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CTD stands for Common Technical Document, a format or set of specifications for an application dossier for the registration of Medicines at major health authorities globally. Managed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The format is now largely replaced by the electronic version, eCTD.
eCTD is the electronic version of the Common Technical Document format, mainly consisting of PDF documents containing the information to be reviewed. The format follows a hierarchal folder structure, with a sequential 4-digit number being the highest level. The eCTD format introduces an XML backbone that provides electronic navigation between documents and in addition holds all the application metadata details. The electronic format also introduces the ability to add and remove documents with operators “new”, “replace” and “delete” allowing viewers to see a “current” view of the application’s lifecycle.
An eCTD TOC is an electronic Table of Contents, also known as the xml. It provides electronic navigation around the dossier via hyperlinks and replaces the need for manually creating and hyperlinking an index that would perform the same function.
When discussing eCTD hierarchy, many will refer to the eCTD 3-tier triangle. In this, Module 1 would sit at the top tier; Module 2 summaries would be found below at 2nd tier and then below on the 3rd would sit Modules 3, 4 and 5.
In reality, once the eCTD sequence folder is opened, all 5 modules will sit on the same level and a hierarchal structure will follow within each of those. Due to this eCTD Structure may be a more relevant term used in industry.
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There are 5 modules in total.
Module 1 is known as Regional Information, due to this it is not part of the overall CTD (Common Technical Document) because the content of that module will not be in common with another region. This module contains administrative documents like the cover letter, application form and labelling. Module document example: 1.2 Application From
Module 2 consists of the summaries and overviews of the quality, non-clinical and clinical information found in Modules 3, 4 and 5 respectively. Module document example: 2.5 Clinical Overview
Module 3 consists of the Quality (chemistry, manufacturing and controls reports) information. Module document example: 3.2.P.2 Pharmaceutical Development
Module 4 consists of the Non-clinical reports of the dossier. Module document example: 4.2.1.1 Primary Pharmacodynamics: Study 123
Module 5 consists of the Clinical reports of the dossier. Module document example: 5.3.3.5 Population PK Study Reports: Study 123
eCTD publishing is the application of electronic navigation to regulatory PDF documents of which are to be placed into structured eCTD locations within a sequential submission. It is usually facilitated by a tool or software that can create outputs in the eCTD format.
Quickly becoming mandated across regions and agencies.
Environmentally friendly, removing the need for printing of paper.
Facilitates electronic linking between documents or content previously submitted.
Dossier modifications are easier to make and more easily seen by reviewers.
Facilitates electronic upload, almost instantaneously compared to physical mail.
With multiple regions accepting, facilitates faster subsequent region resubmissions.
Provides faster more efficient clarity on what is current, proposed, approved or registered.
Essentially, an eCTD is just a CTD with an XML backbone applied.
With an XML, comes automated electronic navigation, created manually in a CTD.
Documents can be given “operators” of “new”, “replace” or “delete” in eCTD, allowing a traceable document lifecycle to be observed, not possible in CTD.
An eCTD provides checksums that identify correct document versions, not a feature of CTD.
We value client confidentiality and can set up a secure file transfer protocol (sFTP) between us and your company within minutes. However PDF’s or a ZIP package in an email are still also fully acceptable.
EMA Gateway, FDA Gateway, CESP, Swissmedic, Health Canada, Portugal Infarmed SMUH-ALTER Portal.
Once a drug substance manufacturer name is in place it cannot be modified going forward or retrospectively, the history of the eCTD must remain as is. Going forward, the new name can be applied in a new sequence at which point another drug substance folder will appear. Subsequent sequences can be submitted under this new folder.
The structure for Module 5, including presentation of clinical study reports and the clinical overview and summaries in Module 2, can be found in the ICH guideline M4E(R2).
Submitted Case Report Forms should include deaths, other serious adverse events, and withdrawals for adverse events.
The structure for Module 3, including the quality overview and summaries in Module 2, can be found in the ICH guideline M4Q.
This phrase refers to the scenario in which a CTD (Paper or Nees) dossier that has already been approved is submitted to an agency in eCTD, facilitating a conversion in format. This submission will likely be the initial in the eCTD application but there are cases where the baseline may be submitted later. It is recommended to submit modules 1 to 3 and possibly follow up with all modules in future.
The PDF specifications are a set of rules and pre-requisites that the PDF document must adhere to regarding aspects like margins, page numbering, version and file size. These specifications change slightly from region to region and are subject to updating, thus the best approach is to source each region’s PDF specification guidance.
Metadata in eCTD submissions can be found in two places. Firstly, the application metadata, typically displays the submission number, applicant name, product name, indication and a few other product details that generally tend not to change from submission to submission. It is also know as the structural metadata. Secondly, is the sequence metadata, which displays the information specific to that sequence, like the sequence number and submission type and description. This is also known as the descriptive metadata.
Transfer dossiers should consist of a cover letter signed by the transferor, the relevant signed (by transferor and transferee) attachments, all the revised product information and revised mock-ups. Guidance on this procedure and what attachments to submit can be found here on the EMA website: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/post-authorisation-procedural-qa/transfer-marketing-authorisation-questions-answers
We recommend leaving the name as is during submission of the transfer, as the transfer submission is still requesting the change. Once the transfer has been filed the name can be changed going forward. However, please be informed that we have had clients request that the applicant name be changed in the metadata at the time of the transfer submission and no agency or validation issues have been received.
Yes, ONIX has experience of submitting safety reports in eCTD format for a number of clients. We submit the CIOMS in the safety report section of the relevant study.
Yes ONIX can, we would require the previously submitted sequences and once we have submitted the PSUR we would provide the submitted PSUR sequence for your client to import into their eCTD software.
Yes, ONIX can submit on your behalf.
In the cover letter you state the contact details of the person who is responsible for eCTD / Regulatory queries, that contact will receive the questions.
Send an original signed letter to the FDA ESG team via courier post and also the scanned letter can be sent via email giving ONIX authorisation to upload on your behalf.
Their pilot had already started and concluded in July 2019; from 1 November 2019 they commenced a REP pilot for clinical trials.
The creation of the AERS, which has now transitioned from PDF to XML files, will be the responsibility of the sponsor. ONIX can make the submission of the AERS (XML) and AERS Attachments (PDF files) via ESG. This will only be the case for NDA applications as this process is not yet available for INDs.