Congressional Craziness: Requiring Population-Level Proof for Harm Reduction

In 2009, anti-tobacco extremists won adoption of the Tobacco Act, which is likely to effectively prohibit tobacco manufacturers from participating in tobacco harm reduction.

The Tobacco Act forbids manufacturers’ communication with consumers about the relative risks of different tobacco products. This prohibition is not limited to commercial speech (i.e., advertising); it could be applied to essentially any public statement by tobacco company scientists or executives. If a manufacturer wants to market a tobacco product as a lower-risk alternative to cigarettes, Section 911 of the law contains evidentiary requirements that are nearly impossible to fulfill, even though the product already has been proven to be safer than cigarettes.

Section 911 is aptly numbered; it will significantly extend a tragic health crisis for legions of inveterate cigarette smokers.

In order to market a smokeless product as a less harmful alternative to cigarettes, a manufacturer has to satisfy the FDA that (a) the product will “significantly reduce harm and the risk of tobacco-related disease to individual tobacco users; and (b) benefit the health of the population as a whole taking into account both users of tobacco products and persons who do not currently use tobacco products.”

Is it possible to implement a clinical trial that could evidence the population benefit of safer tobacco alternatives? A recent analysis, published in Regulatory Toxicology and Pharmacology, attempts to provide an answer. The first author of the study (abstract here) was Lenn Murrelle from Altria; collaborators included statisticians and epidemiologists from consulting firms. It does not provide much hope that a clinical trial will ever be conducted.

Murrelle and colleagues start with some reasonable assumptions. First, they propose to study a very low-risk cigarette alternative such as snus. They designed the clinical trial to include four groups: continuing smokers, smokers who quit altogether, smokers who switch to snus, and nonsmokers. The latter group is important because of the Tobacco Act’s mandate to monitor possible future snus use among those who never used tobacco.

Murrelle used lung cancer as the outcome measure, which was the only practical choice. Smoking is the dominant risk factor for lung cancer, and snus use plays no role in this disease, so this maximizes the differences between continuing smokers and those who quit or switch. In fact, Murrelle assumed that the lung cancer rate among smokers who switch to snus would be the same as that among quitters.

Murrelle et al. found that a clinical trial would need to enroll 8,000 subjects (2,000 in each of the four groups) and follow them for 5 years in order to see differences in lung cancer between smokers who quit or switched to snus, and those who continued to smoke. Most clinical trials enroll a few hundred subjects at most, so 8,000 is an enormous number.

Such a trial, including 5 years of follow-up, would cost tens of millions of dollars. But that’s not the only problem. First, an ethical review board would never permit an investigator to assign a smoker to keep puffing. Challenges with the switch-to-snus group include finding an acceptable product, monitoring compliance and consumption, and determining who pays for the products. The quit-altogether group would be almost impossible to maintain, because sustained quit rates among smokers are so miserable. Finally, it would be terribly awkward to enroll people who don’t currently use tobacco, because they would have to be truthfully informed about the entire study.

The “claim” that might result would be very narrow: “Switching to this (specific) snus product could reduce your risk of lung cancer to the level of quitting tobacco altogether.” Murrelle and colleagues point out that if manufacturers want data for claims involving other diseases and/or products having smaller risk differentials than snus and lung cancer, they might have to enroll up to 10 times the number of subjects. That’s as many as 80,000!

Congress invoked this virtually unattainable population standard under the influence of tobacco prohibitionists. It is important to point out that setting such an extraordinarily high evidentiary bar is unprecedented. For example, consider the lack of such an evidentiary requirement to support the federal requirement for automobile seatbelts, another type of harm reduction. First pioneered by Swedish carmakers Saab and Volvo, (history here), seat belts were mandated by the federal government for all new automobiles starting January 1, 1968 (regulation here). While there was adequate laboratory evidence that wearing seat belts provide protection (but in rare instances slightly increase risks, similar to smokeless), there was virtually no population-level proof until this decade that seat belts actually save lives (an example).

It would have been disastrous if Congress had passed a bill in 1968 requiring population-level evidence before seat belts could be marketed for harm reduction. The same applies to smokeless tobacco.