According to the International council for harmonization (ICH) E6 guidelines, the Investigator Brochure (IB) is a compilation of the clinical and non-clinical data on a product in development that are relevant to the study of the product(s) in human subjects. It is primarily written for investigators and other personnel involved in the execution of a clinical trial, also submitted to ethics committees and regulatory authorities. Its purpose is to provide the investigators and others stakeholders involved in the trial with the information to facilitate their understanding of the rationale and key features of the protocol, such as the dose, dose frequency/interval, methods of administration and safety monitoring procedures. The Investigator Brochure also provides insight to support the clinical management of the study subjects participating in the clinical trial.

The information should be presented in a concise, simple, objective, balanced, and non‑promotional that enable an investigator to understand it and make his/her own unbiased risk and benefit assessment. The type and extent of information available will vary with the stage of development of the investigational product. First and early stage IB usually contains more non-clinical data. In subsequent IBs, non-clinical data can be concised and clinical data can be added.

If the investigational product is marketed and its pharmacology is widely understood by medical practitioners, an extensive Investigator Brochure may not be necessary. Where permitted by regulatory authorities, a package leaflet, or labelling may be an appropriate alternative, provided that it includes current, comprehensive and detailed information on all aspects of the investigational product that might be of importance to the investigator. If a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared.

The contents of investigator brochure is as follows

• Title page
• Table of contents
• List of abbreviations
• Summary
• Introduction
• Physical, chemical and pharmaceutical properties and formulation
• Non-clinical studies
• Effects in humans
• Reference safety information
• Summary of data and guidance for the investigator
• Appendices

The Reference Safety Information (RSI) is usually contained within either an Investigator Brochure or Summary of Product Characteristics (SmPC). This section could be located within or close to section ‘Summary of Data and Guidance for the Investigator’. The RSI is used for the assessment of the expectedness of all ‘suspected’ serious adverse reactions (SARs) that occur in clinical trials. Therefore the RSI is a list of expected serious adverse reactions, which are classified using Preferred Terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA). An expectedness assessment is required to be conducted by the sponsor on each ‘suspected’ SAR to determine expedited reporting of ‘suspected unexpected serious adverse reactions (SUSARs). Any change in RSI is a change to the risk benefit ratio for participants.

The Summary of Data and Guidance for the Investigator section should 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. Thus, additional information of the products safety profile such as identified or potential risks, as well as e.g. potential drug-drug interactions, class effects and so on, should also be included.

The Investigator Brochure should be reviewed atleast annually and updated. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. The timing of the annual review may be in line with the Development International Birth Date of the product and Development Safety Update Report. An urgent update to the safety data in the Investigator Brochure may be deemed necessary by the sponsor or regulatory authorities at any time during the conduct of a clinical trial. The new version of the Investigator Brochure must contain a revision history indicating the changes that were made to the previous version of the document.