The Investigator Brochure – A Key Document in Drug Development
The Investigator Brochure – A Key Document in Drug Development
What is Investigator’s Brochure (IB)?
The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. 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.
The IB also provides insight to support the clinical management of the study subjects 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 his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial. For this reason, a medically qualified person should generally participate in the editing of an IB, but the contents of the IB should be approved by the disciplines that generated the described data. This guideline delineates the minimum information that should be included in an IB and provides suggestions for its layout.
It is expected that the type and extent of information available will vary with the stage of development of the investigational product. If the investigational product is marketed and its pharmacology is widely understood by medical practitioners, an extensive IB may not be necessary. Where permitted by regulatory authorities, a basic product information brochure, package leaflet, or labeling 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 a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared. The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor’s written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. However, in accordance with Good Clinical Practice, relevant new information may be so important that it should be communicated to the investigators, and possibly to the Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and/or regulatory authorities before it is included in a revised IB.
The following table includes explanations of various components of an IND application and links to additional information related to application submission.
General Considerations The IB should include:7.2.1 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.
7.2.2 Confidentiality Statement:
The sponsor may wish to include a statement instructing the investigator/recipients to treat the IB as a confidential document for the sole information and use of the investigator’s team and the IRB/IEC.
7.3 Contents of the Investigator’s Brochure:
The IB should contain the following sections, each with literature references where appropriate:
7.3.1 Table of Contents:
An example of the Table of Contents is given in Appendix 2
A brief summary (preferably not exceeding two pages) should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharma co kinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product.
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 investigational product (s ) pharmacological class 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.
7.3.4 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.
7.3.5 Nonclinical Studies Introduction:
The results of all relevant nonclinical pharmacology, toxicology, pharma co-kinetic, 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 therapeutic and the possible unfavorable and unintended effects in humans.
7.3.6 Effects in Humans Introduction:
A thorough discussion of the known effects of the investigational product(s) in humans should be provided, including information on pharma co-kinetics, metabolism, pharma co-dynamics, dose response, safety, efficacy, and other pharmacological activities. Where possible, a summary of each completed clinical trial should be provided. Information should also be provided regarding results of any use of the investigational product(s) other than from in clinical trials, such as from experience during marketing.
7.3.7 Summary of Data and Guidance for the Investigator:
This section should provide an overall discussion of the nonclinical and clinical data, and should summaries 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.
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 human experience and on the pharmacology of the investigational product.
7.4 APPENDIX 1:
TITLE PAGE (Example)
Name(s): Chemical, Generic (if approved)
Trade Name(s) (if legally permissible and desired by the sponsor)
Replaces Previous Edition Number:
7.5 APPENDIX 2:
TABLE OF CONTENTS OF INVESTIGATOR’S BROCHURE (Example)
– Confidentiality Statement (optional)
– Signature Page (optional)
1 Table of Contents
4 Physical, Chemical, and Pharmaceutical Properties and Formulation
5 Nonclinical Studies
5.1 Nonclinical Pharmacology
5.2 Pharma co-kinetics and Product Metabolism in Animals
6 Effects in Humans
6.1 Pharma co-kinetics and Product Metabolism in Humans
6.2 Safety and Efficacy
6.3 Marketing Experience
7 Summary of Data and Guidance for the Investigator
NB: References on
These references should be found at the end of each chapter, Appendices (if any).
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