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After 10 years of eCTD the standard is fit for rejuvenation. Although eCTD has brought many benefits there is still significant room for improvement. This presentation covers different areas: continuous challenges associated with eCTD, Regulatory guidelines and eCTD viewing
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A decade of eCTD: time to rejuvenate!
Michiel Stam
Manager Regulatory Operations
Qdossier B.V.
04/10/2023 Copyright Qdossier B.V.
Agenda
Introduction
Continuous challenges
Regulatory guidance and specifications
eCTD viewing
eCTD: a rigid structure
Introduction
04/10/2023 Copyright Qdossier B.V.
Rejuvenation
“the hypothetical reversal of the aging process.”
Change directions, we can improve!
The Aging process
First European eCTD: 24th January 2003
eCTD v3.0
EU v0.9
Mandated by EMA (1st January 2010)
Ability to accept e-only (January 2010)
EMA Gateway (2012)(mandatory 1st March 2014
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Version history
ICH eCTD specifications
v3.0 (October 2003)
v3.1 (November 2003)
v3.2 (February 2004)
v3.2.1 (June 2008)
v3.2.2 (July 2008)
EU m1 eCTD specifications
v0.9 (November 2002)
v1.0 (July 2004)
v1.1 (December 2005)
v1.2 (May 2006)
v1.2.1 (October 2006)
v1.3 (May 2008)
v1.4 (August 2009)
v1.4.1 (November 2011)
v2.0 (September 2013)
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The benefits of e-only submissions
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Aspect Paper eCTD
Transport - - + / ++
Handling/ Review - + +
Life cycle management - - +
Archival - - + +
Costs - - +
Continuous Challenges
XML Backbone
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Huh?? Bone?Use the XML backbone!
eCTD viewer vs. Tracking approval
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Baseline of the current EU dossierplease!
Latest submitted or current approved?
Current in eCTD vs. Current Approved
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Source: IRISS Life Cycle Group 2009
Document Lifecycle status
Life cycle operation: “New”
Life cycle status: “Current”
Approval status: “Under review”
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Regulatory Guidance and specifications
FDA –Providing Regulatory Submissions in Electronic Format (draft)
“Although some eCTD tools generate leaf titles that are similar to file names, the two are not related.”
All modules of the eCTD should contain descriptive eCTD leaf titles that are:
Short
Meaningful
Indicative of each document's content
Not including the eCTD section number
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Leaf titles vs. File names
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Swiss Medic - Providing Regulatory Information in eCTD Format version
Hyperlinks are encouraged to facilitate navigation > should not be overused
Only if necessary and of real added value.
Important eCTD titles are consistent with cross references within other documents (e.g. summary document)
Hyperlinks needed if title in eCTD ToC and reference in a summary document do not match
04/10/2023 Copyright Qdossier B.V.
Validation
To assure that what has been submitted is fit for review by the validating agency
Technical: Can technically be processed by agencies?
Business: All data is available to examine the quality, safety and efficacy of the drug
04/10/2023 Copyright Qdossier B.V.
Technical validation > …. < Business validation
Consistency in attribute valuesacross sequences
attributes, file names and folder names within a sequence
Country codes
Language codes
PI Doc types
Proper reference to “Related Sequence”
04/10/2023 Copyright Qdossier B.V.
Additional “common sense” checks
Cover letter and Application form data is reflected correctly in the envelope
Use of meaningful titles; e.g.Proof of Payment vs. Annex 5.2
Note to Reviewer vs. Annex 3
Stability Data Long Term Stability 24 M vs. Stability Data 1
Use of meaningful file names; e.g.de-form-proofpayment.pdf vs. de-form-5.pdf
es-cover-notereviewer.pdf vs. es-cover-3.pdf
stability-data-longterm24m.pdf vs. stability-data-1.pdf
analytical-procedure-identityelisa.pdf
validation-analytical-procedure-identityhplc.pdf
04/10/2023 Copyright Qdossier B.V.
Conflicting guidelines
eCTD: “do not resubmit the same document”
CTD (Renewals): “include a copy of the latest specifications”
eCTD: leave empty
CTD: placeholders “N/A”
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Controlled vocabulary
“Regulatory activity”
HL7: “the provision of information about a regulated product(s) requiring a scientific or regulatory outcome. An activity may include one or many exchanges (examples of exchanges may be eCTD sequences, RPS submission units, etc.)”.
CESP:
04/10/2023 Copyright Qdossier B.V.
Controlled vocabulary
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Controlled vocabulary (Cont’d)
“Working documents means draft versions of summary of product characteristics, package leaflet, and labeling editable by the Danish Health and Medicines Authority”
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QOS and (non-)Clinical overview?
Errors in guidance
<sequence number>-working documents
‘sequence number - workingdocuments’ (no hyphen)
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eCTD viewing
eCTD viewing beyond specifications..
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Source: IRISS Life Cycle Group 2009
Source: IRISS Life Cycle Group 2009
From multiple to single section
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Source: IRISS Life Cycle Group 2009
Source: IRISS Life Cycle Group 2009
Shared documents across sections
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Metadata on
Leaf level
Source: IRISS Life Cycle Group 2009
Viewing across products and countries
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eCTD: a rigid structure
Administrative information
Regional administrative information = country specific information
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Administrative information
Risk management plan:
1.3.8.2 Risk management plan (CA)
1.6.2 Risk management plan (GCC)
1.8.2 Risk management plan (EU+CH)
1.13 Risk management plan (ZA)
1.16 Risk management plan (US)
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Need for harmonisation
eCTD today
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RMP
RMP
Non-GMOGMO
GMO
PSMF RtQOrphan
Envelope information + other metadata
eCTD yesterday
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<cc> -SmPC
SmPC
Country codesAT - AustriaBE - BelgiumCZ - Czech Rep.DE - GermanyDK - DenmarkES - SpainFI - FinlandHR - Croatia
Envelope information + other metadata
Agency codesEMEA = EMADKMA = DHMAUSKVBLAEMPS = ES-AEMPS
Structural update required
eCTD day before yesterday
04/10/2023 Copyright Qdossier B.V.
RMP
RMP
Non-GMOGMO
GMO
RtQOrphan
Envelope information + other metadata
Structural update required
PSMFDSUR
XEVMPD/IDMP principles
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XSD schema defining structure
Regional Implementation
guideline
CV Substance
List of allowed
substance names
CV Substance
List of allowed ATC
codes
ISO 3166-1 List of country codes
Metadata Validation
eCTD tomorrow?
04/10/2023 Copyright Qdossier B.V.
RMP DSUR
RMP +
metadata
DSUR + metadata
Controlled Vocabulary
List of allowed labels
(Agency controlled)
CV List of allowed labels:GMO
Non-GMODSURRMP
v1.0
Allows easy updating of…
Use of the European Agency Acronym
Addition of Other PDF Versions
Addition of Risk Management Plan as a New Submission Type
Revisions Regarding Agency Names and Agency Codes
Source: Release notes EU module 1 specification v2.0
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Concluding remarks
Continuous education needed
Agency focus moves from technical to non-technical aspects
(Much) broader/ leaner technical specifications needed for structure
Well specified implementation guidelines and controlled vocabulary to assure correct use
Correct application assured by validation tools
(Hopefully with some build in consistency checks)
04/10/2023 Copyright Qdossier B.V.
Thank you !
Michiel Stam
Manager Regulatory Operations
www.qdossier.com
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