There are many regulatory documents but perhaps none are more critical to biotechs and startups than the Investigator’s Brochure, which provides a summary of research work completed on an investigational medicinal product (IMP). It fulfils a plethora of purposes in the clinical development process and is often created by a multidisciplinary team. In addition to serving as the primary reference document when investigators are trying to determine whether an adverse event is ‘unexpected’, other functions of the Investigator’s Brochure in the regulatory framework include:

• A regulatory prerequisite for clinical studies (as specified in the ICH E6 Guideline for Good Clinical Practice [1])
• Data source on IMPs for independent ethics committees
• A component of Investigational New Drug applications (USA)
• A partner document for Investigational Medicinal Product Dossier (IMPD) and
• Paediatric Investigation Plan submissions in Europe

The content of an Investigator's Brochure is well defined. The ICH E6 (R2) guideline describes in some detail information on how the IMP behaved in non-clinical studies along with specific guidance to investigators on the drug’s use [1].

At Niche, experience teaches us that it is most helpful to share ‘how’ to deliver new Investigator Brochures and the pitfalls you can encounter along the way. This is probably why our Investigator’s Brochure document template and our Insider’s Insight on how to write your brochure are the most downloaded documents from our Niche Resource Centre [2]. Where are you with your Investigator’s Brochure?

1. The Biotech’s Investigator’s Brochure

Development of your IMP’s first Investigator’s Brochure should be straightforward assuming all the relevant and necessary data sources. Your document should be concise (in the region of 80 to 100 pages), clear and focused while remaining balanced and sufficiently comprehensive to inform an investigator of what they need to know about using the IMP. The author should adopt a simple, objective and non-promotional format that enables a clinician/investigator to easily access the information (particularly the safety data) and apply it to make his/her own unbiased risk assessment. The author should remember that the investigator might be trying to assimilate this information while under stress. Authors beware, biotechs and start-ups often see the Investigator’s Brochure as a surrogate marketing document for their shiny new IMP. And even the most seasoned pharmaceutical executive succumbs to the temptation (from time to time) to make their Investigator’s Brochure the repository of all human knowledge about their drug. It may be necessary to push back against team members who find it difficult to keep their contributions concise.

2. The Investigation Medicinal Product Dossier conundrum

Like the Investigator’s Brochure, the European IMPD is a central piece of the IMP-related documentation required for competent authority permission to conduct clinical trials in the EU. The Investigator’s Brochure and the IMPD offer the opportunity to include overlapping data. Guidance from the EMA (and from the UK Medicines & Healthcare products Regulatory Agency following Brexit) suggests that it is possible to minimise information on nonclinical pharmacology and toxicology in the IMPD by cross-referencing to the Investigator’s Brochure [3,4]. This is often an attractive proposition. Not having to prepare all sections of the IMPD saves time and resource. However, authors need to navigate this pathway with care, in efforts to keep in the Investigator’s Brochure concise the team rarely includes preclinical information on Organisation for Economic Co-operation and Development Good Laboratory Practice compliance (and explanation/justification for noncompliance) or details on relevant analytical methods (which tend to be included in more detailed IMPDs). Failure to provide this sort of supporting information (anywhere in the CTA) is a common reason for rejection of clinical trial applications according to the UK Medicines & Healthcare products Regulatory Agency [5].

3. The Project Management Investigator’s Brochure

The process of Investigator Brochure development often requires the author to identify and liaise with diverse contributors, determining the extent of their contributions, managing quality and ensuring that the contributors employ the correct document style and templates. This task can become more than one of just writing – also requiring skills in coordination, editing and diplomacy. Sometimes, members from non-clinical and CMC departments need closer guidance as they are less familiar with document standards and timeline requirements. Although specific sections of the Investigator’s Brochure might be prepared by specialist team members, the Introduction is one section of the brochure that the author is inevitably required to draft de novo. Concepts behind the IMP are often somewhat ethereal and authors find it challenging to capture these concepts scientifically. Often inspiration can be found in the clinical development plan, presentations and briefing packages originally prepared to secure funding.

4. The Evolving Investigator’s Brochure

The ICH E6 (R2) guideline specifies that an Investigator’s Brochure should be ‘reviewed at least annually and revised as necessary’, and that ‘more frequent revision may be appropriate depending on the stage of development and the generation of relevant new information’ [1]. By ‘relevant new information’ the guideline is alluding to information that substantially influences what is known about the characteristics of the IMP, particularly safety, whereby the information requires a reassessment of the benefits and risks. At each update, the contents of the entire Investigator’s Brochure should be revisited not only in terms of what should be added, but also in terms of how much of the existing content can be reduced. Each new version should be accompanied by a documented summary of changes.

When updating an Investigator’s Brochure the previous edition usually serves as your template. As development progresses the proportion of clinical information in the Investigator’s Brochure will increase (bearing in mind that ideally the overall length stays the same), starting with pharmacokinetics and pharmacodynamics, and then progressing to safety and efficacy information from healthy volunteers and the target population. Conversely, details on the non- clinical information may decrease. It can often be a challenge to convince stakeholders that information appropriate for previous editions should be cut and we find our refresher training to be helpful.

5. One Document, Multiple Indications

When the IMP is intended for use in multiple indications, the sponsor will need to decide whether to prepare separate IBs for the different indications, or whether one document should cover all indications. ICH E6 does not give any specific guidance on which approach is most appropriate, so the route chosen is often quite subjective. Factors that can influence your decision include how closely related the different indications are, differences in the product formulation or route of administration, timings of different development programmes, and whether development programmes for different indications are being conducted by different sponsors. Resource availability is also an important factor in many cases. With multiple Investigator’s Brochures, the extent to which safety information should be included from other indications will need to be appraised on the basis of clinical relevance for the indication in question. Often, more is more. You might want to come and speak to us directly if you have multiple components in combination treatments.

6. The Mature Investigator’s Brochure

As clinical programmes progress, the data being covered by the Investigator’s Brochure expands and the content needs to be reworked so that the overall length remains in the region of ∼100 pages. ICH E6 (R2) specifies that ‘where possible, a summary of each completed clinical trial should be provided’ [1]. However, adding new summaries with each update becomes difficult to contain within the page limits. It may be necessary to create a summary of the overall picture. An overview of absorption, plasma protein binding, metabolism, distribution and elimination can usually be produced for single and multiple dose pharmacokinetic studies. Where appropriate data should be provided on specific subgroups (sex, age, and hepatic and/or renal impairment) as required. Wherever the design of the studies being summarised permit, the provision of pooled efficacy and safety data will give the reader a grasp the IMP’s profile. For safety, a pooled analysis is a good way of highlighting safety signals. It is this may not always be possible to pool efficacy data due to differences in study design (often between early and late phase studies). Under these circumstances, your summary should be provided as a discussion integrating the efficacy findings drawn from across the range of studies conducted.

Finally, the ubiquity of the Investigator’s Brochure in drug development means that teams delivering the document need to be able to apply it flexibly across a spectrum of situations. As these examples show, there are various options and some serve the document’s purpose better than others. However, as has already been alluded to, the real mark of success of an Investigator’s Brochure is its utility. A recent report on a European consensus meeting help to review the role of the brochure concluded that an optimised presentation of data will ensure the best possible understanding of a compound’s characteristics and an optimal benefit-risk assessment which will safeguard the participants in clinical trials [6]. This seems to be advice that anyone preparing to write an Investigator’s Brochure needs to know.

References

1. International Conference on Harmonisation Guideline for Good Clinical Practice E6 (R1).
2. The Investigator’s Brochure: An Insider’s Insight
3. European Commission. Revision 2. Detailed guidance for the request for authorization of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial. Brussels, Belgium: Enterprise Directorate General; 2005.
4. European Commission. Draft Revision 3. Detailed guidance for the request for authorization of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial. Brussels, Belgium: Enterprise Directorate General; 2009.
5. Common issues identified during clinical trial applications: Nonclinical.
6. Rengelshausen J, et al. How to interpret an Investigator’s Brochure for meaningful risk assessment: Results of an AGAH discussion forum. Therapeutic Innovation & Regulatory Science.