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FDA Module 1 Grouped Submissions Q&A

Editor’s Note: Below are responses to the questions submitted by members of industry during GlobalSubmit’s Module 1 Education Series – Grouped Submissions Webinar on June 23, 2015. For the sake of comprehension and as a nod to the M1 fatigue you may be feeling after this month’s crash course, we’ve split our responses into Part I and Part II.

1. What is the difference between grouped submissions and a Trans-BLA?
A trans-BLA was a grouped submission before grouped submissions were enshrined in the M1 specification.

For anyone unfamiliar with the term, a trans-BLA was a CBER concept. A single lead application with content would be chosen and that content would be applied to each BLA affected administratively. The process obviated the need for separate identical submissions, eliminating duplicate data entry, and enhancing efficiency.

The introduction of grouped submissions allows for multiple BLAs to be grouped formally using the new technology and administrative functionality. Content for each affected BLA will now be fully displayed.

2. What is the difference between sub ID and sequence number?
By implementing the new Module 1 specifications, the FDA has introduced the concept of a constant submission-id to help sponsors build regulatory activities. The sub-id concept does slightly change the way we think about sequence number.

Sequence number was not done away with – the number must be unique within the application and include 4 digits.

A submission-id is a sequence number, in fact, it’s the first sequence number for each “new” regulatory activity. The submission-id remains the same for the purpose of building regulatory activities.

In the chart pictured here, sequence number 1004 represents a pre-submission meeting request for a labeling supplement. As the first sequence number in a “new” regulatory activity, the sequence number becomes the submission-id.

Table 1: The relationship between Sub ID and sequence number is a hierarchy
Table 1: The relationship between Sub ID and sequence number is a hierarchy

The relationship between submission-id and sequence number taken directly from The eCTD Backbone Files Specification for Module 1 reads:

“The submission-id element is used to identify each individual regulatory activity (original application, supplement, annual report, etc.) in an application. All submissions that belong to a specific regulatory activity (for example, a supplement and all amendments related to that supplement) should contain the same four (4)-digit number in their submission-id element. The 4-digit submission-id number for each regulatory activity is determined by the sequence-number of the first submission to each new regulatory activity.”

3. When grouping Promotional Labeling and Advertising submissions, can the sponsor submit a single 2253 form or are they required to submit one 2253 form for each application?
Sponsors are only required to submit one 2253 form for grouped Ad Promo submissions.

The OPDP guidance states, “For cases where promotional materials mention multiple products, please note the lead application number on Form FDA 2253 and include an attachment which identifies the other referenced products (e.g., application type and number, trade name, established name).”

4. Is the double folder the only indication of a grouped submission or is there an indication next to each file too?
In GlobalSubmit’s eCTD publishing software, a double folder icon next to a sequence in the main navigation pane tells us that sequence is part of a grouped submission.

There are a few other indicators. If you select Sequence Properties from the main navigation menu, you are directed to the GlobalSubmit Application Wizard. Here all submissions belonging to a group are displayed in the Regulatory Activity In field. The hyperlinks in blue are active, and selecting one will open that application.

Figure 1: Grouped Submissions as displayed in the Regulatory Activity In Field
Figure 1: Grouped Submissions as displayed in the Regulatory Activity In Field

The inventory grid in our Details Pane lists all file references in the selected section. One column in the grid displays the sequence that files is located in. A double folder icon again appears next to a sequence that’s part of a grouped submission.

5. Can grouped submissions be created for applications to the EU and Canada?
The US FDA’s introduction of grouped submissions has no bearing on the specifications in other regions around the world. US FDA applications cannot be grouped to applications being sent to either the Europe (EMA) or Health Canada.

EMA does have centralized procedure eCTD submissions that are made available to National Component Authorities (NCAs) via the Common Repository, thus removing the need for additional copies of each submission.

6. Is it allowable to group Original Applications (IND or NDA) or only supplements, amendments, correspondence, etc…?
Theoretically you could group original applications. However, the Agency is reluctant to endorse doing so. The belief is that differences in module 5 attributes, like indications, would make it impossible.

The current FDA specifications governing grouped submissions state that Application Type and Submission Type have to agree. Accordingly, you would have no trouble grouping NDA labeling supplements. The table below lists recommended uses from the FDA on how grouped submissions. The table can be found in eCTD Backbone Files Specification for Module 1.

Table 2: Recommended Uses of Grouped Submissions per FDA Guidance

7. If you built a Grouped Submission in sequence 0001 and this was not the primary application, sequence 0001 for this application is false. The primary submission is in a different application. A week later, you are submitting 0002 within the application that had false 0001 and it is not grouped. You need to hyperlink to 0001. Can you hyperlink to a document in the 0001 false submission or do you have to do a cross application link to the primary/true 0001 submission?
In this scenario, we’ll say the primary grouped submission is NDA 777999 Sequence 0009. The primary submission was grouped to NDA 555678 Sequence 0001, which has a value of “false” for the application-containing-files attribute.

A week later, you are submitting NDA 555678 Sequence 0002, which is not grouped to the primary or “true” grouped submission.

Speaking only to the capability of GlobalSubmit’s eCTD publishing and review tools, in theory you could do either. Linking to the document in the “false” submission would point the FDA reviewers to the database containing the files. If you choose to create a cross application link to the primary submission, then you would be linking directly to the application containing files.

As a best practice, the Agency would rather a sponsor create a link within the same application rather than linking to another application.

8. Our INDs are currently in paper. Can we use “Grouped Submissions” to submit our eCTD “anchor” submission?
Yes. Grouped submissions could be used to submit an eCTD “anchor” submission for INDs previously submitted in paper.

An example would be a sponsor with three distinct IND applications using the grouped submissions functionality to apply the same annual report to each application.

Note that certain procedural requirements must be met in order to successfully transition an existing application from paper to electronic format. Read the details in an archived eCTD Summit Blog post by clicking the link below.

Transitioning an Existing Application to eCTD (Published January 22, 2013)

9. Can you specify the difference between sequence number and sequence type?
A lot of the information we’ve reviewed as part of the Module 1 Education Series has to do with the FDA guidance documents related to the new M1 specifications. We’d like to stress that while a complete understanding of the Agency specifications and intent behind those specifications is very helpful, you can also rely on the sophistication of your eCTD software system to compensate for any gaps in understanding.

Imagine you are creating a new sequence in an existing application. GlobalSubmit’s software would prepopulate the sequence number based on the previous sequence you created. In our example, you can see the sequence number is 0010 (unique to the application, 4 digits)

Figure 2: The GlobalSubmit Application Wizard shows Sequence Number and Sequence Type
Figure 2: The GlobalSubmit Application Wizard shows Sequence Number and Sequence Type

Sequence type available in the dropdown is contingent upon the Regulatory Activity selected. GlobalSubmit’s Application Wizard is intuitive and determines the dropdown selections for you. An Efficacy Supplement gives Sequence Type options of Presubmission, Application, Amendment, and Resubmission.

10. How do you lifecycle documents submitted not as the Primary application?
In GlobalSubmit’s eCTD publishing software, performing a lifecycle operation on files in any application or sequence belonging to a grouped submission will apply broad to all other grouped submissions. The technology doesn’t dictate that lifecycle operations only be performed in the primary application.

When you’re working in an application that’s part of a grouped submission and you perform lifecycle operations on files that are not included in the grouping, no other files would be modified.

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