Governance and Conduct of Studies
Under subsection (l) paragraph (2), the Family Smoking Prevention and Tobacco Control Act of 2009 (FSPTCA)1 specifically directs the Food and Drug Administration (FDA) to develop regulations or guidance in consultation with the Institute of Medicine (IOM) “on the design and conduct of such studies and surveillance” (emphasis added). The specific requirement to advise the FDA on guidance and regulation for the conduct of studies is significant, as conduct encompasses more than sound study design and research methods.
A proper study design can produce meaningful results, while an improper study design produces meaningless data. In contrast, the improper conduct of scientific studies may encompass not only poor study design and execution, but also unethical or illegal activity. Consequences of improper conduct, such as the falsification, manipulation, or destruction of research findings, not only result in a loss of trust and credibility, but also can result in significant harm. It is critical that all data submitted in support of modified risk tobacco product (MRTP) applications are developed, generated, analyzed, and presented in a way that protects and maximizes credibility, scientific rigor, and public trust.
The mandate to advise the FDA on the conduct of studies was viewed as particularly important by the committee, given the history of the tobacco industry’s efforts to obscure the true health effects of smoking.
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1 Family Smoking Prevention and Tobacco Control Act of 2009, Public Law 111-31, 123 Stat. 1776 (June 22, 2009).
While the industry currently acknowledges the health risks of smoking, this history continues to affect the legitimacy of self-sponsored research associated with their products. To provide confidence in the face of the history of tobacco industry-sponsored and tobacco industry-conducted research, additional measures may be required beyond what otherwise might be expected of industries.
The mandate to advise the FDA on the conduct of studies presented a unique challenge to the committee. The committee concluded that it would be neither helpful nor adequate to simply rearticulate minimum standards for research conduct; the basic standards for the ethically and socially responsible conduct of science are well established. The committee felt strongly that mechanisms to enforce or otherwise affirm minimum standards for the conduct of studies should be addressed, and would be of much greater relevance to the FDA. As such, in this chapter the committee addresses not only the principles for ethical and proper conduct of research, but also the governance mechanisms to ensure the ethical and proper conduct of research as well.
This chapter begins with a brief retelling of the history of tobacco research. The next section explores how the absence of governance and a history of improper conduct have resulted in a situation where the tobacco industry currently lacks the ability to independently produce and disseminate comprehensive and credible data about tobacco products. The chapter concludes with a discussion of one or more independent organizations that may be needed for the governance of tobacco industry studies in support of applications to market MRTPs.
HISTORY OF SCIENTIFIC RESEARCH FUNDED OR CONDUCTED BY THE TOBACCO INDUSTRY
To provide proper context for the committee’s recommendations regarding the design and conduct of studies to support the marketing of MRTPs, it is necessary to briefly review the history of, and lessons learned from, research conducted, funded, or supported by the tobacco industry and its affiliate organizations. An earlier report from the IOM provides a more thorough review of the history of tobacco harm reduction approaches and products (IOM, 2001), so the current section is designed to briefly review the major issues.
Historical Overview of Tobacco Harm Reduction
The issue of reducing the harm associated with tobacco use emerged very early in the growth of the cigarette market in the United States. In the 1930s and 1940s, before smoking-related health effects began to
be widely publicized, a prominent focus of advertising campaigns was irritation, which served as a proxy for health concerns as it was linked to prevalent theories of cancer (Kozlowski and O’Connor, 2010). The mentholated cigarette brand Kool was marketed in ways that highlighted the “soothing” properties and claimed to help ease cold symptoms (Sutton and Robinson, 2004). After the publication of epidemiologic evidence of the harms of cigarette smoking (Doll and Hill, 1950, 1952, 1954; Wynder and Graham, 1950), filtered cigarettes were heavily promoted to smokers to allay health concerns. This resulted in the so called “tar derby” where manufacturers competed to win customers on the basis of lower reported tar and nicotine in cigarettes (Hoffmann and Hoffmann, 1997). On July 18, 1957, John Blatnik led 6 days of Congressional hearings on filtered cigarette advertising,2 the first of its kind in exploring the marketing of tobacco products (Harris, 2011). These hearings revealed that much of this marketing was fallacious, in that filters were largely ineffective, and that tar and nicotine numbers were largely incomparable between brands because manufacturers used different testing methods. The Federal Trade Commission (FTC) and the industry came to an agreement to not use tar and nicotine numbers in advertising in 1960, and themes in cigarette advertising turned more toward lifestyle and imagery (Kozlowski and O’Connor, 2010). By the 1960s, the cigarette market had shifted toward filtered brands.
The demonstration that cigarette tar could induce cancer in animal models resulted in the identification of tar as the primary aspect of concern (Wynder et al., 1953). This led to a widespread belief that reducing exposure to “tars” and nicotine would mitigate some of the associated health risks. Early epidemiologic findings appeared to support this view, inasmuch as those who used filtered brands were somewhat less likely to develop lung cancer (Wynder and Stellman, 1979). At the time, however, it was not broadly accepted that smoking was driven by nicotine addiction, nor that smokers might adjust their smoking behaviors to maintain their accustomed nicotine doses (NCI, 2001). In the early 1960s, the FTC began working with industry to refine a test method to compare brands, and this was implemented beginning in 1964 (NCI, 1997). Many public health advocates and institutions, including the National Cancer Institute (NCI), believed that publicizing tar values and switching to lower tar cigarettes would generate a public health gain (Hoffmann and Hoffmann, 1997). Tragically, rather than decreasing disease risk, the use of these products likely had a profoundly negative effect on the public’s health (NCI, 2001).
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2 U.S. Congress, House of Representatives. Subcommittee of the Committee on Government Operations. False and misleading advertising (filter-tip cigarettes). 85th Cong., 1st Sess. July 18-26, 1957.
In 1968, in response to calls for greater attention to the problem of lung cancer associated with smoking, the NCI established the Tobacco Working Group, an advisory group to establish a research agenda on the development of less hazardous cigarettes (Parascandola, 2005a, 2005b). This working group comprised members from government, academia, and the tobacco industry. From 1968 through about 1980, the Smoking and Health Program spent more than $50 million in research, 74 percent of which was directed toward chemical and biological assays of cigarette prototypes (Parascandola, 2005a). Documents revealed that the industry members of the working group helped to set research priorities and steer research findings and reporting (Parascandola, 2005b).
Internal tobacco industry documents provided insight into the industry’s knowledge of the relationships between cigarette smoking behaviors and cigarette design. The industry’s greater knowledge of human smoking behavior allowed for the design of “elastic” products, from which different amounts of smoke (and nicotine) could be extracted to satisfy consumer needs (Hammond et al., 2006; Kozlowski and O’Connor, 2002). Tobacco companies used many techniques to continue the appearance of relatively healthier cigarettes (Pollay and Dewhirst, 2002). Product features intending to lower toxin yields, as measured by the FTC machine, included air dilution and the reduction of tobacco density (NCI, 2001). The dilution of mainstream smoke by air could be accomplished in a number of ways, including increased paper porosity and diffusivity, porous tipping, and the inclusion of ventilation holes in the filter. These features acted to increase burn rate and to reduce the concentration of smoke taken at the tip. The reduction of tobacco density was achieved through engineered tobaccos, such as “expanded” tobacco, which was essentially “puffed” using gases to decrease density. This modification was advantageous for tobacco companies because less dense cigarettes burn more quickly when left in smoking machines, meaning that the measured tar yields were reduced by virtue of decreasing the number of puffs taken. Filter ventilation, however, was the key feature that drove cigarette elasticity. Ventilation holes were often placed in locations that are likely covered by the smoker’s lips or fingers. Because they also acted to cool smoke and reduce the puff concentration, they also served to make the smoke taste and feel lighter to the smoker (Kozlowski and O’Connor, 2002). Finally, the inclusion of ventilation holes reduced resistance to draw, which in turn made it easier for smokers to draw more smoke from the cigarette for a given amount of puffing effort (Kozlowski and O’Connor, 2002; NCI, 2001). Some products were explicitly designed to be highly elastic, including the product Barclay, introduced by Brown & Williamson in the early 1980s. The filter design used grooved air channels that made it very easy for smokers to compensate, while giving very low
yield for tar, nicotine, and carbon monoxide. The FTC eventually ruled the FTC method did not accurately measure the brand’s delivery (Kozlowski et al., 2005).
Initially, lower-tar cigarettes were marketed as distinct brands. However, this changed when Philip Morris introduced Marlboro Lights in 1972, beginning a broad trend toward product line extensions (Pollay and Dewhirst, 2002). Line extensions carried associations with the parent brand (e.g., taste, quality) and likely attracted more smokers to switch to lower-tar cigarettes. The history of light and low-tar cigarettes shows that tobacco harm reduction research—despite its potential to reduce risk—deserves careful and unique consideration because the migration of smokers toward lower-yield cigarettes has not improved either the health of individuals or the public (Harris et al., 2004; NCI, 2001; Thun and Burns, 2001).
In the 1980s, industry research and development turned toward more radical reengineering of products, in part as a result of rising litigation risk and in response to a growing smoke-free environments movement. In 1989, R.J. Reynolds introduced Premier, which it claimed as a smokeless cigarette. This product was withdrawn and later reengineered as Eclipse, which continued to be sold until 2008. Philip Morris tested various versions of an electrically heated cigarette smoking system, which used an external heating element to heat tobacco on specially designed cigarettes to produce smoke. The Accord, the first such system, was introduced in and the most recent incarnation was the Heatbar, tested by Philip Morris International in Switzerland from 2006 to 2009. Other approaches focused on applying technology to selectively reduce toxicants in traditional cigarette designs (e.g., Advance, Marlboro UltraSmooth, and Omni).
Early in the 2000s, evidence began to emerge from Sweden that showed dramatic reductions in smoking-related disease coincident with a rise in the use of snus, a form of moist smokeless tobacco (Foulds et al., 2003; Henningfield and Fagerstrom, 2001). Snus, as produced in Sweden, was regulated as a food product and thus subject to quality controls that led manufacturers to reduce levels of toxicants such as nitrosamines and heavy metals. These data encouraged some in tobacco control that harm reduction was possible if smokers could be convinced to adopt use of smokeless tobacco (Kozlowski, 2007), while others raised serious concerns about unintended consequences (Tomar et al., 2009). This message was seized upon in the United States, where smoke-free restrictions were growing, and existing smokeless tobacco companies began to aggressively court smokers. By 2009, the two major smokeless tobacco companies—Conwood Sales Company, LLC, and U.S. Smokeless Tobacco Company—had been purchased by the leading cigarette manufacturers (R.J. Reynolds Tobacco Company and Philip Morris, respectively), horizontally integrating
the tobacco market. Both companies introduced forms of snus into the U.S. market, carrying cigarette brand names (Marlboro and Camel).
Other tobacco products have also been promoted as having potential for harm reduction. In 2001, Star Scientific introduced dissolvable tobacco products (Ariva and later Stonewall), lozenges made from powered tobacco that would be used orally and disintegrate. In 2009, R.J. Reynolds followed suit with Camel Strips, Sticks, and Orbs, all different configurations of dissolvable tobacco. In 2006, electronic nicotine delivery systems (commonly referred to as e-cigarettes) emerged; these products have a physical form that resemble a traditional cigarette, but they use electrical heating elements to vaporize a nicotine containing glycerol solution. Some scientists have suggested these products hold promise for harm reduction, if subject to proper testing, regulation, and quality control (Etter et al., 2011).
Scientific Research Conducted, Funded, or Supported by the Tobacco Industry
In examining scientific standards for the design and conduct of studies related to MRTPs, an additional relevant consideration is the past behavior of the newly regulated industry. Cigarette manufacturers stated for more than six decades, either implicitly or explicitly, that cigarettes were not dangerous to health (Cummings, 2003; Cummings et al., 2002). However, industry officials and tobacco scientists were aware of smoking’s relationship to cancer risks as early as the 1940s, with broad internal acceptance seen by the late 1950s (Cummings et al., 2007). The wide discrepancy between internal knowledge and public posturing required efforts to maintain a perception among the general public and policy makers that scientific controversy still surrounded the relationship between smoking and health, and scientific research was essential to this.
Like most industries, tobacco manufacturers have maintained significant research and development arms, with a significant portion focused on product development and testing. Much of this was directed toward optimizing products in terms of taste and nicotine delivery (Carpenter et al., 2007; Cook et al., 2003; Harris, 2011; Hurt and Robertson, 1998; Megerdichian et al., 2007; Wayne et al., 2004). However, the tobacco industry has also engaged in health-relevant research on its products, including nicotine self-administration (DeNoble and Mele, 2006), mental illness (Hirshbein, 2011), and the composition and toxicity of secondhand smoke (Schick and Glantz, 2007a). Philip Morris determined that cigarette filters released inhalable fibers, yet never reported this to consumers (Pauly et al., 2002). Documents reveal that lawyers exerted considerable control over internal research, primarily to guard against product liability lawsuits
(Hanauer et al., 1995). Industry scientists did publish selected internal research, sometimes in the form of monographs or conference proceedings (Dunn, 1973; International Smoking Behaviour Conference and Raymond E. Thornton, 1978), and toxicological and chemical research was often published over the years. In addition to the recognized tobacco-specific journals Tobacco Science and Beitraige zur Tabakforschung [Contributions to Tobacco Research], tobacco industry scientists and consultants served on editorial boards of a number of scientific journals, including Indoor and Built Environment, Inhalation Toxicology, Regulatory Toxicology and Pharmacology, Mutagenesis, and the Journal of Clinical Epidemiology (Bitton et al., 2005; Garne et al., 2005).
A number of companies also sponsored external research, and a review of documents found that tobacco industry lawyers, rather than scientific merit, heavily influenced the selection of external research programs with the intent to improve public relations, divert public focus away from the negative health consequences of tobacco use, and influence policy (Bero et al., 1995). The tobacco industry’s scientific consulting program on secondhand smoke was largely attorney managed and intended to sway public opinion, but it also influenced funded scientists in terms of how they could express their research in public debates and conferences (Muggli et al., 2003). Further analyses of documents show a 40-year effort by Philip Morris USA to fund and influence the work of Dr. Ernst Wynder, a highly respected researcher on smoking and health (Fields and Chapman, 2003). The industry sought to fund research into alternative explanations of smoking-health links, including genetics (Gundle et al., 2010), stress (Landman et al., 2008; Petticrew and Lee, 2011), personality factors (Eysenck, 1991), and environmental pollution. Cataldo et al. (2010) describe industry efforts to gain control of the Framingham heart health cohort study by funding its principal investigator, so as to gain access to the dataset to produce favorable reanalyses questioning the link between smoking and heart disease. Research on secondhand smoke and health was designed and analyzed so as to achieve favorable conclusions (Barnes et al., 2006; Neilsen and Glantz, 2004; Ong and Glantz, 2000; Schick and Glantz, 2005; Tong et al., 2005; Yano, 2005). Other studies have shown that research funded by industry tended to come to different conclusions about secondhand smoke health effects (Barnes and Bero, 1998) and the economic impacts of smoking restrictions (Scollo et al., 2003).
The Tobacco Industry Research Committee, which was created in 1954 in response to emerging evidence of smoking-related cancer risks, later subdivided into the Council for Tobacco Research (CTR), which funded research, and the Tobacco Institute (TI), which focused on lobbying and communications. While the CTR existed, nominally, to fund independent research into smoking and health, it was part of the broader
public relations approach to questioning the validity of smoking-health links. Internal documents show that the organization was controlled by industry lawyers and funded special projects to favored scientists who would reliably cast doubt on smoking-disease claims (Bero et al., 1995). Similarly, the Center for Indoor Air Research (CIAR), organized in 1988, funded external peer-reviewed research as well as special projects. The CIAR was formed in response to growing calls to limit indoor smoking, and in particular the 1986 Surgeon General’s report on involuntary smoking. Barnes and Bero (1996) examined the CIAR’s project portfolio and showed that while 70 percent of the peer-reviewed projects were on topics not related to secondhand smoke, 63 percent of the special projects were related to secondhand smoke. Furthermore, while only 2 percent of the peer-reviewed projects had what could be termed “pro-industry” conclusions, the special projects showed 29 percent in favor of industry (Barnes and Bero, 1996). The industry also supported the Associates for Research into the Science of Enjoyment (ARISE), an organization created in 1988 in direct response to the classification of nicotine as an addictive drug by the U.S. Surgeon General (Landman et al., 2008; Smith, 2006). ARISE aimed to tout the health benefits of the use of legal substances such as tobacco in terms of stress relief and performance enhancement, and received more than 90 percent of its support from the tobacco industry. While ARISE did not sponsor research, it did organize symposia, conferences, and publications that served to disseminate its members’ research (many of whom were funded by the tobacco industry). The Master Settlement Agreement dissolved the TI, CTR, and CIAR in 1998.
Racketeer Influenced and Corrupt Organizations (RICO) Findings
In 1999, the federal government filed against the tobacco industry (Phillip Morris USA, R.J. Reynolds, Brown & Williamson, British American Tobacco, Lorillard, and Liggett) for violating the Racketeer Influenced and Corrupt Organizations (RICO) Act. District Judge Gladys Kessler stated in her 2006 findings of fact that the tobacco companies “conspired together to violate the substantive provisions of RICO.”3 A key element furthering the conspiracy was the coordination of research activities (such as those described above) designed to cast doubt on the health risks of smoking. Kessler noted in the findings of fact that
Defendants attempted to and, at times, did prevent/stop ongoing research, hide existing research, and destroy sensitive documents in order to protect their public positions on smoking and health, avoid or limit liability for smoking and health-related claims in litigation, and prevent regulatory limitations on the cigarette industry.
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3 United States v. Philip Morris USA, Inc., et al., 449 F. Supp. 2d 1, 26 (D.D.C. 2006).
Although the government was not permitted to recover monetary damages (disgorgement of illegal profits, which were estimated at $280 billion), the defendants were ordered to engage in corrective advertising, remove misleading labels from products, and submit to judicial oversight. The ruling has survived several levels of appeal. Most recently, Philip Morris et al. have argued that FDA regulation is a sufficient deterrent to future violations, and thus the RICO case should be vacated. In a recent opinion, Judge Kessler noted that FDA regulation was unlikely to deter defendants’ future bad acts because they were vigorously fighting the regulations via other court cases and regulatory challenges.4
Conclusions on Scientific Research Funded or Conducted by the Tobacco Industry
The history of research conducted, funded, or supported by the tobacco industry is not raised to be retributive or punitive, but simply to acknowledge that past actions reflect on the credibility of the industry’s current research, which may pose a problem for regulators, particularly in the contentious area of MRTPs.
An additional concern is that any perception of cavalier attitudes to tobacco research may tarnish the reputation of the FDA itself. The tobacco control statute places a high-capacity and historically well-trusted agency in the practice of regulating a commodity quite different from the products historically under its purview. The FDA carries a near-unique stature in the degree of public trust it has received, and there are plausible reasons to believe that this reservoir of public trust has imparted stability to the agency and has rendered its difficult combination of tasks easier (Carpenter, 2010).
If data generated for the FDA by tobacco companies is perceived to lack credibility, the FDA could in general, and the Center for Tobacco Products (CTP) could in particular, find its reputation, its scientific credibility, and its public trust severely compromised and perhaps irreversibly damaged. This reputational damage to the FDA and to public health institutions is a critical issue. Concerns about problematic data have surfaced occasionally in the past with the pharmaceutical industry; there is little reason to think that such scandals will not arise with the tobacco industry. Yet given any scandal, the consequences of the perception that the FDA and the CTP wrongly trusted tobacco industry claims will be far worse in terms of public, scientific, and legislative credibility.
These concerns are not isolated; similar concerns have been raised by the National Advisory Council on Drug Abuse (NACDA). In providing guidance to the National Institute on Drug Abuse (NIDA) about providing
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4 United States v. Phillip Morris, Inc. 2011 U.S. Dist. (D.D.C., June 22, 2011).
research funding to potential grantees who also receive money from the tobacco industry, the NACDA made several points to consider, including that receiving funding from the tobacco industry could compromise perceived objectivity and credibility of research, and that “any connection between tobacco industry supported research (or tobacco industry scientists) and NIDA could negatively impact NIDA’s credibility and the public’s trust in NIDA funded research” (NIDA, 2011).
RELEVANCE OF THIRD-PARTY GOVERNANCE
The conduct of tobacco product research presents a case that is unique from other FDA-regulated commodities. First, there is profound public distrust in both the tobacco industry and in the research it sponsors. Since the 1960s, public trust in tobacco companies has been at historical lows compared to virtually all other institutions or industries (Ashley and Cohen, 2003; Harris Interactive, 2003; NCI, 2008), and these patterns have not abated in recent years (Harris Interactive, 2010). Prior to the FSPTCA, commercial tobacco products were not regulated by the FDA (White et al., 2007). As a result, compared to other industries that develop products also requiring premarket approval (the drug and device industries), the tobacco industry does not possess, and will not possess for some time to come, the same degree of organization; accepted measures, methods, and models; and routine involvement and consultation of qualified experts.
The fundamental problem that confronts the FDA is a critical shortage of credible and reliable evidence about the effects of MRTPs. The history of public distrust and the absence of governance in the tobacco industry have created an isolated industry that lacks not only the expertise to produce the necessary range of credible and reliable data, but also the trustworthiness to acquire external expertise and avenues to disseminate acquired data. The committee also recognizes that other industries, including the pharmaceutical and device industries, may develop and sponsor MRTP candidates, and although these institutions should also be held to high standards for the design and conduct of studies, they may not have to overcome the same hurdles in maintaining or restoring credibility to their research.
Role of Governance in Sustaining Credibility in Tobacco Industry Research
The idea that research on commercial products that carry public health risks should be supervised, funded, or structured by independent entities has important precedents and models (Marks, 1997). When pharmaceutical and medical product companies engage universities, medical schools,
or research hospitals to conduct research, the institutions conducting the research studies contractually embed research autonomy into the funding arrangements, and all such studies in human subjects are approved by institutional review boards (IRBs) before they commence. So too, human subjects research is overseen by the National Institutes of Health, the Office of Human Subjects Research of the Public Health Service, and the FDA itself. This is true of all researchers receiving public funds and those conducting research on an FDA-regulated product (FDA, 2010; HHS, 2009; White et al., 2007). Academic and medical journals also exercise a gatekeeping and oversight role for clinical research with human subjects.
The production of reliable and credible data depends upon building rigor, oversight, and independence into the entire research process. It is well recognized that data problems often cannot be detected after study completion; therefore, integrity and accountability need to be built into the research throughout the study’s execution. For balanced and rigorous evaluation of data in support of any marketing application, the FDA has traditionally expected or required independent oversight. Unlike the tobacco industry, clinical research models in the pharmaceutical industry were developed in academic medicine and pharmacology circles in the 20th century, with significant input from pharmaceutical industry partnerships, which had from the 1940s onward sought pharmacological, statistical, and other medical expertise for the improvement of their experimental methods (Marks, 1997). Various officials and bureaus of the FDA itself also participated in the modernization of the research paradigm in pharmaceuticals, either through regulation or through advisory or participatory roles (Carpenter, 2010). The credibility of data in support of new pharmaceutical products or medical devices is, in other words, supported by a national and global infrastructure of research that has taken decades to evolve, and even now it is not free of problems.
The FSPTCA places the CTP in a difficult position. The center will now be regulating tobacco companies as product sponsors, without the long-run institutional knowledge of these companies that is gained through decades of regulation and oversight. There is not an established set of regulatory practices for the review of MRTPs, nor is there an established set of federal research standards for the design, conduct, analysis, monitoring, and completion of studies in support of MRTPs. Development of the “clinical trial” industry for MRTPs is, in a sense, being initiated in the next few years, because current tobacco industry practices suggest a degree of immaturity in the development of methods, measures, and standards (Rees et al., 2009).
Although industry- and company-sponsored studies are very common, they have been largely unregulated in the way pharmaceutical trials have been, and they lack the same level of oversight, governance,
and rigor. A related point is that as major academic journals increasingly refuse to publish tobacco industry-funded research, they do not provide their traditional gatekeeping or oversight role via peer review. This hypothesis gains credence from studies of tobacco industry research, including research done by some of the largest and most established companies, where independent researchers have found significant problems with governance. In one examination of more than 73 different studies with human subjects conducted by R.J. Reynolds from 1985 to 2000, White et al. (2007) report that “in all 73 studies, [informed] consent procedures failed to meet five or more human subjects research standards” (emphasis added). Although R.J. Reynolds formed a human subjects review committee in 1985, the authors conclude that “the committee’s structure and procedures did not meet generally accepted practices of the time regarding community representation, written procedures for adverse events, and other factors” (White et al., 2007).
Similarly, in a December 2009 review of industry research on potential reduced-exposure products (PREPs), Rees et al. (2009) suggest that the industry is catching up to clinical methodology standards now broadly accepted in the academic and medical realms. Basic good research practices such as documentation of data and analysis appear to be lacking from internal industry records, as well as cutting-edge methods of trial design, adaptation of design to hypothesis, and statistical analysis (Rees et al., 2009). Furthermore, switching paradigms that accommodate dual use of a PREP and conventional product, and switching to nicotine replacement therapy or cessation were not observed (Rees et al., 2009). As PREP assessment methods continue to be refined, such methods have become increasingly important to independent investigators. Clinical trial methods need to reflect real-life use patterns within the context of a research study, including ad libitum use of a PREP alone or in combination with conventional products, as well as employment of rigorous controls such as nicotine replacement therapy or forced switching conditions. Perhaps the narrow objective of demonstrating reduced exposure risk compared with a conventional product in support of product claims has constrained the scope of clinical research methods used by the industry.
Because the tobacco industry is currently limited in its ability to produce credible and comprehensive data, at least part of the research base in support of an MRTP may need to be generated by researchers and organizations independent of the sponsors of the MRTP in question. Rees et al. (2009) conclude that “research independent of the tobacco industry is essential to provide an effective and unbiased evaluation of industry claims” and note that “claims for PREPs, both implied and explicit, must ultimately be evaluated independently, by the broader scientific community, using validated assessment strategies and accepted
clinical methodology.” Such independent research oversight would support the generation of credible and scientifically rigorous data that meet the unique challenges that tobacco product research presents.
Conduct and Publication of Tobacco Industry Research
The FSPTCA requires product sponsors to provide evidence that the issuance of an order for the sale of an MRTP will benefit public health, including the effect of marketing the product on users and nonusers of tobacco products. As discussed in later chapters, an essential element in establishing the public health benefit of an MRTP is assessing the effect of the product on high-risk populations, in particular adolescent populations. As such, it is inevitable that product sponsors will need to collect extensive data on the effect of products in these populations in both pre- and postmarket studies. This poses a significant problem to product sponsors, because the tobacco industry currently lacks expertise and experience in conducting behavioral and addiction research in high-risk populations. Recognizing the risks involved, some tobacco companies appear resistant to the notion of conducting the research themselves. This issue was specifically discussed with industry representatives during an open meeting of the committee in May 2011. Representatives from multiple tobacco companies acknowledged that while research on adolescent populations is relevant to support an MRTP application, the companies were at that time reluctant to commence such research and were seeking guidance from the FDA on how best to proceed. In a personal communication, Lars Erik Rutqvist, Senior Vice President of Scientific Affairs of Swedish Match, indicates that industry is very unlikely to conduct research on “sensitive subpopulations such as adolescents…” because of “… ethical and product stewardship concerns.”5 If the position of Swedish Match is generally representative of the tobacco industry, then the risks and issues inherent in research on adolescent and other high-risk populations seem likely to dissuade most tobacco companies from conducting the research themselves. Without a framework that allows the industry to fund independent investigation on adolescents and other high-risk populations, it is likely that major gaps in knowledge about MRTPs will remain.
To assess the health impacts of an MRTP, product sponsors may have universities and research hospitals conduct the requisite studies with tobacco-industry and MRTP-sponsor funding. There are at least two problems with a university- or hospital-based research model with which the FDA and the scientific community may need to grapple. Firstly, many
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5 Personal communication, Dr. Lars E. Rutqvist, Swedish Match AB, Stockholm Sweden, August 5, 2011.
universities disallow tobacco industry funds in support of research on tobacco or tobacco products. As of March 2007, more than 20 academic institutions in the United States instituted policies banning tobacco industry funding of tobacco research. Secondly, even if a university permits tobacco-funded research on its campus, it does not ensure the resulting research will be widely trusted or considered valid by the broader scientific community. The CTP will wish to avoid a regime where product sponsors simply “forum shop” or “venue shop” for those institutions—characterized by a least common denominator of standards—that will permit industry-funded research on tobacco claims. One way of doing so would be to prescribe that whenever a tobacco company contracts with a university to conduct tobacco industry-funded research in support of an MRTP application, it must include in the contract certain essential conditions designed to assure the independence, integrity, and transparency of research.
Similarly, many medical and scientific journals have refused, and will continue to refuse, to publish research funded by tobacco companies or affiliated foundations or institutes. The passage of the FSPTCA will not alone change this fact. If the research supporting MRTP claims is of sufficient academic quality for publication in an academic journal, this refusal of journals to publish tobacco-sponsored research may be de facto prohibitive. Alternatively, if the CTP requires any substantial part of the portfolio of research supporting an MRTP application to consist of actual published research, it may be difficult for sponsors to meet this standard. If a governance framework is created that fosters credible and trustworthy tobacco research, journals may be willing to reconsider acceptance of tobacco industry-sponsored manuscripts.
An additional concern relates to the experience and qualifications of investigators conducting tobacco research. Use of unqualified or inexperienced investigators not only increases the risk for poorly conducted research, but also undermines the credibility of the research findings and research sponsor. Furthermore, use of unqualified and inexperienced investigators may expose research participants to greater risks for harm. It is in the best interest of all stakeholders involved in the evaluation of an MRTP to maintain high standards for the qualifications of investigators. This is embodied in the FSPTCA: according to Section 911(i)(2), the qualifications and experience of investigators conducting postmarket surveillance of MRTPs must be reviewed and approved by the U.S. Department of Health and Human Services (HHS) Secretary. The credibility of the investigators is equally important. Investigators should be free from real or perceived conflicts of interest and biases. It is critical that the investigators involved in research in support of MRTPs and potential MRTPs have adequate qualifications, experience, and credibility.
Another critical component of the FSPTCA assures that MRTP sponsors make and follow through with commitments to design, conduct, and report on postmarketing studies with thoroughness and diligence. The commencement and completion of postmarketing studies has long been a difficult area of regulation for the FDA, especially for Phase IV studies in the area of prescription drug regulation. These studies have often been slow to be completed and in some cases tardy to commence, and a number of independent entities have expressed their concern about the FDA’s ability to commit product sponsors to finish these studies with the due diligence the law requires (Glasser et al., 2007; HHS, 1996; U.S. Government Accountability Office, 2009; Wood et al., 1998). This has been partially addressed by the Food Drug Administration Amendments Act,6 which grants the FDA authority to regulate Phase IV studies and apply penalties if they are not conducted in a timely fashion. Like other features of FDA regulation (e.g., drugs with accelerated approval based upon studies using surrogate endpoint measures) the marketing approval for an MRTP claim under Section 911 of the FSPTCA is, according to law, a conditional and provisional approval. In accordance with the FSPTCA, when the FDA approves an MRTP, it will plan a series of postmarketing studies designed to address questions that were not fully answerable at the premarket stage. An independent tobacco research governance entity (TRGE) can play an important role in the design of these studies and in the monitoring of their completion.
Ethical Considerations of Tobacco Research
Robust standards for the ethical conduct of research have been developed to guide studies that involve human participants. Prominent examples include the Nuremburg Code, the Belmont Report, the Declaration of Helsinki, and the International Conference on Harmonisation Guideline for Good Clinical Practice. These documents, and in particular the Belmont Report, inform the federal regulations for the protection of human research participants, collectively known as the Common Rule (specifically 21 Code of Federal Regulations [CFR] parts 50 and 56 for FDA regulations). The committee affirms the protections enforced by the Common Rule as requisite in all tobacco studies that involve human participants. In addition to the basic protections afforded by the Common Rule, the committee identified several ethical issues in tobacco research worth particular attention.
The first issue is the risk of conducting clinical trials of MRTPs or other tobacco products in populations with a high risk for tobacco initiation
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6 Food and Drug Administration Amendments Act of 2007, Public Law 110-85, 121 Stat. 823 (September 27, 2007).
and addiction, including but not limited to adolescents, certain ethnic minorities, and individuals with mental health disorders. Randomization of participants to a product known to be potentially addictive and hazardous is ethically problematic. The committee maintains that the only circumstances under which an MRTP candidate should be provided to high-risk individuals is when (1) the individual is a current user of conventional tobacco products, (2) the individual does not want to quit using tobacco products or the individual wants to quit using tobacco products, but is unable to quit, (3) the MRTP candidate is not more hazardous than conventional tobacco products, and (4) at the end of the trial the individual is offered the best available treatment option for tobacco cessation.
A related issue is research involving individuals who do not use tobacco products or tobacco product users who are on the verge of quitting. There are certain groups of people, such as adolescents or individuals who are tobacco naive, who are at risk for starting to use an MRTP, and who may be especially vulnerable to developing nicotine dependence. Data on their initial or early reactions to the use of such products are relevant to an estimation of public health risk. In fact, a comprehensive analysis of potential public health impact demands that their vulnerability to chronic MRTP use (and, subsequently, other tobacco use) be empirically or experimentally addressed. However, there are clear potential risks to providing an MRTP or other tobacco products to such populations: e.g., experimental use might foster addiction and life-long use, with all its negative consequences. A decision to engage in research with such populations would, therefore, require the careful consideration of the potential risks and benefits. Generally, the committee concludes that
a. Research involving users of tobacco products is ethically permissible as long as the exposures in the study are not more risky than the hazards from their current tobacco use (i.e., the MRTP being tested is less dangerous than a cigarette for a smoker). Also, standard of care cessation treatment should be made available.
b. Survey research or perception/messaging research among non-smokers is acceptable where the nonsmokers are not being exposed to the product.
c. Experimental research that exposes nonusers to products is ethically problematic; but such research cannot completely be ruled out because it could provide critically valuable information. The ethics, risks, and benefits need to be determined on a case-by-case basis.
Although practically challenging and ethically problematic, research involving high-risk populations is essential to ascertain the characteristics and mechanisms that make them more susceptible to tobacco use. Under
standing these characteristics and mechanisms can help estimate the effect of marketing MRTPs, and can inform interventions to reduce the rates of tobacco use in these populations.
The third issue is the risk of improperly disclosing the substance abuse of a minor to the minor’s parents or guardians in the process of obtaining parental consent for research. Generally, it is critical that a minor’s assent and parental consent be obtained prior to any research involving the minor. However, there are circumstances where obtaining parental consent for the minor’s participation in research will disclose information about the minor’s behavior, including potentially illegal behavior. Disclosure of this information is problematic because it may result in a number of unwanted consequences for the minor. While the assent of minors is always necessary, investigators should also be cognizant of circumstances where obtaining parental consent will violate the confidentiality of the study participant, and where waiver of parental consent is warranted.
A last issue is the inclusion of individuals from high-risk groups with reduced decision-making capacity. Some populations at a high risk for tobacco use, such as adolescents and populations with mental health issues, may have a higher prevalence of individuals with reduced decision-making capacity. When investigators are conducting research involving these high-risk groups, they should be particularly cautious about the inclusion of individuals who lack the capacity to provide meaningful consent.
TOWARD A TOBACCO RESEARCH GOVERNANCE ENTITY
To improve the credibility of the studies in support of an MRTP application under Section 911, tobacco product sponsors and the CTP should consider facilitating the creation of a third party or third parties for the conduct and oversight of these studies. The committee will not recommend a specific model for adoption, but it will instead discuss existing arrangements in other fields and the general properties of a governance entity that would be desirable or appropriate in the MRTP field.
Health Effects Institute Model and Other Potential Organizational Models
The idea for an independent research entity in a contentious area of research on public health risks is not new. In 1980, the Environmental Protection Agency (EPA) and the automobile industry agreed to create a new governance and research organization to resolve conflicts over research on health and air quality. The EPA and automakers had clashed over standards on which the federal government wrote rules enforcing
the National Ambient Air Quality Standards and the tailpipe emissions standards of the late 1970s. Because there was little agreement on the science supporting air quality regulations, it was increasingly difficult for dialogue between industry and regulators to proceed. Led by the efforts of Cummins Engine executive Charles Powers and EPA official Michael Walsh, the Health Effects Institute (HEI) was created in 1980 (Jasanoff, 1990; Keating, 2001).
The HEI is a nonprofit corporation with approximately one-half of its funding coming from the automobile industry and the other half coming from the federal government and other government sources. HEI is based in Boston, Massachusetts, and is well situated among the top research universities and hospitals. A number of scholarly analyses have described the HEI as having successfully managed the boundary between industry and government, as well as between the research community in health effects and the research community in air quality (Keating, 2001).
The HEI has multiple roles, including the funding of research through competitive requests for applications (RFAs). These RFAs serve, like those developed by a grant agency, to create open competition. Such open competition ensures that research funds will not be directed consistently or privately to those recipients most likely to produce certain outcomes, and it also promotes implicit competition among researchers on the basis of research quality and rigor rather than upon loyalty to the financial sponsor.
The relevant organizational structure of the HEI includes a board of directors and three committees. The board of directors is independent of the sponsors of the institute, and it “acts as the principal guardian of the HEI’s objectivity” (quoted in Keating, 2001). The board monitors potential conflicts of interest and oversees the institute’s staff, checks appointments to its expert committees, and monitors sponsored research projects. Below the board rest three committees. The Health Research Committee develops 5-year plans for research and awards research funds to investigators. The Health Research Committee also oversees research investigators and their work. Independently of the Health Research Committee, the Health Review Committee evaluates research produced by HEI-funded investigators and interprets the meanings of such research for policy makers. A third committee, the special Committee on Emerging Technologies, examines new fuels and their potential environmental and health impacts. A key feature of this structure is the independence of the board of directors from the sponsors and from the staff, and the independence of the two principal committees from one another (Keating, 2001).
The Health Research Committee develops and publishes the RFAs through which competitive research is applied for and ultimately funded. Project selection is undertaken by expert panels that convene under the
authority of the committee and review and rank applications. The committee and HEI staff often work with the sponsor of the successful application to refine the scope and methods of the research project, examining research design, methods of analysis, and data. When research commences, the research committee oversees the research, reviewing progress reports from the investigators, overseeing quality audits of the project research, and visiting the investigators’ research sites.
There are important limits to the HEI model that must be considered when thinking about it as a possible prototype for a TRGE. Perhaps the most important difference between the HEI and any TRGE is that the HEI does not fund projects in support of marketing applications; rather, it funds projects that contribute to general knowledge. Hence the commercial stakes of the research funded by the HEI may be somewhat less than the kind of research that could be funded by a TRGE. In particular, it may be problematic for individual tobacco companies to contribute funds to a TRGE if those funds will be used to fund research that potentially benefits a competitor’s product more than its own product. As such, it will be important to distinguish between two different types of research: (1) individual product testing and (2) research that contributes to general knowledge, including research on better methods for product testing. Institutions like the HEI may be better suited to develop study methods or standards, rather than individual product evaluation. It should also be noted that the public health standard articulated in the FSPTCA is different from any other existing premarket approval standard. Additionally, the level of public, medical, and academic distrust in the tobacco industry and its research is much greater than any that has ever buffeted the automobile industry. Important issues of trust would need to be confronted in order for any such model to be entertained.
Another possibility for an organizational model lies in the Reagan-Udall Foundation (RUF), which advises the FDA on modernizing regulatory science. It conducts and oversees studies on regulatory science, particularly in the emerging fields of pharmacogenomics and genomic-based prediction of drug response and adverse event risk. The RUF receives grants from independent foundations for its work in advancing regulatory science, ranging from work in systems toxicology funded by the Komen Foundation to work on antitubercular drugs in the critical path to tuberculosis drug regimens. The RUF has a board of directors composed of a diverse mix of consumer representatives, industry representatives, scientific and medical authorities, and government officials; none of these groups accounts for a majority of the board’s members. The foundation has implemented a number of strategies to attempt to ward off conflict of interest and undue industry influence. The RUF prohibits board members from participating in any activity or matter in which they have a financial
interest. RUF board members must also openly disclose any financial interest they may have, or have had in the past, in entities doing business with the RUF and in any FDA-regulated entity. Additionally, the board requires conflict-of-interest measures be undertaken for each individual project the foundation undertakes. All projects undertaken by the RUF are reviewed by its board of directors and are subject to an independent review. While the RUF has some features, it has not existed for as long as the HEI, and thus it has far less of a track record. It also has no experience in funding projects. Still, the attempted controls for bias and conflict of interest are potentially noteworthy in thinking about a TRGE.
It should be noted that several third-party institutions have been engaged in independent tobacco research, including the Life Sciences Research Office and the Institute for Science and Health. However, the credibility and independence of these organizations have been questioned, which illustrates the importance of oversight, transparency, and governance (Schick and Glantz, 2007b).
Possible Design and Structure of a TRGE
Funding of a TRGE
A TRGE could receive funding from a mix of public and private sources. Independent organizations and foundations would also provide potential sources of funds, especially those foundations specializing in health research and risk reduction. The consideration of industry funding would need to be cautious. Unregulated or unstructured industry funding could potentially contribute to a perception of bias, so it is quite possible that the funding from tobacco companies and potential MRTP sponsors could be structured in a tax-like manner. The HEI model of regular, equalized contributions from members of the industry—with expected contributions independent of research and no bargaining over HEI governance between contributions—would be a useful model for consideration.
Oversight Board
A board of directors or general oversight board for any TRGE should be placed in a position of responsibility for maintaining the credibility and objectivity of the organization. It would be critical to ensure that a TRGE board be independent both of the FDA and the tobacco/MRTP industry. It would be prudent to institute a conflict-of-interest policy with prohibitions on participation in any matter where the board member may have a financial or other conflict of interest or plausible bias. An oversight board would need to be composed of a diverse membership—
nontobacco-related businesses, medicine and academics, consumers—with each individual openly disclosing any potential conflicts of interest. A board could assist the entity in selecting research contractors in any research competition.
Research Protocol Advice
An important feature of the entity would be in ensuring the independent design of research protocols by researchers. Independence of research design from the study sponsor is a critical feature of rigorous research, as the design of a study (its measures, its statistical methods, even the particulars of the hypothesis tested, duration of treatment, and other features) can deeply shape the research outcome. If research funding were provided through a TRGE, the competition might create additional incentives to cleave to robust research design models.
Organization, Oversight, and Training
As with the HEI, a TRGE could monitor contractors’ research performance, provide staff members and/or training for IRB members at universities and contract research organizations, and set up Data Monitoring Committees (DMCs), including Data and Safety Monitoring Boards (DSMBs) and Observational Study Monitoring Boards (OSMBs). Given the nascent character of research in the MRTP field, it would be important for any research team to receive and consider advice midstream on study conduct. Independent monitoring of IRBs and DMCs/DSMBs/OSMBs would also be important, given the lack of broad university- and hospital-based experience in conducting research on MRTPs. It is doubtful that the CTP would be able to handle these responsibilities on its own.
Contract Mechanisms
A TRGE could fund research in several ways. It could issue contracts to independent investigators or contract research organizations, including commercial laboratories as well as hospital or academic contract research organizations. Another possibility and one well worth considering would be an RFA model, not unlike the model of the HEI or the funding models used by government granting agencies. Upon the preparation of an MRTP application that would involve premarket or postmarket clinical studies, the TRGE could develop and post an RFA for each study—or suite of studies—that the sponsor would need to have performed in order for an MRTP application to be considered complete by the CTP. Some (if not many) of the details of these studies would be left unspecified at the time
of the RFA, so that upon the award of an investigator contract the TRGE could participate in the design of the study.
Quality Control
It would be critical for any TRGE to ensure adherence to rigorous quality control measures on the part of researchers conducting studies for an MRTP application to the FDA. Keating identifies a
zealous approach to quality control on the part of HEI-funded investigators. Adherence to quality control guidelines and favorable reports from quality assurance audits, along with rigorous peer review, are the first line of defense against attacks on the credibility of the research (Keating, 2001).
The TRGE could promulgate good research practices for MRTPs in conjunction with academic specialists (e.g., Rees et al., 2009). Consistent with the HEI model and with other forms of research governance at universities and hospitals, the TRGE could perform scheduled or random data audits and other forms of site-specific research investigation. The TRGE could also assist the CTP in ensuring that postmarket studies are being launched, monitored, and completed in a timely fashion.
After extensive consideration of both the unique nature of the tobacco industry, the FSPTCA, and other relevant precedents, the committee identified a number of potential considerations that should guide the governance of tobacco industry studies.
1. Research Funding. Although the funding of such research will usually originate with the company developing the product, there may be cases where sponsors themselves may wish to have the research overseen or conducted independently. The FDA should expect that some of the research performed for MRTP applications that it reviews will be performed or conducted independently, by choice of sponsor. This raises the issue of how such third-party research can be governed.
2. Research with Special Populations. In some cases, especially that of experimentation with adolescents or populations vulnerable to high use rates, the FDA may wish to require or expect that research should be overseen by an independent third party who would be the recipient of tobacco industry study funding but would be responsible for
• choice of investigators,
• funding of investigators,
• oversight of studies,
• data collection,
• analysis of results, and
• publication of results.
3. Data Transparency. It is critical that the public have access to the totality of the data on MRTPs; therefore, all trials should be registered on the National Library of Medicine website Clinicaltrials.gov with the same time limits defined in the Food and Drug Administration Amendments Act (FDAAA) of 2007.
• In addition, for the same reasons, all trial results should be posted at Clinicaltrials.gov within 6 months of the last research participant completing the trial, the trial being terminated, or there being no further activity in the trial.
• Companies may attest annually to their posting of results and trials. The FDAAA penalties for nonposting should apply to tobacco studies.
4. Engaging Academic Researchers. Where a third-party entity carries out some or all of the research, such an entity should work with representatives of academic medical centers and scientific journals to develop a transparent funding process for tobacco studies that will allow academic medical centers to accept such funding and will satisfy the journal editors’ requirements regarding independence from tobacco funding.
5. Communicating Risks and Benefits. Marketing materials for MRTPs should only be allowed to use the conclusions from studies reached by the analysis of the independent entity described above.
6. Research Oversight. Where independent research entities are used, any independent institute
• should have as its mission the performance of high-quality studies to determine the risks of modified tobacco products;
• should be governed by individuals appointed by an organization independent of the tobacco industry and with sufficient scientific stature to inspire public confidence; and
• should receive “core funding” from a tax on tobacco products that will maintain its basic functions, while individual studies will be funded by the interested companies.
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