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INVESTIGATOR’S BROCHURE
Investigational Product
Compound Number:
Chemical or Approved
Generic Name
Trade Name (if applicable)
Effective Date:
DD-MMM-YYYY
Previous Version Number
Author
Effective Date
Department
Company
The information contained in this document is the property of [Enter client name] and
may not be reproduced, published or disclosed to others without written authorisation
from [Enter client name].
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Page 1 of 26
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SPONSOR SIGNATURE PAGE
Sponsor Signatory:
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Date
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TABLE OF CONTENTS
PAGE
ABBREVIATIONS .................................................................................................... 6
1.
SUMMARY ........................................................................................................ 7
1.1.
Physical, Chemical and Pharmaceutical Properties and Formulation ............ 7
1.2.
Nonclinical Pharmacology ............................................................................. 7
1.3.
Nonclinical Pharmacokinetics ....................................................................... 7
1.4.
Toxicology .................................................................................................... 7
1.5.
Metabolic Information.................................................................................... 7
1.6.
Clinical Experience ....................................................................................... 7
2.
INTRODUCTION ............................................................................................... 8
2.1.
Background .................................................................................................. 8
2.2.
Rationale for [Enter Compound Number] ...................................................... 8
2.3.
References ................................................................................................... 8
3.
PHYSICAL, CHEMICAL AND PHARMACEUTICAL PROPERTIES AND
FORMULATION ................................................................................................ 9
3.1.
Pharmaceutical Presentation ........................................................................ 9
3.2.
Physical and Chemical Properties of the Drug Substance ............................ 9
3.3.
Formulation Including Excipients .................................................................. 9
3.4.
Storage and Handling ................................................................................... 9
3.5.
References ................................................................................................... 9
4.
NONCLINICAL STUDIES ................................................................................ 10
4.1.
Nonclinical Test Material ............................................................................. 10
4.2.
Nonclinical Pharmacology ........................................................................... 10
4.2.1.
Nonclinical Pharmacology Studies Performed ............................. 10
4.2.2.
Primary Pharmacodynamics ........................................................ 11
4.2.3.
Secondary Pharmacodynamics ................................................... 11
4.2.4.
Safety Pharmacology ................................................................... 11
4.2.4.1.
Overt central and peripheral effects ............................ 11
4.2.4.2.
Effects on the cardiovascular system ......................... 11
4.2.4.3.
Effects on the respiratory system................................ 11
4.2.4.4.
Effects on the kidney .................................................. 11
4.2.5.
References .................................................................................. 11
4.3.
Pharmacokinetics and Product Metabolism in Animals ............................... 12
4.3.1.
Analytical Methods and Validation ............................................... 12
4.3.2.
Absorption and Pharmacokinetics ................................................ 12
4.3.2.1.
Single dose pharmacokinetic studies with
[Enter compound number] .......................................... 12
4.3.2.2.
Repeat dose toxicokinetic studies with [Enter
compound number]..................................................... 13
4.3.3.
Distribution................................................................................... 13
4.3.3.1.
In vitro studies ............................................................ 13
4.3.3.2.
Whole-body autoradiography studiesError! Bookmark not defined.
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4.4.
4.5.
5.
4.3.3.3.
Distribution into liver and muscleError! Bookmark not defined.
4.3.3.4.
Central nervous system penetrationError! Bookmark not defined.
4.3.3.5.
Liver and blood distribution of 4-FBClError! Bookmark not defined.
4.3.4.
Metabolism .................................................................................. 13
4.3.4.1.
In vitro studies ............................................................ 13
4.3.4.2.
In vivo studies............................................................. 13
4.3.5.
Excretion...................................................................................... 13
4.3.5.1.
Rat ............................................................................. 13
4.3.5.2.
Dog ............................................................................ 13
4.3.6.
Pharmacokinetic Drug Interactions .............................................. 14
4.3.7.
References .................................................................................. 14
Toxicology .................................................................................................. 15
4.4.1.
Single Dose Studies .................................................................... 16
4.4.1.1.
Rat ............................................................................. 16
4.4.1.2.
Dog ............................................................................ 16
4.4.2.
Repeat Dose Studies ................................................................... 16
4.4.2.1.
Mice ........................................................................... 16
4.4.2.2.
Rat ............................................................................. 16
4.4.2.3.
Dog ............................................................................ 16
4.4.3.
Genotoxicity (Mutagenicity) .......................................................... 16
4.4.4.
Reproductive Toxicity................................................................... 16
4.4.4.1.
Fertility and early embryonic development .................. 16
4.4.4.2.
Embryofetal development ........................................... 16
4.4.5.
Local Tolerance ........................................................................... 16
4.4.6.
Carcinogenicity ............................................................................ 17
4.4.7.
Other Toxicity Studies .................................................................. 17
4.4.8.
References .................................................................................. 17
Nonclinical Assessment of Safety ............................................................... 18
4.5.1.
References .................................................................................. 20
EFFECTS IN HUMANS ................................................................................... 21
5.1.
Introduction ................................................................................................. 22
5.2.
Phase I Data ............................................................................................... 22
5.2.1.
Summary of Phase I Clinical Safety ............................................. 22
5.3.
Phase II Data .............................................................................................. 22
5.3.1.
Overall Conclusions of Phase II Clinical Trial Safety and
Efficacy ........................................................................................ 22
5.3.1.1.
Efficacy:...................................................................... 22
5.3.1.2.
Safety: ........................................................................ 22
5.4.
Phase III Data ............................................................................................. 23
5.5.
Marketing (Phase IV) Data .......................................................................... 23
5.5.1.
Regulatory Approval ....................... Error! Bookmark not defined.
5.5.1.1.
Regulatory approval grantedError! Bookmark not defined.
5.5.1.2.
Regulatory approval rejectedError! Bookmark not defined.
5.5.2.
Marketing ........................................ Error! Bookmark not defined.
5.5.2.1.
Countries where the investigational product is
marketed ....................... Error! Bookmark not defined.
5.5.2.2.
Countries where the investigational product
has been withdrawn....... Error! Bookmark not defined.
5.5.3.
Additional Clinical Information ......... Error! Bookmark not defined.
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6.
SUMMARY OF DATA AND GUIDANCE FOR THE INVESTIGATOR .............. 24
6.1.
Development Core Safety Information ........................................................ 24
6.2.
Posology and Method of Administration ...................................................... 24
6.3.
Contraindications ........................................................................................ 25
6.4.
Special Warnings and Special Precautions for Use .................................... 25
6.5.
Interactions ................................................................................................. 25
6.6.
Use during Pregnancy and Lactation .......................................................... 25
6.7.
Undesirable Effects..................................................................................... 25
6.8.
Overdose .................................................................................................... 25
6.9.
Drug Abuse and Dependency ..................................................................... 25
6.10. Other Potentially Clinically Relevant Information for the Investigator ........... 25
6.11. References ................................................................................................. 25
7.
APPENDICES ................................................................................................. 26
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ABBREVIATIONS
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1.
SUMMARY
This section should contain a brief (maximum of two pages) summary highlighting the
significant points included in this document. The following subheadings should be
addressed. If they are not applicable then state this.
1.1.
Physical, Chemical and Pharmaceutical Properties and
Formulation
1.2.
Nonclinical Pharmacology
1.3.
Nonclinical Pharmacokinetics
1.4.
Toxicology
1.5.
Metabolic Information
1.6.
Clinical Experience
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2.
INTRODUCTION
2.1.
Background
Briefly state the investigational product (IP) chemical name, generic name (if approved)
and trade name (if approved). List the active ingredients and confirm which
pharmacological class the IP is in. Briefly discuss its expected position within this class
(i.e., the advantages it is expected to have over other products in that class).
Identify the anticipated prophylactic, therapeutic or diagnostic indication(s) that the IP is
being developed to address.
2.2.
Rationale for [Enter Compound Number]
Briefly discuss the rationale for performing research with the IP. Provide information on
the general approach to be followed in developing/evaluating the IP.
2.3.
References
Insert references relating to this section.
Alternatively, if there are not a large number of references, a single reference section can
be place at the end of the document with the reference subsections being removed.
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3.
PHYSICAL, CHEMICAL AND PHARMACEUTICAL
PROPERTIES AND FORMULATION
3.1.
Pharmaceutical Presentation
Describe the IP substance. Give a brief summary of the relevant pharmaceutical
properties.
3.2.
Physical and Chemical Properties of the Drug Substance
[Enter client name] Compound
Number:
Approved Name (USAN):
Other Names:
Chemical Name (IUPAC):
Molecular Formula:
Molecular Weight:
Physical Form:
Solubility (at ambient temperature)
3.3.
:
Formulation Including Excipients
Describe the formulation to be used including the excipients. Justify the use of this
formula if clinically relevant. Provide information on structural similarities to other
known compounds.
3.4.
Storage and Handling
Provide instructions for the storage and handling of the IP in its dosage form.
3.5.
References
Insert references relating to this section.
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4.
NONCLINICAL STUDIES
4.1.
Nonclinical Test Material
State what material was used in the nonclinical studies and what form that material took.
4.2.
Nonclinical Pharmacology
This section should include the results of all relevant nonclinical pharmacology studies.
Summarise the pharmacological aspects of the IP studied in animals and those of its
significant metabolites. Outline the methodology used and the study results and discuss
what relevance these findings have to the proposed therapeutic use in humans. Highlight
any possible unfavourable or unintended effects these results indicate might occur in
humans.
4.2.1.
Nonclinical Pharmacology Studies Performed
A range of in vitro and in vivo studies have been performed in order to characterise the
pharmacodynamics of [Enter compound number]. Table 1 presents a list of the
nonclinical pharmacology studies conducted to date.
Table 1
Species
tested
List of Studies Investigating the Pharmacology of [Enter compound
number]
Number/ sex
of animals
per group
Unit
dose
Dose
interval
Route of
administration
Duration
of dosing
Duration of
post-exposure
follow-up
Discuss the results of these studies including the following information:
-
Nature and frequency of pharmacological effects.
-
Severity or intensity of pharmacological effects.
-
Time to onset of effects.
-
Reversibility of effects.
-
Duration of effects.
-
Dose response.
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If applicable compare and discuss the therapeutic index (i.e., the effective and nontoxic
dose findings) in the same animal species. The subheadings below may be helpful.
4.2.2.
Primary Pharmacodynamics
4.2.3.
Secondary Pharmacodynamics
4.2.4.
Safety Pharmacology
4.2.4.1.
Overt central and peripheral effects
4.2.4.2.
Effects on the cardiovascular system
4.2.4.3.
Effects on the respiratory system
4.2.4.4.
Effects on the kidney
4.2.5.
References
Insert references relating to this section.
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4.3.
Pharmacokinetics and Product Metabolism in Animals
The pharmacokinetics and disposition of [Enter compound number] have been
characterised chiefly in the [Enter animal species], the main species used in nonclinical
safety assessment studies. Table 2 presents a list of all pharmacokinetic studies
performed with [Enter compound number].
Table 2
List of Pharmacokinetic and Metabolism Studies Performed During
the Development of [Enter compound number]
Type of Study
Route of
Dose or Concentration
Administration
(mg/kg)
Species
No./Sex/
Group
Pharmacokinetic
Toxicokinetic
Distribution
Metabolism
Excretion
4.3.1.
Analytical Methods and Validation
Succinctly describe the analytical methods used to measure the blood and tissue levels of
the IP. Outline the validation process relating to these methods.
4.3.2.
Absorption and Pharmacokinetics
4.3.2.1.
Single dose pharmacokinetic studies with [Enter compound number]
Discuss the absorption and pharmacokinetic results of any single dose pharmacokinetic
studies.
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4.3.2.2.
Repeat dose toxicokinetic studies with [Enter compound number]
Discuss the absorption and pharmacokinetic results of any repeat-dose toxicokinetic
studies.
4.3.3.
Distribution
Discuss the results of studies in all species that have investigated IP, and metabolite,
distribution. Review both local and systemic bioavailability. The following subheadings
may be helpful.
4.3.3.1.
In vitro studies
4.3.3.2.
In vivo studies
4.3.4.
Metabolism
Summarise the biological transformation of the IP both in vitro and in vivo.
4.3.4.1.
In vitro studies
4.3.4.2.
In vivo studies
4.3.5.
Excretion
Discuss the excretion of the IP and its metabolites in appropriate animal species (adjust
subheadings if required).
4.3.5.1.
Rat
4.3.5.2.
Dog
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4.3.6.
Pharmacokinetic Drug Interactions
4.3.7.
References
Insert references relating to this section.
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4.4.
Toxicology
The toxicity of [Enter compound number] has been evaluated in single and repeat dose
oral studies of up to 12 months’ duration. The reproductive and genetic toxicity of [Enter
compound number] has also been investigated. A listing of these studies is presented in
Table 3.
Table 3
List of Toxicology Studies Performed During the Development of
[Enter compound number]
Type of Study/Dose
Duration
Route of
Administration
Species
([Enter compound number] Dosage)
Animals/
Sex/Group
Single Dose
Repeat Dose
Genotoxicity
Reproductive Toxicity
Local Tolerance
Other Toxicity
Key:
DRF = Dose range finding
M = male; F = female
NA = Not applicable
Discuss the results of these studies and include the following information:
-
Nature and frequency of toxic effects.
-
Severity or intensity of toxic effects.
-
Time to onset of effects.
-
Reversibility of effects.
-
Duration of effects.
-
Dose response.
The subheadings below may be useful.
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4.4.1.
Single Dose Studies
Include information on single dose studies under the appropriate species heading.
4.4.1.1.
Rat
4.4.1.2.
Dog
4.4.2.
Repeat Dose Studies
Include information on repeat dose studies under the appropriate species heading.
4.4.2.1.
Mouse
4.4.2.2.
Rat
4.4.2.3.
Dog
4.4.3.
Genotoxicity (Mutagenicity)
4.4.4.
Reproductive Toxicity
4.4.4.1.
Fertility and early embryonic development
4.4.4.2.
Embryofetal development
4.4.5.
Local Tolerance
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4.4.6.
Carcinogenicity
4.4.7.
Other Toxicity Studies
For example irritancy and sensitisation.
4.4.8.
References
Insert references relating to this section.
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4.5.
Nonclinical Assessment of Safety
[Enter compound number] is a [Enter drug class]
[Enter compound number] has undergone an extensive nonclinical safety evaluation
including safety pharmacology, single and repeat dose toxicity, reproductive and genetic
toxicity studies. The key toxicological findings are presented in Table 4.
Table 4
Summary of Key Toxicology Findings
Mouse
Findings
NO – Not observed
Rat
Rabbit
Dog
Effect No Effect Effect No Effect Effect No Effect Effect No Effect
Dose
Dose
Dose
Dose
Dose
Dose
Dose
Dose
(mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg)
* Single doses
The following section should only be completed if human studies have been performed.
A comparison of systemic exposure to [Enter compound number] achieved in the
toxicology species and in humans is presented in Table 5.
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Table 5
Comparative Assessment of Mean Systemic Exposure after Oral
Administration of [Enter compound number] in Toxicology Species
and Humans
Species
(Duration)
Dose
(mg/kg)
Sex
Mouse
(3 months)
30
M
F
M
F
M
F
M
F
M
F
M
F
M
F
M
F
M
F
F
F
F
100
(NOAEL)
300
Rat
(6 months)
3
15
(NOAEL)
100
Dog
(12 months)
3
10
(NOAEL)
30
Rabbit
(EFD)
Human
Single dose
10 days
3
10
30
(NOAEL)
100
100
Cmax
(ng/mL)
[range]
AUC(0-t)
(ng.h/mL)
[range]
Ratio of Animal to Human
Exposure
Cmax
AUC(0-t)
M
M
Key:
EFD = Embryofetal development
NC = Not calculable
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4.5.1.
References
Insert references relating to this section.
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5.
EFFECTS IN HUMANS
This section should include a thorough discussion of the effects of the IP in humans. A
summary of each completed clinical trial should be provided as well as any additional
information obtained through alternative methods e.g., experience during marketing.
For first-time-in-human IBs this section can be deleted. Alternatively, if dose selection
for human studies is based on pharmacokinetic modelling, any relevant modelling data
can be presented in this section.
The following areas should be covered where the information is available:
-
Pharmacokinetics:
o Pharmacokinetic summary including metabolism, absorption, plasma
protein binding, distribution and elimination.
o Bioavailability of the IP (absolute and/or relative).
o Differences in pharmacokinetic profile in population subgroups such as
the elderly, renally impaired etc.
o The effect of food on the pharmacokinetic profile.
o The effect of other drugs on the pharmacokinetic profile. It is particularly
important to investigate drugs known to affect the cytochrome P450 (CYP)
pathway as well as drugs commonly co-prescribed for the condition being
investigated.
-
Safety and Efficacy
o Summarise the safety profile of the IP and its metabolites.
o Summarise the pharmacodynamic profile of the IP and its metabolites.
o Summarise the efficacy of the IP and its metabolites.
o Discuss the observed dose response.
o It can be helpful to use tables to summarise adverse drug reactions
(ADRs).
o Discuss the important differences in ADR incidence and patterns across
subgroups or indications.
o Describe the possible risks and anticipated ADRs in future studies based
on the current experience with the IP.
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o Describe any precautions that should be taken or special clinical
monitoring that should be performed.
5.1.
Introduction
A listing of clinical studies is presented in .
Table 6
List of Clinical Studies Performed During the Development of [Enter
compound number]
Study ID
Objectives
Study Design
Population
No. of subjects
Dose Regimens
5.2.
Phase I Data
5.2.1.
Summary of Phase I Clinical Safety
5.3.
Phase II Data
5.3.1.
Overall Conclusions of Phase II Clinical Trial Safety and Efficacy
In summary, these studies provided the following evidence regarding:
5.3.1.1.
Efficacy
1.
2.
5.3.1.2.
Safety
1.
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2.
5.4.
Phase III Data
5.5.
Marketing (Phase IV) Data
List those countries where regulatory approval has been granted or rejected.
List those countries where the IP is currently being marketed and has been withdrawn
from the market.
Discuss any additional information gained through the marketing process.
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6.
SUMMARY OF DATA AND GUIDANCE FOR THE
INVESTIGATOR
For first-time-in-human IBs, state that no data are available on the relationship of AEs to
administration of the IP, because no studies have yet been conducted in human subjects.
For IPs in early phase development, state that limited data are available on the
relationship of AEs to administration of the IP, because clinical experience is limited. In
this case, state that the guidance for the investigator is based on nonclinical data and on
the results of any Phase I/II studies.
6.1.
Development Core Safety Information
[Enter compound number]
The Development Core Safety Information (DCSI) for an investigational product is
derived from all of the available safety information at the time of compilation; this
includes nonclinical safety data and data available from the clinical study programme.
The DCSI is an integral part of the Investigator's Brochure and documents the adverse
events which, based on the information available so far, could be reasonably assumed to
be associated with [Enter compound number] and therefore considered expected for the
purposes of expedited reporting to regulatory authorities and investigators. Because the
product is investigational, the DCSI is provisional and can be updated and amended at
any time. As further information becomes available, the DCSI will be reviewed to assess
the appropriateness of continued inclusion of any events or the addition of new events in
the document.
Some events presented in the DCSI may have been identified from ongoing, blinded
clinical studies. If this is the case, these data may not be presented elsewhere in the
Investigator's Brochure, however they will be described more fully once the studies have
been completed and the final data have been unblinded and analysed.
This section should provide an overall discussion of the nonclinical and clinical data and
summarise the information from various sources on different aspects of the IP. If reports
on related products have been published then these may be discussed if appropriate (i.e.,
if it could help the investigator to anticipate ADRs relating to this drug class).
The following subheadings may be helpful.
6.2.
Posology and Method of Administration
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6.3.
Contraindications
6.4.
Special Warnings and Special Precautions for Use
6.5.
Interactions
6.6.
Use during Pregnancy and Lactation
6.7.
Undesirable Effects
6.8.
Overdose
6.9.
Drug Abuse and Dependency
6.10.
Other Potentially Clinically Relevant Information for the
Investigator
6.11.
References
Insert references relating to this section.
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7.
APPENDICES
Add appendices as appropriate.
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