An Investigator’s Brochure is a collection of clinical and non-clinical data about the investigational products that are the focus of the study. The brochure should provide an ongoing insight into the clinical trial study participants during the duration of the trial.
The purpose of an Investigator’s Brochure is to provide Investigators and other crucial people involved in the trial with enough information to help their understanding of the reasons for and compliance with the key features of a clinical trial protocol including dose, dose frequency, methods of administration and safety monitoring procedures.
The information featured in an Investigator’s Brochure should be presented in a concise, simple, objective, balanced and non-promotional manner so an Investigator has a clear understanding and can make their own unbiased risk-benefit assessment. A medically qualified professional should be involved in the editing process of the Investigator’s Brochure.
The information included in the Investigator’s Brochure will differ depending on the stage of development of the investigational product (medicinal product, device or therapeutic intervention). The International Council for Harmonisation’s guidelines states that if the investigational product is marketed and the pharmacology is known by medical practitioners, a comprehensive Investigator’s Brochure is not necessary and sometimes a brochure or leaflet with up-to-date and detailed information will be used instead.
An Investigator’s Brochure should be reviewed every year and revised as necessary in accordance with a Sponsor’s written instructions. If new information is important enough, the Investigators and Human Research Ethics Committee (HREC) need to be informed before it is included in the updated Investigator's Brochure. The Sponsor ensures that an up-to-date Investigator’s Brochure is made available to Investigators, while the Investigators are responsible for providing an updated copy of the Investigator’s Brochure to the relevant Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs).
If an investigational product is provided by a Sponsor-Investigator, detailed background information about the trial protocol which contains current information described in the outline should be included.
A complete and thorough Investigator’s Brochure should include the following:
7.2.1 Title Page
- Sponsor’s name, identity of investigational product including research number, chemical or approved generic name, trade name and release date.
- Edition number and date if the current Investigator’s Brochure replaces a previous one.
7.2.2 Confidentiality Statement
A statement which reminds Investigators and other recipients to treat the Investigator’s Brochure as a confidential document and an important resource for the Investigators team and the Institutional Review Boards (IRBs) and Independent Ethics Committee (IEC).
7.3 Contents of the Investigator’s Brochure
7.3.1 Table of Contents
7.3.2 Summary
- Not longer than 2 pages.
- Highlighting significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic and clinical information available that is relevant to the state of clinical development of the investigational product.
7.3.3 Introduction
- An introduction which includes a chemical name (generic and trade names), all active ingredients, the investigational product’s pharmacological class and expected position within this class, the rationale for performing research with the investigational product and the anticipated prophylactic, therapeutic or diagnostic indications.
- The general approach to follow when evaluating an investigational product.
7.3.4 Physical, Chemical and Pharmaceutical Properties and Formulation
- A description of the investigational product substances including the chemical and or structural formulae and the brief summary of the relevant physical, chemical and pharmaceutical properties.
- For safety measures, a description of the formulations to be used including excipients (a substance formulated with the active ingredient of a medication) should be provided and justified if clinically relevant.
- Instructions for the storage and handling of the dosage should be provided.
- Structural similarities to other known compounds should be mentioned.
7.3.5 Non-Clinical Studies
Introduction
- Results of the relevant pharmacology, toxicology, pharmacokinetic and investigational product metabolism studies should be provided in a summary form.
- The summary should address the methodology used, the results, and discussion of the relevance of findings on the investigated therapeutic, and possible unfavourable and unintended effects in humans.
Information Provided May Include the Following, as Appropriate, if Known/Available:
- Species tested
- Number and sex of animals in each group
- Unit dose (milligram/kilogram)
- 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
A table and list format should be used whenever possible to make the presentation easier to understand.
The following sections should include 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 non-toxic dose findings in the same animal species should be compared (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 rather than on a mg/kg basis.
Non-Clinical Pharmacology
- A summary of the pharmacological aspects of the investigational product, and, where appropriate, its significant metabolites studied in animals, should be included.
- The summary should incorporate studies that assess potential therapeutic activity (efficacy models, receptor binding and specificity) as well as those that assess safety (special studies to assess pharmacological actions other than the intended therapeutic effects).
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.
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 dose
- Repeated dose
- Carcinogenicity (the ability to produce cancer)
- Special studies (irritancy and sensitisation)
- Reproductive toxicity
- Genotoxicity (mutagenicity)
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 pharmacokinetics, metabolism, pharmacodynamics, 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.
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. gender, 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/product’s (including metabolites, where appropriate) safety, pharmacodynamics, efficacy and dose response that were obtained from preceding trials in humans (healthy participants 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 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 Investigator’s Brochure 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 Investigator’s Brochure should identify countries where the investigational product has been approved and marketed.
- Any important information arising from the marketed use should be summarised (e.g. formulations, dosages, routes of administration, and adverse product reactions).
- Should identify all the countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration.
7.3.7 Summary of Data and Guidance for the Investigator
- 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.
- The Investigator can be provided with the most detailed 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 to help the Investigator to anticipate adverse drug reactions or other problems in clinical trials.
The overall of this section is to provide the investigator with a thorough understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be required 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).
7.4 APPENDIX 1:
Title Page (Example)
Sponsor’s Name
Product:
Research Number:
Name(s): Chemical, Generic (if approved)
Trade Name(s) (if legally permissible and desired by the sponsor)
INVESTIGATOR’S BROCHURE
Edition Number:
Release Date:
Replaces Previous Edition Number
Date:
7.5 APPENDIX 2:
TABLE OF CONTENTS OF INVESTIGATOR’S BROCHURE (Example)
- Confidentiality Statement (optional)
- Signature Page (optional)
1. Table of Contents…………………….
2. Summary………………………………
3. Introduction……………………………
4. Physical, Chemical, and Pharmaceutical Properties and Formulation…………………………….
5. Nonclinical Studies……………………
5.1 Nonclinical Pharmacology……………
5.2 Pharmacokinetics and Product Metabolism in Animals………………………………………..
5.3 Toxicology……………………………..
6. Effects in Humans…………………...
6.1 Pharmacokinetics 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
- Publications
- Reports
These references should be found at the end of each chapter
Appendices (if any)