Key Points
- The authors argue that RCTs primarily measure efficacy under controlled conditions, while RWE can add evidence on real-world effectiveness, reach and consumer behavior.
- Their framework is summarized as “Impact = Reach × Efficacy,” suggesting that strong clinical efficacy may translate into limited population impact when uptake is low.
- The commentary calls for greater use of longitudinal, actual-use, market and postmarket evidence for fast-evolving categories including ENDS, heated tobacco and nicotine pouches.
- The authors disclose significant ties to JUUL Labs and acknowledge that RWE is vulnerable to confounding and selection bias; they argue that it should complement rather than replace randomized trials.
2Firsts
September 8, 2026
A commentary published on August 25 in the international open-access, peer-reviewed Harm Reduction Journal argues that randomized controlled trials remain essential for determining whether smoking cessation and tobacco harm reduction interventions work under controlled conditions, but real-world evidence can provide information that trials often cannot fully capture, including consumer uptake, longer-term use, complete switching and population-level impact.
The article, Bridging evidence gaps: the role of real-world data in tobacco harm reduction, was written by authors affiliated with Pinney Associates, JUUL Labs and the University of Catania, among other institutions. Its central argument is that RWE and randomized evidence should function as complementary sources rather than substitutes for one another.
Three days after the commentary was published, the U.S. Food and Drug Administration authorized the JUUL2 device and its Virginia Tobacco and Polar Menthol pods for marketing. In explaining the decision, FDA highlighted data on adult smokers completely discontinuing cigarettes and switching to JUUL2. There is no known direct link between the commentary and the regulatory decision, but their timing has placed real-world behavior and complete switching at the center of a current industry discussion.
RCTs Do Not Fully Capture Real-World Smokers or Product Use
The commentary begins by distinguishing efficacy from effectiveness.
Randomized controlled trials are designed to establish whether an intervention works under controlled conditions. The authors continue to regard RCTs as an essential part of the evidence base for smoking cessation.
They argue, however, that trial populations and study environments can differ materially from routine use.
Smoking cessation trials often recruit people who are already motivated to quit and willing to use a specified treatment. Participants may receive products free of charge, structured counseling, adherence support and intensive follow-up. In real-world settings, smokers vary more widely in motivation, health status, product preference and adherence, and may have to pay for treatment themselves.
The commentary cites a nationally representative U.S. analysis in which approximately 66% of adults with nicotine dependence had at least one characteristic commonly used to exclude people from smoking cessation trials, including smoking fewer than 10 cigarettes per day or lacking motivation to quit.
The authors therefore argue that RCTs can establish whether an intervention works under controlled conditions without necessarily showing how many smokers will adopt it or how large its population-level effect will be.
“Impact = Reach × Efficacy” Puts Uptake Alongside Clinical Performance
The article summarizes its central framework as:
Impact = Reach × Efficacy
Under this approach, clinical efficacy is only one component of population impact. The number and type of smokers who actually adopt an intervention also matter.
The commentary cites evidence suggesting that only around 15% of adults who smoke intend to quit within the next month.
Traditional pharmaceutical and medical cessation approaches are generally used by people actively seeking treatment. ENDS and other non-combustible nicotine products may follow a different pathway because they can also be adopted as consumer products.
Some adults may begin using an e-cigarette without a prior intention to quit smoking and later reduce or completely discontinue cigarettes. The authors argue that these unplanned switching pathways are difficult to capture in conventional cessation trials centered on people who have already committed to quitting.
RWE Can Add Evidence on Uptake, Complete Switching and Long-Term Use
The article identifies multiple potential sources of real-world evidence, including electronic health records, insurance claims, registries, population surveys, retail sales, mobile-device data, websites and social media.
Such evidence can help researchers examine who actually adopts a product, whether consumers continue using it, whether dual use develops, whether smokers completely stop smoking cigarettes, and how behavior changes over longer periods after market introduction.
The authors argue that this is particularly relevant for fast-evolving categories such as e-cigarettes, heated tobacco and nicotine pouches.
Traditional trials are expensive and time-consuming, while nicotine products, delivery technologies, flavors and market structures can change rapidly. A device used when a trial begins may no longer represent the dominant market by the time results are published.
The commentary therefore calls for triangulation across different study designs, combining controlled efficacy evidence with data on how products perform under real-world conditions.
PATH and JUUL Purchaser Studies Illustrate Real-World Switching Pathways
The authors use the U.S. Population Assessment of Tobacco and Health study and the Adult JUUL Switching and Smoking study as examples of what observational evidence can add.
They cite longitudinal PATH findings associating ENDS use with subsequent smoking discontinuation, including among adults who initially had no plans to quit.
The commentary also cites the naturalistic ADJUSST study of more than 50,000 U.S. adult JUUL purchasers. Among participants who reported current and established smoking at baseline, the cited research reported that around 51% were no longer smoking at 12 months and around 58% at 24 months.
These findings come from observational research. ADJUSST followed adults who had already chosen to purchase JUUL products, rather than smokers randomly assigned to the product, so the figures should not be interpreted as randomized cessation rates.
Snus Experience Is Used to Examine Population-Level Substitution
The commentary also cites observational evidence from Norway and Sweden, where snus has been widely used alongside declines in cigarette smoking.
The authors refer to studies in which snus was a commonly reported method of stopping or replacing cigarettes and link its real-world uptake with smoking patterns in those countries.
These national experiences are observational and do not independently establish that one product caused changes in national smoking prevalence or tobacco-related mortality. The cases are used to support the broader argument that population-level product substitution may be difficult to assess through conventional cessation trials alone.
U.S. Regulation Already Requires a Population-Level Risk-Benefit Assessment
The commentary extends its argument to FDA tobacco regulation.
Medicinal nicotine products in the U.S. are primarily reviewed through the drug pathway, where clinical safety and efficacy evidence is central. ENDS are reviewed under the FDA tobacco product framework through the Premarket Tobacco Product Application process.
The PMTA standard requires FDA to determine whether marketing a new tobacco product would be appropriate for the protection of the public health, or APPH. That determination considers potential risks and benefits to the population as a whole, including current tobacco users and non-users.
The authors argue that a population-level regulatory standard creates a role for behavioral, actual-use and longitudinal evidence beyond traditional clinical trials.
JUUL2 Authorization Brings Complete Switching Into Focus
On August 28, FDA announced marketing authorization for three JUUL2 products.
The agency said application data showed that 19.9% to 34.6% of adult smokers using the tobacco-flavored JUUL2 pod completely stopped smoking cigarettes at six weeks. Among those using the menthol-flavored pod, the reported range was 28.4% to 49.3%.
FDA included the potential benefit of adult smokers completely switching to the authorized products in its population-level assessment alongside risks to youth and people who do not currently use tobacco.
The agency also emphasized the distinction between complete switching and dual use, noting that smokers need to completely transition away from cigarettes to obtain the greatest potential health benefit.
A marketing granted order does not mean that FDA has “approved” the products. It means the agency determined that permitting their marketing met the APPH standard.
There is no known evidence that the JUUL2 decision was connected to the commentary. Their appearance within the same week nevertheless underscores the regulatory importance of complete switching, adult user behavior and population-level risk-benefit assessment in current ENDS regulation.
Authors Call for “Reach” to Play a Larger Role in Some Regulatory Decisions
The commentary argues that the U.S. tobacco regulatory framework already accommodates multiple forms of evidence, including longitudinal cohorts, actual-use research, national surveys and postmarket monitoring.
The authors argue that RWE could be used more extensively in some regulatory questions, particularly flavored ENDS.
Their position is that regulators assessing non-tobacco or non-menthol products could consider not only whether a product produces higher switching effectiveness than a tobacco-flavored alternative, but also whether it reaches a larger number of adult smokers.
That is a policy argument advanced by the authors, not an existing FDA requirement.
Confounding and Selection Bias Remain Key Limitations of RWE
The commentary explicitly acknowledges substantial methodological limitations in real-world evidence.
The most important is confounding.
An observed association between ENDS adoption and smoking cessation does not mean that the product was the only factor responsible for the outcome. Motivation to quit, use of other tobacco or nicotine products, health behavior, mental health, individual characteristics and social environment may all affect both product adoption and smoking outcomes.
Selection bias also matters because consumers who voluntarily choose a particular product may systematically differ from those who do not.
The authors point to propensity-score matching, longitudinal structural equation modeling and instrumental-variable analysis as methods that can strengthen observational analyses.
Their conclusion is that RWE should complement, not replace, RCTs: randomized trials provide evidence on controlled efficacy, while real-world studies provide evidence on how products are actually adopted and used.
Commentary Discloses Significant JUUL Labs Ties
The article is a commentary rather than a new independent clinical trial or systematic review.
Gem Le is an employee of JUUL Labs.
Arielle Selya is employed by Pinney Associates, which has consulted for JUUL Labs on nicotine vapor products and tobacco harm reduction since 2019. The competing-interest disclosure states that JUUL Labs partly funded Selya’s work in preparing the manuscript and provided comments on a near-final draft.
Riccardo Polosa reports research funding and consulting relationships with multiple pharmaceutical, nicotine and tobacco harm reduction organizations and companies, including JUUL Labs.
The article’s funding section states that there was “no funding for this Commentary,” while its competing-interest declaration separately discloses JUUL Labs’ support for Selya’s work.
These disclosures are material context for interpreting the commentary’s arguments on ENDS, RWE and regulatory policy.
Evidence Generation Could Become a Core Regulatory Capability
For manufacturers of e-cigarettes, heated tobacco and nicotine pouches, the framework outlined in the commentary extends product evaluation beyond premarket performance and laboratory evidence.
Premarket evidence can include chemistry, toxicology, clinical research, actual-use studies and switching behavior. After launch, postmarket evidence can track complete switching, dual use, continued use, consumer uptake and broader population behavior.
For nicotine companies, the ability to generate credible longitudinal and population-level evidence could therefore become an increasingly important capability alongside product development, quality systems and regulatory submission expertise.
The commentary does not establish that regulators globally are converging on a single RWE standard. It does, however, sharpen a question that is becoming increasingly relevant for fast-evolving consumer nicotine products: how regulators should assess both whether a product works under controlled conditions and who uses it, how it is used and whether it replaces combustible cigarettes in the real world.
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