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January/February, 2007

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Testing PREPs

Staff Report

While the debate continues within the tobacco industry and among health advocates about the viability of potential reduced-exposure products (PREPs), manufacturers are still exploring this possibility and, in turn, scientists are looking into the best ways of testing these products.

At the 60th annual Tobacco Science Research Conference held in Montreal last fall, scientists from the Life Sciences Research Office (LSRO) in Bethesda, Md., presented a report on “Evaluating Potential Reduced-Risk Tobacco Products.” According to that report, “There appears to be a consensus of opinion on the types of scientific testing needed to assess a tobacco product’s potential to reduce risk in individual smokers; however, scientific opinions vary regarding the reliability of currently available testing methods.”

The LSRO study focused on testing “reduced-risk” tobacco products, which are somewhat different than “reduced-exposure” products. The term “PREPs” refers to products (tobacco products or nicotine replacement therapies) that could potentially result in reduced exposure to toxicants from a given instance of tobacco use. However, the Institute of Medicine stressed that “reduced exposure” did not necessarily assure “reduced risk” to the individual user, or “reduced harm” to the larger population.

LSRO’s Reduced Risk Review Project, however, notes three key conclusions from the IOM’s 2001 report, “Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction”:

  • There are sufficient data to suggest that, for many diseases attributable to tobacco use, reducing risk of disease by reducing exposure to tobacco toxicants is biologically and clinically feasible. However, no PREPs have yet been evaluated comprehensively enough (including for a significant time) to provide evidence for concluding that they are associated with a reduced risk of disease compared to conventional tobacco use. Such impact likely will not be directly or conclusively demonstrated for many years.
  • Surrogate measures of tobacco-related diseases exist that could be used to give guidance or to help predict whether or not PREPs are likely to be risk-reducing. Available candidate surrogate measures must be further validated and more must be developed in order to be useful for PREP evaluation and regulation.
  • The public health impact of PREPs is unknown. They are potentially beneficial, but the net impact on population health could, in fact, be negative.
The IOM report also described the inherent tension facing the scientific and public health communities: “There is an urgent need to evaluate products and/or claims, but the science base is incomplete.”

Testing One, Two, Three...
The IOM committee identified the objective of a PREP risk assessment as follows: “to determine if the risk of harm from the use of the PREP is less than the risk of harm in the absence of a PREP.” They defined the risk management objective as “... primarily to verify whether or not a product is associated with either exposure reduction or harm reduction.”

Furthermore, according to the IOM, “The PREP risk assessment process will be challenging because no single definitive study, either human or experimental animal study, would stand up to rigorous scientific scrutiny to be used in such a process. Therefore, today, several types of data will be needed that includes both experimental animal studies and human clinical data, with a definitive plan to conduct epidemiological and surveillance studies....

“With more research, the regulatory process might be able to identify key types of data needed for the risk assessment process. At this point in time, however, it can only be concluded that both experimental and clinical human studies would be needed, and that this would include both the consideration of exposure to individual PREP constituents and as a complete mixture.”

In 2003, the World Health Organization’s Scientific Advisory Committee on Tobacco Product Regulation noted that the ideal evaluation of purported harm reduction would be based on measures of disease outcomes from human epidemiological studies of individuals followed before and after they switched to the new product. However, the Committee recognized that more timely measures are necessary for regulatory oversight and provision of accurate information to the public. Noting that the data likely to be available will be limited, the WHO Committee identified five key aspects of PREPs for study: physical and chemical characteristics of the tobacco and tobacco smoke; uptake of toxicants by smokers and nonsmokers; toxicity; addiction potential; and disease risk.

The U.S. public health community got into the act in 2005 when a meeting of multidisciplinary experts was convened by the National Cancer Institute, National Institute on Alcoholism and Alcohol Abuse, and the Centers for Disease Control to develop guidelines for the evaluation of PREPs on both individual and population levels. The conference participants identified the kinds of studies and research tools necessary to assess PREPs, and their conclusion was that there is no currently available set of measures available for determining the relative health risks.

Two of the largest U.S. tobacco companies created their own testing programs. The R.J. Reynolds Tobacco Co. developed and applied a protocol for testing its Eclipse product in 2000 through product characterization, smoke chemistry, short-term bioassays, animal studies, and clinical studies of exposure and effect. That same year Philip Morris USA developed and applied a similar approach to its Accord brand.

In general, the testing methods suggested and used to assess PREPs prior to marketing with reduced-risk claims are similar, but there are some noteworthy differences. First is the public-health emphasis on including an evaluation of the potential addictiveness in the assessment of individual risk reduction. Another is the inclusion of data regarding population risks, such as behavioral assessments, survey data, and evaluations of the marketing and advertising messages on perceptions of and demand for the product.

Scientific Uncertainties
In any scientific testing, risk assessment plays a key role. A human health risk assessment is a systematic review and evaluation of data relating to the risks posed by occupational or environmental chemicals, consumer products, food components and drugs, and other potential health hazards.

In the case of PREPs, risk assessments are comparative in nature, according to the LSRO report. Products with characteristics intended to pose reduced risks are compared to conventional cigarettes that have shown through human epidemiological studies to cause significant and severe harm. The pre-market evaluation and risk assessment of PREPs focuses on the individual smoker; many of the parties involved in PREP testing protocol have indicated that population risk be assessed after the product has been marketed.

There is also the question of scientific uncertainties; in the case of PREP assessments, these uncertainties stem from an incomplete understanding of the mechanisms by which smoking conventional cigarettes causes disease, which will also apply to the interpretation of evidence for risk reduction for PREPs.

“Weight of evidence” also comes into play. The term refers to a process that assigns levels of importance to evidence based on a number of factors, such as the quality of the study and relevance to the outcome of interest. Weight of evidence also refers to the “preponderance of the evidence” — that is, considering all of the evidence developed in the testing process, is it more likely than not that the risks of a PREP will be less than those posed by cigarette smoking?

After the risk assessment is completed, a decision will be made concerning the appropriate action to be taken in light of conclusions reached on comparative risks of using a PREP vs. smoking conventional cigarettes. The decision-making process must

integrate the results of the risk assessment with other considerations, such as ethical, social, economic, and political considerations.

For scientists and much of the tobacco industry, the question is: Is the scientific evidence sufficient to conclude that the PREP is likely to reduce risk in individuals who use the product instead of smoking? That, however, may not be enough for public health organizations, such as WHO, which asks, “What evidence is needed to demonstrate that a tobacco product is safe for individual users?”

The question focuses on product safety, not relative risk. According to most public health organizations, if the goal is safety, then it is best achieved when the source of harm is eliminated. These agencies do not support the use of tobacco products as possible tools to reduce the harms of smoking. That, of course, is not a surprise: Since the ultimate goal of public health and tobacco control organizations is a tobacco- and nicotine-free world, the fact that reduced-exposure and reduced-risk products do not contribute to abstinence from tobacco makes them a target.

While tobacco harm reduction, in general, has not been widely embraced within the public health and tobacco control communities — particularly the use of tobacco-based products that have been demonstrated to pose less risk than conventional cigarettes — manufacturers will no doubt continue to explore and test these products for smokers seeking a less hazardous alternative to their habit, one that doesn’t require total abstinence.


Tobacco International - January/February, 2007

BMJ


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