Friday, January 23, 2009

The eCTD Summit is moving!

We are re-locating The eCTD Summit to a new location that will allow us to provide additional content such as RSS feeds, upcoming events and more.

From now on, no new posts will appear on this site. New posts will appear on:

http://theectdsummit.com/summit/

Please visit us there, bookmark the page, and sign up for an RSS feed so you will be automatically notified of new posts!

Kathie

Tuesday, January 20, 2009

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.]
  • Friday, January 9, 2009

    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".)