Note: The contents of publications discussed in this newsletter are the responsibility of their authors alone, and findings and conclusions are those of the authors and do not necessarily represent the views of FDA.
In This Issue…
On April 30, 2019, FDA authorized the marketing of Philip Morris Products S.A.’s IQOS “Tobacco Heating System” through the premarket tobacco product application (PMTA) pathway. The electronic device heats tobacco-filled sticks wrapped in paper to generate a nicotine-containing aerosol. While FDA now permits the tobacco products to be marketed in the U.S., this does not mean these products are safe or “FDA approved.” FDA has placed stringent marketing restrictions on heated tobacco products, aimed at preventing youth access and exposure to the new products.
In this issue of Spotlight on Science, read about the scientific review of this recent product authorization, along with other news about CTP’s research initiatives and science-based regulatory policy.
- FDA Authorizes IQOS Heated Tobacco Products
- New Smokeless Tobacco Reference Products Available to Test for Harmful and Potentially Harmful Constituents
- Question and Answer with Matt Holman, Ph.D., Director of CTP’s Office of Science
- FDA Seeks More Information about Seizures Following E-Cigarette Use
- FDA Warns Companies Marketing E-Liquids That Imitate Cough Syrup
- Scientific Workshop on Youth Tobacco Cessation
- CTP Research
FDA recently authorized the marketing of new tobacco products manufactured by Philip Morris Products S.A.: the IQOS “Tobacco Heating System.” The electronic device heats tobacco-filled sticks wrapped in paper to generate a nicotine-containing aerosol. While FDA now permits these tobacco products to be marketed in the U.S., this does not mean the products are safe or “FDA approved.”
Following a rigorous science-based review through the premarket tobacco product application (PMTA) pathway, FDA determined that authorizing IQOS for the U.S. market is appropriate for the protection of the public health because, among several key considerations, the products produce fewer or lower levels of some toxins than combusted cigarettes. FDA has also placed stringent marketing restrictions on the products, aimed at preventing both youth access and exposure to the new products.
FDA is continuing its substantive scientific review of the company’s modified risk tobacco product (MRTP) applications.
Through FDA’s scientific evaluation of the company’s PMTAs, peer-reviewed published literature, and other sources, the agency found that the aerosol produced by the IQOS Tobacco Heating System contains fewer toxic chemicals than cigarette smoke, and many of the toxins identified are present at lower levels than in cigarette smoke. Additionally, IQOS delivers nicotine in levels close to combusted cigarettes, increasing the likelihood that IQOS users may be able to completely transition away from combusted cigarettes to use IQOS exclusively. Available data, while limited, also indicate that few non-tobacco users would be likely to choose to start using IQOS, including youth.
While the authorization of this new tobacco product doesn’t mean it is safe, the review process makes certain that the marketing of the product is appropriate for the protection of the public health, taking into account the risks and benefits to the population as a whole. This includes the increased or decreased likelihood that existing tobacco product users will stop using tobacco products, and the increased or decreased likelihood that those who do not use tobacco products will start using them.
Mitch Zeller, J.D., director of FDA’s Center for Tobacco Products, said: “Importantly, FDA is putting in place postmarket requirements to monitor market dynamics such as potential youth uptake. We’ll be keeping a close watch on the marketplace, including how the company is marketing these products, and will take action as necessary to ensure the continued sale of these products in the U.S. remains appropriate.”
These non-combusted cigarettes meet the definition of a cigarette in the Federal Food, Drug and Cosmetic Act. Therefore, these products must adhere to existing restrictions for cigarettes under FDA regulations, as well as other federal laws that, among other things, prohibit television and radio advertising. In addition, to further limit youth access to the products and exposure to their advertising and promotion, FDA is placing stringent restrictions on how IQOS is marketed—particularly via websites and through social media platforms—by including requirements that advertising be targeted to adults. FDA will evaluate new available data regarding the products through postmarketing records and reports required in the marketing order. The agency may withdraw a marketing order if it, among other reasons, determines that the continued marketing of a product is no longer appropriate for the protection of the public health, such as if there is significant youth uptake.
New Smokeless Tobacco Reference Products Available to Test for Harmful and Potentially Harmful Constituents
On May 14, the University of Kentucky’s Center for Tobacco Reference Products released four smokeless tobacco reference products designed for investigational purposes. These reference products can help researchers and regulators determine levels of several harmful and potentially harmful constituents (HPHCs) present in smokeless tobacco products. Prepared in collaboration with FDA’s Center for Tobacco Products, the four smokeless tobacco reference products—1S4 (Swedish Style Snus), 1S5 (Snus), 3S3 (Moist Snuff) and 3S1 (Loose Leaf Chewing Tobacco)—are certified for moisture content, pH, and amounts of nine HPHCs:
- Nicotine (Total and Free)
- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
- N-nitrosonornicotine (NNN)
In March 2012, FDA issued a draft guidance that identified these nine HPHCs, which include nitrogen-containing compounds, metals, polyaromatic hydrocarbons, and aldehydes, in smokeless tobacco products for which manufacturers and importers must test and report quantities to FDA. Making smokeless tobacco reference products such as 1S4, 1S5, 3S3, and 3S1, available will help tobacco researchers and testing laboratories assure the reliability of measured quantities of HPHCs and also support industry efforts to meet current federal requirements for reporting HPHC quantities in smokeless tobacco products.
Matt Holman, Ph.D., has over 17 years of experience working as a regulatory scientist and has been the director of CTP’s Office of Science since January 2017. In this Q&A, Dr. Holman speaks to the future of tobacco regulatory science as it evolves with the technology and introduction of new and novel tobacco products.
Q: What is the biggest challenge facing your organization today?
A: I would say the rapidly evolving marketplace. The marketplace today looks very different than it did almost ten years ago at the inception of CTP, and it continues to evolve. I expect that, in a year from now, it will look even more different. It’s a challenge to keep pace with a marketplace that has not only a diversity of products, but also multiple impacted populations. For example, at a high level, there are users and nonusers of tobacco products. It’s important that we understand how both groups, each with their own population subsets, perceive the products we regulate and how changes in the marketplace might impact their perceptions and behavior going forward.
To tackle this challenge, I’m looking to get more real-time data from the field and the lab, and from peer-reviewed manuscripts. If we are to keep pace with such an evolving marketplace, we constantly need fresh data on a variety of products in different subpopulations within the United States. Data is key.
Q: What expected or emerging regulatory science innovation do you believe will have an impact on our understanding of tobacco going forward?
A: This relates to what I was just speaking about. In recent years, many have spoken about “big data,” which is this notion that solid research can come from our ability to collect large volumes of data in real time. The challenge is finding the tools to rapidly conduct surveillance and to quickly analyze the harvested data. I think as these solutions evolve, they will have a tremendous impact on our ability to effectively regulate such a diverse and varied marketplace.
FDA has become aware that some people who use e-cigarettes have experienced seizures, with most reports involving youth or young adult users. Seizures or convulsions are known potential side effects of nicotine toxicity and have been reported in the scientific literature in relation to intentional or accidental swallowing of e-liquid or other misuse. However, a recent uptick in voluntary reports of adverse experiences with tobacco products that mentioned seizures occurring with e-cigarette use signal a potential emerging safety issue. FDA continues to monitor all adverse experiences reported to the agency about the use of e-cigarettes and encourages the public to report cases of individuals who use e-cigarettes and have had a seizure via the online Safety Reporting Portal.
Since June 2018, FDA observed a slight but noticeable increase in voluntary adverse experience reports mentioning seizures. In addition to the voluntary reports to the FDA Safety Reporting Portal (SRP), FDA examined reports from poison control centers between 2010 and early 2019 and determined that, between the poison control centers and FDA, there were a total of 35 reported cases of seizures mentioning use of e-cigarettes within that timeframe. Due to the voluntary nature of these case reports, there may be more instances of seizure in e-cigarette users than have been reported.
Seizures had been reported among first-time e-cigarette users and experienced users. In a few situations, e-cigarette users reported a prior history of seizure diagnosis. A few reported cases had indicated seizures in association with use of other substances such as marijuana or amphetamines. Seizures had been reported as occurring after a few puffs or up to one day after use. Most of the self-reported data that FDA received did not contain any specific brand or sub-brand information about the e-cigarette.
While detailed information is currently limited, FDA is alerting the public to this important and potentially serious health issue. Health care providers should be aware that seizures may be associated with e-cigarette use—redacted reports of past incidents are available on FDA’s website and may assist medical evaluations of seizures.
FDA is seeking more information about seizures following e-cigarette use to identify common risk factors and understand if any e-cigarette product attributes such as nicotine content or formulation may contribute to seizures. If you or someone you know experiences any unexpected health or safety issues with any tobacco product, please report it through the SRP. You may also upload relevant attachments such as medical records or product images.
When reporting an adverse experience, please be sure to include:
- The name of the manufacturer
- The brand name, model, and serial number of the device or e-liquid, if applicable
- Where the device or e-liquid was purchased
- Whether the device or e-liquid was modified in any way or whether there was a device malfunction
- Whether other tobacco products, medications, supplements, or other substances were used
- Whether there were any other symptoms (i.e., nausea, vomiting) or warning right before the adverse experience, such as change in the user’s behavior, alertness, vision or hearing
- Details about product use preceding the event (duration, amount and intensity of e-cigarette use)
- Details about health effects, including specific areas of the body affected, how symptoms progressed, how long they lasted, the course of the recovery, and the medical testing or care and decisions rendered
FDA issued warning letters to two companies for manufacturing, selling, or distributing nicotine-containing e-liquids that misleadingly look like prescription cough syrups. These products not only use labeling with statements, representations, and graphical elements that imitate legitimate ingestible cough medications, but they also have a list of ingredients that mimics a drug facts label. The warning letters follow actions taken in 2018 by FDA against makers and sellers of other e-liquids that misleadingly looked like kid-friendly food products, such as juice boxes, candy, and cookies.
“Efforts to encourage the innovation of novel and potentially less harmful products such as e-cigarettes for currently addicted adult smokers will be severely undermined if bad actors put the public, and kids in particular, at risk in this outrageous fashion,” said former FDA Commissioner Scott Gottlieb, M.D. “FDA will continue to crack down on misleading labeling and advertising and illegal and dangerous e-liquids that may entice youth or put consumers at risk."
On May 15, FDA held a public scientific workshop titled, “Youth Tobacco Cessation: Science and Treatment Strategies.” Introductory comments were provided by Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research and the afternoon session was introduced by Norman Sharpless, M.D., Acting FDA Commissioner. Workshop participants discussed the unique challenges associated with youth tobacco addiction and cessation, the current science regarding youth tobacco use and addiction, and treatment strategies to support youth tobacco cessation. Specific discussions included sessions on adolescent brain development and the potential effects of nicotine, limited treatment options for adolescent tobacco use disorders, the differences in adolescent e-cigarette users of today and adolescent smokers in the past, and the challenges of conducting research in the adolescent and young adult populations. There were presentations on current public education campaigns directed toward youth (e.g., CTP’s “The Real Cost” campaign), as well as evaluation of previous efforts and lessons learned that could benefit future actions. A summary of the workshop will be made publicly available in the near future.
A Conversation with CTP Scientist Karen Cullen, Ph.D.
What is the purpose of the National Youth Tobacco Survey (NYTS)?
The NYTS is a large survey conducted each year that focuses exclusively on tobacco use among youth. FDA collaborates with the Centers for Disease Control and Prevention (CDC) to administer the survey to middle and high school students each year. We use it to monitor a variety of aspects of tobacco use, including trends in current tobacco use, exposure to tobacco marketing, susceptibility to use, use of flavored tobacco products, etc. We’re also able to learn whether there are differences in tobacco product use by different characteristics. In addition, the data collected each year are useful in tobacco prevention and control programs. Since it’s a large, nationally representative, repeated, cross-sectional survey, it’s a very valuable source of data.
What are some limitations you face and how do you overcome the limitations?
When the 2018 data were first reported, we saw a huge increase in youth e-cigarette use from the previous year. One of the first questions we asked was which brands of e-cigarettes youth were using. Unfortunately, although we’ve asked about brands in past surveys, we weren’t able to answer that question directly because we hadn’t asked youth which e-cigarette brands they used in the 2018 survey. We recognized the continued importance of asking about the brand of e-cigarettes that youth were using, so we added that question to the 2019 survey.
We’re also limited in how many questions we can ask, because the questionnaire needs to be completed in a single class period at school, which is about 40 minutes. For the 2019 survey, we moved from asking these questions on a paper-and-pencil scantron form to electronic data collection on tablets. With the paper and pencil, each question was asked to every student. So, if we asked a student about her cigarette use and she never smoked a cigarette, she still had to go through all of the other questions about cigarettes and indicate that she never used them. In this new format, she would skip those cigarette-specific questions since they aren’t relevant to her situation. In addition to reducing the respondent burden, particularly among non-users of these products, we’ve been able to ask additional questions since transitioning to an electronic survey without needing more time from the students to complete the survey.
Researchers Encouraged to Request Access to Restricted Use Files from Waves 2 and 4, Apply to Biospecimen Access Program
FDA and the National Institutes of Health (NIH) have announced the availability of the restricted-use questionnaire data files (RUF) from Wave 4 of the Population Assessment of Tobacco and Health (PATH) study collected December 2016 – January 2018. In addition, biomarker restricted-use files (BRUF) are now available for Wave 2 and contain the results of laboratory analyses from the specimens collected from adult participants between October 2014 – October 2015. Qualified researchers may apply for access through the PATH Study Restricted Use Files webpage.
In addition, the Biospecimen Access Program webpage provides information on how to access the urine, serum, and plasma collected from adult PATH Study participants during Wave 1.
The PATH Study is a household-based, nationally representative, longitudinal cohort study of youth (12-17 years old) and adults in the United States. The study was launched in 2011 to inform FDA’s regulatory activities under the Family Smoking Prevention and Tobacco Control Act. For the latest announcements, data releases and updates, new publications, upcoming events, and other information for PATH Study data users, join the PATH Study Data User Forum. The forum is hosted by the National Addiction and HIV Data Archive Program (NAHDAP) through the Inter-university Consortium for Political and Social Research (ICPSR) at the University of Michigan, and enables researchers using PATH Study data to submit and answer questions.
- Social media mentions of Electronic Nicotine Delivery Systems (ENDS) battery-related overheating, fires, and explosions: findings from a pilot study. Int J Environ Res Public Health 2019 Apr 12;16(8):1308
- Peer crowd segmentation for targeting public education campaigns: hip hop youth and tobacco use. Prev Med Rep 2019 Mar 15;14:100843
- Waterpipe or hookah-related poisoning events among U.S. adolescents and young adults. J Adolesc Health 2019 Mar 6 [Epub ahead of print]
- Vital signs: tobacco product use among middle and high school students--United States, 2011-2018. MMWR Morb Mortal Wkly Rep 2019 Feb 15;68(6):157-64
- The role of sexual identity in tobacco information-seeking behaviours and perceptions. Health Educ J 2019 Mar;78(2):203-13
The Family Smoking Prevention and Tobacco Control Act tasked FDA with regulating the manufacturing, distribution, and sale of tobacco products. Approaching this mission with a regulatory plan rooted in science, CTP seeks new research addressing the following areas: toxicity, addiction, health effects, behavior, communications, marketing influences, and impact analysis of regulatory actions. Featured below are some current CTP funding opportunities. You can find more information by clicking on the appropriate funding opportunity announcement (FOA) number.
Scientific Conference Grant Program
The Scientific Conference Grant Program recognizes the value of small, high-quality conferences and scientific meetings that are relevant to FDA’s mission and to public health.
R13 - FDA Scientific Conference Grant Program
FOA Number: PAR-16-378
Next Application Due Date: Oct. 11, 2019
Letter of Intent Due Date: Eight weeks before application due date
Tobacco Regulatory Science
The Tobacco Regulatory Science Program, FDA’s partnership with NIH to foster tobacco regulatory research, offers funding for scientists whose research can inform CTP’s regulatory activities.
RO1 - Tobacco Regulatory Science
FOA Number: RFA-OD-19-019
Next Application Due Date: July 19, 2019
Letter of Intent Due Date: 60 days prior to the application due date
This Funding Opportunity Announcement (FOA) invites R01 applications to support biomedical and behavioral research that will provide scientific data to inform tobacco product regulation to protect public health. Research projects must address the research priorities related to CTP’s regulatory authority. Research results from this FOA are expected to generate findings and data that are directly relevant in informing FDA’s regulation of the manufacture, distribution, and marketing of tobacco products to protect public health.
K01 - Mentored Research Scientist Career Development Award in Tobacco Regulatory Research
FOA Number: RFA-OD-18-005 (independent clinical trial not allowed) or RFA-OD-18-006
Next Application Due Date: July 19, 2019
This award provides support for an intensive, supervised career development experience of three, four, or five protected years in biomedical, behavioral, and social science research. This experience will inform the development and evaluation of tobacco regulation and will foster research independence. Projects must address one of FDA’s research priority areas.
K99/R00 - Pathway to Independence Award in Tobacco Regulatory Research
FOA Number: RFA-OD-18-007 (independent clinical trial not allowed) or RFA-OD-18-008
Next Application Due Date: July 19, 2019
This FOA aims to increase and maintain a strong cohort of talented independent investigators conducting research that will inform the development and evaluation of tobacco product regulations. This program is designed to facilitate the timely transition of outstanding postdoctoral researchers from mentored, postdoctoral research positions to independent, tenure-track or equivalent faculty positions. This program will provide NIH research support during this transition in order to help awardees launch competitive, independent research careers.
FDA Broad Agency Agreement
Solicitation Number: FDABAA-19-00123
FDA puts out agency-wide proposal requests through a special tool called the Broad Agency Announcement (BAA). Since 2012, FDA has utilized the BAA to solicit novel theories and methods for developing and evaluating regulated products, including tobacco products, by drawing on external sources, such as industry, academia, and other government agencies in areas where FDA has limited expertise or capacities. These proposals help to give FDA a better understanding of what innovative scientific and technical solutions may be available to solve difficult regulatory science problems. CTP participates in the BAA solicitation, and tobacco priority topics are included in sections 1, 2.6, and 5.