The investigator's brochure
An investigator's brochure compiles what is known about an investigational product for the investigators who study it in humans, and it also serves regulators, ethics committees and prospective partners. Producing one means knowing who reads it and for what, what ICH E6 asks each section to contain and who supplies it, how to keep the document concise and current from one edition to the next, and the reference safety information it carries.
Purpose and readers
The brochure is a compilation of the clinical and nonclinical data on the investigational products relevant to studying them in human participants, and its purpose is to give investigators and others involved in the trial the information that lets them understand the rationale for, and comply with, many key features of the protocol — the dose, the dose frequency or interval, the methods of administration and the safety monitoring procedures. The brochure also provides insight to support the clinical management of participants during the trial. It is a living compilation of the product's nonclinical and clinical data that gives the investigator background such as the dosing rationale. It summarises the main elements of the entire development programme to date, primarily so that investigators conducting clinical studies can assess the benefits and risks of the investigational product; beside information on the product itself, it gives an overview of the nonclinical and clinical findings with guidance for investigators on using the product, based on medical interpretation of those findings.
The brochure is like an encyclopaedia of everything known about the product — its chemistry, the preclinical information and the clinical data already known — and it is written at the same time as the protocol and the informed consent form. It can run to two hundred pages and sits on the investigator's desk, so that if a participant has a side effect during a trial, the investigator can turn to it to find out quickly whether this has happened before, what is known about it, and what should be done.
The brochure's central readers are the investigators and staff performing a study within the product's development plan. The same document is also part of submissions to regulatory authorities, particularly those seeking approval to begin studies in humans, and an important document in the regulatory approval of a trial. Ethics committees use it when deciding on ethical approval of a study. It also goes to a potential investor or a business partner seeking a licensing agreement. The key messages may differ with the audience, and those to the regulatory authorities have a quite different emphasis from those to the investigator.
A good brochure should be easy to read and give the reader clear insight into the characteristics of the substance being investigated, and it clearly describes the rationale and key aspects of the nonclinical and clinical studies and their contribution to the development programme. From the information it provides, the investigator should be able to make an informed, unbiased and independent benefit-risk assessment of the appropriateness of a particular protocol and perform a study of high quality. The key messages to the investigator are a good understanding of the drug — its safety, its efficacy and the value it will add if approved for clinical use — and of the rationale and design of the protocol; if these are clear, the outcomes to expect from the investigator are willingness to do the study, adherence to the protocol and timelines, and assurance of the safety of participants and of accurate, high-quality data. A template for planning a brochure for a specific study, aimed at the team conducting it, names as its key messages an understanding of the drug — its pharmacokinetics, safety and efficacy — and of the development plan, and an understanding of the key elements of the protocol; it names ICH E6 as the guideline and company documentation and literature as the information sources. A brochure aimed at the FDA or EMA, an ethics committee or a potential investor would be planned with a template of its own.
The brochure in regulatory submissions
The brochure has other regulatory uses: it is a requirement for investigational new drug applications in the United States and for investigational medicinal product dossier and paediatric investigation plan submissions in Europe, and it can form the basis of other documents needed for regulatory interactions, such as briefing packages and some of the summaries required when applying for marketing authorisation.
ICH, the US Food and Drug Administration and the European Medicines Agency provide the same guidelines but give the brochure different emphasis. ICH and the FDA stand at two ends of a spectrum: ICH regards the brochure as a good-clinical-practice document written to properly inform the investigator, while the FDA sees it as part of the investigational new drug application, with a stronger emphasis on safety. The European Medicines Agency also regards the brochure as a good-clinical-practice document. The agency addresses the regulatory concerns in the investigational medicinal product dossier of the clinical trial application, which makes it possible to keep the brochure simple and investigator-oriented.
Responsibility for the brochure and the number of brochures
ICH E6 makes the availability of a current brochure a regulatory prerequisite that sponsors must fulfil when they intend to conduct clinical studies. Under ICH E6(R3), the sponsor is generally responsible for ensuring an up-to-date brochure is developed. In an investigator-initiated trial, the sponsor-investigator should establish whether a brochure is available from the licence or marketing authorisation holder, and if they are themselves providing the product they should supply the necessary information to the site staff. Where regulatory authorities permit, current scientific information such as a basic product information brochure — a summary of product characteristics, a package leaflet or labelling — may be an appropriate alternative, provided it includes current, comprehensive and detailed information on all aspects of the product that might matter to the investigator. If an authorised product is being studied for a new indication, a brochure specific to that new use should be prepared unless there is a rationale for having only one.
Where the product is intended for use in multiple indications, the sponsor has to decide whether to prepare separate brochures or cover all indications in a single one; in 2014 ICH E6 gave no specific guidance on this, so the approach taken was often quite subjective. The decision can depend on how closely related the indications are, differences in formulation or route of administration, the timings of the different development programmes, and whether the programmes are being conducted by different sponsors. Where separate brochures are used, how much safety information from the other indications to include has to be appraised on the basis of clinical relevance to the indication in question.
Table of contents
In 2014 Section 7 of ICH E6 provided what was essentially a table of contents, almost always used unchanged: summary; introduction; physical, chemical and pharmaceutical properties and formulation; non-clinical studies; effects in humans; and summary of data and guidance for the investigator. In ICH E6(R3) the specification is Appendix A, which sets out the minimum information a brochure should include and expects the type and extent of information available to vary with the product's stage of development.
The title page provides the sponsor's name, the identity of each product — research number, chemical or approved generic name, and trade names where legally permissible and desired by the sponsor — and the release date; an edition number, a reference to the number and date of the edition it supersedes, and the cut-off date for data included in the version are all suggested, and a signature page may be included where appropriate. The sponsor may include a confidentiality statement instructing the investigator and other recipients to treat the brochure as a confidential document for the sole information and use of the investigator and institution, the site staff, the regulatory authorities and the ethics committee. Each of its content sections should include its literature references — publications or reports — at the end of the chapter where appropriate.
Within that order, the optional confidentiality statement and signature page come before the table of contents; the nonclinical section divides into pharmacology, pharmacokinetics and product metabolism in animals, and toxicology; effects in humans divides into pharmacokinetics and product metabolism in humans, safety and efficacy, and marketing experience; the summary of data and guidance for the investigator closes the body; and references follow it, with appendices of publications and reports.
The sections
Some or all of the sections after the introduction may be supplied in some form by members of the product team.
Summary
ICH E6(R3) asks for a brief summary, preferably not exceeding two pages, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic and clinical information available that is relevant to the product's stage of clinical development. The summary is often all a busy investigator will read and needs to get the key information and messages across clearly and concisely, and it should be reviewed by an experienced clinician.
The summary should give a high-level overview of all the sections that follow. In practice the two-page length is rarely achieved, especially in later versions that already contain a large amount of information. Keeping the summary brief is often easiest for a writer involved from the first edition; a writer who inherits a later version with an already lengthy summary can find it a challenge to convince the team that what has worked in previous editions now needs substantial revision.
Introduction
ICH E6(R3) asks for a brief introductory statement giving the chemical name and the generic and trade names where approved; all active ingredients; the pharmacological class and the product's expected position within it, such as its advantages; the rationale for performing research with it; the anticipated prophylactic, therapeutic or diagnostic indications; and the general approach to be followed in evaluating it.
The introduction should give a high-level overview of the product and the setting in which it is investigated, stressing any potential advantages over other products in the class and giving an overview of the investigational approach conducted or intended. It is one section a writer inevitably has to draft de novo, typically from the clinical development plan and any presentations and briefing packages prepared previously.
Physical, chemical and pharmaceutical properties and formulation
ICH E6(R3) asks for a description of the product substances including chemical or structural formulae, with a brief summary of the relevant physical, chemical and pharmaceutical properties. So that appropriate safety measures can be taken during the trial, the formulations to be used are described, excipients included, and justified where clinically relevant, and instructions for storing and handling the dosage forms are given. Any structural similarities to other known compounds should be mentioned.
The section is brief, and its material is typically supplied by the sponsor's chemistry, manufacturing and controls department, though the writer may need to adapt it to the brochure's format. It should give the investigator enough information about the product — and, where relevant, the drug substance — to assess the potential risks associated with the drug itself or with any excipients, and it also carries the storage and handling information, including any preparation steps needed before administration, such as reconstitution or dilution.
Nonclinical studies
ICH E6(R3) asks the nonclinical section to summarise the results of all relevant pharmacology, toxicology, pharmacokinetic and metabolism studies, addressing the methodology used, the results, and a discussion of the relevance of the findings to the product and to the possible unfavourable and unintended effects in humans; it defines a nonclinical study as a biomedical study not performed on human participants. The information given may include, as appropriate and where known, the species tested; the number and sex of animals in each group; the unit dose; the dose interval; the route of administration; the duration of dosing; information on systemic distribution; the duration of post-exposure follow-up; and results covering the nature, frequency, severity or intensity, time to onset, reversibility, duration and dose response of the pharmacological or toxic effects. Tabular format and listings should be used wherever possible to make the presentation clearer. The narrative that follows should discuss the most important findings, including the dose response of the observed effects, their relevance to humans and any aspects to be studied in humans. Where applicable the effective and nontoxic dose findings in the same animal species should be compared — that is, the therapeutic index should be discussed — and the relevance of that to the proposed human dosing addressed, with comparisons made in terms of blood or tissue levels or human equivalent dose rather than on a milligram-per-kilogram basis wherever possible.
The pharmacology subsection summarises the pharmacological aspects of the product and, where appropriate, its significant metabolites studied in animals, incorporating studies of potential therapeutic activity such as efficacy models and receptor binding and specificity, and studies assessing safety such as special studies of pharmacological actions other than the intended therapeutic effect. The pharmacokinetics and metabolism subsection summarises the pharmacokinetics, biological transformation and disposition of the product in all species studied, discussing absorption, local and systemic bioavailability of the product and its metabolites, and their relationship to the pharmacological and toxicological findings in the animal species. The toxicology subsection summarises the toxicological effects found in relevant studies in different animal species, under the headings single toxicity, repeated dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance, and other toxicity studies, as appropriate.
In a first edition the nonclinical studies have a key function, because they are the sole evidence on which benefits and risks can be assessed before the product is first given to humans. A complete summary of the non-clinical profile is required, although details of exploratory studies may sometimes be omitted where more complete studies provide the same type of information. How much there is to summarise varies with the programme, and it may be less for a human plasma protein, for which only limited animal testing is possible, than for a new chemical entity intended for an oncology indication with a high potential for toxicity. In the structure ICH E6 provided in 2014, the toxicology section should be subdivided into single and multiple dose toxicology, carcinogenicity, special studies specific to the type of product, such as irritancy studies for a product applied topically, reproductive toxicity and mutagenicity. Beyond study design and the species or test systems used, ICH E6 in 2014 asked the summaries to include, as applicable, the nature, frequency and intensity of pharmacological or toxic effects, their time to onset and duration, and their reversibility. Where a large number of studies are available, it can help to tabulate the details of each study, often in an appendix, and give focused summaries of results and interpretations, supported by tables and figures, in the section itself.
What the writer is handed for that section varies. Depending on the sponsor's process the writer may receive more or less complete sections including tables and figures, in which case the main task may be limited to language and formatting for consistency with the rest of the brochure and with any style conventions. At the other end the writer may be asked to generate text and tables de novo from final reports, which is the best case, or from sometimes non-validated information of varying quality in slide decks and ad hoc documents produced previously for other purposes, which is the worst case, rare but known to happen. Until a writer has some experience of summarising non-clinical studies, this section can be daunting.
A study reported in April 2018 examined 109 brochures for phase I and II trials obtained from German institutional review boards, one of which supplied 97 reviewed between 2010 and 2016. They covered eight of the twelve therapeutic areas the European Medicines Agency distinguishes, all the trials were privately funded, and 48 brochures came from the twenty-five largest pharmaceutical companies; seven of the trials were first in human, and the rest mentioned at least some clinical evidence for the product. The 708 unique preclinical efficacy studies described in the brochures were rated for whether they reported the elements that help address threats to validity, whether they referenced a published report, and which way their results went. Fewer than 5 per cent described elements such as randomisation, sample size calculation or blinded outcome assessment; 89 per cent gave no reference to a published report; only 6 per cent reported an outcome showing no effect; and in 82 per cent of the brochures every preclinical study was described as reporting positive findings. The study's authors concluded that most brochures for phase I and II studies did not let evaluators systematically appraise the strength of the supporting preclinical findings, that the very rare reporting of studies showing no effect raises concerns about potential design or reporting biases, and that poor design and reporting of these studies thwart the risk-benefit evaluation during ethical review.
Effects in humans
ICH E6(R3) asks for a thorough discussion of the known effects of the product in humans, covering pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy and other pharmacological activities, with, where possible, a summary of each completed trial and of any ongoing trial whose interim results may inform the safety evaluation, and information on any use of the product outside clinical trials, such as marketing experience. That list in effect provides subheadings that may suit the section. Phase 1 studies focus on pharmacokinetics, pharmacodynamics and metabolism, usually in healthy subjects, while phase 2 and 3 studies provide efficacy data from the target population and the most comprehensive safety information, from longer-term use. Before human data are available, the section should not be used to speculate but should focus on the available data. Where the product belongs to a known class, the class's human safety and efficacy data should be reviewed.
Self-contained summaries of each completed trial, added at each update, are often the easiest way to give the summary of each trial the guideline asks for where possible, but they should not be the only approach: kept as concise as possible, they should ideally be supplemented by a synthesis of the overall picture emerging from the individual studies.
The pharmacokinetics subsection presents, where available, pharmacokinetics including metabolism as appropriate and absorption, plasma protein binding, distribution and elimination; bioavailability, absolute where possible or relative using a reference dosage form; population subgroups such as sex, age and impaired organ function; interactions such as product-product interactions and food effects; and other pharmacokinetic data such as the results of population studies performed within trials. The pharmacokinetic synthesis should be structured from single and multiple dose studies covering absorption, plasma protein binding, metabolism, distribution and elimination. As appropriate, the pharmacokinetic information may be analysed for specific subgroups as well as for the population as a whole, at a minimum typically by sex, age and hepatic or renal impairment. The synthesis should also present the potential effects of other drugs and of food on the product, the product's potential effects on other drugs, and population pharmacokinetic analyses.
The safety and efficacy subsection summarises what preceding trials in healthy volunteers or patients showed about safety, pharmacodynamics, efficacy and dose response, and discusses the implications. Where several trials have been completed, summaries of safety and efficacy across trials by indication in subgroups may give a clear presentation, and tabular summaries of adverse drug reactions with their frequency and nature across all the trials and studied indications would be useful, with important differences in reaction patterns or incidences across indications or subgroups discussed. The brochure should describe the possible risks and adverse drug reactions to be anticipated from prior experience with the product and with related products, and the precautions or special monitoring to be undertaken as part of its investigational use.
Wherever study designs permit, a pooled analysis of efficacy and safety can give a synthesis based on more subjects than any individual study. For efficacy this may not always be possible because of differences in study design, and the synthesis should then be an integrating discussion of the findings across the range of studies. For safety a pooled analysis is almost always meaningful for eliciting potential signals, but it is often logistically impossible for a brochure because of resourcing and prioritisation, and a side-by-side tabular summary of safety data from different studies can then also provide insight. Pooled analyses are rarely conducted specifically for a brochure, so writers generally work with the side-by-side summary unless one happens to be available close to the time of preparing the brochure for another purpose, such as a regulatory submission. Whichever route is taken, the aim is that the investigator can readily understand the types of safety issue patients treated with the product may meet.
Marketing experience identifies the countries where the product has been marketed or approved, summarises any significant information arising from marketed use such as formulations, dosages, routes of administration and adverse drug reactions, and identifies all the countries where the product did not receive approval or registration or was withdrawn. If the product has been marketed anywhere by the time the brochure is prepared, the sponsor's post-marketing safety information also needs to be summarised. Such data are generally not collected as rigorously as trial data, but they will often cover more subjects than the pre-marketing trials can; this part is typically supplied by the sponsor's pharmacovigilance department.
As with the nonclinical section, the writer may be given text, tables and figures that only need revising for language and consistency, or may be given the clinical study reports and asked to write the clinical section de novo; in that case it is important to work closely with the sponsor so that the desired messages are synthesised from the studies, including the interpretation of efficacy and safety analyses across population subgroups.
Summary of data and guidance for the investigator
ICH E6(R3) asks for an overall discussion of the nonclinical and clinical data, summarising the information from the various sources on the different aspects of the product wherever possible, so that the investigator has the most informative interpretation of the available data and an assessment of what it implies for future trials. Published reports on related products should be discussed where appropriate, since they could help the investigator anticipate adverse drug reactions or other problems. The section's overall aim is to give the investigator a clear understanding of the possible risks and adverse reactions and of the specific tests, observations and precautions a trial may need, grounded in the available physical, chemical, pharmaceutical, pharmacological, toxicological and clinical information; and guidance should be provided on recognising and treating possible overdose and adverse drug reactions, based on previous clinical and nonclinical experience and on the pharmacology of the product.
The section can be viewed as a kind of discussion section, in which the totality of the non-clinical and clinical experience is summarised and interpreted so that inferences for the product's use in future studies can be drawn, and any non-clinical finding of potential concern is discussed against what has been observed clinically or what may be anticipated. It should also carry practical information for managing subjects being treated with the product, and where applicable draw on published knowledge of other drugs in the same class. It generally contains subheadings also used in prescribing information, such as therapeutic indications, contraindications, and warnings and precautions for use, so the section may be viewed as a precursor of the prescribing information prepared when marketing approval is applied for. Unless writers are medically qualified they are unlikely to be asked to prepare it de novo; it is likely to come from the sponsor, with the writer conducting a linguistic and consistency check against the rest of the brochure.
Length and concision
ICH E6 asks for the information to be presented in a concise, simple, objective, balanced and non-promotional form that enables a clinician or potential investigator to understand it and make their own unbiased risk-benefit assessment of the appropriateness of the proposed trial. From the investigator's perspective, overloading the brochure in an attempt to satisfy regulatory authorities might prevent the transfer of key messages, and key messages not conveyed clearly and concisely might affect the safety of participants and the quality of data collection.
In 2014 the guideline gave no recommendation for the overall length of a brochure. In practice a brochure should not need to exceed about a hundred pages, a shorter document can also be sufficient, and it is essential to bear conciseness in mind from the outset. Team members asked to reduce their contributions often push back, and the writer should argue that it is almost always possible to retain the key messages while reducing length.
With time in short supply, a brochure can tend to become inflated with information to make it supposedly complete, and the result can often be quite unreadable; all too often, new information is simply added at each update. A brochure should ideally be reworked at each update so that its overall length still stays within about a hundred pages. At each update the entire contents should be revisited not only for what should be added but for how much of the existing content can be reduced or omitted.
Production across disciplines
ICH E6(R3) asks for a medically qualified person to be involved in generating the brochure, while its contents should be approved by the disciplines that generated the data described.
A brochure's writer also has to be a good project manager, and the brochure can be among the more challenging documents in this respect because it covers the entire development programme, so the writer often has to obtain material from team members across a range of functions. Members of non-clinical and chemistry, manufacturing and controls departments are sometimes less familiar with the document standards a brochure requires and less sensitive to the tight timelines involved, so the writer is often the person who has to address that by interacting with them directly to make sure they understand which material is required and by when.
Depending on the sponsor's approach, the process may begin with the writer identifying the people to interact with for each section. Where those people will supply text, tables or figures, it can help to be proactive about the format — distributing the correct template or a link to it, or, for an update, the final version of the previous edition, which usually serves as the template for the next. Perfect formatting and consistency in what comes back is unrealistic, and making it consistent is the writer's job anyway; supplying the template nevertheless increases the chances of receiving material in a usable form.
Tracking the review and revision of individual sections is another project-management task, and if nobody else owns it the writer should draw up timelines for writing, reviewing, revising and finalising and circulate them so that everyone knows when the approved document is needed. Ideally those steps are planned for the brochure as a whole, so that team members from different functions can consider the totality of what is being presented. In practice some contributions arrive later than others and become rate-limiting, which has to be planned for, for example with truncated review cycles separate from those for the main document; such situations have many permutations, and a writer should develop strategies for minimising the risk to the overall timeline.
As a living document needing regular updating, the brochure gives the writer an interesting opportunity to interact with a diverse team drawn from the functions contributing to the product's development. Whichever process the sponsor uses — coordinating and revising contributions, or writing some or all of the document from reports and other source material — the writer's responsibility is the same: that the information presented is as concise, complete and focused as possible, and that the document is structured so that it effectively communicates what an investigator needs in order to evaluate the benefits and risks of using the product.
Updating the brochure
A brochure is first required for the first clinical study in humans, and from then on it is a living document. ICH E6(R3) asks for the brochure to be reviewed at least annually and revised as necessary in compliance with the sponsor's documented procedures, and more frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. Relevant new information is information that substantially influences what is known about the product, especially its safety, to the extent that it has to be communicated for the benefits and risks to be reassessed. It may be important enough that it has to be communicated to the investigators, and possibly to the ethics committees and regulatory authorities, before it is included in a revised brochure. Some sponsors issue an addendum to the brochure when relevant new information has to be communicated rapidly.
Early brochures contain only preclinical data; over time the brochure combines nonclinical and clinical data, and late brochures contain mainly clinical data. Nonclinical information is crucial before human studies begin but can progressively be reduced as clinical data, such as pharmacokinetics and safety in humans, become available. The first edition emphasises non-clinical information and contains no clinical information at all; at each subsequent update the proportion of clinical information increases, starting with pharmacokinetics and pharmacodynamics and progressing to safety and efficacy data from the target population, while the detail given to the non-clinical work may be reduced as the product's clinical performance becomes better understood.
The information should be kept up to date and obsolete data removed; once data from studies in humans are available, they can replace most of the safety data from animal studies. A common mistake is to add clinical data without reducing the nonclinical information, which makes the brochure unduly bulky, and busy clinicians often do not have the time to peruse reader-unfriendly documentation. Keeping it succinct and clear by removing unnecessary nonclinical data as the clinical development advances makes the document easier to read, facilitates the transfer of key messages, and thereby safeguards the safety of participants and lets clinicians form unbiased and independent benefit-risk decisions.
Reference safety information
The brochure provides the reference safety information for a product in development. The reference safety information is a cumulative list of the adverse reactions expected for the product, which should include information on their frequency and nature, and it is included in the brochure or in alternative documents according to applicable regulatory requirements. It provides an important reference point for expedited reporting of suspected unexpected serious adverse reactions in the trial: the list should be used to determine the expectedness of a suspected serious adverse reaction and then whether its reporting needs to be expedited in accordance with applicable regulatory requirements.