 Batch Analyses Results of batch analytical testing, including batch numbers, batch size and dates of manufacture. AUT-G0004.01 17/29

Certificates of analysis (signed) should be provided where deemed necessary by the IMB for batches of comparator product (and for over-encapsulated product, if relevant) to be used in the study. If not available at the time of submission, they may be provided before commencement of the study. 2.1.P.8 Stability If the comparator is packaged in a different container to that in which it is marketed, stability data should be provided or the product may be tested concurrently with the study. A suitable shelf life should be proposed, based on the original manufacturer s expiry date. If no stability testing is carried out, the expiry date should not exceed 25 % of the remaining time between the date of re-packaging and the expiry date on the original container or a six months period from the date the product is repackaged, whichever is earlier. For comparator products subject to any processing, stability data may be provided with the application with a proposed shelf life supported by the data. Alternatively a commitment to test concurrently and provide the results on an on-going basis may be acceptable, with a suitable proposal for an expiry date based on the expiry date of the original manufacturer. SECTION 2.1A - APPENDICES 2.1.A.1 Facilities and Equipment 2.1.A.2 Adventitious Agents Safety Evaluation 2.1.A.3 Novel Excipients 2.1.A.4 Solvents for Reconstitution and Diluents AUT-G0004.01 18/29

2.2 PRE-CLINICAL (PHARMACOLOGY AND TOXICOLOGY) DATA The sponsor should provide summaries of pre-clinical pharmacology and toxicology data for any IMP to be used in the clinical trial. They should also provide a reference list of studies conducted and appropriate literature references. Full data from the studies and copies of the references should be made available on request. The summaries of the studies conducted should allow an assessment of the adequacy of the study and whether the study has been conducted according to an acceptable protocol. The sponsor should provide a critical analysis of the available data, including justification for the approach taken, and an assessment of the efficacy and safety of the product in the context of the proposed clinical trial rather than a mere factual summary of the studies conducted. The studies needed as a basis for the pre-clinical section of the full IMPD are outlined below and detailed in relevant EU guidelines (available from the EMEA website www.emea.eu.int). All studies should be conducted according to currently acceptable state-of-the-art protocols. In addition, they should meet the requirements of Good Laboratory Practice guidelines where appropriate. The test material used in the toxicity studies should be representative of that proposed for clinical trial use. 2.2.1 Pharmacodynamics 2.2.1.1 Brief Summary A brief outline of the mechanism of action of the IMP in the context of the proposed clinical indication should be included. 2.2.1.2 Primary Pharmacodynamics Prior to first administration to man, sufficient pharmacodynamic data should be provided to demonstrate proof of principle, i.e. evidence to support the potential efficacy of the IMP in the proposed condition. This should include suitable in vitro and/or in vivo models. 2.2.1.3 Secondary Pharmacodynamics The potential for pharmacological or physiological effects other than the therapeutic effect, i.e. secondary pharmacology, should be considered. Available data should be summarised and discussed. 2.2.1.4 Safety Pharmacology Safety pharmacology includes the assessment of the effects of the IMP on vital functions, e.g. the cardiovascular, central nervous and respiratory systems, these AUT-G0004.01 19/29

should be evaluated prior to Phase I (Human Pharmacology) studies. 1 These evaluations may be conducted as a part of toxicity studies or as separate studies. GLP compliance is normally required. 2.2.1.5 Pharmacodynamic Interactions The potential for co-administration of other products and any possible interaction, based on known mechanisms of action, should be considered prior to Phase II (Therapeutic Exploratory) studies. In particular, potential interactions with hormonal birth control methods should be assessed prior to exposure of women of childbearing potential. 2.2.1.6 Discussion and Conclusion A brief, critical analysis of the available data should be included. 2.2.2 Pharmacokinetics 2.2.2.1 Brief Summary An introduction to the proposed formulation and the proposed clinical administration should be included. 2.2.2.2 Methods of Analysis The methods of analysis used in each study should be stated, including; accuracy, precision, linearity, limits of detection etc. The method should be validated for the medium, e.g. rat plasma or dog serum. The analyte should be clearly stated, e.g. salt or free base. For comparison, quantitative results should be converted to the same units and tabulated, e.g. mm or mg/ml not both. Statistical methodology should be clearly stated, where relevant. 2.2.2.3 Absorption Exposure data from animal models should be evaluated prior to first administration in man. 2 These evaluations may be conducted as a part of toxicity studies or as separate studies. The data should be sufficient to allow interpretation of the submitted preclinical studies and to support the proposed clinical trial protocol. The data can be presented in tabular format to allow for cross species comparison, results should be expressed in the same units, e.g. µg/ml or mm, not both. Human data should be included where available. 2.2.2.4 Distribution Data from distribution studies in relevant species should be available by the time Phase I (Human Pharmacology) studies have been completed. AUT-G0004.01 20/29

2.2.2.5 Metabolism Data from metabolism studies in vitro and in relevant species should be available by the time Phase I (Human Pharmacology) studies have been completed. 2.2.2.6 Excretion Data from excretion studies in relevant species should be available by the time Phase I (Human Pharmacology) studies have been completed. 2.2.2.7 Pharmacokinetic Interactions The potential for co-administration of other products and any possible interaction should be considered prior to Phase II (Therapeutic Exploratory) studies, e.g. saturability of metabolic, absorption or elimination routes, inhibition or induction of metabolic enzymes. In particular, potential interactions with hormonal birth control methods should be assessed prior to exposure of women of childbearing potential. 2.2.2.8 Other Pharmacokinetic Studies Any other relevant information should be presented. 2.2.2.9 Discussion and Conclusions (including evaluation of toxicokinetics) Pharmacokinetic and toxicokinetic data should be integrated into the overall efficacy and safety assessment in a brief, critical analysis. For example; the relevance of the species used, the impact of formulation and route of administration, exposure comparisons for safety studies etc., could be discussed. 2.2.3 Toxicology Studies should be conducted according to GLP and in line with internationally recognised protocols. In vivo studies should be supported by appropriate toxicokinetic data, sample analysis should be available from all dose groups, including controls. 2.2.3.1 Brief Summary The available toxicology should be described briefly and the approach explained in the context of the proposed clinical trial. 2.2.3.2 Single Dose Toxicity The single dose (acute) toxicity of the IMP should be evaluated in two mammalian species (one non-rodent) prior to first human exposure. Single dose or dose escalation study designs are considered acceptable. AUT-G0004.01 21/29

2.2.3.3 Repeated Dose Toxicity The primary goal of repeated dose toxicity studies is to characterise the toxicological profile of the IMP following repeated administration. The protocol can be tailored to the test compound and the proposed use, but should follow the most recent guidelines. 3 The recommended duration of repeated dose toxicity studies is usually related to the duration, therapeutic indication and scale of the proposed clinical trial. In principle, the duration of animal toxicity studies conducted in two mammalian species (one non-rodent) should be equal to or exceed the duration of the clinical trial, up to the maximum recommended duration of chronic toxicity studies. 4 Minimum Duration of Repeated Dose Toxicity Studies (weeks) Duration of Clinical Trial Rodents Non-Rodents Phase I / II Phase III Phase I / II Phase III Single Dose 2-2 - Up to 2-weeks 2 4 2 4 Up to 1-month 4 12 4 12 Up to 3-months 12 26 12 12 Over 3-months - 26-26/40 * Up to 6-months 26 26 - Over 6-months 26 26/40 * - *Chronic toxicity studies of 6-months duration are recommended in the EU, however if a study of 9-months duration has been conducted for another jurisdiction this is accepted, to avoid duplication. 2.2.3.4 Genotoxicity Studies 2.2.3.4.1 In vitro studies Prior to first human exposure, in vitro studies for the evaluation of mutagenicity and chromosomal damage should be completed. Studies can be presented in tabular format, including; cell line, metabolic activating system, dose range, cytotoxic/cytostatic effects. If equivocal or positive findings occur then additional testing should be performed and the issue should be discussed in some detail. 5 The standard battery of tests for genotoxicity should be completed prior to Phase II (Therapeutic Exploratory) clinical trials. 6 2.2.3.4.2 In vivo studies As part of the standard battery of tests for genotoxicity, in vivo studies should be completed prior to Phase II (Therapeutic Exploratory) clinical trials. 6 These studies should be supported by pharmacokinetic and/or toxicokinetic data. AUT-G0004.01 22/29

2.2.3.5 Carcinogenicity Studies Completed carcinogenicity studies are not usually needed prior to clinical trials unless there is cause for concern. 7 An evaluation of the need for carcinogenicity studies should be conducted prior to Phase III (Therapeutic Confirmatory) studies and the justification presented. 2.2.3.6 Reproduction Toxicity Studies Reproduction toxicity studies should be conducted as is appropriate for the population that is to be exposed. 2.2.3.6.1 Men and Women-Not-of-Childbearing-Potential Men and women-not-of-childbearing-potential may be included in Phase I/II clinical trials prior to conducting reproduction toxicity studies, provided that evaluation of the reproductive organs is performed in repeated dose toxicity studies. 1 A male fertility study should be completed prior to the initiation of Phase III clinical trials. 9 2.2.3.6.2 Women-of-Childbearing-Potential For women-of-childbearing-potential there is a high level of concern for the unintentional exposure of an embryo/foetus before sufficient information is available for a benefit:risk assessment. Pregnancy is normally excluded prior to clinical trial and avoided while on clinical trial by means of highly effective birth control, testing and monitoring for pregnancy may form part of longer-term clinical trial protocols. Assessment of the embryotoxicity and teratogenicity potential of treatment 10 should be completed prior to Phase I/II clinical trials and female fertility studies 10 prior to Phase III clinical trials in women-of-childbearing-potential. 1 The peri- and post-natal development study 10 should be submitted at marketing approval or earlier if there is cause for concern. 1 If women whose pregnancy status is unknown are likely to be enrolled in the clinical trial then the full range of reproduction toxicity studies and genotoxicity studies should be available prior to clinical trial approval. 1 2.2.3.6.3 Pregnant Women Pregnant women are not normally included in clinical trials. Prior to the inclusion of pregnant women in clinical trials, all reproduction toxicity studies 9, 10 and the full battery of genotoxicity tests 6 should have been conducted. In addition, safety data from previous human exposure are generally needed. Highly effective birth control is defined as a method which results in a low failure rate, i.e. <1% per year, when used consistently and correctly. For subjects using a hormonal products, assessment of potential interactions between the product and the treatment under evaluation should be conducted. AUT-G0004.01 23/29

2.2.3.7. Local Tolerance The local tolerance of the IMP should be studied in animals using routes relevant to the proposed clinical administration. 1, 8 The evaluation of local tolerance should be performed prior to human exposure and may be incorporated into other toxicity studies. 2.2.3.8 Other Studies Additional pre-clinical studies are considered appropriate if the IMP s physicochemical / biochemical characteristics, previous studies or clinical findings have indicated specific safety concerns. 2.2.3.9 Discussion and Conclusions A brief, critical analysis of the available data should be included. Deviations and omissions from standard approaches should be justified. The safety data should be interpreted in the context of the proposed clinical use, any potential adverse effects should be highlighted for monitoring during the clinical trial. 2.2.4 Special Circumstances 2.2.4.1 Incomplete Data A reduced package of pre-clinical studies may be accepted in certain circumstances, for example: (a) when the clinical trial is in a life-threatening condition for which there are limited treatment options, e.g. cancer, 12 or (b) when the clinical trial uses a single sub-pharmacological (micro-) dose of a product, e.g. PET imaging. 13 These issues will be assessed on a case-by-case basis. 2.2.4.2 Biotechnology Derived Products The same type and standard of information regarding pre-clinical efficacy and safety issues should be addressed in these applications, i.e. proof of principle, pharmacokinetic parameters, potential impact on other organs / systems (in particular the immune system). Nonetheless, it is acknowledged that many of the standard toxicity tests are unsuitable for these products and alternative approaches may need to be applied. Particular emphasis should be placed on relating a product s physicochemical and biochemical characteristics to the efficacy and safety assessment, the impact of the formulation on the active agent should also be considered. Issues relating to biotechnology derived products are addressed in the EU guideline. 11 These products will be assessed on a case-by-case basis. AUT-G0004.01 24/29

2.2.4.3 Gene Therapy Gene therapy is an evolving field, state-of-the-art safety evaluation should always be applied. Of particular concern would be issues such as; viral safety, immunogenicity, insertional mutagenesis and germ-line insertion. 14 Gene therapy clinical trials will always be approached on a case-by-case basis. 2.2.4.4 Paediatric Populations Data from pharmacodynamic, safety pharmacology and pharmacokinetic studies, as well as appropriate repeated dose toxicity studies, all reproduction toxicity studies and the full battery of genotoxicity studies should be available prior to the initiation of clinical trials in paediatric populations. Data from previous adult exposure would normally also be available and may provide the most relevant safety information. The need for carcinogenicity studies should be addressed prior to long-term exposure of paediatric patients. 1 Paediatric clinical trials will always be approached on a caseby-case basis. AUT-G0004.01 25/29

References 1. CPMP/ICH/286/95 modification Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. 2. CPMP/ICH/384/95 Note for guidance on toxicokinetics: a guidance for assessing systemic exposure in toxicology studies. 3. CPMP/SWP/1042/99 Note for guidance on repeated dose toxicity. 4. CPMP/ICH/300/95 Note for guidance on duration of chronic toxicity testing in animals (rodent and non-rodent) 5. CPMP/ICH/141/95 Note for guidance on genotoxicity: guidance on specific aspects of regulatory genotoxicity tests for pharmaceuticals. 6. CPMP/ICH/174/95 Note for guidance on genotoxicity: a standard battery for genotoxicity testing of pharmaceuticals. 7. CPMP/ICH/140/95 Note for guidance on the need for carcinogenicity studies of pharmaceuticals. 8. CPMP/SWP/2145/00 Note for guidance on non-clinical local tolerance testing of medicinal products. 9. CPMP/ICH/95 Note for guidance on reproductive toxicology: toxicity on male fertility. 10. CPMP/ICH/386/95 Note for guidance on reproductive toxicology: detection of toxicity to reproduction for medicinal products. 11. CPMP/IICH/302/95 Note for guidance on pre-clinical safety evaluation of biotechnology derived pharmaceuticals. 12. CPMP/SWP/997/96 Note for guidance on the pre-clinical evaluation of anticancer medicinal products. 13. CPMP/SWP/2599/02 Position paper on non-clinical safety studies to support clinical trials with a single microdose. 14. CPMP/BWP/3088/99 Note for guidance on the quality, pre-clinical and clinical aspects of gene transfer medicinal products. AUT-G0004.01 26/29

2.3 CLINICAL TRIAL AND PREVIOUS HUMAN EXPERIENCE DATA 2.3.1. Clinical pharmacology A rationale for the use of the drug in the proposed clinical trial should be given and consideration given to the following points where quantitative information from studies in humans is available. - Mechanism of the primary pharmacological action in man. - Secondary pharmacological affects. - Comparison with other standard drug substances in the same class. - The presence of any active metabolites which may contribute to its primary or secondary pharmacological activity. - Interactions with other compounds that may be used concomitantly during the trial. Information should be provided under the following headings: 2.3.1.1 Brief summary 2.3.1.2 Mechanism of primary action 2.3.1.3 Secondary pharmacological effects 2.3.1.4 Pharmacodynamic interactions 2.3.2 Clinical pharmacokinetics Information on the extent of absorption, distribution, metabolism and excretion should be provided for the proposed dose and route of administration and for any other doses or modes of administration that are available. Consideration should also be given to the following points where applicable. - Justification for the dose used in the proposed therapeutic trial. - Effects on dosage form, route of administration, age, gender, race and food on the bioavailability. - Comparison of human and animal pharmacokinetic parameters especially for species used in toxicity studies. - Interactions with other compounds that may be used concomitantly during the trial. Information should be provided under the following headings: AUT-G0004.01 27/29

2.3.2.1 Brief summary 2.3.2.2 Absorption 2.3.2.3 Distribution 2.3.2.4 Elimination 2.3.2.5 Pharmacokinetics of active metabolites 2.3.2.6 Plasma concentration-effect relationship 2.3.2.7 Dose and time-dependencies 2.3.2.8 Special patient populations 2.3.2.9 Interactions 2.3.3 Human exposure 2.3.3.1 Brief summary 2.3.3.2 Overview of Safety and Efficacy 2.3.3.3 Healthy subject studies All studies conducted with the drug in normal human volunteers must be reported. Summary information should be quantitative with a description of the trial and the number of subjects exposed to the drug and to the duration of exposure. A summary of all the safety data should be provided and discussed in relation to the toxicity findings and any anticipated requirements for safety monitoring. 2.3.3.4 Patient studies All studies conducted with the drug in patients must be reported. Summaries of the use of the drug in patients with the proposed indication or indications should be provided. The information should give a clear description of the trial, the numbers of patients exposed to the drug, the doses used, the route of administration and the duration of the trial and quantitative results. All safety data should be provided in a summary with a discussion in relation to the toxicity studies and any anticipate requirements for safety monitoring. A detailed discussion should be provided where the toxicity findings appear to predict adverse events that occurred in patient studies. Information from post marketing surveillance or pharmacovigilance on the safety of the drug in clinical practice should be provided in summary form outlining specifically any areas of safety concern that might be relevant for the proposed trial. AUT-G0004.01 28/29

2.3.3.5 Previous human experience When a drug proposed for clinical trials in Ireland has been used extensively as a licensed product in other countries and adequate safety data from that use can be provided, a clinical trial authorisation may be granted without completing the recommended package of toxicity studies. The details necessary will depend on the applicant providing a justification of why some of the toxicity studies should not be performed and reassurance of the relevance and adequacy of the safety data in relation to the compound to be used in the proposed clinical trial. 2.3.4 Benefits and risks assessment AUT-G0004.01 29/29