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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.



To provide the understanding a) investigators and b) others involved in the trial

Why this information is required?

To facilitate the understanding of the rationale for the study and their compliance with, many key features of the protocol,

-- the dose, dose frequency/interval --methods of administration IV, oral.. --clinical management and --safety monitoring procedures

y The only official guidance for preparing an IB

is given in the ICH E6 guideline on GCP (e.g. CPMP/ICH/135/95). However, this guideline provides only general recommendations for the structure and content of an IB, and the style of presentation is left to the discretion of the sponsor.

Presentation of IB
y a concise, simple, objective y non-promotional form..


ENABLES a clinician, or potential investigator, y to understand it and y make his/her own unbiased risk-benefit assessment

A medically qualified person should generally participate in the editing of an IB

y What is the type and to what extent the

information of the IP should be provided?

e.g., Marketed investigational product its pharmacology is widely understood by medical practitioners, an extensive IB may not be necessary

IB review
y The IB should be reviewed at least annually and

revised as necessary in compliance with a sponsor's written procedures.

y If any new information has to be added to the

IB, it should be communicated to the investigators, and possibly to the (IRBs)/ (IECs) and/or regulatory authorities before it is included in a revised IB.

y If the trial is an investigator sponsored


Wholl prepare the IB?

y If the trial is sponsored by pharma company

Wholl prepare the IB?

y Whose responsibility is to up-to-date IB?

IB contents
Title Page
y An edition number y The sponsor's name, y The identity of each investigational product

i.e., research number, y Chemical or approved generic name, y Trade name(s) where legally permissible and desired by the sponsor), and y The release date.

Confidentiality Statement
y Sponsor may wish to include a statement

instructing the investigator/recipients to treat the IB as a confidential document

y For the use of

a) investigator and his team and b) IEC/IRB

A brief summary of IP (preferably not exceeding two pages)

y the significant physical, y chemical, y pharmaceutical, y pharmacological, y toxicological, y pharmacokinetic, y metabolic, and y clinical information

relevant to the stage of clinical development of the investigational product.

Introductory statement for the drug

y chemical name (generic and trade name(s) when y y

y y

approved) of the IP(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 expected prophylactic, therapeutic, or diagnostic indication(s).

y Physical, Chemical, and Pharmaceutical Properties y Formulation excipients including the chemical

and/or structural formula(e)

y Instructions for the storage and handling of the

dosage form(s)
y Any structural similarities to other known


Nonclinical Studies
y All relevant nonclinical pharmacology, toxicology,

pharmacokinetic, and investigational product metabolism studies so far..

y The methodology used, the results, and a

discussion of the relevance of the findings

y possible unfavorable and unintended effects in


Nonclinical Study information

y Species tested y Number and sex of animals in each group y Unit dose (e.g., milligram/kilogram (mg/kg)) y Dose interval y Route of administration y Duration of dosing y Information on systemic distribution y Duration of post-exposure follow-up

Nonclinical Study information

y 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

y Tabular format/listings should be used

Nonclinical Pharmacology
A summary y that assess potential therapeutic activity (e.g., efficacy models, receptor binding, and specificity) y that assess safety (e.g., special studies to assess pharmacological actions other than the intended therapeutic effect(s)).

Pharmacokinetics and Product Metabolism in Animals

y the pharmacokinetics and

y biological transformation and disposition

of the investigational product in all species studied.

Toxicology in animals
y Single dose y Repeated dose y Carcinogenicity y Special studies (e.g., irritancy and sensitisation) y Reproductive toxicity y Genotoxicity (mutagenicity)

Effects in Humans (clinical data)

Information on: y pharmacokinetics, y pharmacodynamics, y dose response, y safety, y efficacy, and y other pharmacological activities y Where possible, a summary of each completed clinical trial

Pharmacokinetics and Product Metabolism in Humans

y metabolism, as appropriate, and absorption,

plasma protein binding, distribution, and elimination). y Bioavailability of IP (absolute, and/or relative) using a reference dosage form. y Population subgroups (e.g., gender, age, and impaired organ function). y Interactions (e.g., product-product interactions and effects of food).

Safety and Efficacy

y Established safety, y pharmacodynamics, y efficacy, and y dose response

That were obtained from preceding trials in humans (healthy volunteers and/or patients).

y Important differences in adverse drug

reaction patterns/incidences across indications or subgroups should be discussed.

y A description of the possible risks and

adverse drug reactions to be anticipated on the basis of prior experiences

Marketing Experience
The IB should identify countries where the investigational product has been marketed or approved. y Significant information arising from the marketed use should be summarized (e.g., formulations, dosages, routes of administration, and adverse product reactions). y 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

After all this requirements...

yagain ySummary of Data and

Guidance for the Investigator This section should provide an overall discussion of the nonclinical and clinical data.


y TITLE PAGE (Example) y SPONSOR'S NAME y Product: y Research Number: y Name(s): Chemical, Generic (if approved) y Trade Name(s) (if legally permissible and desired by the


Release Date:

Appendix 2