Annex 1 on Stream I: Implementation of eCTD version 4.0
(Status: Draft for eSub CMB final, dated 17.12.2014)
Scope
This annex will provide the following details:
· what pre-requisites have already been identified and what they could be,
· when an optional use for the different European Procedures might be possible,
· how and when a regular use might be mandated (although the time scope of the roadmap ends 2018),
· how the transition from v.3.2.2 to v.4.0 might be organised and managed; and
· what this transition will presumably include.
The outline of Stream I describes the optional use of eCTD v4.0 from Q1 2017 onwards and visualises the expected migration from eCTD v3.2.2 to v4.0. This outline implies already that the specification will be ready for use at that time. However, a number of conditions are necessary to be realised before optional use can be allowed.
Pre-requisites
This chapter summarises one basic, and three major necessary pre-requisites for the usage of eCTD v4.0 in Europe.
Two major steps have been achieved:
· In September 2014 the under-lying standard on Regulated Product Submission (RPS) based on HL7 Version 3 became normative. This finalised standard is expected to be published by the end of 2014[1]. This standard was serving as the technical basis for the improved specification of eCTD. All Change Requests received for eCTD v3.2.2 have been reviewed and subsequently postponed from implementation into v3.2.2 as these are to be achieved with the version 4.0 of the eCTD standard. There is an expectation, that eCTD v4.0 will cover all requirements collected so far including a number of improvements compared to version 3.2.2.
· At the ICH meeting in November 2014 the package described above with all relevant documents for this new version has reached Step 2 and will be published for public consultation at the end of 2014.
The ICH Step 4[2] is planned for the end of 2015 and this will start the regional implementation and is therefore one of the major pre-requisites for the usage of v4.0.
The ICH package (Step 2) for public consultation will include:
Document / DescriptionICH eCTD v4.0 DRAFT Implementation Guide / Instructions for the harmonized portions of the eCTD v4.0 message specification
DRAFT ICH Code List / Harmonized controlled vocabularies
Specification for Submission Formats / Describes the way the files should be constructed for inclusion in eCTD v4.0.
M8 Genericode Schema and Files / Computable list of controlled vocabularies for eCTD v4.0
The draft of the regional EU Implementation Guide (EU IG) is expected to be released by the end of February 2015 for public consultation which will run until late May 2015. This will include necessary technical guidance how to create a message and technical validation criteria (need to be used together with the ICH Implementation Guide).
A message, i.e. the XML file in line with the eCTD specification v4.0, will be complete only if the common part (ICH) and the regional part (EU) will be created as one single message (one submissionunit.xml file only).
The roadmap towards acceptance of the Step 4 document package will include public consultation and acknowledgement and confirmation by the EU Telematics Governance structure.
It is planned that the draft EU IG outlined by the eCTD Maintenance Group will be confirmed by the eSubmission CMB and acknowledged by the IT-Directors Executive Committee, the IT Directors Group and the EU IT Management Board. Although this specification will neither interfere with architectural aspects of the European Network nor establish new metadata sets not yet in use, the Telematics Enterprise Architecture (EA) Board and the EU Data Network Board will also be informed accordingly. This process is planned to be managed prior to publication of the draft EU IG. This will likely lead to addition of new European controlled terms as necessary.
In summary, the appropriate information and decision involvement in favour of version 4.0 of the eCTD specification need to be assured as a second major pre-requisite.
In parallel to the formal aspects, it would be necessary that all stake-holders become familiar with any change introduced by v4.0. One of the major differences will be that a dedicated viewing tool (i.e. not an Internet-Browser) is required in all cases as eCTD v4.0 does not provide a style sheet as before and all elements are referenced by ID. A display of content will be possible only if the full access to controlled vocabularies provided by ICH or EUTCT is guaranteed. Perhaps in a second step, additional tool capabilities and additional capabilities of the under-lying systems, i. e. Single submission portal and Common repository, are needed for agencies to create messages should the 2-way-communication be implemented .
Assuming these pre-requisites are fulfilled by the end of 2015, the new specification could be used by industry, if appropriate compiling or publishing tools are available. However, in order for these submissions to be accepted, the receiving regulatory bodies will need to have a viewing or review tool installed. It should be noted that all agencies need to implement a viewing tool as a prerequisite; and for cost efficiency they may prefer a common solution. Due to difficulties one can expect to agree rapidly on a common solution, this action should be started as soon as possible. In any case, it will be necessary that the implementation is harmonised across Europe to ensure timely adoption of eCTD v4.0.
Therefore the availability of publishing and reviewing tools for eCTD v4.0 is the third major pre-requisite. EMA might consider a status update from the EU member states on their eCTD v4.0 acceptance at certain milestones of the migration phase.
From a practical point of view the training of staff, availability of additional technical and practical business guidance on regional level and the experience gained with the standard in addition to the availability of the tools are basic pre-requisites which need to be planned carefully in advance. The HMA eSubmission Roadmap including this annex should create the awareness of all parties involved in the upgrade process for agencies as well as for applicants.
Principles and Expected Advantages of eCTD v4.0
Using eCTD v4.0, a light folder structure that is flatter than the current hierarchy, can be introduced as the presentation of the contents will be governed by so called contextOfUse elements, replacing the folder hierarchy and folder naming conventions. However, for EU Module 1 the current folder structure is proposed to be maintained at least keeping the first sub-level of structure. However, this is still a matter of decision and should be carefully discussed during public consultation of the Draft EU eCTD v4.0 Implementation Guide.
The contextOfUse element will reference a document element and provides a combination of keywords to order the content and to describe the context of use of the file. The document element will reference always exactly one file (except in case deleting the file from the current view). All life cycle activities will be executed via the contextOfUse element.
To keep an intended order of contextOfUse elements with the same set of keywords a priority number will be used. The keyword element will indicate keywords defined by the implementation guides and will become publicly available. Alternatively, the keyword element will indicate keywords defined by the sender as part of the message and apply to all elements of all submission units assigned to an application of the respective applicant.
All elements will be described together in one submissionunit.xml file (containing common and regional information).
The HL7 RPS standard[3] offers the options to;
· accommodate regulatory changes without delay
· accommodate major technical changes
· allow simplification of life cycle
· allow more flexibility of dossier granularity
· allow grouping of documents
· assigning submission units to different applications by only referencing a sequence number and application ID
· referencing documents across applications (equivalent to the term dossier) and
· in general, applicability to all kind of products without changes of the tools.
For instance, the standard can be implemented for veterinary products by simply changing the contextOfUse code list and defining some specific keywords relevant for veterinary products. Steps towards moving from a VNeeS to a “vCTD” format for veterinary applications based on the HL7 RPS standard should be reviewed to assess the feasibility and added value as an additional project.
In addition – in case the option of 2-way-communication will be implemented – all responses from regulators as well as dossier relevant documents exchanged between agencies can be included into the dossier structure by means of two way communication. Whether a versioning of documents is needed and if yes how it can be achieved is a matter of further specification.
Time point of use
If the above mentioned pre-requisites have been achieved as planned, the optional use of eCTD v4.0 messages would be feasible from the beginning of 2017. For purely national procedures a local agreement can be made. In Centralised Procedures viewing capabilities would need to be provided in case not all national agencies will have a viewing tool installed or an updated version of their viewing tool available. Decentralised and Mutual Recognition Procedures may also run only in cases where all NCAs in the concerned member states have installed at least a simple viewing tool.
The tool availability across the network may become a road block to implementation. An early involvement of tool developers (vendors) in the process seems advisable.
Assuming the development of appropriate tools has happened, the optional use of eCTD v4.0 messages could be started early 2017. The experiences collected and training of people in industry and agencies could potentially allow mandating use of eCTD v4.0 from Q1 2019 onwards. It is considered that a staggered approach, as currently planned for mandatory use of eCTD v3.2.2, could be repeated to implement eCTD 4.0.
This could mean for example the following:
New MAA in CP: Q1 2019
New MAA in DCP from Q3 2019
New MAA in MRP from Q1 2020
Mandatory switch in all procedures, especially for national applications, will be at the discretion of the Agency involved, however is not foreseen to be required earlier than Q3 2020.
For all stakeholders the evaluation of the expected workload for transitioning from v3.2.2 to v4.0 is very important and to some extent concerning. The ICH Implementation Guide describes a onetime transition from v3.2.2 to v4.0 based on the current regulatory view of a dossier. This means that all valid content of a dossier in eCTD format v3.2.2 will be mapped in a way that document elements can be referenced in the future according to the eCTD specification v4.0. Transitioning to eCTD v4.0 will work whether the dossier in eCTD v3.2.2 format as been baselined or not. It needs to be considered carefully whether all parts of the dossier need to be included in the transition to eCTD v4.0. It needs to be noted that those parts which are not yet in eCTD format cannot be transitioned. According to current guidance[4] baselines must not include large-volume modules like module 4 and 5. However, as per the current plan all procedures are expected to be submitted in eCTD format v.3.2.2 by Q1 2018 and this would mean that any transition after this time point will apply to all types of dossiers and the parts submitted in eCTD v3.2.2 format. The transition sequence has to be built by the applicant.
The transition workload will depend from a business decision on whether a dossier needs to be switched entirely to eCTD v3.2.2 in advance or whether it remains acceptable that only parts of a dossier are switched, or that the use of eCTD can start even with single documents. Transition to eCTD v4.0 will be possible only for those parts already in eCTD format v3.2.2. Any advantage of version 4.0 can be achieved only after transition.
Different from transition – forward compatibility from version 3.2.2 towards version 4.0 of eCTD submissions – guidance needs to be established on how current dossiers can be switched into eCTD once version 4.0 is implemented. Presumably, the same rules on baselining can be applied as for the switch towards eCTD v3.2.2 at the moment.
Next steps to do
Action / DueICH Implementation Package will be posted / Dec 2014
Preparing the EU Regional IG / Nov 2014 – End of Feb 2015
EU Regional IG need to be posted on eSubmission web page / 28 Feb 2015
Public Consultation phase / 2 Mar – 22 May 2015
Review and discuss the comments / 6 June – 11 June 2015 (ICH meeting)
Update the Implementation Package / Afterwards June 2015
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[1] The documentation on the standard will be published on this web site: http://www.hl7.org/implement/standards/product_section.cfm?section=5&ref=nav
[2] For details see at http://www.ich.org/about/process-of-harmonisation.html
[3] see footnote 1
[4] http://esubmission.ema.europa.eu/tiges/docs/eCTD%20Guidance%20v3.0%20final%20Aug13.pdf supporting technical aspects and
http://www.hma.eu/277.html supporting business aspects of building baselines.