Under 21 CFR 314.81(b)(3)(i) for drugs and 21 CFR 601.12(f)(4)) for biologics, after a product has been approved, any materials that are intended to be used for the promotional purposes are required to be sent down to the FDA at the time of initial dissemination. These types of submissions must be accompanied by FDA Form 2253 Transmittal of Advertisements and Promotional Labeling for Drugs for Human Use and are often referred to as "2253 submissions".
Historically, these types of submissions were transmitted to the FDA in paper format. However, in 2015, with the update of the US Module 1 Specification, and the release of the draft guidance for Advertising and Promotional Submissions, sponsors were able to begin constructing and transmitting Ad Promo submissions in eCTD format. In June 2019, the final guidance was released, kicking off a 2-year grace period before it will be mandatory to submit select types of advertising and promotional submissions in eCTD format. 2253 submissions will fall under this mandate, so it is critical to use this time to understand the requirements assess your program's preparation.
In this article, we will take a look into the documentation required for 2253 submissions, along with the requirements specific to eCTD, and how you can translate them into a valid and compliant submission.
There are a few general requirements to keep in mind when submitting 2253s in eCTD format:
2253 submissions may not be bundled with any other NDA/BLA submissions (CMC Amendments, General Correspondence, etc.)
Materials intended to be submitted to consumers must be submitted separately from materials intended for health care professionals
Multiple materials can be submitted in a single 2253 submission, so long as the materials are all directed towards the same audience
2253 submissions may not be bundled with other types of Ad-Promo submissions (ex. Correspondence)
A cover letter in Module 1.2 or a 356h form should never be submitted
2253 Submissions should utilize version 3.3 of the US Module 1.
There are 3 main categories of documentation required for a 2253 form: a completed 2253 form, a copy of the Promotional Material, and copy of the most current version of the product label.
FDA Form 2253
As the name of the submission suggests, a completed 2253 form must be included. Sponsors should always be using the most current version of the form that can be found on the FDA's website. FDA provides detailed instructions on how to fill out this form. The 2253 must be placed in the eCTD structure in Module 1.1.
It is strongly recommended to utilize digital signatures when signing FDA forms. However, if this is not possible, and your organization uses wet ink signatures, ensure that you submit an unsigned version of the 2253 as well as the scanned signed form.
Promotional Material (clean/annotated)
For each material that is listed on the 2253 form, a clean copy of the material as it will appear to its audience should be provided. For each material, it will have its own separate folder in Module 15.2.1. The clean version should be placed in the subfolder Module 126.96.36.199.
It is also recommended by the FDA for sponsor's to supply an annotated version of the material that calls out each claim, and has an annotation that links directly to the source that can back it up. This annotated version would be placed in Module 188.8.131.52, and copies of the references would be placed in Module 184.108.40.206.3 and 220.127.116.11. However, it is important to note that this is only a recommendation, not a requirement. For more information on the publishing of an annotated material, check out check out WAYS' post regarding accelerated approval products.
Current Product Labeling
With every 2253 submission, there must be a copy of the current, approved product label submitted as new in Module 1.14.6. The preferred format for this copy of the label is PDF. Sponsors can either elect to physically submit the label with each 2253 submission, or create a cross reference leaf - either approach is acceptable, as long as a copy of the label appears in section 1.14.6 for the 2253 submission with a new operator.
As touched on in our previous post regarding accelerated approval products, there are several metadata requirements for Module 1.15 and its subsections. The table below clarifies the metadata requirements for a 2253:
Finally, the screenshot below provides an example of a final backbone of a 2253 submission:
WAYS recently hosted a free webinar as part of our ongoing Ad-Promo education series, touching on this submission type, as well as several others in the Ad-promo space - the full recording can be accessed at: https://www.waysps.com/on-demand-webinars
Finalized FDA Guidance: https://www.fda.gov/media/128163/download
Materials from previous CDER presentations on Ad-Promo in eCTD: