The Substantive Review Process:
Once a premarket tobacco application has been accepted and filed by the FDA it moves to the substantive review phase where a team of FDA subject matter experts perform a comprehensive review to determine if all the necessary information is present. If there are gaps in the application, the review team will document these in a deficiency letter that is sent to the submitter. Submitters should not be surprised when a deficiency letter is 15 pages or more with dozens of points being listed. At this point the review process is paused while the submitter responds. Typically, no more than 90 days are provided to respond, during which a strategy to address each FDA concern must be developed, any additional testing or studies must be conducted, and additional publishing to integrate the new information into the application all must be completed. When the additional information has been received by the FDA the review process will resume. A marketing order decision will made based on this information and this information only. The application including amendments generated in response to the deficiency letter must collectively demonstrate that the product(s) included in the application meet the public health standard mandated in the Tobacco Control Act.
Common Application Deficiencies:
- Formatting Errors – Inconsistent formatting and common publishing errors are often cited as reasons for a Refuse to Accept (RTA) or Refuse to File (RTF) ruling, but deficiencies can also be cited if the FDA review team does not understand how an application is organized and/or cannot find all the information that is referenced within an application. The FDA is accustomed to reviewing applications that are submitted in a familiar format to them, so conformance to formatting protocols during authoring can be impactful in facilitating FDA application review
Potential observations:
- Body of application does not conform to the eTTD format and required content plan
- Missing supporting documents or supporting documents that cannot be opened
- Improper hyperlinks
- Information in a supporting document that is out of context
- Information in a supporting document that does not refer to the proper product
- Missing or inadequate reviewers guide
- Typographical errors in critical modules
- Product Testing – The FDA requires basic analytical testing to be performed on all new tobacco products to enable an assessment of product safety. This includes, but is not limited to, measurements of basic constituents such as nicotine, Propylene Glycol (PG), and Vegetable Glycerin (VG), testing for constituents contained on the published abbreviated Harmful and Potentially Harmful Constituents (HPHCs) list (aerosol), water activity, pH, and microbial load (including endotoxins).
Potential observations:- Omitted or incomplete testing without scientific justification
- Test method validation shortcoming
- Use of laboratories without the proper credentials
- Scientific assessment of the analytical data is missing or is inadequate
- Insufficient Bridging Arguments – The FDA allows reduced testing if appropriate scientifically supported bridging arguments can be made to other similar products that have been fully tested. Sound bridging arguments are most relevant for two products that share common attributes. A full explanation of how the products in question are similar, combined with supporting data collected on both products, is required to demonstrate the validity of the bridging argument. Bridging is best supported using one full data set as a foundation and a smaller data set demonstrating product similarities as measured in a subset of testing.
Potential observations:- Insufficient shared chemical and/or physical properties to support a bridging argument
- Insufficient description of shared properties to a support bridging argument
- Insufficient data to scientifically support a bridging argument
- Inadequate Manufacturing and Quality Control Systems – An applicant must demonstrate, through documentation, that the manufacturing and quality control systems used to make a product are adequate to consistently produce a product that meets the product specification and is safe for consumer use.
Potential observations:
- Missing or incomplete standard operating procedures and work instructions
- No process or equipment validation performed
- Missing or inadequate product stability and/or release testing
- Missing or inadequate product release testing
- Missing or inadequate control of raw material suppliers
- Missing or inadequate process change control
- Adverse event reporting procedure is missing or not compliant
- The included controls were not in place during the production of samples used in application related testing
- Missing or inadequate systems in place to meet periodic reporting requirements
- Marketing – Because of the addictive nature of tobacco products, the FDA is keenly interested in understanding how these products are labeled, marketed, and advertised. The FDA has issued guidance on Tobacco Product Perception and Intention (TPPI) studies that should be conducted on your products to demonstrate compliant labeling, advertising, and marketing, that the targeted consumer demographic is age appropriate, that the targeted consumer is a current user of tobacco products, and that the product is not designed to attract new or underage users.
Potential observations:
- Marketing and advertising plan includes using social media outlets that are not age- gated
- Labels and packaging are designed to attract new and/or underage users
- Products are sold in locations with a poor track record of age verification
- No established plan to track sales demographics and/or reseller compliance with plans
Corrective Action Strategies:
- Get a gap assessment performed on your application by an established, experienced regulatory firm preferably with experience in Premarket Tobacco Applications
- Do not wait to receive a deficiency letter to start the remediation process if your application has significant gaps
- If you feel additional data or studies will be required to keep your application moving forward in the review process, start collecting that data as soon as possible. Collecting additional data in a compliant and timely fashion will require a written protocol and getting your project in the queue of a reputable Contract Research Org (CRO) to execute that protocol. These activities often take months to execute. Data generated by non-credentialed sources is of little value.
- Simply having your application republished by a professional regulatory publishing group following the guidelines established by the FDA can eliminate many questions you might receive in a deficiency letter. Again, this takes time.
- If you are a brand holder that outsources the production of your products to an external Contract Manufacturing Organization (CMO), audit that CMO to ensure that they are operating in a compliant manner. Do their production and quality systems meet the minimum expected Good Manufacturing Practices (GMP) requirements? If not, consider moving your products to a CMO with an established tobacco product Masterfile that demonstrates compliant manufacturing and quality systems on file with the Agency.
- Internally perform or have a reputable third-party perform a thorough vetting of your sales and marketing practices for conformance with the FDA’s expectation. Where, how, and to whom your products are advertised, marketed, and sold is extremely vital information to support the claim that your products should be allowed to remain on the market.
- Prepare a plan for post market surveillance now, document that plan and make it part of your submission.
Final Notes on Deficiency Responses
Time is the most precious resource in this process! Acting early (before receipt of a deficiency letter) will give you the best chance to keep your products moving toward market authorization. A response to a deficiency letter will likely be the last opportunity to add to and improve your application while still in the active review process. The next chance to rework your application will be after you receive a negative ruling and are forced to take your products off the market.
Article written by VINCENT ANGELICO, Director of Science and Regulatory Affairs