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.