Targeted Regulatory Writing Techniques.

Clinical Documents for Drugs and Biologics, 121

edited by Linda Fossati Wood and MaryAnn Foote
© 2009 Birkhäuser Verlag Basel/Switzerland

Chapter 8.
Investigational medicinal products dossier
Linda Fossati Wood

MedWrite, Inc., Westford, Massachusetts, USA

Introduction

Before human clinical trials can be started in the European Union (EU), the spon-
sor must request authorization to conduct clinical trials through a submission called
a Clinical Trial Authorisation (CTA). This application includes a group of scientific
documents called an Investigational Medicinal Products Dossier (IMPD). The EU
has provided for two types of IMPDs, a full IMPD and a simplified IMPD, based on
whether the product has been described previously in another CTA or a marketing
authorization application [1]. This chapter discusses only the full IMPD, since the
complexities inherent in determining the type and level of documentation to include
in a simplified IMPD are beyond the scope of this book.
Guidance on the structure and content of an IMPD is provided by the European
Commission (EC) in ENTR/F2/BL D(2003) CT1 Revision 2, dated October 2005.
The IMPD consists of a group of documents, with cross-references to other docu-
ments, such as the investigator’s brochure, the clinical protocol, or another IMPD.
The IMPD has a general structure:

u Quality (chemistry, manufacturing, and controls) data

u Nonclinical pharmacology and toxicology data
u Previous clinical trial and human experience data
u Overall risk and benefit assessment

Because regulatory writers usually only write the text for the clinical sections (previ-
ous clinical trial experience and the overall risk and benefit assessment), the chapter
focuses on clinical sections. Should the regulatory writer be asked to write the non-
clinical material, it is possible to use the same strategies as described for the clinical
text.
122 Linda Fossati Wood

Previous clinical trial and human experience data

The guideline for the IMPD has a suggested outline for clinical information (Ap-
pendix XII). The contents of the outline are similar to those found in the Common
Technical Document (CTD) outline for the clinical sections of the CTD in module
2, but the numbering system is different. The IMPD suggested outline is not consid-
ered to be exhaustive and does not need to be followed exactly [1].
In general, at the time the CTA is submitted, the investigational product has
likely not been used in humans, so it is possible that the section will have no data.
In this situation, it is possible to state ‘Not applicable.’ On occasion, a CTA may be
required despite the fact that human testing has already been conducted on the
investigational product. It may be that testing took place in a different region of
the world, the indication tested was different, or some change was required to the
manufacturing methods. In the event that human data are available, there are two
general strategies for writing the clinical section of the IMPD.
The first strategy cross-references the investigator’s brochure (that should have
existing human data included in text and tabular format) and deletes the suggested
outline. This strategy is appropriate if the brochure contains sufficient detail for an
assessment of safety.
The second strategy cross-references the investigator’s brochure but uses sec-
tions of the IMPD outline to expand on details that are also summarized in the
investigator’s brochure to allow the health authority to fully understand safe use
of the investigational product. Details in the brochure that are expanded should
be placed in the appropriate section of the IMPD outline. These expanded details
generally come from clinical study reports, although they may also be found in pub-
lished literature. Study reports do not need to be submitted.

Overall risk and benefit assessment

This section is intended to be a brief and integrated (ie, including quality informa-
tion and both nonclinical and clinical research) summary of all risks (safety con-
cerns) and potential benefits to a subject undergoing testing in the proposed clinical
trial. The description should include anticipated risks (based on quality, nonclinical,
and clinical study data) and methods to be used to attenuate these risks to subjects
in the proposed clinical trial (as described in the protocol).
An example illustrates the types of information to consider for the risk and ben-
efit assessment and a proposed associated risk and benefit statement for the fictional
drug xerimax:

Quality:
Store xerimax at 2°– 4°C, reconstitute with 10 mL normal saline, then rotate the
syringe gently until the solution is clear.