ÌÇÐÄvlog

The public health effect of e-cigarettes is debated because of their uptake by youth and potential benefit for adults who smoke. Although e-cigarettes have been proposed as a less harmful substitute for cigarettes that could promote smoking cessation or reduction,¹ a 2016 review concluded the published evidence is imprecise, is subject to study design biases, and that little is known about the effects of newer types of e-cigarettes, such as pod devices,² that may deliver nicotine more effectively.^3,4 Therefore, an important question is whether new and ongoing studies will address these gaps and help improve our understanding of the effects of e-cigarettes on smoking cessation or reduction. Here, we examined the characteristics of completed and ongoing domestic and international clinical trials registered in the World Health Organization Registry Network, including outcomes evaluated, treatment comparisons, and characteristics of the e-cigarette tested.

We searched all registries under the World Health Organization Registry Network (Table 1) from inception to January 11, 2021, to identify trials studying the effects of e-cigarettes on smoking cessation or reduction. The terms smoking or cigarette were used to ensure the broadest number of trials identified. For registries where multiple terms could not be searched simultaneously (ie, smoking OR cigarette), separate searches were conducted, combined, and deduplicated. Search results were screened manually to locate English-language records for trials studying e-cigarette use with primary or secondary outcomes of smoking cessation, reduction, or related biomarkers. For eligible trials, we recorded information about participants, study design, primary/secondary outcomes, and e-cigarette characteristics (eg, device, nicotine concentration, flavor). This study did not require institutional review board approval because it was based on publicly available information, according to 45 CFR §46. Informed consent was not needed because no patient data were used. We used Excel version 16.37 (Microsoft) for descriptive statistics and SPSS version 26 (StataCorp) to conduct χ² tests (2-sided P &±ô³Ù; .05).

We identified 29 completed and 37 ongoing trials on 4 registries (Table 1). Thirty-five of 66 completed and ongoing trials (53%) were recruiting individuals motivated to quit smoking, and only 23 (35%) included behavioral support for cessation. Smoking abstinence was a primary or secondary outcome for 49 trials (74%), while 17 (26%) assessed smoking reduction only. Although completed and ongoing trials had similar sample sizes (median [interquartile range], 140 [54-363]), durations (median [interquartile range], 12 [6-24] weeks), comparators (eg, nicotine replacement therapy: 23 of 66 [35%]), and outcomes, ongoing trials were less likely to assess outcomes at 6 months or longer (ongoing, 14 of 37 [38%]; completed, 21 of 29 [72%]; χ²â€‰= 7.80 [n = 66]; P = .005).

Regarding e-cigarette device characteristics, none of the completed trials reported studying newer pod devices and only a small proportion of ongoing trials did (6 of 37 [16%]) (Table 2). Nicotine concentration was reported in about half (36 of 66 [55%]) of completed and ongoing trials, but e-cigarette flavors were reported rarely (5 of 66 [8%]).

We identified 66 completed and ongoing registered trials examining the effects of e-cigarettes on smoking cessation or reduction. Completed and ongoing trials had similar characteristics, with modest sample sizes and duration, most lacking behavioral support to quit, and very few testing newer e-cigarette devices that are designed to deliver nicotine more similarly to cigarettes.^3,4 Moreover, ongoing trials were less likely to evaluate outcomes at 6 months, which is a standard outcome used in meta-analyses.^2,5 These findings support previously identified limitations of e-cigarette trials⁶ and highlight how ongoing studies may not address critical evidence gaps.

This study was limited to trials in the World Health Organization Registry Network. Despite certain registration requirements (eg, from funders, regulatory agencies, journals), not all trials are registered and information may be incomplete for some records. However, registries are the best source to understand characteristics of ongoing trials that are not yet reporting results. Our evaluation suggests that additional studies will be needed to address important questions about the degree to which e-cigarettes, especially newer devices, influence cigarette cessation.

Corresponding Author: Krysten W. Bold, PhD, Department of Psychiatry, Yale School of Medicine, 34 Park St, CMHC New Haven, CT 06519 (krysten.bold@yale.edu).

Accepted for Publication: July 14, 2021.

Published Online: September 1, 2021. doi:10.1001/jamapsychiatry.2021.2468

Author Contributions: Ms Hung and Dr Bold had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Hung, Wallach, Bold.

Supervision: Wallach, O’Malley, Bold.

Conflict of Interest Disclosures: Dr Wallach reported grants from the Laura and John Arnold Foundation and the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation outside the submitted work. Dr O’Malley reported grants from the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse; personal fees for being a member of the American Society of Clinical Psychopharmacology Clinical Trials initiative supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna Pharmaceuticals, Ethypharm, Indivior, Lundbeck, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical; nonfinancial support from Amygdala Neurosciences; study medications from AstraZeneca and Novartis; personal fees from Alkermes, Dicerna Pharmaceuticals, Opiant Pharmaceuticals, and Emmes Corporation as a data and safety monitoring board member for the National Institute on Drug Abuse Clinical Trials Network; and has been involved in a provisional patent application with Yale University and Novartis outside the submitted work. Dr Bold reported grant from the Patterson Foundation during the conduct of the study. No other disclosures were reported.

Funding/Support: Research reported in this publication was supported in part by the National Institute on Drug Abuse (grant U54DA036151) and the US Food and Drug Administration Center for Tobacco Products (Drs Bold and O’Malley). Dr Wallach is supported by the National Institute on Alcohol Abuse and Alcoholism (grant K01AA028258). Dr Bold is supported by the National Institute on Drug Abuse (grant K12DA000167).

Role of the Funder/Sponsor: The funding organization and sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the US Food and Drug Administration.