The Investigator's Brochure (IB) is the document that tells clinical investigators what is known about an investigational product. ICH E6(R3) describes it 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," and gives its purpose as helping investigators understand the rationale for, and comply with, key features of the protocol: "the dose, dose frequency/interval, methods of administration and safety monitoring procedures."

In the US, an IB is a required part of the IND under 21 CFR 312.23(a)(5). In practice it is required wherever a sponsor runs trials of an unapproved product, and it has to be kept current for the life of the programme.

The content standard is Appendix A of ICH E6(R3). This guide walks through that structure and then the problems that most often cause an IB to be reworked.

The structure in ICH E6(R3) Appendix A

E6(R3) says the IB should contain the following sections, "each with literature references (publications or reports) included at the end of each chapter, where appropriate":

  1. Table of contents
  2. Summary. "Preferably not exceeding two pages," highlighting the physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic and clinical information relevant to the current stage of development.
  3. Introduction. Chemical, generic and trade names; active ingredients; pharmacological class and expected position in that class; the rationale for the research; the anticipated indications; and the general approach to evaluating the product.
  4. Physical, chemical and pharmaceutical properties and formulation. The substance, including structural formula; the formulation and excipients; storage and handling instructions.
  5. Nonclinical studies. Pharmacology, pharmacokinetics and product metabolism in animals, and toxicology, in summary form.
  6. Effects in humans. Pharmacokinetics and metabolism in humans, safety and efficacy, and marketing experience if any.
  7. Summary of data and guidance for the investigator. The integrated discussion.

The title page should give the sponsor, the product identity and the release date, and E6(R3) suggests including an edition number, the edition it supersedes, and "the cut-off date for data inclusion in the version."

Appendix A also sets the tone. The IB should be "concise, simple, objective, balanced and non-promotional," so that a clinician can "make their own unbiased risk-benefit assessment." A medically qualified person should be involved in writing it, and the content should be approved by the disciplines that generated the data.

Where IBs go wrong

1. The reference safety information is an afterthought

The reference safety information (RSI) is the part of the IB with the most regulatory consequence. E6(R3) says it "provides an important reference point for expedited reporting of suspected unexpected serious adverse reactions (SUSARs)" and should include "a list of adverse reactions, including information on their frequency and nature." That list is what determines whether a serious adverse reaction is expected, and therefore whether it must be reported quickly to regulators.

Common RSI problems:

  • It lists adverse events, not adverse reactions. The RSI should contain reactions the sponsor considers causally related, not every event seen in trials.
  • It is buried in prose. Investigators and pharmacovigilance staff need to find it quickly. Put it in a clearly labelled section or table.
  • It changes without control. An RSI update changes which future events are expected. It needs version control and a clear effective date, because the DSUR judges expectedness against the RSI in effect at the start of each reporting period. See our guide to writing a DSUR.
  • It is too broad. Listing every theoretically possible reaction as "expected" can suppress expedited reports that regulators want to see. Regulators look for an RSI that reflects actual evidence.

2. Nonclinical findings are summarised but not interpreted

E6(R3) asks that the nonclinical section discuss "the relevance of the findings to the investigated product and the possible unfavourable and unintended effects in humans," including "the dose response of observed effects, the relevance to humans and any aspects to be studied in humans." A table of NOAELs with no interpretation leaves the investigator to work out what to monitor.

It is also specific about how to compare doses: "Whenever possible, comparisons should be made in terms of blood/tissue levels or human equivalent dose rather than on a mg/kg basis." Margins quoted only in mg/kg are a common reviewer comment.

E6(R3) encourages tables: "Tabular format/listings should be used whenever possible to enhance the clarity of the presentation." For each study, the reader should be able to see species, group sizes, dose, route, duration and the main findings, including reversibility.

3. The tone drifts into promotion

IBs are often adapted from investor or partnering material, and it shows. Words like "breakthrough", "best-in-class" or "excellent safety profile" have no place in the IB. The standard is objective and balanced: report what was observed, including unfavourable findings, at the same level of prominence as favourable ones.

4. The "summary of data and guidance" is missing or thin

Section 7 is the part investigators actually use, and the one most often skimped. E6(R3) says its 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 for a clinical trial," and that it should include guidance "on the recognition and treatment of possible overdose and adverse drug reactions." A good section 7 connects each risk to a monitoring step, and each monitoring step to the protocol.

5. The IB is out of date

E6(R3) says the IB "should be reviewed at least annually and revised as necessary." It also notes that important new information "may be so important that it needs to be communicated to the investigators and possibly to the IRBs/IECs and/or regulatory authorities before it is included in a revised IB." Two practical consequences:

  • Keep a change log, and state the data cut-off date on the title page.
  • Align the annual IB review with the DSUR cycle, so the IB, the RSI and the DSUR tell the same story.

6. The IB and the protocol disagree

The dose, the route, the formulation, the exclusion criteria and the safety monitoring in the protocol should all be traceable to the IB. When the protocol monitors liver function weekly but the IB never mentions hepatic findings, or the IB's formulation differs from the one in the pharmacy manual, reviewers and ethics committees notice.

7. A new indication reuses an old IB

E6(R3) says that if an authorised product is studied for a new use, "an IB specific to that new use should be prepared unless there is a rationale for only one IB." A marketed label alone may be an acceptable alternative only where regulators permit and it is current and detailed enough.

A checklist before release

  • Data cut-off date, edition number and superseded edition on the title page.
  • Summary no longer than about two pages.
  • RSI in a clearly labelled place, listing adverse reactions with frequency, and version-controlled.
  • Nonclinical findings interpreted for human relevance, with exposure-based margins.
  • Effects in humans current to the data cut-off, including any marketing experience.
  • Section 7 gives specific guidance: what to monitor, how to recognise and manage likely reactions, overdose.
  • References at the end of each chapter.
  • Approved by the disciplines that generated the data, with medical input.
  • Consistent with the current protocol and pharmacy manual.

Where automation helps

Most IB work is synthesis: nonclinical study reports into summary tables, clinical data into the effects-in-humans section, and both into section 7, then doing it again every year. Asthra's Investigator's Brochure authoring drafts each section from your source reports and the prior IB, cites every statement, and carries forward unchanged content while flagging what the new data change. The RSI and the overall risk judgement stay with your safety physician.

FAQ

How often should an IB be updated? E6(R3) says it should be reviewed at least annually and revised as necessary, with more frequent revision when relevant new information arises.

Is the IB the same as the reference safety information? No. The RSI is one section of the IB: the list of adverse reactions used to judge expectedness for expedited reporting.

Can a product label replace the IB? For an authorised product, E6(R3) says that, where regulators permit, a basic product information brochure such as the SmPC or label may be an appropriate alternative if it is current and detailed enough. A new indication usually needs its own IB.

How long should the IB summary be? E6(R3) says preferably no more than two pages.

Sources