Updated: May 19
Background on Subpart H/E Products
For life-threatening diseases where there is no current marketed treatment, the FDA may allow for an accelerated approval under section 233 506(c) of the FD&C Act, 21 CFR 314 (subpart H) for drugs, and 21 CFR 601 (subpart E) for biologics. In these cases, the approval could potentially be granted based on early Phase I/II clinical data.
Products falling under subpart H/E are required to have all Advertising and Promotional items reviewed by the FDA before dissemination is allowed. As mentioned in our previous post, with the implementation of the final guidance, it will be mandatory for these submissions to be in eCTD format in June of 2021.
Before marketing approval is granted, sponsors must submit any materials intended to be disseminated within the first 120 days following approval. These are known as Presubmission Accelerated Launch submissions.
After marketing approval is granted, and following the initial 120 days post-approval, sponsors must submit any new materials a minimum of 30 days before the intended circulation date, to allow for agency review and feedback.
Once materials are finalized, the traditional formal Final 2253 submission is required.
In this article, we will take a deeper dive into the first submission type listed above, and demonstrate how the requirements listed in the FDA guidance translate into the compilation of an eCTD submission. Note: we will be specifically referencing sections unique to the Module 1 US v3.3 specification, as that will be the required format for both CDER and CBER after the transition period.
Constructing Presubmission Accelerated Launch Submissions
As mentioned above, the first critical Ad-Promo submission for a Subpart H/E product must occur before the PDUFA date, and contain all materials intended for release in the first 120 days following marketing approval. As with all Ad-Promo submissions, materials targeted towards Health Care providers must be submitted separately from those targeted towards consumers and should not be combined with any other documents to be submitted to the marketing applications. This means that there are likely two simultaneous submissions to prepare: one containing materials for professionals, and another for consumers.
Similar to the standard cover letter, sponsors should include a correspondence document that addresses the nature of the submission, and includes a list of all materials being submitted. This will be placed in Module 18.104.22.168. Section VI.E of the guidance goes into greater detail on what should be included in this document. This element should not be a submitted in Module 1.2 – all promotional related correspondence needs to fall under Module 1.15.
All materials will be grouped under a Module 15.2 folder specifically indicated for “Presubmission Accelerated Launch.” Each individual promotional piece will get a separate Module 15.2.1 folder with the following subsections:
Module 22.214.171.124 – Should contain the clean version of the piece, as it is intended to appear in distribution.
Module 126.96.36.199 – Should contain an annotated version of the piece, with clear references (specific page numbers/ sections) to the source of the claims, either in the FDA approved PI or other reference sources. Annotations should be linked out to the reference files contained in 188.8.131.52 & 184.108.40.206 – not to files located within the eCTD structure of the marketing application.
Module 220.127.116.11 – Should contain the most current version of the FDA approved PI, with highlights on the supporting information referenced in the promotional piece. Note: even if the annotated version does not reference any part of the PI, a full copy of the PI should be submitted in this section.
Module 18.104.22.168 – If applicable, any other references that support claims made in the piece that are not contained in the PI. References should be submitted as separate PDFs, with the supportive information highlighted.
For CBER Products only, a 2253 form should be provided in Module 1.1 with all materials listed, and Box 14 filled out to indicate this is a “Draft” submission. Do NOT submit a 2253 form for this submission type for CDER products. For both CDER and CBER products, a 356h form should not be submitted.
Note: Per the US validation criteria, annotations are traditionally not allowed in PDF files, and must be made permanent in the document. However, Module 1.15 is exempt from this rule – annotations can be present in the form of comment boxes in Adobe without issue.
As with any eCTD submission to a marketing dossier, the standard submission level metadata elements should be provided: Company Name, DUNS number, Application Number, Applicant Contacts, Submission Type/Subtype, and Submission ID. Notable for this particular submission type:
“Submission Type” should be “Promotional Labeling Advertising”, Subtype should be “Original.”
Ad Promo submissions MUST have a named labeling contact
Submission ID for any Original Promotional Labeling Advertising Sequence should match the sequence number
The “Submission Description” field should be informative to the reviewer – see section VI.A of the final guidance for specific suggestions from the agency
One thing to note about all types of Ad-Promo submissions, is that the Module 1.15 Folders require additional metadata. The table below highlights the required elements, and how they should be populated for a Presubmission Accelerated Launch sequence.
The screenshot below gives a visual for how this structure comes together to form the eCTD backbone. The required metadata fields for Module 1.15 and its subsections are noted in red text.
Pre-launch submissions for Subpart H/E products can be large and time-consuming to prepare. They tend to be finalized closed to the PDUFA date, which is often a pressing time for sponsors as they also are responding to the agency’s final inquiries. As these products are rare, it can be intimidating to properly prepare these submissions for the first time with confidence. The WAYS staff is well-versed in this area, and can provide expertise and guidance to ensure a high quality final product.
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