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".)

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.

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.

• 
  

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.

EMEA and PMDA Update at DIA

EMEA and PMDA provided an update on eCTD status at the traditional "Update on Regulatory Authority Experience" session.

Tim Buxton was the speaker from EMEA. He provided the following statistics on eCTDs received between July and December 2007:

• Centralised Procedure: 14 new applications, 80 variations
• National Procedures (as reported by national compentent authorities): 659 new applications, 611 variations

Tim also mentioned that seven EU authorities already accept eCTD only without paper.

Next, Tim discussed the new EU M1 guidance, which incorporates 24 change requests. Tim stressed that this guidance is mandatory by December 31, 2008, and that this is a hard deadline because the most significant change, which is related to pediatric information, is needed immediately (in the short term, put this in the "Other" slot in M1). He also mentioned that the new tracking table for MRP/DCP goes into the same slot as the cover letter.

To access the new M1 specification, see http://esubmission.emea.europa.eu/eumodule1/docs/EU%20M1%201.2.1/EU%20%20M1%201.3/EU%20M1%20Specification%20v1.3%20FINAL%20.zip

To access the underlying CTD Guidance "Volume 2B Notice to Applicants: Medicinal products for human use: Presentation and format of the dossier: Common Technical Document (CTD), see http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/b/update_200805/ctd_05-2008.pdf

Tim discussed the (relatively) new XML application. The EMEA has been disappointed that sponsors are not using it more extensively, and would like to encourage sponsors to begin using it as soon as practical.

Tim was asked about the intention of developing a submission gateway. The EMEA already has a gateway for ISCRs, similar to the FDA's. They plan on developing a gateway for eCTD, but are not able to announce a date at this point.

Yasuhiro Araki spoke next, representing PMDA. He presented the eCTD review process in detail. PMDA is ready and able to accept eCTDs and has developed tools and processes in support of eCTD, but as of May 2008 has received only 9 original applications (17 sequences) and 71 reference applications (100 sequences). Reference applications are essentially review aids with paper being the official copy.

Japan still needs paper for M1 and M2 - the main reason for thisis the use of external experts in the review process.

EMEA Announces Statement of Intent Regarding eCTD and eSubmissions

EMEA has reinforced its position on implementing the electronic-only submission of information in support of marketing authorisation applications in the centralised procedure, and, ultimately, implementation of the Electronic Common Technical Document (eCTD) as the required format for electronic submissions, in two new documents dated 22 January 2008:

• EMEA implementation of electronic-only submissions and eCTD submissions in the centralised procedure: Statement of Intent
• EMEA implementation of electronic-only submissions and eCTD submissions in the centralised procedure: Statement of Intent - Questions and Answers relating to strategic and general aspects of the implementation

Some key points in the Statement of Intent and accompanying Q&A include:

• From 1 July 2008, the EMEA will accept electronic-only submissions, either in eCTD format or non-eCTD format (eCTD is the recommended electronic format), with no additional requirement for paper copies. By the deadline, all national competent authorities must accept electronic-only submissions, the format for these submissions being eCTD.
• From 1 January 2009, the EMEA will strongly recommend electronic-only submissions, either in eCTD or non-eCTD format (eCTD is the recommended electronic format), and paper will be an exception to the general e-format recommended for any application.
• From 1 July 2009, the EMEA will strongly recommend eCTD-format electronic-only
  submissions. Paper and other electronic formats will be an exception to the general e-CTD format recommended for any application.
• The EMEA is committed to the eCTD as the preferred format for submissions. Submitting any other electronic format may affect the quality and speed of the procedure and the feedback received.
• The Statement of Intent does not mean that eCTD submission must be mandatory in each Member State by the deadline; merely accepted without paper.
• EMEA stressed that these points apply only to the centralised procedure.

Key provisions include the establishment of a central repository and a single review tool for eCTDs submitted using the centralised procedure, which are necessary steps to eliminate the need for hard copies.

The EMEA gave some recommendations on implementing eCTD in the EU, and also has promised a further Q&A document on practical and technical aspects of eCTD implementation in the centralised procedure. During the February 7th International Regulatory Update session at the DIA Doc Management conference, Tim Buxton of the EMEA stated that this guidance will include the detailed process for submitting eCTD to the EMEA and will also discuss digital signatures.

Another key point stated by the EMEA is "The vendor market in eCTD builder tools and consultancy on all aspects of eCTD preparation and submission is mature, and companies should research these options, if applicable, for engaging external expertise. The EMEA is unable to list or recommend specific vendors. However, companies interested in gaining more information relating to software should contact pharmaceutical trade associations active in the EU for details of existing eCTD Topic Groups."

The planning horizon for full electronic-only implemention is now approaching the minimum time in which eCTD readiness can be fully achieved. It's time for sponsors doing business in Europe to become fully prepared if they are not eCTD-ready right now.