The eCTD consists of 5 primary modules:
• m1-administrative-information-and-prescribing-information
• m2-common-technical-document-summaries
• m3-quality
• m4-nonclinical-study-reports
• m5-clinical-study-reports
Each of the 5 modules is divided into one or more elements, each with a distinct element identifier that represents a CTD table of contents location. The steps should be completed as shown in the following example, where all files are submitted for modules 1 through 5:
1. Select an element that best corresponds to the CTD table of contents location for a document or file being submitted. For example, select the element <m2-7-3-summary-of-clinical-efficacy> to submit the summary of clinical efficacy document.
2. Specify any additional element attribute as appropriate; in this example, specify the ‘indication’
attribute to identify the subject of the efficacy summary in 2.7.3.
3. Create a child <leaf> element within the <m2-7-3-summary-of-clinical-efficacy> element.
4. Provide the relative location and file name of the actual file in the “xlink:href” attribute for the leaf element.
5. Provide a descriptive and concise title for the file in the <title> element of the leaf element.
6. Provide information for the appropriate attributes of the leaf element as described in Table 6-8.
Table 6-8 describes each of these elements and attributes in further detail.
Table 6-8
Element Attribute Description/Instructions Example Any table of
A table of contents element
represents a grouping of one or more files related to a specific section of the Common Technical Document. A number of TOC elements can be further defined by the use of attributes. The eCTD DTD defines the following attributes at various places in the eCTD: substance, manufacturer, product-name, indication, excipient, dosage-form (e.g., 2.3.S and 3.2.S have two ‘free text’ attributes: substance and manufacturer; 5.3.5 has the additional ‘free text’ attribute, indication). To be consistent with the CTD General Q&A, values for these attributes should be included where specified as is appropriate. There is currently no standard terminology list for any of these attributes and applicants should carefully choose the text of these attributes as they can not be easily changed during the life cycle of the application.
One or more child <leaf> elements can be declared for a parent table of contents element.
It is possible to extend a table of contents element by providing a
<node-extension> element. Node extensions should only be added at the lowest level of the defined table of contents elements. Using node extensions is discouraged and should be done only when unavoidable.
Please refer to regional guidance before using node extensions. See the section “Instructions for extending XML eCTD DTD
elements” in this appendix (Example 6-5).
ID A unique identifier for this location in the XML instance.
id403 (note: At this level, ID is optional) xml:lang The primary language used by the
files in this entire section of the submission. Use ISO-639 standard language abbreviations
en
Element Attribute Description/Instructions Example
<leaf> A leaf element is a reference to a file.
One or more leaf elements can be declared for a table of contents element.
application-version
This is the version of the file format produced by the software application that was used to create this file.
PDF 1.4
font-library Reserved for Future Use
ID The ID attribute is intended to be a unique reference within the submission that can be used to reference the item from another item within the XML document. An XML ID value begins with an alphabetic character or underscore.
If an applicant is using an internal ID generator that uses only numbers, appending this generated number to a leading alphabetic character or underscore will create a valid ID value.
id050520
NOTE: See the XML-ID
recommendations on the W3C website for info on the composition of this attribute value (http://www.w3.org/TR/xml-id/#processing)
checksum The checksum value for the file being submitted.
e854d3002c02a61fe5cbe926fd97b001
checksum-type
The checksum algorithm used. MD5
modified-file
The purpose of the modified-file attribute is to provide the location of the leaf that is being modified (i.e.
replaced, appended or deleted) by the leaf element. The modified-file attribute should have a value when the operation attribute has a value of append, replace or delete. The modified-file attribute points to the
“index.xml” file and the leaf ID of the leaf being altered.
../0001/index.xml#a1234567
operation Indicates the action to be performed.
You should select one of the following valid values:
• new
• replace
• append
• delete
See the section Operation Attribute in this appendix for details on the meaning of these values.
new
version The file submitter’s internal version number or version identification for the file.
V23.5
Element Attribute Description/Instructions Example xlink:href Provides the reference to the actual
content file. You should use the relative path to the file and the file name. The content file does not need to be in the same sequence as the leaf element that refers to it.
0000/m2/27-clin-sum/literature-references.pdf
xlink:role Reserved for Future Use xlink:show Reserved for Future Use
xlink:type Fixed value of “simple” simple keywords Reserved for Future Use
<title> As part of the leaf element, this element contains a practical name for the file being referenced by the leaf.
Study Report 1234
NOTE: Leaf titles should be concise;
1024 bytes (512 characters) are proposed as the maximum length
ID Unique identifier for this location in the XML instance. Leaf ID starts with an alphabetic character or underscore.
a1234567
NOTE 1: See the XML-ID
recommendations on the W3C website for info on the composition of this attribute value (http://www.w3.org/TR/xml-id/#processing)
NOTE 2: At this level, ID is optional
<link-text> Reserved for Future Use
<xref> Reserved for Future Use
Example 6-1: Instructions for a Simple New Submission
7The following XML fragment demonstrates the submission of a clinical overview of efficacy as a single PDF document.
<?xml version = "1.0" encoding = "UTF-8"?>
<!DOCTYPE ectd:ectd SYSTEM "util/dtd/ich-ectd-3-x.dtd">
<?xml-stylesheet type="text/xsl" href="util/style/ectd-2-1-x.xsl"?>
<ectd:ectd xmlns:ectd = "http://www.ich.org/ectd" xmlns:xlink = "http://www.w3c.org/1999/xlink">
<m2-common-technical-document-summaries>
<m2-5-clinical-overview xml:lang = "en">
<leaf ID="s123456" operation = "new" xlink:type = "simple" checksum-type=“md5”
checksum = "e854d3002c02a61fe5cbe926fd973401" xlink:href = "m2/25-clin-over/clinical-overview.pdf" application-version = "PDF 1.4">
<title>Clinical Overview</title>
</leaf>
</m2-5-clinical-overview>
</m2-common-technical-document-summaries>
</ectd:ectd>
This submission includes the file “clinical-overview.pdf” in the relative directory “m2/25-clin-over/” (i.e.
the one starting below the dossier number directory). The file is “new” and has a descriptive name of
“Clinical Overview”
The regional review application should treat this as a new submission to be associated with the submission identified in CTD module 1, which is region specific.
7 Note that these XML examples are examples only and do not necessarily contain all of the elements and
If this is the first submission for Dossier CTD 123456, all the files in this submission would typically be in the ctd-123456\0000 directory and below.
Example 6-2: Instructions for an Amendment, Supplement, or Variation
In the previous example, a clinical overview was submitted. In this example, it is replaced by an updated version.
To replace a file, add the replacement <leaf> element under the same element as the original file.
If this is the second submission for Dossier CTD 123456, all the files in this submission would typically be in the ctd-123456\0001 directory and below.
<?xml version = "1.0" encoding = "UTF-8"?>
<!DOCTYPE ectd:ectd SYSTEM "util/dtd/ich-ectd-3-x.dtd">
<?xml-stylesheet type="text/xsl" href="util/style/ectd-2-1-x.xsl"?>
<ectd:ectd xmlns:ectd = "http://www.ich.org/ectd" xmlns:xlink = "http://www.w3c.org/1999/xlink">
<m2-common-technical-document-summaries>
<m2-5-clinical-overview xml:lang = "en">
<leaf ID=“a123457” operation = "replace" xlink:type = "simple" checksum-type="md5" checksum =
"502e9ab5827431f077340cea3b5e465a" xlink:href = "m2/25-clin-over/clinical-overview-revised.pdf"
application-version = "PDF 1.4" modified-file = "../0000/index.xml#s123456">
<title>Clinical Overview</title>
</leaf>
</m2-5-clinical-overview>
</m2-common-technical-document-summaries>
</ectd:ectd>
Example 6-3: Instructions for Multiple Indications
Multiple therapeutic indications use an additional attribute associated with the <m2-7-3-summary-of-clinical-efficacy> and the <m5-3-5-reports-of-efficacy-and-safety-studies> elements to allow multiple indications to be submitted. There is currently no standard terminology list for ‘indication’. Applicants should choose these attributes carefully as they can not be easily changed during the life cycle of the application. The only way this can be accomplished currently is to delete all the leaf elements with the incorrect attribute value and provide new leaf elements for those files with the modified attribute value.
Applicants should consult with the regional authority before attempting to modify these attributes to discuss the appropriateness of, and approach to be taken for, this type of change. The following table shows the use of these attributes.
Table 6-9
Element Attribute Description/Instructions Example
<m2-7-3-summary-of-clinical-efficacy> indication Name of the indication Pain
<m5-3-5-reports-of-efficacy-and-safety-studies>
indication Name of the indication. Pain
Note that the indication attribute is used by the regulatory authority to apply to all the table of contents elements beneath the <m2-7-3-summary-of-clinical-efficacy> and <m5-3-5-reports-of-efficacy-and-safety-studies> elements. The following example expands on the instance showing the submission of information about two indications (pain and nausea).
<?xml version = "1.0" encoding = "UTF-8"?>
<!DOCTYPE ectd:ectd SYSTEM "util/dtd/ich-ectd-3-x.dtd">
<ectd:ectd xmlns:ectd = "http://www.ich.org/ectd" xmlns:xlink = "http://www.w3c.org/1999/xlink">
<m2-common-technical-document-summaries>
<m2-7-clinical-summary>
<m2-7-3-summary-of-clinical-efficacy indication = "pain">
<leaf ID=“s123456“operation = "new" xlink:type = "simple" checksum-type=“md5“ checksum =
"5aa5c0e630a700af869e4c72535fc922" xlink:href = "m2/27-clin-sum/summary-clin-efficacy-pain.pdf">
<title>pain efficacy summary</title>
</leaf>
</m2-7-3-summary-of-clinical-efficacy>
<m2-7-3-summary-of-clinical-efficacy indication = "nausea">
<leaf ID=“a123457“ operation = "new" xlink:type = "simple" checksum-type=“md5“ checksum =
"bde4d34dc80678a266352daf450c3962" xlink:href = "m2/27-clin-summ/summary-clin-efficacy-nausea.pdf">
<title>nausea efficacy summary</title>
</leaf>
</m2-7-3-summary-of-clinical-efficacy>
</m2-7-clinical-summary>
</m2-common-technical-document-summaries>
<m5-clinical-study-reports>
<m5-3-clinical-study-reports>
<m5-3-5-reports-of-efficacy-and-safety-studies indication = "pain">
<m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication>
<leaf ID=“a123458“ operation = "new" xlink:type = "simple" checksum-type=“md5" checksum =
"a4529c4a257f07f8a0ec591dde854578" xlink:href = "m5/53-clin-stud-rep/535-rep-eff-safety-stud/pain/pain-sr1.pdf">
<title>pain study report 1</title>
</leaf>
</m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication>
</m5-3-5-reports-of-efficacy-and-safety-studies>
<m5-3-5-reports-of-efficacy-and-safety-studies indication = "nausea">
<m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication>
<leaf ID=“a123459“ operation = "new" xlink:type = "simple" checksum-type=“md5“ checksum =
"c5c39f594b2070a57bea66e58860efcf" xlink:href = "m5/53-clin-stud-rep/535-rep-eff-safety-stud/nausea/nausea-sr15.pdf" >
<title>nausea study report 15</title>
</leaf>
<leaf ID = "a123460" operation = "new" xlink:type = "simple" checksum-type = "md5" checksum
= "15faf198015f3599acabb7755c2d6b0c" xlink:href = "m5/53-clin-stud-rep/535-rep-eff-safety-stud/nausea/5351-stud-rep-contr/xyz0015/nausea-sr15.pdf">
<title>nausea study report 15</title>
</leaf>
</m5-3-5-1-study-reports-of-controlled-clinical-studies-pertinent-to-the-claimed-indication>
</m5-3-5-reports-of-efficacy-and-safety-studies>
</m5-3-clinical-study-reports>
</m5-clinical-study-reports>
</ectd:ectd>
Example 6-4: Instructions for Multiple Drug Substances, Manufacturers, and Products
Multiple drug substances use additional attributes associated with the <m3-2-s-drug-substance> element to allow unique combinations of the drug substance name and manufacturer to be submitted. There are currently no standard terminology lists for these attributes. Applicants should choose these attributes carefully as they can not be easily changed during the life cycle of the application. The only way this can be accomplished currently is to delete all the leaf elements with the incorrect attribute value and provide new leaf elements for those files with the modified attribute value.Applicants should consult with the regional authority before attempting to modify these attributes to discuss the appropriateness of, and approach to be taken for, this type of change. The following table shows the use of these attributes in 3.2.S.
Table 6-10
Element Attribute Description/Instructions Example
<m3-2-s-drug-substance> substance Name of one of the drug substances Acetaminophen manufacturer Name of the manufacturer of the drug substance My Supplier Example 6-4A:
This is an example of a section of the instance showing the submission of information about two drug substances (acetominophen and codeine), one of which is supplied by two manufacturers:
<m3-2-body-of-data>
<m3-2-s-drug-substance substance = "Acetaminophen" manufacturer = "My Supplier">
<leaf ID=“a123456” operation = "new" xlink:type = "simple" checksum-type=“md5” checksum =
"b002e4544c02361fe54be926ae777012" xlink:href = "m3/32-body-data/32s-drug-sub/acetaminophen-my-supplier/acetaminophen.pdf">
<title>Acetaminophen - My Supplier Data</title>
</leaf>
</m3-2-s-drug-substance>
<m3-2-s-drug-substance substance = "Acetaminophen" manufacturer = "Bulk Company 2">
<leaf ID=“a123457” operation = "new" xlink:type = "simple" checksum-type=“md5” checksum =
"0000cdfa05b1e995f88057150414a783" xlink:href = "m3/32-body-data/32s-drug-sub/acetaminophen-bulk-company-2/acetaminophen2.pdf">
<title>Acetaminophen - bulk company 2 data</title>
</leaf>
</m3-2-s-drug-substance>
<m3-2-s-drug-substance substance = "Codeine" manufacturer = "Drug company 2">
<leaf ID=“a123458” operation = "new" xlink:type = "simple" checksum-type=“md5” checksum =
"f555a3234f65623fe54be926ee435354" xlink:href = "m3/32-body-data/32s-drug-sub/codeine-drug-company-2/codeine-quality-data.pdf">
<title>codeine - drug company 2 data</title>
</leaf>
</m3-2-s-drug-substance>
</m3-2-body-of-data>
Multiple drug products use additional attributes associated with the <m3-2-p-drug-product> element to allow unique combinations of the drug product name and dosage form to be submitted. Applicants should choose these attributes carefully as they can not be easily changed during the life cycle of the application.
The only way this can be accomplished currently is to delete all the leaf elements with the incorrect attribute value and provide new leaf elements for those files with the modified attribute value. Applicants should consult with the regional authority before attempting to modify these attributes to discuss the appropriateness of, and approach to be taken for, this type of change. The following table shows the use of these attributes in 3.2.P.
Table 6-11
Element Attribute Description/Instructions Example
<m3-2-p-drug-product> product-name Name of one of the drug products Wonder drug
dosageform Dosage form Capsule
manufacturer Manufacturer of the drug product Company A Example 6-4B
This is an example of a section of the instance showing the submission of information about two drug products (a capsule and a tablet):
<m3-2-body-of-data>
<m3-2-p-drug-product product-name = “Wonder drug” dosageform=“Capsule” manufacturer=“Company
<leaf ID=“a123456” operation = "new" xlink:type = "simple" checksum-type=“md5” checksum =
"f27cd9e659d8acf7baab10cc753d733c" xlink:href = "m3/32-body-data/32p-drug-prod/capsule-5mg/32p1-desc-comp/description-and-composition.pdf">
<title>Wonder drug capsule product information</title>
</leaf>
</m3-2-p-drug-product>
<m3-2-p-drug-product product-name = “Wonder drug” dosageform=“Tablet” manufacturer=“Company A”>
<leaf ID=“a123457” operation = "new" xlink:type = "simple" checksum-type=“md5” checksum =
"7490d74c3d5e442ad57daa155253eb16" xlink:href = "m3/32-body-data/32p-drug-prod/tablet-5mg/32p1-desc-comp/description-and-composition.pdf">
<title>Wonder drug tablet product data</title>
</leaf>
</m3-2-p-drug-product>
</m3-2-body-of-data>
Example 6-5: Instructions for Extending XML eCTD DTD Elements
An applicant can extend the definition of an element by creating node extensions beneath a defined table of contents element. Using node extensions is discouraged and should be done only when unavoidable. Please refer to regional guidance before using node extensions. The child element <node-extension> should be used for each new table of contents node created. The <title> element value is inherited from the parent element. You should only extend the lowest level of defined elements. For example you can extend the
<m2-3-r-regional-information> element but not the <m2-3-quality-overall-summary> element since the latter is not the lowest element defined in the table of contents.
The following is an example of a section of an eCTD instance in which the applicant extends the <m2-3-r-regional-information> to provide specific regional information as requested by a regulatory authority. The title element associated with the <node-extension> describes the extension. Alternatively, the regional information in this example could have been provided as a <leaf> element under the <m2-3-r-regional-information> element without the use of a “node extension”.
<m2-common-technical-document-summaries>
<m2-3-quality-overall-summary>
<m2-3-r-regional-information>
<node-extension>
<title>special-summary</title>
<leaf ID=“a123456” operation = "new" xlink:type = "simple" xlink:href = "m2/23-qos/extra-quality-sum.pdf" checksum-type=“md5” checksum = "7490d74c3d5e442ad57daa155253eb16">
<title>Extra Quality Summary </title>
</leaf>
</node-extension>
</m2-3-r-regional-information>
</m2-3-quality-overall-summary>
</m2-common-technical-document-summaries>
To update a file that has been submitted as an extended node, you should submit the replacement file using exactly the same element and “node extension” information, including the <title> element for the <node-extension>. This makes it possible for the regulatory authority to locate the original file and update its status.
Example 6-6: Instructions for Submitting Sections as Paper
During the transition to fully electronic submissions of the CTD, some regions will accept that some sections can be submitted as paper only. Please refer to regional guidance. These sections should be identified in the XML eCTD instance by including a PDF file in the instance that describes the content and location of the paper section. For example, the PDF file might consist of only one page with the name of the CTD document and the physical volume number and tab identifier. The <title> element in the XML eCTD instance could indicate that this is a paper submission.