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2
Governance and Conduct of Studies
Under subsection (l) paragraph (2), the Family Smoking Preven-
tion 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 destruc -
tion 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 sub mitted
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.
1 Family Smoking Prevention and Tobacco Control Act of 2009, Public Law 111-31, 123 Stat.
1776 (June 22, 2009).
45
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46 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
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 commit -
tee 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 com -
mittee 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
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GOVERNANCE AND CONDUCT OF STUDIES
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 men-
tholated 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 cig-
arette 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 con -
cern (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).
2U.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.
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48 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
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 indus-
try’s knowledge of the relationships between cigarette smoking behav-
iors 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 appear-
ance of relatively healthier cigarettes (Pollay and Dewhirst, 2002). Prod-
uct 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
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GOVERNANCE AND CONDUCT OF STUDIES
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. How -
ever, 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 ver-
sions 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
1990, 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 tradi -
tional 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 con-
cerns 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 integrat -
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50 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
ing 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 configura -
tions 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 reduc -
tion, 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 smok -
ing’s relationship to cancer risks as early as the 1940s, with broad inter-
nal 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 mak-
ers 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 signifi-
cant 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 indus-
try has also engaged in health-relevant research on its products, includ-
ing 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
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GOVERNANCE AND CONDUCT OF STUDIES
(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 Pharmacol-
ogy, 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 pro-
grams 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 pro -
gram 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 confer-
ences (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 lobby-
ing and communications. While the CTR existed, nominally, to fund inde-
pendent research into smoking and health, it was part of the broader
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52 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
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 smok-
ing. 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” conclu-
sions, 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 publica-
tions 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.
3 United States v. Philip Morris USA, Inc., et al., 449 F. Supp. 2d 1, 26 (D.D.C. 2006).
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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 cred -
ibility, and its public trust severely compromised and perhaps irreversibly
damaged. This reputational damage to the FDA and to public health insti-
tutions 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 provid -
4 United States v. Phillip Morris, Inc. 2011 U.S. Dist. (D.D.C., June 22, 2011).
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54 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
ing research funding to potential grantees who also receive money from
the tobacco industry, the NACDA made several points to consider, includ-
ing that receiving funding from the tobacco industry could compromise
perceived objectivity and credibility of research, and that “any connec-
tion 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 short-
age 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 exper-
tise to produce the necessary range of credible and reliable data, but also
the trustworthiness to acquire external expertise and avenues to dissemi -
nate 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 cred-
ibility 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 pharmaceuti-
cal and medical product companies engage universities, medical schools,
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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 con-
ducting research on an FDA-regulated product (FDA, 2010; HHS, 2009;
White et al., 2007). Academic and medical journals also exercise a gate-
keeping 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 rigor-
ous 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 indus -
try 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 pharmacologi-
cal, 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 para-
digm 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, moni-
toring, 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 com-
mon, they have been largely unregulated in the way pharmaceutical
trials have been, and they lack the same level of oversight, governance,
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the National Ambient Air Quality Standards and the tailpipe emissions
standards of the late 1970s. Because there was little agreement on the sci-
ence 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 uni-
versities 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 devel-
ops 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 investi-
gators and interprets the meanings of such research for policy makers. A
third committee, the special Committee on Emerging Technologies, exam-
ines 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
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authority of the committee and review and rank applications. The com-
mittee and HEI staff often work with the sponsor of the successful appli -
cation to refine the scope and methods of the research project, examining
research design, methods of analysis, and data. When research com-
mences, 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 com -
mercial 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 differ-
ent 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 auto -
mobile 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 regula-
tory science. It conducts and oversees studies on regulatory science, par-
ticularly 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 regula-
tory 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
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64 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
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 ques-
tioned, 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 poten-
tial 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 mem-
ber may have a financial or other conflict of interest or plausible bias. An
oversight board would need to be composed of a diverse membership—
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GOVERNANCE AND CONDUCT OF STUDIES
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 indepen-
dent 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 par-
ticulars 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 per-
formance, provide staff members and/or training for IRB members at
universities and contract research organizations, and set up Data Monitor-
ing 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
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66 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
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 investiga-
tors. 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 uni-
versities 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.
CONCLUSIONS
After extensive consideration of both the unique nature of the tobacco
industry, the FSPTCA, and other relevant precedents, the committee iden-
tified a number of potential considerations that should guide the gover-
nance 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 over-
seen 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,
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GOVERNANCE AND CONDUCT OF STUDIES
• 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 com -
pleting the trial, the trial being terminated, or there being no further activ-
ity in the trial.
• Companies may attest annually to their posting of results and rials.
t
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 represen-
tatives 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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