FDA advisory committee largely rejects modified risk claims for heat-not-burn tobacco products

The Tobacco Product Scientific Advisory Committee (TPSAC) to the Food and Drug Administration (FDA), has voted against allowing Phillip Morris International (PMI) to make certain modified risk claims on its heat-not-burn tobacco product, IQOS.

The IQOS system uses a heating blade to electronically heat reconstituted tobacco inside of a cigarette-like heating stick, creating an aerosol that is inhaled by the user. The temperature is regulated by the device and held beneath the temperature at which tobacco burns. The system also includes a rechargeable battery. PMI claims that heating is a safer way to consume tobacco than burning.

PMI was seeking approval to make modified risk claims about three products – IQOS Regular, IQOS Smooth Menthol and IQOS Fresh Menthol. PMI was seeking approval for the following claims:

  • Scientific studies have shown that switching completely from cigarettes to the
    IQOS system can reduce the risks of tobacco-related diseases.
  • Switching completely to IQOS presents less risk of harm than continuing to smoke
  • Scientific studies have shown that switching completely from cigarettes to the
    IQOS system significantly reduces your body’s exposure to harmful or potentially
    harmful chemicals.

As part of the modified risk approval process, FDA convenes experts in biomedical, social and behavioral and public health tobacco research to seek their professional opinions about the validity of the claims and the effect on the health of both users and nonusers. PMI was not seeking approval to bring IQOS to market in the US at this meeting. The premarket approval application is a separate process. IQOS is already available in Japan, South Korea and parts of Europe.

The two-day meeting included presentations from scientists and representatives from PMI and the FDA followed by 3-minute comments from about 30 members of the public representing various stakeholders and interests. Committee members peppered PMI and FDA representatives with questions throughout the meeting that hinted at their skepticism and concerns about the products and the modified risk claims.

Scientists and representatives from PMI presented data from chemical, preclinical and human studies on IQOS products in support of their claims. According to PMI data, the IQOS system releases substantially lower levels of the harmful constituents compared to combustible cigarettes, and IQOS use showed less evidence of harm and smoking-related disease. PMI representatives reiterated that this product is targeted at smokers and narrowly focused its modified risk claims on smokers who completely switch from using combustible cigarettes to IQOS.

FDA scientists then presented their evaluation of the scientific data included in PMI’s application. FDA scientists were able to independently verify PMI’s claims that substantially lower levels of harmful or potentially harmful chemicals are released from IQOS products but also noted that based on exposure to harmful ingredients, smoking 10 heatsticks would be equivalent to smoking 1 to 3 combustible cigarettes.

The comments from members of the public were overwhelmingly in favor of approval of these modified risk claims. Supporters strongly believed that IQOS products could help smokers who had failed other cessation methods and that these products were a safer alternative to cigarettes. Some expressed concern about overregulation and stifling innovation.

Ultimately, the committee voted against approving the first two claims but voted in favor of the third. The committee agreed that use of IQOS exposes the user to lower levels of harmful chemicals but voted 5-2 (with one abstention) that PMI did not show that reduced exposure was “reasonably likely to translate to a measurable and substantial reduction” in death or disease.

Some sticking points throughout the meeting included the definition of “complete switching”, which PMI defined as 70-100% use of IQOS and up to 30% combustible cigarette use. Committee members did not believe that there was enough evidence for some of the claims or that the studies were conducted for a sufficient length of time to draw a conclusion. Committee members also found the wording of the claims confusing and worried about implying a benefit from partial – not complete – switching. Committee members were concerned that the limited reduction in biomarkers of potential harm after switching to IQOS was also not sufficient to support the claims of reduced harm. Furthermore, the committee thought that the likelihood of complete switching – the circumstance upon which claims were predicated – was low compared to the higher likelihood of combined combustible cigarette and IQOS use. However, the committee did agree that IQOS would probably not appeal to youth, adults who have never smoked or former smokers. Many of the committee members drew comparisons to e-cigarettes and raised concerns over vulnerable populations and the popularity of menthol tobacco products to African Americans.

The committee’s decisions are non-binding. Instead, the FDA will consider the votes, opinions and discussion of the committee while making its final decision on PMI’s modified risk claims in the coming months.

Additional Resources

2018 TPSAC Meeting Materials and Information

National Academies releases report, “Public Health Consequences of E-Cigarettes”

A long anticipated study by the National Academies of Sciences, Engineering and Medicine on the health effects on e-cigarettes found a substantial level of evidence that youth and young adults who use e-cigarettes are at greater risk of trying combustible cigarettes.

The study, “Public Health Consequences of E-cigarettes”, was commissioned by the Food and Drug Administration to provide information about the health effects of e-cigarettes on individual users as well as the population at large, especially on vulnerable populations such as youth and pregnant women. The resulting report is over 600 pages long and addresses a number of health effects, including impacts on the cardiovascular and respiratory systems and the oral cavity and cancer risk. The committee that issued the report grouped their numerous conclusions by the level of evidence supporting each finding, with conclusive being the highest level of evidence, followed by substantial, moderate, limited, and insufficient at the lowest level. The committee also described health effects for which there were no available data to draw a conclusion.

In addition to finding that e-cigarette use increased the risk of combustible cigarette use among youth and young adults, the committee also found a moderate level of evidence that for youth and young adults who had ever used combustible cigarettes, e-cigarette use increased the intensity (defined as “the number of cigarettes smoked per smoking day”) and frequency (the number days a cigarette was used in the past 30 days) of subsequent combustible cigarette use. There was also limited evidence that in the short-term, e-cigarette use increased the duration of subsequent combustible cigarette use among youth and young adults who had ever tried combustible cigarettes.

The report included a chapter on the available evidence on the oral health effects of e-cigarettes that focused specifically on periodontal disease. The committee noted that because e-cigarettes are such a recent arrival on the tobacco products market, “there is a lack of rigorously designed studies examining the effects of e-cigarettes on oral health”. All conclusions were based on limited evidence. One study showed that certain markers of periodontal disease were elevated in both male e-cigarette users and cigarette smokers compared to non-smokers. (Note: the report incorrectly states: “The men who smoked cigarettes had a significantly higher plaque index and probing depth than group 2 [e-cigarette users] or group 3 [non-smokers].” AADR has notified the committee of the error.) Another study indicated that switching from combustible cigarettes to exclusive e-cigarette use improved oral health. However, yet another study showed that switching from smoking to e-cigarettes increased gingival inflammation in smokers after two weeks. In vitro studies showed that the nicotine and flavoring in e-cigarette vapors may harm oral tissues and that menthol flavoring can cause DNA damage and inflammation. The committee noted a lack of epidemiological studies on the association between e-cigarette use and periodontal disease.

Notably, the committee did not include any information on oral or oropharyngeal cancer or other oral health effects.

On the issue of the efficacy of e-cigarettes as smoking cessation devices, the committee found a moderate level of evidence that more frequent e-cigarette use increased the likelihood that a smoker would be able to successfully quit and that nicotine-containing e-cigarettes were more effective in smoking cessation than non-nicotine e-cigarettes. The conclusions were based on two different types of studies – observational studies versus randomized control trials, respectively – but the level of evidence was rated as moderate for both conclusions. However, due to an insufficient level of evidence, the committee could not say whether e-cigarettes were more or less effective as smoking cessation devices compared to quitting “cold turkey” or using FDA-approved cessation treatments. There was also no evidence for or against the claim that dual use of combustible cigarettes with e-cigarettes is less harmful than exclusive use of combustible cigarettes.

The committee was able to conclusively say that completely switching from combustible cigarettes to e-cigarettes reduced exposure to the harmful chemicals found in combustible cigarettes and that there is a substantial level of evidence that complete switching results in many decreased adverse health effects. However, there was also a substantial level of evidence that e-cigarettes use results in dependence.

Finally, the committee identified a number of research needs to more thoroughly understand the health effects of e-cigarettes, including the need for both short and long-term studies and the need to improve the quality and methods of e-cigarette research.

Additional Resources

National Academies website, “Public Health Consequences of E-Cigarettes” nationalacademies.org/ecighealtheffects

Report release webinar: https://youtu.be/vifAY4YcVbQ

Full report, “Public Health Consequences of E-Cigarettes”


All of Us Research Program Seeks Input on Research Priorities

The All of Us Research Program aims to build one of the largest, most diverse datasets of its kind for health research, with one million or more volunteers nationwide, who will sign up to share their information over time. Researchers will be able to access participants’ de-identified information for a variety of studies to learn more about the biological, behavioral, and environmental factors that influence health and disease. Their findings may lead to more individualized health care approaches in the future.

Using IdeaScale, the All of Us Research Program is collecting ideas through a tool known as a “use case” that outlines and describes research questions that the All of Us Research Program could help answer.

The information provided will be used at the All of Us Research Priorities Workshop on March 21–23, 2018, to identify key research priorities and requirements (such as data types and methods) for future versions of the All of Us protocol.

You can ensure that dental, oral and craniofacial research is included in the All of Us Research Program by:

1. Voting for the following ideas submitted by the National Institute of Dental and Craniofacial Research by Friday, February 9:

2. Clicking here to be directed to IdeaScale, where you can see the ideas submitted by others or add your own idea by Friday, February 9.

3. Sending your idea to sajiboye@iadr.org that may be submitted on behalf of AADR by COB Friday, January 26.

Thank you for your engagement in this research initiative.

AADR submits comments to the Opioid Policy Steering Committee

AADR has submitted comments in response to the Food and Drug Administration’s (FDA) request for public comment on additional steps the FDA can take to reverse the opioid abuse epidemic. AADR’s comments strongly emphasized the need for both prescriber and patient training.

The FDA Opioid Policy Steering Committee (OPSC) was established in May 2017 and tasked with developing strategies for fighting the opioid abuse epidemic. The OPSC’s four focus areas are 1) decreasing exposure to opioids and preventing addiction; 2) supporting opioid use disorder treatment; 3) promoting the development of new, less addictive pain therapies and 4) improving enforcement and revisiting the benefit/risk assessment of opioid therapies.

The request for comment was a follow-up to the National Academy of Medicine (NAM) report, “Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use”. AADR member Dr. Eli Eliav, an orofacial pain researcher at the University of Rochester, was a member of the NAM committee.

In comments to the OPSC, AADR stressed the importance of controlling the opioid abuse epidemic while allowing access to opioids for patients who really need them for pain control. AADR supported the NAM committee recommendations for more research to better understand pain and opioid use disorders, the opioid epidemic and public health considerations to inform the regulatory process. AADR supported the recommendation by the American Dental Association that nonsteroidal anti-inflammatory drugs should be the first-line pain medication for acute dental pain and advocated for the implementation of a national, mandatory prescription drug monitoring program. AADR also recommended mandatory provider training on how to prescribe opioids, recognize possible abuse and treat chemically-dependent patients.

For AADR’s full letter to the OPSC, please click here.

AADR submits comments on inclusion of pediatric research in All of Us Research Program

AADR has submitted comments in response to request for public input on the inclusion of pediatric research in the All of Us Research Program, formerly the Precision Medicine Initiative. Currently, children are excluded from the All of Us Research Program, along with prisoners and adults who are unable to give consent. The Child Enrollment Scientific Vision Working Group of All of Us requested input on the types of research questions that could be answered with the enrollment of children. AADR submitted the following comments in response:

Question 1
What are the most critical short-, medium-, and long-term precision medicine research questions that could be addressed by the inclusion of pediatric populations in the All of Us Research Program?

Short term (0-5 years)

Orofacial clefts affect 1/700 live births and are associated with environmental, dietary and genetic factors. Future studies should integrate genetics with cleft phenotypes, identify and describe the contribution of candidate genes and describe the interaction between genetic and environmental risk factors (Parker SE et al. 2010. Birth Defects Res A Clin Mol Teratol. 88(12):1008-16; Dixon MJ et. 2011. Nat Rev Genet. 12(3): 167-178; Li C et al. 2017. JDR 96(11): 1184 – 1191). Childhood dental caries remain a public health concern marked by pronounced health disparities. There is evidence of heritability of dental caries but few known associated loci (e.g., ACTN2) and polymorphisms (Stanley BO. 2014. JDR 93(7):626-32). The strength of the evidence supporting these associations is limited due to small sample sizes and reliance on candidate-gene study designs. Researchers currently do not understand the magnitude and the mode of influence of these loci and polymorphisms on caries risk in children (Divaris K. 2017. Dent Clin N Am. 619-625), especially in the context of environmental factors like fluoride exposure (Shaffer JR et al. 2015. Hum Genet. 134(2):159-67). Understanding the composition and function of the oral microbiome in health and disease will also help investigators precisely dissect the etiology of caries on an individual level and lead to more effective preventive and therapeutic modalities.

Medium (5-10 years)

In 5-10 years, All of Us could help scientists understand the genetic, lifestyle and environmental factors that contribute to oral health disparities in children and that are not completely explained by differences in socioeconomic status. A better understanding of the biological underpinning of oral and craniofacial conditions in children can help explain how social deprivation and other upstream factors can have such profound impact on multiple, clinical oral health endpoints. For example, All of Us could help elucidate the impact of genetics and epigenetics (a mechanism that may illuminate previously uncharacterized links between social factors, environmental exposures and biological or clinical outcomes) on intermediate oral and craniofacial phenotypes such as tooth anatomy, salivary factors, the oral microbiome as well as directly on oral disease susceptibility (Divaris K. 2016. JDR 95(3):248-254).

Long (more than 10 years)

Understanding how oral health and disease develop over time requires longer follow-up periods than what is typically feasible with a research project grant. The inclusion of pediatric research in All of Us will enable longitudinal studies of oral and craniofacial health among large, population-based samples. Gaps in knowledge that need to be addressed include the impact of craniofacial developmental diseases, such as cleft lip/palate and enamel hypomineralization and hypoplasia, on susceptibility to or exacerbation of other diseases; common risk factors between oral and other diseases leading to common prevention and treatment strategies; the quantification of risk for certain oral diseases like dental caries (Divaris K. 2016. JDR 95(3):248-254); caries progression from ages 0-18; and oral health across the lifespan. The health of children with complex medical conditions or with cancer can be further compromised when they have untreated caries lesions. The development of effective means for the prevention or management dental caries among this and other pediatric populations with special health care needs is critical.

All of Us should collect and bank saliva and other biological specimens (e.g., plaque) to enable genetic and microbiome analyses, as well as studies on how salivary factors change from infancy over the life course. Saliva collection methods for valid downstream omics (e.g., genomics, microbiomics and proteomics) analyses in very young children need to be studied.

Question 2

What are the key gaps in current pediatric study designs that might be appropriate for All of Us to address through the enrollment of children (for example, preconception studies, sibling studies)? 

All of Us should enroll families and follow these family cohorts over time. Children are subject to the behaviors, environment and resources of their caregivers, e.g., caregiver oral health literacy is associated with the oral health status of the child (Vann WF et al. JDR. 89(12):1395-400).  Maternal periodontitis treatment may improve low birth weight, but the evidence is low quality (Iheozor-Ejiofor Z et al. 2017. Cochrane. (6)) due to study sizes and possibly treatment intervention at the end of the first trimester versus preconception.

All of US should include community-based participants, i.e., individuals enrolled regardless of health or disease status. Oral and craniofacial research has relied on case-control study designs or clinic-based samples, but these designs are subject to numerous biases.

All of Us should enroll racially/ethnically diverse children from younger age groups. Precision oral health studies (e.g., genome-wide association studies) have been mostly conducted in children of European decent and have included few children under the age of 6, the cutoff age for early childhood caries. Many studies of oral diseases have also been conducted in small cohorts or clinical (care-seeking) samples. A larger, diverse pool of community-based (not necessarily care-seeking or clinic-attending) participants can alleviate previous challenges with low statistical power, validity, reproducibility and generalizability (Divaris. 2017. Dent Clin N Am. 619-625).

Question 3
What are the research resources that the inclusion of children into the All of Us Research Program could potentially generate (for example: registries, databases, or innovative methods)?

The data generated from All of Us will enable the refinement, validation and ultimately improvement of current caries risk assessment tools (Divaris K. 2016. JDR 95(3):248-254) and the generation of more precise algorithms for the prediction of disease occurrence, time to disease development, and disease severity as well as methodologies in genetics and social and behavioral research. The dental research community will greatly benefit from using samples stored in biobanks for future research. The inclusion of pediatric research in All of Us will enable hypothesis generation and testing for future research. It is expected that the availability of such rich biorepositories (offering opportunities for ‘deep phenotyping’) and other big data sources (allowing ‘wide’ research explorations) will accelerate scientific discovery and the potential for translation of research findings to meaningful, individual and population health-improving solutions in the oral and craniofacial domain.


AADR Comment on Prenatal Fluoride Exposure Study in Mexico

AADR Comment on “Prenatal Fluoride Exposure and Cognitive Outcomes in Children at 4 and 6–12 Years of Age in Mexico” by Bashash, M. et al. in Environmental Health Perspectives published online September 19, 2017

The findings reported by Bashash et al. add to the scientific literature on associations between fluoride exposure and cognitive outcomes. Their epidemiologic study using 299 mother-child pairs in Mexico examined maternal urinary fluoride levels, as a proxy measure of pre-natal fluoride exposure, and two measures of cognitive outcomes in their children at age 4 and 6 -12 years. Their findings must be taken into context with previous studies, including the New Zealand Dunedin longitudinal study that did not find an association between fluoridated water and IQ.

It is also important to note that Bashash et al. used data from a longitudinal birth cohort study in Mexico (ELEMENT) originally designed to examine how environmental exposures to metals and other chemicals affect pregnant women and children, and not to examine the specific relationship between fluoride exposure and cognitive development. The current study is examining samples of urine from two cohorts, the first to investigate prenatal lead exposure (1997-2001) and the second, the effect of calcium supplementation (2001-2006). As an examination of fluoride was not part of the original study design, there are no data on total fluoride intake by the pregnant mothers or their children, other than the fact that Mexico does not have community water fluoridation. Exposure to fluoride would be from naturally occurring in water supplies, fluoridated salt, and other dietary and environmental sources.

Some places in Mexico with high concentrations of naturally-occurring fluoride in water also have high concentrations of arsenic, a known neurotoxin. As the authors noted, information regarding the study population’s exposure to arsenic or other environmental toxins was not available, and therefore, could not be ruled out as a confounding variable. Given such lack of exposure data, among other limitations clearly cited by the authors, the results should not alter current policy recommendations on the use of fluorides for caries prevention.

The AADR concurs with Bashash et al. that the ability to extrapolate their findings to how exposures may impact general populations is limited given the lack of data on fluoride exposure and fluoride pharmacokinetics during pregnancy. The authors conclude that their findings must be confirmed in other populations. The AADR agrees with the authors that these findings reinforce the need for additional research.

AADR notes that fluoride has been an important tool in reducing the prevalence of dental caries in the United States. Specifically, the Centers for Disease Control and Prevention named community water fluoridation one of the top 10 public health achievements of the 20th century. Other fluoride interventions include the application of topical fluorides including fluoride varnish, the use of fluoride supplements and fluorides in toothpaste. As a result, caries prevalence in children has been reduced dramatically as has the number of older adults with total tooth loss in the United States.

Senate appropriations committee approves $2 bil NIH increase for FY 2018

Today, the Senate Appropriations Committee approved a $2 billion increase in the budget of the National Institutes of Health (NIH) to $36.1 billion for FY 2018. If enacted, this would constitute a 6% increase over FY 2017. The Senate spending bill includes $400 million for the BRAIN initiative, a $140 million increase; $290 million for the All of Us Research Program, a $60 million increase; and increases to to every NIH institute and center, according to the Senate Appropriations press release. Importantly, the bill also prohibits capping indirect costs at 10%.

Earlier this summer, the House Appropriations Committee approved a spending bill that only provided an additional $1 billion – a 3% increase. The National Institute for Dental and Craniofacial Research (NIDCR) received a $6 million increase in this bill, only a 1.6% increase over FY 2017 levels.

Update: The Senate Appropriations Committee has released the bill text. The spending bill provides for an additional $14 million over FY 2017 for NIDCR, which is a 3% increase over FY 2017.

AADR submits comments on NIDCR FY 2019 proposed research initiatives

AADR has provided input on the National Institute of Dental and Craniofacial Research’s (NIDCR’s) Proposed Research Initiatives for FY 2019. Each year, NIDCR solicits input from its stakeholders as the institute decides on which areas to focus research efforts for future fiscal years. The research themes outlined in the request for comment will be used to guide research initiatives for FY 2019 but do not fully capture the entire research portfolio of NIDCR. Instead these initiatives serve as research goals for the institute and can be further developed into funding opportunities. The proposed initiatives are:

  • Advancing Our Understanding of Enamel Development
  • Basic and Translational Research on HIV and AIDS-Related Pathogens in the Oral Cavity
  • Bioinformatics/Data Science Jumpstart for Dental, Oral, and Craniofacial Diseases
  • Biological Factors Underlying Dental, Oral, and Craniofacial Health Disparities
  • Biology of Aging in Dental, Oral, and Craniofacial Tissues
  • Dental Practice-Based Research Networks
  • FaceBase 3 – Bioinformatics and Data Management Hub
  • Precision Imaging of Oral Lesions
  • Understanding Gene-Environment Interactions in Dental, Oral, and Craniofacial Diseases

In its letter to NIDCR Director, Dr. Martha J. Somerman, AADR strongly supported the proposed initiatives. AADR also urged NIDCR to incentivize collaboration between researchers and provided additional feedback on the proposed initiatives on enamel development, HIV/AIDS and precision imaging of oral lesions. To view the full comments, please click here.

AADR joins over 100 organizations to oppose cuts to indirect costs

AADR joined over 100 organizations to oppose the 20% cut to the National Institutes of Health (NIH) budget and the reduction in NIH support for indirect research costs proposed in President Trump’s FY18 budget request. From the letter:

Conducting high-quality medical research for our country carries expenses, including essential costs for maintenance and development of state-of-the-art labs, utilities such as precision climate control, security protections for handling dangerous chemicals, proper disposal of hazardous waste, and personnel to support required administrative and compliance work, among others. It simply is not possible to carry out medical research without incurring such expenses, and NIH support for F&A helps offset a portion of these real research costs.

Please click here for the full text of the letter sent to Mick Mulvaney, Director of the Office of Management and Budget, and Dr. Tom Price, Secretary of the Department of Health and Human Services.

Trump releases R&D priorities for FY19

President Trump has released his research and development (R&D) priorities for FY19 in a memo from Office of Management and Budget (OMB) Director Mick Mulvaney to executive agency heads. The memo specifically mentions the aging population, the opioid crisis and research that leads to “more efficient and effective healthcare” as top health research priorities. The memo also prioritizes STEM education and workforce development for all Americans, specifically mentioning women and other underrepresented groups.

This is President Trump’s first memo outlining his scientific priorities. The Obama administration’s first memo on science and technology was similarly light on specifics but included more detailed initiatives in subsequent years, such as the BRAIN Initiative, combating antibiotic resistance and the Precision Medicine Initiative. However, the memo is in stark contrast to President Trump’s FY17 and FY18 budget proposals, which each proposed severe cuts to the National Institutes of Health (NIH) and other health agencies.

Other priorities outlined in the memo do give cause for concern. First, the emphasis on budget neutrality would make it virtually impossible to grow the biomedical research enterprise. The Trump administration has previously targeted indirect, or facilities and administration, costs as a means of shrinking the NIH’s budget, and these costs may be targeted again. Second, the memo emphasizes reducing duplicative efforts across federal agencies. While this is not a new idea, it is concerning in the context of the previously proposed reorganization of NIH that would also move the Agency for Healthcare Research and Quality (AHRQ) into the NIH. Finally, the memo emphasizes the role of the federal government in basic and early-stage research and that of the private sector in late-stage, applied research, specifically stating agencies should “identify existing R&D programs that could progress more efficiently through private sector R&D, and consider their modification or elimination where Federal investment is no longer needed or appropriate”. Basic research is often the focus of federal research investments and applied research is taken up by the private sector, but in the context of President Trump’s previous budget proposals, this may indicate that the Trump administration still aims to shrink the federal research budget to make room for other priorities. Ultimately, the research community will have to wait until the release of the President’s FY19 budget proposal to fully understand how the Trump administration envisions translating these priorities into federal R&D investments going forward.

AADR will continue to monitor both formal and informal indications of the Trump administration’s federal R&D priorities and intentions and continue to engage and educate members of Congress on the importance of providing robust funding for biomedical research. Please continue to monitor the Government Affairs and Science Policy blog for how members can be engaged in these efforts.