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Kathie

FDA to begin rejecting eCTDs for significant technical issues

Due to the increased adoption of the eCTD and number of submissions received by the U.S. FDA, submission quality is receiving increased focus and attention at the U.S. FDA. In recent conversations with FDA officials, they have expressed a commitment to increase their diligence and oversight with respect to submission quality and have signaled their intention to begin rejecting eCTD sequences having significant technical issues. Although no specific date has been established for this step, expect an announcement of intent early in 2009, with enforcement beginning some months later.

What are Significant Technical Issues?

Significant technical issues are those defined in eCTD validation criteria However, expect these criteria to be updated and re-issued based on several factors:

Enhancement of FDA's Validation Software. FDA recently updated their validation software (GlobalSubmit VALIDATE Version 5). The updated software detects additional errors not documented in the current validation criteria. These error checks were added based on feedback from FDA IT staff and reviewers. The new software went live in CBER on November 18th, and in CDER on November 24th.

Analysis of Error Trends. The new software also allows the FDA to fulfill a PDUFA mandate to report back to sponsors on eCTD errors. Specifically, PDUFA IV Information Technology Plan, DRAFT, December 2007, requires reports on “Total number of standards-based electronic submissions that fail to comply with FDA electronic submission standards, along with a distribution of these submission failures across categories of failure or problem type”. After studying the distribution of eCTD submission errors, FDA may choose to re-classify the severity of some of the errors.

Issues and Inefficiencies Caused by Problematic eCTDs. FDA also experienced problems with invalid data (especially application and sequence numbers) in the course of moving to VALIDATE 5 and integrating with other databases and systems at FDA. This caused a significant amount of manual processing to address the problems and resulted in delays in the upgrade and integration process. As the number of eCTD sequences received by the FDA is growing exponentially, they cannot continue to accept sequences that need to be manually corrected before they can be loaded and made available to reviewers.

Groundwork Already Established

This action should not come as a major surprise to sponsors. FDA has been laying the groundwork for this step for some time. FDA validation criteria defines the impact of a high severity error as “The error is a serious technical error which prevents the processing of the submission and will require resubmission. The submission is considered not received by FDA.”

In the guidance document “Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Receipt Date”, they say:

The FDA will consider a technically deficient application not received until the technical deficiencies are resolved and the application is resubmitted. Examples:

Defect in media, lack of electronically readable application form, re-use of sequence number, missing index.xml and/or us-regional.xml, virus

High priority errors identified in validation criteria

Sanctions are also discussed in Section IIH of "Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications".

Impact and Recommendations

FDA anticipates that the step may result in the rejection a few percent of all sequences, based on the quality of submissions currently being received. It is not their intent to issue Refuse to File for a rejection, but it will prevent the PDUFA clock from starting, resulting in a significant cost impact to sponsors. Delays also increase the chance of a complete response - which stops or extends the PDUFA clock.

I strongly recommend that all organizations who produce eCTDs establish quality processes and procedures to ensure the quality of submissions. Tools that support eCTD review and validation are essential to ensure the overall quality and integrity of the submission to avoid costly errors and the potential rejection of the submission sequences. However,even the best tool must be used in combination with a thorough, repeatable, documented process in order to yield consistently excellent results.

[Note in the interest of full disclosure - I presently serve as the Director of Professional Services for GlobalSubmit.]

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.

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.

Anyone notice Updated EMEA Documents posted?

If you visit the EMEA eSubmission: What's new page, you will see that several new documents have been posted (date says July 27th, but I think it was really after that...).

The updated documents are:

Updated EU Telematics EU eCTD Change Request/Q&A Tracking Table

EU Validation Criteria v2.0

EA Practical/Technical Q&A on eCTD Submission V0.4

Updates to the CR/Q&A

These updates are mainly in support of the recent EU Updated M1 v1.3 (see my previous post on this topic). There are about 10 new change requests (see those startng with CR-20080415) and one new Q&A (22, not yet answered).

Updates to the Validation Criteria

Validation criteria changes are minor and are described at the end of this Excel document in a table. I've reproduced them here, with my comments in square brackets:

1. Criterion #37 deleted (see EU CR Q&A Tracking Table CR-20080610) [this was a DPI check that turned out to not be technically feasible with the valdidation tool being used.]

2. Reference of criterion #44 changed from EU Q&A 13 to ICH Q&A 36 (see EU CR Q&A Tracking Table CR-20080610-01 [although this is described as a "change" this is in fact a new criterion, stating "There are no unreferenced files in M1, M2, M3, M4 & M5 folders (including subfolders but excluding ‘util’ subfolders)" and having a priority of A, Serious".]

3. Criterion #18 changed to indicate that a title must exist with a delete operation - (see EU CR Q&A Tracking Table CR-20080610-02) [the critieria was changed from saying a title is not required for a file that has an operator of delete to saying that it is required.]

Updates to the EMEA Practical/Technical Q&A

In addition to the usual minor updates and fixes, I identified the following more significant changes from version 0.3. [By the way, it's not an easy process to compare these documents! PDF comparision results are difficult to use and I had to go through a number of cumbersome steps to convert to Word and compare. It would be nice if EMEA included more detailed info in their change log...]

FILE FORMATS Q2

The answer to Q2 has been enhanced with the bolded information and the example corrected as shown below.

Q2. As the EMEA requires the submission of RTF/Word documents for the Product Information (SPC, Labelling and Package Leaflet) and for some Module 2 documents, in addition to PDF, how should these Word documents be handled?

All Product Information Word/RTF files submitted to the EMEA (outside the eCTD backbone and therefore it not necessary to observe eCTD file naming conventions) should be named using the following convention, including the full application number/procedure application numberonly if this is known at the time of submission:

ProductName-H-ApplicationNumber-ProcedureType-ProcedureNumber-PI-language
code

Example: WonderPil-H-640-S-15-PI-en

Note the correction here - the previous document had a reference to a “product number”. Strangely, this example is repeated later in the document (see FILE NAMING Q1) but was not corrected there.

SUBMISSION MEDIA Q2

EMEA clarified the answer to Q2 by adding the note appearing in bold text below:
Q2. Must hard media be used for the submission of eCTD i.e. can secure email (Eudralink) be used?

Hard media (e.g. CD, DVD) must be used for the submission of all eCTDs. Eudralink can be used for eCTD in addition to hard media, but not as the sole medium for submission.

Please note that this requirement for hard media applies to EMEA as an agency, and may not be reflected in all National Competent Authorities involved in the Centralised Procedure – individual guidance from NCAs should be sought if necessary.

eCTD and PIM Q2

EMEA clarified when PIM may not need to be submitted within an eCTD:

Q2. If PIM is submitted with an eCTD submission, how should this be done?

It is expected that PIM submissions will be more numerous than eCTD submissions during a typical procedure, since PIM is a two-way exchange mechanism designed to support the management of the product information, the part of the dossier subject to the most change and rapid amendment during any procedure. Therefore, there will be some PIM submissions made without an accompanying eCTD via Eudralink. However, it is expected that, when a major lifecycle eCTD submission is provided as specified
in the response to Q1 under ‘Submission Milestones’ in this document, then the latest PIM submission will be included within the eCTD submission, if applicable, to ensure alignment. (The PIM submission does not have to be included within the eCTD submission at such points, however, and can be submitted as a separate PIM submission even if submitted simultaneously with the eCTD, as is detailed in the PIM specification).

SUBMISSION MILESTONES Q1

EMEA provided clarification about when labeling translations are needed:
Q1. When, in a procedure, at a minimum, does EMEA expect an eCTD submission to be provided?

Updates to key milestones

1. Initial submission (Day 0 of procedure)


2. Response to business validation issues (if required)


3. Response to List of Questions (i.e. Day 121 for a new application)


4. Response to List of Outstanding Issues (i.e. Day 181, if required)


5. Application as agreed at Opinion (inc. agreed EN product information if changed at CHMP)


6. Provision of translations (i.e. Day 215 for a new application)*


7. Provision of final agreed updated translations following linguistic review (it is not also required to send interim working versions of the product information before this point as eCTD) **


8. Decision (i.e. final amended documentation if any changes occur during the Standing Committee phase)

** Note also that it is not required that interim working versions of the product information documents exchanged during the linguistic review phase are followed up by an eCTD containing PDFs, or on hard media – only the original and final agreed translations should be submitted in this manner.

CONVERSION OF EXISTING APPLICATIONS TO eCTD Q1

A clarification was added about submission of reformatted documentation:

The submission of reformatted documentation (commonly referred to as a ‘baseline’ submission, although the corresponding eCTD DTD submission type value for such a submission with re-formatted information is ‘reformat’) should preferably occur simultaneously (but separately) with the submission of a variation, line-extension or renewal.

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RPS 2 News

On July 24th, 2008, a kickoff meeting was held at FDA's Whiteoak facility for Regulated Product Submission (RPS) Version 2. For those of you who have not been following RPS, it is a Health Level Seven (HL7) standard to facilitate the processing and review of regulated product information. The goal of RPS is to create a regulated product submission message that:

Is general enough to handle all regulated products such as drugs, biologics, medical devices, vet meds, combination products and food products

Allows sponsors to send regulatory information using predefined parameters to identify and catalog their content

Provides enough information to allow regulators to support structured review by providing the ability to consistently locate specific information

July's kickoff meeting was attended by over 50 representatives from the FDA, EMEA, Health Canada, MEB, PMDA, and a number of vendors and pharma companies, despite significant weather issues that caused flight delays and cancellations. The focus of the kickoff meeting was on requirements gathering and further refinements to scope (there is already a project scope statement, but it could benefit from more input from outside the US).

The group broke up into around eight teams to refine and add to specific requirements topics. Topics included Two-Way/Communicate Regulatory Action, Referencing/Within Docs/to External Warehouse, Forms Data, and several others.

Next steps for the initiative include:

Determining how to organize sub groups. Formation of a leadership team and organization of a development team, a testing team, etc. are being discussed. Issues around leadership (such as determining how decisions are made and who is responsible for what aspects) are especially important.

Continuing to push forward with requirements. FDA has PDUFA imposed deadline of September 2012 for implemenation of RPS 2, so consistent progress is essential.

Progress is being made through ongoing meetings. A biweekly meeting is held (on a rotating schedule to accomodate participants from time zones all over the world) to advance requirements. A weekly leadership currently has a focus on infrastructure and subgroups - progress on organizing the testing group being especially important right now.

If you would like to stay informed on RPS,you can receive updates via a list service by registering at Health Level 7 - Subscribe to List Services. Upcoming meetings and other events will be announced via the list service, and you can still participate in these meetings and events - membership and participation are not limited to a closed group.

Improved and Reorganized iRegulatory eCTD resource pages

Many of you have probably benefited from the "eCTD Resource Page" in the past. For both previous and new users, there's some good news - the site iRegulatory eCTD resource pages has been updated and expanded.

The site features basic background, links to regualatory agencies, vendors and other eCTD resource pages, and a discussion forum for posting comments or questions. It's a great opportunity for the eCTD community to exchange information, so I encourage you to check it out and post your comments or questions. (But remember I'm still looking for comments and responses to postings on this forum :-( since I haven't received any yet.)

Submit Documents With Tracked Changes?

Recently, I have come across several instances where applicants or regulators have discussed submitting documents with tracked changes. Clearly, there is some guidance for this in the area of EU and US labeling, but this was the first that I had heard of it potentially being done elsewhere in a dossier.

The first was at DIA, where Norman Schuff of the FDA recommended submitting Module 3 replacement documents with tracked changes shown.

Later, I encountered a sponsor that said that they needed to submit modified protocols showing tracked changes in the US., for their eINDs. They also indicated that some European authorities are asking for these "tracked changes" documents. The different authorities require some combination of this "tracked changes" protocol, an updated protocol incorporating amendments, and an amendments document (basically an errata listing and justifying changes).

I consulted several colleagues, and they all shared my thoughts - most sponsors go out of their way to ensure that documents don't contain tracked changes, several of them having been "bitten" in the past due to legal issues around retaining tracked changes. In fact, some have investigated techology solutions for removing tracked changes - for example, see the PleaseTech product PleaseErase.

For sponsors using EDMS and PDF renditioning tools, there may also be issues around generating renditions showing tracked changes, if the copy of MS Word on the rendition server is set up not show tracked changes. At best, it seems like something you would want to do "sometimes" - and rendition servers, like other computer elements, like to operate off rules.

Are any of you out there in the sponsor community submitting documents other than labeling with tracked changes showing? If so, I would love to hear your background and thoughts on this topic!

What's New in EU Module 1 Specification Version 1.3 (May 2008)

Europe recently made some fairly significant changes to eCTD Module 1 Guidance. You can see and download the specification, release notes, examples, and overall package at: http://esubmission.emea.europa.eu/eumodule1/. Look for an update from your publishing vendor as DTD and publishing tool changes are needed to support the new spec - and remember that EMEA has said that they require compliance by the end of 2008, so plan now for system updates and any validation impact they may have.

The following changes were determined by comparing the new EU Module 1 Specification Version 1.3 (May 2008) against the previous approved version 1.2.1 (October 2006).

Changes to Main Body

• Acceptability of XML for cover letter, variation form and renewal form.
  Inability to accept digital signatures.


• Instruction not to use placeholders for content sections that are absent, but to discuss in summary documents instead.


• Confirmation that files in M1 can be referred to in index.xml and files in M2-M5 can be referred to in eu-regional.xml.


• Additional guidance on the envelope, covering the “eu-envelope” values of "emea", "common" and specific member state values. (See the section Envelope.)


• Additional guidance on directory structure. The recommended directory structure for the use of country and language identifiers is described in Appendix 2. In general, Modules 1.0, 1.2, 1.3.2, 1.3.3, 1.3.4, 1.3.5, ‘Additional Data’ and ‘Responses’ have country subdirectories. Module 1.3.1 (Product Information) has both country and language subdirectories. (see the section Directory / File Structure.)


• Additional guidance on node extensions (finally). Discusses use, placement and nesting. (See the section Node Extensions.)

Changes to Appendix 1: Envelope Element Description

• Changes to agency element – has been changed from agency-name, mandatory, repeatable to an agency parent element and code, with the code mandatory and unique.


• Addition of new submission types (metadata valid values).


• Removal of the Country element under Related Sequence.


• Updates to guidance and examples around Related Sequences.


• Changes to Appendix 2: Directory / File Structure for Module 1


• Note that the operation attribute for the eu.regional.xml should always be set to ‘new’.


• Instructions on the placement of a “tracking table” (this is within the context of the Cover Letter). (See “MRP/DCP Tracking Table Description”, Version 0.1, May 2008.)


• Additional/clarified guidance on naming of labels for one language or multiple languages.


• Addition of element for 1.10 Information relating to Paediatrics.


• Instruction that “Additional Data” should only be used for information required for National, MR and Decentralised Procedures and not being applicable for the Centralised Procedure.


• Recommendation against the use of custom stylesheets.

Changes to Appendix 2.1: Destination Codes

• New destination (country) code Common


• Removed * stating that Bulgarian and Romanian languages should not be used before those countries join the EU.

What Does It Mean?

Some of these changes will be taken care of by your eCTD tool or in how it is used by your publishers. Others may require changes in your processes

• If you have been using placeholder documents, you will need to update your process to discuss "missing" documents in summaries (this is not really new - the authorities have been stating this position in meetings and presentations for some time)
• You may want to review your use of node extensions in organizing your clinical study documents
• You will need to introduce the "tracking table" for MRP/DCP
• Ensure that you are not using the "Additional Data" section for the Centralised procedure
• Review your use of metadata since new values and changes have been introduced
• Ensure that your procedures are in place for creating, reviewing and approving documents 1.10 Information relating to Paediatrics.

With the recent clarifications to the use of the Related Sequence in both US and EU, now is also a good time to make sure your team understands how to use this critical piece of metadata.

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Changes to CTD Guidance in Europe

Recently, a new edition of “Volume 2B Notice to Applicants: Medicinal products for human use: Presentation and format of the dossier Common Technical Document (CTD)”, Edition May 2008 (http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/b/update_200805/ctd_05-2008.pdf) was posted on EudraLex. This replaces the June 2006 edition.

In addition to updates and correction of references, the main changes in the Notice to Applicants are:

• Addition of 1.10 Paediatrics section
• Addition of a table to M1 for generics: OVERVIEW OF THE CHOSEN REFERENCE PRODUCT FOR COMPARABILITY
• Clarification on “report justifying that the application concerns a new therapeutic indication and that significant preclinical or clinical studies have been carried out in relation to this new indication” to be placed in 1.5.3 (Extended) Data / Market Exclusivity as needed.

Application forms were also re-issued - see http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol2_en.htm#2b.

Next posting will examine related changes to the EU M1 specification.