Investigator's brochure: what it must contain and how often FDA, ICH and the EU require updates

At a glance

• ICH E6(R3) describes the investigator’s brochure (IB) as a compilation of the clinical and nonclinical data on the investigational product that are relevant to its study in humans, written so investigators understand and follow the protocol’s dose, administration and safety monitoring.
• In the US, an adverse reaction is “unexpected” for IND safety reporting if it is not listed in the IB, or not at the specificity or severity observed (21 CFR 312.32(a)). In the EU, expectedness is set by the reference safety information (RSI) in the IB or SmPC.
• The three regimes set different update rules. 21 CFR 312.55(b) requires the sponsor to keep investigators informed of new observations, E6(R3) asks for updates as significant information arises and a review at least annually, and EU Regulation 536/2014 Article 55 requires updates on new relevant safety information and a sponsor review at least once a year.
• FDA may place a study on clinical hold if the IB is misleading, erroneous or materially incomplete (21 CFR 312.42(b)(1)(iii)).
• For an authorised product used within its marketing authorisation, the EU treats the approved SmPC as the IB, and E6(R3) allows basic product information as an alternative where regulators permit it.

What the IB is, and the job it does

ICH E6(R3) defines the IB as “a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human participants” (Appendix A, A.1). Its purpose is to help investigators and others on the trial understand the rationale for, and comply with, key features of the protocol, such as the dose, dose frequency or interval, methods of administration and safety monitoring procedures. The EU Clinical Trials Regulation uses almost the same definition (Article 2(2)(23)) and the same statement of purpose (Annex I, point 26).

In the US, Part 312 does not define the IB. It lists what the brochure must contain (312.23(a)(5)) and requires a sponsor, other than a sponsor-investigator, to give each participating investigator a copy before the investigation begins (312.55(a)).

That makes the IB more than background reading. Three things depend on it:

• Whether a serious suspected adverse reaction is unexpected, and so goes to the regulator as an expedited report, is decided against the IB (312.32(a), E6(R3) A.1.2).
• On Form FDA 1572 the investigator commits that they have read and understand the information in the IB, including the potential risks and side effects of the drug (312.53(c)(1)(vi)(f)). The Form FDA 1572 guide covers the rest of that statement.
• A misleading, erroneous or materially incomplete IB is a ground for a clinical hold of a Phase 1 study, and through 312.42(b)(2)(i) of Phase 2 and 3 studies as well (312.42(b)(1)(iii)).

When you need one, and when product information can stand in

Each regime handles marketed products and investigator-led studies differently.

United States. The IB obligation in 312.55(a) applies to a sponsor other than a sponsor-investigator, and the IND includes an IB “if required under 312.55” (312.23(a)(5)). Where no IB is required or available, Part 312 measures expectedness against the risk information in the general investigational plan or elsewhere in the current application (312.32(a)). Some studies of marketed drugs need no IND at all, which the IND exemption guide covers.

ICH E6(R3). The sponsor is generally responsible for ensuring an up-to-date IB exists. In an investigator-initiated trial, the sponsor-investigator should find out whether the marketing authorisation holder has a brochure. Where regulators permit it, basic product information such as an SmPC, package leaflet or labelling may serve instead, provided it gives current, comprehensive and detailed information on every aspect of the product that might matter to the investigator. If an authorised product is being studied for a new indication, an IB specific to that use should be prepared unless there is a rationale for only one IB (A.1.1, 3.15.1).

European Union. An IB must be submitted with the application (Annex I, point 25). If the investigational medicinal product is authorised and used in accordance with its marketing authorisation, the approved SmPC is the IB. If the conditions of use in the trial differ, the SmPC is supplemented with a summary of the nonclinical and clinical data that support that use (Annex I, point 28).

Device investigations run under separate rules that this guide does not cover.

What goes in it: a section map

E6(R3) Appendix A sets the minimum structure, and expects the type and extent of information to vary with the stage of development (A.2). The table puts each section next to the matching item in 21 CFR 312.23(a)(5).

E6(R3) section	What it covers	US 312.23(a)(5) item
A.2.1 Title page	Sponsor name, identity of each product (research number, chemical or generic name, trade name where permitted), release date. E6(R3) also suggests an edition number, the edition superseded and the data cut-off date	None
A.2.2 Confidentiality statement	Optional instruction to treat the IB as confidential	None
A.3.1 Table of contents		None
A.3.2 Summary	Preferably no more than two pages of the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic and clinical information	None
A.3.3 Introduction	Chemical, generic and trade names, active ingredients, pharmacological class, rationale for the research, anticipated indications, general approach to evaluation	None
A.3.4 Physical, chemical and pharmaceutical properties and formulation	Substance description with chemical or structural formula, formulation including excipients, storage and handling	(i) Description of the drug substance and formulation, including the structural formula if known
A.3.5 Nonclinical studies	Nonclinical pharmacology, pharmacokinetics and metabolism in animals, toxicology, with the relevance of findings to humans	(ii) Pharmacological and toxicological effects in animals, (iii) pharmacokinetics and biological disposition in animals
A.3.6 Effects in humans	Pharmacokinetics and metabolism in humans, safety and efficacy from earlier trials, marketing experience including countries where approval was refused or withdrawn	(ii) and (iii) to the extent known in humans, (iv) safety and effectiveness from prior clinical studies
A.3.7 Summary of data and guidance for the investigator	Overall discussion of the data, possible risks and adverse reactions, the tests, observations and precautions needed, and guidance on recognising and treating overdose and adverse drug reactions	(v) Possible risks and side effects, and precautions or special monitoring

The EU Regulation does not set out IB chapters. It requires the IB to be prepared in accordance with the state of scientific knowledge and international guidance (Annex I, point 25), presented in a concise, simple, objective, balanced and non-promotional form (point 27), and, where the IB is not an SmPC, to contain a clearly identifiable section called the reference safety information (point 30). E6(R3) A.1.2 uses the same presentation standard and adds that a medically qualified person should be involved in writing the IB, with its contents approved by the disciplines that generated the data.

The reference safety information decides expectedness

The RSI is the part of the IB that safety reporting runs on. E6(R3) calls it the reference point for expedited reporting of suspected unexpected serious adverse reactions (SUSARs), and says it should list adverse reactions with their frequency and nature, for use in deciding expectedness (A.1.2). Sponsors are to assess expectedness against that RSI, or alternative product information, under the applicable regulatory requirements (3.13.2(c)).

The three texts frame expectedness differently:

• In the US, Part 312 does not use the term RSI. An adverse event or suspected adverse reaction is unexpected if it is not listed in the investigator brochure, or not at the specificity or severity observed. Hepatic necrosis is unexpected if the IB mentions only elevated hepatic enzymes or hepatitis. An event the IB mentions only as occurring with the drug class, or as anticipated from the drug’s pharmacology, but not as occurring with the drug itself, also counts as unexpected (312.32(a)).
• In the EU, the sponsor sets expectedness in the RSI, on the basis of events previously observed with the active substance, not anticipated pharmacological properties or events related to the subject’s disease (Annex III, point 6). The RSI sits in the SmPC or the IB (Annex III, point 7), and the version in force when a SUSAR occurs is the one that applies (Annex III, point 8).
• ICH E6(R3) defers to applicable regulatory requirements and points to ICH E2F for more on the RSI (3.13.2(c)).

The US test reads against the whole brochure, while the EU test reads against one defined RSI section and only observed events. The two are not the same test, and a single IB used in both regions has to satisfy each on its own terms. A reviewer should check this point for any global program.

The EU text also states the consequence of an RSI change directly: changing the RSI changes the number of adverse reactions reported as SUSARs (Annex III, point 8). Adding a reaction to the RSI is a safety decision with reporting effects, and it deserves the review that implies. The SUSAR reporting guide and the expedited safety reporting guide cover the reporting clocks.

Keeping it current: US, ICH and EU update rules

	US, 21 CFR Part 312	ICH E6(R3)	EU, Regulation 536/2014
Event-driven update	Keep each investigator informed of new observations, particularly on adverse effects and safe use, by revised IBs, reprints, reports, letters or other means (312.55(b))	Develop and update the IB as significant new information becomes available (3.15.1)	Update the IB where new and relevant safety information becomes available (Article 55(2))
Periodic review	No fixed frequency in Part 312. If the IB was revised, the IND annual report includes a description of the revision and a copy (312.33(d))	Review at least annually and revise as necessary under the sponsor’s documented procedures (A.1.1)	Sponsor review at least once per year (Article 55(2))
Before the revision is ready	Important safety information goes to investigators under 312.32 (312.55(b))	Relevant new information may need to reach investigators, and possibly IRBs/IECs and regulators, before it is in a revised IB (A.1.1)	Not set out in Article 55
Who receives it	Each participating investigator, before the investigation begins (312.55(a))	Investigators (3.7.2) and the IRB/IEC, which should receive the current version when the IB is updated (2.4.3)	The investigator (Article 55(1))

The periodic-review row is where the regimes diverge. E6(R3) and the EU Regulation both set an annual minimum. Part 312 sets none, and works through continuous investigator information instead. The texts are not aligned on this point, and each applies in its own jurisdiction, so a program that runs in more than one region has to check the IB against each rule separately. The IND annual report guide covers what 312.33 asks for.

Running the update as a process

Who writes the IB varies by company, often a medical writer working with clinical science, safety and nonclinical teams. The process is the same:

1. Trigger. Log every event that could change the IB: new nonclinical findings, an aggregate safety review (E6(R3) 3.13.1 notes that safety review may lead to updates of the protocol, IB and consent materials), a new formulation, or the annual review date.
2. Decide the vehicle. A full new edition, or an interim communication such as an addendum or a letter to investigators. Part 312 explicitly allows reports and letters (312.55(b)). The word “addendum” does not appear in any of the three texts, so treat it as a document your SOP defines.
3. Review and approve. The disciplines that generated the data approve their sections, with a medically qualified person involved (A.1.2). If the RSI changes, safety physicians sign that change separately.
4. Distribute. Send the new version to every investigator and track receipt. Under E6(R3), the IRB/IEC should receive the current version (2.4.3). Check whether new risk information also needs to reach participants through updated consent, which the informed consent guide covers.
5. File. Keep each edition, the superseded edition and the distribution record. The essential documents guide covers where each copy lives in the TMF and the investigator site file.

IB vs package insert or SmPC

A package insert or SmPC describes a product for its approved use. An IB describes what is known for the use under study. When the two coincide, the regimes allow the label to do the IB’s job: the SmPC is the IB in the EU for use within the marketing authorisation (Annex I, point 28), and E6(R3) accepts basic product information where regulators permit it (A.1.1).

When they diverge, the label is not enough. A new indication under E6(R3) calls for an IB specific to that use unless a single IB can be justified (A.1.1), and under the EU Regulation an SmPC used outside its authorised conditions must be supplemented with the supporting nonclinical and clinical data (Annex I, point 28). Where several Member States have different SmPCs for the same product, the sponsor chooses one for the whole trial, the one best suited to patient safety (Annex I, point 29).

The IB and the IMPD in the EU

An EU application carries both an IB and an investigational medicinal product dossier (IMPD). The IMPD gives information on the quality of the product, its manufacture and control, and data from nonclinical studies and clinical use (Annex I, point 36). The IB is written for the investigator, the IMPD for the assessor. The reporting Member State assesses the completeness and adequacy of the IB as part of the Part I assessment (Article 6(1)(e)). The EU Clinical Trials Regulation guide covers the assessment as a whole.

Where IBs go wrong

• The tone is promotional. Both E6(R3) and the EU Regulation require a balanced, non-promotional presentation (A.1.2, Annex I, point 27). Efficacy claims written like marketing copy invite a challenge.
• The RSI is out of date, or buried. In the EU the RSI must be a clearly identifiable section (Annex I, point 30), and a late update changes which reactions count as SUSARs.
• Marketing experience is incomplete. E6(R3) asks the IB to identify countries where the product is marketed, and also where it was refused approval or withdrawn (A.3.6(c)).
• The IB is stale when it reaches the site. An IB that misses a known risk is the kind of deficiency 312.42(b)(1)(iii) describes.
• Edition control is loose. Without an edition number, release date and data cut-off date, a site cannot tell which version an investigator signed against.

A section skeleton you can adapt

There is no official FDA IB template in Part 312, which lists required content (312.23(a)(5)) but not a format. The skeleton below is our own, built from the E6(R3) Appendix A headings. Adjust depth to the stage of development.

1. Title page: sponsor, product identifiers, edition number, release date, edition superseded, data cut-off date
2. Confidentiality statement
3. Table of contents
4. Summary (two pages at most)
5. Introduction
6. Physical, chemical and pharmaceutical properties and formulation
7. Nonclinical studies: pharmacology, pharmacokinetics and metabolism in animals, toxicology
8. Effects in humans: pharmacokinetics and metabolism, safety and efficacy, marketing experience
9. Summary of data and guidance for the investigator
10. Reference safety information: a clearly marked list of expected adverse reactions with frequency and nature
11. References at the end of each chapter

For the regulatory place of the IB in an IND, see the 21 CFR 312 overview, the IND application guide and the Form FDA 1571 guide. If the brochure is still in draft when you plan to file, the pre-IND meeting guide covers what FDA can tell you before submission. Investigators can find their side of the obligations in the principal investigator responsibilities guide.

Sources

• ICH E6(R3) Guideline for Good Clinical Practice, Appendix A
• 21 CFR Part 312, Investigational New Drug Application, eCFR text up to date as of 14 April 2026
• Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use