Regulatory Questions and Answers: the Investigator’s Brochure

Mar 25 • Biopharmaceutical, Clinical trail • 939 Views • Comments

Regulatory Questions and Answers: the Investigator’s Brochure
By Douglas Fiebig

I work for Novo Nordisk and I’m responsible for our IB SOP. I’ve been asked if I know about any official guidelines for the
format of AE tabulations for IBs. I have not been able to find any, so our AE tabulations are based on the tabulations we
use for our clinical trial reports. Do you know if there are official guidelines? And then I have another question. Does your
department ever receive comments such as, ‘No comments on the content, BUT, I have a general comment that I have
raised many times, must our IB’s be such boring documents, not at all inviting the investigators to read them? I think they
should be written much more like our product monographs, using colours, figures, graphs, and even pictures, etc. I mean
this very seriously!’


The first part of the question is quickly answered. The only official guidance for preparing an IB is given in the ICH E6
guideline on GCP (e.g. CPMP/ICH/135/95). However, this guideline provides only general recommendations for the
structure and content of an IB, and the style of presentation is left to the discretion of the sponsor. Thus the most
pragmatic approach to generating AE tabulations in IBs is to use the format chosen by the sponsor for other
documentation, such as study reports or registration summaries. In this way, data programmers don’t have to establish a
specific format for IBs, and often it will probably be possible to use tabulations in the IB that were originally generated for
other documentation.


Regarding whether IBs could be made less ‘boring’, as most of us know from personal experience, boring literature
tends not to be read in any detail, if at all, and so a boring IB is unlikely to be regarded by an investigator as an essential
resource from which relevant information can be gleaned about the product being tested. The issue of what exactly
constitutes a boring document (IB or otherwise) is undoubtedly subjective, but in general terms I would consider a
document as inherently boring when its style of presentation, for whatever reason, tends to deter the intended audience
from reading it.


The style of presentation in any document has two basic components: the organisation of the material to be included
and the formatting of the content (the colour, figures, pictures, etc. referred to in the question). As medical writers, we
generally have little influence on the scope of the material to be included in an IB, and no influence on whether an
investigator is predisposed to consult an IB, but what we certainly can and should aim to influence is the ease with which
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investigators can access the material presented should they turn to the IB for information.


So the question is: what is an appropriate style of presentation to achieve this aim? Personally I see no need for flashy
colours, input from graphic artists, luxury quality papers, etc. We have to remember that a common problem confronted
by medical writers when preparing an IB is a shortage of time and information. The realities of deadlines being brought
forward, reports often existing only as drafts, if at all, (particularly the case with preclinical studies in early-stage IBs),
‘final’ tables of data needing further cycles of revision, etc, mean that preparing an IB often becomes the classic dilemma
of doing the best job with the information available, in the time available. Under these conditions, the scope for artistic
input to an IB is obviously limited, especially for early editions in view of the high attrition rate of compounds in Phase I of
clinical development. The time involved for any such artistic input would not be justified under the generally tight timelines
involved when preparing an IB, where the emphasis clearly has to be placed on ensuring the accuracy and
completeness of the material presented (i.e. the quality of the content). Perhaps we also shouldn’t underestimate the
potential for glossy literature produced by the pharmaceutical industry to arouse suspicion.


Apart from the general lack of time for artistic input, while it might be tempting to think that the use of colours and
pictures might make an IB inherently more interesting, in fact a user-friendly layout, the intelligent use of in-text tables
and graphs, and a clear and concise text are undoubtedly the medical writer’s most potent weapons for reducing
boredom in any documentation. The basic principle behind a well-prepared IB that captures the reader’s attention is
much the same as in all medical writing, which is to highlight the important features of the development programme to
date in a competent fashion, with the medical writer providing the competence. In essence, given the often extensive
amount of research that has to be reported, the readability of the IB really needs to be ensured by having the main body
of the text provide a series of take-home messages for the investigator. Further details are then provided in a hierarchical
manner, with the text supported by in-text tables and graphs, which in turn are supported by the tables of all studies,
which themselves are supported by the original reports archived by the sponsor. Realistically, the items most likely to be
read, at least in the first instance, are the high-level summaries (one to two pages for each major section) and perhaps
selected in-text tables and graphs, so special attention has to be paid to ensuring that these summaries really do convey
the required messages.

My take-home messages in response to the original questions are therefore:
– There are no official guidelines on AE tabulations for IBs. Use the format your company uses for other documentation.
– Elaborate artwork is generally not justified or necessary to make IBs less ‘boring’.
– The use of clear and concise text together with intelligently planned in-text tables and figures ensures that an IB is not
only a document that fulfills a legal obligation, but also a useful resource for investigators who need to be informed about
the product they are testing.


Dr Douglas Fiebig, Aventis Pharma Deutschland,

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