The public health consequences of e‐cigarettes: a review by the National Academies of Sciences. A call for more research, a need for regulatory action

Electronic nicotine delivery systems (ENDS) are less harmful than combustible cigarettes but lack demonstrated safety. They may help some smokers to quit, while enticing future generations to smoke. The US regulatory environment has restricted research on ENDS for tobacco cessation yet extended the time for open market sales. Calls for further research ought not to stall regulatory action. Electronic nicotine delivery systems (ENDS; e.g. e-cigarettes) have gained world-wide attention. Gaps in the evidence on ENDS have contributed to varied opinions, many passionately at odds. The National Academies of Sciences’ (NAS) review of more than 800 research papers on ENDS was congressionally mandated and sponsored by the US Food and Drug Administration (FDA) to summarize the state of the science and identify research needs 1. The NAS report provides a useful summary for policymakers, practitioners and researchers internationally and sheds light on the nuances in the risk/benefit equation for ENDS. Of the nearly 50 conclusions in the NAS report, the strongest evidence (deemed as substantial or conclusive) is listed in Box 1. Are ENDS harm-reducing or harm-creating? The answer is probably both. That is, ENDS may be harm-reducing for smokers seeking to quit (i.e. when the comparator is combustible tobacco), while harm-creating for former or never smokers, particularly among youth, for whom ENDS use appears to increase the risk of future use of combustible tobacco. Being less harmful than combustible cigarettes, which contribute to the deaths of two in three long-term users 2, 3, does not mean ENDS are safe. ENDS aerosol contains nicotine, which is addictive; ultrafine particles, that can be inhaled deeply into the lungs; flavorings such as diacetyl, a chemical linked to serious lung disease; volatile organic compounds; cancer-causing chemicals; and heavy metals such as nickel, tin and lead, although all at lower levels than in combusted tobacco smoke 4. This list is limited by the chemicals assayed to date. Other toxicants, yet to be determined, may be created by repeated heating of the plastic and metal devices. The NAS findings were incorporated into a dynamic population model, and the conclusion was a net public health benefit with reduced loss of life when modeled out to 2050. These gains, however, were lost when extended to the year 2070, to capture more fully the future consequences of uptake among young people today 1. Shorter-term modeling may be short-sighted in prioritizing the benefits of ENDS use among aged smokers over the harms that will be incurred by future generations. Regarding research gaps, the NAS report identified insufficient evidence on the effectiveness of ENDS as cessation devices. The health benefits of ENDS use among continued smokers (i.e. dual users) are unproven, and the long-term health effects for ENDS users and the effects of maternal ENDS use on fetal development are unknown 1. In contrast, FDA-approved nicotine replacement therapies have demonstrated effectiveness in helping smokers quit with few and mild side-effects, low likelihood of inducing dependence, and without abuse potential among youth or evidence of transitioning youth to combustible tobacco products. From a hierarchy of evidence perspective 5, the most conclusive/substantiated conclusions on ENDS are based upon anecdotal reports (e.g. exploding devices, topical exposures) and laboratory studies, with a cavernous gap in high-quality evidence to inform the central issues of concern (e.g. can ENDS aid smoking cessation; do young ENDS users become smokers; what are the health effects among dual users?). Only two randomized controlled trials of ENDS for cessation, one conducted in Italy, the other in New Zealand, have been published. No randomized controlled trials of ENDS for cessation have been conducted in the United States. The imbalance in research evidence is largely an artifact of the regulatory environment. The FDA extended its authority to regulate ENDS 6, prohibiting sales to minors (which many states had already enacted); requiring cessation claims to undergo drug evaluation review (which no company has sought to date); and setting a deadline of 2 years for existing ENDS manufacturers to submit tobacco product applications (later extended another 4 years to August 2022). As a result, there is no incentive for ENDS manufacturers to invest in the regulatory process for FDA approval of therapeutic claims. Further, as ENDS are marketed as ‘switching’, rather than quitting, devices, they also elude the restriction on cessation claims 7, despite ENDS now being the leading product used by US adult smokers attempting to reduce or quit combustibles 8. Meanwhile, US researchers remain unable to empirically evaluate ENDS as a treatment for quitting smoking. Lacking a motivated industry partner, researchers are impeded by the FDA's requirement for pre-clinical data before accepting an investigational new drug (IND) application to study ENDS as a treatment for quitting smoking. Further, the delay in product standard regulations for ENDS has resulted in a myriad of highly variable e-liquids and devices entering the market, complicating research efforts and the generalizability of research findings. Regulations to ensure standardization, quality control and reporting requirements for e-liquids and the devices, batteries and chargers are needed, as are restrictions on ENDS advertising, packaging and flavors. For example, the European Union (EU) and Canada restrict ENDS advertising to youth; the EU requires graphic health warnings and limits the nicotine strength of e-liquid to ≤ 20 mg/ml, and Canada bans confectionary ENDS flavors. The NAS considered toxicity of flavorings, with little attention to attraction among youth despite the US Surgeon General concluding that many ENDS flavors are marketed to youth 4; flavor varieties now exceed 15 500 9, including ‘Hello Kitty’ and cotton candy. ENDS are now the leading tobacco product used by youth in the United States (> 2 million) 10, of whom > 80% report attraction to the ENDS flavors 11. JUUL, with a majority (> 70%) of ENDS market share in the United States and expanding internationally, is extremely popular and problematic on middle- and high-school campuses 12. The fruit- and confectionary-flavored JUUL pods in the United States contain 59 mg/ml nicotine, three times the EU limit. In April 2018, six leading health groups sued the FDA for inaction, and Commissioner Gottlieb announced FDA's efforts to address youth access to ENDS by issuing warning letters and investigating JUUL's marketing and online sales 13. Referenced in these FDA materials are regulatory gates through which ENDS will need to pass for FDA review although, for now, the gates remain wide open. In the 2 years since the FDA established its authority to regulate ENDS, with pre-market review required of any new or modified products, JUUL lookalikes (e.g. Phix, Rubi, Smok Fit) have freely come to market. Lacking federal action, counties such as San Francisco have banned characterizing flavoring in all tobacco products, including ENDS, despite a > $12 million RJ Reynolds counter-campaign. The NAS report identified numerous research priorities. ENDS have been on the US market unregulated for more than 10 years. On average, it takes 17 years to translate research findings into practice 14. The call for research should not be an excuse for inaction, nor should research costs fall largely upon federal funders. When drugs or medical devices are developed, industry supports the bulk of the research for pre-market regulatory review. The ENDS companies have contributed minimally to the research base and with no incentive to do so, given that they can continue to sell their product freely. Conflict of interest concerns can be addressed with standard regulatory oversight. Unregulated, heavily marketed, delivering an addictive drug (nicotine) to the lungs through heated plastic and metal devices, mass-produced in China with variable quality control in manufacturing and materials, ENDS are a diverse group of products. There are hopes, including among the FDA leadership, that ENDS may be a tool in transitioning nicotine in combustible cigarettes to non-addictive levels. That ENDS will be part of the solution to the endgame for combustible tobacco is a hypothesis lacking strong evidence. Needed is research on a well-controlled product, rather than what currently is unfolding in the United States: a population-level, natural experiment lacking regulatory oversight. J.J.P. has served as an expert witness in lawsuits against the tobacco companies and has provided consultation to pharmaceutical and technology companies that make medications and other treatments for quitting smoking. She is the immediate past President of the Society for Research on Nicotine and Tobacco.

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