Over time, you will need not only to submit new content but also to modify content previously submitted to a regulatory authority. The specifications provide operations for this purpose.

Used when a newer version of a document is being provided to replace an earlier version already submitted to a regulatory authority.

A document that has been replaced will have a red icon as a visual indication that the document is no longer current.

Used when a document is being provided to add onto or expand upon a document already submitted to a regulatory authority.

Used when a document is no longer relevant to the current status of an application, for example, a document related to a contract manufacturer who is no longer being used to manufacture the product.

Lifecycle relationships can be added, removed, or modified any time after a file reference is added. To view or modify lifecycle relationship for a file reference, select the document in the navigation tree and click the Relationships tab, where a user can remove relationships. By default, by adding a document to lifecycle, the leaf title is automatically inherited from the existing document upon addition, allowing for less work in manually modifying leaf titles.

The tab displays two sections showing all file references related to the selected file reference:

See the following sections for more information:

Lifecycle Documents through Multiple Sequences

Add Relationships

Lifecycle Operators in Studies or Repeat Sections

The Delete Operator

The modifying file reference is the file reference that replaces or appends to an existing file reference (generally a file reference that has already been submitted to a health authority). The modifying file reference must be editable (not have a Final state and in a containing folder reserved by the publisher making the change).

When the selected file reference is the modifying file reference, you will create the relationship in the section of the Relationships tab labeled File References that I Replace, Append to, Link to, Delete, or Reactivate. You can choose the relationship of the file reference as:

The modified file reference is the file reference that is being replaced, appended to, or linked to by another file reference (generally a new file reference). It may have a Final state since it is not being changed as it was already submitted to the agency.

When creating relationships, a file reference must be selected from a previous sequence to modify. By default, available documents will be available in dropdown list from the current eCTD section throughout the application. The dropdown box will display information about each file reference, including its title, state, and sequence number. This can be done in two views: Origin and Life Cycle

​Relationships via Origin View

Relationships via Life Cycle View

Add a Relationship in Different eCTD Sections

All eCTD operators can be applied to a document in the Origin view through the Relationships tab. If this tab is not showing, navigate to View > Tabs. Select the Relationships option and it will appear in the Details pane.

If the operator is added to the modifying reference, or the one doing action, the relationship will be added to the File References that I Replace, Append to, Link to, Delete, or Reactivate section.

When the selected file reference is the reference being modified, or previously submitted file, the relationship will be added from the File References that Replace, Append to, Link to, Delete, or Reactivate me.
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Note: The Delete operator can ONLY be added in Origin view. Additional information on the Delete operator can be found in “The Delete Operator” section.

In the example below:

In eCTD format, only documents with a state of Current, or New can be replaced, and a selected reference can only have a relationship for one document. If a document has already had a lifecycle operator associated with it and another relationship is added, Publish will throw an error message.

In Life Cycle view, the Replace and Append lifecycle operators can also be added via drag and drop.

In Life Cycle view, set an Active Sequence for Publish to write to.

Find the file reference to modify and drag and drop the new document on top of the existing document.
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Choose the correct relationship from the popup.

The operators will be added to the application.

Normally, a relationship relates to a file reference contained in the same eCTD section. However, if a document relates to a reference in a different eCTD section, click the small button next to the Section field to display the TOC to choose the other section, as shown in the following image. Once the correct section is selected, the File dropdown will repopulate with file references from that section. This must be done in Origin view.

To modify previously submitted file references in studies or repeatable sections, the sequence metadata must be first created in the new sequence, ensuring that the replacing documents or placeholders will be set in the correct location of the tree and show correctly for an agency reviewer.

Please see the “Add Application Metadata Repeatable Sections” section. Once the correct metadata has been added, the lifecycle process will be the same as mentioned in the previous sections.

The Delete operator is often not used, as any old documents will often be replaced or appended. However, in case of an incorrect document being submitted to an agency, or incorrect sequence metadata causing logistical problems, the Delete function can be used to remove the document from consideration. The Delete operator can only be added to a document in Origin view.

Note: The Delete operator is only used to remove documents from consideration that have already been submitted to a health agency. Prior to submission, any extraneous or incorrect documents in a submission can simply be removed.

Select the document to be deleted in the sequence it was submitted in and choose the Relationships tab in the Details pane.

In the section labeled File References that Replace, Append to, Link to, Delete, or Reactivate me, choose Deleted By in the relationships dropdown.

Select the sequence where the deletion will take effect. The sequence that will contain the deletion must be listed as In Progress.

Publish will add a placeholder that appears in the sequence deleting the previously submitted document. The new placeholder will have a dark grey icon. This is the indicator for the agency that the older document is no longer to be considered in the application.

If a sponsor’s best practice is to add a placeholder first and then apply an operator, select the placeholder and use the top half of the Relationships tab labeled File References that I Replace, Append to, Link to, Delete, or Reactivate.

Choose the Delete relationship and locate the file to be deleted. Both file references will appear with grey icons after the relationship is created. The following figure shows an example of deleting using a placeholder.