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Investigator’s Brochure
Investigational Product Compound Number:Chemical or Approved Generic Name
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Effective Date: / DD-MMM-YYYY
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TABLE OF CONTENTS
Page
ABBREVIATIONS......
1.SUMMARY......
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......
2.INTRODUCTION......
2.1.Background......
2.2.Rationale for [Enter Compound Number]
2.3.References......
3.PHYSICAL, CHEMICAL AND PHARMACEUTICAL PROPERTIES AND FORMULATION
3.1.Pharmaceutical Presentation......
3.2.Physical and Chemical Properties of the Drug Substance......
3.3.Formulation Including Excipients......
3.4.Storage and Handling......
3.5.References......
4.NONCLINICAL STUDIES......
4.1.Nonclinical Test Material......
4.2.Nonclinical Pharmacology......
4.2.1.Nonclinical Pharmacology Studies Performed......
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......
4.3.Pharmacokinetics and Product Metabolism in Animals......
4.3.1.Analytical Methods and Validation
4.3.2.Absorption and Pharmacokinetics
4.3.2.1.Single dose pharmacokinetic studies with [Enter compound number]
4.3.2.2.Repeat dose toxicokinetic studies with [Enter compound number]
4.3.3.Distribution
4.3.3.1.In vitro studies
4.3.3.2.Whole-body autoradiography studies
4.3.3.3.Distribution into liver and muscle
4.3.3.4.Central nervous system penetration
4.3.3.5.Liver and blood distribution of 4-FBCl
4.3.4.Metabolism
4.3.4.1.In vitro studies
4.3.4.2.In vivo studies......
4.3.5.Excretion
4.3.5.1.Rat
4.3.5.2.Dog
4.3.6.Pharmacokinetic Drug Interactions
4.3.7.References......
4.4.Toxicology......
4.4.1.Single Dose Studies
4.4.1.1.Rat
4.4.1.2.Dog
4.4.2.Repeat Dose Studies
4.4.2.1.Mice
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
4.4.6.Carcinogenicity
4.4.7.Other Toxicity Studies
4.4.8.References......
4.5.Nonclinical Assessment of Safety......
4.5.1.References......
5.EFFECTS IN HUMANS......
5.1.Introduction......
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..
5.3.1.1.Efficacy:......
5.3.1.2.Safety:......
5.4.Phase III Data......
5.5.Marketing (Phase IV) Data......
5.5.1.Regulatory Approval......
5.5.1.1.Regulatory approval granted......
5.5.1.2.Regulatory approval rejected......
5.5.2.Marketing......
5.5.2.1.Countries where the investigational product is marketed
5.5.2.2.Countries where the investigational product has been withdrawn
5.5.3.Additional Clinical Information......
6.SUMMARY OF DATA AND GUIDANCE FOR THE INVESTIGATOR
6.1.Development Core Safety Information......
6.2.Posology and Method of Administration......
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......
7.APPENDICES......
ABBREVIATIONS
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
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.
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.
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 1List of Studies Investigating the Pharmacology of [Enter compound number]
Species tested / Number/ sex of animals per group / Unit dose / Dose interval / Route of administration / Duration of dosing / Duration of post-exposure follow-upDiscuss 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.
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 2List of Pharmacokinetic and Metabolism Studies Performed During the Development of [Enter compound number]
Type of Study / Route of Administration / Dose or Concentration(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.
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
4.3.6.Pharmacokinetic Drug Interactions
4.3.7.References
Insert references relating to this section.
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 3List 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.
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 DoseStudies
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
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.
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 4Summary of Key Toxicology Findings
Mouse / Rat / Rabbit / DogFindings / Effect Dose (mg/kg) / No Effect Dose (mg/kg) / Effect Dose (mg/kg) / No Effect Dose (mg/kg) / Effect Dose (mg/kg) / No Effect Dose (mg/kg) / Effect Dose (mg/kg) / No Effect Dose (mg/kg)
NO – Not observed * 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.
Table 5Comparative Assessment of Mean Systemic Exposure after Oral Administration of [Enter compound number] in Toxicology Species and Humans
Species(Duration) / Dose
(mg/kg) / Sex / Cmax
(ng/mL)
[range] / AUC(0-t) (ng.h/mL)
[range] / Ratio of Animal to Human Exposure
Cmax / AUC(0-t)
Mouse
(3 months) / 30 / M
F
100
(NOAEL) / M
F
300 / M
F
Rat
(6 months) / 3 / M
F
15
(NOAEL) / M
F
100 / M
F
Dog
(12 months) / 3 / M
F
10
(NOAEL) / M
F
30 / M
F
Rabbit
(EFD) / 3 / F
10 / F
30 (NOAEL) / F
Human
Single dose / 100 / M
10 days / 100 / M
Key:
EFD = Embryofetal development
NC = Not calculable
4.5.1.References
Insert references relating to this section.
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:
- Pharmacokinetic summary including metabolism, absorption, plasma protein binding, distribution and elimination.
- Bioavailability of the IP (absolute and/or relative).
- Differences in pharmacokinetic profile in population subgroups such as the elderly, renally impaired etc.
- The effect of food on the pharmacokinetic profile.
- 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
- Summarise the safety profile of the IP and its metabolites.
- Summarise the pharmacodynamic profile of the IP and its metabolites.
- Summarise the efficacy of the IP and its metabolites.
- Discuss the observed dose response.
- It can be helpful to use tables to summarise adverse drug reactions (ADRs).
- Discuss the important differences in ADR incidence and patterns across subgroups or indications.
- Describe the possible risks and anticipated ADRs in future studies based on the current experience with the IP.
- 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 6List of Clinical Studies Performed During the Development of [Enter compound number]
Study ID / Objectives / Study Design / Population / No. of subjects / Dose Regimens5.2.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
5.3.1.2.Safety
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.
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
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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