Linking across applications
Cross-application linking is an important timesaving feature of an eCTD because it allows a sponsor to reuse submission documents
and to apply granular document updates (either during the building of the current submission or while applying a lifecycle
attribute in a future sequence) to all linked occurrences elsewhere across related product applications. This life-cycle management
ability increases efficiency for the publisher and aids in the consistency of information presented throughout the product
application portfolio. In addition, because the XML backbone is a common format across all eCTD applications, sponsors building
an NDA can use cross-application linking through a leaf title that references back to the IND document without republishing
that document in the NDA submission.
For this function to work, a reviewer's software must be compatible with the sponsor's submission building tools. To ensure
that the two systems will work together, FDA is urging sponsors to set up a cross-referencing compatibility test with reviewers
(by e-mail at email@example.com
) before the submission is sent (1). In general, FDA uses "ind" as the prefix for IND; "nda" as the prefix for NDA; "mf" as
the prefix for Drug Master Files, and so forth. However, FDA has reported that failed links are a common cause of confusion
and delay as the reviewer is left to research or query grayed out leaf titles in the eCTD viewer (1).
The following is a list of instances in which cross-application linking works best:
- Nonclinical reports (if applicable).
- DMF documents
- Literature references
- Any other document where granularity or content does not change between the IND and NDA or impact the review process.
Dos and don'ts
As discussed, the biggest "do" is to include FDA when planning and setting up cross-reference links in a submission or application
to avoid problems that could lead to delays or refusals to file. Other important issues include:
- Leaf titles: Although it's not necessary to alter leaf titles in IND documents that may be referenced in later submissions
or applications, it is important to make subsequent reference leaf titles in the NDA very descriptive so that reviewers know
immediately that documents reside in an earlier application or submission.
- Section m1.4.4: Place a tabular document under m1.4.4 that itemizes every cross-application link being used. In cases where
links are broken, this helps reviewers to navigate to the right reference document.
- Clinical study reports: Resubmit clinical study reports in full in the NDA. One exception is the protocol, which typically
does not change between the IND and NDA.
- Application numbers: Use a six-digit application number. If necessary, pad with zeroes to make six digits. For example, if
your application number were 12345 you would have to submit 012345 on the CTD as the application number. Also, sequence numbers
should always be four numeric digits (e.g., no commas, hyphens, spaces).
- Submission: Send submissions to the FDA document room. If sent directly to a reviewer, the submission doesn't get entered
into the electronic tracking system and it may not be considered officially received.
- Refrenced files: Include all required eCTD files, either referenced in the US Regional XML, the Index XML, or an STF XML.
- Sequence numbers: Don't submit duplicate sequence numbers. FDA officials have noted that this happens often when sponsors
don't have internal processes set up for adequate sequence number control (1).
- Node extensions: Don't use node extensions in preparing the eCTD, as FDA viewing tool may not know how to handle them and
it is very likely that the information you include in the node extension won't appear where you think it will.
- Style sheets: Avoid sending customized style sheets.