Usage Examples
- The IB was updated with Phase 2 safety data before the Phase 3 sites were initiated.
- That event is listed in the current reference safety information, so it is expected and not an expedited SUSAR.
- Send the IRB the current IB version along with the amendment package, not the one they reviewed last year.
What is Investigator's Brochure (IB)?
The Investigator's Brochure is the sponsor-maintained compilation of clinical and nonclinical data on an investigational product, functioning as its pre-approval labeling: the reference investigators use to judge risk-benefit and comply with the protocol.
The Investigator's Brochure exists because an investigator is asked to give an unapproved product to a human being on the strength of data they did not generate. ICH E6(R3) defines it as the compilation of clinical and nonclinical data that lets investigators understand the rationale for the protocol's dose, dose frequency, route of administration and safety monitoring, and make their own unbiased risk-benefit assessment.
The Investigator's Brochure covers the product itself: chemical and pharmaceutical properties, nonclinical pharmacology and toxicology, effects in humans, and the reference safety information used to judge expectedness. The IB stops at the product; trial conduct belongs in the protocol. Where regulators permit, an authorised medicinal product can be supported by basic product information such as the SmPC or labelling instead, unless a new indication is being studied.
The Investigator's Brochure is applied as a live document, not a filing artifact. Sponsors give the current version to each participating investigator before the investigation begins, review it at least annually, and push safety-critical findings to investigators, IRBs/IECs and regulators ahead of the next revision. Each version change then propagates into SUSAR expectedness assessment, protocol amendments and the DSUR, where version control becomes the real workload.
Not to be confused with
- Clinical trial protocol
- the protocol specifies what the trial does; the IB states what is known about the product. ICH E6(R3) positions the IB as the reference that makes the protocol's dose and monitoring choices intelligible, not as the document that imposes them.
- Package insert / SmPC
- approved labeling describes a use a regulator has authorised. The IB describes an investigational use nobody has approved, and is written non-promotionally for investigators rather than for prescribers.
- Reference safety information (RSI)
- RSI is one component inside the IB: the list of expected adverse reactions used to judge SUSAR expectedness. Changing the RSI changes expedited reporting obligations; changing the rest of the IB usually does not.
- DSUR
- the DSUR reports what happened during a defined reporting period. The IB states the current cumulative knowledge of the product, and supplies the reference safety information the DSUR's expectedness assessments are measured against.
Two sources bind: 21 CFR Part 312 for US INDs, and ICH E6(R3) wherever GCP applies.
What you must do
- 1Give each participating clinical investigator the investigator brochure before the investigation begins, unless the sponsor is a sponsor-investigator21 CFR 312.55
- 2Include in the IND a brochure covering the drug substance and formulation, pharmacological and toxicological effects, pharmacokinetics and biological disposition, prior human safety and effectiveness data, and anticipated risks and side effects21 CFR 312.23(a)(5)
- 3Keep every participating investigator informed of new observations on the drug as the investigation proceeds, particularly adverse effects and safe use, via periodically revised brochures or equivalent means21 CFR 312.55
- 4Review the IB at least annually and revise it as necessary under the sponsor's documented procedures, revising more often when the development stage or new information warrantsICH E6(R3) Appendix A.1.1
- 5Communicate relevant new information to investigators, and where warranted to IRBs/IECs and regulatory authorities, before it is incorporated into a revised IBICH E6(R3) Appendix A.1.1
- 6Maintain reference safety information listing adverse reactions with their frequency and nature, and use that list to determine expectedness for expedited SUSAR reportingICH E6(R3) Appendix A.1.2
Common mistakes
Treating annual review as the update schedule
ICH E6(R3) sets annual review as a floor, not a cadence. When a dose-limiting toxicity or new contraindication emerges mid-trial, the obligation is to communicate it to investigators before the revised IB exists. An IB that trails the safety database undermines every consent discussion conducted against it.
Editing the reference safety information without tracing the reporting consequences
RSI defines expectedness, so widening or narrowing that list silently changes which events become expedited SUSARs. A case assessed against a different RSI version than the one in force at the time of the event is an inspection finding and a reporting-timeline breach at once.
Writing the IB as a promotional document
E6(R3) requires a concise, simple, objective, balanced and non-promotional presentation so the investigator can reach their own unbiased risk-benefit assessment. Selective framing of nonclinical toxicology or early efficacy invites reviewer questions and destroys the document's standing as the site's safety reference.
When This Matters
- The IB was updated with Phase 2 safety data before the Phase 3 sites were initiated.
- That event is listed in the current reference safety information, so it is expected and not an expedited SUSAR.
- Send the IRB the current IB version along with the amendment package, not the one they reviewed last year.
Frequently Asked Questions
At least annually, and sooner whenever significant new information emerges. ICH E6(R3) Appendix A.1.1 requires annual review and revision under the sponsor's documented procedures, and notes that some new information is important enough to be communicated to investigators, IRBs/IECs, and regulatory authorities before it appears in a revised IB.
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