In my previous post on my love/hate relationship with eCTD 4, I hinted at how metadata is very different in the upcoming version of the electronic Common Technical Document (eCTD). In the current version 3.2.2 – and all the previous versions, for that matter – the hierarchical XML structure is tagged in places with metadata, and documents below that point in the hierarchy inherit those attributes. This ranges from the drug product, substances (whether active or excipient), dose form, and manufacturer, to the indication and study identifier (number and title) for grouping clinical and non-clinical study files. All of those are defined by the sponsor/market authorisation holder (MAH) and are merely raw text. In fact, it is common to use “all” for the product or dose form, if Quality information applied to all the variations that might be in the application.
The diagram below shows part of the current version of the eCTD’s hierarchical structure, and (in green) where the metadata gets assigned.
There are also sets of coded terms that are associated with certain document types: Forms in the US have a Form Code issued by FDA; promotional advertising materials have a few coded attributes, and the study tagging files used to group all the documents associated with a study have codes for the study document type (for both clinical and non-clinical), and species, duration, and type of control (for non-clinical studies).
For all of those – except for a couple items applied to the parts of a study report – the metadata term will apply to any number of files contained within the XML element for that section, such as all of section 3.2.P – the Drug Product. In comparison, eCTD 4 has no hierarchical organization. Instead, each table of contents element (saddled with the XML element name of ‘contextOfUse’ which can’t in any rational way be made plural) is presented in a list with no structure or order, just a code indicating the place in the TOC, and references to any applicable keywords.
This makes the XML for eCTD 4 rather verbose, but it’s still a tiny file compared to, say, clinical datasets. The good news is that this doesn’t mean extra work for Regulatory Operations. Publishing tools such as those in ARIM will just output the right XML. However, there’s a slightly bigger challenge when importing a sequence, because the definition of a keyword value might happen in a previous sequence.
ARIM’s means of setting up the metadata for a submission already puts you on the right foot: The Quality section items (Product, Dose Form, Substance, Manufacturer), and other items such as clinical Indications are defined when setting up a new submission. When your sequence is created, each metadata item (or group of them – more on this in the next post) results in a branch of the table of contents: each indication, each substance, etc., is automatically populated in the submission.
For eCTD 4 you will still work with metadata the same way, because you’re building the same table of contents. The details of how metadata work in eCTD 4 will be in a future post. To support that, though, ARIM will:
- Enable you to create a code that is unique to the application, that is associated with each term
- Provide the terms and codes used in previous sequences of the same application, to ensure that the codes continue across sequences
- Provide a way for you to change the display name of a term while keeping the same code – this is something new for eCTD 4, which allows misspellings to be corrected, or for a manufacturer to change its name.
- Enable entry of a few new metadata items:
- Facility – For sections 2.3.a.1 and 3.2.a.1, this is designed to be more flexible than the Manufacturer used in the current version
- Component – For sections 2.3.a.2 and 3.2.a.2, this covers either a product or a substance – rather than permitting both
- Excipient – For sections 3.2.a.3 and 3.2.p.4 (and its subsections) – previously this would be a substance
- Descriptor – For sections 3.2.s.7.3 and 3.2.p.8.3 – this describes the stability study
- Container – For section 3.2.p.7
As you prepare for FDA’s planned eCTD 4 pilot next year, contact ACUTA for more information on how ARIM will help you improve submission processes.
Photo credit Marco Verch