The NDA Marriage – Complementing Regulatory Strategies with Technical Solutions

Jillian Lee

The presentation “The NDA Marriage” was given by Jillian Lee, Senior Global Submission Specialist at Bayer Health Care AG, at LORENZ userBridge.14 in Milan, Italy.

In her presentation, Jillian Lee outlined an approach for concurrent submission applications.

Background: sequential regulatory requirements
Bayer’s mission is “Science For A Better Life”. For the pharmaceuticals division, this means – making available safe, effective, and potential life-saving options to patients as quickly as possible. Currently however, technical barriers prevent the submission of a NEW indication for a drug while the first indication is still in the initial approval process with health agencies.

So a solution is needed to reduce the overall review timelines and potentially help in “fast-tracking” approvals. The answer is simple, although technically complex: enable concurrent applications.

Technical solution: Cross Application Referenced File
LORENZ introduced the “Cross Application Referenced File” feature in docuBridge 5.2 to handle precisely this sort of situation. According to Health Canada’s specifications, a file submitted once in any application should not be resubmitted again. Instead, the revised item should reference to the file previously published.

A cross-application reference is a link from the submission xml (Product Y) that when selected opens a file originally submitted in a different application (Product X). The physical file of a cross-application referenced file is not published.

(It is important to note here that when referring to a file submitted in a different application, the document should be added in the Node Content pane in order to apply lifecycle operators in the future.)

Regional Approach: US FDA
The FDA uses the term “cross application linking” for this procedure. It may be used for submissions where the same information needs to be submitted to multiple applications. Examples include submitting the same information across a group of INDs for the same product (e.g. safety reports), or submitting the same information across a group of NDAs of a product family (e.g. CMC information for a shared drug substance).

Instructions for this are not yet readily available on the FDA’s website, but can be obtained by contacting the FDA: ESUB@fda.hhs-gov

Here we can visually compare the life of a single NDA with a so-called NDA marriage:

Single life NDA:

Typical life of a NDA

Source: Presentation Slides of Jillian Lee

NDA marriage:

NDA Marriage

Source: Presentation Slides of Jillian Lee

This “marriage” process leads to concurrent review of the 2 applications.

The cross application reference feature can be used in all modules of the eCTD, and can have lifecycle operators applied to them, such as:

  • Submit as NEW file
  • REPLACE an existing file in the application
  • A cross application reference file can later be replaced by a physical file
  • A cross application reference file can have a lifecycle operator DELETE

The hyperlinks made to a cross application referenced file in NDA1 open to the physical file in NDA2.

Regional approach: Health Canada
Health Canada restricts reviewers’ access to sequences that are not yet approved, so when submitting Indication B while Indication A has not yet been approved, the information or documents that are identical for both do not need to be submitted again, but instead simply cross referenced to open in Reviewers’ view for Indication B. The sequence number for where the physical file was submitted should be added to the node title to indicate the reuse.

Physical replacement of a file is sometimes needed; to open the Reviewers’ visibility of a document REPLACED in Indication B, a cross reference can be made in an additional sequence for Indication A.

Other solutions are possible
Agencies have shown great flexibility in working with sponsors to try to create technical solutions for concurrent applications. The same desired outcome can potentially be achieved in slightly different ways, and different agencies may take varied approaches. Sponsors should work with their agencies to find the best solution for them – and most importantly, the best outcome for patients!

Elsmari Eggers

Written by Elsmari Eggers, Head of Education & RA Consulting at LORENZ Life Sciences Group.


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