7
Implementation of a Science-Based Policy of Harm Reduction

Scientific evidence establishes unequivocally that tobacco use causes serious adverse health effects in humans and that the nicotine delivered by tobacco is a highly addictive drug. The ultimate public health goal of tobacco policy is to eliminate the excess morbidity and mortality associated with tobacco use. The only scientifically proven way to accomplish this is to eliminate tobacco use by preventing initiation by those who have never used tobacco, achieving cessation for those who currently use tobacco, and preventing relapse by former users of tobacco. Achieving this goal will protect tobacco users themselves and those affected by environmental tobacco smoke (ETS). But because nicotine is a highly addictive drug, quitting tobacco use is extremely difficult for many people. Despite overwhelming evidence and widespread recognition that tobacco use poses a serious risk to health, some tobacco users cannot or will not quit. For those addicted tobacco users who do not quit, reducing the health risks of tobacco products themselves may be a sensible response. This is why many public health leaders believe that what has come to be called “harm reduction” must be included as a subsidiary component of a comprehensive public health policy toward tobacco.

Some public health officials oppose the adoption of harm reduction strategies because of concerns that promoting this approach will not, over the long term, prove to be beneficial to public health or to the individual tobacco users who might otherwise have quit (Ferrence et al., 2000; Warner et al., 1997). Whatever the merits of this position, marketplace forces already at work have put this issue on the public policy agenda, and new



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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction 7 Implementation of a Science-Based Policy of Harm Reduction Scientific evidence establishes unequivocally that tobacco use causes serious adverse health effects in humans and that the nicotine delivered by tobacco is a highly addictive drug. The ultimate public health goal of tobacco policy is to eliminate the excess morbidity and mortality associated with tobacco use. The only scientifically proven way to accomplish this is to eliminate tobacco use by preventing initiation by those who have never used tobacco, achieving cessation for those who currently use tobacco, and preventing relapse by former users of tobacco. Achieving this goal will protect tobacco users themselves and those affected by environmental tobacco smoke (ETS). But because nicotine is a highly addictive drug, quitting tobacco use is extremely difficult for many people. Despite overwhelming evidence and widespread recognition that tobacco use poses a serious risk to health, some tobacco users cannot or will not quit. For those addicted tobacco users who do not quit, reducing the health risks of tobacco products themselves may be a sensible response. This is why many public health leaders believe that what has come to be called “harm reduction” must be included as a subsidiary component of a comprehensive public health policy toward tobacco. Some public health officials oppose the adoption of harm reduction strategies because of concerns that promoting this approach will not, over the long term, prove to be beneficial to public health or to the individual tobacco users who might otherwise have quit (Ferrence et al., 2000; Warner et al., 1997). Whatever the merits of this position, marketplace forces already at work have put this issue on the public policy agenda, and new

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction products are being developed and offered as harm-reducing alternatives to conventional tobacco products. The task before this committee is to address the science base for implementing a harm reduction approach, and for assessing the impact of such an approach on public health. The committee’s task is not to recommend whether or not tobacco harm reduction should be pursued. Furthermore, the committee’s effort to carry out its charge should be understood as only one component of a comprehensive tobacco control policy. This report shows that the prospect of harm reduction presents both promise and uncertainty. For tobacco and pharmaceutical companies to be investing in products that reduce exposure to tobacco toxicants could be a salutary development. Nonetheless, despite advances in understanding tobacco toxicology and the pathophysiology and epidemiology of tobacco-related diseases, little is known about the health effects of using products that reduce exposure to one or more tobacco toxicants or about the public health consequences of promoting tobacco-related products or pharmaceutical products as potential reduced-exposure products (PREPs). It will take many years of research to develop definitive data. It is also clear, however, that action must be taken now, even as better data are being developed, to respond to the already emerging market for PREPs and to ensure that the necessary data are developed, that consumers are accurately informed, and that the public health is fostered. Until adequate data are available, individual and regulatory choices will by necessity have to be made on the basis of predictions of risk and harm reduction based on inference from indirect evidence. Action should therefore be taken not only to monitor the market, but also to shape it as scientific knowledge unfolds. Despite continuing ambivalence among some health officials about the wisdom of embracing harm reduction as a public health policy, numerous consumers will be taking steps in this direction, with or without scientific guidance. The aggregate effect of these decisions might make an important contribution to public health— or might further exacerbate the problems posed by tobacco products. Policy makers must use the best that science has to offer to ensure that the harm reduction strategies pursued by tobacco and pharmaceutical manufacturers and by individual consumers will truly reduce harm, and to the greatest extent possible. The committee was drawn by its charge into considering how best to implement the scientific and policy recommendations in this report and, in so doing, was necessarily required to address some features of a regulatory framework for PREPs. The regulation of tobacco products is most certainly controversial and many approaches have been proposed. Tobacco regulation conceivably includes taxation, access by minors, point of sales, etc. For the purposes of this report the regulatory framework

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction considered is narrow and focused exclusively on evidence and any necessary powers required to assess harm reduction products, be they pharmaceutical or tobacco-related. Other aspects of possible tobacco regulation are outside of the charge of this committee. The committee did come to conclude that regulation of PREPs is necessary and feasible. First, effective regulation is a necessary precondition for advancing scientific knowledge on the toxicology and clinical effects of these products, for developing the data necessary for systematic risk assessment, and for monitoring the impact of such products on the public health through appropriate postmarketing surveillance and the collection of long-term epidemiological data. Second, regulation is needed to ensure that the product labeling and advertising do not mislead consumers and accurately describe the products’ risks, including the uncertainties that can only be resolved after long-term use. Consumers should not use these new products on the basis of explicit or implicit claims that these products carry less risk than traditional tobacco products unless such claims are true. Absent careful regulation of industry claims about these products, informed choices by consumers will not be possible, the potential benefit of a harm reduction strategy is likely to go unrealized, and the long and unsettling saga of light cigarettes may well be repeated. Finally, regulation is also needed to foster integrated, coherent, and equitable policies with respect to the scientific testing, labeling, and advertising of the diverse array of PREPs marketed by tobacco and pharmaceutical companies. NEXT STEPS: AN OVERVIEW Although the science base for tobacco harm reduction (summarized in Chapter 5 and described in detail in Chapters 9–16) is extensive, the committee identified many gaps and limitations. To improve the science base for a harm reduction strategy for tobacco products and to protect public health, the committee’s scientific findings and conclusions must be translated into a comprehensive policy framework that includes the following elements: a substantial and sustained research program to address the critical unresolved questions that are susceptible to scientific resolution, as identified in this report; a strong surveillance program that will serve both as an “early warning system” for identifying problems associated with PREPs and as an epidemiological tool for evaluating long-term health consequences; a well-designed program of public health education (including media campaigns) to help people understand that preventing the

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction initiation of smoking and assisting smokers to quit constitute the only proven methods of minimizing tobacco-related harm, that the health benefit of using PREPs remains uncertain, and that this uncertainty will not be resolved for many years; and an integrated program of federal regulation of both tobacco-related PREPs and pharmaceutical PREPs designed to protect public health and to facilitate the research, surveillance, and public education activities described above. The remainder of this chapter will set forth the committee’s recommendations regarding the regulation of PREPs. As discussed in Chapter 4, the current regulatory situation leaves conventional tobacco products essentially unregulated while imposing stringent regulatory controls on the development and marketing of pharmaceutical PREPs. Modified tobacco products with exposure reduction claims currently fall into a twilight zone of regulatory uncertainty. Previous reports of the Institute of Medicine (IOM, 1994, 1998) have recommended that Congress enact a comprehensive regulatory statute delegating to an appropriate agency, preferably the Food and Drug Administration (FDA), “the necessary authority to regulate tobacco products for the dual purpose of discouraging consumption and reducing the morbidity and mortality associated with use of tobacco products.” The need for comprehensive tobacco regulation, as recommended in these previous reports, is reinforced by the Supreme Court’s ruling, on March 21, 2000, that the FDA lacks comprehensive authority over tobacco products under the Federal Food, Drug and Cosmetic Act (Food and Drug Administration, et al. v. Brown & Williamson Tobacco Corporation et al., 2000). These reports also recommended that the designated agency be authorized to regulate the design and constituents of tobacco products—for example, by adopting “performance standards” that set limits for the levels of toxicants in all tobacco products and/or by regulating the levels of, or exposure to, nicotine. This committee endorses these recommendations. This committee’s charge focuses specifically on products that purport to reduce exposure to tobacco toxicants. In this context the need for federal regulation is made more urgent by the recent introduction of Advance and the expansion of Eclipse into the marketplace and by the likely introduction of other tobacco-related PREPs, including oral nicotine and Swedish snus, in the future. The FDA already has the authority to regulate certain of these new or modified tobacco products as drug-delivery devices or as “drugs” if the manufacturer claims that the product prevents disease by reducing the health risks of using tobacco. The scope of the FDA’s jurisdiction is unclear, though, if the manufacturer goes no further than claiming that the product reduces exposure to known tobacco

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction toxicants (Page, 1998). Whatever the reach of FDA’s current jurisdiction over modified tobacco products, the existing regulatory framework for all tobacco products, including tobacco-related PREPs is inadequate to provide a basis for informed consumer choice and to protect the public health. Accordingly, the committee recommends that Congress enact legislation enabling a suitable agency to regulate tobacco-related products that purport to reduce exposure to one or more tobacco toxicants or to reduce risk of disease, and to implement other policies designed to reduce the harm from tobacco use. Regulatory classifications are traditionally based on the use(s) of a product and/or the claims associated with it. The outline of a sensible regulatory classification is therefore as follows: conventional tobacco products and modified products that are marketed without claims of reduced exposure to tobacco toxicants or reduced risk of disease; modified tobacco products or tobacco-like products, whether tobacco containing or not, that are marketed with such claims; and pharmaceutical products and medical devices, whether nicotine containing or not, that are marketed with a claim of effectiveness for cessation of, or significant reduction in, smoking. The committee’s charge is directed to products in categories 2 and 3 (all PREPs). The legal structure for regulating pharmaceuticals in category 3 is already fully in place under the federal Food, Drug and Cosmetic Act (FDCA) and administered by the FDA. The committee has therefore largely focused on products in category 2, a classification that encompasses any tobacco-related product marketed as a PREP—that is, with claims of reduced exposure to tobacco toxicants or reduced risk of disease—presumably involving a novel design or a modification of a conventional tobacco product. In the interest of placing recommendations concerning the regulation of tobacco-related PREPs in the larger regulatory context, the committee has embraced several recommendations in previous reports of the IOM (1994, 1998) with respect to conventional tobacco products (category 1 above). Thus, several of the principles outlined below apply to conventional tobacco products as well as to tobacco-related PREPs. Taken together with the drug and device laws already in place, the overall regulatory system should be sufficiently broad and flexible to encompass all relevant product innovations and to respond to new scientific knowledge in the years ahead. Manufacturers of tobacco products and pharmaceuticals should be encouraged to develop and introduce new products that will reduce the burden of tobacco-related disease. How

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction ever, manufacturers of new products should not be allowed to escape regulatory oversight by claiming that their products are dietary supplements, herbals, botanicals, or foods or that they make no explicit claims. PRINCIPLES FOR REGULATING POTENTIAL REDUCED-EXPOSURE PRODUCTS In the remainder of this chapter, the committee offers its judgment for consideration of the challenging scientific issues presented by the complex array of new products offered with claims bearing on tobacco harm reduction. Specifically, the committee proposes 11 principles that it believes should govern the regulation of new or modified tobacco products and pharmaceutical products with harm-reducing potential. The overall regulatory structure builds on the foundation of existing regulatory law, with appropriate adaptations to take into account the unique history and toxicity of tobacco products. The committee’s approach reflects the following general configuration: All tobacco products would be subject to requirements for certain testing and reporting and to the regulation of labeling and advertising. A manufacturer who wishes to market a new tobacco product as a PREP—a product with a claim, whether explicit or implicit, of reduced exposure to one or more tobacco toxicants or of reduced risk of adverse health effects (compared with conventional products)— would be required to receive from the regulatory agency prior approval of the claim based on scientific evidence presented by the manufacturer that the claim is not false or misleading; products for which risk reduction claims are made would be subject to postmarketing epidemiological studies. New brands and modifications of conventional tobacco products without health claims would be permitted to enter the market without prior regulatory approval if they are certified to present “no greater risk” than products already on the market. Pharmaceutical products and medical devices, whether nicotine containing or not, with health claims for reduction of smoking would continue to be subject to the current requirements of the FDCA. The committee believes that the agency charged with regulating tobacco PREPs should have a public health orientation and should be given authority over all tobacco products, including conventional ones. The scientific expertise needed to regulate both categories of products is similar. This agency will require a competent scientific review staff, including

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction molecular biologists, pharmacologists, toxicologists, physicians, epidemiologists, statisticians, and scientists experienced in the technology of tobacco product design and manufacture. In addition, it will need social scientists and marketing experts experienced in the evaluation of product labeling and the regulation of advertising. The agency must also have an analytical laboratory capable of testing a wide range of conventional and modified tobacco products and a product surveillance program staffed with epidemiologists and data management experts. Finally, it will need an enforcement and legal staff and appropriate administrative and information technology personnel. Some of these functions already exist for tobacco products at the Food and Drug Administration (disease claims), at the Federal Trade Commission (FTC; regulation of advertising and enforcement staff), and at the Centers for Disease Control and Prevention (CDC; analytical laboratory). But no agency currently has the comprehensive mandate or staff necessary to fulfill the policies recommended by the committee. This committee, like previous IOM committees (IOM, 1994, 1998), believes that the FDA would be an appropriate site for this regulatory function, but other administrative locations are certainly possible. The important point is that the requisite authority be lodged in a suitable federal regulatory agency with sufficient expertise and resources to execute the mission successfully. The committee notes the efforts of some states, notably Massachusetts in particular, to take on some of the regulatory challenges created by the federal government’s failure to establish comprehensive regulatory authority over tobacco products. However, patchwork state legislation is not a satisfactory long-term response to the problem. The only adequate response is for Congress to confer comprehensive authority on a suitable federal agency. Summary of Regulatory Principles A science-based regulatory framework for implementing tobacco harm reduction should conform to the following 11 principles: Manufacturers of tobacco products, whether conventional or modified, should be required to obtain quantitative analytical data on the ingredients of each of their products and to disclose such information to the regulatory agency. All tobacco products should be assessed for yields of nicotine and other tobacco toxicants according to a method that reflects actual circumstances of human consumption; when necessary to support claims, human exposure to various constituents of tobacco

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction smoke should be assessed using appropriate biomarkers. Accurate information regarding yield range and human exposure should be communicated to consumers in terms that are understandable and not misleading. Manufacturers of all PREPs should be required to conduct appropriate toxicological testing in preclinical laboratory and animal models and appropriate clinical testing in humans to support the health-related claims associated with each product and to disclose the results of such testing to the regulatory agency. Manufacturers should be permitted to market tobacco-related products with exposure reduction or risk reduction claims only after agency approval based on scientific evidence (a) that the product substantially reduces exposure to one or more tobacco toxicants and (b) if a risk reduction claim is made, that the product can reasonably be expected to reduce the risk of one or more specific diseases or other adverse health effects, compared with whatever benchmark product the agency requires to be stated in the labeling. The “substantial reduction” in exposure should be sufficiently large that independent scientific experts would anticipate finding a measurable reduction in morbidity and/or mortality in subsequent clinical or epidemiological studies. The labeling, advertising, and promotion of all tobacco-related products with exposure reduction or risk reduction claims must be carefully regulated under a “not false or misleading” standard, with the burden of proof for the claim resting on the manufacturer not the government. The responsible agency should have the authority and resources to conduct surveys of consumer perceptions relating to these claims. The regulatory agency should be empowered to require manufacturers of all products marketed with claims of reduced risk of tobacco-related disease to conduct postmarketing surveillance and epidemiological studies as necessary to determine the short-term behavioral and long-term health consequences of using their products and to permit continuing review of the accuracy of their claims. In the absence of any claim of reduced exposure or reduced risk, manufacturers of tobacco products should be permitted to market new products or modify existing products without prior approval of the regulatory agency after informing the agency of the composition of the product and certifying that the product could not reasonably be expected to increase the risk of cancer, heart disease, pulmonary disease, adverse reproductive effects, or other adverse health effects, compared to similar conventional tobacco

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction products, as judged on the basis of the most current toxicological and epidemiological information. All added ingredients in tobacco products, including those already on the market, should be reported to the agency and be subject to a comprehensive toxicological review. The regulatory agency should be empowered to set performance standards (e.g., maximum levels of toxicants; definitions of terms such as “low tar”) for all tobacco products, whether conventional or modified, or for classes of products. The regulatory agency should have enforcement powers commensurate with its public health mission, including the power to issue subpoenas. Exposure reduction and risk reduction claims for drugs and devices that are supported by appropriate scientific and clinical evidence should be allowed by the FDA. The following sections elaborate on each of these principles. Principle 1: Disclosure of Product Ingredients Manufacturers of tobacco products, whether conventional or modified, should be required to obtain quantitative analytical data on the ingredients of each of their products and to disclose such information to the regulatory agency. The manufacturers of tobacco products have detailed and extensive knowledge of the composition, curing, and blending of tobacco; the ingredients of their products; and the composition of tobacco smoke. They also have detailed quantitative information on the tobacco in each of their brands of cigarettes and smokeless products, since each is blended to achieve the desired taste and levels of nicotine and other ingredients. Manufacturers also conduct major research and development programs aimed at developing new products. Currently, there is no requirement for disclosure of this information to an appropriate regulatory body. Such disclosure is prerequisite to any meaningful scientific appraisal of the comparative risks of different tobacco-containing products or the potential for risk reduction offered by modified products. For smoked products, analytical information on the smoke and the concentrations of smoke components that are absorbed under actual smoking conditions may be even more important than knowledge of the product ingredients themselves. For smokeless tobacco products, whether conventional or modified, similar information on the concentrations of major ingredients in saliva and blood are equally important. The disclosure of quantitative information on ingredients (with appropriate safeguards to protect trade secrets) is a standard requirement in regulatory laws relating to drugs,

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction biologics, devices, food additives, toxic chemicals, and environmental contaminants and should be required of all tobacco products, whether conventional or modified. Although FTC regulation requires public reporting of some constituents in cigarette smoke, manufacturers are not required to report brand-specific information about the nicotine content or other properties (e.g., nitrosamine level) of the material that forms the tobacco rod. Under legislation enacted in 1986, manufacturers of smokeless products are required to report total nicotine content to the secretary of the Department of Health and Human Services (HHS), but the secretary may not release the data. Under the same legislation, tobacco manufacturers are required to submit lists of additives to the tobacco (but not to filters or papers) to the secretary of HHS. Information about the quantity of additives and their presence in specific brands is not required, and the secretary is bound to safeguard the information from public disclosure. In 1993, attorneys for six cigarette manufacturers released a combined list of 599 additives. The following year, ten manufacturers of smokeless products released a list of additives in their products. Three states have enacted legislation requiring disclosure of additives in tobacco products (U.S. DHHS, 2000). Principle 2: Yield Assessment All tobacco products should be assessed for yields of nicotine and other tobacco toxicants according to a method that reflects actual circumstances of human consumption; when necessary to support claims, human exposure to various constituents of tobacco smoke should be assessed using appropriate biomarkers. Accurate information regarding yield range and human exposure should be communicated to consumers in terms that are understandable and not misleading. The actual yield—that is, the amount of toxicants inhaled by an individual—from particular cigarettes varies considerably among smokers. As discussed in Chapter 11, this is because the standard yield is measured by a machine that smokes cigarettes in a mechanical and standardized way, whereas smokers can and do smoke their cigarettes with different numbers of puffs and different depths of inhalation. As a result, for any product, the temperature of combustion and the composition of the smoke varies among smokers depending on the pattern of smoking. The information required to address the relative harmfulness of tobacco products will be available only if an improved methodology for ascertaining the range of actual toxicant yields in human consumers is developed and applied; only then will there be a scientific basis for developing some of the features of a harm reduction program, including, for example, accurate labeling, meaningful definition of terms such as “low tar”, and reasonable standards for yields of tar, carbon monoxide (CO), or nicotine.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Although the limitations of the FTC’s current methodology for assessing cigarette yield is generally acknowledged, no definitive steps have been taken to replace it. In 1994, the President’s Cancer Committee and the National Cancer Institute (NCI) issued a report criticizing the current approach and recommending adoption of a new one. In 1997, the FTC issued a proposed revision of the methodology and a proposed format for disclosing test results in advertising and labeling. However, many proponents of a new approach urged the FTC to defer action pending judicial clarification of the FDA’s authority and possible congressional enactment of comprehensive regulation for tobacco products. It is time for the FTC— or, ideally, an agency with regulatory authority over tobacco products— to adopt a new standardized methodology to assess the range of toxic exposures to smokers under actual conditions of human smoking. Although the focus of yield assessment has been smoked tobacco, an analogous methodology should also be developed for smokeless products. Without quantitative information on the absorption of various constituents under normal product use, it is impossible to assess comparative exposures and comparative risks. The committee embraces the conclusions and recommendation on this issue set forth in the IOM (1994) report Growing Up Tobacco Free: [T]he regulatory agency, as its first step, should develop a sound methodology for ascertaining the actual yields of nicotine, tar, or any other constituents of tobacco products, based on human consumption. Human exposure to some constituents of tobacco smoke can be assessed by use of biochemical markers of exposure to those constituents, although at present this methodology is technically difficult and still imprecise; however, it is likely that better exposure measures will be developed in the future. In any case, even the currently available measures of human exposure are likely to provide a better indicator of relative risk than do the standard cigarette smoking machine yields. At a minimum, the smoking machine tests can be modified to reflect the range of ways in which people actually smoke, including numbers of puffs and blocking of ventilation holes, to determine likely ranges of delivery. In addition, the manufacturers of tobacco products could be directed to submit information to the regulatory agency regarding the actual yields of their products in humans for particular brands of tobacco products, based on use of prescribed protocols. A variety of regulatory initiatives relating to tar and nicotine yields can be envisioned. At a minimum, the regulatory agency should take steps to assure that consumers are informed about the meaning of statements regarding tar and nicotine yields, about the behavioral influences on exposure, and about the relative importance of the characteristics of the cigarette and the way it is smoked. The agency might also require that tar and nicotine yields be presented in a standard format, such as

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Based on current knowledge, Congress should enact specific warning and format requirements now, and should delegate regulatory responsibility for future modifications to the secretary of health and human services. The secretary should ensure that ongoing research is conducted on the effectiveness of prescribed warnings. Congress lacks the institutional expertise and flexibility to monitor the efficacy of regulatory innovations and to respond to new information. Authority to amend the warnings should be delegated to an appropriate regulatory agency. The secretary should be empowered to modify the format or content of existing warnings and to prescribe additional warnings, whenever such action is reasonably necessary to achieve effective communication of significant information regarding the health consequences of tobacco use or to discourage consumption of tobacco products. The committee endorses this recommendation. The need to implement this approach is all the more evident now in light of the emerging market for products that purport to reduce the risk of tobacco use. One of the recurrent questions in the regulation of health claims is when to permit a claim that a product may reduce the risk of disease. Such a statement may be misleading even though it is not false. Assuming substantial proof of exposure reduction, what type of evidence must be produced in support of a claim that the product may, as a result, reduce the risk of disease? Is inference based solely on the existence of a dose-response relationship sufficient? How strong must the evidence be? What is the significance of counterevidence? How much weight should be given to favorable changes in biomarkers that are biologically rational but not yet proven to be true surrogate end points? Although these are questions that will have to be addressed by the regulatory agency in due course, the committee itself is disinclined to permit claims that the product “may” or “might” reduce the risk of disease (or that “growing evidence suggests that the risk is reduced”) unless, as judged by the regulatory agency after review of data by an independent scientific advisory committee, the degree of exposure reduction is likely to result in a meaningful decrease in tobacco-related morbidity or mortality that can be measured in subsequent epidemiological studies. Another question must then be faced. Assume that the agency finds insufficient evidence under such a demanding standard to support a claim that the exposure-reducing product “may reduce the risk” of a particular disease. Should the manufacturer be permitted to make the statement (which is not false) as along as it is accompanied by a disclaimer to the effect that the regulatory agency has not approved the statement? This approach is receiving increasing attention in other regulatory contexts in light of a few judicial decisions holding that regulatory agencies must allow manufacturers to make the unproven statement, together with a

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction disclaimer, under the First Amendment (Gilhooley, 2000). The committee assumes that the First Amendment does not require such a permissive approach and is inclined to be much more cautious in light of the history of public health mistakes in tobacco product innovation. In the committee’s judgment, in the absence of sufficient scientific evidence to support a claim that a product may reduce the risk of disease, any claim of reduced exposure to tobacco toxicants should be accompanied by a statement that the health consequences of the change are unproven (or unknown). Given that considerable time will be needed to enact appropriate legislation, to staff a new regulatory agency, and to bring whole classes of products into a new regulatory system, a number of modified tobacco products with risk-reduction claims may enter the marketplace in coming years without regulatory review, assuming they are positioned not to fall under the drug or device laws. The committee views this situation with alarm but cannot offer a ready solution. Perhaps tobacco manufacturers would be willing to demonstrate their good faith by agreeing to voluntarily submit claims of reduced exposure or reduced harm to FDA, FTC, CDC, or some other appropriate agency for its review and comment, and to conform to agency suggestions pending legislative action. The committee emphasizes, however, that any purported harm-reducing products that have been put on the market before enactment of regulatory legislation should not be grandfathered or exempted from rigorous scientific and regulatory scrutiny. Principle 6: Postmarketing Surveillance The regulatory agency should be empowered to require manufacturers of all products marketed with claims of reduced risk of tobacco-related disease to conduct postmarketing surveillance and epidemiological studies as necessary to determine the short-term behavioral and long-term health consequences of using their products and to permit continuing review of the accuracy of their claims. The committee has repeatedly emphasized that since definitive information on the ultimate value of a PREP cannot be determined at the time of its initial marketing, the true extent of its long-term benefit (or possible harm) will remain uncertain unless specific surveillance and epidemiological studies are conducted after the product is marketed. The FDA already has the authority to require pharmaceutical manufacturers to conduct such studies for the purpose of monitoring drug-related health risks. The designated regulatory agency for tobacco-related PREPs should have equivalent authority to require manufacturers who seek to make reduced-risk claims to sponsor surveillance and epidemiological studies in appropriate cases. These studies should be designed to assess not only the

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction benefit of the product in reducing the risk of smoking but also the degree to which the product has served to maintain as smokers those who might otherwise have quit and/or to recruit new smokers. The quality of these studies should be high so that the results can permit modification of claims as knowledge evolves. The committee envisions that a plan or protocol for such a study (or studies) would commonly be required at the time of approval of the claim. Whether a postmarketing study is necessary should be judged by the regulatory agency on a case-by-case basis. The agency can also be expected to take steps to ensure the scientific integrity of such studies by requiring appropriate monitoring and, where necessary, an independent safety monitoring board. In addition to the authority to require manufacturers to sponsor postmarketing studies, the regulatory agency should also have in-house expertise in epidemiology. Such expertise is needed to deal competently with scientists in industry and peers in the field, to operate an adverse event reporting system, and to sponsor selected studies when necessary. As discussed in Chapter 6, the regulatory agency, in collaboration with other public health agencies, should conduct an active program of surveillance for all tobacco products, including conventional ones, modified products that are not accompanied by health claims, and PREPs. It is particularly important for public health authorities to monitor patterns of initiation and progression of use, including the interactions of product use (substitution and supplementation), for all PREPs. Principle 7: “No Increased Risk” Threshold for All Tobacco Products In the absence of any claim of reduced exposure or reduced risk, manufacturers of tobacco products should be permitted to market new products or modify existing products without prior approval of the regulatory agency after informing the agency of the composition of the product and upon certifying that the product could not reasonably be expected to increase the risk of cancer, heart disease, pulmonary disease, adverse reproductive effects, or other adverse health effects, compared to similar conventional tobacco products, as judged on the basis of the most current toxicological and epidemiological information. Conventional tobacco products are well established in the marketplace, and the committee recognizes that, regardless of the adverse health consequences of using these products, this situation is likely to continue for the foreseeable future. These products are already subject to a limited regulatory system that includes certain health warnings and other labeling requirements and some restrictions on advertising and promotion. The committee considered whether modified versions of established tobacco products, or new brands, that are marketed without health claims should be required, on public health grounds, to satisfy any new regulatory

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction requirements and, if so, whether manufacturers should continue to be permitted to put such conventional products on the market without prior agency approval. The committee concludes that any new regulatory system should ensure that all newly marketed tobacco products pose no increase in health risks, and ideally a new system should move products toward reduced potential for harm. To this end, the committee recommends that manufacturers be permitted to introduce a new product or make significant changes to an already marketed conventional tobacco product only if, on the basis of currently known toxicological and epidemiological information, the product could not reasonably be expected to increase the risk of disease. Implementation of this regulatory principle requires the definition of a standard for comparison. Although the responsibility for developing such a standard will rest with the regulatory agency, the committee can envision several possibilities: the most popular brand, the most (or least) harmful brand on specified dimensions, a toxicity profile that is representative of a sales-weighted average brand, or a standardized product of known composition. Because toxicant yields do not necessarily reflect health effects and because different standards may be appropriate for different products, the establishment of standards or reference products may require the type of information that would evolve from the regulatory agency’s experience with the disclosure of ingredients in individual products (principle 1) and the added-ingredients review (principle 8). Such standards might be promulgated through guidelines and performance standards (principle 9). To implement this approach, manufacturers should be required, before marketing a product, to submit ingredient information to the agency and to certify that the criterion of no increased risk is met (premarket notification). Whatever comparative standard is adopted for the product, the committee believes that a judgment of no increased risk should be based on the most current toxicological and epidemiological data. Manufacturers should not use the most dangerous products of the past as an appropriate standard for any new product. Consumers should rightfully expect that all new tobacco products, even those marketed without health claims, are at least no more hazardous than similar contemporaneously marketed products. The committee considered whether premarket approval by the regulatory agency should be required for modifications and new brands of conventional tobacco products without claims of reduced exposure or reduced risk, and rejected this approach in favor of premarket notification and certification by the manufacturer. Although some product modifications may be undertaken to improve taste or other features linked to consumer satisfaction, future innovation in the tobacco market in this

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction country is likely to focus on changes that purport to reduce risk. Because the main regulatory purpose of a requirement for no increased risk is to help establish the baseline for future comparisons and to stimulate development and use of protocols for tobacco product risk assessment, premarket notification is sufficient. The committee also did not want to see the regulatory agency burdened with a high volume of premarket approval decisions for products that have no claims of and no potential for improving the public health. Nevertheless, the regulatory agency should have the authority to seek the removal of a product from the market in the event that the “no increased risk” standard is not met. Principle 8: Added-Ingredient Review All added ingredients in tobacco products, including those already on the market, should be reported to the agency and be subject to a comprehensive toxicological review. The ingredients added to tobacco products should be subject to a review that is similar to the FDA review of food additives conducted more than two decades ago to determine if those additives were generally recognized as safe and not subject to additional regulation. Although many of the ingredients added to tobacco products are generally recognized as safe when used as food additives, such an understanding may not apply when these substances are combusted and/or inhaled in smoke. A review of added ingredients would establish a baseline of knowledge about the ingredients, including chemicals, papers, and filters, as well as the toxicological testing that has been conducted on them; it would thereby facilitate an informed appraisal of the potential effects of product modifications. This review should be conducted by independent panels of experts reporting to the regulatory agency, with the objective of identifying those ingredients that add no significant toxicity to tobacco products and therefore can be considered safe in the context of this use. Sufficient knowledge of the toxicity of many of the constituents and ingredients of tobacco products may already be available (see Chapter 10) to begin this review. If adequate information is not yet available, the regulatory agency should have the authority to require the in vitro and animal testing that is judged necessary by the expert panels conducting the review. Such a review would begin to rationalize the risk assessment of ingredients in tobacco products. It would also open this field to the same scientific discourse that is now applied to food additives, environmental contaminants, and toxic chemicals, substances that are no longer introduced into use without independent scientific scrutiny or regulatory review. Tobacco products are the last remaining legally marketed toxic products in our marketplace that are tolerated without such review. A review of

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction added ingredients would provide a scientific basis for guidelines or performance standards to limit possible toxicants like pesticides or filter fibers, if such limits are judged necessary for health reasons. It would also facilitate the review of new products by establishing conditions under which added ingredients, such as flavoring agents and papers, would be considered safe for use without additional data or review. An added-ingredients review would be a large administrative undertaking requiring several years of effort. It would also require the cooperation of the tobacco industry in submitting data. The committee believes that such a review would be in the interests of both manufacturers and consumers. It would permit credible scientific judgment regarding the extent to which nontobacco ingredients in tobacco products contribute to overall toxicity, would build scientific bridges between the tobacco industry and the toxicology community at large, and as noted above, would facilitate the regulatory review of new products. The committee notes that the review of food additives has been conducted without public disclosure of trade secrets, such as the composition of spices and flavoring agents, and believes that this principle should be respected in any review of the ingredients added to tobacco products. Principle 9: Performance Standards The regulatory agency should be empowered to set performance standards (e.g., maximum levels of toxicants; definitions of terms such as “low tar”) for all tobacco products, whether conventional or modified, or for classes of products. Performance standards, including maximum permissible levels, are promulgated under many regulatory laws, including those related to drugs, medical devices, and environmental pollutants. As noted above, successful implementation of a harm reduction strategy as an element of the nation’s tobacco policy will require proactive government efforts in research, education, and surveillance as well as regulation of specific products. Accordingly, as scientific knowledge evolves regarding product risks and consumer preferences, the regulatory authority should be empowered to require product modifications to eliminate unreasonable risks. (A similar recommendation appears in the 1994 IOM report.) The committee has not attempted to draft precise statutory criteria to guide the agency’s discretion in adopting performance standards. However, the committee does assume that the agency would not be empowered to ban nicotine from tobacco products. Performance standards might take the form of limits on the concentrations of toxic ingredients in the product or the smoke; sets of limits that taken together would qualify a smoked product to be labeled as high, average, or low on a risk scale; or a list of reviewed ingredients that could

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction be used without challenging the no increased-risk standard. A performance standard cannot be adopted without good scientific data, deliberate planning, and careful monitoring to ensure that it is achieving the desired goal. As the FTC test for tar and nicotine illustrates, even well intended performance standards can sometimes be subverted, with perverse and unintended health consequences. Performance standards aimed at setting definitions for terms must therefore be thought through with great care and be subject to change as experience is gained. Such standards will undoubtedly require a public rule-making process, meaning considerable time for their adoption. Principle 10: Enforcement Powers The regulatory agency should have enforcement powers commensurate with its public health mission, including the power to issue subpoenas. The committee envisions that any regulatory agency for tobacco-related products would need the usual enforcement authorities conferred on public health regulatory agencies, such as the FDA, FTC, CPSC, and Environmental Protection Agency (EPA). The committee anticipates that this agency would also have an appropriate technical and legal staff concerned with issues of enforcement. The committee specifically recommends that the agency have among its powers the authority to require the monitoring of scientific studies sponsored by manufacturers and to inspect manufacturers, investigators, and contractors to verify the data submitted in these studies. Such powers are necessary to ensure the quality and integrity of these studies. The agency should also have the authority to remove from the market ingredients or products that do not meet the test of no increased risk; to prohibit claims that are not supported by adequate scientific data; to seize products that are improperly labeled; to act promptly against advertising campaigns and promotional materials that are false or misleading; and to require corrective action. Principle 11: Regulation of Drugs and Devices Exposure reduction and risk reduction claims for drugs that are supported by appropriate scientific and clinical evidence should be allowed by the FDA. The committee recommends no new legislation regarding the regulation of pharmaceutical products and medical devices intended to assist people to stop smoking. What will be needed is effective policy coordination between FDA regulators responsible for drugs and devices and whatever agency is charged with administering any new legislation related to tobacco products.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction The committee also recommends that the FDA be prepared attitudinally and technically to approve both exposure reduction and risk reduction claims for drugs, when such claims are supported by appropriate scientific data. It is clear that the current FDA standard for all approved smoking cessation products is “quit rates” and that long-term use of pharmaceutical PREPs with cigarettes, which might be employed in a harm reduction strategy, is discouraged by the labeling approved for these products (Hughes et al., 1999). While the committee again emphasizes that cessation of smoking is the desired goal for all smokers, it also concludes that drugs with exposure reduction and risk reduction claims, if properly regulated and proved efficacious, have a place among the treatment modalities that should be available to current smokers. The committee judges, for example, that statements such as “helps recruitment into treatment clinics” or “reduces the use of cigarettes without compensation” are appropriate indications if supported by adequate data from clinical trials. The committee also concludes that for persons addicted to nicotine, a nicotine-containing drug product is preferable to a cigarette or other tobacco-containing product as a chronic source of nicotine. The FDA should therefore be prepared to consider the chronic administration of nicotine products as a reasonable exposure reduction strategy, again if supported by valid clinical data. Transitional Regulation of Tobacco-Related PREPs as Drugs Although the committee believes that adequate regulation of tobacco-related PREPs requires new legislation conforming to the preceding principles, the potential utility of the existing authority of the FDA and FTC should not be overlooked, and some of the committee’s recommendations could be implemented by these agencies in the absence of new authority. The FDA presently has the authority to regulate any product, including new or existing tobacco products, as drug-delivery devices or as drugs, on the basis of an expressed or implied claim by the manufacturer that the product prevents disease by reducing the health risks of tobacco (Page, 1998). FDA can find that a manufacturer intends to make such a claim by looking at any relevant source, including advertising. See United States v. “Sudden Change” (United States v. “Sudden Change,” 1969) and National Nutritional Foods Assn. v. FDA (National Nutritional Foods Assn. v. FDA) (objective evidence). Claims that PREPs respond to concerns about smoking-related illnesses or cancer can be regarded as disease prevention claims. In its recommendations for regulating the risk reduction claims for PREPs, this report identifies the type of testing and post-approval studies that should be conducted. The committee recommends that FDA use these

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction testing standards under its existing authority in regulating PREPs that make claims for reduced risk of disease. FDA can regulate products that are both drugs and devices under its authority over medical devices. In the case of medical devices that require premarket approval, the agency can determine what testing needs to be done to provide a “reasonable assurance” of safety and effectiveness and can set performance standards for class II devices where appropriate (21 U.S.C.; Page, 1998). The products can be considered safe on a relative basis in light of their capacity for risk reduction, even though tobacco itself was not considered safe in FDA v. Brown & Williamson (Food and Drug Administration, et al. v. Brown & Williamson Tobacco Corporation, et al., 2000). Post-approval testing has been allowed and required for new drugs (Page, 1998). Exposure reduction claims, such as low tar, have not been regulated by FDA as disease claims, and its authority to do so is uncertain (Page, 1998). A new law designed specifically to regulate tobacco-related PREPs can give a regulatory agency clear authority with respect to exposure-related and smokeless claims. Even for disease prevention claims, new legislation can confirm the agency’s authority and the type of tests and manner in which the agency should regulate claims. Moreover, the legislation recommended by the committee would provide the agency new authority to obtain data on ingredients of all tobacco products, permit additional disclosures to consumers about toxicants in tobacco, give enhanced authority (and review when needed) over advertising and labeling claims for PREPs, guard against increased risks from new or modified tobacco products, and authorize a toxicology review and performance standards for tobacco products. FDA’s authority with respect to disease claims would continue if the new authority recommended under this report were given to FDA, with whatever modifications were made by statute. If the authority were given to a new agency, FDA’s authority over disease claims for PREPs should be revoked only if the new agency has authority that is at least as extensive as FDA’s present authority. SUMMARY In this chapter, the committee has addressed key elements of a regulatory framework for implementing the scientific and policy recommendations made in the body of the report. In the committee’s judgment, harm reduction is a feasible and justifiable public health policy—but only if it is implemented carefully to achieve the following objectives: manufacturers have the necessary incentive to develop and market products that reduce exposure to tobacco toxicants and that have a reasonable prospect of reducing the risk of tobacco-related disease;

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction consumers are fully and accurately informed of all of the known, likely, and potential consequences of using these products; promotion, advertising and labeling of these products are firmly regulated to prevent false or misleading health claims, whether these claims are explicit or implicit; health and behavioral effects of all PREP use are monitored on a continuing basis; basic, clinical, and epidemiological research is conducted to establish with reasonable scientific certainty the actual health benefits of PREPs to individuals and the population as a whole; and harm reduction is implemented as a component of a comprehensive national tobacco control program that emphasizes abstinence-oriented prevention and treatment. The committee nevertheless acknowledges that a regulatory system of the type outlined in this report will require sustained congressional support and substantial public funding. It will also impose new direct and indirect costs on the tobacco industry. The committee emphasizes, however, that the regulatory system proposed in this report is not to be viewed in isolation. It is proposed as an essential component of a package of public policy initiatives (including research, education, and surveillance) that this committee believes is necessary to realize whatever benefit tobacco or pharmaceutical product innovation can offer in reducing the nation’s burden of tobacco-related illness and death. The committee notes again that public health benefits may not emerge, even if the public and private investment in these initiatives is made. In the absence of this investment, however, the hoped-for benefits are highly unlikely to materialize. REFERENCES 21 U.S.C. 360e(d)(2) Ferrence R, Slade J, Room R, Pope M. 2000. Nicotine and Public Health. Washington, DC: American Public Health Association. Food and Drug Administration et al. v. Brown & Williamson Tobacco Corporation et al., 2000. 529 U.S. 120. Gilhooley, 2000. Constitutionalizing food and drug law. Tulane Law Review 74:815–882 Hughes JR, Cummings KM, Hyland A. 1999. Ability of smokers to reduce their smoking and its association with future smoking cessation. Addiction 94(1):109–114. IOM (Institute of Medicine). 1994. Growing Up Tobacco Free. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1998. Taking Action to Reduce Tobacco Use. Washington, DC: National Academy Press. National Nutritional Foods Assn. v. FDA, 504 F.2d 761, 789 (2d Cir. 1974)

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Page, JA. 1998. Federal regulation of tobacco products and products that treat tobacco dependence: are the playing fields level? Food and Drug Law Journal 53: Supp 11–42. U.S. DHHS (U.S. Department of Health and Human Services). 2000. Reducing Tobacco Use; A Report of the Surgeon General. Atlanta, GA: USDHHS, Centers for Disease Control and Prevention. United States v. “Sudden Change,” 409F.2d 734, 739 (2d Cir. 1969). Warner KE, Slade J, Sweanor DT. 1997. The emerging market for long-term nicotine maintenance. JAMA 278(13):1087–1092.