Recommendations to improve FDA premarket tobacco product application review to follow statutory mandates and improve scientific rigor

On October 21, 2022, Lauren Lempert presented at one of the Regan-Udall Foundation Expert Panels listening sessions on how to improve FDA operations of FDA’s Center for Tobacco Products operations. She and I followed up with a written comment letter detailing many of the problems with the tobacco product application processes, including both the premarket tobacco product application (PMTA) and modified risk tobacco product (MRTP) processes.

In general, CTP’s premarket tobacco product application review process has not followed statutory mandates or scientific rigor. We offered the following recommendations to improve CTP’s application review process which are supported in detail in the our comment letter (which is reproduced in full after this summary):

1.     CTP’s actions must be consistent with the Findings section of the Tobacco Control Act which underscores Congress’s intent that FDA protect public health through a rigorous premarket application process focused primarily on the impacts to youth. Therefore, CTP’s procedures must ensure that CTP is implementing the law as Congress intended. 

2.     CTP must put the burden of proof on the applicant to demonstrate that authorizing a specific product is appropriate for the protection of the public health, rather than following its current practice of authorizing products unless FDA can demonstrate that the marketing authorization is not appropriate. 

3.     CTP must explicitly and transparently define “net benefit to public health” and include explicit quantified comparisons of risks and benefits in all applications to determine whether the applicant demonstrated that the product under review confers net health benefits and is therefore appropriate for the protection of the public health.  

4.     CTP must clearly state what trade-off it is willing to accept: how many adults must quit completely to make it worth sacrificing how many kids to a lifetime of nicotine addiction? 

5.     CTP must define quitting or “switching completely” to mean 100% switching from cigarettes to the proposed new tobacco product consistent with the plain meaning of the term. 

6.     CTP must require applicants to demonstrate that, as actually used as consumer products (not as clinically supervised medical cessation treatments) the design characteristics of their specific new tobacco product (in contrast to the general product class) leads to smokers quitting. 

7.     CTP’s scientific review of premarket applications must not only properly apply the mandated public health standard, but must also appropriately consider valid scientific evidence.  

8.     CTP must stop accepting unsubstantiated reduced harm claims about e-cigarettes and other new tobacco products and should instead engage the rapidly growing published scientific evidence on the health effects of these products. 

9.     CTP’s determination that any particular product should obtain marketing authorization must be based on the scientific evidence presented in the application for the specific product, as required by the Tobacco Control Act, and not on an unsubstantiated predetermination that e-cigarettes in general will help adult smokers quit and therefore should remain on the market.  

10.  CTP’s application review process should require and focus on appropriate scientific studies, including: 

  • impacts on youth and youth perception; 
  • actual use studies of how the products are used in the real world as consumer products, rather than randomized controlled clinical trials; 
  • studies of the impacts of the particular toxicants found in the products under review; and  
  • the expanding literature on the range of health impacts of e-cigarettes and other new products. 

11.  CTP should hold applicants and itself to the same high scientific standars that the government applies when preparing Surgeon General Reports on tobacco and health. 

12.  CTP’s premarket application process must be more transparent, including: 

  • explicitly quantifying what trade-off it is willing to accept: how many adults must quit completely to make it worth sacrificing how many kids to a lifetime of nicotine addiction? 
  • So long as the products have been on the market, publicly posting a list of all PMTAs and posting Marketing Denial Orders and related TPLs with appropriate redactions for confidential commercial information. 

Here is the full letter (also available as a PDF):

November 7, 2022

Dear Members of the Reagan-Udall Foundation’s Tobacco Independent Expert Panel,

Thank you for the opportunity to provide additional input following Lauren Lempert’s presentation at the Reagan-Udall Foundation’s public stakeholder meeting on October 21, 2022. 

Since most of the members of the Expert Panel come from a pharmaceutical background, it is important to emphasize the basic point that the Center for Tobacco Products (CTP) is not the Center for Drug Evaluation and Research (CDER). Unlike medicines which may be approved as safe and effective by CDER for specific patients with specific clinical conditions to be delivered using specific dosing protocols, CTP can only authorize or permit the marketing of tobacco products as consumer products. 

In particular, CTP cannot limit which adults over age 21 use tobacco products or how adults use them.[1]  Specifically, CTP should end its practice of assuming that e-cigarettes are medicines to quit smoking. If a company wants to market their e-cigarettes as smoking cessation devices, they must seek CDER’s approval.

As discussed in detail below, to date the FDA has acted as if it can only disallow an application for a new tobacco product if the FDA demonstrates that such an authorization is not appropriate for the protection of public health.  CTP needs to place that burden of proof on the applicant as Congress intended and the law requires.

  • The Findings section of the Tobacco Control Act underscores that Congress intended FDA to protect public health through a rigorous premarket application process focused primarily on the impacts to youth

Expert Panel members should carefully study the Findings section of the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) which clearly lays out in 49 separate findings Congress’s intent in enacting this law.[2] These findings make clear that Congress’s main goal was to end the “pediatric disease” (Finding 1) of tobacco use and ensure that future generations of children, young adults, and adults do not become dependent on tobacco products because nicotine, an addictive drug (Finding 3).[3] Congress found (Finding 8) that federal, state, and other public health officials recognize that the tobacco industry must be subject to “ongoing oversight.” Finding 14 lays out the costs in terms of lives lost as well as dollars spent on health care costs related to tobacco-induced disease. Finding 24 explains that the tobacco industry targets young people as “replacement smokers” for adults who succumb to tobacco-related diseases. Finding 29 squarely places the responsibility of the health crisis on the tobacco industry, and Finding 30 gives FDA the responsibility to provide regulatory solutions.

Importantly, in stark contrast to a comment made by one of the industry speakers during the October 21 session, Congress’s intent was to make the premarket tobacco product application (PMTA) process rigorous because, as the cornerstone of the Tobacco Control Act, it is a way to prevent more dangerous products from entering the market and addicting kids. Finding 36 provides: “It is essential that the Food and Drug Administration review products sold or distributed for use to reduce risks or exposures associated with tobacco products and that it be empowered to review any advertising and labeling for such products. It is also essential that manufacturers, prior to marketing such products, be required to demonstrate that such products will meet a series of rigorous criteria, and will benefit the health of the population as a whole, taking into account both users of tobacco products and persons who do not currently use tobacco products.” In keeping with this express intent, Tobacco Control Act section 910 places the burden of proof on the applicant to demonstrate that authorizing the sale of a new tobacco product is “appropriate for the protection of the public health” (APPH). In contrast, to date, the FDA has acted as if it can only disallow an application for a new tobacco product if the FDA demonstrates that marketing authorization is not appropriate for the protection of public health.  This shift in the burden of proof is incorrect; CTP should not authorize any new tobacco product under the PMTA pathway unless an applicant has met its mandatory burden of proof.

Additionally, Tobacco Control Act section 3(4) states that one of the purposes of the law is “to provide new and flexible enforcement authority to ensure that there is effective oversight of the tobacco industry’s efforts to develop, introduce, and promote less harmful tobacco products.” Here Congress again clearly expressed its intent to require FDA to engage in rigorous review and oversight for products that manufacturers wish to market with reduced harm claims. The modified risk tobacco product (MRTP) process, delineated in Tobacco Control Act section 911(g), requires applicants to demonstrate that the proposed MRTP product, “as actually used by consumers, will (A) significantly reduce harm and the risk of tobacco-related disease to individual tobacco users; and (B) benefit the health of the population as a whole taking into account both users of tobacco products and persons who do not currently use tobacco products [including youth].”

The Expert Panel’s recommendations should include changes to CTP procedures to ensure that CTP is implementing the law as Congress intended. To date, the FDA has acted as if it can only disallow an application for a new tobacco product if the FDA demonstrates that such an authorization is not appropriate for the protection of public health.  CTP needs to place that burden of proof on the applicant as Congress intended and the law requires.

  • CTP must determine whether proposed new tobacco products confer net health benefits when applying the “appropriate for the protection of the public health” standard

CTP is mandated by law to assess whether e-cigarettes and other new tobacco products are “appropriate for the protection of the public health.” That is the legal standard, and, as noted above, it is different from CDER’s. 

FDA recognizes that APPH means a net benefit to public health:

FDA interprets the APPH standard to require a showing [by the applicant company] that permitting the marketing of a new tobacco product would have a net benefit to public health based upon the risks and benefits to the population as a whole, which includes youth, young adults, and other vulnerable populations. In determining whether permitting the marketing of a new tobacco product would result in a net benefit to public health, FDA weighs the potential negative public health impacts (e.g., harm from initiation and use among nonusers, particularly youth) against the potential positive public health impacts (e.g., benefit from adult users of more harmful tobacco products completely switching).[4] [emphasis added]

In reaching this determination, CTP must consider the risks and benefits to the population as a whole, and weigh not only any benefits that might accrue to adults if they can truly switch completely, but also the known risks to youth and other non-users from initiation that could lead to a lifetime of nicotine addiction.

Therefore, to show that the APPH standard has been met, FDA must quantify the net health benefits. FDA must find that more adults are achieving or are highly likely to achieve benefits that outweigh the known risks to kids.

To date, however, FDA has avoided making the needed quantified comparisons and statements.  The Expert Panel should recommend that FDA include such quantifications in all PMTA decisions in a transparent way.

The risks to youth are well-established. FDA recently reported,[5] based on its 2022 National Youth Tobacco Survey (NYTS),[6] that about 1 in 10 or more than 2.5 million kids are currently using e-cigarettes, and 1 in 4 of these users are using e-cigarettes daily, indicating heavy addiction. Moreover, not only are e-cigarettes attracting kids, but lots of them will go on to smoke cigarettes. More than two dozen published studies have found that e-cigarette use increases the risk of cigarette smoking.[7]

At the October 21 hearing, several industry speakers made unsubstantiated claims that e-cigarettes are the best, if not only way, to help cigarette smokers quit and FDA routinely assumes that e-cigarettes help at least some smokers “switch completely” (i.e., quit smoking).  In contrast, while it is well-established that e-cigarettes have increased youth addiction to nicotine, the cessation efficacy of e-cigarettes as consumer products (authorized by CTP) as opposed to medicines given in a clinically supervised situation (as might be approved by CDER) remains unproven.  Quite the contrary, FDA has ignored consistent evidence that when used as consumer products, e-cigarettes do not help smokers quit.[8]   Indeed, the two most recent three-year longitudinal studies show that e-cigarette use substantially reduces smoking cessation.[9]

The Expert Panel should recommend that FDA actively engage the current scientific literature on the effects of e-cigarette use as consumer products on smoking cessation.  Given the consistent evidence that e-cigarettes as actually used as consumer products do not overall help smokers quit cigarettes, FDA should require that any applicant claiming that their specific e-cigarette (or other new tobacco product), in contrast to e-cigarettes in general, leads to smokers quitting in actual use.  Applicants should also be required to describe the specific design considerations that lead their e-cigarette (or other new tobacco product) to behave differently than the product class in general.

The Expert Panel should recommend that FDA define “switching completely” as the term implies to mean 100% or virtually 100% switching.  This is important because FDA authorized the sale of Philip Morris’ IQOS heated tobacco product even though the IQOS MRTP application defined “switching completely” as using cigarettes up to 30% of the time.[10]   Only cutting cigarette consumption by 70% is unlikely to have much benefit in term of cardiovascular disease, where the dose-response relationship between cigarettes consumed and disease risk is highly nonlinear.[11]

Finally, the FDA needs to be transparent about the quantitative trade-off it is willing to accept between new youth nicotine addicts (and their long-term health risks) and any purported benefits to adults.  Simply put, to determine the net public health benefit, the Expert Panel should recommend that FDA clearly state what trade-off it is willing to accept: How many adults must quit completely to make it worth sacrificing each kid to a lifetime of nicotine addiction?

  • CTP should stop uncritically accepting unsubstantiated reduced harm claims about e-cigarettes

Several industry speakers at the October 21 hearing stated that e-cigarettes are “95% less harmful” than cigarettes based on a 2014 paper by David Nutt and others.[12] It is important to understand that the Nutt et al paper is not based on any actual empirical evidence.  It is simply summarizing opinions of “experts” selected by Nutt without citing any actual evidence. Indeed, in describing their own work, the Nutt et al authors noted, “A limitation of this study is the lack of hard evidence for the harms of most products on most of the criteria [for assessing the quality of evidence].” When this paper was written over 7 years ago, there were only 54 papers published on the health effects of e-cigarettes; today there are more than 10,450 papers.[13]  In particular, the Nutt et al estimate has been thoroughly discredited.[14] 

It is illegal for tobacco companies to make unsubstantiated claims about purported reduced risks or harmfulness of their tobacco products without first demonstrating those reduced risks through the separate (from the PMTA) application process known as the Modified Risk Tobacco Product or MRTP process described at Section 911 of the Tobacco Control Act to obtain an FDA order permitting such claims.[15]  Congress recognized this and stated in Finding 37: “Unless tobacco products that purport to reduce the risks to the public of tobacco use actually reduce such risks, those products can cause substantial harm to the public health to the extent that the individuals, who would otherwise not consume tobacco products or would consume such products less, use tobacco products purporting to reduce risk. Those who use products sold or distributed as modified risk products that do not in fact reduce risk, rather than quitting or reducing their use of tobacco products, have a substantially increased likelihood of suffering disability and premature death.[16] The FDA recognizes that costs to society of the widespread use of products sold or distributed as modified risk products that do not in fact reduce risk or that increase risk include thousands of unnecessary deaths and injuries and huge costs to our health care system.” Among the nine Congressional findings concerning unsubstantiated reduced risk claims, Finding 42 states: “Permitting manufacturers to make unsubstantiated statements concerning modified risk tobacco products, whether express or implied, even if accompanied by disclaimers would be detrimental to the public health.”

The Expert Panel should take note of the rapidly accumulating evidence base on e-cigarettes (and other new tobacco products as relevant evidence accumulates) and recommend that the FDA take care to ensure that applicants integrate the latest scientific evidence into their PMTA and MRTP applications and that the FDA apply the latest scientific evidence when assessing those applications.  In particular, consistent with Congressional intent, FDA should require actual evidence of reductions in harm, rather than theoretical arguments or citations to outdated evidence to support claims of reduced harm.

  • FDA’s scientific review of premarket applications has been flawed

In October 2021, FDA authorized the marketing of RJ Reynold’s Vapor Company’s Vuse Solo e-cigarette products. These were the first e-cigarette products to obtain marketing granted orders through the premarket tobacco product application (PMTA) pathway. Our review[17] of the FDA’s TPL decision summary for Vuse Solo found that FDA did not adequately consider Vuse’s popularity with youth and evidence that e-cigarettes expand the nicotine market and stimulate cigarette smoking, did not consider design factors that appeal to youth, and that FDA traded youth addiction for unproven adult benefits without quantifying those risks and benefits. FDA did not address evidence that e-cigarettes used as consumer products do not help smokers quit and promotes relapse in former smokers and did not discuss evidence that dual use is more dangerous than smoking.

FDA narrowly focused on the fact that e-cigarettes deliver lower levels of some toxicants without addressing direct evidence of adverse health effects, downplaying significant evidence of other substantial harms. FDA cited but did not act on its own study[18] showing no all-cause mortality benefit from e-cigarettes and improperly considered e-cigarettes’ high abuse liability and potential for high youth addiction and undermining tobacco cessation. Taken together, FDA’s marketing decision for Vuse Solo was not based on a showing that marketing these products would be appropriate for the protection of the public health because they did not show a net public health benefit.

We also reviewed the TPLs for subsequently authorized e-cigarettes (eight Logic Technology e-cigarette products and four NJOY Ace products), and found that FDA similarly failed to quantify the net public health benefit for those products. (As discussed below, we were only able to obtain the TPLs for these products after submitting FOIA requests and are still awaiting the TPLs for six RJ Reynolds Vapor Vuse Vibe and Vuse Ciro products and two NJOY Daily products. Although we obtained a copy of the NJOY Ace TPL, FDA has still not made this TPL publicly available on its website.[19])

Previously we analyzed[20] the TPL and marketing order for Philip Morris’s IQOS heated tobacco product to determine whether FDA had met the Tobacco Control Act’s statutory requirements. We found that the evidence submitted to FDA did not demonstrate a reduction in long-term disease risks and that IQOS aerosol emitted toxins with carcinogenic and genotoxic potential, some at higher levels than in conventional cigarettes. As with the Vuse Solo PMTA, the IQOS PMTA did not appropriately consider the health impacts of dual use, the product’s attractiveness to youth, or data showing that consumers do not accurately perceive the addiction risks of IQOS. Despite FDA’s own scientists’ recommendations and independent research showing that IQOS presents serious risks to users including cytotoxic, genotoxic, hepatotoxic, cardiovascular, and pulmonary risks, FDA concluded that IQOS is appropriate for the protection of the public health. We concluded that FDA’s marketing decision for IQOS disregarded valid scientific evidence and misapplied the public health standard mandated by law

The Expert Panel should recommend that CTP hold applicants and itself to the same high scientific standards that the government applies when preparing Surgeon General Reports on tobacco and health.  (CTP Director Brian King is intimately familiar with these standards because he was responsible for preparing several Surgeon General Reports when he worked at the CDC Office on Smoking and Health.) 

  • FDA prejudged e-cigarette applications

Some of these deficiencies in FDA’s premarket review of tobacco product applications may have stemmed from policies baked in by its previous leadership. Matt Holman, who had served as the Director of CTP’s Office of Science from January 2017 until July 2022 when he left to work for Philip Morris International, developed an approach to embracing so-called reduced risk products. In an August 2020 memo released under the Freedom of Information Act[21] detailing FDA’s plan for dealing with the expected flood of PMTAs, Dr. Holman laid out policy goals which prejudged e-cigarettes as a good thing before conducting the required thorough analyses of specific evidence for particular e-cigarette PMTAs. In particular, the memo described FDA’s “public health goals” including: “Ensure a variety of ENDS [electronic nicotine delivery systems] have an opportunity to remain on the market to facilitate adult smokers switching to less harmful tobacco products.” This statement embodies FDA’s assumption – unsupported by current evidence – that e-cigarettes as consumer products help smokers “switch completely” and that there are clear benefits of “switching completely.”

The memo also demonstrates a fundamental misunderstanding of CTP’s mission, which is not to “ensure” that a variety of e-cigarettes remain on the market for adult smokers, but to determine whether any particular e-cigarette product – as it will actually be marketed and used, including by youth – is appropriate for the protection of the public health.[22]

The Expert Panel should recommend that FDA’s marketing authorizations be based, as required by the Tobacco Control Act, on its determination that the specific product that is the subject of the PMTA is appropriate for the protection of the public health based on the scientific evidence presented in that application in light of the most current scientific literature, not on a predetermined decision to ensure that e-cigarettes remain on the market.

  • FDA’s application reviews should focus on factors relevant to e-cigarettes

To help make its determination of net public health benefit, the Expert Panel should recommend that FDA’s review process require and focus on appropriate scientific studies, including:

  1. Studies that provide direct evidence of the potential impacts of new tobacco products on youth, including youth perception studies. These youth impacts must be analyzed before the products hit the market, rather than allowing them on the market and using kids as guinea pigs in real-world experiments.
  • Studies of adults in the real world, rather than controlled clinical trials which might be appropriate for therapeutic drug reviews by CDER, but not for consumer tobacco product reviews by CTP. Because e-cigarettes are used in the real world as recreational consumer products by both adults and kids, not as medicines under clinical supervision, FDA’s review should focus on actual use, which very often includes dual use. Randomized controlled trials (RCTs) are considered the “gold standard” for drug reviews by CDER because ideally, they reflect how drug would be used (including indications and contraindications for use and dosage regimes) in a clinical environment. In contrast, because CTP has no power to put constraints on how e-cigarettes are used by consumers as recreational products in the real world, CTP should rely on population-based studies which study unmanaged, actual use by real people in real life, not on RCTs.[23]
  • Studies of the impacts of toxicants found in e-cigarettes. FDA’s application decisions should not be based solely on the outdated Harmful and Potentially Harmful Constituents list (HPHC). This 2012 list focused on toxicants found in cigarettes and is heavily weighted towards carcinogens, but the major health effects identified for e-cigarettes also include cardiovascular and pulmonary impacts. This was recognized by FDA in 2019 when it proposed a new HPHC list which would add 19 toxicants including glycerol, propylene glycol, and other toxicants found in e-cigarettes.[24] In addition to these toxicants, CTP should also analyze flavorants in proposed e-cigarette products that may be dangerous when inhaled in e-cigarettes, even if benign when ingested as a food additive.  FDA should finalize the updated HPHC list quickly.
  • FDA’s application process must be more transparent

Although FDA has repeatedly announced its commitment to transparency, its application process is increasingly opaque.

First, as discussed above, the FDA needs to be transparent about the quantitative trade-off it is willing to accept between the harms to youth and any purported benefits to adults. The Expert Panel should recommend that FDA clearly state how many adults must quit completely to make it worth sacrificing each kid to a lifetime of nicotine addiction.

FDA’s website that posts its Marketing Granted Orders has become increasingly less transparent. The TPLs are important documents for the public health community because they explain CTP’s scientific justification for authorizing the marketing of new tobacco products. Previously, FDA posted the full TPLs for each MGO (and in 2019 even posted the Environmental Assessments). But recently, FDA has only posted four-page Executive Summaries of the TPLs, instead of the full decisions.  And these Executive Summaries are primarily boiler-plate descriptions of the process rather than information specific to the applicant product.

The general public and scientific and public health communities need to understand how FDA reaches its scientific conclusions and marketing decisions. But to get access to the full TPLs which contain this information, we have been forced to submit FOIA requests, which were all immediately denied, and then to follow up with time consuming FOIA appeals. Unfortunately, we have had to go through the same tedious FOIA process for every marketing decision.

In the case of NJOY Ace, Ms. Lempert submitted a FOIA request on May 16, 2022. It was not until September 28, more than five months after the MGO was first issued on April 26, that FDA finally produced the redacted TPL, a document that is only 44 pages in total, with 18 redacted pages.

And as of November 6, 2022, the FDA had still not posted the full TPL on its website – only the 4-page executive summary is available, leaving the rest of the public in the dark.[25]

There is generally no reason for CTP to not publicly post a list of all e-cigarette PMTAs for e-cigarettes that were already on the market at the time the applications were submitted. The Expert Panel should recommend that FDA post the TPLs for those e-cigarettes that have been denied marketing authorization. These documents, as the TPLs for authorized e-cigarettes, contain essential information about CTP’s scientific evaluations and how CTP determines what products are or are not appropriate to protect the public health. Because these products have been on the market for years, they are not secret and there is no commercial disadvantage to manufacturers from disclosure.

The Expert Panel should recommend that so long as the products have been on the market, FDA should publicly post the PMTAs and Marketing Denial Orders (MDO) with appropriate redactions for trade secrets or other confidential commercial information. CTP should verify claims made by tobacco companies that the sections they mark as “(b)(4)” trade secrets are truly confidential commercial information deserving of trade secret protection.

  • Recommendations

CTP’s premarket tobacco product application review process has not followed statutory mandates or scientific rigor. We offer the following recommendations to improve CTP’s application review process:

  1. CTP’s actions must be consistent with the Findings section of the Tobacco Control Act which underscores Congress’s intent that FDA protect public health through a rigorous premarket application process focused primarily on the impacts to youth. Therefore, CTP’s procedures must ensure that CTP is implementing the law as Congress intended.
  • CTP must put the burden of proof on the applicant to demonstrate that authorizing a specific product is appropriate for the protection of the public health, rather than following its current practice of authorizing products unless FDA can demonstrate that the marketing authorization is not appropriate.
  • CTP must explicitly and transparently define “net benefit to public health” and include explicit quantified comparisons of risks and benefits in all applications to determine whether the applicant demonstrated that the product under review confers net health benefits and is therefore appropriate for the protection of the public health.
  • CTP must clearly state what trade-off it is willing to accept: how many adults must quit completely to make it worth sacrificing each kid to a lifetime of nicotine addiction?
  • CTP must define quitting or “switching completely” to mean 100% switching from cigarettes to the proposed new tobacco product consistent with the plain meaning of the term.
  • CTP must require applicants to demonstrate that, as actually used as consumer products (not as clinically supervised medical cessation treatments) the design characteristics of their specific new tobacco product (in contrast to the general product class) leads to smokers quitting.
  • CTP’s scientific review of premarket applications must not only properly apply the mandated public health standard, but must also appropriately consider valid scientific evidence.
  • CTP must stop accepting unsubstantiated reduced harm claims about e-cigarettes and other new tobacco products and should instead engage the rapidly growing published scientific evidence on the health effects of these products.
  • CTP’s determination that any particular product should obtain marketing authorization must be based on the scientific evidence presented in the application for the specific product, as required by the Tobacco Control Act, and not on an unsubstantiated predetermination that e-cigarettes in general will help adult smokers quit and therefore should remain on the market.
  • CTP’s application review process should require and focus on appropriate scientific studies, including:
    1. impacts on youth perceptions and use;actual use studies of how the products are used in the real world as consumer products, rather than randomized controlled clinical trials;studies of the impacts of the particular toxicants found in the products under review; and
    1. the expanding literature on the range of health impacts of e-cigarettes and other new products.
  1. CTP should hold applicants and itself to the same high scientific standards that the government applies when preparing Surgeon General Reports on tobacco and health.
  1. CTP’s premarket application process must be more transparent, including:
    1. explicitly quantifying what trade-off it is willing to accept: how many adults must quit completely to make it worth sacrificing each kid to a lifetime of nicotine addiction?
    1. So long as the products have been on the market, publicly posting a list of all PMTAs and posting Marketing Denial Orders and related TPLs with appropriate redactions for confidential commercial information.

Sincerely,

Lauren Kass Lempert, JD, MPH

Law and Policy Specialist

Stanton A. Glantz, PhD

Professor of Medicine (retired)     

Encl:    Vuse Solo paper

            IQOS paper

            Beltre and Holman memo

FOOTNOTES


[1] It is illegal under Federal law to sell tobacco products to youth under 21 and the FDA has the authority to limit the marketing of tobacco products to people under 21, although it has not exercised the full extent of that power.

[2] FDA.  Section 2 of the Tobacco Control Act Findings.  https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/section-2-tobacco-control-act-findings

[3] Nicotine is present in all tobacco products, including e-cigarettes which came under CTP’s authority in 2016 with the passage of the “Deeming Rule.” Since April 2022, e-cigarettes with synthetic nicotine as well as tobacco-derived nicotine are included in CTP’s jurisdiction. 

[4] Food and Drug Administration.  Technical Project Lead (TPL) Review of PMTAs: PM0000529.PD1-PM0000531.PD1, PM0000535.PD1-PM0000537.PD1, PM0000540.PD1-PM0000541.PD1 for several Logic Technology Development e-cigarette products. 2022. https://www.fda.gov/media/158374/download (accessed 19 Aug 2022). Page 4.

[5] Food and Drug Administration. Results from the Annual National Youth Tobacco Survey, October 6, 2022. https://www.fda.gov/tobacco-products/youth-and-tobacco/results-annual-national-youth-tobacco-survey

[6] Cooper, Maria, et al. “Notes from the Field: E-cigarette Use Among Middle and High School Students—United States, 2022.” MMWR. Morbidity and Mortality Weekly Report 71 (2022). https://www.cdc.gov/mmwr/volumes/71/wr/mm7140a3.htm?s_cid=mm7140a3_w

[7] Khouja JN, Suddell SF, Peters SE, Taylor AE, Munafo MR. Is e-cigarette use in non-smoking young adults associated with later smoking? A systematic review and meta-analysis. Tob Control 2020;30:8-15; Yoong SL, Hall A, Turon H, Stockings E, Leonard A, Grady A, Tzelepis F, Wiggers J, Gouda H, Fayokun R, Commar A, Prasad VM, Wolfenden L. Association between electronic nicotine delivery systems and electronic non-nicotine delivery systems with initiation of tobacco use in individuals aged < 20 years. A systematic review and meta-analysis. PLoS One 2021;16:e0256044

[8] For two recent meta-analyses on this point, See Chen, Ruifeng, et al. “Effectiveness of e-cigarettes as aids for smoking cessation: evidence from the PATH Study cohort, 2017–2019.” Tobacco Control (2022) and Wang, Richard J., Sudhamayi Bhadriraju, and Stanton A. Glantz. “E-cigarette use and adult cigarette smoking cessation: a meta-analysis.” American journal of public health 111.2 (2021): 230-246.

[9] https://pubmed.ncbi.nlm.nih.gov/35256929/ and https://pubmed.ncbi.nlm.nih.gov/35131948/

[10] See our published analysis of FDA’s marketing authorization for IQOS: https://pubmed-ncbi-nlm-nih-gov.ucsf.idm.oclc.org/32601147/

[11] Keith R, Bhatnagar A. Cardiorespiratory and Immunologic Effects of Electronic Cigarettes. Curr Addict Rep. 2021 Mar 5:1-11. doi: 10.1007/s40429-021-00359-7. Epub ahead of print. PMID: 33717828; PMCID: PMC7935224.

[12] Nutt DJ, Phillips LD, Balfour D, et al. Estimating the harms of nicotine-containing products using the MCDA approach. Eur Addict Res. 2014;20(5):218–225

[13] See this recently published report that contains a summary of the current state of scientific knowledge on e-cigarettes: https://gem.godaddy.com/p/09d6831?pact=34037-166639209-13033929154-93fd8f1b153d5d6f1c70653de4f490c5472e45e6

[14] Eissenberg et al, Invalidity of an Oft-Cited Estimate of the Relative Harms of Electronic Cigarettes, Am J Public Health, 2020 Feb;110(2):1610162. Doi: 10.2105/AJPH.2019.305424. Available: https://pubmed.ncbi.nlm.nih.gov/31913680/

[15] https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/section-911-federal-food-drug-and-cosmetic-act-modified-risk-tobacco-products#:~:text=Regulations%20and%20Guidance-,Section%20911%20of%20the%20Federal%20Food%2C%20Drug%2C%20and%20Cosmetic,Act%20%2D%20Modified%20Risk%20Tobacco%20Products&text=In%20General.,with%20respect%20to%20such%20product.)

[16] https://www.fda.gov/tobacco-products/advertising-and-promotion/modified-risk-tobacco-products

[17] Glantz, SA, Lempert LK. Vuse Solo e-cigarettes do not provide net benefits to public health: A scientific analysis of FDA’s marketing authorization. Tobacco Control (2022) (in press) [copy attached]

[18] Chang JT, Anic GM, Rostron BL, Tanwar M, Chang CM. Cigarette Smoking Reduction and Health Risks: A Systematic Review and Meta-analysis. Nicotine Tob Res 2021;23:635-642

[19] Premarket Tobacco Product Marketing Granted Orders, available at: https://www.fda.gov/tobacco-products/premarket-tobacco-product-applications/premarket-tobacco-product-marketing-granted-orders.

[20] Lempert, LK and Glantz S, Analysis of FDA’s IQOS marketing authorization and its policy impacts, Tobacco control 30.4 (2021): 413-421. https://pubmed.ncbi.nlm.nih.gov/32601147/ [copy attached]

[21] Beltre R, Holman M. Office of Science (OS) Premarket Application Review Prioritization Plan,  31 Aug 2020.  Available at https://profglantz.files.wordpress.com/2022/05/fda-memorepmta-3aug2020.pdf

[22] See https://profglantz.com/2022/05/31/fda-prejudged-e-cigs-as-good-before-it-evaluated-a-single-application/ , https://profglantz.com/2022/07/27/fda-science-leader-matt-holman-leaves-fda-for-pmi/

[23] See Wang RJ, Bhadriraju S, Glantz SA. E-Cigarette Use and Adult Cigarette Smoking Cessation: A Meta-Analysis. Am J Public Health 2021;111:230-246.

[24] FDA In Brief: FDA seeks comment on proposed additions to list of harmful and potentially harmful constituents found in tobacco products, including electronic nicotine delivery systems such as e-cigarettes and e-liquids, August 2, 2019. Available: https://www.fda.gov/news-events/fda-brief/fda-brief-fda-seeks-comment-proposed-additions-list-harmful-and-potentially-harmful-constituents; Harmful and Potentially Harmful Constituents in Tobacco Products; Established List; Proposed Additions; Request for Comments, 84 FR 38032. Available: https://www.federalregister.gov/documents/2019/08/05/2019-16658/harmful-and-potentially-harmful-constituents-in-tobacco-products-established-list-proposed-additions

[25] https://www.fda.gov/tobacco-products/premarket-tobacco-product-applications/premarket-tobacco-product-marketing-granted-orders

Published by Stanton Glantz

Stanton Glantz is a retired Professor of Medicine who served on the University of California San Francisco faculty for 45 years. He conducts research on tobacco and cannabis control and cardiovascular disease/

One thought on “Recommendations to improve FDA premarket tobacco product application review to follow statutory mandates and improve scientific rigor

  1. This is great stuff.

    There are a number of additional ways that FDA could dramatically improve how it manages the PMTA process and better protect and promote the public health consistently with the purposes and requirements of the Tobacco Control Act. To focus just on a couple of the most important, FDA should also:

    1) Ensure that is PMTA orders allowing the marketing of any product include additional requirements and restrictions on the product, its packaging and labeling, its advertising, other marketing, and sale that available evidence and experience indicates would prevent and reduce youth use and prevent and reduce youth or adult harm-increasing uses of the product without disproportionately reducing the harm-reducing use of the product. At the very minimum, FDA should at least ensure that the marketing orders formally require the applicants to do everything the PMTA says the applicant plans, proposes, or expects to do to prevent and reduce youth use and prevent or reduce harm-increasing uses of the product.

    2) Require applicants to reference and address any published research findings that are inconsistent with claims made in the PMTA submitted by the applicant or that otherwise indicate that the PMTA’s conclusions, finding, or claims are less favorable than presented.

    3) Require applicants to show that they have made a good faith effort to make their product as minimally harmful as possible and to ensure that the packaging and labeling of the product does not attract youth and helps to prevent or discourage harm-increasing uses of the product — at least to the extent possible without disproportionately dissuading adult users of more harmful tobacco products from trying the product and using it in harm-reducing ways.

    Like

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