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.]