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Archive for the ‘eCTD Validation’ Category

News Roundup Part 1: Agency News

posted by Kathie Clark @ 8:32 PM
Thursday, August 12, 2010

Today’s post is a round-up of recent eSubmission-related news from the agencies, based on posts from my twitter account, www.twitter.com/kathie_clark.  Next time, a roundup of articles and conferences.

The regulatory authorities haven’t put out much in the way of major updates recently, but there have been some updates worth noting:

The individual agencies in Europe have also issued some updates:

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Top FDA Processing Issues with eCTD: A Recent Update

posted by Kathie Clark @ 8:15 AM
Wednesday, May 19, 2010

At a  GPhA/FDA Labeling Workshop on April 14, 2010, Virginia Ventura of CDER’s Office of Business Informatics presented CDER Update eCTD & Gateway Submissions.  Along with lots of other useful information, Ms. Ventura provided an assessment of the current Top Processing Issues with Esubs:

Description

Percent of total

Unable to extract info from PDF form (sponsor did not use fillable form)

52%

Missing form (356h, 1571 or 2252)

13%

Bad Characters (per eCTD Spec) in file or folder names

10%

Duplicate sequence (sponsor sent twice)

10%

“High” validation errors

7%

Media empty or corrupted

4%

Wrong application number in us-regional.xml

2%

Invalid submission type identified (eCTD submitted as non-eCTD or vice versa)

1%

Valid application number with incorrect type (combination is valid but not Sponsor’s application)

1%

 

Certainly, the high percentage of submissions not using fillable forms is startling – Ms. Ventura mentioned that most of these are ANDAs.  She spells out the solution for using 356h fillable forms (including their correct use with annual reports) – consult the presentation for details.  She also stresses that the correct use of fillable forms results in your submission getting to the reviewer much quicker (best case an amazing 10 minutes!).

The amount of High Severity validation errors is also concerning, as the presentation reiterates what the FDA has said before - High Errors = Submission cannot be accepted.  Therefore, up to 7% of these submissions may have been rejected, resulting in time off the PDUFA clock in many cases.

All of this serves as a wake-up call that validation and submission QC are more important than ever.  Be sure to read the presentation for more tips on STFs, QC of us-regional.xml, use of the gateway, and many other quality issues and considerations.

(1 Comment )

Agency News, Documents and Presentations (Recent eCTD and eSubmissions News Part 2)

posted by Kathie Clark @ 6:29 PM
Thursday, April 1, 2010

As promised, here is an expanded list of posts published recently on my twitter account, this time related to agency news:

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Update from the Regulators: Health Canada

posted by Kathie Clark @ 8:42 PM
Tuesday, January 5, 2010

Well,it’s back to business after the holiday break… and as promised, here’s my update on what’s happening at Health Canada.

At the recent DIA eSubmissions conference, Health Canada’s Vianney Caron presented an update on eCTD at Health Canada.

The E-Review Program

The purpose of Health Canada’s E-Review program is to support branch business processes throughout the health product life cycle across product lines using an integrated secure electronic environment that facilitates the exchange of information and conforms to international standards.

Health Canada has made a lot of progress in E-Review recently.  Important milestones achieved include:

  • Implementation of an electronic document management system (RDIMS) for Drug Master Files
  • Establishment of business process for receipt, validation, processing & storage of eCTDs, supported by SOPs
  • Initiation of a pilot providing remote users (e.g. teleworkers and external reviewers) access to electronic submissions via Citrix Web Office
  • Recent update of guidance documents (see my previous post Analysis: New, final Health Canada eCTD Guidance for Industry)

Regulatory Activities in eCTD Format

Metrics were provided on eCTDs received:

Cumulative through September of 2009:

  • Total number  of Dossiers: 205 (Pharmaceutical 182, Biologic 23)
  • Total number  of Regulatory Activities: 457 (Pharmaceutical 322, Biologic 126, Pharmacovigilance 9)
  • Total number  of Sequences: 2318

Totals for 2009 (as of September), received from 53 sponsors:

  • Total number  of Dossiers: 53 (59 in 2008)
  • Total number  of Regulatory Activities: 145 (151 in 2008)
  • Total number  of Sequences: 841 (748 in 2008)

Health Canada is not seeing a significant rise in applications and sequences received, such as has been experienced by the FDA and EMEA – perhaps because they still require at least part of the dossier in paper.  As of 2009, 8.7% of regulatory activities are received in eCTD format.

eCTD Validation

Sponsors are improving the quality of their submissions to Health Canada.  In 2009, 4.5% of sequences failed validation.  This is down considerably from previous years: 8.3% failed in 2008 and 11% failed in 2007.

Top 10 errors and warnings encountered during validation include:

1.    Inactive bookmarks -no link destination

2.    Inactive hyperlinks -no link destination

3.    External links -pointing to the folder or destination that does not exist in the folder structure on the CD/DVD. The folder or destination would only exist in the sponsor’s repository.

4.    Incorrect naming of the 3011 form; correct name is hc-sc-3011-en.pdf

5.    Unreferenced files in the index.xml or ca.regional.xml

6.    Life cycle management of the document: invalid file reference or no previous ID found

7.    Subfolders created in ca regional folder

8.    Missing top level folder

9.    Missing attestation letter; content as per eCTD Guidance, letter needs to be dated and signed

10. Printed content of MD-5 Checksum does not match the one in the index-md5.txt file

Preliminary Experience with eCTD

Health Canada reports that they have buy-in from all stakeholders, but no legal basis to make eCTD mandatory.  They continue to experience logistical and process issues.  Reviewers perceive that paper & electronic in parallel is difficult and the process is excessively manual.  Validation is perceived as an extra step.  Other review issues including understanding lifecycle management in the eCTD and dealing with scanned documents and resolution of graphics.

Some upcoming milestones include the retirement of hybrid submissions as of January 2010 (this month).  A date is yet to be announced for accepting fully electronic submissions.

Assessment of Hybrid Pilot

Health Canada surveyed reviewers participating in their hybrid pilot with some interesting results:

  • 41% say they are almost ready for submissions filed in the hybrid filing format, and 59% say they are totally ready
  • Using the electronic hybrid filing format, 44% of reviewers believed that their review/screening time remained the same and 39% believed that their review/screening time decreased.  50% believe that this format will save time in the future.
  • Reviewers recommended the following next steps: 47% wanted to continue the hybrid filing format, 24% wanted electronic only, and 29% wanted electronic only with Print on Demand
  • When asked if they would be comfortable with e-Only (no paper), 53 % would be very comfortable, 29% would be somewhat comfortable, and 18% would not very comfortable)

Next Steps at Health Canada

Health Canada defined their next steps as:

  • Opening the scope to more electronic submissions
  • Revising the DTD and guidance for the Canadian Module 1
  • Implementing two-way secure electronic communication (secure channel, secure email and gateway)
  • Improving their tracking system and integrating it with a workflow system
  • Strengthening international collaborations

Health Canada closed by saying that they strongly recommend electronic submissions in eCTD format, and support the development of common standards.  They will be expanding the existing infrastructure to support as many application types across product line as possible.  Questions can be sent to them at ereview@hc-sc.gc.ca.

(1 Comment )

EU Issues Updated Validation Criteria (minor changes)

posted by Kathie Clark @ 8:38 PM
Tuesday, May 5, 2009

Today, EMEA posted an updated version of EU eCTD Validation Criteria (V2.1) on their eSubmissions: What’s New page.

Changes are minor and include:

  • Introduction of new check 11: “The checksum of the index.xml, when calculated by the validation tool, should match the checksum provided in the index-md5.txt” [This is pretty straightforward and was already being checked at the FDA.]
  • Change in the category of check 10 “The regenerated checksum for every referenced file is the same as each associated checksum provided in the backbone file (e.g. eu-regional.xml)” from A (Serious) to C (Low).  [This in general appears to support a trend in regulatory agencies not placing much importance on checksums – possibly based on the fact that external tampering with eCTDs submitted to an authority is highly unlikely either with gateway submissions or hard media submissions.]
  • Re-numbering of existing checks 11-44 based on the introduction of new check 11
  • Replacement of reference to EU DTD 1.2.1 with 1.3

Overall, the comment was that the criteria were updated “to explicitly support EU M1 v1.3 and to include a new criterion no.11 on the calculation of the checksum.”

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FDA eCTD Rejection (“Failure to Receive”)

posted by Kathie Clark @ 10:47 PM
Friday, March 6, 2009

At the DIA Doc Management conference, the FDA presenters spoke with one voice on their intention to start rejection sequences that have what they consider significant technical flaws.

Gary Gensinger reviewed the guidance that has been issued by FDA on this topic (see my previous post) and the three types of eCTD Validation:

  • Automated Submission Receipt (ASR) Validation – automated step performed as your submission is accepted and loaded into CDER’s tracking system  
  • eCTD Tool – detailed automated technical validation performed after the submission has been registered with the tracking system.  The FDA uses GlobalSubmit VALIDATE 5 for this validation.
  • Qualitative Validation – checks performed by staff members for problems such as TOC issues, bookmark and hyperlink issues, or dataset problems

The most common problems encountered during ASR validation include:

  • No Electronically Fillable Form Found (Gary noted that the lack of a fillable form essentially turns your gateway submission into a media submission and slows its availability to the reviewers)
  • No 356h, 1571, or 2252 Form Found
  • Unable to determine location of form
  • Application number in us-regional.xml and form do not match
  • Mismatch between application type and form

The eCTD tool validation done with GlobalSubmit VALIDATE 5 enforces the criteria defined in Specifications for eCTD Validation Criteria.  For those of you who have received validation reports back from FDA, those reports were generated directly from GS VALIDATE.

Virginia Ventura also discussed validation in her presentation “CDER eCTD & Validation, Issues Update”.  As always, Ginny’s presentation gave helpful, practical advice. Ginny gave the following as top reasons for rejection:

  • Duplicate Submission
  • us-regional.xml / form mismatch
  • us-regional.xml cannot be read / nonstandard eCTD
  • Sent to the wrong Center
  • Portions sent outside the eCTD (extra folders with non-referenced files)
  • Empty folder      

In discussing rejections, she made the following points:

  • Rejections will be communicated by fax to the fax number indicated in your cover letter
  • If the submission is a gateway submission, rejection will also result in a return gateway message – check your inbox!
  • If your Module 1 is incorrect, do not be surprised when your submission is rejected! CDER will not correct your Module 1.            

Separately, we have been hearing that FDA already stepped up the rejection process.  Below is an example of the rejection notice issued by FDA for technically deficient submissions. 

 

Rejection Notice

 

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FDA to begin rejecting eCTDs for significant technical issues

posted by Kathie Clark @ 2:29 AM
Wednesday, January 21, 2009

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 and CDER in late November.

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.

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

posted by Kathie Clark @ 12:19 PM
Tuesday, November 25, 2008

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.

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Common eCTD Mistakes - as Described by FDA

posted by Kathie Clark @ 1:22 AM
Friday, November 7, 2008

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…

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