Evidence Domains

The evidence to support the marketing authorization of an MRTP will come from studies of health effects, addictive potential, and risk perception. In this section the committee provides a brief summary of the studies within those evidence domains.

Health Effects

Laboratory analysis of the performance and of the constituents of tobacco products will be the first step in the evaluation of any new product. These analyses involve standard methods of extraction, sample cleanup, analytic identification, and quantitation. There are important limitations to laboratory analysis of product performance and composition. Laboratory analysis of constituents may not reflect constituent uptake under conditions of use. Smoking machines do not replicate human smoking conditions, and there is no proven way to replicate the many ways humans use tobacco. It is crucial, therefore, to describe the smoking regimen or other extraction methods employed.

The second step in the evaluation of MRTPs will be preclinical studies of toxicity. These assays are essential in identifying particularly risky or toxic products that should not be tested in humans, as well as products that have reasonable potential to reduce risk and, therefore, should proceed to clinical evaluation. Evaluation of products in vitro should precede in vivo assays. Although it is not possible to make laboratory animals use tobacco products the way humans do, and there are inherent interspecies differences that prevents meaningful extrapolation of human effects, it is still informative to observe the effect of tobacco products in live animal models. The number of animal studies required to characterize an MRTP preclinically could potentially be reduced by setting composition standards or limits or establishing standards for certain categories of MRTPs. Assays of toxicity in humans will also be essential, in particular assays of urinary mutagenicity and sister chromatid exchange in peripheral lymphocytes.

Biomarkers of exposure measure human exposure to constituents of tobacco and could include the constituents themselves, their metabolites, or protein (or DNA) binding products of the constituents or their metabolites. These biomarkers have the potential to bypass many of the uncertainties in product composition analysis and provide a realistic and direct assessment of carcinogen and toxicant dose in an individual. Biomarkers of exposure should be validated before their use.

When the FDA evaluates studies, it is important that it ensures the constituents of a product are accurately and precisely measured, that

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