E-liquid manufacturer Riot Squad announced it’s premarket tobacco product applications (PMTA) have moved on to the substantive review phase of the regulatory process. The U.S. Food and Drug Administration has until Sept. 9 to make a decision on the more than 2 million remaining PMTAs from the nearly 7 million submitted.
Credit: Riot Labs
Ben Johnson, Riot Squad’s CEO, said the company has always been positioned as a disruptor in the sector. “We had a laser-like focus on creating the most premium e-liquids on the market and coupled it with a brand with attitude,” he said. “The goal has always been to help people quit smoking. Continuous innovation – like our most recent PMTA going into the substantive review phase – and adopting a leadership role within the sector, is what will allow us to achieve that goal.”
The UK-based company sells to 86 countries around the world, according to a press release. The substantive review phase the final stage before the FDA grants or denies a marketing order. In order to receive a marketing order, Riot Squad must provide sufficient data to ensure its products are appropriate for the protection of public health.
The FDA has so far issued an estimated 34 marketing denial orders (MDO) for an estimated 360,000 products. The agency refused to file more than 4.5 million applications from the JD Nova Group.
Riot Labs was established in 2016 by Johnson who has an extensive background in pharmaceuticals. He set out to build Riot Squad into an innovative brand, with the aim of “encouraging consumers to find the confidence to give up smoking and engage in a healthier alternative.”
Update: On Sept. 8, 2021 Riot Squad received a marketing denial order (MDO) from the FDA for its flavored (other than tobacco) e-liquid PMTAs.
In August, the U.S. Food and Drug Administration issued 29 warning letters to firms it says were manufacturing and selling unauthorized electronic nicotine delivery system (ENDS) products. The agency advised the companies that selling products which lack a marketing authorization is “illegal and therefore they cannot be sold or distributed in the U.S.” The companies did not submit a premarket tobacco product application (PMTA) by the Sept. 9, 2020 deadline.
Credit: Андрей Яланский
While each of these 29 warning letters cites specific products as examples of tobacco products that lack the required premarket authorization, collectively these firms have listed a combined total of more than 268,000 products, according to the FDA.
In a first for ENDS products, two of the warning letters went to companies for selling after their PMTAs were not accepted. “Both Vapor Boss, LLC, and Kaleidoscope Custom Vapor Lounge, LLC have continued to sell ENDS products after receiving “Refuse to Accept” (RTA) determinations from the agency following submission of their premarket tobacco applications,” the FDA stated. “These are the first warning letters issued for an application that was submitted by the Sept. 9, 2020 deadline that subsequently received a RTA determination.”
Companies who receive an RTA determination must remove any products currently on the market or risk enforcement action by FDA, according to the agency. Companies may resubmit a complete application for these products at any time, however the products may not be marketed unless they receive a marketing granted order.
FDA also issued the first warning letter to a company that submitted premarket applications for some, but not all, of its products. The company (Maduro Distributors d/b/a The Loon) submitted a premarket application covering 18 products, but it manufactures and sells additional products not covered by the premarket application and thus lacking premarket authorization.
From January through August 2021, FDA has issued a total of 169 warning letters to firms selling or distributing more than 17 million unauthorized electronic nicotine delivery system (ENDS) products and that did not submit premarket applications by the Sept. 9 deadline, according to the agency.
On FDA’s Warning Letters page, you can find all of these warning letters by entering “Center for Tobacco Products” in the “Issuing Office” box in the “Filter by” section of the search tool.
The U.S. Food and Drug Administration stated on Friday, Sept. 3 that it had issued another round of marketing denial orders to 31 companies encompassing an estimated 300,000 products. “After issuing marketing denial orders (MDOs) to three companies for their flavored [electronic nicotine-delivery systems] ENDS products last week, @FDATobacco issued MDOs to an additional 31 companies for approximately 300,000 flavored ENDS products from Aug 27 through Sept. 2,” the agency tweeted.
Credit: Chase4Concept
Several of the MDOs were issued to companies that are not confirmed to be currently marketing their products. The regulatory agency did not release the names of the companies.
According to it’s website, the FDA does plan to release the names of the companies that received MDO. Previously, the agency only gave the names of the three manufacturers who it sent the first series of MDOs for a vapor products. “FDA understands that the public may be interested in the specific names of the currently marketed products subject to the negative decisions,” the FDA website states. “However, before releasing this information, FDA needs to ensure the Agency is not releasing the applicant’s commercial confidential information. Given the large number of products involved, sharing this information requires additional time and resources. Accordingly, FDA is actively exploring options related to this issue.”
In a release, the FDA stated that companies receiving these MDOs may have submitted premarket applications for other products “(such as ENDS devices, tobacco-flavored ENDS, or menthol-flavored ENDS),” and those products, if still pending, remain under review at FDA.
“FDA continues to make substantial progress reviewing the unprecedented number of applications received by the Sept. 9, 2020, court-ordered deadline for submission of premarket applications for deemed new tobacco products,” the release states. “The aggregate information on these actions will be provided within our regular updates on the Tobacco Product Applications: Metrics and Reporting page.”
As of Sept. 3, the FDA website lists 27 companies that have been issued MDOs:
Great American Vapes
JD Nova Group LLC
Vapor Salon
Big Time Vapes
J-Vapor LLC dba North Shore Vapor
SS Vape Brands Inc. Dba Monster Vape Labs
Custom Vapors
The Vaping Tiger
Gothic Vapor
TrendSetters E-liquid LLC
SWT Global Supply
Diamond Vapor
American Vapor Group
MV Enterprises
Planet of the Vapes
CITTG dba Orgnx E Liquids
Vapors of Ohio Inc. dba Nostalgic Vapes
Buckshot Vapors Inc.
Royalty Premium E Juice
Imperial Vapors
Midwest Vape Supply
Dominant Vapor
Mountain Vaporz
Sir Vapes -A-Lot
Loveli Design LLC dba
Alice in Vapeland
Nicquid
The first MDOs were announced on Aug. 26. The products from JD Nova Group, Great American Vapes and Vapor Salon didn’t provide adequate information to show their products offered enough benefit to adult smokers sufficient to overcome the public health threat posed by the “well-documented, alarming levels” of youth use of such products.
The FDA has received applications from over 500 companies covering more than 6.5 million tobacco products. The agency refused to file more than 4.5 million applications from the JD Nova Group. The FDA has until Sept. 9, 2020 to make a decision on the remaining estimated 2 million remaining PMTAs.
All of the premarket tobacco product applications (PMTAs) that have received marketing denial orders (MDOs) from the U.S. Food and Drug Administration have been for flavored products other than tobacco. On Aug. 31, the agency issued MDOs to three companies for only their other-than-tobacco flavored e-liquids, bringing the total number of companies known to have received MDOs to six. According to Filter, approximately 800 PMTAs were denied in the recent round of denials.
Credit: Veeranggull
“Dimitris Agrafiotis, the self-described ‘Vapin’ Greek’ who runs International Vapor Solutions, a consultancy firm, told Filter that three e-liquid companies companies he represents—two of them large and one medium-sized—were sent marketing denial orders (MDOs) by the agency,” Alex Norcia writes. “None of the PMTAs Agrafiotis helped file were totally finished, and the companies’ intention was to send more data piecemeal to the agency as substantial product stability testing wrapped up. Agrafiotis said he could not reveal the names of the companies because of nondisclosure agreements.”
Norcia was able to confirm that the FDA had issued additional MDOs, after it issued its first-ever MDOs for products from JD Nova Group, Great American Vapes and Vapor Salon for an estimated 55,000 products on Aug. 26. In its first MDO release, the agency stated that more marketing decisions would be forthcoming. The agency stated it would continue to review other premarket tobacco applications for non-tobacco flavored electronic nicotine-delivery systems (ENDS) to determine whether there is sufficient product-specific scientific evidence of a benefit to adult smokers to overcome the risk posed to youth.
“If the applications contain evidence of this type, the FDA will conduct further in‐depth scientific evaluation as to whether the evidence satisfies that statutory standard for authorization,” the FDA spokesperson explained to Norcia. “But in the absence of this evidence, the agency intends to issue an MDO. We know that flavored tobacco products are very appealing to young people, therefore assessing the impact of potential or actual youth use is a critical factor in our decision-making about which products may be marketed.”
Many in the vaping industry believe that the FDA will not approve a PMTA for a non-tobacco flavored product. A major e-liquid manufacturer recently told Vapor Voice that the agency may not immediately enforce the marketing of some flavored e-liquids for open systems that have submitted a PMTA, but the agency “will never give marketing approval for a flavor other than tobacco and menthol.”
The FDA’s review of new tobacco products before they can be legally marketed ensures that they meet the standard Congress set in the law to protect the public health, according to the agency. The agency noted that “the evidence of benefits to adult smokers for such products would likely be in the form of a randomized controlled trial or longitudinal cohort study.” The FDA stated that there is the possibility that other types of evidence may exists that could be adequate if sufficiently robust and reliable. However, because the evidence was absent in these applications, the FDA issued MDOs.
The FDA has received applications from over 500 companies covering more than 6.5 million tobacco products. The agency refused to file more than 4.5 million applications from the JD Nova Group. According to the FDA release, the products subject to an MDO for a premarket application may not be introduced or delivered for introduction into interstate commerce. If the product is already on the market, the product must be removed from the market or risk enforcement.
In June, the Agrafiotis’s three clients got a letter from the FDA that their PMTAs had been received and would be moving onto the review stage, according to the Filter story. Last week, his clients drafted letters to the FDA, stating that they would be sending further information. “They have done substantial scientific work and testing,” Agrafiotis said. “They invested some real money in this.” One company, which filed 45 product applications, spent close to $1 million. “Some of the PMTAs were not complete, and some of them were more complete than others.” Of all his clients’ applications, only those for tobacco or menthol flavors now remain pending.
“It’s not clarified exactly why they were denied,” Agrafiotis said. “The FDA mentioned youth. The usual spiel. And I was honest with my clients that some of the product names might be considered appealing to youth by the FDA. I’m very honest with the industry.”
Agrafiotis added that now each company he represents is moving into the synthetic nicotine space. One of the large companies is totally transitioning to synthetic nicotine, a legal gray area, because it does not want to spend any more money on the PMTA process. The other was beginning to explore synthetic nicotine as a stopgap solution while pursuing legal action against the FDA. Numerous companies that have received either a warning letter or MDA from the FDA have chosen to start using synthetic nicotine in order to attempt to avoid FDA regulation.
The FDA has not stated whether or not it believes it has the authority to regulate synthetic nicotine.
The U.S. Food and Drug Administration issued the first marketing denial orders (MDOs) for electronic nicotine delivery system (ENDS) products today. In a press release, the regulatory agency determined that the premarket tobacco product applications (PMTAs) for about 55,000 flavored ENDS products from three applicants lacked sufficient evidence they appropriately protect public health.
The products from JD Nova Group, Great American Vapes and Vapor Salon subject to this action are non-tobacco-flavored ENDS and that include flavors such as Apple Crumble, Dr. Cola and Cinnamon Toast Cereal. The FDA states the products didn’t provide enough benefit to adult smokers sufficient to overcome the public health threat posed by the “well-documented, alarming levels” of youth use of such products.
Credit: Stan Cuic
“Congress gave the FDA the authority to regulate tobacco products to protect the public from the harmful effects of tobacco use through science-based regulation,” said acting FDA Commissioner Janet Woodcock. “Ensuring new tobacco products undergo an evaluation by the FDA is a critical part of our aim to reduce tobacco-related disease and death. We know that flavored tobacco products are very appealing to young people, therefore assessing the impact of potential or actual youth use is a critical factor in our decision-making about which products may be marketed.”
According to the TMA/Vapor Voice PMTA Tracker, Vapor Salon submitted 327 flavors in four sizes and 12 nicotine strengths covering approximately 47,108 submissions. Great American Vapes was also captured by the TMA/Vapor Voice PMTA Tracker with 150 flavors, including the Dr. Cola flavor mentioned in the CTP’s MDO release.
The FDA’s review of new tobacco products before they can be legally marketed ensures that they meet the standard Congress set in the law to protect the public health, according to the agency. The agency noted that “the evidence of benefits to adult smokers for such products would likely be in the form of a randomized controlled trial or longitudinal cohort study.” The FDA stated that there is the possibility that other types of evidence may exists that could be adequate if sufficiently robust and reliable. However, because the evidence was absent in these applications, the FDA issued MDOs.
The agency will continue to review other PMTAs for non-tobacco flavored ENDS to determine whether there is sufficient product-specific scientific evidence of a benefit to adult smokers to overcome the risk posed to youth. If the applications contain evidence of this type, the FDA will conduct further in‐depth scientific evaluation as to whether the evidence satisfies that statutory standard for authorization. But in the absence of this evidence, the agency intends to issue an MDO.
The FDA has received applications from over 500 companies covering more than 6.5 million tobacco products. The agency refused to file more than 4.5 million applications from the JD Nova Group. Although the agency has issued other negative actions for some applications, this is the first set of MDOs the FDA has issued for applications that have reached the substantive scientific review portion of premarket review.
According to the release, the products subject to an MDO for a premarket application may not be introduced or delivered for introduction into interstate commerce. If the product is already on the market, the product must be removed from the market or risk enforcement. The MDOs announced today do not include all ENDS products for which the companies submitted applications. Applications for the rest of the products remain under consideration.
Credit: FDA
“Flavored ENDS products are extremely popular among youth, with over 80 percent of e-cigarette users between ages 12 through 17 using one of these products. Companies who want to continue to market their flavored ENDS products must have robust and reliable evidence showing that their products’ potential benefit for adult smokers outweighs the significant known risk to youth,” said Mitch Zeller, director of the FDA’s Center for Tobacco Products. “The burden is on the applicant to provide evidence to demonstrate that the marketing of their product meets the statutory standard of ‘appropriate for the protection of the public health.’ If this evidence is lacking or not sufficient, the FDA intends to issue a marketing denial order, which requires the product to be taken off or not introduced to market.”
The agency also stated that the scientific review of menthol ENDS, as compared to other non-tobacco-flavored ENDS products, raises “unique considerations.” While menthol-flavored ENDS are not included in the these current FDA decisions, the regulatory agency stated that its reviews will “similarly examine whether the evidence in the application demonstrates a benefit to existing adult users that outweighs the known youth use” of ENDS products.
The American Lung Association commented via Twitter that it stands “firmly with the science that no flavored tobacco products are appropriate for the protection of public health, and all should be removed.”
Greg Conley, president of the advocacy group American Vaping Association, said the three companies targeted by FDA had minimal market share and chastised the agency for going after “low-hanging fruit.” Conley also stated via Twitter that its not a foregone conclusion that all or most pending flavored e-liquid applications will be rejected before the agency’s Sept. 9th deadline. He stated that how the FDA will handle products from manufacturers that submitted requests for extensions and have attempted to supplement their PMTAs are still unknown.
“The FDA never intended to fairly regulate open-system vape products. From the 2014 draft release of the agency’s Deeming Rule until today, the Center for Tobacco Products has looked forward to the moment it would eliminate the ‘wild west’ of the independent industry,” stated Conley.
Scott Gottlieb, who served as FDA commissioner during the Trump administration, blamed e-cigarette manufacturers for their predicament, saying “many companies had ample time, and the benefit of guidances that we issued, to provide a path toward compliance, so they could demonstrate their value as tools that could help current smokers quit combustible tobacco. Many of them chose to fight the laws Congress enacted, and the FDA, and they didn’t invest in demonstrating the public health benefits that they asserted.”
The FDA has until Sept. 9, 2020 to make a decision on the remaining estimated 2.5 million PMTAs.
As the FDA’s deadline to approve marketing applications nears, industry experts look back on the submission process.
By Chris Howard and Rich Hill
It’s been nearly a year since many of us filed premarket tobacco product applications (PMTAs) to the U.S. Food and Drug Administration for new tobacco products, so now seems like a perfect time to reflect on what we took away from the experience. Below you will find a Top-10 list of learnings from the front line.
1. Everyone (and no one) is an expert.
From day one, we worked with dozens of consultants, researchers, similarly situated companies, regulators, outside counsel and other stakeholders. Which groups provided the most insight?
Answer: It certainly wasn’t the ones who claimed to definitively know everything about a particular facet of the PMTA. Rather, we felt most confident when working with those who acknowledged the inherent uncertainty in the process. The ability to speak candidly with these individuals enabled us to collaborate to best achieve our goals of meeting FDA expectations. We learned the least from those who “guaranteed” us security or made promises about what the FDA needs/wants.
2. The FDA is not the enemy.
Believe it or not, the agency isn’t out to get you. The Center for Tobacco Products (CTP) is not maliciously trying to ensure that all applications for new tobacco products are denied. Despite what you read from frustrated vapers on Twitter, the team at the CTP is doing what they are required to do—assessing whether new tobacco products are appropriate for the protection of public health.
Yes, it is expensive and requires a lot of work to meet this standard, but collaborating with the FDA is a much better approach to achieving this goal compared to taking an adversarial posture. If a combustible cigarette can receive a market order, then there is clearly a path for modern oral products and electronic cigarettes to do the same.
3. Money talks.
Unfortunately, not too many shortcuts are acceptable when it comes to a PMTA, so as a result, the entire process is expensive. While you can reduce your spend by seeking discounts, collaborating with others, etc., the fact remains that you will need to make a substantial investment in this work.
Throughout the process, we sought the best deals without sacrificing quality and looked for ways to reduce costs wherever we could, but we still spent a significant sum for our product applications. The greatest potential PMTA cost savings really begins with what products you intend to put through the process. Doing a full, scientifically sound PMTA for 1,000 stockkeeping units (SKUs) is not realistic. Make hard choices about your products in the beginning and pare your list down—this will generate your greatest cost savings.
4. Not all labs are created equal.
This may seem obvious, but just because a lab is certified, has a slick website and talks a good game doesn’t mean they have the scientific rigor or physical capacity to complete your project. Many labs jumped into the “PMTA testing game”—but the solid labs delivered on time and provided scientifically sound methods and results. How do you choose a solid partner?
Answer: Seek out laboratories that have a reputation working with your products. They don’t have to be the biggest, but they need to be experienced with the testing you are seeking. Audit them with external consultants. Do they have sufficient equipment and personnel to handle the throughput you need to finish on time (especially with competing client demands)? Ultimately, you get what you pay for. You can go to the cheapest labs, but there is no guarantee that you will get results on time or on target.
5. No kids allowed.
This goes without saying, but vapor products are obviously for adults only. We are all aware of the concerns regarding youth usage of vapor products, and you can be sure that the FDA places a priority on this topic. Take the time to describe the practices you employ to deter youth usage of your products.
Don’t try to guess the minimum you need to do to achieve the goal. Rather, show the FDA that you are willing to spare no expense when it comes to this issue. We drafted company marketing standards and have shared them industrywide to encourage others to adopt the same.
6. The perfect is the enemy of the good.
A premarket tobacco application for a handful of SKUs can consist of tens of thousands of pages. Given this, we can confidently say that forgetting to indent a paragraph is not going to be determinative in whether the FDA ultimately decides to grant you a market order.
Details obviously matter, but prioritize conveying your message(s) clearly by prioritizing substance over form. A misplaced semicolon isn’t going; to make the difference.
7. Tell your story.
Which story matters the most? Is it what you read this morning online about Juul and kids?
Answer: No, the FDA isn’t evaluating your application based on what others in the industry are doing. Your application is the opportunity to tell the story of why your products are appropriate for the protection of public health. Don’t be consumed by details about what is going on with other products.
8. From here to there
Finding a publishing partner that can handle your application is critical. Not all electronic publishers do large-scale projects. Many publishers want more time for loading and checking your application than you realistically can afford. Some publishers work with 20–30K pages exclusively (which doesn’t work as most PMTAs far exceed that page count).
Clearly communicate your timelines and ensure that your publisher’s project management teams can meet expectations. Because it’s the final step in the submission process, publication is naturally a bit of a scramble—which makes it prone to errors. Develop a dedicated quality control process so that you can confirm that your publisher submitted your complete application.
9. It’s not over until it’s over.
You will undoubtedly feel a sense of relief following the submission of your application, but we caution you to keep your eye on the prize. The FDA will inevitably have questions about your products in the form of a deficiency letter, so you need to stay focused on responding with the detail required.
These questions will come with deadlines, so do not wait until the last minute to prepare your response. Nothing would be worse than fumbling the ball at the goal line.
10. Uncertainty is the only certainty.
Anyone working in the vapor industry during the past five years knows exactly what I am talking about. The PMTA process is effectively in its infancy and, as such, several variables are subject to change. Is this a reason to give up on harm reduction and your individual goal of securing a market order?
Answer: No. Embrace the changes as they arrive and do your part to help the FDA develop a clear path forward for your future applications. This evolving regulatory environment provides an opportunity for you to help shape changes. Those who back away won’t have this luxury.
Chris Howard is the vice president, general counsel and chief compliance officer of E-Alternative Solutions, an independent, family-owned innovator of consumer-centric brands. Rich Hill serves as regulatory compliance director for E-Alternative Solutions.
The PMTA process has had some errors and challenges as the FDA’s decision deadline looms.
By Timothy S. Donahue
The U.S. Food and Drug Administration’s process for premarket tobacco product applications (PMTAs) has not been perfect. The regulatory agency has less than three weeks to complete its review of the more than 2 million PMTA submissions that remain of the more than 6 million received (the FDA refused to file more than 4 million submissions from the JD Nova Group). Given the unprecedented number of applications and other factors, the likelihood of the FDA reviewing all the applications by Sept. 9, 2021, is low.
“We will continue to allocate our resources with the goal of working as quickly as possible to transition the current marketplace for deemed products to one in which all products available for sale have undergone a careful, science-based review by [the] FDA,” an FDA spokesperson told Vapor Voice. “With that being said, as with all unauthorized products generally, if products are not authorized by Sept. 9, 2021, and do not come off the market at that time, they risk FDA enforcement.”
A court ruling requires the FDA to complete review of all submitted PMTAs by Sept. 9, 2021. Only a positive order issued by the FDA would allow a company to continue to be marketed according to the terms specified in the order letter.
“At a recent House hearing, acting FDA Commissioner Janet Woodcock pledged the FDA would make every effort to conclude review of the PMTAs from the top five vaping companies by the fall deadline,” said Gregory Conley, president of the American Vaping Association. “The FDA does not exactly have the best track record on keeping to their pledges, but it seems likely that decisions will be made on, at minimum, the tobacco and menthol varieties of Juul, Vuse, NJOY, etc., by September.”
Unfair warning
Complicating matters further, the regulatory agency has also recently been accused of issuing unwarranted warning letters, of leaving companies off its list of accepted PMTAs and of having technical issues with its PMTA filing software. As of July 26, the FDA had issued 135 warning letters for the marketing of illegal vaping products. The majority of those letters centered on e-liquids produced and sold online by small-sized vape shops. As the FDA continues its blitz, however, some companies who submitted PMTAs by the Sept. 9, 2020, deadline have allegedly received warning letters in error.
According to Facebook posts from the American Vaping Manufacturers Association (AVM), at least two companies have received warning letters for products for which they had submitted timely PMTAs. Posts acknowledged that the FDA corrected its mistake in a follow-up letter after receiving complaints from the companies. While the number may be small, it does suggest that the regulatory agency is overwhelmed by the number of submissions it is reviewing.
Credit: Chris Titze Imaging
According to the FDA spokesperson, there has been only one instance where the regulatory agency removed a warning letter from its website after it was discovered that the company had submitted a timely PMTA. The agency did not mention the company by name and said the error had been corrected.
The FDA said the list may change as some companies may not have responded to requests or have not had their PMTA accepted yet. It should be noted that in its guidance document released in January 2020 that identified its enforcement priorities for electronic nicotine-delivery system (ENDS) products, the FDA stated that it “may prioritize enforcement of certain new deemed tobacco products that are marketed without market authorization, including as warranted based on changed circumstances, new information or to better address minors’ use of those products.”
The FDA also recently started listing closeout letters for companies that had responded to warning letters on its website. When the FDA completes an evaluation of corrective actions via a follow-up inspection, it may issue a closeout letter if the agency’s evaluation shows that the issues noted in the warning letter have been addressed.
Recently, however, the agency removed those letters from its website. The FDA offered no explanation for the removal of the closeout letters. Companies such as Dr. Crimmy’s V-Liquid, Bulldog Vapor and CC Apothacary had closeout letters posted, but then it seemed they were removed.
The FDA spokesperson said that the letters are still on the website; however, accessing them changed slightly. Users must now use the search functions to access response and closeout letters. “Any closeout letters issued to firms since Sept. 9, 2020, including Dr. Crimmy’s V-Liquid, Bulldog Vapor [and] CC Apothecary, are still posted on [the] FDA’s website,” the spokesperson said. “On [the] FDA’s ‘Warning Letters’ page, you can find the closeout letters by listing ‘Center for Tobacco Products’ under ‘Issuing Office’ and filtering for ‘Closeout Letter’ under ‘Letters with Response or Closeout.’”
The FDA often lists only a few illegal products in a warning letter. It then states that there may be more, but it is impossible to know if the warnings encompass all the company’s registered products. The agency states that it is the responsibility of the company to only sell products with a submitted PMTA.
Companies that receive warning letters from the FDA have to submit a written response to the letter within 15 working days from the date of receipt describing the company’s corrective actions, including the dates on which it discontinued the violative sale and/or distribution of the products. The response must also detail the company’s plan for maintaining compliance with the Food, Drug and Cosmetic (FD&C) Act in the future.
Warning letters are expected to continue to be issued for illegal vapor products as the deadline for FDA action moves closer, and their volume is likely to pick up after the Sept. 9 deadline. The FDA has not said if it intends to ask for an extension on the deadline; however, the U.S. Small Business Administration recently sent a letter to the FDA asking the regulatory agency to request an extension.
Making the list
There are other issues with the FDA PMTA process as well. Recently, the FDA released a list of products that are legal for sale in the U.S. As of Aug. 9, 372 companies had submitted PMTAs for more than 6 million products. Of those products, 99.9 percent are standalone e-liquid products—and of those, 80 percent of the e-liquid submissions were from a single company, according to ECigIntelligence, a vapor industry data and research firm.
At least five companies that filed PMTAs were allegedly erroneously left off the list, according to social media posts by an AVM representative. In its own investigation, Vapor Voice found that Humble Juice Co. had submitted a timely PMTA, received an acceptance letter and was subsequently left off the FDA’s list of approved products. The FDA has corrected the error for Humble. The AVM did not name what companies were left off the list or had falsely received warning letters.
The FDA stressed it has not independently verified the information provided by applicants about the marketing status of their products. In addition, the list excludes entries of products from companies that did not provide information on the current marketing status of their products to the FDA so that the agency could determine whether the existence of the application could be disclosed. It is possible companies were left off the list because they did not respond to the FDA before publication of the list.
As stated on the FDA’s website, the lists are not comprehensive or intended to cover all currently marketed deemed tobacco products that a company generally might manufacture, distribute or sell without risking FDA enforcement. The FDA stated that it was making the list available to the public to be transparent and increase stakeholder knowledge of these products. However, the list is only one source of information, and retailers should discuss with their suppliers the current status of any particular tobacco product’s application and marketing authorization, according to the FDA.
“Due to the large volume of information that needed to be processed to generate the list, it is likely that some information may have been inadvertently excluded during the development of the list. After initial posting of the list, FDA has received inquiries from companies about certain products they believe should have been included on the public list,” the spokesperson said. “We are reviewing these requests, and will update the list, if appropriate, to ensure accuracy. In general, due to the large amount of data in the files, FDA has also stated minor edits and corrections may be made to the list files to ensure accuracy, and the files will also be updated to reflect actions taken on the applications for the products.”
Shaky submissions
The PMTA submission process has also suffered from technical problems. Several companies have complained that the FDA’s software that manufacturers must download to submit PMTA data has randomly left out some files that the companies are uploading. At least two companies that have helped prepare more than 500 PMTAs have acknowledged the issue and have presented the problem to the FDA.
“We did 15 PMTAs for various clients and just all of a sudden had somebody come up and they got a deficiency letter asking for information that was included in their submission. We started looking through it, and it’s missing. We then spent a bunch of time going through every single one and found several others that were missing one or two files,” one of the companies that discovered errors told Vapor Voice. “We reached out to the FDA, got a basic response … ‘we’re aware of this; we’ll get back to you’ type of thing. We believe it’s a bug in the agency’s eSubmitter program.”
The FDA spokesperson said that the agency’s Center for Tobacco Products (CTP) submitters have three options for electronic submissions:
1. FDA hosts the Electronic Submission Gateway (ESG) used by all FDA centers for the past 20-plus years. It requires registration and maintaining a security certificate, which has an associated fee. CTP receives electronic submissions directly through the ESG from a small number of companies.
2. CTP provides a simpler zero-cost alternative to using the ESG directly with the FDA eSubmitter software and the CTP Portal. Using the CTP Portal requires obtaining a free account and using the FDA eSubmitter tool to create a valid package of files, which the CTP Portal will upload. Submitters must download the FDA’s eSubmitter software if they intend to use the free CTP Portal. Instructions for use are on the FDA webpage, and detailed technical specifications for creating valid eSubmitter packages can be found under Electronic Submission File Format and Technical Specifications.
3. Electronic files can be mailed to CTP Document Control Center (DCC) on physical media such as CD, DVD or flash drive.
Credit: Yuri Hoyda
The eSubmitter errors that some companies have found may be user error, according to the FDA. The inclusion of invalid file types in the upload package may make it appear as if certain files were left off. A common invalid file type users attempt to include are zero-sized files, according to the FDA.
“A user may unintentionally include *.tmp files, which are temporary files of zero size that the user’s computer creates when it is moving files from one location to another. If a user moves files they are uploading during the loading process, the .tmp file their computer created will become part of the package manifest and appear in the eSubmitter file count,” the spokesperson said. “A user may think they are sending 500 application files, but if one is a .tmp file, they are only sending 499 files related to the application.”
The CTP eSubmissions help desk recommends submitters create a file list and review the file types to be used in the submission against the list of invalid file types. After uploading to the CTP Portal, they can compare the list of valid files against the CTP Portal upload manifest to ensure all files were included. If files were found to not be included, they could be submitted separately, according to the FDA.
“In general, FDA intends to send only one deficiency letter (if appropriate),” the spokesperson said. “It is the applicant’s responsibility to ensure all information has been submitted to FDA and to review all files that were uploaded to the software prior to submission to FDA.”
Because of these issues, some companies are offering free PMTA deficiency reviews for companies that submitted them to the FDA. Delphinus Consulting and Blackbriar Regulatory Services have said they have programs to help companies find faults in their PMTA submissions.
After the deadline
How the vaping industry changes on Sept. 9 remains to be seen. Large companies may soon dominate the U.S. vapor market while e-cigarettes produced by smaller companies may disappear, according to new research by ECigIntelligence. The data firm carried out an assessment of the FDA’s “accepted” list in order to understand how the U.S. market may change in a post-PMTA regulated market.
Analysis of PMTAs shows that more applications for simpler disposables and cigalike devices were submitted than applications for open systems. According to the research, the simpler products usually come from large companies while the open systems usually come from smaller businesses. Only about 30 open system brands have filed PMTAs, implying that 85 percent of open system brands will be removed from the market, even if all 30 filed PMTAs are approved.
“This may indicate the discouragement nontobacco companies face when applying for PMTA approval,” said ECigIntelligence’s managing director, Tim Phillips. “The PMTA process can be a grueling one for nontobacco companies without sufficient financial means or knowhow. And if smaller brands are to become less prevalent in this category, consumers may soon only have the option of a few models provided by a handful of big companies.”
While the industry awaits decisions from the FDA, vape sales are rising. IRI data for U.S. convenience stores shows that dollar and unit sales for electronic smoking devices each climbed approximately 14 percent for the four weeks ending June 13. A 12-week review revealed a gain of 16.3 percent in dollar sales and 18.6 percent in unit sales.
Whether these trends will continue after Sept. 9 is anyone’s guess.
The U.S. Food and Drug Administration has informed e-liquid manufacturer Bantam Vape that its non-tobacco flavored electronic nicotine delivery system (ENDS) products are now in the agency’s formal scientific review stage of the premarket tobacco product application (PMTA) process, according to a press release. Scientific review is the final step in the PMTA process prior to FDA’s decision to grant a marketing order.
Bantam is seeking marketing orders from FDA for its suite of e-liquid products. Credit: Bantam Vape
“Following the receipt of Bantam’s filing letter, it has waited in anticipation for FDA to begin the next step in the PMTA process – formal scientific review,” said Bantam spokesperson Anthony Dillon. “As we approach the one-year anniversary of the filing deadline, this action represents a critical stage in FDA’s consideration of Bantam’s request for a marketing order.”
The FDA completed a preliminary review of Bantam’s PMTAs in November 2020, making its applications eligible for formal substantive review. During the substantive review phase, FDA will conduct an in-depth evaluation of Bantam’s scientific studies and other materials it submitted in conjunction with the brand’s applications.
This includes FDA’s consideration of Bantam’s product testing for harmful and potentially harmful constituents (HPHCs) and physical characteristics of the e-liquids and aerosol at multiple time points; an analysis of leachable chemicals and stability testing of its e-liquids at multiple time points; microbial testing of the final e-liquids at multiple time points; in vitro toxicity testing including Ames, micronucleus and neutral red uptake (NRU) studies; four pharmacokinetic and topography studies for multiple flavors at various nicotine concentrations; and consumer surveys to understand the demographic and usage patterns of its e-liquids. Multiple comprehensive, quantitative risk assessments across many areas of potential risk for the Bantam products were also provided to FDA, demonstrating that Bantam products are appropriate for the protection of public health.
Additionally, to ensure Bantam’s ongoing ability to provide consumers with “high-quality, science-based e-liquid products” following the Sept. 9, 2021 deadline, the brand submitted a formal extension request to FDA. Bantam is hopeful that FDA will grant the extension, which would provide the regulatory agency with additional time to review Bantam’s complete applications and allow the brand’s products to remain on the market while the applications are under review.
“Entering the coveted scientific review phase is a significant development. This is especially true given FDA’s growing enforcement actions against non-compliant brands,” said Dillon. “Bantam remains confident in its PMTA submissions and will continue to engage with FDA in order to obtain the marketing orders needed to stay on the market moving forward.”
In this article, Broughton Nicotine Services Head of Scientific Affairs Paul Hardman outlines the factors that can lead to data gaps in premarket tobacco product applications (PMTAs), what prompts a deficiency letter and how you can respond quickly and appropriately.
What is a deficiency letter?
Deficiency letters are sent to those who have submitted a PMTA with incomplete or insufficient data for the U.S. Food and Drug Administration to make a decision on whether the product is “appropriate for the protection of the U.S. public health.”
Why have I received a deficiency letter?
There are common causes of deficiencies that prompt the arrival of a letter. These could include a PMTA that lacks information that was mistakenly considered unimportant by the electronic nicotine-delivery systems (ENDS) company but is actually required by the FDA.
Applicants may also have been rushed to meet last year’s Sept. 9 deadline, leaving the company submitting the PMTA with insufficient time to collate and provide the required data. Similarly, the timeframe required to submit the application may not have left enough time to complete stability studies of the required length to provide a range of data. The FDA is, understandably, keen to understand the stability of a product over its expected shelf life.
Other reasons include:
A lack of integration between different studies—often submissions provide extensive data for some workstreams but are light in others. It is important that appropriate data is provided for all product analysis, nonclinical and human subject studies—and that data and approaches are integrated across all areas.
Different interpretation of “scientifically justified”—many elements of the PMTA guidelines indicate that approaches applied need to be justified by scientific data. However, as all products differ, there is a level of ambiguity in terms of what this looks like and what is required.
Poor “bridging” of data—the FDA welcomes the bridging of scientific data between similar products where appropriate. However, bridging that is not, in the opinion of the FDA, sufficiently scientifically justified will be highlighted and raised as a deficiency.
What will be in a deficiency letter?
Despite the name, it won’t just be a letter. The deficiency packs issued by the FDA are very detailed, outlining positive aspects about your application and areas for improvement and attention.
There will be multiple pages covering different points, with sections covering all products or particular products in a bundled PMTA and perhaps highlighting deficiencies for particular timepoints.
What is the aim of the deficiency letter?
Once a PMTA application has been accepted for filing, the next stage is substantive scientific review, which results in either a deficiency letter, a request for environmental information, a market order granted or a market order denied. The FDA will notify the submitting company when their application enters substantive scientific review.
The FDA intention of the deficiency letter pack is to support you in providing the required information. Each will typically cover what you need to do to remedy the deficiency and what data you need to provide to allow the FDA to carry on with a substantive scientific review—and the FDA has confirmed that, for deemed products (those on sale in the U.S. on or before Aug. 8, 2016), you will only receive one deficiency letter based on the agency’s current high workload with the many applications in process. The FDA has said this may be reviewed in the future once the backlog is cleared. Generally, for deemed products, you will have only 90 days to respond to the deficiency letter with all the relevant data that has been requested.
Information could include examples of what meets the FDA’s requirements and advice on how you could better explain or justify the information provided. There is no set response to a PMTA application. The FDA has received an extensive number of applications, which are reviewed by a team of people, so inconsistencies may arise between different responses. Also, take note that answering all the queries in a deficiency letter does not necessarily guarantee that your application will eventually be granted a marketing order.
How can I prepare for a deficiency letter?
As an ENDS company, you might have a good idea of possible data gaps within your submission and understand whether you are likely to receive a deficiency letter. Or, you may believe that what you have provided is appropriate and adequate. Either way, it is best to be prepared.
Steps can be taken to ensure you are ready for any eventuality, the most important one being to ask for help. Scientific and regulatory ENDS specialists can undertake gap analysis to identify any possible deficiencies so that steps can be taken now to provide what is required.
You can also ensure you fill any missing data gaps. If there is information that is clearly missing or inadequate, put studies in place to collect the data now. Remember, there are only 90 days to respond to a deficiency letter, which may not be sufficient time to obtain the information required.
Another piece of advice would be to start stability studies now if you are in any doubt that the stability data you provided may not be sufficient in terms of duration. Putting studies in place now will help you stay ahead of the game if this aspect of your submission is questioned.
Finally, you should always cross-check requirements. It is surprising how many companies miss out key sections, such as an executive summary or environmental assessment. Although omission of key sections is likely to lead to the FDA refusing to accept or refusing to file the application prior to reaching the substantive review phase, it makes sense to compare the detail of what you have provided with the list of requirements from the FDA to check if you have overlooked anything.
Recently, the FDA confirmed that addendums of additional data can be submitted to them before the commencement of the substantive scientific review stage for the process. This is fantastic news for manufacturers who had submitted dossiers that were not as comprehensive as they would have liked; if your application has not yet entered substantive scientific review, you now have the opportunity to submit additional data at no penalty to your application. However, if you plan to do this, it is important to contact the FDA and describe the anticipated plan of data generation and submission—and be quick. If you leave this too late and your application does enter substantive scientific review, you run the risk of any addendums being detrimental to your application and a shortening of the FDA’s enforcement discretion.
How can I be prepared for, or minimize the chance of, receiving a deficiency letter?
ENDS companies most prepared to respond appropriately will be those that are expecting the letter and have the required data ready or those that avoid receiving a letter altogether by providing information upfront. Companies such as Broughton Nicotine Services can help at any stage of the process, either prior to submission or during substantive scientific review, troubleshooting when there is a refuse to file/accept decision and also helping with preparation for and response to deficiency letters.
Broughton Nicotine Services can help you undertake a gap analysis on your submission and generate the required information. Contact our regulatory consulting team to book a meeting so that we can help you advance a smoke-free future.
This article was supplied on behalf of Broughton Nicotine Services.
The JD Nova Group submitted premarket tobacco product applications (PMTAs) for an estimated 4.5 million products, approximately two-thirds of the total number of PMTA submissions. Today, the U.S. Food and Drug Administration issued a Refuse to File (RTF) letter to the company. The letter notified JD Nova that the majority of their PMTAs did not meet the filing requirements for a new tobacco product seeking a marketing order.
Credit: Tashatuvango
“This RTF does not apply to all product applications submitted by JD Nova. The remaining product applications the company submitted by the Sept. 9, 2020 deadline are still moving through the review process,” the FDA stated in a press release. “As a result of this RTF action, the company must remove approximately 4.5 million products from the market or risk enforcement action by FDA. The company may resubmit a complete application for these products at any time. However, the products may not be marketed unless they receive a marketing granted order.”
During the filing stages of application review, the FDA reviews for basic information to ensure applications contain the required material for scientific review, according to the release. If required contents for filing are missing, the FDA refuses to file the application.
“JD Nova was issued the RTF letter because the company’s applications for these products lacked an adequate Environmental Assessment (EA),” the release states. “Under FDA’s regulations implementing the National Environmental Policy Act (NEPA), an EA must be prepared for each proposed authorization, and an EA adequate for filing addresses the relevant environmental issues.”
JD Nova was one of more than 360 companies included on a recent list of products that had submitted a timely PMTA to the FDA and was allowed to market products for up to one year, until Sept. 9 2021, or until the FDA makes a regulatory decision such as refusing to file a PMTA.
From January through July 2021, the FDA has issued more than 135 warning letters to firms selling or distributing more than 1,470,000 unauthorized ENDS and that did not submit premarket applications by the Sept. 9 deadline. One company, Visible Vapors, had more than 15 million products registered with the FDA. On FDA’s Warning Letters page, you can find these warning letters by searching “Center for Tobacco Products” under “Issuing Office.” The regulatory agency has issued at least two warning letters in August so far.
