eCTD becomes more and more mandatory in different regions and for various submission types. Soon only the eCTD format will be accepted throughout the marketing authorisation of drugs. One of the regions announcing eCTD as a mandatory format to be used for drug applications is Health Canada.
1. Mandatory use of the Electronic Common Technical Document (eCTD) format
eCTD becomes more and more mandatory in different regions and for various submission types. Soon only the eCTD format will be accepted throughout the marketing authorisation of drugs. One of the regions announcing eCTD as a mandatory format to be used for drug applications is Health Canada.
In July 2016, Health Canada has stated that as of January 1st, 2018, the following regulatory activity types, as well as all additional information and subsequent regulatory activities/transactions (as per section 1.3 of the Guidance Document Preparation of Drug Regulatory Activities in eCTD Format) for human drugs, must be filed in eCTD format:
- New Drug Submission (NDS);
- Supplement to a New Drug Submission (SNDS);
- Abbreviated New Drug Submission (ANDS); and
- Supplement to an Abbreviated New Drug Submission (SANDS).
Regulatory activities for the following are recommended, however, not mandatory for filing in eCTD format:
- Master Files;
- Clinical Trial Applications (eCTD CTA pilot only);
- Drug Identification Number (DIN) Applications and Post-Authorization Division 1 Changes (PDC) for Human drugs.
Regulatory activities for the following currently remain out of scope for filing in eCTD format; they must be filed in “non-eCTD electronic-only”:
- Medical Devices;
- Veterinary Drugs.
When applicable, regulatory transactions must be sent via the Common Electronic Submissions Gateway (CESG).
2. eCTD requirements
Having a look on the eCTD requirements, the content based requirements are not changing and will be the same as for paper CTD submissions. However, having a look on the electronical part of the eCTD format there are various requirements to be considered.
The figure hereafter shows an overview of how an eCTD in Canada should look like:
From a hierarchical perspective, the highest folder within a Canadian eCTD, the so called Top Level Folder, must contain the sequence number folder which will include all other folders and respective content.
For the Top Level Folder a naming convention was specified, which requires the name to match the Dossier Identifier number (e.g. e123456) obtained. This number, obtained from Health Canada, is a a unique identifier for a specific drug product and stays unique throughout the dossier/drug product lifecycle.
As shown in the picture above, the sequence number folder will include the regional m1 part, the m2-m5 subfolders (as required), and the eCTD related technical files as the util subfolder, the eCTD backbone file (index.xml), and the eCTD calculated checksum file (index-md5.txt).
The m1 folder must contain a ca folder which should contain all Module 1 specific files as well as the Canadian Module 1 Backbone file (ca-regional.xml). No other subfolders should be present in the m1 folder.
The structure of Modules 2 to 5 (m2-m5) can be retrieved from the ICH Electronic Common Technical Document Specification, Health Canada’s Guidance Document: Preparation of Drug Regulatory Activities in the Common Technical Document (CTD) Format.
The util folder contains the technical auxiliary files for an eCTD, the so-called DTD & Stylesheets. The DTD folder deposits the structure for module 1 and module 2-5 (as required from the different regions and the ICH).
The Stylesheets are technically used to display xml files and make them readable within a browser. The xml backbone is used as a navigation file which actually represents a Table of Content of the submission, avoiding clicking through the deep structure of an eCTD. As an eCTD is somehow divided between m1 the regional part and m2 to m5 the ICH part, there are two xml backbones provided. The regional backbone (ca-regional.xml) located in module 1 to easily navigate through the regional specific content and a separate xml backbone file (index.xml) for easy navigation through m2 to m5.
Each first regulatory activity within a dossier, must always start with sequence number 0000. Every new information specific to this dossier, must be provided with a new sequence, always using a 4-digits sequence number incrementally (e.g. 0001). If for any reasons, a sequence has been technically rejected, the sequence number should be kept the same as the failed one and be resubmitted once the technical issues have been solved. Other than that, e.g as of content rejection, a new sequence should be provided using the next incremental number within a dossier.
3. Canadian Module 1 Backbone
3.1 Envelope Information
The envelope information can be extracted out of the ca-regional.xml. The regional backbone as already mentioned, is not only used for easy navigation but is used also for extracting the submissions key data information as well as defined metadata at a glance. The required envelope information differs from region to region.
An overview of Health Canada’s envelope information is presented hereafter:
The <applicant> Element
This mandatory element contains the sponsor’s name, i.e. the company which is submitting this regulatory transaction. Great care should be taken to ensure accuracy and consistency with this content. For example, the values “My Company” or “My Company, Inc.” or “My Company, Inc” are all different which may cause difficulties or delays in the processing of the regulatory transaction.
The <product-name> Element
This mandatory element contains the drug name, i.e. the product which is being addressed in this application. Great care should be taken to ensure accuracy and consistency with this content. For example, the values “My Product” or “My product” or “My Product” (note the double space!) are all different which may cause difficulties or delays in the processing of the regulatory transaction.
The <dossier-identifier> Element
This mandatory element contains the unique identifier assigned to this dossier by Health Canada. It must be in the format “e999999”, i.e. a lower case letter followed by six digits. It is expected that the sponsor will acquire a valid dossier identifier from Health Canada before submitting the initial regulatory transaction.
The <dossier-type> Element
This mandatory element contains the type of dossier, i.e. from a simplistic perspective, whether it is a pharmaceutical or biologic regulatory activity. . The content of this element is taken from a list of values defined by Health Canada
The <regulatory-activity-type> Element
This mandatory element contains the type of the regulatory activity, i.e. from a simplistic perspective, what regulatory purpose this filing is addressing.. The content of this element is taken from a list of values defined by Health Canada
The <sequence-number> Element
This mandatory element contains a four-digit number which is the unique identifier for this sequence (regulatory transaction) inside the overall dossier. The schema ensures that the content is in the format “9999”, i.e. four digits. Internally at Health Canada further validation will be performed to ensure that the number is unique within the dossier and is greater than previously filed sequence.
The <sequence-description> Element
This mandatory element describes the sequence (regulatory transaction) based upon a series of possibilities.
The <related-sequence-number> Element
This optional element contains the four-digit sequence number of the first sequence in this regulatory activity. The schema ensures that the content is in the format “9999”, i.e. four digits.
Source:
3.2 The xml structure of Module 1
The xml file of Module 1 contains two categories of elements:
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- Heading elements which act as an electronic Table of Contents to organize the documents submitted in Module 1. However, there are additional heading elements called node-extensions which can be created at pre-defined sections within an eCTD structure in order to group documents.
- Leaf elements which describe one document along with additional information such as the defined metadata or the document related lifecycle information (new, replaced, delete, append). Each document is linked and can be retrieved easily.
Important to consider when filing an eCTD, is to place each document on the lowest level of the eCTD tree. No document is allowed to be added inside a heading element which contains sub-headings.
In addition, it should be mentioned that there will be a difference between the physical folder structure within an eCTD and the xml structure/headings shown in the xml backbone. The software vendor which is used to prepare and file eCTD’s, usually provides the respective headings shown as folders within the application sticking to the xml headings defined by Health Canada. After eCTD has been published, the heading structure will be shown in the xml backbone where else the physical folder structure will not represent the same folder hierarchy and might only contain files. This output complies to Health Canada’s eCTD specification.
4. Technical Validation for eCTD formats submitted to Health Canada
Once an eCTD has been filed and published, the next item on the list should be the technical validation. Before sending an eCTD over to the authority it must be validated from a technical perspective. This step should not be skipped, as any technical invalidity would lead to a rejection. Make sure your eCTD submission complies to the technical requirements specified by the respective regional authority. Health Canada has also defined various test steps to be proofed when submitting an eCTD.
As of January 1st, 2017 the profile to be used for Canadian eCTD submissions is: CA eCTD – Profile 4.
Any warnings and errors should be corrected, and a valid test result must be present before sending it over to Health Canada.
5. The Common Electronic Submissions Gateway became mandatory (CESG)
On January 1st, 2017, Health Canada has announced that the CESG will be mandatory for all regulatory transactions under 10GB in size (including first transactions) prepared in the eCTD format. Because most transactions fall within this size limit, sponsors are strongly advised to obtain CESG accounts as soon as possible.
Sponsors providing files greater than 10 GB should continue to use media. For detailed information on how to file using media, refer to Section 3.2 (ii) of the Guidance Document – Preparation of Regulatory Activities in eCTD Format.
6. References
- https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/ectd/notice-creation-canadian-module-1-backbone-2012-health-canada-consultation-document.html#a4.2
- https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/ectd/preparation-drug-submissions-electronic-common-technical-document.html
- https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/ectd/notice-validation-rules-regulatory-transactions-submitted-health-canada-electronic-common-technical-document-format-2016-12-1.html
