Given the long time for such cohorts to mature, emphasis might also be placed on establishing a complementary cohort of former smokers, because these persons will have the highest risk of recurrence in shorter periods of time. Biomarkers used in the former-smoker cohort that are found to be predictive of risk could then be used sooner in short-term epidemiological studies of PREPs.

Another group of subjects that might provide useful information about PREPs would be persons with surgically resectable cancers who will remain at high risk for developing new primary tumors or experience recurrence. These products might reduce the risk of either, so cohorts should be established to study these persons. Such studies would also provide valuable data for the worthiness of biomarkers.

SPECIAL ISSUES IN STUDY DESIGNS

Harm Reduction Compared to What Exposures?

Depending on study design, different exposure comparisons can be made, some of which are more applicable than others. For the development of biomarkers that are tested first in the laboratory setting (in vitro and in vivo animal studies), authentically synthesized tobacco carcinogens, or components of a reference cigarette (i.e., the tar fraction or cigarette smoke condensate from a Kentucky reference cigarette), would be preferable. Levels of exposure should be quantitated accurately so that the results can be interpreted in relation to the range of human exposures.

Experimental human studies in which the product is initially tested would optimally be compared to both reference cigarettes and separately to the smokers’ usual cigarettes, where a range of smokers and cigarette types are used (i.e., low- and high-tar contents, menthol). The decreasing use of nonfilter cigarettes would make comparison to nonfilter cigarettes a low-priority consideration.

The comparison group for short- and long-term epidemiological studies would have to be usual cigarettes, because it is not feasible to ask persons to smoke reference cigarettes, which are not designed for appeal. Thus, these studies must carefully characterize smoking behavior, and a range of cigarette types and smoking behaviors must be included.

Harm Reduction Compared to What Risks?

It is clear that any PREP will likely bring some risk of cancer to the user. Comparison groups could be either never smokers, former, smokers or continuous smokers. Preferably, a PREP should reduce risk for the



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