7.
INVESTIGATOR'S BROCHURE
7.1
Introduction
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 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 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.
Generally,
the sponsor is responsible for ensuring that an up-to-date IB is made
available to the investigator(s) and the investigators are responsible
for providing the up-to-date IB to the responsible IRBs/IECs. In the
case of an investigator sponsored trial, the sponsor-investigator should
determine whether a brochure is available from the commercial manufacturer.
If the investigational product is provided by the sponsor-investigator,
then he or she should provide the necessary information to the trial
personnel. In cases where preparation of a formal IB is impractical,
the sponsor-investigator should provide, as a substitute, an expanded
background information section in the trial protocol that contains the
minimum current information described in this guideline.
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7.2
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. An example is given in Appendix 1.
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
7.3.2
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.
7.3.3
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 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.
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7.3.5
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 therapeutic 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 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
dose
- Repeated
dose
- Carcinogenicity
- Special
studies (e.g., irritancy and sensitisation)
- Reproductive
toxicity
- Genotoxicity
(mutagenicity)
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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 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's/products' (including metabolites, where appropriate) safety,
pharmacodynamics, efficacy, and dose response that were 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 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, and adverse product 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.
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 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 human experience and on the pharmacology of the
investigational product.
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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
1.
Publications
2. Reports
These
references should be found at the end of each chapter
Appendices (if any)
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