Appendix A. INVESTIGATOR’S BROCHURE

ICH HARMONISED GUIDELINE
GOOD CLINICAL PRACTICE (GCP) E6(R3)

Step 5, 23 January 2025. 

Date for coming into effect 23 July 2025

A.1 Introduction

The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) [1] that are relevant to the study of the product(s) in human participants. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for and their compliance with many key features of the protocol, such as the dose, dose frequency/interval, methods of administration and safety monitoring procedures.

[1] For the purpose of this guideline, the term investigational products should be considered synonymous
with drugs, medicines, medicinal products, vaccines and biological products.

A.1.1 Development of the Investigator’s Brochure

Generally, the sponsor is responsible for ensuring that an up-to-date IB is developed. In the case of an investigator-initiated trial, the sponsor-investigator should determine whether a brochure is available from the product license/marketing authorisation holder. If the investigational product is provided by the sponsor-investigator, then they should provide the necessary information to the investigator site staff. Where permitted by regulatory authorities, the current scientific information such as a basic product information brochure (e.g., summary of product characteristics package leaflet, or labelling) may be an appropriate alternative, provided that it includes current, comprehensive and detailed information on all aspects of the investigational product that might be of importance to the investigator. If an authorised medicinal product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared unless there is a rationale for only one IB. The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor’s documented procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. Relevant new information may be so important that it needs to be communicated to the investigators and possibly to the institutional review boards/independent ethics committees (IRBs/IECs) and/or regulatory authorities before it is included in a revised IB.

A.1.2 Reference Safety Information and Risk-Benefit Assessment

The reference safety information (RSI) contained in the IB provides an important reference point for expedited reporting of suspected unexpected serious adverse reactions (SUSARs) in the clinical trial. This RSI should include a list of adverse reactions, including information on their frequency and nature. This list should be used for determining the expectedness of a suspected serious adverse reaction and subsequently whether reporting needs to be expedited in accordance with applicable regulatory requirements (see section 3.13.2(c)).

The IB also provides insight to support the clinical management of the participants during the course of the clinical trial. The information should be presented in a concise, simple, objective, balanced and non-promotional form that enables a clinician or potential investigator to understand it and make their own unbiased risk-benefit assessment of the appropriateness of the proposed trial. For this reason, a medically qualified person should be involved in the generation of an IB, but the contents of the IB should be approved by the disciplines that generated the described data.

A.2 General Considerations

These considerations delineate the minimum information that should be included in an IB. It is expected that the type and extent of information available will vary with the stage of development of the investigational product.

The IB should include:

A.2.1 Title Page

This should provide the sponsor’s name, the identity of each investigational product (i.e., research number, chemical or approved generic name and trade name(s) where legally permissible and desired by the sponsor) and the release date. It is also suggested that an edition number and a reference to the number and date of the edition it supersedes be provided along with the cut-off date for data inclusion in the version. Where appropriate, a signature page may be included.

A.2.2 Confidentiality Statement

The sponsor may wish to include a statement instructing the investigator and other recipients to treat the IB as a confidential document for the sole information and use of the investigator/institution, investigator site staff, regulatory authorities and the IRB/IEC.

A.3 Contents of the Investigator’s Brochure

The IB should contain the following sections, each with literature references (publications or reports) included at the end of each chapter, where appropriate:

A.3.1 Table of Contents

A.3.2 Summary

A brief summary (preferably not exceeding two pages) should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic and clinical information available that is relevant to the stage of clinical development of the investigational product.

A.3.3 Introduction

A brief introductory statement should be provided that contains the chemical name (and generic and trade name(s) when approved) of the investigational product(s); all active ingredients; the pharmacological class of the investigational product(s) and its expected position within this class (e.g., advantages); the rationale for performing research with the investigational product(s); and the anticipated prophylactic, therapeutic or diagnostic indication(s). Finally, the introductory statement should provide the general approach to be followed in evaluating the investigational product.

A.3.4 Physical, Chemical and Pharmaceutical Properties and Formulation

A description should be provided of the investigational product substance(s) (including the chemical and/or structural formula(e)), and a brief summary should be given of the relevant physical, chemical and pharmaceutical properties.

To permit appropriate safety measures to be taken in the course of the trial, a description of the formulation(s) to be used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and handling of the dosage form(s) should also be given.

Any structural similarities to other known compounds should be mentioned.

A.3.5 Nonclinical Studies

Introduction

The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic and investigational product metabolism studies should be provided in summary form. This summary should address the methodology used, the results and a discussion of the relevance of the findings to the investigated product and the possible unfavourable and unintended effects in humans.

The information provided may include the following, as appropriate, if known/available:

• Species tested

• Number and sex of animals in each group

• Unit dose (e.g., milligram/kilogram (mg/kg))

• Dose interval

• Route of administration

• Duration of dosing

• Information on systemic distribution

• Duration of post-exposure follow-up

• Results, including the following aspects:

    - Nature and frequency of pharmacological or toxic effects

    - Severity or intensity of pharmacological or toxic effects

    - Time to onset of effects

    - Reversibility of effects

    - Duration of effects

    - Dose response

Tabular format/listings should be used whenever possible to enhance the clarity of the presentation.

The following sections should discuss the most important findings from the studies, including the dose response of observed effects, the relevance to humans and any aspects to be studied in humans. If applicable, the effective and nontoxic dose findings in the same animal species should be compared (i.e., the therapeutic index should be discussed). The relevance of this information to the proposed human dosing should be addressed. Whenever possible, comparisons should be made in terms of blood/tissue levels or human equivalent dose rather than on a mg/kg basis.

(a) Nonclinical Pharmacology

A summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites studied in animals should be included. Such a summary should incorporate studies that assess potential therapeutic activity (e.g., efficacy models, receptor binding and specificity) as well as those that assess safety (e.g., special studies to assess pharmacological actions other than the intended therapeutic effect(s)).

(b) Pharmacokinetics and Product Metabolism in Animals

A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied should be given. The discussion of the findings should address the absorption and the local and systemic bioavailability of the investigational product and its metabolites and their relationship to the pharmacological and toxicological findings in animal species.

(c) Toxicology

A summary of the toxicological effects found in relevant studies conducted in different animal species should be described under the following headings where appropriate:

• Single toxicity
   
• Repeated dose toxicity
   
• Genotoxicity
   
• Carcinogenicity
   
• Reproductive and developmental toxicity
   
• Local tolerance
   
• Other toxicity studies
   

A.3.6 Effects in Humans

Introduction

A thorough discussion of the known effects of the investigational product(s) in humans should be provided, including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy and other pharmacological activities. Where possible, a summary of each completed clinical trial and ongoing trials where interim results are available that may inform the safety evaluation should be provided. Information should also be provided regarding results of any use of the investigational product(s) other than from clinical trials, such as from experience during marketing.

(a) Pharmacokinetics and product metabolism in humans

A summary of information on the pharmacokinetics of the investigational product(s) should be presented, including the following, if available:

• Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution and elimination)
   
• Bioavailability of the investigational product (absolute, where possible, and/or relative) using a reference dosage form
   
• Population subgroups (e.g., sex, age and impaired organ function)
   
• Interactions (e.g., product-product interactions and effects of food)
   
• Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s))

(b) Safety and Efficacy

A summary of information should be provided about the investigational product’s/products’ (including metabolites, where appropriate) safety,

pharmacodynamics, efficacy and dose response that was obtained from preceding trials in humans (healthy volunteers and/or patients). The implications of this information should be discussed. In cases where a number of clinical trials have been completed, the use of summaries of safety and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular summaries of adverse drug reactions, including information on their frequency and natures for all the clinical trials (including those for all the studied indications) would be useful. Important differences in adverse drug reaction patterns/incidences across indications or subgroups should be discussed.

The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of prior experiences with the product under investigation and with related products. A description should also be provided of the precautions or special monitoring to be done as part of the investigational use of the product(s).

(c) Marketing Experience

The IB should identify countries where the investigational product has been marketed or approved. Any significant information arising from the marketed use should be summarised (e.g., formulations, dosages, routes of administration, adverse drug reactions). The IB should also identify all the countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration.

A.3.7 Summary of Data and Guidance

This section should provide an overall discussion of the nonclinical and clinical data and should summarise the information from various sources on different aspects of the investigational product(s), wherever possible. In this way, the investigator can be provided with the most informative interpretation of the available data and with an assessment of the implications of the information for future clinical trials.

Where appropriate, the published reports on related products should be discussed. This could help the investigator to anticipate adverse drug reactions or other problems in clinical trials.

The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and adverse reactions and of the specific tests, observations and precautions that may be needed for a clinical trial. This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological and clinical information on the investigational product(s). Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that is based on previous clinical and nonclinical experience and on the pharmacology of the investigational product.


Author: © European Medicines Agency, 2025. Reproduction is authorised provided the source is acknowledged.

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