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Although the US Food and Drug Administration’s (FDA’s) Premarket Tobacco Product Application (PMTA) submission deadline on September 9, 2020, has passed, the fact remains that electronic nicotine delivery system (ENDs), e-liquid, vape and smokeless tobacco product companies will need to continue to comply with the PMTA regulatory pathway. As a result, these organizations will be engaging with the FDA as PMTA submissions are reviewed.

Rather than worrying about a timely submission, many companies are now waiting to see if they will receive deficiency letters from the Agency for the PMTA applications that have been submitted. FDA Attorney, Marc Sanchez Esq., provides insights as to the various types of deficiencies PMTA applicants may receive and how to best handle deficiency letter responses. He also answers other frequently asked questions regarding PMTA deficiency letters.

The three phases of deficiency letters

First and foremost, a deficiency letter is a letter issued by the FDA requesting additional information or notifying the applicant that critical information is missing from a regulatory submission, or in this instance, the PMTA application that has been submitted to the FDA. When a deficiency letter is issued, it signals that the FDA is refusing to progress the submission to the next phase, and the letter serves to inform applicants as to the reasons why the application cannot progress to the next stage of the regulatory review process. There are three phases in which an applicant may receive a deficiency letter after submitting their PMTA application:

Acceptance phase

There are very few reasons applicants may receive a deficiency letter during the acceptance phase, as this phase determines if applications have been submitted for a tobacco product, and if so, whether the product is subject to the PMTA regulatory pathway. If the product is deemed to be a tobacco product and therefore subject to the PMTA, it is possible that a deficiency letter could be issued during the acceptance phase due to a disorderly application, as Sanchez mentions, “If you really do not have your filing together – whether it is disorganized or uploaded incorrectly, it could happen.”

Filing phase

Thus far, a majority of applicants who have received deficiency letters from the FDA are receiving these letters during the filing phase. The FDA verifies whether the required components of the application are present during the filing phase, prior to starting their scientific review, and if required sections of the application are missing or inadequate data has been provided, the application cannot progress, and the Agency cannot assign a reviewer.

According to Sanchez, inadequate environmental assessments account the majority of applicants who receive deficiency letters during the filing phase. Furthermore, cGMP and descriptions of manufacturing methods may not contain enough detail. Once deficiencies are addressed at the filing phase, applicants find themselves back at the acceptance phase, ready to begin the review process again.

Scientific review phase

Very few PMTA applicants, if any, have made it to this phase, as it is still very early on in the review timeline for PMTA submissions. If applicants were to receive deficiency letters in this phase, Sanchez anticipates they will be akin to other FDA scientific review deficiencies, as has been seen with medical devices.

These deficiencies will be more interactive than what applicants experience in the previous two steps. The FDA will provide a timeframe, which is undetermined at this time, for the applicant to respond to all stated deficiencies. This may require applicants to generate and submit additional data or information, and further testing on behalf of the applicant may be required to fully address deficiencies in their PMTA filing. This will provide an opportunity for the FDA to obtain clarity on observed discrepancies and acquire answers for anything more the Agency may have questions about. It is important to note that these letters will still be a “one-and-done” type response. If applicants do not comply with the FDA’s request within the stated timeframe, they will not be allowed to continue the PMTA process, and therefore will be unable to obtain marketing authorization for their products.

Proper FDA deficiency letter responses

The FDA recommends applicants adhere to the following format when responding to any deficiency letter:

• 1. Restate the identified Agency issue, and
• 2. Provide one of the following:
• a. the information or data requested;
• b. an explanation as to why the issue is not relevant to the marketing authorization decision; or
• c. alternative information and an explanation describing why the information adequately addresses the issue.

The FDA also recommends applicants provide the deficiency number and an identical restatement of the Agency’s question when responding to a specific deficiency. If applicants are responding to a follow-up from a previous deficiency, both the original and follow-up deficiency letter information should be included and referenced.

Sanchez states, “It is better to give them all the information you think they may need so no, or fewer, follow-ups are needed. I do advise to be strategic, but forthcoming.”

If the response becomes lengthy, the Agency encourages applicants to organize the information with a table of contents, lists of figures and/or tables, and any other organizational tactics the applicant believes will be necessary to assist the FDA in their review.

Frequently asked questions

Am I still able to submit a PMTA?

Yes, at this time, applicants are still able to submit PMTAs. The PMTA regulatory pathway is in place and if an application is submitted now, applicants may not have the same safe market stay as previous submissions that met the September 9, 2020 deadline. However, if an applicant’s product falls within the parameters of the PMTA regulatory guidance, they must obtain market authorization from the FDA to bring their products to market while complying with federal regulations.

What happens if an applicant is unable to respond to a deficiency letter within the time allotted?

Currently, applicants can try re-filing their PMTA submission in the CTP portal. However, any safe harbors keeping products on the shelf may be revoked and the applicant will find themselves back at the start of the review and submission process.

What is the allotted response timeframe to respond to an FDA deficiency letter?

The timeline for response to a PMTA deficiency letter varies depending on what phase the application is in. In the acceptance phase, at this time there, is no timeframe and applicants can take as long as needed to respond. In the filing phase and scientific review phase, it is currently undetermined. However, Sanchez anticipates it will be a standardized response window for all, and based on previous FDA deficiency letters, it could range from 60 to 90 days or even longer, as has been the case with medical devices, which is currently a 180-day response time.

What happens if an applicant has filed a letter of intent (LOI) with the FDA for the PMTA?

If an applicant has filed a letter of intent (LOI) to collect data, they should begin collecting, or should have already begun to collect, said data. Waiting for receipt of a deficiency letter from the FDA could put the applicant between a rock and a hard place, as the deadline is hard and fast with very few exceptions for extensions. To ensure compliance with regulations, applicants should start working to gather the data now, or begin anticipating what additional data the FDA may request in response to these letters.

I received a refuse to file letter from the FDA. What does this mean, and what are my next steps?

These letters are letters similar to the deficiency letters in the sense that the PMTA application is missing critical information. However, the biggest difference is the applicant is unable to respond in order to continue to move the application through the review process. Instead, the applicant must address the missing data and resubmit the entire PMTA application. The most common reasons applicants are receiving these letters are:

• Lacking robust environmental assessment reports and calculations;
• Not including enough detail for the quality procedures and manufacturing practices, and
• Missing information regarding ENDS specifications.

Finding the right laboratory and legal partner to support PMTA submissions and deficiency responses

Finding the right lab and legal partner for your PMTA submission and deficiency letter responses is crucial. Their expertise and experience working with the FDA is one of the top criteria you should consider in addition to open and continued communication, according to Sanchez.

Working with the FDA is a serious matter and regulatory submissions and interactions need to be handled with the utmost professionalism. Having a lab and legal partner who has worked in the regulatory space previously and has experience interacting with FDA is what sets them apart from other labs and legal partners. Additionally, applicants will want to ensure the communication style and approach of their scientific and legal partners is aligned with the expectations of the FDA. Partnering with a communicative, open organization that provides a primary point of contact is ideal. PMTA filings are stressful and partnering with an organization that leaves you guessing or chasing after them for updates adds unnecessary stress and burden.

Element has decades of experience working on a wide range of regulatory submissions, supporting FDA filings and deficiency responses. Our consultative team of scientific experts have extensive experience supporting PMTA filings, and our dedicated Project Management teams facilitate and ensure open and continual communication with clients.