Long-awaited final guidance has been released which confirms the Premarket Tobacco Product Application (PMTA) process for companies who intend to continue to sell e-cigarette products within the US market. This guide provides an overview of how recommendations differ from those previously outlined in the draft guidance, and considers what the latest changes might mean for businesses in this sector.
Final Guidance and clarity from FDA
The release of final guidance from the US Food and Drug Administration (FDA), confirms their expectations in terms of a PMTA. Our recent guide, What is a PMTA? explains what’s involved in a premarket tobacco product application, the types of businesses this relates to, the deadlines for submission and how to make a start.
In summary, the structure and general process for undertaking and submitting a PMTA has not changed. Likewise, neither has the brief, in terms of what the FDA would like businesses to demonstrate regarding their new products.
However, there have been changes in a number of areas, in terms of the types of studies FDA expect companies to undertake. Some new recommendations have been introduced whilst other recommendations have been scaled down or revised.
The list of Harmful and Potentially Harmful Constituents (HPHCs) FDA expects manufacturers to analyse in their products, as appropriate, has changed. Previously, there was a list of 29. Some have been removed, with others being added, so now the list stands at 33. And, depending upon your formulation, this number could be even higher, as the guidance also recommends testing for flavorants that can be respiratory irritants (as identified through your non-clinical studies). Our ENDS HPHCs - What's new and why article explains these changes in detail.
The behavioral surveys element of the human subject studies is now more important than ever - given FDA’s emphasis in the guidance on the requirement to understand if a product is likely to increase youth uptake and use.
In addition to potential use by youth or young adults, the FDA also seek clarification on a product’s likely impact on levels of use by other vulnerable groups.
For product analysis, FDA recommend data sets spanning a minimum of 3 different batches, with 7 replicates per batch (depending upon the variability demonstrated in the method validation). Previously the suggested number of replicates per batch was 10.
FDA do not expect applicants to conduct long-term studies (defined as those with a duration in excess of 6 months) to support an application.
In terms of biomarkers of potential harm and biomarkers of exposure, literature reviews are acceptable in place of clinical studies to provide information on the long-term health impacts of products.
Additional points to note
FDA will specify how many product samples they require and it’s important these are arranged as soon as possible. If samples are the last part of the submission to make it complete, FDA’s review period won’t begin until they receive the samples.
A new acronym appears in the guidance, namely APPH, ‘Appropriate for the Protection of Public Health’ – expect to become very familiar with this new term if you operate in the Electronic Nicotine Delivery Systems (ENDS) sector …
FDA continues to recommend full toxicology assessments of product ingredients, including flavors, so obtaining full ingredient listings will support FDA’s decision regarding APPH.
What do these changes mean for ENDS businesses?
So, no dramatic changes to the PMTA pathway. In FDA’s own words, “If you have taken measures consistent with the draft guidance, they will generally be consistent with the recommendations herein”. However, ENDS companies may be wise to consider the background and driving forces behind some of the changes that have been made.
Arguably, whilst FDA have clarified the importance they place on elements which determine APPH e.g. behavioral studies, they have also enabled a more streamlined pathway where long-term studies are not expected. Could this be leading to a shift forward in the submission deadline? In our recent article, ‘Maryland ruling – will this bring the PMTA deadline forward?’ the possibility of this is certainly something that ENDS businesses need to be prepared for.
To start putting plans in place for your PMTA submission, contact us to arrange a meeting to discuss your requirements.