The Investigator’s Brochure (IB): A Comprehensive Guide

What is an Investigator’s Brochure?

The term Investigator’s Brochure (IB) refers to a compilation of the clinical and non-clinical data on an investigational product (IP) that are relevant to the study in human subjects, and that are presented in a concise, objective, balanced, non-promotional form. This definition aligns with the recent ICH E6(R3) Guideline on Good Clinical Practice (GCP).

The IB is used by trial investigators, their site teams, ethics committees or institutional review boards (IRBs), and sponsor-monitoring personnel, to understand the investigational product and support protocol compliance (dose, dosing interval/frequency, administration method, and safety monitoring).

Why the IB Matters

The IB underpins informed, safe, scientifically sound trial conduct which helps investigators assess the risk/benefit for participants in a meaningful way, and regulatory compliance with GCP-style frameworks in the UK/EU and globally. It also provides a controlled, versioned reference for risks, precautions, and monitoring expectations throughout the trial.

In the EU/EEA under the EU Clinical Trials Regulation (EU) 536/2014, the sponsor provides the IB, and the sponsor reviews it at least annually and updates it when new and relevant safety information becomes available (Article 55(1)–(2)).

In the US context (under the 21 CFR Part 312 Investigational New Drug (IND) regime), the IB forms part of the submission materials and is essential for investigator oversight. US IND rules also require the sponsor to provide an investigator brochure to each participating investigator before the investigation begins and to keep investigators informed of new observations as the investigation proceeds (21 CFR 312.55).

In short: it is a living cornerstone document that must be kept current as new information emerges. Where an investigational product is already marketed and its pharmacology and safety profile are widely understood, an extensive IB may not always be necessary, and regulators may permit an alternative product information document (provided it’s current and sufficiently detailed for trial use).

Key ways the IB supports protocol delivery and participant safety include:

Protocol and dosing rationale
The IB provides the foundation for decisions on starting dose, escalation/de-escalation logic, dosing intervals, route of administration, duration of exposure and anticipated safety events, drawing on non-clinical pharmacology/toxicology, PK/PD, prior clinical experience (if any), and known or anticipated adverse reactions.

Monitoring and dose management
The IB helps define administration (dose, frequency, route), key PK/PD parameters to monitor, required safety laboratory tests, stopping/modification criteria, and considerations for special populations or conditions.

Safety risk management
The IB summarises adverse reactions, serious adverse reactions (SARs), expectedness (where applicable), monitoring recommendations, and contraindications/warnings/precautions in a balanced, non-promotional form.

Investigator preparedness
The IB supports protocol compliance, safety oversight, adverse event response, ethics/IRB queries, and informed-consent discussions on risks and potential benefits.

Overall, it links the product evidence base to practical trial conduct and safety oversight.

Core Contents and Structure

The IB is typically structured in a way that aligns with guidance from ICH E6(R3) and national regulatory expectations. Because the latest version of ICH E6(R3) includes an Appendix A specifically for the IB, it is useful to check headings and alignment.

In practice, the structure is designed for quick use: clear front matter, a short summary, a logical evidence flow (non-clinical → human), and a dedicated “Summary of Data and Guidance for the Investigator” section that translates evidence into practical monitoring and risk management expectations. Sponsors align headings to the ICH appendix and local submission expectations.

Typically, the IB will include the following sections:

1. Title/Cover page — Title of investigational product, sponsor name, product identifiers (e.g. code/research number and names as applicable), version number/date, confidentiality statement.
2. Table of Contents — Clear indexing for ease of use by investigator/site.
3. Summary — Concise (often kept short for usability) overview of the purpose of the IB, product development summary, key findings, major risks and benefits.
4. Background and Introduction — Identity of the product (including active ingredients where relevant), pharmacological class, rationale for development, anticipated indications, and overall approach to evaluation.
5. Physical, Chemical & Pharmaceutical Properties & Formulation – Where applicable, key properties and formulation information (including excipients where clinically relevant), handling/storage considerations, and relevant comparability/changes.
6. Data from Non-clinical Studies — Pharmacology, toxicology, pharmacokinetics and metabolism (as applicable), ADME (absorption, distribution, metabolism, excretion), genotoxicity, carcinogenicity, reproductive toxicity (as appropriate).
7. Effects in Humans/Human Clinical Experience (if any) — PK/PD data, safety data, efficacy (if applicable), dosing/administration, population summaries.
8. Safety Information — Known adverse reactions, serious adverse reactions (SARs), monitoring recommendations, special populations, contraindications/precautions.
9. Marketing Experience (where applicable) – Countries/regions where authorised, key learnings from routine use (including formulations/doses/routes where relevant), and withdrawals/non-approvals where relevant.
10. Summary of Data and Guidance for the Investigator — Integrated interpretation of non-clinical and clinical information to provide a clear understanding of risks/adverse reactions and the tests, observations, and precautions needed for the trial. Where helpful, tabular summaries can make key safety patterns easier to interpret quickly.
11. Investigator Guidance — Suggested dose/regimen, monitoring plan, instructions for adverse event reporting, dose modification or stopping criteria, special populations, investigator responsibilities.
12. Appendices — Supporting tables, data listings, conversion tables, glossary of terms, references.
13. Change History / Version Control Log — Each version of the IB is clearly logged with version number/date, data-cut-off date for the contents, summary of changes, effective implementation date, and accountable distribution list to all investigators/sites.
    

Labelling varies by template and development stage, but the aim is a concise, objective, non-promotional IB that lets users find critical information quickly.

In UK/EU practice, the IB may also include a clearly identified Reference Safety Information (RSI) section (more on that later). For example, under the EU Clinical Trials Regulation 536/2014 the placement and versioning of RSI is inspected.

Responsibilities and Update Cycle

Different individuals have different responsibilities regarding an IB. The sponsor is responsible for preparing the IB (or ensuring a current IB is available) and for making it available to investigators. In commercial-sponsor trials, the sponsor typically owns version control, change control, and distribution. In investigator-initiated trials, a sponsor-investigator may assume responsibility. IB preparation and updates are typically reviewed by medically qualified personnel to ensure the safety interpretation is appropriate and the tone remains objective and non-promotional.

Investigators are responsible for using the current version of the IB, applying it to their monitoring and safety oversight, integrating the information into informed-consent discussions, and complying with adverse event / serious adverse event reporting requirements as per protocol and regulatory obligations (e.g., under 21 CFR 312 in the US). Where required, investigators should also ensure the current IB is available to their IRB/IEC/ethics committee for initial and ongoing review.

In the EU/EEA under the EU CTR, the sponsor must review the IB at least once per year and update it when new and relevant safety information becomes available (CTR Article 55(2)).

IRB/IEC/ethics committee handling: As part of submissions for ethics review, a current copy of the IB (or equivalent product information brochure, where permitted) is typically provided, and updated versions should be provided during the trial in line with applicable regulatory requirements.

Update Cycle

The IB should be reviewed at least annually. Older versions of ICH guidance (e.g., E6(R1)) stated “reviewed at least annually and revised as necessary”.

In addition to the annual review, out-of-cycle safety updates are required when new significant safety information becomes available (for example: new serious adverse reactions, new findings from non-clinical studies, new safety signal assessments, or material new information from marketed use where applicable) that may affect risk/benefit assessment, monitoring, consent or trial conduct.

In the EU/UK context, approval of the IB (or an IB amendment) may be required by the national competent authority (NCA) or ethics committee if the IB change constitutes a “substantial amendment” to a clinical trial.

In UK/EU practice: under EU CTR 536/2014 sponsors are expected to align IB/RSI updates with the annual Development Safety Update Report (DSUR) cycle. NHS/UK-based sponsors may face inspection of RSI/IB version control, expectedness logic, change-management compliance.

US Context

In the United States, 21 CFR Part 312 lays down sponsor and investigator responsibilities under an IND. While it does not specify “IB update every 12 months”, the sponsor must notify investigators and regulatory authorities of significant new safety information (e.g. under 21 CFR 312.32(c)(1)(i) and (ii) for Suspected Unexpected Serious Adverse Reactions (SUSARs)). The IB is often part of the investigator submission material under the IND and hence becomes part of the oversight documentation.

In addition, investigators must assure that an IRB responsible for initial and continuing review and approval oversees the proposed study (21 CFR 312.66), which reinforces the importance of maintaining an up-to-date IB in the investigator site file and within the ethics review documentation set.

Guidance for Investigators

An IB will typically contain a section titled “Summary of Data and Guidance for the Investigator”, whose overall aim is to 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 in the clinical trial.

Below is a checklist for investigators, mapped to common IB sections:

Pre-dose (before first subject enrolment)

• Confirm you have the latest version of the IB (check version number/date and data-cut-off).
• Read the Summary and Background sections to understand the investigational product, mechanism of action, non-clinical and clinical experience.
• Check the planned dose/regimen and rationale (see Investigator Guidance section).
• Review inclusion/exclusion criteria in the protocol in the context of IB safety information (contraindications/precautions).
• Ensure you understand key monitoring parameters, safety labs, stopping rules (see Safety Information & Investigator Guidance sections).
• Confirm informed-consent documentation reflects the known risks/benefits derived from the IB.
• Ensure your site team has access to the IB and understands how to use it for safety monitoring.
• If included, review any guidance on recognition and management of overdose and severe adverse reactions.

During dosing (while subjects are on the investigational product)

• Monitor for anticipated adverse reactions described in the Safety Information section of the IB.
• Follow the monitoring frequency, dose-modification and stopping criteria specified in the Investigator Guidance section.
• Report any adverse events (AEs) and serious adverse events (SAEs) per protocol, investigator site file (ISF) and regulatory obligations.
• Refer back to the IB for guidance if a new or unexpected adverse reaction occurs (e.g., is it described in the IB? If not, it may qualify as a SUSAR).
• Document any dose modifications or interruptions in line with IB guidance.

Safety management (throughout the trial)

• Regularly check for IB version updates — when a new version is issued, familiarise yourself with the Change Log/Version Control section.
• Use the IB (especially the “Summary of Data and Guidance to Investigator”) to support internal review of accumulated safety in your site/cohort.
• If new safety signals arise at your site, consult the IB and liaise with the sponsor on whether an out-of-cycle IB update is warranted.
• Provide feedback to the sponsor and the IRB/IEC (if required) about evolving safety observations (e.g., investigator-observed patterns not yet captured in the IB).
• Archive prior IB versions and maintain documentation of distribution to your site team/investigators.

Reference Safety Information (RSI) EU/UK Perspective

In the EU/UK context, the concept of Reference Safety Information (RSI) is critical and typically forms part of (or is referenced by) the IB.

The RSI is a document or a section of the IB listing the expected serious adverse reactions (SARs) for the investigational medicinal product (IMP) for the purpose of assessing whether a reported adverse reaction is expected or unexpected. If a serious adverse reaction occurs that is not included in the RSI (or is more severe/frequent than listed), it may qualify as a Suspected Unexpected Serious Adverse Reaction (SUSAR) which triggers expedited reporting.

The RSI supports pharmacovigilance in clinical trials: it helps the sponsor/investigator determine whether a reported event is “expected” (hence normal) or “unexpected” (hence requiring expedited reporting) and supports competent authorities in trial oversight.

Submission expectation (EU CTR): Always indicate in the clinical trial application cover letter where the RSI is located. If the IB is not an SmPC (Summary of Product Characteristics), it should contain a clearly identifiable section titled “Reference Safety Information (RSI)”.

Placement & Change-control

The RSI is typically located in the IB under a section clearly marked “Reference Safety Information for assessment of expectedness of Serious Adverse Reactions” (or similar), or it is referenced clearly. Changes to the RSI (e.g. adding a new expected SAR, frequency updates, and mitigation/monitoring updates may require controlled versioning, approval and distribution, and may trigger a substantial amendment process under EU CTR expectations.

It is essential that the correct version of the RSI is used for expectedness assessment — specifically, the version valid at the “onset date” of the SAR must be used, not the version at receipt date or reporting date. Many EU National Competent Authorities (NCAs) expect RSI updates to align with the annual DSUR reporting cycle (data-lock point) and the annual IB update.

When an IMP has an EU marketing authorisation and is used in accordance with that authorisation, section 4.8 of the SmPC can be used as the RSI. If the IMP is used outside the (EU) indication of its marketing authorisation within the trial, section 4.8 of the SmPC should only be used as RSI where scientifically justified by the sponsor in the clinical trial application cover letter; otherwise, the RSI should be a clearly separated specific section within the IB.

If there are no expected SARs, this should still be handled explicitly within the RSI approach (rather than leaving RSI absent or ambiguous), consistent with EU CTR Q&A expectations. EU CTR Q&A materials also describe conditions for adding a new SAR to the RSI and related change control expectations.

MedDRA Level

RSI lists should use MedDRA (Medical Dictionary for Regulatory Activities) Preferred Terms (PTs) for adverse reactions to ensure consistency and automated checking of expectedness vs reported event terms. Frequency categories should be provided (for example using CIOMS categories such as very common, common, uncommon, rare, very rare) or number of exposed subjects, as applicable.

Changes per ICH E6(R3) to the IB Requirements

The newly finalised ICH E6(R3) Guideline — adopted 6 January 2025 — brings specific updates to the IB requirements.

Key changes for the Investigator’s Brochure include:

• The guideline explicitly lists the IB content in Appendix A (whereas in previous versions the IB was referenced in the body of E6(R2)).
• New requirement for RSI: the guideline states “This RSI should include a list of adverse reactions, including information on their frequency and nature” and “This list should be used for determining the expectedness of a suspected serious adverse reaction”.
• Increased emphasis on fit-for-purpose, risk-proportionate approaches: the level of detail in the IB should correspond to the risk profile of the product and trial design (rather than a “one-size-fits-all” approach).
• Strengthened emphasis on data governance, metadata, versioning, documentation of review, update cycles and data-cut-off logic in the IB structure.
• Clarified roles and responsibilities for sponsors and investigators (including oversight of third-party providers) which reinforces the IB’s role within the overall GCP framework.

In practice, sponsors and investigators should ensure their IB templates, change-control processes and distribution records are updated to reflect these new E6(R3) expectations. Implementation timelines vary by region, so sponsors should check local regulator communications when planning updates.

Investigator’s Brochure for Medical Devices (When Applicable)

While much of the IB guidance is written in the context of medicinal products (investigational drugs/biologics), when an investigational medical device (or a combination product) is involved, the IB may require additional or adapted content.

Devices may give rise to risk types such as mechanical, electrical, software, implantable, human-machine interface issues — rather than primarily pharmacological/toxicological risks seen in drugs. Therefore, the “investigational product” description must reflect the device’s design, technology, human factors, materials, use scenarios, intended use, prior bench (laboratory non-clinical tests e.g., mechanical/electrical/software performance), animal/human experience, software versioning, and device-specific safety events.

For combination products (e.g., drug + device) the IB may need to address both the pharmaceutical and the device elements and how the combination interacts (for example: device delivering the drug; device modifying pharmacokinetics; device part failure, etc.).

Specific device-regulatory standards need to be considered (for example ISO 14155 – Clinical investigation of medical devices for human subjects – Good Clinical Practice) rather than simply applying drug trial rules wholesale.

In the EU MDR context, MDCG 2024-5 provides specific guidance on the expected content of an Investigator’s Brochure for clinical investigations of medical devices, including administrative details and structured investigational device information, and it reinforces that the IB should be concise, objective, balanced and non-promotional.

Investigators in device trials need to use the IB (or equivalent Investigator’s Device Brochure) to understand device-specific risks, device failure contingencies, monitoring of device performance, criteria for device removal/replacement or malfunction, training for device use, etc.

Version control is especially important in device trials (e.g., when a new device version, software version or firmware update is introduced) as it may trigger an IB amendment or investigator training update.

Where applicable under EU MDR processes, device IB updates may also create notification obligations to competent authorities/member states, so sponsors should build this into change-control and release planning (in addition to investigator/site distribution).

In short: when applying the IB concept to devices (or combination products), adapt the content to reflect the device-risk modalities and regulatory standards applicable to devices — while retaining good GCP-style structure and version control.

Benefits and Limitations

A good Investigator’s Brochure should help investigators and reviewers find what matters quickly: what is known about the investigational product and what that means for safe trial conduct.

Benefits

• Provides a single, structured reference that supports safe conduct and protocol compliance (including dosing and monitoring expectations).
• Supports consistent risk/benefit assessment and safety monitoring decisions across sites and teams.
• Helps harmonise expectations between sponsor, investigator and regulator/ethics committee through a shared evidence base.
• Supports audit and inspection readiness through clear version control, change history, and distribution records (including RSI alignment where applicable).

Limitations

• Bloating where the IB is too long, making it harder to use in practice and reducing value at site level.
• Outdated content when updates are late, leaving sites working from stale safety information.
• Weak version control if the current IB is not reliably distributed, increasing compliance and oversight risks.
• Unclear guidance when instructions are vague or read as promotional, reducing day-to-day usefulness.
• RSIissues in the EU/UKwhere a poorly controlled RSI can compromise SUSAR assessment and attract inspection findings.
• Mismatch between IB and protocol when dosing or monitoring guidance differs between documents, creating confusion and deviations.
• Over-standardisation where a one-size-fits-all IB is used even when a leaner, risk-based approach would be more appropriate.

Mitigation Strategies

These mitigations focus on keeping the IB usable while maintaining clear update control and traceability.

• Keep the IB concise but complete — emphasise investigator guidance and safety information rather than exhaustive data dump.
• Maintain strict version control, cut-off dates, change-summaries, investigator distribution logs.
• Align the IB release/update schedule with other safety deliverables (e.g., DSUR, annual review, site training).
• Use clear headings, an executive summary and quick-reference guidance for investigators.
• For RSI, ensure the list is up-to-date, uses MedDRA PTs, frequencies clearly defined, and version logic documented.
• Ensure regular training of site staff on new IB versions and changes, and that investigator/trial staff acknowledge receipt.
• Periodically review investigator feedback as to IB usability; refine structure if needed.

Next Steps for Sponsors and Investigators

• If you are preparing a new IB or reviewing an existing one, the steps below provide a simple checklist to confirm the document is fit for use, current, and controlled. Review your organisation’s IB template against the ICH E6(R3) Appendix A checklist and update accordingly.
• Ensure your IB version-control and change-management system is robust — audit trails, distribution logs, version history.
• Confirm the RSI section is up-to-date (especially for EU/UK trial sites), uses MedDRA PTs and aligns with the DSUR cycle.
• At investigator sites, confirm the most recent IB version is in the investigator-site file, signed-off by the investigator, and that site staff are trained on any changes.

Incorporate a regular (annual) review of the IB into your trial-governance calendar, and ensure triggers are defined for out-of-cycle updates in the event of new safety signals or product changes.

Conclusion

The Investigator’s Brochure is a foundational document that bridges investigational product development with the practical conduct of a clinical trial. It supports protocol design, investigator training, dosing and monitoring decisions, safety oversight and regulatory compliance. With the advent of ICH E6(R3) and evolving regulatory expectations (especially in the EU/UK regarding Reference Safety Information), sponsors and investigators must ensure their IBs are current, clearly structured, version-controlled and aligned with the trial’s risk profile. Investigators must treat the IB not simply as an archive but as a living tool for safe, ethical and well-conducted research.

Our QInscribe team supports sponsors with clear, inspection-ready clinical documentation and biometrics delivery aligned to ICH GCP and EU/US expectations. If you would like support with IB development, updates, RSI governance, statistics or programming for your next study, please request a consultation and a member of our business development team will be in touch.