eCTD: Literature in the Article 8(3) Mixed Application (EU)

This short post concerns the submission of Literature References in "Full Mixed" applications under Article 8(3). I don't think it is discussed in any eCTD specific guidance (or if it is, I couldn't find it!) so I thought it might be useful to share this information with you.

Article 8(3) applications are full MAA applications detailed in Directive 2001/83/EC. This type of application normally requires the submission of the results of both pre-clinical and clinical trials in Modules 4 and 5.

There does exist, however, the option to submit what is described as a "full mixed" application which contains literature references in place of (rather than to supplement) Study Reports. The content of these references must therefore fulfil the requirements of the Directive:

A justification for not having performed certain tests/trials and for providing literature references instead, should be provided as to why the references provided by the applicant can replace the study reports, and how the results presented fulfil the requirements as set out in the Annex I to Directive 2001/83/EC.

For publishing purposes, temptation (and logic) might suggest that these references are placed in either Module 4.3 or 5.4 depending upon the type of report the references replace.

However, the EMA's "Innovative Products Q&A" suggests otherwise:

Such literature references, when replacing required study reports, should be included in the relevant Module 4/5 indents and should be summarised in Module 2 as required for any other study report. “Supportive-only” literature references (i.e. provided in addition to study reports), should be provided in the CTD sections for "references" and do not need to be summarised in Module 2.

So, for the purposes of the "full mixed" application, it is important to remember that there exists two types of Literature, which for the purposes of eCTD, will need to be treated differently.

Those references which replace Study Reports must be placed in the relevant Module 4 or 5 Study Report folder where the "replaced" Study Report would otherwise sit, whereas those which support Study Reports will need to be placed in either 4.3 or 5.4.

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Source: EMA "Innovative Products Q&A, Question 3: What will be the legal basis for my application?" http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000021.jsp&mid=WC0b01ac0580022711

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