For the purposes of fairness and completeness, I am sharing the response from study authors to my criticism of the recently published clinical trial of very low nicotine cigarettes. The text below is the response. At the bottom, after "The Rest of the Story" title, I offer just a few comments.
It has come to our attention that Dr. Michael Siegel has twice raised concerns in posts to his blog about a peer-reviewed publication of ours published in Preventive Medicine (https://pubmed.ncbi.nlm.nih.gov/40623557/). The report details results from a federally-supported pilot trial that we conducted examining the use of very low nicotine content cigarettes during pregnancy. In our opinion, Dr. Siegel has drawn the wrong conclusions in asserting that the trial was unethical and suggesting that the paper should be retracted. There are four aspects of Dr. Siegel’s concerns on which we wish to comment.
1. There is no question that smoking cessation is the ideal during pregnancy. Indeed, we have worked for the past 25 years to develop a highly effective perinatal smoking-cessation intervention and together have published more than 40 peer-reviewed papers in this area. However, not all pregnant women are able to quit, even with the best interventions currently available, and we need to consider other ways to reduce the adverse impacts of smoking during pregnancy. The U.S. Food and Drug Administration (FDA) is considering implementing a national nicotine reduction policy that would lower the nicotine content in cigarettes to minimally addictive levels to decrease the likelihood that youth who experiment with smoking get addicted and to increase the likelihood that people who are already chronic smokers will quit. Of course, any such national policy regarding nicotine levels in cigarettes would inevitably reach pregnant women who are continuing to smoke. From the time such a policy was proposed, there were concerns that reducing the nicotine content of commercial cigarettes might lead to sustained compensatory smoking (that is, smoking more cigarettes per day to try to reach usual nicotine level, leading to more smoke exposure and the adverse consequences that engenders) which could potentially outweigh the expected public health benefits of the policy. Fortunately, this has not proven to be the case in multiple studies and trials with not-pregnant people who continue to smoke. Given that there is a sizeable proportion of women who continue to smoke after learning they are pregnant, it is inevitable that pregnant women will be impacted by this policy. As such, it is important to the FDA to know how they respond to very low nicotine content cigarettes so that can be taken into consideration in weighing the potential population health benefits and costs of implementing such a policy. For that reason, we received a competitive research grant funded collaboratively by the National Institute on Drug Abuse and FDA to investigate how a national policy reducing the nicotine content in commercial cigarettes to minimally addictive levels might impact vulnerable populations including pregnant women.
2. The trials we designed including this one with pregnant women who smoke underwent many layers of peer review for scientific merit and research ethics before being funded or implemented. These trials including this one with pregnant women also adhered to all ethical guidelines for federally supported research. It is important to note that for safety purposes this particular trial was preceded by two laboratory studies, the first in not-pregnant women and the second in pregnant women, where participants smoked very low nicotine content cigarettes in a highly controlled laboratory setting to look for any evidence of compensatory smoking or other potential adverse effects during acute exposure to these reduced nicotine content cigarettes. Observing no substantive issues, we then proceeded to trials where the duration of exposure was extended. Paralleling the acute exposure studies, the protocol for the present extended-exposure study with pregnant women was based on that of an earlier trial we conducted with not-pregnant women. The trial with not-pregnant participants showed that providing them with very low nicotine content cigarettes reduced overall cigarette consumption and biomarkers of smoke and tobacco exposure without engendering sustained compensatory smoking. Only then did we move on to the study of extended exposure with pregnant women. Again, we want to emphasize that this extended-exposure trial with pregnant women underwent competitive peer review before being selected for joint funding by the National Institute on Drug Abuse and the FDA. It underwent additional review by FDA staff and was reviewed and approved by the Institutional Review Boards (IRBs) at all trial sites prior to initiation. Following approval, the study was monitored by an independent Data and Safety Monitoring Board made up of professional experts in tobacco research and research ethics. A small number of participants completed each protocol prior to initiation of the full study to ensure there were no glaring safety issues. The trial was also registered on ClinicalTrials.gov prior to initiation. Following practices used in our prior studies, all of the primary outcomes were published in a peer-reviewed journal. Any issues, ethical or otherwise, raised by reviewers or oversight committees at any stage in this process were addressed to their satisfaction or they would not have permitted the research to proceed.
3. Important to emphasize is this trial on which Dr. Siegel commented was NOT a smoking-cessation trial. Instead, it was a study designed to investigate how a national nicotine reduction policy might impact women who continue to smoke after learning they are pregnant. While this trial was not on smoking cessation, all potential participants were advised to quit. Indeed, the third sentence of the trial consent form stated, “It is known that smoking is harmful and all smokers are encouraged to quit smoking.” A subsequent section detailed the risks of smoking generally (“All cigarettes are harmful to a person's health and can lead to cardiovascular (heart) disease, respiratory (lung) disease, cancer and other health problems.”) and of smoking during pregnancy (“Smoking during pregnancy can lead to miscarriage, preterm delivery, stillbirth, low birth weight, problems with the placenta, birth defects such as cleft palate, sudden infant death syndrome (SIDS), and early childhood behavioral problems.”). In reiterating that the trial did not offer smoking cessation treatment, potential participants were also told that if they were seeking treatment, trial staff would help them find a treatment program. The consent form also assured potential participants that if they enrolled in the trial but later wanted to quit smoking, they could still continue in the study and receive all scheduled monetary compensation for doing so.
Women who reported that they planned to quit smoking in the next 30 days and those who had made a quit attempt in the past 30 days that resulted in 3 or more days of smoking abstinence were excluded from participating in the trial. Enrolled participants were subsequently asked at each of the 12 weekly study visits whether they were currently abstaining from smoking. If so, they were offered the National Cancer Institute’s smoking cessation booklet, Clearing the Air, and a referral to the state quitline. Those who were still smoking were asked if they were planning to quit before the next weekly study visit. If so, they were also offered the booklet and quitline referral and were asked what day they planned to quit. Finally, all trial completers were offered the booklet and quitline referral at the end of the intervention period.
In summary, all potential participants were encouraged to quit and were offered assistance to do so at every stage of the trial, starting at the screening assessment and continuing at weekly intervals throughout the study period. Moreover, if they wanted to quit, they were assured that they could do so and still continue in the study with full monetary compensation so that the loss of potential earnings from being enrolled in the study was not a barrier to quitting.
4. Regarding the free cigarettes provided by the trial, as noted previously, one of the main concerns about very low nicotine content cigarettes is that people who smoke them might engage in compensatory smoking. To ensure that any evidence of compensatory smoking would be picked up if it were present, it is convention in trials assessing the risks and benefits of cigarettes with different nicotine levels to provide research cigarettes to all participants free, including those in the control conditions. The protocols for these trials also include provisions for withdrawing participants who show evidence of compensatory smoking to prevent additional harm. Prior trials that have given very low nicotine content cigarettes to not-pregnant people have not found any evidence of sustained compensatory smoking in the vast majority of participants, as was the case in the present trial with pregnant women. Three participants, one in the usual brand condition and two in the very low nicotine content cigarette condition, were withdrawn when their breath carbon monoxide levels exceeded 50 ppm, a cutoff set by the FDA for this trial. Among the remaining participants, as shown in the top panel of Figure 2 in the published report, there was no change in the total number of cigarettes smoked per day in either condition; that is, participants did not smoke more even though they were given free cigarettes. Indeed, smoke exposure, as measured by breath carbon monoxide levels, decreased significantly over time among participants in both conditions, as shown in Table 2. Thus, there is no evidence that participating in this trial worsened smoking outcomes among the majority of the participants; on the contrary, there is some evidence of a small benefit for many.
In closing, we recognize that cigarette smoking is one of the greatest public health problems we have faced as a country. As noted above, we have devoted several decades of our careers developing and testing more effective smoking-cessation interventions for perinatal women and mothers of young children. Unfortunately, smoking cessation interventions are not enough to reduce the terrible adverse effects of smoking on population health, including women who are pregnant. Hence, the FDA’s consideration of implementing a national nicotine reduction policy is a tobacco regulatory effort to protect people from the addiction caused by current nicotine levels in commercial cigarettes. The results of the trial to which Dr. Siegel responded, along with our other work on the effects of very low nicotine content cigarettes in vulnerable populations, provide FDA with critical information that they will weigh in evaluating the potential benefits and harms to U.S. population health of implementing such a policy. Again, we have conducted this research in an ethical manner and have adhered to all research ethical guidelines and requirements of which we are aware.
Sarah H. Heil, PhD
Professor, Departments of Psychiatry and Psychological Science
Associate Director, University of Vermont Tobacco Center of Regulatory Science
Associate Director, Center on Rural Addiction
Stephen T. Higgins, PhD
Professor, Departments of Psychiatry and Psychological Science
Director, University of Vermont Tobacco Center of Regulatory Science
Director, Vermont Center on Behavior and Health
Virginia H. Donaldson Professor of Translational Science
University Distinguished Professor
The Rest of the Story
Just a few comments:
1. First, I do not question the integrity of the authors, all of whom have made substantial contributions to the field of smoking cessation and reduction of tobacco-related morbidity and mortality. I also do not question that there were multiple rounds of review by institutional review boards and that the study was deemed to meet all regulatory ethical standards. I think what I am actually questioning is the decision of the institutional review boards and how they concluded that the study "minimized exposure to unnecessary risk."
2. I agree that very low nicotine cigarettes could be a successful policy. Bringing all cigarettes to below non-addictive levels could be a game changer in that it separates the toxic nature of cigarette smoking from the chemical addiction element of smoking. In fact, I have been critical of the FDA for the last 16 years for not requiring cigarettes to bring nicotine levels down to the non-addictive range, something they could have done back in 2009 and have failed to do every year since then.
3. I agree that understanding whether compensatory smoking occurs with very low nicotine products is important. I agree that there is preliminary data to suggest that the use of these cigarettes could reduce harms to people who are unable to quit smoking. So I don't question the value of the research.
4. I am convinced by the response that there are enough potential benefits to the use of very low nicotine cigarettes that the intervention arm of the study is not problematic. It is the control arm that concerns me.
5. My specific concern about the control arm is whether the study "minimized exposure to unnecessary risk." This is a critical condition for all studies, even if they offer potential benefits to participants and even if the benefits outweigh the risks. Studies must do what is reasonably possible to minimize exposure to possible harm, especially when those risks are unnecessary. I am just having trouble understanding how a protocol that instructs pregnant smokers to continue smoking is minimizing exposure to unnecessary risks. In no way is it necessary for them to continue smoking. The appropriate way to minimize unnecessary risks in this study would have been to provide - at a minimum - usual care, which consists of a physician advising a patient to quit and providing behavioral interventions. Simply offering information or a quitline number is not sufficient, in my view, to constitute usual care.
6. Finally, I commend the authors for taking the time to respond to my concerns, especially in the absence of my writing a formal letter to the editor. This response is very much appreciated.
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