MEDLINE INDIA - GOOD CLINICAL PRACTICE GUIDELINES

The Investigator’s Brochure is a compilation of the clinical and non-clinical data on the Investigational Product(s) that are relevant to a study of the product(s). It provides the investigator(s) and others involved in the study with the information on the rationale to facilitate compliance with the key features of the protocol, such as the dose, dose frequency/interval, methods of administration and safety monitoring procedures. The IB also provides background material to support the clinical management of the study subjects. The information contained in the IB should be in a concise, simple, objective, balanced, and non-promotional form to enable an understanding 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. The IB should be revised whenever necessary in compliance with the sponsor’s written procedures, the stage of development and the generation of relevant new information. However, any relevant new information that is considered important should be communicated to the Investigator(s), Ethics Committee and the Regulatory Authorities immediately, even before it can be methodically included in the IB.

Contents of the Investigator’s Brochure

The IB should include Sponsor’s name, the reference number allocated to the study, the identity of each investigational product (ie. research number, chemical or approved generic name, and trade name(s) where legally permissible and desired by the sponsor). The IB should bear an edition number and date. Besides, wherever applicable it also bears a reference to the number and date of the edition it supersedes.

The Sponsor may wish to include a statement instructing the readers to treat the IB as a confidential document for the sole purpose of the Study for which it has been prepared.

The IB should contain the following sections, each with literature references where appropriate:

2 Introduction: This section includes information relevant to the stage of clinical development including the significant physical properties , chemical properties, pharmaceutical, pharmacological (pharmacological class, advantages over other substances in that class and rationale for performing the proposed study), toxicological, pharmacokinetic, metabolic, and clinical information (anticipated prophylactic/ therapeutic or diagnostic indication(s)) of all active ingredients. The introductory statement should necessarily provide the general approach to be followed in evaluating the Investigational Product.

3 Physical, Chemical, and Pharmaceutical Properties and Formulation parameters: A description should be provided of the Investigational Product substance(s), including the chemical and / or structural formula(e), and a brief summary of the relevant physical, chemical and pharmaceutical properties. Any structural similarities to other known compounds should be mentioned. Information should also be provided on the excipients.

Appropriate storage and dosage handling instructions should also be given.

4 Non-clinical Studies: Information provided should include data relating to non-clinical pharmacology, pharmacokinetics, metabolism profile in animals and toxicology. The results of all relevant non-clinical pharmacology, toxicology, pharmacokinetic, and the Investigational Product metabolism studies should be provided in summary form, stating the methodology used, the results, and a discussion of the relevance of the findings to the investigated therapeutic effects besides the possible unfavourable effects in humans.

The information provided may include the following, as appropriate, if known/available:

· Number and sex of animals in each group

· Unit dose (mg/kg)

· Route of administration

· Duration of dosing

· Information on systemic distribution

· Duration of post-exposure follow-up

· Results, including the following aspects:

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 non-toxic 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) Non-clinical Pharmacological (Pharmacodymanics)

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 (eg. 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.

A summary of the toxicological effects found in relevant studies conducted in different animal species should be described under the following headings where appropriate:

5 Effects in Humans:

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. Brief summaries of other clinical studies conducted on the same product should be provided if available.

(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 (eg. gender, age, and impaired organ function).

Interactions (eg. Product-product interactions and effects of food).

Other pharmacokinetic data (eg. results of population studies performed within clinical trial(s).

(b) Safety and Efficacy

Information should be provided about the Investigational Product(s)’ (including their metabolites, where appropriate) safety pharmacodynamics, efficacy and dose response(s) that were obtained from preceding trials in humans (healthy volunteers and/or patients). The implications of the information should be discussed. In cases where a number of clinical studies 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) Regulatory & Post-marketing Experiences

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 (eg. 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.

6 Summary of Data and Guidance for the Investigator

This section should provide an overall discussion of the non-clinical and clinical data, and should summarise the information from various sources on different aspects of the investigational product(s), wherever possible. Available published reports on related products should be discussed.

The information given in this section should provide the investigator with a clear understanding of the possible risks and adverse reactions.

Guidance should also be provided on the recognition and treatment of possible overdose and adverse drug reactions.

APPENDIX IV