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Sponsor: Substance: Product:
Research Number:
E<liticn Number:
Releas..!D;tte:
Replaces Previous Edition Number:
1h,:; Invest:.gator Brochure is the pr::;perty of XX. The Investigator Brochure must be kept in a
confiuential 111an,1er a,1u may only be used in connectim; .vitr, clinical st.•Jdies on )(.X It m 1st
be returned to XX 11pon request. No part of this b,·o , 11,1,re may be reproduced without written
permission.ft-om XX
0
Prepared by:
_
Approved by:
_
Dat
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D'lte ---------
Jnvestigator signature page
Investigr.tor signature :.:,a5e
rl'lvestigators Brochure
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Sponsor: XX
Investigator Brocl1t11e Version No:
DrngName.
InYestigator,:;
Inve:,tigators
Narne:
Clii-ic
......................................................................
<>1.d
Addre)::i
.......................................................
Statement:
Investigator's Brochure is a confidential ducurr ent. :t must not be given to any third party
with0ut written pennissi0n from foe XX.
Any photocopying, canning or any other form ofreprol uction of thi:=: document is strirt:y
prohibitec: witiout a written pennis ion from XX.
I here0J acknowiedge the receipt of one copy of foe IB with foe above identification and will
keep the document under lock. I will return the document immediately upon request from XX
I also confirm that I have read it and that all my 4ueries have been answered to my
satisfaction.
Signature
Date
Clarification of s1g.nat tre
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Table of Con..:ents
TIGATC:R'S
BxlC:CHU.i{.E ......................................................................
XX...................................................................................................................................................... 1
Investigator signature page..........................................................................
1
........... .................... 1
Tai:le of Contents .............................................................................. ........... ....................... 3
List of tables................................................................
........... ..................................................... 5
List of figures ................................................................ ........... .............. ........... ....................... 5
List of Abbreviations................................................................. .............. ........... ........................ 5
2
Sunnnary .....................................................................
3
Introduction....................................................................... .............. ...........
4
Physical, Chemical, and Pharmaceutical Properties and Formulation...... ........... ............... 8
4.1
.............
5
........... ......... 7
Dn1g substance ...................................................................................- ...........'"• ········ 8
4.1.1 v1anufacturer:................................................................
4.2
........... ........... ............... 6
...........
........... .............. 8
Drug Product. ...................................................................................................................... 8
4.2.1
Dosage Form, Aoute of Administration and Dosing Regimen ................................ 8
4.2.2
Composition ................................................................................................................ 8
4.2.3
Manufacturer ............................................................................................................... 8
4.2.4
Container closure systems:......................................................................................... 8
4.2.5
Storage and handling .................................................................................................. 8
Non Clinical studies .................................................................................................................. 9
5.1
Introduction ......................................................................................................................... 9
5.2
Non Clinical Pharmacology ............................................................................................. 10
5.2.1
Brief Sununary .......................................................................................................... 10
5.2.2
Mechanism of Action ............................................................................................... 10
5.2.3
In vitro Effects .......................................................................................................... 10
5.2.4
In vivo Lffects ........................................................................................................... 10
5.2.5
Discussion of the Pharmacology Findings .............................................................. 10
5.3
SafetyPham1acology ....................................................................................................... l0
5.3.1
Cardiovascular Function........................................................................................... 10
5.3.2
CN3 Effects............................................................................................................... 10
5.3.3
Respiratory Function ................................................................................................ 10
5.3.4
Discussion of the .::iafety Pharmacology Findings................................................... 10
5.4
Phannacokinetics and Product Metabolism in Animals ................................................ 10
5.4.1
Breif .3ummary ......................................................................................................... 10
5.4.2
Discussion of the Pharmacokinetics ......................................................................... 10
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6
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Toxicology ........................................................................................................................ 10
5.5.1
Brief Sunm1ary of Toxicology.................................................................................. 10
5.5.2
Gentoxicity ................................................................................................................ 12
5.5.3
Toxicity to reproduction ........................................................................................... 12
5.5.4
Local tolerance .......................................................................................................... 12
5.5.5
Discussion of the Toxicology ................................................................................... 12
Effects in Hun1ans .................................................................................................................. 13
6.1
Introduction ....................................................................................................................... 13
6.2
Phannacokinetics and Product Metabolism in Humans................................................. 13
6.3
Safety and Efficacy .......................................................................................................... 13
6.4
MARKETil-JG EXPERIENCE ........................................................................................ 13
Summary of data and guidance for investigators ................................................................... 14
7.1
Name of the developmental product ............................................................................... 15
7.2
Quantitative and qualitative composition ........................................................................ 15
7.3
Phannaceutical fom1 ........................................................................................................ 15
7.4
Clinical particulars............................................................................................................ 15
7.4.1
Therapeutic indications............................................................................................. 15
7.4.2
Posology and method of administration................................................................... 15
7.4.3
Contraindications ....................................................................................................15
7.4.4
Special warnings and precautions for use ............................................................... 15
7.4.5
Interaction with other medicinal products and other fom1s of interaction ............ 15
7.4.6
Pregnancy and lactation............................................................................................ 15
7.4.7
Effects on ability to drive and use machines ........................................................... 15
7.4.8
Undesirable effects ................................................................................................... 15
7.4.9
Overdose .................................................................................................................... 15
7.5
Phannacological properties .............................................................................................. 15
7.5.1
Pharmacodynamic properties ................................................................................... 15
7.5.2
Phannacokinetic properties ...................................................................................... 15
7.5.3
Nonclinical safety data ............................................................................................. 15
7.6
Clinical Studies................................................................................................................. 15
7.7
Pharmaceutical properties ................................................................................................ 15
7.7.1
List of excipients ....................................................................................................... 15
7.7.2
Incompatibilities ........................................................................................................ 15
7.7.3
Stability ..................................................................................................................... 15
7.7.4
Special precautions for storage ................................................................................ 15
7.7.5
Nature and contents of the container. ...................................................................... 15
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Special precautions for disposal .......................................................................... 15
References ........................................................................ Error! Bookmark not defined.
List of tables
List of figui·es
List of Abb,:eviations
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Summary
Su111ma1y A briefsumma,y (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 develop111e11t of the investigational product.
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Introduction
A brief introductor:y 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 rationaleforpe1fonning research with the
investigational product(s), and the anticipated prophylactic, therapeutic, or diagnostic
indication(!,). Finally, the introductory statement should provide the general approach to be
followed in evaluating the investigational product.
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4 Physical, Chemica:, and Pharmaceutical Properties and Formulation
4.1
Drug substance
A descriptfon should be provided of the investigational product substance(s) (including the
che111ical and/or structural fomntla(e)), and a b,.;ejsu1111nmy should be given of the relevant
physical, chemical, and pharmaceutical properties. Any stmctural similarities to other known
co111pounds should be mentioned.
4.1.1 Manufacturer:
4.2
Drug Product
To permit appropriate safety measures to be taken in the course of the trial, a description of
the fonnulation(s) to be used, including exdpients, should be provided and justified if
chnica11y relevant.
4.2.1 Dosage Form, Route of Administration and Dosing Regimen
4.2.2 Compo:::.i1.ion
4.2.3 Manufacturer
4.2.4 Container-c!osu. e systems:
4.2.5 Sto• age and handling
Instructions for the storage and handling of the dosagefonn(s) should also be given.
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Non Clinical studies
Introduction
The results of afl relevant nonclinical pharmacology, toxicology, pharmacokinehc, and
investigational product metabo/;sm studies should be provided in sw1111w1y form. This
sunm,aty 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 thefolfowing, as appropriate, if
known/available:
• Species tested
• Number and se, of animals in each group
• Unit dose (e.g., mifligram/kilogram (mg/kg))
• Dose interval • Route of administration
• Duration o/ dosil1g
• Information o;; systemic distrib1.fion
• Duration of post-exposurefolfow-up
• Results, including the following aspects:
. Nature and frequency of phannacological 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//;stings 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, tile 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 lnanan dosing should be addressed
Whenever possible, comparisons should be made in terms of blood/tissue levels rather than
on a mg/kg basis.
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Non Clinical Pharmacology
A summmy of the pharmacological aspects of the investigational product and, where
appropriate, its significant 111etabolites studied in ani111als, should be included Such a
summmy should incorporate studies that assess potential therapeutic activity (e.g. efficacy
models, receptor binding, and specificity) a.swell as those that assess safety (e.g., special
studies to assess pharmacological actions other than the intended therapeutic effect(s)).
5.2.1 Brief Summary
5.2.2 Mechanism of Action
5.2.3 In vitro Effects
s 2.4
In vivo Eftects
5.2.5 Discussion of the Pharmacology Findings
5.3
.3afety Pharmacology
Cardiovascular, respirato1y function and potential CNS effects of calmangafodipir were
assessed in the XX' toxici v studies.
5.3.1 Cardiovascular Function
5.3.2 CNS Effects
5.3.3 Respiratory Function
5.3.4 Discussion of the Safety Pharmacology Findings
5.4
Pharmacokinetics and Product Metabolism in Animals
A s11111mmy of the phannacokinetics and biological transformation and disposition of the
investigatfonal product in all species studied should be given. The discussion of the findings
should address the abso,ption 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.
5.4.1 Breit Summary
5.4.2 Discussion of the Pharmacokinetics
5.5
5.5.1
7oxicology
Srief Summary of Toxicology
A su11m1my of the toxicological effects found in relevant studies conducted in different animal
species should be described under the following headings where appropriate:. Single dose.
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Repeated dose . Carcinogenicity . Special studies (e.g. hTifancy and sensitisation) .
Reproductive toxicity. Genotoxicity (,nuragenicity)
Table 3. Ournne uf rt'peat <1ose toxi Jty program with calwt1ngafodip.r
Study Title
(Number) and Gi.,P
status
5.5.1.1
Test System
1-vfethod and
fi·equency
of dosing
Dose in umol/kg and
mg/kg within
parenthesis
Testing
Facility
Repeat Dose Toxicity Studies iu Rats
Tab -,,, 4. Dosing seized lie in the X-mont!t rat to:xici!y study
Gr.
No.
Group
Designation
I
Control
2
Low Dose
3
MrdDose
4
High Dose
lJose Level
(µmol/kg)
Multiple of
JvfR.HD*
Dose
volume
(mL/kg)
Number of animals
Main
Male Female
Recove1y
Male Female
*MRHD = Maximal Recommended Human Dose
5.5.1.2
Repeat Dose Toxicity Studies in Dogs
Table 5 Dosing schedule in the X-month dog toxicity study
Gr.
No.
Group
Designation
I
Control
2
Low Dose
3
1vfid Dose
4
High Dose
Dose Level
(µmol/kg)
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JvfRHD*
Dose
volume
(mL/kg)
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Number of animals
Recove1y
Main
Male Female lvfale Female
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5.5.2
Gentoxicity
5.5.3
Toxicity to reproduction
5.5.4
Local tolerance
Confidential
5.5.5 Discussion of the roxicology
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Effects in Humans
Introduction
A thorough discussion of the known effects of the investigational product(<;) in humans should
be provided, including information on pharlllacokinetics, metabolism, pharmacodynamics,
dose response, safety, efficacy, and other pharmacological activities. Where possible, a
summary of each colllpleted clinical trial should be provided. Information should also be
provided regarding results of any use of the investigational product(s) other than fi"om in
clinical trials, such as from expehence during marketing.
6.2
Pharmacokinetics and Product Metabolism in Humans
A swnmmy of information on the pharmacokinetics of the investigational product(<;) should
be presented, including the following, if available:. Pharmacokinetics (including metabohslll,
as appropriate, and absorption, plasma protein binding, distribution, and elimination) ..
Bioavailability of the investigational product (absolute, where possible, and/or relative) using
a reference dosagefon11.. 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 pe1fon11ed within clinical trial(s).
6.3
Safety and Efficacy
A swnlllmy of information should be provided about the investigational product's/products'
(including llletabolites, where appropriate) safety, phan11acodynamics, efficacy, and dose
response that were obtained fi"om 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 swmnaries of adverse drug reactions for all the clinical trial<; (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. nie 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).
6.4
MARKETING EXPERIENCE
n1e IB should identify countries where the investigational product has been marketed or
approved. Any significant information arising from the marketed use should be sunm1arised
(e.g., formulations, dosages, routes of administration, and adverse product reactions). n1e IB
should also identify all the countries where the investigational product did not receive
approval/registration for marketing or was withdrawn from marketing/registration.
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Summary of data and guidance for investigators
This section should provide an overall discussion of the nonclinical and clinical data, and
should su111marise the information from various sources on different aspects oftl,e
investigational product(s), wherever possible. In this way, the investigator can be provided
with the most informative interpretation of the available data and wit!, an assessment of the
i111plications of the informationforfllture clinical trials. Where appropriate, the published
reports on related products should be discussed This could help the investigator to anticipate
adverse drug reactions or otlzerproblems in clinical trials. Tile overall ai111 oftlzis 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 treatlllent of possible overdose and adverse drug reactions that is based
on previous hu111an experience and on the pharll/acology of the investigahonal product.
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7.1
Name of the deve/0 1mental product
7.2
'Quantitative and qualitafJVe composition
7.3
eharmaceui'ical form
7.4
Clinical particulars
Confidential
7.4.1 Thera,>eutic indications
7.4.2 Posology and method of administration
7.4.3 Contraindications
7.4.4 Special warnings and precautions for use
7.4.5 Interaction with other medicinal products and other forms of
interaction
7.4.6 Pregnancy and lactation
7.4.7 Effects on ability to drive and use machines
7.4.8 Undesirable effects
7.4.'..:J Overdose
7.5
Pharmacological properties
7.5.1 Pharmacodynamic properties
7.5.2 Pharmacokinetic properties
7.5.3 Nonclinical safety data
Clinical tudies
7.7
Pharmaceutical properties
7.7.1 List of excipients
7.7.2 Incompatibilities
7.7.3 Stability
7.7.4 Special precautions for storage
7.7.5 Nature and contents of the container
7.7.6 Special precautions for disposal
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References
NB: References on:
1. Publications
2. Reports-These references should be found at the end of each chapter
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