USFDA eCTD Module 1 v2.3: Considerations for Transition

Introduction

One of the biggest changes to the electronic common technical document (eCTD) in the past few years was the introduction of the United States Food and Drug Administration’s (USFDA) newest module 1 specifications and corresponding technical files. The new specifications v2.3 and the XML Document Type Definition (DTD) v3.3 were developed to enhance USFDA’s ability to process eCTD submissions and enable additional submission types that were previously not accepted in eCTD format.

After a lengthy testing period, USFDA began accepting submissions using the new v2.3 specifications in June 2015 and has now received thousands of submissions using the new module 1. While uptake has been good, most submissions were applications being submitted to USFDA for the first time, starting from a clean slate with the new specifications.

Transitioning existing applications to the new module 1 adds complexity to eCTD publishing but should not be treated as roadblock. Here we will discuss preparing existing applications for the transition and ways to smooth the process for a successful transition.

Advantages of the New Module 1

Prior to the updated module 1 specifications, the Center for Drug Evaluation and Research (CDER) Office of Prescription Drug Promotion (OPDP) was not able to receive submissions for promotional labeling and advertising in eCTD format. Submissions were either sent in paper format or in a mixed paper and electronic format on physical electronic media. The reviewers lacked a tool to view the submissions in the context of the application and the other advantages of the eCTD format like life cycle on documents and the efficiency of receiving and processing the submissions through the Electronic Submissions Gateway (ESG) and access in the Electronic Document Room (EDR).

The inclusion of promotional labeling and advertising submission in the eCTD environment was more than enough reason for USFDA to update the specifications, as there is a high volume of these submission (in a recent calendar year, CDER’s OPDP received 46,494 Form FDA 2253 submissions), but there are some additional advantages realized by USFDA with the new module 1:

  • Additional regional administrative information for automated processing of submissions
  • Clear submission hierarchy in tracking systems based on the submission-id
  • Ability to accept grouped submissions
  • Ability to update regional submission metadata independent of the DTD

The last bulleted point above is significant. Prior to the new module 1, USFDA was not able to keep up with new submission types or forms that were required to be submitted in the eCTD. Previously these values were hard coded into the DTD file and each time an update was required (e.g. a new form was introduced), it would be necessary to update the DTD to create a new section or to update the hard coded metadata. This prevented updates to the specifications as any update to the DTD would be extremely disruptive to the publishing operations of industry. New forms were routinely submitted in the cover letters section, and this section became a placeholder for any documents that were left without a home.

The new module 1 specifications, v2.3, changed this shortcoming by introducing separate “attribute lists” to handle attributes like submission types and form types. The design of modern eCTD publishing systems allows these lists to be treated as external vocabulary files that are not hard coded into the software. An update to the vocabulary files does not require substantial changes to the software to enable the use of a new form type. Only the attribute file itself must be changed. This allows eCTD software vendors to be faster to production with changes after USFDA releases a new attribute.

The use of grouped submissions is also a benefit that can be realized by industry. Imagine a product price catalog that must be submitted to OPDP. Without grouped submissions, the same documents would need to be prepared and transmitted numerous times, requiring the submission of a separate eCTD sequence to each application. The concept of grouped submissions will now allow a firm to prepare documents once in eCTD format and apply it to multiple applications on the OPDP side in a single transmission. There is potential for saving a large amount of work in regulatory operations after gaining experience with using grouped submissions.

Considerations for Transition

Building Regulatory Activities

Each sequence sent to USFDA in the new module 1 must be assigned to a single regulatory activity. This is accomplished via the newly introduced submission-id element. The submission-id has a similar function to the related-sequence-number element that it replaces, but the business rules for using submission-id are now more clearly defined, reducing the opportunity for error.

A common submission-id is used to group sequences into their respective regulatory activity. For example, a meeting request sent to a New Drug Application (NDA) might be the first submission to a new application. This is sequence number 0001 and it is also submission-id 0001 signifying the beginning of a new regulatory activity. In this case the regulatory activity or submission-type is the original application and the submission-sub-type is presubmission. The next submission to our example is a meeting briefing package and its sequence number is 0002, but it still belongs to the original application regulatory activity, so the submission-id remains 0001. Finally, sequence 0003 is the application itself, and it also belongs to the original application regulatory activity, so the submission-id remains 0001.

 

Description submission-id sequence-number submission-type (regulatory activity) submission-sub-type
Meeting request 0001 0001 original application presubmission
Meeting briefing package 0001 0002 original application presubmission
Application 0001 0003 original application application

 

Understanding that the submission-id is used to group sequences into their correct regulatory activity is key to success in the new module 1. The module 1 specifications (v2.3)[1] contain more examples of this grouping and there are presentations[2] archived on the USFDA eCTD website that deliver even more explanation for the use of submission-id.

The Transition Message

Whether transitioning directly from paper to the new module 1 or from an existing eCTD using the v1.3 specifications, there are a few vital details to consider to prepare the transition message. USFDA has published a helpful document titled the eCTD Technical Conformance Guide[3] that provides the relevant technical details.

The following are excerpts from the eCTD Technical Conformance Guide:

When transitioning to eCTD format, do not resubmit documents already submitted in paper or other electronic format. Provide only new or changed information. For example, if your original application was submitted in paper in 2010 and now a supplement will be submitted to the application in eCTD format, you should not resubmit electronic copies of documents and eCTD backbone files for the previously submitted paper files.

In general, it is not necessary to resubmit information. For a Drug Master File (DMF) that is transitioning from paper to eCTD it is acceptable to resubmit the entire DMF upon conversion, but it is not required.

Transitioning from Paper to eCTD using us-regional (DTD) v3.3: The initial eCTD submission should be coded according to the current regulatory activity. The submission-id should match the sequence number of the transition sequence.

If the transition submission is an amendment to the original application (continuing an existing regulatory activity), the submission should be coded as original application for the submission-type, application for the submission-sub-type, and the submission-id and sequence number should match. FDA prefers 0000 for the submission-id and sequence number when transitioning from paper. Sequence numbers should generally be continued consecutively after the transition.

If the transmission submission is starting a new regulatory activity, like a new supplement or annual report, the transition message should be coded as appropriately for the submission-type (e.g. efficacy supplement or annual report) and the submission-id and sequence number should match.

Transitioning from us-regional (DTD) v2.01 to us-regional (DTD) v3.3: The initial eCTD submission should be coded according to the current regulatory activity. The submission-id should match the sequence number of the initial eCTD submission to that regulatory activity. It is important to use a value for the submission-id that exists as a us-regional v2.01 sequence that has already been processed in the application.

If the original application was submitted as sequence 0000 using DTD v2.01 and the transition is being made with the first amendment, the transition message should be coded as an amendment to the original application and use the submission-id of 0000 and sequence number of 0001. Using the submission-id of 0000 ensures that the amendment is correctly associated with its relevant regulatory activity in the review system.

If the transition message from DTD v2.01 to DTD v3.3 is a new regulatory activity like a supplement or annual report, the submission-id and sequence number of the transition will match, indicating that a new regulatory activity is starting.

Promotional Materials

In order to submit promotional materials in eCTD format to CDER’s OPDP, it is necessary to transition the application to the new module 1. Documents for promotional materials are primarily submitted in section 1.15 and there are numerous business rules surrounding building these submissions and the correct use of attributes. Again USFDA has provided some helpful documentation to guide the publishing process. The first document is the Draft Guidance for Industry: Providing Regulatory Submissions in Electronic and Non-Electronic Format—Promotional Labeling and Advertising Materials for Human Prescription Drugs.[4] This draft guidance outlines the authority behind requesting promotional material submissions, the content required for each type of submission, and provides examples of values for the various attributes required to describe the submission and documents.

The submission of promotional materials in eCTD format will be mandatory. When the draft guidance referenced above is made final, a 24-month clock will begin. At the end of that time period, CDER and CBER will require certain promotional material submissions in eCTD format:

  • Promotional materials submitted in fulfillment of the postmarketing reporting requirements (i.e. Form FDA 2253 submissions or “2253 submissions”)
  • Presubmission of promotional materials for accelerated approval products

While some promotional material submission types will not be required, USFDA strongly encourages firms to submit these other types of promotional material submissions in eCTD format.

The best technical resource for preparing promotional material submissions published to date by USFDA is a presentation titled FDA Update: Submission of Promotional Materials.[5] This presentation covers both the content and format for submissions and general considerations applicable to promotional material submissions.

Managing Sequence Numbers

Many firms have separate publishing groups that handle the creation and submission of promotional material submissions. Once these submissions transition to the eCTD format, these groups will require training on various eCTD tools and processes. With the high volume of promotional material submissions, it will be necessary to create a plan to manage eCTD sequence numbers across the various publishing groups. Any duplication in eCTD sequence numbers will result in a rejection of the duplicate submission by USFDA.

If a single publishing group is designated to handle both promotional and non-promotional eCTD submissions, the issue is minor and normal submission planning activities should prevent duplication. Unlike some other regulatory authorities, USFDA does not require sequence numbers to arrive consecutively, i.e. it is acceptable to submit sequence out of order. Firms can choose to designate a block of eCTD sequence numbers to be used only for promotional material submissions (e.g. starting with sequence number 5000 for promotional material submissions). This will ensure that sequence number collisions do not occur as each group can manage their assigned block separately.

Conclusion

Transitioning to the new USFDA module 1 seems challenging and maybe even daunting at first. There are new pieces of metadata to manage while preparing submissions (e.g. a corporate D-U-N-S number and contact information). The good news is that these values are reused from submission to submission. Once the correct information has been identified it will not likely change.

A transition is required for each application and it is not possible to downgrade back to the older specifications and DTD. Once a submission has been made using the new specifications, all future submissions to that application should also use the new specifications. Since the new module 1 will eventually be required for marketed products, it is advisable to start preparing for transition now to gain experience with the new structure, metadata, and tools for publishing.

Support for the new USFDA module 1 began in LORENZ docuBridge® in April 2014. In the months and years since, further improvements have been made to enable a smooth transition and LORENZ continues to identify additional features to unlock the full potential of the new specifications.

 

[1] http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM163552.pdf
[2] http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm229642.htm
[3] http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM465411.pdf
[4] http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM443702.pdf
[5] http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM448757.pdf


Jared Lantzy
Written by Jared Lantzy, Manager Global Regulatory Agencies and Processes at LORENZ Life Sciences Group.

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