Methods to assess potential reduced exposure products

18 Pages·2005·0.35 MB·English

Nicotine & Tobacco Research Volume 7, Number 6 (December 2005) 827–844
Methods to assess potential reduced exposure
products
Dorothy K. Hatsukami, Gary A. Giovino, Thomas Eissenberg, Pamela I. Clark,
Deirdre Lawrence, Scott Leischow
[Received 10 December 2004; accepted 30 June 2005]
The availability of tobacco products purported to reduce toxin exposure or potentially reduce health risks
necessitatesthedevelopmentofmethodsandidentificationofbiomarkersthatcanbeusedtoassesstheseproducts.
These assessments occur on multiple levels and stages, from identifying constituents in the tobacco products and
smoke, to human exposure and health effects trials, to postmarketing surveillance. A conference of
multidisciplinary experts was convened to present and discuss methods and biomarkers to assess these products
andtoconsidertheinfrastructurenecessarytofacilitatetheevaluationprocess.Althoughnocurrentlyavailableset
of measures was thought to be sufficient for determining the relative health risk of potential reduced exposure
products, this paper provides a blueprint for future research toward this end.
Introduction users want to quit, few are successful on single quit
attempts,andonly10%–20%arereadytoquitinthe
Tobacco harm reduction, as a method to reduce
immediate future (Etter, Paernegger, & Ronchi,
mortality and morbidity, has been receiving increas-
1997; Prochaska & Goldstein, 1991). Third, the
ing attention both in the United States and inter-
number of cigarettes smoked demonstrates a dose–
nationally. Harm reduction refers to ‘‘minimizing
response relationship to disease (National Cancer
harms and decreasing total morbidity and mortality,
Institute, 1997; Stratton et al., 2001), and recent
without completely eliminating tobacco and nicotine
modeling based on data from the American Cancer
use’’(Stratton,Shetty,Wallace,&Bondurant,2001).
Society’s Cancer Prevention Study I has suggested
Although cessation and prevention should remain
that the greater the reduction and the earlier the age
the primary methods for tobacco control, several
of reduced smoking, the greater the number of years
reasons have been provided to support considering
of life saved (Burns, 1997). Methods that have been
loweringtobaccotoxinexposureandaddictivenessas
proposed to reduce harm have ranged from modify-
a strategy to reduce negative health consequences.
ing tobacco to reduce toxicants to long-term use of
First, although smoking rates have been decreasing
nicotine replacement products.
consistently since the 1960s, the age-specific preva-
Because of the introduction of tobacco products
lence of cessation among ever-smokers (also known
that were marketed with implied or direct claims of
asquitratio)hasleveledoffinrecentyears(Giovino,
reduced tobacco toxin exposure or reduced health
2002). Second, even though the majority of tobacco
risks,theInstituteofMedicine(IOM)waschargedin
December 1999 by the U.S. Food and Drug
Dorothy K. Hatsukami, Ph.D., University of Minnesota Cancer Administration (FDA) to address four questions
Center, Minneapolis, MN; Gary A. Giovino, Ph.D., Roswell Park
Cancer Institute, Buffalo, NY; Thomas Eissenberg, Ph.D., Virginia and to ‘‘formulate scientific methods and standards
CommonwealthUniversity,Richmond,VA;PamelaI.Clark,Battelle by which potential reduced exposure products
Centers for Public Health Research & Evaluation, Baltimore, MD;
(PREPs) could be addressed.’’ The four questions
Deirdre Lawrence, Ph.D., Scott Leischow, Ph.D., National Cancer
Institute,Bethesda,MD. were the following: (a) Does use of the product
Correspondence: Dorothy K. Hatsukami, Tobacco Use Research decrease exposure to the harmful substances in
Center,UniversityofMinnesota,2701UniversityAvenueSE,#201,
tobacco? (b) Is this decreased exposure associated
Minneapolis,MN55414,USA.Tel:[phone];Fax:+1(612)
627-4899;E-mail:[email protected] with decreased harm to health? (c) Are there
ISSN1462-2203print/ISSN1469-994Xonline#2005SocietyforResearchonNicotineandTobacco
DOI:10.1080/14622200500266015
828 METHODSTOASSESSPREPS
surrogate indicators of this effect on health that effects (Hatsukami, Henningfield, & Kotlyar, 2004;
could be measured in a time frame sufficient for Stratton et al., 2001). Individual risk involves
product evaluation? and (d) What are the public assessing toxin exposure, addictiveness, and disease
health implications of tobacco harm reduction risk within individuals. Individual risk can be
products? determinedbyconductingbothshort-andlong-term
After reviewing the scientific evidence, the IOM clinical trials using biomarkers for exposure and for
report described the following conclusions: (a) health effects. Population effects involve assessing
‘‘Reducing risk of disease by reducing exposure to tobacco use behavior such as the rate of uptake,
tobaccotoxicantsisfeasible,’’butitalsostatedthat(b) maintenance,cessation,andrelapseasaresultofthe
‘‘potential reduced exposure products (PREPs) have introduction of the product and the effects of
not been evaluated comprehensively enough to pro- product use on morbidity and mortality.
videascientificbaseforconcludingtheyareassociated Population effects can also be determined by
withreducedriskofdiseasecomparedtoconventional evaluating contributors to product use including
tobacco use.’’ The report also concluded that (c) consumerperceptionoftheproduct,productpromo-
‘‘surrogatebiologicalmarkersthatareassociatedwith tion and placement in retail stores, cost, availability,
tobacco related diseases could be used to offer policies such as tobacco use bans, and changes in
guidanceastowhether or not PREPsare likelytobe normative beliefs.
risk-reducing,’’ (d) ‘‘currently available PREPs have Figure1 offers a heuristic model illustrating the
been orcould be demonstrated toreduce exposureto various components and steps in testing PREPs that
some of the toxicants in most conventional tobacco takes into account both individual and population
products,’’ (e) ‘‘regulation of all tobacco products, diseaserisk.Thismodelisbasedontheprinciplesfor
including conventional ones as recommend in IOM, evaluating PREPs described in the IOM report
(Stratton et al., 2001). Testing involves both pre-
1994, as well as all other PREPs is a necessary
market evaluation (step 1 and 2) and postmarket
preconditionforassuringascientificbasisforjudging
evaluation (step 3). At each step of this three-step
the effects of using PREPs and for assuring that the
model,testingresultsmustbeevaluatedtodetermine
health of the public is protected,’’ and (f) ‘‘the public
whether sufficient evidence supports an appropriate
health impact of PREPs is unknown. They are
risk–benefit ratio to permit proceeding to the next
potentially beneficial, but the net impact on popula-
step or to eventual market distribution. This ratio
tionhealthcould,infact,benegative.’’
can be based on the following:
These conclusions highlight the need for and
urgency in developing a comprehensive strategy to N
Extent of reductions in toxin exposure and
evaluate these products and approaches. The cur-
addictiveness and any other heath claims asso-
rently existing PREPs include (a) modified tobacco
ciated with the product;
products that contain reduced levels of one or more N
Addictiveness or health risk compared with
toxins (e.g., cigarettes with reduced tobacco-specific
conventional brands of tobacco, including mar-
nitrosamines through new curing processes, the
keted brands with the lowest level oftoxicity, and
addition of catalysts to reduce polycyclic aromatic
with cessation;
hydrocarbon carcinogens produced by smoke, the N
Adequateness and accuracy of information pro-
use of genetically modified plants to reduce nicotine
vided to the consumer about the extent of toxic
or nitrosamines, or the use of filters to selectively
exposure from the product or relative health risk
reduce toxicants), (b) cigarette-like devices, such as
(e.g., adequacy of the evidence to support claims
those that heat rather than burn tobacco, and (c)
of reduced toxicity of a PREP, and if meaningful
oral noncombustible products, such as smokeless
reductions of exposure or risk are found, then
tobacco, that are modified to reduce exposure to
the accurate interpretation of the data by con-
specific toxicants. Other reduced exposure app-
sumers);
N
roaches include reduced tobacco use either through
Effects of claims (if such claims are permitted),
the use of medicinal products or other tobacco
marketing, and promotion efforts on consumer
products (e.g., oral tobacco for cigarette smoking)
perception of the product;
N
and long-term maintenance on medicinal nicotine.
Unintended and unwanted consequences such as
The urgency for evaluation of PREPs is also high-
increased morbidity or mortality as a result of
lighted by past experiences with low-yield cigarettes.
increased prevalence of tobacco use or other
Low-yield cigarettes were considered ‘‘safer’’ by
changes in tobacco use behavior.
consumers, in some cases leading to continued
smokingandwithnosignificantreductionsindisease When the product is being offered for consump-
(National Cancer Institute, 2001). tion, including in test marketing, evaluation of the
Evaluation of these products must involve con- risk–benefit ratio must be performed by an indepen-
sideration of both individual risk and population dent body of experts.
NICOTINE&TOBACCORESEARCH 829
Figure1. Threestepmodelforpotentialreducedexposureproduct(PREP)evaluationwithassessmentoccurringby
anindependent scientificpanelor regulatory agencyaftereachstep.
A comprehensive strategy for testing PREPs complexbecauseofthefrequentneedtoquantifythe
initially involves testing for product toxicity or differences in risk between various highly toxic
hazard identification, and preclinical cell and animal products and the vast number of constituents that
testing. According to the IOM report, hazard need to be considered.
identification involves some of thefollowing compo- An independent group of scientists and regulators
nents: (a) Identifying toxicants in the PREP that are should use available preclinical data (a) to assess
known to cause adverse health effects, (b) determin- whether selected products are likely to substantially
ing the extent to which the compounds targeted for reduce risk, taking into account the risk reduction
reduced exposure are causally linked to tobacco- potentialofproductssuchasmedicinalnicotine,and
related disease, (c) determining how the contents of (b) to assess whether further premarket testing is
the PREP compare with those of conventional worth pursuing (L. T. Kozlowski, Strasser, Giovino,
tobacco products, (d) identifying unique toxicants Erickson, & Terza, 2001). However, the role of
in the PREP compared with conventional tobacco preclinical testing (animal or cell preparations) is
products, and (e) identifying unique toxicants that extremely limited. Because preclinical testing cannot
may be associated with second-hand smoke. Once predict exposure or risk reduction when a product is
thesetoxicantsareidentified,thenextentofexposure used by humans, the results must not be used as a
to toxicant ingredients (e.g., dose) should be basis for advertising and promotion of PREPs.
measured based on machine-determined yields that After this first evaluation, human testing is neces-
simulate human smoking behavior. The range of sary. The primary aim of human clinical testing is to
doses that is observed can be applied to preclinical determine individual risk, that is, the extent of
testing on cells or in animals (e.g., tests for exposure to toxins and health effects or the potential
cytotoxicity or mutagenicity) that will provide riskfordiseaseresultingfromuseoftheproducts,the
qualitative information about the toxicity of these potential for persistent use of the products, and the
ingredients.Futureresearchgoalsshouldincludethe pattern of use of the products. Premarket consumer
development of preclinical tests that can quantita- perception testing can help to determine potential
tively measure relative toxicity between the com- individualaswellaspopulationharm.Perceptionsof
parison compounds. Furthermore, the extent of thehealthrisksorharmsassociatedwithproductscan
differences in exposure needed to result in mean- affect the individual’s decision to use them and the
ingful differences in risk is a critical question that extent to which the population participates in the
needstobeaddressed.Thistaskismadedifficultand purchase of the products. Premarket consumer
830 METHODSTOASSESSPREPS
perception testing involves determining how the Table1. Steeringcommitteemembers.
consumers perceive and interpret the information
DavidAshley,Ph.D.,CentersforDiseaseControland
andimagesdeliveredtothem,andiftheseperceptions Prevention,Atlanta,GA
and processing of information are accurate or WilliamCorrigall,Ph.D.,NationalInstituteonDrugAbuse,
Rockville,MD
misleading.Thepurposeofconsumerproducttesting
MirjanaDjordjevic,Ph.D.,NationalCancerInstitute,Bethesda,
is to ensure that claims and marketing of a product MD
will lead theconsumer tomake aninformed decision JoanneFertig,Ph.D.,NationalInstituteonAlcoholAbuseand
Alcoholism,Bethesda,MD
basedonanaccurateunderstandingofvalidinforma-
DorothyHatsukami,Ph.D.,UniversityofMinnesota,Minneapolis,
tion,andtoensurethattheproductdoesnotappealto MN
StephenHecht,Ph.D.,UniversityofMinnesota,Minneapolis,MN
youth,thosewhowouldhavequitotherwise,orthose
DeirdreLawrence,Ph.D.,M.P.H.,NationalCancerInstitute,
whohavepreviouslyquit. Bethesda,MD
Once the risk–benefit ratio is considered promis- ScottLeischow,Ph.D.,NationalCancerInstitute,Bethesda,MD
CeliaWinchell,M.D.,FoodandDrugAdministration,Rockville,
ing,thenpopulationeffectsofPREPsaftertheyenter
MD
into the market need to be assessed. This assessment
is accomplished through postmarketing surveillance
and epidemiological studies. Postmarketing evalua- product toxicity and preclinical evaluation of the
tionisconductedtoensurethatPREPsdonotresult products is an important step in assessing PREPs,
inincreasedinitiationoftobaccouse,maintenanceof this meeting focused primarily on human testing. A
tobacco use in those who wereinterested in quitting, steering committee (Table1) comprised of represen-
or relapse to tobacco use in former tobacco users. tatives from each of the government agencies and
Furthermore, the use of PREPs should not result in twouniversity-basedscientistsdevelopedthemeeting
an increase in morbidity and mortality. It is not agenda. Three topic were selected to examine
acceptabletoreduceindividualriskattheexpenseof methods for evaluation: Human clinical testing;
increasing population harm. Therefore, through the premarket testing of consumer perceptions, product
use of long-term, longitudinal surveys, the actual marketing, and promotion; and postmarketing eva-
reduction in harm through the use of PREPs can be luation. Biomarkers for four categories of diseases
determined. An important point to remember is that or negative health outcomes were also discussed:
thedifferentstagesinvolvedintestingtheseproducts Cardiovascular disease, pulmonary disease, cancer,
are bidirectional rather than unidirectional; that is, and fetal toxicity. A leader was selected for each
resultsfromhumanevaluationcaninformpreclinical topic, and this leader subsequently selected the team
evaluation including product design. Similarly, post- members for his or her topic (Table2).
marketing surveillance results can inform clinical or Themembersofthemethodsgroupswereaskedto
preclinical evaluation of products. address the following questions for their assigned
Because of the number of years required to topics:(a)Whataretheprimaryissuesassociatedwith
determine whether PREPs result in harm to health, the evaluation of the products? (b) What are the
proxies for disease outcome are needed. Therefore, methods and measures to address these issues? (c)
essential measures for determining the impact of What is the necessary infrastructure needed to
PREPs are biomarkers for toxin exposure, injury, evaluate the PREPs? The biomarker groups were
and disease risk. When comparing the health effects asked to identify potential biomarkers that could be
of a PREP, researchers must look for differences in used to evaluate PREPs based on their mechanistic
the levels of biomarkers associated with the PREP relationship to disease and evidence showing differ-
and the currently used tobacco product, and ideally encesbetweensmokersandnonsmokers,changeswith
the impact of this difference on health must be cessation, a dose–response relationship with number
determined.Thesebiomarkersneedtocoverabroad of cigarettes per day, and changes with reduction in
range of tobacco-related diseases to ensure that smoking. Ideally, changes in the levels of biomarkers
products that decrease biomarkers for one disease should result in changes in the risks for disease.
category do not increase them in another category. Unfortunately,limiteddataareavailableontheextent
In an effort to facilitate development of research of biomarker change necessary to induce a beneficial
priorities and expand and update the IOM guide- healtheffect.Therefore,predictivevalidity,oneofthe
lines in the evaluation of PREPs, the National hallmarksfordeterminingavalidbiomarker,wasnot
Cancer Institute, National Institute on Drug Abuse, included as a criterion for assessing biomarkers. The
National Institute on Alcoholism and Alcohol biomarkers groups also were asked to speculate on
Abuse, and the Centers for Disease Control and potentiallypromisingbiomarkers.
Preventionconvenedameetingtodevelopguidelines Each group was asked to present its finding at
for the evaluation of PREPs on both individual and a meeting held on February 26 and 27, 2004, in
population levels. Both methods and biomarkers for Washington, D.C. This meeting included an invited
evaluation were addressed. Although evaluation of expert panel (Table3) and representatives from
NICOTINE&TOBACCORESEARCH 831
Table2. Topicleadersandworkgroupmembers. governmental agencies, and was also open to the
public. After each presentation, the audience raised
Methods
Humanclinicaltrials questions and provided feedback. After the meeting,
DorothyHatsukami,Ph.D.,aUniversityofMinnesota, eachworkgroupwasresponsibleforintegratingthese
Minneapolis,MN
comments into a written document. The final
ThomasEissenberg,Ph.D.,aVirginiaCommonwealth
University,Richmond,VA document was then sent to the expert panel for their
JRichardCrout,M.D.,CroutConsulting,Bethesda,MD review. The subsequent content of the two papers,
JackHenningfield,Ph.D.,PinneyAssociates,Bethesda,MD
one on methods and one on biomarkers, represents
Consumerperception
PamelaClark,Ph.D.,aBattelleCenterforPublicHealth the deliberations of these groups. This article
Research&Evaluation,Baltimore discusses issues and methods associated with testing
PaulSlovic,Ph.D.,DecisionResearch,Eugene,Oregon
PREPs, and a separate paper discusses biomarkers
NeilWeinstein,Ph.D.,RutgersUniversity,NewBrunswick,
NJ for testing PREPs (Hatsukami, Benowitz, Rennard,
Postmarketingsurveillance Oncken, & Hecht, in press). Note that the guidelines
GaryGiovino,Ph.D.,aRoswellParkCancerInstitute,
andissuesoutlinedherecanbeusedforevaluatingall
Buffalo,NY
MichaelCummings,Ph.D.,RoswellParkCancerInstitute, tobacco products.
Buffalo,NY
StevenStellman,Ph.D.,M.P.H.,ColumbiaUniversity,New
York,NY
Biomarkers Human clinical trials
Cardiovascular
NealBenowitz,M.D.,aUniversityofCalifornia, Issues in clinical trials of PREPs
SanFrancisco,CA
AnneBurke,Ph.D.,UniversityofPennsylvania, Clinical trials are part of the essential second step of
Philadelphia,PA evaluating PREPs (Figure1). As described below,
JohnCooke,M.D.,Ph.D.,StanfordUniversity,Stanford,CA
clinical trial design must account for moderating
Pulmonary
StephenRennard,M.D.,aUniversityofNebraska,Omaha, factors that can influence a PREP’s impact, while
NE incorporating methods and measures that allow the
MarkFrampton,M.D.,UniversityofRochester,Rochester,
trialtoaddressimportantquestionssuchas(a)Does
NY
DavidRiley,M.D.,RobertWoodJohnsonMedicalSchool, the PREP result in reduction in toxin exposure/
Piscataway,NJ uptake and harmful health effects? (b) What is the
Cancer
StephenHecht,Ph.D.,aUniversityofMinnesota, abuse liability of the PREP? (c) How is the PREP
Minneapolis,MN used? and (d) Does the PREP make future cessation
StevenBelinsky,Ph.D.,LovelaceRespiratoryResearch
attemptslesslikely?Thesequestionscanbeanswered
Institute,Albuquerque,NM
PeterShields,M.D.,GeorgetownUniversityLombardi instudiesthatapproximatephaseI–IVclinicaltrials,
CancerCenter,Washington,DC as defined by the FDA.
StevenTannenbaum,Ph.D.,MassachusettsInstituteof
Technology,Cambridge,MA
Fetaltoxicity
Methods
CherylOncken,M.D.,M.P.H.,aUniversityofConnecticut
HealthCenter,Farmington,CT
Moderating factors that can influence the impact of a
PeterFried,Ph.D.,CarletonUniversity,Ottawa,Ontario
TheodoreSlotkin,Ph.D.,DukeUniversityMedicalCenter, PREP. Many moderating factors can influence the
Durham,NC effects of a PREP (Table4). These factors require
Note.aTopicleader. consideration because they may affect tobacco use
behavior and disease risk. Type of tobacco used is
Table4. Moderatingvariablestoconsiderforhumanclinical
Table3. Expertpanelmembers. trials.
DavidAshley,Ph.D.,CentersforDiseaseControland Characteristicsoftobaccouser
Prevention,Atlanta,GA Typeoftobaccouse
DavidBurns,M.D.,UniversityofCalifornia,SanDiego,CA Degreeofdependence
GregConnolly,D.M.D.,M.P.H.,MassachusettsDepartmentof Amountoftobaccouse
PublicHealth,Boston,MA Durationoftobaccouse
MirjanaDjordjevic,Ph.D.,NationalCancerInstitute,Bethesda, Interestinquitting
MD Recentcessationactivity
JeffersonFowles,Ph.D.,InstituteofEnvironmentalScienceand Gender
Research,Porirua,NewZealand Ethnicityorrace
GeorgeHammons,Ph.D.,PhilanderSmithCollege,LittleRock, Physicalandmentalhealthstatus
AR Physiologicalphenotype
JonathanSamet,M.D.,JohnsHopkinsUniversity,Baltimore,MD Metabolicactivations
DavidShurtleff,Ph.D.,NationalInstituteonDrugAbuse, Detoxification
Bethesda,MD Metabolism
FrankVocci,M.D.,NationalInstituteonDrugAbuse,Bethesda, Genotype
MD Disease
MitchZeller,J.D.,PinneyAssociates,Bethesda,MD Addiction
832 METHODSTOASSESSPREPS
one example, because oral tobacco confers less sum, several potentially interrelated moderating
individual disease risk than does combustible variables can influence PREP effects.
tobacco (Hatsukami, Lemmonds, & Tomar, 2004).
Degree of dependence, indexed with biochemical
Methodological issues for evaluating PREPs. Several
measures such as cotinine levels or self-report
methodologicalissuesarerelevanttoassessingPREP
scales, such as the Fagerstro¨m Test for Nicotine
effects (Table5). First, the study population should
Dependence or the Nicotine Dependence Syndrome
reflect the population of tobacco users likely to use
Scale (Colby, Tiffany, Shiffman, & Niaura, 2000;
the PREP. For example, many smokers of light and
Stratton et al., 2001), may influence key variables
ultralight cigarettes are especially concerned about
such as the extent or persistence of use and PREP-
the health risks from smoking (Giovino et al., 1996)
induced changes in smoking behavior. Amount and
andthusmaybemostlikelytouseaPREP.Relative
duration of tobacco use are also important; amount
to smokers trying to quit, smokers primarily inter-
serves as an indicator of frequency of behavior ested in reducing their cigarette intake may have
whereas duration may be a better predictor of risk more health, psychiatric, and alcohol use problems
for some diseases (Doll & Peto, 1978; Flanders, (Lemmonds, Mooney, Reich, & Hatsukami, 2004),
Lally, Zhu, Henley, & Thun, 2003). Tobacco user which may limit the extent of beneficial effects from
gender influences sensitivity to nicotine, treatment usingaPREP.Thesmoker’scessationbehavior,such
outcomes, pharmacotherapy response, and extent as interest in quitting or past quit attempts, is likely
of uptake of carcinogens and disease risk and to influence the use of the PREP and should be
outcome (Connett et al., 2003; Melikian et al., controlled for or stratified in the comparisons.
2004; Perkins, 2001). Ethnicity and race can also Second, unbiased assignment to carefully consid-
affectthedegreeofdependenceanddiseaseoutcome. ered controlconditionsiscritical. Controlconditions
Forexample,AfricanAmericantobaccousersreport for PREP evaluation might include use of (a)
lower indicators of dependence and higher incidence conventional tobacco products (Breland, Buchhalter,
of tobacco-related disease (Caraballo, Giovino, Evans, & Eissenberg, 2002; Hecht et al., 2004), (b)
Pechacek, Mowery, & Richter, 1998; Emont, 1996; standardized products, although these types of
Pe´rez-Stable,Herrera,Jacob,&Benowitz,1998;U.S. products are not considered sufficient (e.g., Eclipse
Department of Health & Human Services, 1998; Expert Panel, 2000), (c) medicinal nicotine
Wagenknecht, Cutter, & Haley, 1990). (Hatsukami, Lemmonds, Zhang et al., 2004), or (d)
The effects of PREPs may differ based on users’ no tobacco or nicotine products (i.e., abstinent users
mentalorphysicalhealthstatus,withpotentiallyless or nonusers; Breland, Acosta, & Eissenberg, 2003).
reduction in disease risk observed in populations These conditions provide valuable reference points
with a history of disease or a current disorder. and allow consumers to understand the relative risks
Concurrent medications may lead to induction of associatedwithPREPs.
enzymes that influence toxin exposure. Other mod- Third, both controlled and ad libitum use should
erating variables include individual differences in be considered in assessing PREPs. Controlled
physiological phenotypes (e.g., individual differences tobacco use allows a direct comparison of the toxin
in metabolic activation or detoxification of toxins, exposure associated with each PREP, whereas ad
capacityandefficiencyofDNArepair;Strattonetal., libitumuseprovidesamoreaccuratepictureoftoxin
2001) and genotypes that confer susceptibility to uptake in the natural environment.
disease or addiction (Lerman & Niaura, 2002). In Fourth, a comprehensive battery of exposure,
injury, or disease biomarkers is essential in PREP
evaluation. Future research must identify a panel of
Table 5. General methodological issues in human clinical
trials. biomarkersthatreflectdifferentdiseasestatessothat
determinationscanbemadethatreductionsobserved
Characterizationofpopulation
Randomassignmentofsubjectstoexperimentalconditions in one area (e.g., carcinogen exposure) are not
Controlgroup achieved at the expense of increases in another (e.g.,
Conventionalbrandoftobacco
abuseliabilityorheartdisease;Breland,Buchhalteret
Standardizedbrandoftobacco
Medicinalnicotine al., 2002; Breland, Evans, Buchhalter, & Eissenberg,
Abstinentsmokersornonsmokers 2002; Fagerstro¨m, Hughes, & Callas, 2002). A
Controlledvs.adlibitumsmoking
thorough assessment panel should include a general
Comprehensivesetofbiomarkers
Studyduration anduniformsetofbiomarkersthatcanbeusedinthe
Dictatedbystudygoalandoutcomemeasures evaluation of all PREPs, in addition to biomarkers
Stabilizationoftobaccousebehavior
thatarespecifictotheproductsbeingassessed.
Verificationofproductuseorreductionintobaccoconsumption
Monitoringofadverseevents Fifth, it is important to consider goals, outcome
Clinicalevents measures (e.g., metabolic half-life of biomarkers),
Otherunexpectedorunintendedconsequences
and in some cases, stabilization of PREP use
NICOTINE&TOBACCORESEARCH 833
behavior when determining study duration. For Table6. Measuresforhumanclinicaltrials.
example, in laboratory studies examining PREP
Exposureorchemicalbiomarkers
acute effects, study duration may be a few hours Frequencyandamountoftobaccouse
(e.g., Breland, Buchhalter et al., 2002; Breland, Tobaccousetopography(e.g.,numberofpuffs,puffduration,
puffvolume,puffvelocity)
Evans et al., 2002; Buchhalter, Schrinel, &
Biomarkersforexposure(e.g.,nicotine,cotinine,carbon
Eissenberg, 2001). However, if the goal of the study monoxide,carcinogenuptake)
is to examine human exposure and disease risk Pharmacokinetics
Biomarkersofhealtheffects
measures in a naturalistic environment, then a study
Earlycellularorbiologicaleffects
maylastdays(e.g.,Brelandetal.,2003;Fagerstro¨m, Biologicallyeffectivedose
2000; Hatsukami, Lemmonds, Zhang et al., 2004) or Biologicalinjury
Otherdisease-relatedoutcomes
months(Hechtetal.,2004;Keely,Hughes,&Hirsch,
Functionalbiomarkers
2001). Directlyobservedbiomarkers
Sixth, special attention should be given to assess- Abuseliabilitymeasures
Subjectiveresponsestoproduct
ment and verification of compliance with protocol- Reinforcingeffects
specific tobacco use restrictions. However, except in Moodeffects
Sideeffects
inpatient settings, compliance can be difficult to
Behavioralresponsestoproduct
verify. On an outpatient basis, when the PREP Drugchoiceparadigm
involves tobacco reduction or abstinence, biochem- Productself-administration
Durationofuse
ical verification is possible (e.g., by assessing the
Dependence
tobacco alkaloid anatabine, or tobacco-specific Withdrawalsuppression
nitrosamines such as total NNAL; Hecht et al., Withdrawalsymptoms
2004). For PREPs that specifically involve tobacco
use reduction, the extent to which anatabine, total carcinogens, are essential (Breland et al., 2003;
NNAL levels, or other biomarkers should be Hecht et al., 2004). Exposure assessments could also
lessenedtoindicatecomplianceis,todate,uncertain. include examining PREP-delivered toxin pharmaco-
If the PREP involves a continued normal rate of kinetics, including metabolism and clearance rates.
tobacco use (e.g., a tobacco-containing PREP Biomarkers of health effects include early chemi-
intended to reduce toxin exposure), then investiga- cal, biological, and functional effects that are or
tors may need to identify procedures that maximize shouldberelatedmechanisticallytodiseaseoutcome.
compliance while also encouraging accurate report- These measures incorporate biologically effective
ing of product intake (e.g., multiple compliance dose, injury, or other disease-related outcomes
measures, return of used and unused product, (Stratton et al., 2001). Examples of these measures
contingent payment). would include carcinogen-DNA adducts, lipid per-
Finally, adverse events (e.g., increased blood oxidation, chromosomal aberrations, mitochondrial
pressure, higher than normal laboratory tests) mutations, lipids, F2 isoprostanes, white blood
need to be monitored to assess for unintended or count, blood pressure, or FEV1. These biomarkers
unexpected consequences of PREP use. may describe components or mechanisms of the
disease process and may be used as tools for further
research to determine their relationship to disease
Measures
risk. In addition to these types of biomarkers,
Exposure and health effects. The measures related to directly observable measures such as visual inspec-
potential harm involve assessing toxin exposure or tion of airways or birth weight can be considered as
health effects (Table6). With regard to assessing the biomarkers of health effects.
dose of toxin exposure, the most obvious measure is
actual tobacco use, complemented with topographi- Abuse liability of PREPs. Another important com-
cal features such as (in smokers) puff number, ponent of assessing PREPs includes determining
duration, volume, and velocity as well as interpuff their abuse liability, that is, the potential for
interval.Generally,self-reportmeasuresarecommon addiction(Table6).NoPREPshouldhaveincreased
(e.g., Bolliger et al., 2000; Carpenter, Hughes, abuse liability relative to existing conventional
& Keely, 2003; Etter, Laszlo, Zellweger, Perrot, products. Abuse liability may be measured in
& Perneger, 2002; Fagerstro¨m, Tejding, Westin, & several ways, including assessing the subjective
Lunell, 1997; Hurt et al., 2000; Rennard et al., 2002; effects that it produces (Griffiths, Bigelow, & Ator,
Wennike, Danielsson, Landfeldt, Westin, & 2003). Subjective effects measures include the
Tonnesen, 2003) but can be confounded by changes Addiction Research Center Inventory (Houtsmuller,
in use topography (e.g., Hecht et al., 2004). Thus Fant, Eissenberg, Henningfield, & Stitzer, 2002;
measures of actual toxin uptake, such as carbon Houtsmuller, Henningfield, & Stitzer, 2003;
monoxide, nicotine or cotinine, anatabine, and Jasinski, 1977; W. R. Martin, Sloan, Sapiro, &
834 METHODSTOASSESSPREPS
Jasinski, 1971; Schuh, Schuh, Henningfield, & which PREPs are used, compared with conventional
Stitzer, 1997), the Duke Cigarette Evaluation Scale tobacco products (e.g., instructions and information
(Lee, Malson, Moolchan, & Pickworth, 2004; Rose, provided about the PREP, PREP cost and access,
Behm,Westman,&Johnson,2000;Westman,Levin, availability of alternatives; Hughes et al., 1991).
& Rose, 1992), the Profile of Mood States
(McNair, Lorr, & Droppleman, 1992; Schuh et al.,
Evaluating PREP effects on maintenance of tobacco
1997), and a variety of items assessing the valence
use. Understanding the extent to which long-term
and magnitude of drug effects (e.g., Houtsmuller
abstinence from all tobacco products is hindered or
et al., 2002, 2003). In these studies, subjective
facilitated by PREPs is critical and can be ascer-
responses have been compared across drugs or
tained by (a) assessing changes in motivation to quit
products being tested. Other studies have asked
on the Contemplation Ladder (Biener & Abrams,
participants to indicate their preference for PREPs
1991; Carpenter et al., 2003; Kotlyar, Jensen, Li, &
(e.g.,Schneideretal.,2004;Schuhetal.,1997).Other
Hatsukami, 2004) or similar measures (Etter et al.,
measures have included assessment of palatability,
2002; Fagerstro¨m, 2000), (b) assessing whether
pleasantness, satisfaction, sensory effects, and extent
subjects have progressed on their stages of change
of feeling dependent on the product (e.g.,
(Etter et al., 2002; Prochaska, DiClemente, &
Houtsmuller et al., 2002, 2003; Lee et al., 2004;
Norcross, 1992), (c) determining the number of quit
Schneideretal.,2004;Schuhetal.,1997;Westetal.,
attempts in which abstinence has been sustained for
2000). Another method of measuring abuse liability
at least 24hr (e.g., Bolliger et al., 2000; Carpenter et
involves determining behavioral responses, such as
al., 2003), and (d) determining the total duration of
asking participants to choose PREPs they would
abstinence. The gold standard is the abstinence rate
like to self-administer after a sampling period (e.g.,
associated with use of a PREP compared with
Fagerstro¨m et al., 2002). The extent to which
conventionalproducts.Studiesshouldnotrelysolely
participants use a PREP is presumed to be related
on motivations to change as predictive of long-term
directly to the PREP’s abuse liability (Hughes et al.,
abstinence. The ideal PREP may well be one that
1991; West et al., 2000). Duration of use (‘‘How
reduces toxin exposure and harmful health effects of
long do participants persist in the use of the
tobacco in the short term and does not compromise
product?’’) is also relevant (e.g., Shiffman, Hughes,
complete tobacco abstinence in the long term.
Di Marino, & Sweeney, 2003; West et al., 2000).
Finally, examining PREP effects on the suppression
of tobacco-related withdrawal symptoms or craving
Premarket consumer testing
is relevant, because withdrawal suppression is
thought to maintain tobacco use (e.g., Breland Issues in premarket testing of product presentation
et al., 2003; Breland, Buchhalter et al., 2002; characteristics
Houtsmuller et al., 2003; Pickworth, Fant, Nelson,
PremarkettestingofconsumerperceptionsofPREPs
Rohrer,&Henningfield,1999;Schneideretal.,2004;
is important to ensure that claims conveyed about
West et al., 2000).
these products or marketing efforts are accurate and
WhenexaminingPREPabuseliability,researchers
notmisleading.Theimportanceofthistypeoftesting
should consider testing different doses (Houtsmuller
is underscored by studies showing that many
et al., 2002, 2003; Hughes et al., 1991; Schuh et al.,
smokers were misled about the health benefits
1997) and the use of appropriate negative and
associated with light, mild, and ultralight cigarettes,
positive control conditions (e.g., Houtsmuller et al.,
and by reports indicating that because of this
2002, 2003).
misperception, a number of smokers chose not to
quit smoking (National Cancer Institute, 2001).
Patterns of use. Because using multiple products Recently, studies have been conducted on the
(e.g., usual brand and a PREP) can lead to greater perception of claims that are made for PREPs. The
toxicity, an examination of naturalistic use patterns results are of concern. In a study conducted by
is important in assessing actual exposure (Keely et Shiffman, Pillitteri, Burton, and Di Marino (2004),
al., 2001). For example, use of smokeless tobacco the aim was to assess smokers’ and ex-smokers’
instead of smoking may reduce individual disease perceptions of PREPs and how PREP claims may
risk (e.g., Levy et al., 2004). However, this beneficial affect interest in quitting among smokers or in
effect may be lessened if smokeless products are resuming smoking among ex-smokers. A random-
used in conjunction with cigarettes (Hatsukami, digit-dialedsurveywasusedtocontact1,000smokers
Lemmonds,&Tomar,2004) orareused tomaintain and 499 ex-smokers. Risk reduction claims asso-
contrived tobacco use under circumstances in which ciated withR. J.Reynolds’s Eclipse were read tothe
asmokercannotsmoke.Laboratorystudiescanalso participants, and perception and potential effects of
reveal factors that might contribute to the extent to these claims were assessed. Examples of these claims
NICOTINE&TOBACCORESEARCH 835
include ‘‘Best choice for smokers is to quit but graphicrepresentationsofthesedatathatbestconvey
Eclipseisthe second best choice,’’ ‘‘Maypresent less information in a way that is interpreted accurately is
risk of cancer,’’ and ‘‘Contains far less of the many anotherimportantareaofinvestigation.Forexample,
compounds found in cigarette smoke that are the use of visual scales that show exposure from
believedtocontributetotheriskofcancerandother nonsmoking at one end and exposure to medium- or
illnesses.’’Between81%and91%ofsmokersandex- high-yield conventional cigarettes at the other end
smokers thought Eclipse was safer than regular maybeareadilycomprehensiblemethodofconveying
cigarettes, and 24%–26% believed Eclipse was the data to laypersons.Lessons may be learned from
completely safe (e.g., equivalent to not smoking). theexperienceoftheFDA’sdevelopmentandtesting
About 57% of smokers were interested in using offoodlabels.Thenecessityofthisareaofinvestiga-
Eclipse, with the greatest interest among contempla- tion is emphasized by studies showing that most
tors (i.e., smokers who expressed interest in quitting smokers are unaware of the tar yield of their own
within the next 6 months). The survey also showed cigarettes; could not correctly determine and under-
that 21% of smokers lost interest in quitting after stand the implications of the relative tar levels of
hearing about Eclipse, and 6.2% of ex-smokers were cigarettes; and rely mostly on misleading labels such
interested in Eclipse, with even a higher rate of as light, ultralight, or mild (Cohen, 1996; Etter,
interest (15.2%) among young adults who had Kozlowski, & Perneger, 2003; L. Kozlowski et al.,
stopped smoking within the past 2 years. Although 1998). Also, accurately perceived information on
one of the limitations of this study is that the survey changes in specific components may nevertheless be
assessedintentratherthanactualbehavior,itraisesa misleading if not accompanied by information about
cautionary note that promotion of PREPs, particu- componentsthathavenotchanged.
larly without regulatory oversight for the scientific Although no standard methods have been
basis for making these claims, could have untoward described for testing consumer perceptions of
effects on public health. tobaccoproducts,severalmethodologicalissuesbear
Ideally, tobacco companies would not be able to discussion. One important issue is the need to target
advertise their cigarette products, and it is debatable the testing in a population that is potentially
whether they should be allowed to advertise any interested in these PREP products. Furthermore,
claims for reduced exposure or reduced health risks. recruiting smokers or other tobacco users who have
However, given the lack of current restrictions on diverse characteristics and describing these charac-
advertisement and promotion, premarket testing is teristics is necessary to determine how these attri-
an important component of evaluating PREPs. butesmayinfluencetheirperceptionsofPREPs.For
Evaluation of these products may entail two example, participants need to be characterized on
purposes:(a)Regulatory(i.e.,Doesthispresentation smoking status (e.g., never-smokers, former smo-
and promotion of the product adhere to an agreed- kers), stage of smoking (experimenters vs. regular
upon standard including assurance that the claims smoker), past and present efforts to reduce cigarette
arenotfalseormisleading?)or(b)publichealth(i.e., consumption or switch to a lower-yield cigarette,
Are thepresentation and promotionlikelyto leadto past quit attempts, difficulty in quitting smoking,
beliefsorbehaviorsthattobaccocontrolforceswant stage of change (thinking about quitting in the next
to prevent, such as maintenance of tobacco use in 6 months or within the next month), or motivation
those who would have quit otherwise?). The optimal and intention toquitor decreasesmoking.Perceived
situation is when these two purposes merge. pressure from peers, family, or health care providers
may also be a determinant of how PREPs are
perceived. Other characteristics that bear considera-
Methods
tionarethetypeofcigarettescurrentlysmoked(e.g.,
Testing of consumer perceptions of PREPs includes ultra low yield, low yield, or regular), the degree of
assessing reactions (a) to product characteristics tobacco dependence and extent of smoking (occa-
presented via advertising (e.g., newspaper, magazine, sional user vs. regular user), the degree of concern
Internet)andotherpromotionalmethods,imagesand about smoking-related health, and the general and
text, and packaging and (b) to implicit and explicit individual perceptions of risk associated with smok-
reduced harm claims in these presentations. As a ing. Concerted effort should be made to include
preliminary step, decisions by a regulatory agency individuals that represent a spectrum of ages
must be made about what the science supports and (adolescents, young adults, adults, and older adults)
whether labels should reflect reduced exposure to and are from different ethnic and socioeconomic or
specificsmokeconstituents,basedonhumanexposure educational backgrounds. Most of these variables,
methods, or go so far as to provide estimates of including gender, have been observed to influence
reduced risk of specific smoking-related diseases. perceptions and use of low-yield and ultra-low-yield
Furthermore determining the text, format, and cigarettes or PREPs (e.g., Etter et al., 2003; Gilpin,
836 METHODSTOASSESSPREPS
Emery,White,&Pierce, 2002;Hamiltonetal.,2004; Asanaddedareaofresearch,productpresentation
Shiffman et al., 2004; Shiffman, Pillitteri, Burton, characteristicsmayinfluencesmokers’perceptionsof
Rohay, & Gitchell, 2001a, 2001b). thesensoryandreinforcingeffectsofthePREPsand
Severalavenuesforconsumerassessmentofproduct the experience of using them (Pollay & Dewhirst,
presentation and labeling include focus groups; 2002, 2003). For example, color, image, and exten-
individual testing; mall-intercept interviews; and sion of well-known brands may influence the
Internet, mail, and telephone surveys. Focus groups perception of product taste (Pollay & Dewhirst,
aremostusefulforinitialexplorationofthereactions 2002).Ontheotherhand,ifaftertryingaPREP,the
elicitedinconsumersinresponsetoproductcharacter- smokerrejectsthesensoryandhedonisticqualitiesof
istics.Individualtestingcanbeusedformorein-depth the PREP, he or she is unlikely to adopt it, in spite
understandingofmessageprocessingandpreferences. of any implicit or explicit reduced-harm claims.
It is recommended that some of the testing of the Furthermore several studies have demonstrated that
product presentation characteristics be performed in the somatic or sensory sensations experienced by an
situ; that is, the content should be tested in the individual may shape his or her perception of
environment inwhichthe consumer will encounterit. perceived health threat or protections (Brownlee,
When consumers are explicitly directed to evaluate Leventhal, & Leventhal, 2000; Leventhal et al.,
PREP characteristics and messages, they are likely to 1997). Supporting the contributions of sensory
responddifferentlythaniftheirattentionhadnotbeen effects onproduct perceptionaretwostudiesfinding
directed to these issues. This distinction between that advertising information on the deceptiveness
central and peripheral processing is well established about the sensory effects of smoking light cigarettes
in the persuasion literature (Petty, Haugtvedt, & had the greatest impact on changing beliefs about
Smith,1995;Petty&Wegener,1999).Althoughtesting safety and toxin delivery of light and ultralight
of print advertising intended for magazines or the cigarettes,intenttoquit,andpreferenceforcigarettes
Internet can be done in a laboratory setting, retail (Shiffman, Burton et al., 2001; Shiffman, Pillitteri
advertising will need to be tested in an actual retail et al., 2001a). It is necessary then, in evaluating
environment,orwithinavirtualretailexperience. consumer perceptions of a PREP, to consider how
An innovative method of assessing the behavioral the product presentation influences sensory and
impactofaproductisdescribedinastudyconducted reinforcing qualities of the PREP and how the
byShiffman,Burton,andassociates(2001)usingthe sensoryexperiencesfromthePREPinfluencepercep-
ARS Persuasion test, a method to test the effective- tion of health benefits.
ness of commercial television advertising. This test
involves presenting the advertisement, which is
Measures
embedded in a pilot television show that the
participants are presumably reviewing, and deter- The assessment of consumer perceptions and assur-
mining the pre-post shift in brand choice in an ance of adequate interpretation of information
environment that simulates product purchase. That requiresexposureto severalmethods ofcommunica-
is,theparticipants’shiftinproductchoiceofferedas tion—print ads or packages, Internet, radio adver-
prizes is determined before and after viewing the tisements, retail store advertisements, and product
advertisements. A control group that has no expo- placement. Participants in consumer testing should
sure to the advertisement is used as a comparison be asked both general questions about the product
group.Ideally,thedesignshouldcomparedifferences and specific questions about product presentation
in postmessage choice only between the exposed and characteristics. In other words, how the individual is
control groups. Making a premessage choice focuses interpreting the information in the advertisement,
attention on the advertisement and alters the way in packaging, and labeling should be assessed. More
which the message is processed. Conceivably, to specifically, measures should include assessment of
assess the effects of PREPs on quitting behaviors, comprehension, beliefs, and behavioral intention
smokerswhoareinthepreparationoractionstageof (Bates, McNeill, Jarvis, & Gray, 1999; Cohen,
quitting can be exposed to a PREP advertisement 1996; Etter et al., 2003; Gilpin et al., 2002;
andtheextentofPREPchoicesafterexposuretothe Hamilton et al., 2004; L. Kozlowski et al., 1998;
advertisement can be compared with those of a Pollay & Dewhirst, 2002; Shiffman, Burton et al.,
controlgroupwithnoexposuretotheadvertisement. 2001;Shiffmanetal.,2004;Shiffman,Pillitterietal.,
Finally, population surveys can provide estimates 2001a, 2001b). Comprehension items include inquir-
forpopulationimpact,asdescribedintheaforemen- ingaboutwhetherharmfultoxinshavebeenreduced,
tioned random-digit-dialed telephone survey con- to what extent, and the meaning of the reduction of
ductedtodeterminesmokerandex-smokerreactions specific toxins; whether risk for disease has been
to PREP cigarettes claiming reduced risk (Shiffman reduced, which diseases have been reduced, and to
et al., 2004). whatextent;thepotentialaddictionofthePREPand