Response from Investigators of Clinical Trial of Very Low Nicotine Cigarettes

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.  

More Reasons Why the Clinical Trial of Low Nicotine Cigarettes for Pregnant Smokers Was Unethical

Last week, I explained that a recent clinical trial of very low nicotine cigarettes for pregnant smokers was unethical because neither the intervention nor control groups were offered usual care: being instructed by a physician to quit smoking and being offered behavioral interventions, as specified by the U.S. Preventive Services Task Force. However, in addition to this ethical breach, there are several other aspects of the research which contribute to its impropriety.

The Rest of the Story

1. Unethical medical care: Physicians do not give up on our patients. We do not assume that a patient is incapable of complying with our medical advice. No physician should assume that a patient is permanently unable to quit smoking. Most ex-smokers tried to quit multiple times before finally succeeding. The presence of failed quit attempts does not mean that the next attempt will also fail. We are supposed to serve as coaches or supporters of our patients. Our role is to help them achieve healthier behavior, not to help them maintain unhealthy behavior. 

Because the physicians of these patients did not give them clear and unequivocal advice to quit smoking, they were unable to treat these patients in an ethical manner. The fact that the patients had indicated that they did not plan to quit in the next month is no excuse to assume that there is no desire to quit or that physician advice to quit might influence the patient. 

It is important to note that according to the article, the exclusion criterion was not that the patient stated that they didn't want to quit; it was they didn't plan to quit. The two relevant exclusion criteria were: (1) currently trying to quit smoking or planning to quit in the next month; and (2) past-month cessation attempt resulting in >3 days of abstinence. So someone who really wanted to quit but had not tried to do so and did not plan to do so in the next month was essentially abandoned. Instead of being helped to quit smoking, they were just thrown into a group with instructions to continue smoking as usual.

It is also important to recognize that although quitting smoking is exceedingly difficult and only about 3% of all smokers quit successfully each year, CDC data indicate that "56.1% of women who smoked before pregnancy quit smoking while pregnant." Thus, the chances are actually better than not that a pregnant women who smokes entering pregnancy will end up quitting before giving birth. 

2. Giving pregnant women free cigarettes to smoke: In this study, the control group subjects were not simply instructed to continue smoking as usual. They were actually provided with a supply of free cigarettes of their usual brand. Moreover, rather than provide them with fewer cigarettes than they normally smoke as an encouragement to cut down, they were actually given more than they needed in order to accommodate possible increases in smoking. Furthermore, subjects were provided with a fresh supply of free cigarettes every week: "At each weekly visit, they returned unused cigarettes and were resupplied." 

The primary ethical principle of medicine is "to do no harm." Here, physicians were doing harm by providing deadly cigarettes to pregnant women, knowing that these cigarettes would invariably cause harm to the fetus. Some of the effects that smoking has on the fetus are: inhibiting growth, damaging the lungs and brain, raising the risk for birth defects, raising the risks for stillbirth and SIDS, and increasing the risk of low birth weight. Some of the effects that smoking has on the pregnant women are: doubling the risk of abnormal bleeding during both pregnancy itself and during delivery and increasing the risk of premature rupture of membranes, placenta previa, and placental abruption.

It is one thing for these harms to occur if a woman makes an informed choice to smoke during pregnancy and goes out and purchases cigarettes. It is another thing for physicians to facilitate this damage by actually supplying those cigarettes for free throughout 12 weeks of the pregnancy. Cost is known to be a stimulator for smoking cessation. Here, the healthcare team was taking away that potential barrier to continued smoking and essentially playing the role of an enabler. 

It is also worth pointing out that because this was a federally funded study, it was actually taxpayer funding that went to purchase cigarettes for these pregnant women for 3 months.

Has Ethics in Medical Research Completely Disappeared? Study Assigns Half of Pregnant Women Subjects to Continue Smoking

A clinical trial published last week in the journal Preventive Medicine randomized pregnant women who smoked to either continue smoking their usual brand or to switch to a very low nicotine content cigarette brand. The study did inquire whether the subjects wanted or intended to quit smoking and excluded those who did. Nevertheless, after this initial indication of their present intentions, the subjects randomized to the "control" group were instructed to continue smoking their usual brand of cigarettes. The subjects in the "intervention" group were also instructed to continue smoking, but to do so using the very low nicotine cigarette brand.

The Rest of the Story

This trial raises the question of whether it is ethical to have a control group that is instructed to continue smoking, which is knowingly going to cause fetal harm to these pregnant women. 

The answer is a resounding "No." This is unethical research.

The key criterion in determining whether instructing a control group to continue doing a behavior known to be harmful to them is whether or not they are being offered "usual care." In other words, if usual care for pregnant women smokers being treated by obstetricians was to do nothing to change their smoking behavior if they did not express an initial desire to quit or did not think they were going to quit, then this trial would have been ethical. 

However, usual care for pregnant smokers who did not express an initial desire to quit is not to do nothing. And it is certainly not to instruct them to continue smoking!

According to the guidelines set forth by the U.S. Preventive Services Task Force, usual care for pregnant smokers is: "advise them to stop using tobacco, and provide behavioral interventions."

In order to meet basic ethical standards in medical research, the control arm of the study would had to have consisted of advising the patients to quit smoking and providing behavioral interventions to help them quit smoking. Instructing the patients to continue smoking as usual is not consistent with this usual care guideline.

The intervention protocol for this clinical trial was also unethical because it offered a treatment that is worse than standard care. These pregnant women, too, were instructed to continue smoking, rather than being advised to quit smoking and provided with behavioral interventions to help them quit smoking.

The only ethical way to conduct this study would have been to offer both groups the minimum standard care, meaning that both groups of patients should have received clear instructions to quit smoking and immediately provided with effective behavioral interventions that have been shown to increase smoking cessation. On top of that standard care, it would have been acceptable to provide one group with very low nicotine cigarettes to use if they were unable to comply with the physician's recommendation to quit smoking.

Absent a physician's clear recommendation to quit smoking and absent being provided with a behavioral intervention to enhance the chances of smoking cessation, this clinical trial failed to provide even a minimum standard of medical care and is therefore unethical human subjects research.

There are two potential counterarguments to this position but both fail.

First, one could argue that since these women did not plan to quit smoking, no harm was being done by assigning them to a group with instructions to continue smoking. However, this argument fails because these women were knowingly harmed by instructing them to continue a behavior known to harm the fetus and failing to provide the minimum standard of care typically offered to pregnant smokers outside of the research setting.

Second, one could argue that the women were not prevented from quitting smoking if they chose to. However, this lands fall short of the ethical standard. It is not enough to allow nature to take its course if standard practice calls for medical intervention -- namely, the U.S. Preventive Services Task Force's recommendation to advise quitting and provide behavioral modification therapies. 

Since the trial appears to have been completed, I cannot call for a discontinuation of the study. However, I am calling for the retraction of the study for violation of research ethics and some sort of compensation for the study participants.  

Anti-Vaping Physician Claims that a Single Vape Can Cause Severe and Irreversible Lung Disease

In an article posted late last month on Medscape, a physician claimed that using even a single vape can cause severe and irreversible lung damage.

Here is what she writes:

"Vaping has become a global health epidemic affecting everyone from high schoolers all the way to adults. This has gained popularity in recent years, but what people don't know is that vaping has now been shown to be linked to irreversible lung damage. It has been linked to conditions such as bronchiolitis obliterans, which is narrowing and scarring of the small airways due to diacetyl, which is found in nicotine liquid in vapes. Also, vaping has been linked to lung collapse,which can then cause hospitalizations and require patients to have chest tubes, or EVALI, which is a significant, life-threatening disease that can leave patients on a ventilator. 

It's important for us to counsel our patients and to advise our patients that these risk factors do exist when using their vapes every day or even socially on occasion. It only takes one time to try it to end up with any of these irreversible lung conditions."

 

The Rest of the Story

 

The rest of the story is that this physician is, unfortunately, lying. It is simply not true that it takes only one time to try vaping to end up with irreversible lung disease. The claim is ridiculous on its face. Even if you smoke an actual tobacco cigarette you cannot end up with irreversible lung disease. It takes years and years (if not decades) of smoking before you develop irreversible lung damage. So clearly, you're not going to develop irreversible lung disease from a single vape. It's not even clear at this point whether years of vaping will lead to chronic lung disease. There is no evidence that vaping causes bronchiolitis obliterans. Furthermore, the EVALI scare was caused not by e-cigarettes, but by black market THC vape carts that had been laced with vitamin E acetate. 

 

The question is: why does this physician feel a need to completely over-exaggerate the risks of vaping in order to try to dissuade youth from vaping? What this tells me is that subconsciously, she realizes that what she is trying to convince people of is a load of crap and so the only way she can try to make it credible is to actually make it so unbelievable that people's fear overtakes their rational thought processes.

 

Years ago, we tried the same thing with secondhand smoke. We scared people into believing that only 20 minutes of exposure to secondhand smoke could cause you to drop dead from a heart attack. In fact, it was that claim that led me to start this blog in the first place. 

 

Sometimes it is easier for people to believe a huge lie than a smaller one. So the more exaggerated the claim, the more people are likely to believe it. This is because the exaggerated claim generates an emotional response, leading to the person interpreting the response based on their limbic system (the emotional part of the brain) rather than their brain cortex (the rational part of the brain). 

 

Were this physician to advise smokers trying to quit not to use e-cigarettes because of its pulmonary effects, that would essentially be malpractice. Were she to list methods proven effective to quit smoking, but omit e-cigarettes (the single most effect approach to smoking cessation short of quitting cold turkey), that would be tantamount to malpractice. 

 

Whoops.