Goodby NeeS!

Sounds like EMEA stayed busy through the holiday season as they posted four new or updated guidance documents at the end of December. Most significantly, EMEA implementation of electronic-only submissions and mandatory eCTD submissions in the centralised procedure: Statement of Intent tells us:

"From 1 January 2010, the EMEA will mandate the use of the eCTD format for all electronic-only submissions for all applications (new and existing) and all submission types. Rapporteurs and CHMP members will not receive paper copies or other electronic formats."

As with the rest of the EMEA's statements and guidelines pertaining to eCTD, this only applies to the Centralised Procedure.

A "matching" statement of intent for non-eCTD electronic submissions tells of the retirement of NeeS. It also announces the introduction of a set of specific guidelines on submission structure, format and presentation, which non-eCTD submissions should adhere to for the centralised procedure from 1 February 2009 until such time as the eCTD format is mandatory. These guidelines are found in EMEA implementation of electronic-only submissions eCTD submission: Practical guidelines relating to Non-eCTD submissions.

Finally, the highly useful document EMEA Implementation of Electronic Submissions and eCTD Submissions Statement of Intent Q&A Relating to Practical and Technical Aspects has been re-issued. Changes are minor and include asking for virus checking information in the cover letter instead of a reviewer guide, and acknowledging a discrepancy between the eCTD file naming
convention and the PDF file naming requirements for EPAR (product information) documents (you are advised to use eCTD file naming conventions for the time being).

My collegue discussed this announcement with EMEA representatives this week, and they have indicated that although they are not in a legal position to require electronic submissions, they strongly recommend against paper submissions.

(P.S. After an internal struggle, I suppressed the urge to label this post "It's Been NeeS".)

More news and updates from the EU agencies

As the EU authorities continue their progress towards welcoming eSubmissions, information continues to surface on their web sites and elsewhere.

The Swedish National Authority (MPA) has updated their web site with new eSubmission information - see Electronic submissions to the MPA. The MPA maintains a dedicated email address (eSubmissions@mpa.se) for general questions on electronic submissions. They also provide guidance on media, cover letters, handling of MS Word documents, etc. Some of the information is only in Swedish (which BabelFish unfortunately won't translate!).

If you visit the web site of the Spanish agency La Agencia Española de Medicamentos y Productos Sanitarios, look for a Welcome link in the top toolbar to access some content in English. Click the Electronic Submission link and look for the link to Instructions for electronic submission eCTD/NEES Pilot Phase. The agency has instructions for generating electronic submissions, to take effect in January 2009. The agency requuires sponsors to register new authorizations and variations in the AEMPS Regulatory Tool: RAEFAR, and to use the Belgian tool eCTDchecker on NEES submissions. A more detailed guide is available in Spanish: Guide AEMPS v1.11 .

Finally, an interesting presentation on Electronic Submissions in Hungary, by Dr. Gergely Zajzon of National Institute of Pharmacy is available. Since 2006, the National Institute of Pharmacy (OGYI) in Hungary has been accepting full electronic eCTD applications, without any printed sections of the dossier. Dr. Zajzon's presentation discusses status, progress, challenges, requirements for eCTD and NEES in Hungary, and the agency's ongoing program to digitize paper submissions.

How's Your Italian??

I'm honored to have been referenced on a new Italian eCTD web site, the eCTD.it User Group. The site references a post of mine about Gary Gensinger's remarks at DIA on a page called eCTD: The Quality of the Dossier:

http://www.ectd.it/knowledge/introduzioni/77-ectd-la-qualita-del-dossier Fortunately, my ability to read and speak Italian like a native served me well here... Just kidding ;-)

But seriously, there are some interesting articles on this site. You can access a translated version by googling "ectd.it" and clicking on the Translate this Page link (for some reason this only seems to work from www.google.com and not from my google toolbar). With this approach, Google will continue to translage the pages as you follow the links.

Common eCTD Mistakes - as Described by FDA (Part 2)

Continued from last time... Notes from my discussion with Virginia Ventura.

Virginia mentioned lack of a cover letter, or lack of a useful cover letter, as a significant issue. Although the cover letter is not a regulatory requirement, it serves as the reviewers' "Road Map" to the submission, and Virginia can't understand why a sponsor would not take advantage of the opportunity to provide clarity on the structure and contents of the submission. Her recommendations here:

• When you reference documents in your cover letter, provide hyperlinks to those documents.
• Review your cover letter closely for accuracy. Mistakes in the cover letter can cause significant confusion.

We discussed the concept of providing more detailed reviewer guides as well. Again, these are not a regulatory requirement, but some companies consistently provide well-structured guides that make reviewing much easier. These should not just reproduce the TOC, but might included details and discussions such as the following:

• How the eCTD was constructed (for example, using which software package) and how it was submitted (via the gateway, etc.)
• Version of specs used
• Brief description of pivotal studies, with mention of where they are located and hyperlinks to key documents and summary sections
• Discussion of how study reports were constructed (ICH granularity, etc.)

You also may wish to discuss placement issues (for example, when a study could legitimately be placed in more than one section), instances when the same document was submitted in more than one section, etc.

As a reminder, FDA has organized documents related to electronic submissions on http://www.fda.gov/cder/regulatory/ersr/. This is a great collection of resources, and Virginia mentioned that not all sponsors are aware that this page exists before they contact her.

Specifically pertinent to this post, FDA has a posted presentation, eCTD Validation, available on their website. This was presented by Don Duggan in February at DIA EDM in Philadelphia.

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.