Scientific Standards for Studies on Modified Risk Tobacco Products (2012) / Chapter Skim
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6 Decision Making and Oversight of MRTP Studies: Findings and Recommendations
6 Decision Making and Oversight of MRTP Studies: Findings and Recommendations
Pages 221-246
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the inte gration of all the evidence for the FDA's regulatory decisions about these products, including mathematical modeling and simulation techniques, and (2) the comparative nature of the harm reduction claims that the FDA will be evaluating.
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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.
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In addition, other study designs will be necessary to provide evidence on the public health effects of MRTPs, including retrospective cohort studies, case-control studies, crossover or case-crossover designs, and comparative effectiveness research methods. Different study designs will be necessary depending on the circumstances and the research question.
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Those include subjective evaluations in laboratory contexts, acute self-administration studies in laboratory contexts, use in extended residence facilities, and natural environment contexts where long-term use can be studied in real-world circumstances via RCTs, cross-sectional survey studies, and longitudinal cohort studies. Evaluation of reinforcement value in a laboratory setting is particularly important because the results of these studies reliably correspond to an agent's addictive potential in real-world use.
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Premarket research will play an essential role in developing the messages that the tobacco industry can use to communicate information about MRTPs to consumers. This research will determine consumers' ability to accurately understand messages that communicate information about the risks, benefits, and conditions of use pertaining to the MRTP itself and compared to existing tobacco products.
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Study designs must also carefully consider the degree of control imposed on experimental designs. Internal and external validity should be balanced not only within studies but also across studies of the same product.
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There are also a number of ethical issues associated with conducting human subjects research involving MRTPs. The first issue is the risk of conducting clinical trials of MRTPs or other tobacco products in popu lations with a high risk for tobacco initiation and addiction, including but not limited to adolescents, certain ethnic minorities, and individuals with mental health disorders.
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Public availability of data provided in an MRTP application is discussed in the Family Smoking Prevention and Tobacco Control Act of 2009 (FSPTCA) .2 2 Family Smoking Prevention and Tobacco Control Act of 2009, Public Law 111-31, 123 Stat.
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Beyond merely amassing evidence in support of the modified risk claims, higher-level processing of the evidence is needed to inform deci sion making. It is probable that, depending on their construction, intended uses, and desired claims, different MRTP applications could require dif
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tobacco use • Consistency of findings across relevant subpopulations of interest (e.g., low socioeconomic status, racial/ethnic minorities) Modeling and • Population predictions show reduction in smoking-related synthesis morbidity and mortality following the introduction of an MRTP with no significant evidence of uptake by nonusers (especially adolescents)
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would be difficult to support. However, if the identical product were available in other TABLE 6-2 Four Broad Scenarios for an MRTP Application Modified Exposure Modified Risk (Special Rule)
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The Role of Modeling Empirical studies employing a variety of designs, such as prospective, retrospective, randomized, or cohort designs, are expected to provide fundamental information about the societal impact of MRTPs. Considerations for the design and conduct of such studies are discussed in other sections of this report.
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Mathematical modeling and simulation analysis provide a complementary approach to the conduct of empirical studies that can be useful at each stage of the regulatory process for MRTPs. Modeling has already been used in the evaluation of smoking behaviors and related interven tions (Mendez et al., 2008; TPSAC, 2011)
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Thus, model-based analyses can inform and augment current knowledge from clinical practice and empirical observation for the underlying mechanisms of MRTP utilization, smoking behavior, and outcomes. Third, model-based analyses allow researchers and decisions makers to explore "what if" questions relevant to decision making, which would not be practical to assess in empirical studies.
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Standard components of the regulatory process, such as advisory panels, can take on a significant role in the assessment of face validity for models used on MRTP regulation. 4 David M
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For example, a model developed on the basis of currently available information can be linked to future empirical studies of the impact of an MRTP and validated partly or fully using data from those studies. Uncertainty Uncertainty accounting refers to the systematic examination, assessment, and reporting of the uncertainty in model inputs and assumptions, estimates of model parameters, and summary measures of the results (Bilcke et al., 2011)
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Using leading brands as a comparator also avoids potential mischief in comparing an MRTP to a product that is little used but may inflate the apparent risk reduction of the MRTP. In some cases, when desiring a reduced exposure or risk claim, the comparison product will be a product within the same product class (e.g., cigarette-like MRTP versus leading brand cigarette)
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The history of deceptive behavior by the tobacco industry undermined the trust of the public as well as the public's confidence in the industry's ability to rigorously conduct studies that will generate the data needed to evaluate these products. Therefore, the committee's recommendations are designed to articulate the minimum standards for producing credible and reliable evidence to demonstrate that the marketing of an MRTP is consistent with the protection of public health.
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Recommendation 1: The FDA should require that studies submitted in support of an MRTP application address all key research domains needed to forecast and monitor the product's public health impact, including: • product composition and performance; • addiction potential and likelihood for initiation or persistence of use; • human exposure to harmful and potentially harmful constituents; • perceptions about the product's effects and likelihood of addic tion; and • effects of the product on human health and surrogates of human health. Finding 2: Phased Approach to New MRTPs.
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Also, these methods can provide reliable evidence on human exposure. Recommendation 3: The FDA should require randomized controlled trials in the following domains: • Exposure reduction • Self-administration of the MRTP • Effects on use of conventional tobacco products These randomized controlled trials should include multiple comparison products (such as nicotine replacement products, conventional cigarettes or smokeless tobacco, placebo preparations, and alternative nicotine delivery systems)
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Finding 5: Modeling of Public Health Outcomes. Mathematical modeling and simulation analysis provides a complementary approach to the conduct of empirical studies that can be useful at each stage of the regulatory process for MRTPs.
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reporting criteria for clinical trials, the Strengthen ing the Reporting of Observational Studies in Epidemiology (STROBE) statement for observational studies, the publication criteria of the International Council of Medical Journal Editors, and the reporting criteria of the International Conference on Harmonization.
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Use of a trusted third party, particularly for products developed by the tobacco industry, could provide an avenue for the production of credible evidence needed by the FDA to evaluate tobacco products. Ultimately, such a research structure could encourage and support the production and dissemination of credible and reliable evidence about the effects of tobacco products on the public's health.
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Those standards not only protect human participants, but also build credibility into any data that are provided to the FDA, particularly by the tobacco industry. Institutional credibility and trustworthiness is particularly relevant in this context, given the history of unethical and illegal practices of the tobacco industry.
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2009a. Assessing consumer responses to potential reduced-exposure tobacco products: A review of tobacco industry and independent research methods.
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