A Considered Review of the Practicalities of Implementing eCTD 4.0

Part 2: Concepts, Terminologies, and Structured Data Reliance

Previously we reviewed the people and process considerations during an eCTD 4.0 implementation. Here we review the impacts of new concepts, terminologies, and the increased reliance on structured data.

Socialize new concepts and terminologies

While continuing to maintain eCTD 3.2.2 submissions the transition to eCTD 4.0 will require significant investment in end-user education; socializing the new eCTD 4.0 terminologies and concepts will be an important step. Ensuring an understanding of the new context of use (CoU) concept and how these will equate to the eCTD headings and be used in conjunction with both required and optional agency and sender defined keywords, along with the requirement to use priority numbers to assign order within a CoU will be fundamental to the successful implementation.

Users will also need to adjust their understanding of life cycle which will be managed at the CoU level rather than at the document level. The new lifecycle statuses, where ‘New’ is replaced by ‘Active’ and ‘Delete’ is replaced by ‘Suspend,’ will need to be communicated with clear lifecycle examples provided. Additionally, the impact of removing the append lifecycle status and the additional flexibility for replacing documents (one document with many or many replaced by one) will need to be incorporated into updated business processes, again clear lifecycle examples showing before and after will be especially important during the transition phase.

Although likely less impactful, the new sequence code numbering, moving to a new numbering format ranging from 1 and 999999, should be understood well ahead of time.

Controlled Vocabularies

Along with many other ongoing initiatives including IDMP, DADI in the EU, and PQ CMC in the US, the reliance on structured data increases hugely with the introduction of eCTD 4.0. The increasing number of controlled vocabularies and sender-defined keywords will facilitate the review by agencies and ultimately result in a faster review cycle and an accelerated timeline for drugs to market. However, there is no single source for the controlled vocabularies; these will be defined by multiple sources including the International Council for Harmonisation (ICH), National Competent Authorities (NCA), and the Regulated Product Submission (RPS) Health Level Seven (HL7) standard. ICH will define many of the controlled vocabularies required for Modules 2 to 4 but for Module 1 these will be defined by the NCAs, additionally, eCTD 4.0 will also require MAHs to create and maintain sender-defined keywords.

Multiple Controlled Vocabularies will be introduced, and these will need to be accessible to publishing systems. For Modules 2 -4 ICH have defined 143 CoU headings, each having its own specific code for inclusion in the XML. For many of the CoU headings, keywords will need to be associated; some mandatory, some optional, some defined by ICH, and others defined by sender. In the EU SPOR Referentials will be the source for the Controlled Vocabularies and there will clearly be an overlap with IDMP.

In the table below we can see that for the repeat dose toxicity CoU, the study id_study title, document type, species and route of admin are required whereas the duration, study group order & group title are optional. Different scenarios will mandate the use of the optional values, for example where there is more than one grouping within a CoU study group order and group title will be required.

eCTD 4.0 Graph 1 — Source: ICH_eCTDv4_0_CV_v4

The table below references the ICH keyword sets and the number of values contained within each e.g., Document Type contains 73 values. Each Code Set has their own set of rules; for some there are very specific uses; Route of Admin is only required for Toxicity Studies; the Study Group Order Type should only be used in conjunction with the study id/ Study Title keyword.

Sender Defined Keywords

The ICH and NCAs also mandate the use of Sender defined keywords, many of those required for Modules 2 & 3 will already be defined in RIM systems e.g. Substances & Excipients, Manufacturers, Dosage Forms & Indications. To avoid duplication of effort & data misalignments it is vital that these values are obtained from a single source. Industry will need to agree on the naming conventions and define processes for ensuring that any new values or modifications are well controlled.

NCAs will define controlled values for Module 1; the FDA have defined 120 context of use values and in addition each country / region will have specific requirements.

Maintaining CVs will incur additional data administrator resources which will impact RIM teams. The increased use of structured data will require more disciplined ways of working when authoring documents, focusing less on the narrative and more on the structure incurring additional QC requirements to ensure the correct CVs have been assigned and associated.

3-point plan