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.

Update to FDA Guidance

On June 11th, 2008, FDA issued a Revision 2 of "Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications" (http://www.fda.gov/cder/guidance/7087rev2.pdf). The previous version, Revision 1, dated from April 2006.

So what's new? Very little.

The updates are all administrative in nature, and basically consist of:

• Revisions to title page for FDA's new address
• Minor revisions in language to remove references to hybrid submissions and eNDAs, which are no longer accepted without a waiver
• Updated reference to ICSR guidance in the Periodic safety update reports section

The latter update is merely the replacement of the previous text:

"You should provide bookmarks for each of the sections and subsections of this report. ICSR and ICSR attachments should be provided as described in the guidance for industry Providing Regulatory Submissions in Electronic Format — Postmarketing Periodic Adverse Drug Experience Reports. "

with:

"ICSR and ICSR attachments should be provided as described in FDA’s guidance for industry on electronic submission of postmarketing ICSRs (Available under the topic "Electronic Submission" on CDER and CBER’s guidance Web pages)."

One anticipated change that did not appear in this document was the decrease of the maximum recommended path length. ICH/FDA guidance currently states that the path length can be up to 230 characters. However, for those using the gateway to submit, the gateway adds characters to the path. FDA said at DIA in June that they recommend limiting the path to 150 characters, and reminded the audience that FDA reviewers do not see the folder names so their significance in the US is minimal. Path length problems can result in documents not being seen in the agency's viewer because it is not given all of the necessary information.

ANDA Checklist

Another fairly recent CTD/eCTD related update was the revision of the ANDA checklist on May 28th. (the previous version was dated October 17, 2007). It is posted as PDF (http://www.fda.gov/cder/ogd/anda_checklist.pdf) and MS Word (http://www.fda.gov/cder/ogd/anda_checklist.doc). The Word version is more useful as the PDF is not a fillable form. Changes here include:

• Addition of the Model Bioequivalence Data Summary Tables in 2.7
• Removal of the requirement for MS Word for 5.2 Tabular Listing of Clinical Studies

This brings up a topic that not everyone is aware of - the OGD wants MS Word versions submitted for the QOS and Clinical Summary (Bioequivalence). In presentations, their reviewers have also said that they prefer the QOS submitted as a single document, rather than in modular components.

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.