Common eCTD Mistakes - as Described by FDA

I recently had a great chance to talk to Virginia Ventura of FDA's Electronic Submission Support Team about the common mistakes made by sponsors in preparing eCTDs. Virginia told me that mistakes are not confined to small or inexperienced companies. In many cases, these errors result from a lack of basic QC. Here are some examples:

Not updating documents that were created based on templates intended for paper.

Of course, adding hyperlinks is a big part of this. In some cases, sponsors have not only failed to add hyperlinks, but have retained references to paper volumes, which are of course useless in the eCTD environment.

My colleague Shannon Strom, Director of Regulatory Operations at Cato Research, gave a great example of the need to change practices at a recent presentation: consider the previous practices of using a sentence such as:

Tables 1-3 Indicate The Significant SAEs Reported For Each Clinical Study.

This was fine in the paper world, but in the eCTD world, it gives the publisher no way to hyperlink to Table 2! Thus a better structure is:

All Significant SAEs Reported For Each Clinical Study Are Indicated In Table 1, Table 2, And Table 3.

Bottom line: make sure your documents have been updated for proper presentation in an electronic environment, and as always, keep the reviewer in mind! Virginia says that the FDA has received a number of submissions that were essentially "un-reviewable" due to lack of hyperlinking.

Lack of consistency in the Application Number
The application number appears in four places in an eCTD:

The regional backbone (us-regional.xml in the US)

The root folder of the eCTD content

The application form

The cover letter

It's really important that the application number matches in all four places. (By the way, if it does not match, the FDA will consult your cover letter for arbitration - so heaven help you if it's wrong!)

That also brings up the topic of using the PDF Fillable Form provided by FDA for your application form. They really want you to do this!! Virginia says that lack of a fillable form is the #2 error that the FDA sees for eCTDs. (Interestingly, the #1 error is clicking twice when submitting via the gateway - this causes your submission to be submitted twice, resulting in a number of errors, as you would expect.)

More on my talk with Virgina next time...

eCTD on the Agenda at Upcoming ICH Meeting

A public ICH meeting is planned for 14 November 2008 in Brussels, Belgium. See Brussels ICH Public Meeting, Nov. 14, 2008 for the details and agenda.

The agenda includes a session on standards development for the electronic exchange of information (chaired by Andrew Marr). That session will include, among other topics, an update on eCTD from Joe Cipollina.

RPS 2 Vancouver Working Group Meeting

An RPS2 Working Group meeting was held in Vancouver the week of September 15.

The working group discussed a number of business scenarios including:

Two Way Communication – Pre-Submission Correspondence

Submission Activities – Request Submission Number

Submission Activities – Meeting Request and Responses

Notification of Decision or Action

Request/Response for Additional information during a review cycle

Follow-up/Postmarket Correspondence

Referencing – Permit Use of Master file, Master Access File or Third Party Documentation

Referencing – Comparison Information

Referencing – Reference Information sent to an external party

Referencing - Paper Submission

Labeling Negotiations

Interim Actions (i.e., complete response letter, tentative approval, non-final actions, hold decisions, etc.)

Administrative Actions – Technical/Validation Reports/Errors

Some of these scenarios were removed from requirements iteration #1 or merged with other scenarios.

Still time to sign up for webinars

It's not too late to sign up for the two remaining entries in GlobalSubmit's 2008 Executive Webinar Series: Mastering the eCTD.

This series has been very well received to date and has covered topics such as:

Mastering eCTD operators

Best practices in submission reviewing

Introduction To Regulated Product Submissions (RPS)

Scanned Input Preparation

Understanding Regional Differences

eCTD File Formats

The seminars are free, but are only open to those working directly in the pharmaceutical industry and not to consultants or vendors.

Remaining topics in the series include:

Archiving Options and Best Practices (October 1)

Working With Metadata (October 22)

After that, the series is done for the year.

ICH Publishes Updates to eCTD Specification

ICH has published a new eCTD specification (version 3.2.2) and STF specification (v2.6.1), as promised some time ago. This was done with little fanfare - the announcement and links to the documents can be seen at:

eCTD News

For those of you who monitor What's New on the ICH website? - the updates did not merit a mention there.

The changes resulted from a June meeting, the documents are dated July 2008 and were published on the ICH web site at the end of August.

Only the narrative portion of the document was changed. The DTD and stylesheet have remained unchanged. (In addition, the "valid-values.xml" file has been updated to change file tag "randomisations-scheme" to "randomisation-scheme").

Changes to the spec are mainly clarifications and items that have been tracked in the Q&A Document (updated version 1.15.1 has been posted), so there really shouldn't be anything alarming... For the STF document, the cumulative STF approach has been removed (as FDA does not allow it) and other minor updates made.

One nice thing is that the PDFs of these documents are properly bookmarked in Acrobat :-) !

RPS has a wiki!

Regulated Product Submissions (RPS) now has a Wiki (or more accurately, it's part of the overall HL7 Wiki).

To get there, go to Main Page HL7 Wiki. You will have to log in, but you can use the following credentials for read only access:

user name: wiki
password: wikiwiki

(You must create a user name and password if you want to contribute.)

Once you get there, click on the Regulated Product Submissions link in the Projects category.

There is not much in the main area, but following the RPS R2 Project link at that point will give you access to write-ups on Scope and Domain Analysis, as well as a link to business scenarios. Look for information and updates to be posted fairly often.

Cross Application Links in eCTD

A little while ago, a client asked me about referencing documents submitted in one application from another application. Her question was in the context of an IND and an NDA, both submitted in eCTD format - did she have to re-submit documents in her NDA that had already been submitted in her IND?

The ICH guidance is basically silent on this subject, although the structure does not specifically prohibit any valid relative link. EMEA has stated that it is not allowed - in "EU Region Question and Answer and Specification Change Request Document", see question 13:

"In the EU it is possible to refer to a file located in the same sequence or any previous sequence of the same eCTD. It is not possible to refer to other eCTDs."

If you think about it a little, it requires each agency to maintain a specific set of folders in order for the links to work, and for the sponsor to understand what that structure is.

For example, if the agency stores eCTDs in a known folder path like this:


then I could provide a relative file path from my "NDA" 222222 back to files in my "IND" 111111. But if the agency does not maintain that exact folder structure, my links will break.

Gary Gensinger of FDA has said in several presentations that FDA will accept references to documents in other applications.

In order to do this, your publishing tool must be able to handle this scenario. A leaf must exist in your new application (you cannot reference leafs from other applications, only content files). You will need to know:

Name of the file

Location in Original Submission

Access in through the hlink:xref element, and the operation attribute is NEW.

Gary provided the following example:



With the following commentary:

You want to reference a leaf submitted in 0000 of your IND 012345 for NDA282166, sequence 0000 - Your file is named study-report.pdf in 5.3.5.2. Using the following relative path will allow you to reference the study report:

../../IND012345/0000/m5/5352/study-report.pdf

../ gets you out of the 0000 submission in NDA 282166
Adding ../ gets you out of the NDA 282166
Adding IND012345/0000/m5/5352 gets you to your files location


What I haven't heard is how many people are taking FDA up on this offer.

By the way, the RPS specification will be designed to allow cross application referencing from the start, and will not reply on a relative folder path.