Investigator Brochure: Content, Updates, and Best Practices

The Investigator’s Brochure (IB) compiles all available clinical and nonclinical data on an investigational drug. It enables the investigator to understand the product they are administering, assess the benefit-risk ratio for their patients, and recognize expected adverse events. As a mandatory component of the clinical trial application dossier, it must be reviewed at least once a year. At CLINACT, a CRO of the MultiHealth Group, we draft and update investigator’s brochures on behalf of sponsors.

What is the investigator's brochure?

The BI is a document drafted and maintained by the sponsor. It is not specific to a single trial; rather, it pertains to the product and is used for all trials that evaluate it. It serves a dual purpose: it informs the investigator so that he or she can make informed medical decisions, and it provides regulatory authorities and ethics committees with the scientific basis justifying the trial.

It accompanies the product throughout its development. An initial version is drafted before the first human trial, based solely on nonclinical data, and is then expanded in each phase to include the clinical results obtained. Its introduction and data synthesis are often based on a systematic review of the literature.

Its content is governed, in particular, byICH E6(R3), the Good Clinical Practice guideline, whose Appendix A is devoted to the Investigator’s Brochure. In the European Union, Regulation (EU) No. 536/2014 requires it to be a mandatory part of the marketing authorization application and mandates that it be updated as soon as new and relevant safety information becomes available.

The investigator's brochure follows a standardized structure

ICH E6 provides a standard outline, which most sponsors adopt as is to make it easier for reviewers to read.

Section	Expected Content
Title Page and Privacy Policy	Product name, edition number, date, version replaced, confidentiality notice
Abstract	A summary of approximately 2 pages covering physical, chemical, pharmacological, toxicological, and clinical data
Introduction	Therapeutic class, rationale for development, intended indications
Physical and Pharmaceutical Properties	Formula, formulation, storage and handling conditions
Nonclinical Studies	Pharmacology, pharmacokinetics and metabolism, animal toxicology
Effects in Humans	Pharmacokinetics, observed safety and efficacy, and postmarketing experience, if applicable
Summary and Recommendations	Data Interpretation, Precautions, Recommended Monitoring, Reference Safety Information (RSI)

The last section is the most useful for investigators in their day-to-day work. It translates the data into practical guidelines: what effects to monitor, what interactions to avoid, and what steps to take in the event of an overdose.

The reference security information is the most sensitive part

The BI contains the Reference Safety Information (RSI). This is the list of adverse reactions considered to be expected for the product. It determines whether a serious adverse reaction is “unexpected” and, therefore, whether it must be reported as a SUSAR to the authorities within the regulatory timeframes.

An RSI that is too broad obscures signals. An RSI that is too restrictive leads to an increase in reports. In Europe, a change to the RSI is generally considered a substantial change that must be approved before it can be implemented. The drafting process is therefore carried out in close collaboration with the pharmacovigilance team.

In terms of format, the RSI takes the form of a separate, clearly identified table listing the expected serious adverse events by MedDRA term, along with their observed frequency. The RSI must include serious adverse events for which the available data provide reasonable evidence of a causal relationship with the investigational drug. European guidelines further stipulate that a fatal or life-threatening event should generally remain unexpected.

BI updates follow a specific schedule

The sponsor must review the BI at least once a year. In practice, the annual update is often aligned with the period covered by the annual safety report (DSUR), which ensures consistency between the two documents. An update may also be initiated at any time:

• new nonclinical results, such as a long-term toxicology study;
• completion of a clinical trial and availability of its clinical trial report;
• safety signal or newly identified adverse event;
• a change in the formulation or manufacturing process.

Each new edition must be communicated to the investigators and submitted via CTIS in accordance with the applicable regulatory process, which depends on the nature and impact of the changes made. A table summarizes the changes from the previous version.

Best Practices for Writing a Business Proposal

1. Stick to the facts. A BI report is not a promotional document. Unfavorable data must be included on the same footing as other data. A first draft generated by generative AI must be reviewed with the same level of rigor.
2. Writing for a clinician. The investigator is not a toxicologist. Each nonclinical finding must be linked to its significance for humans.
3. Ensure consistency. Dosages, populations, and adverse effects must be consistent with the protocol, the CSR, and the DSUR.
4. Track versions. The edition number, date, and summary of changes make it easier to review them.

When the drug is already authorized and used in accordance with its marketing authorization conditions, the Summary of Product Characteristics (SmPC) may replace the Investigator’s Brochure. For medical devices, Regulation (EU) 2017/745 (MDR) and ISO 14155:2026 also govern the content of the Investigator’s Brochure.

Have MultiHealth Group write your investigator brochure

Medical writers, regulatory experts, and pharmacovigilance specialists work together at MultiHealth Group to produce business intelligence that is consistent with your entire dossier. Learn more about our expertise in medical and scientific writing and regulatory affairs, or contact our teams.

Frequently Asked Questions About the Investigator Brochure