FDA: You Can Run Models, But You Can’t Hide Facts About Smokeless Tobacco

In a recent New England Journal of Medicine article, FDA researchers went to great lengths to conceal the fact that smokeless tobacco (ST) use has an entirely negligible impact on life expectancy.

The article, “Potential Public Health Effects of Reducing Nicotine Levels in Cigarettes in the United States,” (here) by Benjamin Apelberg and colleagues, was the centerpiece of FDA Commissioner Scott Gottlieb’s March 15 announcement of a radical nicotine reduction rule for cigarettes.  Drawing from the research, an FDA press announcement (here) declared that if cigarettes were minimally- or non-addictive by 2020, approximately 5 million additional adult smokers would quit smoking within just one year; only about 1.4 percent of the U.S. adult population would smoke cigarettes by 2100, in part, because more than 33 million people would avoid becoming regular smokers; more than 134 million years of life [would be] gained among the U.S. population.

While it is entirely unclear how nicotine reduction would produce the first two results, there is a fundamental flaw in Apelberg’s model that mainly affects the third, years-of-life, claim.  Correcting for that error, the model would likely confirm that ST products are nearly risk-free.

Apelberg estimates excess deaths among smokers by linking participants from National Health Interview Surveys (NHIS, 1997-2004) to the National Death Index (NDI) through 2006.  He also estimates deaths among users of ST, but uses an entirely different dataset – smokeless users who were enrolled in 1982 in the American Cancer Society Cancer Prevention Study II.

Apelberg’s use of two data sets -- NHIS for smokers and CPS-II for ST users – violates a basic rule of modeling: all inputs should be from the same or similar sources.  NHIS should have been used for analysis of both groups.  That was the procedure, for example, when Michael Fisher and colleagues used NHIS and NDI to produce a stable estimate for all-cause mortality among smokers and ST users (here). 

Apelberg may have used CPS-II because it shows that ST users’ mortality rate was 18% higher than that of never tobacco users.  Had he used NHIS, he would have had to acknowledge that smokeless users had no significant risks, as Fisher documented only a 5% excess that was not significant (HR= 1.05, CI = 0.90 – 1.23) (here).

The FDA analysis was biased through the use of exaggerated risks from an American Cancer Society study that has never been evaluated by independent researchers (here, here and here).  In this way, the FDA hid the negligible health impact of ST use.

A letter I submitted to the New England Journal of Medicine describing the flaw was not accepted.

Negligible Evidence of Radical Nicotine Reduction Benefit

An August 17 commentary in the New England Journal of Medicine (here) by FDA Commissioner Scott Gottlieb and Center for Tobacco Products Director Mitchell Zeller raises some concern about the agency’s new tobacco regulation strategy.

The piece touches on “less harmful tobacco products,” which Commissioner Gottlieb wrote favorably about earlier (here), but it includes descriptors – “potential” (four times) and “conceivable” (once) – that suggest the authors are not convinced that e-cigarettes are truly lower-risk. Smokeless tobacco, already demonstrated to be vastly safer than cigarettes, isn’t mentioned.

In their commentary, the FDA officials advocate for radical nicotine reduction (RNR) in cigarettes. 

RNR is a variation on a failed concept: supply-side elimination of popular products.  Full-on cigarette prohibition was adopted, then jettisoned, in 12 states from 1899 to 1909 (here). During Prohibition a decade later, brewers tried to market an alcohol-free product called near beer (here).  That bombed just as badly as Vector Group’s RNR cigarettes in 2003 (here).  Any new RNR products will likely be rejected as well, causing smokers to seek out higher-nicotine-level products, licit or otherwise.

Despite a significant expenditure of taxpayer dollars on RNR research, this approach has not been demonstrated to reduce adult smoking. For example, a $29 million clinical trial by Dr. Neal Benowitz, reported in 2015, produced dismal results (my review here).

The FDA commissioner and his co-author remain optimistic: “A recent 6-week study by Donny et al. showed that cigarettes with lower nicotine content reduced nicotine exposure and dependence, as well as the number of cigarettes smoked, as compared with cigarettes with standard nicotine levels.”  They are referring to another 2015 report (here), but that study’s results were unimpressive as well.

Dr. Eric Donny recruited 840 smokers uninterested in quitting, and randomly provided them with one of seven types of cigarettes to use for 6 weeks: their usual brand, a full-nicotine study cigarette and five others with varying low nicotine levels (2% to 33% of the full-nicotine cigarette).  Subjects were paid up to $835 for 10 clinic visits, which probably contributed to a 92% completion rate.

While it was not surprising that smokers using reduced nicotine cigarettes had lower nicotine levels in their urine, most of the low-nicotine smokers (73-81%) admitted that they smoked three or four “wildcat” cigarettes (products not distributed as part of the study) on 24-35% of days in the trial.

There was little consistency regarding changes in dependence.  On the Wisconsin scale, smokers in all groups had lower scores after six weeks than at baseline, with only one of the reduced nicotine groups significantly lower than the full-nicotine group.  On the Fagerström scale, three low-nicotine groups were significantly lower than the full-nicotine group, but the changes from baseline were not impressive.  In other words, it is not clear if the low-nicotine cigarettes reduced dependence.

The number of cigarettes smoked in the Donny study is interesting.  At baseline, every group was smoking about 15 cigarettes per day.  Although Commissioner Gottlieb and Mr. Zeller imply that low-nicotine groups smoked fewer cigarettes at the end of the study, they actually averaged 15-16 cigarettes per day.  Smokers of usual-brand and full-nicotine cigarettes smoked 21-22 per day after six weeks, an increase of 6-7.  Perhaps Donny contributed to this increased consumption by providing full nicotine cigarettes for free.

Like the Benowitz study, the Donny study does not prove that reduced-nicotine cigarettes produce meaningful benefits for smokers.

It should be noted that the Donny study was supported by $93.3 million in grants from the National Institute on Drug Abuse and the FDA.