Reading ICH E3 as guidance rather than a template
ICH E3 is a guideline for the clinical study report, not a template, and the writer is free to adapt its structure to the study. The industry disputed the point until 2012, when ICH's questions and answers on E3, drafted by medical writers, clarified it. The freedom they confirm extends to material E3 does not address.
ICH E3 as a framework for the report
E3 is a guidance document rather than a template, and it should be interpreted flexibly to produce a report tailored to the individual study. It provides a framework for distilling voluminous study data into a comprehensible report that integrates with the other documents in the dossier submitted for review.
The dispute over reading E3 as a template
Reports written to E3 are mandatory portions of a CTD-based application for approval of a new medicinal drug, and on the surface some E3 requirements appear to conflict with some CTD requirements, particularly those of the electronic version. Within the industry some people read E3 as a rigid template and refused to modify it, while others advocated modifying it, though not always in the same way. The incompatible readings led to lengthy and often vituperative discussions inside biotechnology and pharmaceutical companies, and the discussions delayed the writing of reports and the submission of applications. The misconception that E3 was a fixed template that could not be deviated from was far-reaching, and the questions and answers (Q&A) on E3 sought to correct it.
How medical writers obtained the 2012 questions and answers
A global group of medical writers, a subgroup of the Drug Information Association's Medical Writing Special Interest Area Community, identified conflicts between E3's requirements and those of the common technical document, proposed ways of resolving them and presented the findings to FDA advisors. Recognising that industry strife could delay the delivery of needed medicines, the FDA agreed to support a series of clarifying questions and answers. In June 2011 the group submitted a concept paper justifying the need to the ICH Steering Committee, and the committee convened an international working group of medical writers who used the paper to develop the questions and answers. The chair of the Steering Committee signed the finalised document on 7 June 2012, a year after the concept paper, to help create efficient, compliant and scientifically accurate reports.
What the questions and answers settle
ICH published its Q&A on E3 in 2012. The Q&A focuses on aligning E3 with the requirements of the common technical document, and of its electronic version in particular.
The Q&A also addresses whether the headings in E3 should be interpreted as a template. It states that E3 is a guideline and not a rigid template. After years of debate about using E3 as a definitive template, this clarified what experienced report authors had long held. One writer finds reading the headings as a template understandable to a certain extent, because E3 contains phrases such as "efficacy and safety variables should be provided in section 14", which does sound like a reference to Section 14 of a report rather than of the guideline. The same writer holds that naming the title page "Chapter 1" is rather absurd, and perhaps a reflection of how keen companies are not to irritate health authorities by withholding what they believe is expected, and so counts the clarification a victory for common sense.
The Q&A holds that flexibility is inherent in the use of E3, and it encourages modifications and adaptations to the structure that lead to better display and communication of information. Intelligent adaptations are permissible, especially those that allow the electronic submission of a CTD-based drug application.
Restructuring the report, and appropriately placing material the guidelines do not specifically cover, is welcomed if it improves clarity. At its simplest, this may mean reorganising the text sections of a phase I safety and pharmacokinetic report, for example, and including the full pharmacokinetic report in an appropriately placed ad hoc appendix. Restructuring for its own sake, however, can lead to differing report structures within a marketing authorisation application, which may be unhelpful for the regulatory reviewer.
Material E3 does not address
E3 primarily addresses efficacy and safety studies, although it suggests that a similar approach can be taken for clinical pharmacology studies. Pharmacokinetics and pharmacodynamics are a major feature of many reports, particularly in the earlier phases of development, so sections clearly need to be created for those results, and the Q&A makes that explicit. Outcome measures such as quality of life, which were less common when the guideline was drafted than they later became, likewise need some flexibility for appropriate presentation.
Where E3 does not address a type of information or topic, or does not specify where it goes, as with pharmacokinetic results, the Q&A allows the results to be placed in appropriately identified subsections. For topics E3 does not specifically cover, such as pharmacokinetics, pharmacodynamics, pharmacogenomics, biomarkers and devices, the Q&A considers new headings and new appendices in the report appropriate.