REVIEW

An efficient early phase 2 procedure to screen medicationsfor efficacy in smoking cessation

Kenneth A. Perkins & Caryn Lerman

Received: 2 October 2013 /Accepted: 13 November 2013 /Published online: 3 December 2013# Springer-Verlag Berlin Heidelberg 2013

AbstractRationale Initial screening of new medications for potentialefficacy (i.e., Food and Drug Administration (FDA) earlyphase 2), such as in aiding smoking cessation, should beefficient in identifying which drugs do, or do not, warrantmore extensive (and expensive) clinical testing.Objectives This focused review outlines our research on de-velopment, evaluation, and validation of an efficient crossoverprocedure for sensitivity in detecting medication efficacy forsmoking cessation. First-line FDA-approved medications ofnicotine patch, varenicline, and bupropion were tested asmodel drugs, in three separate placebo-controlled studies.We also tested specificity of our procedure in identifying adrug that lacks efficacy, using modafinil.Results This crossover procedure showed sensitivity (in-creased days of abstinence) during week-long “practice” quitattempts with each of the active cessation medications (posi-tive controls) versus placebo, but not with modafinil (negativecontrol) versus placebo, as hypothesized. Sensitivity to med-ication efficacy signal was observed only in smokers high inintrinsic quit motivation (i.e., already preparing to quit soon)and not smokers low in intrinsic quit motivation, even ifmonetarily reinforced for abstinence (i.e., given extrinsicmotivation).Conclusions A crossover procedure requiring less time andfewer subjects than formal trials may provide an efficient

strategy for a go/no-go decision whether to advance to subse-quent phase 2 randomized clinical trials with a novel drug.Future research is needed to replicate our results and evaluatethis procedure with novel compounds, identify factors thatmay limit its utility, and evaluate its applicability to testingefficacy of compounds for treating other forms of addiction.

Keywords Medication screening . Pharmacotherapy .

Nicotine dependence . Addiction

Introduction

Despite passage of a half century since the first U.S. SurgeonGeneral’s Report on health risks of tobacco smoking(USDHEW 1964), persistent cigarette smoking by nearly50 million Americans is still the greatest preventable cause ofmortality in the U.S. at 20 % of all deaths, or over 400,000 peryear (Rostron 2013; USDHHS 2010). Worldwide, these prev-alence and mortality numbers are tenfold higher and rising(Giovino et al. 2012), foreshadowing continuing severe publichealth problems for decades to come. Despite most smokersstating a desire to quit, only a fraction actually do try to quiteach year (e.g.,Wewers et al. 2003). Moreover, 5% or fewer ofthose quit attempts are successful at 1 year (CDCP 2011), eventhough many quit attempts involve medication use (Hugheset al. 2009). Without efficient development of more effectivemedications, disappointing quit rates are likely to continue(e.g., Hughes 2011). This overview summarizes work from2004–present in developing and validating a novel, efficientprocedure to provide an early signal for medication efficacy(Perkins et al. 2006; Perkins et al. 2008b, 2010, 2013b).

In brief, our current procedure involves a within-subjectcomparison in the number of abstinent days during separateweek-long “practice” quit attempts (e.g., Carpenter et al.2011) under active medication versus placebo conditions,

K. A. Perkins (*)Western Psychiatric Institute and Clinic, University of PittsburghSchool ofMedicine, 3811 O’Hara Street, Pittsburgh, PA 15213, USAe-mail: perkinska@upmc.edu

C. LermanCenter for Interdisciplinary Research on Nicotine Addiction,Department of Psychiatry and Annenberg School forCommunication, Abramson Cancer Center of the University ofPennsylvania, 3535 Market Street, Suite 4100, Philadelphia,PA 19104, USA

Psychopharmacology (2014) 231:1–11DOI 10.1007/s00213-013-3364-6

testing smokers high in quit interest (wanting to quit soon,generally within the next 3 months). We tell them the study isaimed at assessing “short-term effects of medication,” and thatparticipation may help them “learn how to be successful whenyou quit smoking permanently.” The initial quit week is whenmedication efficacy may be most critical, since abstinencewith medication over the first 1–2 weeks of a quit attemptstrongly predicts later cessation outcome (e.g., Kenford et al.1994; Wileyto et al. 2004; Ferguson et al. 2009; Ashare et al.2013), as also discussed in detail under “Further consider-ations.” Because the duration of attempting to quit during ourprocedure is brief for each medication condition, our dailyoutcome measure for cessation, assessed at brief visits eachweekday, is no smoking at all in the prior 24 h. Importantly,we use the stringent criterion of CO<5 ppm as the objectivebiochemical validation of abstinence, to allow detection ofeven a brief lapse (Perkins et al. 2013a; see also Wileyto et al.2004). Also, study sessions are scheduled for afternoons toallow assessment of mid-day CO (rather than CO just afterwaking; e.g., Perkins et al. 2009). Participants receive approx-imately $15/visit, which is intentionally kept modest so thattheir interest in participation is not overly swayed bymonetaryreimbursement, rather than the optional free treatment to helpmake a permanent quit attempt provided after the study toattract those with high quit interest. (The total amount ofreimbursement varied among our past studies because of thevariable number of required visits to complete each study andthe randomization of subjects in two studies to presence vs.absence of additional monetary reinforcement for each quitday, as explained below in the detailed description of each.)

The rationale for a new early screening procedure andlimitations of existing procedures are discussed next, followedby details of research conducted to develop, test, and validateour procedure. Further research showing the predictive valid-ity of our primary outcome measure of week-long days quit, aconsideration of our procedure’s limitations, and future direc-tions of this approach are then provided.

Rationale for a new procedure in early human testingof cessation medications

Development of new medications for smoking cessation hasbeen hampered by the need to identify promising new com-pounds (e.g., Gorodetzky and Grudzinkas 2005) and ineffi-ciencies in their evaluation (Bough et al. 2013; Lerman et al.2007). Accelerating this success may require more efficientdetection of efficacy for cessation in these novel medications,to better guide preparations for their formal testing in clinicaltrials. Efficient early screening is mainly defined here byobtaining a valid answer as to the likely clinical efficacy of amedication versus a comparison (i.e., placebo or current stan-dard treatment) using the smallest sample of participants and/

or shortest duration of testing possible (Kola 2008; Lesko2007; Streiner 2007). Dozens of drugs have been tested forefficacy in smoking cessation over the last 20 years, but few ofthese have shown success (Benowitz and Peng 2000; Fouldset al. 2006; Harmey et al. 2012; Hughes et al. 2004; Schnolland Lerman 2006; Polosa and Benowitz 2011). Such “failed”clinical trials (i.e., those in which a drug shows no efficacy)constitute unproductive uses of time and resources that ideallyshould be devoted to more promising candidate drugs.

The costs and time involved in medication developmentincrease with each subsequent step in the evaluation processup to regulatory approval by governmental regulatory agen-cies, such as the U.S. Food and Drug Administration (FDA),the British Medicines and Healthcare Products RegulatoryAgency, or similar organizations (e.g., DiMasi et al. 2003;USDHHS 2004; see also McCormick and Olsen 2013). Inbrief, the FDA phases of human research to obtain approvalfor new medications are as follows (Vocci 1996). Preclinicalanimal studies with a compound showing likely safety char-acteristics and potential translational findings in experimentalmodels (Miczek and deWit 2008) are followed by FDA phase1 testing of safety and tolerability in humans (Butz andMorelli 2008), and treatment efficacy is usually not a focus.Drugs successful in phase 1 can proceed to phase 2, whichfirst provides initial tests of therapeutic efficacy in highlycontrolled studies of otherwise healthy patients. These studiesare often labeled “phase 2a” or “early phase 2”, to differentiatethe first evaluations of evidence for efficacy in a select groupof participants from the somewhat more extensive singleclinical trials with more representative patients typical of“phase 2b” or “late phase 2” (Sheiner 1997). Success in phase2 leads to phase 3 confirmation of that evidence for treatmentefficacy in large, heterogeneous patient samples often studiedin multi-site clinical trials, prior to FDA approval of themedication for commercial marketing. Phase 4 follows FDAapproval of the new medication and usually involves post-marketing surveillance of possible adverse effects, explorationof new treatment indications, etc.

Fewer than 10 % of all new compounds entering phase 1human testing for any treatment indication eventually succeedin becoming FDA-approved and marketed (USDHHS 2004),perhaps comparable to the low success rate in novel drugsevaluated for smoking cessation, as suggested above. There-fore, the efficient use of resources to speed delivery of med-ications to patients needing them partially requires that drugsunlikely to be effective be so identified as early as possible anddropped from further consideration (Kola 2008; Paul et al.2010). Efficient phase 2a evaluation of initial efficacy iscritical since continuing into phase 2b, and certainly phase 3,of drug development involves committing substantial re-sources and time to test the drug’s clinical efficacy in largenumbers of patients (e.g., Kroboth et al. 1991; Sheiner 1997),in this case, smokers wanting to quit permanently. Note that

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the medication development issues to be outlined here involveonly research on detecting evidence of clinical efficacy forsmoking cessation, not smoking reduction (e.g., Levy et al.2007; Stead and Lancaster 2007), during early phase 2 testing.Not discussed are numerous other factors that can influencecommercial decisions to proceed with efforts to bring a newmedication to market (e.g., its safety, or its efficacy comparedwith existing treatments; DiMasi et al. 2003; Kola 2008; seealso Lerman et al. 2007). Moreover, not included here butwarranting research attention are strategies to encourage farmore smokers to use existing efficacious medications to quitsmoking, as well as methods to foster their appropriate use asdirected (e.g., Cummings and Hyland 2005; Mahtani et al.2011; Shiffman 2007; see also Perkins et al. 2008a).

Inefficiencies are also common in development of newmedications to treat other drug dependence problems (e.g.,Amato et al. 2011; Koob et al. 2009; Pierce et al. 2012) andhave prompted FDA to establish the Critical Path Initiative tofoster greater innovation in medication development proce-dures (Woodcock and Woosley 2008). The Executive Sum-mary of the initial FDA report calling for this Initiative stated:“Not enough applied scientific work has been done to createnew tools to get fundamentally better answers about how thesafety and effectiveness of new products can be demonstrated,in faster time frames, with more certainty, and at lowercosts….As a result, the vast majority of investigational prod-ucts that enter clinical trials fail.” (USDHHS 2004). Later, thisreport notes “…a striking feature of this path is the difficulty,at any point, of predicting ultimate success with a novelcandidate…..[and] inability to predict these failures beforehuman testing or early in clinical trials dramatically escalatescosts.” Among the Initiative’s recommended changes is vali-dation of new biomarkers and surrogate endpoints to helpstreamline early clinical trials and improve the cost-effectiveness of medication development (e.g., Lesko 2007;Paul et al. 2010). In the current paper, we describe our decadeof effort to develop, test, and validate an efficient new earlyphase 2 testing procedure to evaluate initial evidence ofefficacy in novel medications to treat smoking cessation,which may have applicability in similar initial evaluations ofmedications to treat other substances of abuse.

Limitations of current early phase 2 testing

A key question in enhancing early phase 2 research efficiencyis how to determine, in the shortest time and/or with the fewestsubjects, whether a novel medication has evidence of treat-ment efficacy to inform the conduct of subsequent clinicaltrials. Ideally, positive results for an active novel medication(e.g., versus placebo) in early phase 2 should support proceed-ing to the larger late phase 2 assessments of the medication forcessation in randomized clinical trials, while negative results

in early phase 2 should indicate the novel medication may notbe sufficiently efficacious as to warrant costs and time of latephase 2 testing. The most common early phase 2 approach,small (or “pilot”) randomized clinical trials of smokers tryingto make a permanent quit on active versus placebo, can bevalid in predicting that medication’s efficacy in large phase 3trials, if sufficiently powered (e.g., N =190 in Ferry andBurchette 1994). Yet, they often may be inconclusive due toa lack of statistical power for between-groups comparisonsresulting from their typically small sample sizes (often fewerthan 50 per group; e.g., Benowitz and Peng 2000; Schnoll andLerman 2006; Farid and Abate 1998). Also, they can still be atime-consuming and expensive proposition for testing a novelcompound of totally unknown efficacy, especially if the trial isnot so small (Paul et al. 2010).

A second typical, though secondary, approach for trying todetect initial efficacy in a novel cessation medication (andoften incorporated into phase 1 studies of safety testing) is toassess brief responses on measures indirectly related to cessa-tion among volunteer smokers after short-term exposure toactive versus placebo medication, often using within-subjectscomparisons. These measures usually focus on whether thedrug blunts abstinence-induced symptoms, such as withdraw-al or craving, or briefly attenuates positive effects of acutesmoking by assessing reduction in ad lib cigarette consump-tion or in the reinforcing effects of smoke intake (e.g., Lermanet al. 2007). However, as outlined next, changes in thesemeasures are not strongly predictive of cessation outcome(i.e., quit initiation or duration), perhaps partly because thesubjects in these tests tend to be non-quitting smokers beingpaid to participate, who are more numerous and easy to recruitthan smokers actively trying to quit (Wewers et al. 2003). As aconsequence, such research using known effective medica-tions as model drugs very often does not provide resultsclinically consistent with the cessation efficacy of those drugsin formal randomized trials (Perkins et al. 2006).

In studies of abstinence-induced symptoms, for example,nicotine gum was shown in one recent study to have no effecton relieving craving or withdrawal during 6 h abstinence innon-quitting smokers (Brown et al. 2013). Also, smokers paidto undergo 3 days of enforced abstinence for the study showedcraving relief but no withdrawal relief from 21 mg nicotineversus placebo patch (Teneggi et al. 2002), or showed onlylimited withdrawal relief but no craving relief from 300 mgbupropion versus placebo (Shiffman et al. 2000). These symp-toms can help determine medication efficacy for aiding ces-sation in smokers attempting to quit permanently (e.g.,Lerman et al. 2002; Shiffman et al. 2006; Foulds et al. 2013)but may have limited validity for detecting medication effica-cy in those abstaining temporarily just for study purposes.

Regarding attenuation of smoking’s positive effects, a com-parable inpatient study of non-quitting smokers found nosignificant decrease in ad libitum smoking due to using two

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21-mg nicotine patches per day, or 42 mg in total, comparedwith use of placebo patches (Benowitz et al. 1998). Similarly,acute bupropion dose-dependently increased ad libitumsmoking over 3 h in non-quitting smokers, contrary to itsefficacy for cessation and as also found in this study withthe comparison drug of amphetamine (Cousins et al. 2001).Fewer studies of varenicline effects versus placebo in non-quitting smokers have been reported, but one recent between-groups study found no significant effects of varenicline orbupropion versus placebo in delaying smoking onset duringa 50-min cigarette access period following instructed over-night abstinence in 62 non-quitters (McKee et al. 2012).Latency to smoke was delayed by either medication amongthe subgroup of 27 reporting they typically smoked within5min of waking (McKee et al. 2012). However, more researchis needed to determine whether delaying acute smoking laten-cy in this manner relates to success with cessation, or ratherwith tobacco reduction (e.g., Levy et al. 2007; Stead andLancaster 2007). Other research has shown little influence ofvarenicline on smoking topography or craving over 21 days innon-quitters (e.g., Ashare et al. 2012).

If these results, showing modest or no medication effectson reducing withdrawal or smoking behavior in non-quittingsmokers, had comprised the initial tests of efficacy in earlyphase 2 screening of these medications for cessation, theymayhave discouraged proceeding with further clinical testing (i.e.,late phase 2 or phase 3). Thus, these current early phase 2approaches generally involve under-powered and/or expen-sive small clinical trials with quitting smokers that may oftenbe valid but impractical for testing novel drugs of totallyunknown efficacy, or brief lab-based studies of acute drugeffects in non-quitting smokers that are practical but ofteninvalid (Perkins et al. 2006).

Overview of procedure development

We have long proposed that screening of novel cessationmedications may be more efficient if initial human studiesfor early phase 2 efficacy testing optimally combine thepractical advantages of the lab tests with the validity of clinicaltrials (e.g., Perkins et al. 2006; Lerman et al. 2007), a strategythat guided the development of our procedure. We proceededunder the assumption that a dependent measure that moreclosely approximated the clinical outcome of interest wouldproduce findings with greater clinical validity, as recommend-ed for preclinical studies to justify phase 1 human testing (seeMiczek and deWit 2008). During each of our studies, we haveused smoking abstinence as the main index of efficacy andfocused on testing smokers with high quit motivation, designfeatures which are typical of clinical trials but not of labstudies. Yet, to achieve adequate statistical power with onlya modest sample (i.e., greater efficiency), we have employed a

within-subject, cross-over design (Cleophas 1993; Cohen1988; Fletcher et al. 1990), typical in lab studies but not inclinical trials. Further enhancing power is our use of thequantitative dependent measure of number of days quit permedication period, rather than the dichotomous measure ofquit/not quit at one follow-up assessment point (Cohen 1988).The high predictive clinical significance of days quit duringbrief abstinence attempt periods is described below (in “Val-idation of days quit efficacy measure” under the “Furtherconsiderations” section; see also Ashare et al. 2013).

In this development research, we used FDA-approved ces-sation medications as model drugs (i.e., positive controls) todetermine the sensitivity of our early phase 2 procedure indetecting efficacy (Koob et al. 2009). Each of our threeprimary studies to test this procedure is described in moredetail below. Using diagnostic test terminology (e.g., Glarosand Kline 1988), we have demonstrated that our procedurehas: (1) sensitivity in confirming efficacy in all three first-linecessation medications (NRT patch, varenicline, bupropion)and (2) specificity in verifying lack of efficacy in a medicationknown to be ineffective for cessation (modafinil). The ulti-mate purpose of this procedure is to detect evidence of treat-ment efficacy in novel compounds for smoking cessation, andperhaps for treating other addictions and behavioral problems.Its over-riding goal is not to replace traditional randomizedlate phase 2 clinical trials but to improve the efficiency of theearly phase 2 testing which informs the decision of whetherthe time and costs of such trials are warranted (Perkins et al.2006). This procedure may accelerate medication develop-ment by increasing the efficiency by which promising drugsdo, and unpromising drugs do not, proceed to these largerphase 2 clinical trials. It may be particularly useful in evalu-ating medications already FDA-approved for other indications(and thus already successful in phase 1) but suspected ofefficacy for smoking cessation (i.e., “repurposing”; Harmeyet al. 2012), as occurred with bupropion (Ferry 1999). Poten-tial strengths and limitations of our procedure and its potentialalternative applications are addressed in the final sections ofthis paper.

Crossover procedure validation studies

Sensitivity to transdermal nicotine patch efficacy We beganthis effort by evaluating effects of nicotine versus placebopatch on ability to abstain during a brief quit period, as afunction of participants’ level of quit motivation (Perkinset al. 2008b). Our goal was to test whether the signal formedication efficacy is greater in smokers who are high in quitinterest versus most typical smokers, who are low in currentquit interest. We used two ways to vary quit motivation: (1)“intrinsic”motivation due to their pre-existing high (n =47) orlow (n =93) quit interest (i.e., whether they were already

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intending to quit permanently soon, within 1 month, or notintending to quit soon, within the next 6 months), and (2)“extrinsic” motivation via randomization to presence (n =71)versus absence (n =69) of monetary reinforcement for dailyabstinence ($12/day), similar to contingency management forcessation (e.g., Stitzer et al. 1986). The objective of this firststudy was to identify the optimum sample for demonstratingsensitivity to a medication’s efficacy, and thus of primaryinterest was the interaction of each quit motivation variablewith medication condition (nicotine versus placebo) on num-ber of quit days. We hypothesized that smokers high in “in-trinsic” quit motivation would exhibit greater differences ineffects of active versus placebo medication on number of daysquit, compared with those low in “intrinsic” quit motivation(Perkins et al. 2006). On the other hand, efforts to increase“extrinsic”motivation via monetary reinforcement alone havelong been demonstrated to increase quitting (Stitzer et al.1986), even in smokers not otherwise motivated to quit (i.e.,those with low intrinsic quit interest; Romanowich and Lamb2010a). If such extrinsic quit motivation increased sensitivityto a medication’s efficacy for cessation, our early phase 2cross-over procedure likely could be completed more quicklyand easily, maximizing testing efficiency; a subject sample ofnon-quitting smokers monetarily reinforced daily for quittingwould likely be far easier to recruit compared with smokershigh in intrinsic quit interest (Wewers et al. 2003).

Because no medication “run-up” is needed for transdermalnicotine (e.g., Mulligan et al. 1990), all subjects smoked nor-mally during weeks 1 and 3 and were instructed to try to meetquit criteria for 4 days (Tues–Fri) each during weeks 2 and 4 onone patch condition or the other (in counter-balanced order). Asnoted, abstinence was defined at daily visits by the criteria ofCO<5 ppm and self-report of no smoking at all in the prior24 h. The commonly used CO cutoffs for abstinence of 8 or10 ppm (SRNT 2002) have lower sensitivity for detectingrecent smoking (Javors et al. 2005; Perkins et al. 2013a), whichclearly impacts outcome results for any test of a medication’sefficacy for abstinence. Study visits were brief, mostly entailingassessment of CO and self-report measures of withdrawal,craving, adverse effects, etc. These afternoon visits werescheduled a few days per week in weeks 1 and 3 during adlib smoking and on all 5 weekdays to verify daily quit statusduring weeks 2 and 4. Subjects applied the nicotine (21 mg) orplacebo patch every Mon–Fri AM, with patches available underblind conditions and in counter-balanced order between sub-jects across weeks. (Quit days for formal study analyses wereassessed Tues–Fri because the first day of patch use was Mon,which did not allow enough time to test patch effects onmeeting the 24-h quit criteria by theMon PM session.) To allowcomparable testing of efficacy for cessation in both crossoverconditions, week 3 required resumption of ad lib smoking as a“washout” period following the first patch condition in week 2and prior to the second patch condition in week 4.

Results in Fig. 1 showed that nicotine (vs. placebo) patchduring 1 week use increased days of abstinence in smokerswho were high, but not low, in intrinsic quit interest (Perkinset al. 2008b), with a significant interaction of nicotine×intrin-sic quit interest (p <0.005). Specifically, nicotine patch rough-ly doubled the number of abstinent days versus placebo patchduring these short-term quit attempts in smokers with highintrinsic quit interest (p <0.001; partial eta squared effect sizeof 0.317), while those low in intrinsic quit interest showed nodifference between patch conditions. In contrast, there was nointeraction of nicotine×extrinsic quit interest (monetary rein-forcement for abstinence), despite a main effect of money in

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Fig. 1 Mean (SEM) days of abstinence during brief quit attempts onactive medication versus placebo in three separate crossover studies,testing smokers high or low in intrinsic quit interest in the NRT andvarenicline studies but only smokers high in quit interest in thebupropion/modafinil study.**p ≤0.01, ***p<0 .001 for difference fromplacebo

Psychopharmacology (2014) 231:1–11 5

enhancing number of quit days (p <0.005), similar to studiesof monetary reinforcement alone, without medication (e.g.,Kollins et al. 2010; Lamb et al. 2010). The triple interaction ofnicotine×intrinsic interest×extrinsic interest also was notsignificant.

After completing the study, all participants were offered briefcessation counseling (see Perkins et al. 2008a) to help make apermanent quit attempt as a benefit of study participation. Tohelp us validate their high versus low intrinsic quit interest, wealso assessed self-report of recent smoking behavior after2 weeks post-study in all participants, regardless of originalquit interest. During this brief follow-up phone contact on theircurrent smoking, they were asked if they had “not quit or cutdown”, “cut down but did not quit”, or “quit”, and then for howlong if they said they had “quit”. Only if this quit lasted at least24 h was it considered a true post-study quit attempt, whichoccurred in 62 % of those high, compared with 18 % of thoselow, in intrinsic quit interest as assessed at study screening,consistent with expectations. Responses at this point wereexpected to be valid since there was no longer any contingencyfor being quit and subjects had already received payment forstudy participation, ending study contact. Those with highintrinsic quit interest who were unable to quit for 24 h post-study may have required greater cessation assistance to besuccessful. (Even if those identified as such had not truly beenhigh in intrinsic quit interest at screening, despite ability toqualify for the study if low in quit interest, their inclusion herewould be expected to dilute the effect of intrinsic quit interest onsensitivity to nicotine vs placebo patch on the study quit days.)

Thus, in this first test, high intrinsic quit motivation (pre-existing quit interest) enhanced nicotine patch efficacy overplacebo (i.e., increased sensitivity), while extrinsic quit moti-vation (money for each quit day) did not. Furthermore, otherresults of this initial study showed the feasibility of our cross-over design for this research: (1) There were no significantorder effects of nicotine and placebo patch on abstinence, (2)no subject declined to resume smoking during week 3, be-tween the patch conditions, and (3) the total participant drop-out rate was below 20 %. Feasibility of this procedure is alsoaddressed in “Further considerations,” below, along withmorediscussion of the association of number of study days quitwith post-study quit status.

Sensitivity to varenicline efficacy Results of this first study,with nicotine patch, were informative in validating our earlyphase 2 procedure. However, the importance of recruitingsmokers high in intrinsic quit motivation to detect efficacy ina potentially broad array of novel medications required cross-validation of these findings with another medication. Conse-quently, our follow-up study validated the sensitivity of thisprocedure with varenicline versus placebo (Perkins et al. 2010),using a similar within-subjects, cross-over design and the com-parison of subgroups high versus low in intrinsic and extrinsic

quit interest. As in our patch study, intrinsic quit motivationcomprised smokers already high (n =57) versus smokers low(n =67) in current quit interest, and extrinsic motivation in-volved subgroups randomized to presence (n =61) versus ab-sence (n =63) of monetary reinforcement for daily abstinence.The only difference in this study was that an extra week wasneeded for adequate dose run-up with each medication condi-tion (including placebo, to maintain double-blind). Thus, allsubjects engaged in two 3-week phases (six weeks in all), eachphase involving a week of ad lib smoking without medication(baseline), a week of ad lib smoking during medication run-up,and a week of attempting to quit while on the full medicationdose (1.0 mg varenicline BID) or placebo. Brief visits for eachstudy phase were scheduled a few days in each of the first2 weeks and every weekday of the “quit week” (week 3), andthe primary dependent measure was the number of days absti-nent out of five (Mon–Fri), verified daily by CO<5 ppm.

Similar to our patch study, results showed a significantinteraction of varenicline×intrinsic quit interest on numberof quit days (p =0.05), with greater sensitivity to vareniclinein smokers high versus low in intrinsic quit interest (effectsizes of 0.373 and 0.121, respectively), as also shown inFig. 1. (Note in Fig. 1 that varenicline did show some efficacyin those with low quit interest, perhaps demonstrating evi-dence of its robustness for aiding cessation; Gonzales et al.2006). The interaction of varenicline×extrinsic quit interest(reinforcement) was not significant (p >0.10), as with thetriple interaction of varenicline×intrinsic interest×extrinsicinterest. Among all subjects, varenicline (vs. placebo) in-creased continuous abstinence on all 5 days throughout thequit week (21.0 % vs. 8.1 %, p <0.001). However, medicationorder effects were found, as those who received varenicline inthe first phase quit more days overall (i.e., with each medica-tion condition) than those who received placebo first. Yet, thevarenicline×medication order interaction was not significant(p >0.20), because the increase in quit days due to vareniclineversus placebo was similar regardless of when varenicline wasreceived, lessening the impact of drug order on interpretingmedication efficacy. Also very consistent with the patch study,post-study validation of intrinsic quit interest during thefollow-up phone contact showed that quitting for at least24 h was found in 61 % of those high, versus 11 % of thoselow, in intrinsic quit interest.

Therefore, we replicated with varenicline our key findingwith nicotine patch (Perkins et al. 2008b) that sensitivity toeffects of medication versus placebo on increasing days ofabstinence depended on testing smokers with high intrinsicquit motivation but not high extrinsic motivation (daily mon-etary reinforcement for quitting). An important implication isthat the results of efforts to test medications in non-treatment-seeking smokers who are low in intrinsic quit motivation mayhave lower predictive validity with respect to cessation effi-cacy in the target population, even if monetary reinforcement

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for quitting is utilized. Our findings may also be relevant foracute laboratory modeling of lapse behavior in those not highin quit interest, such as tests of medication or other effects onability to delay smoking initiation over 1–2 h after overnightabstinence when every few minutes of refraining fromsmoking is monetarily reinforced (e.g., Mueller et al. 2009;McKee et al. 2012).

Sensitivity to bupropion efficacy and specificity testing withmodafinil Using this procedure, our study with vareniclinereplicated our patch results by demonstrating the influenceof these between-subjects factors of intrinsic and extrinsic quitmotivation on enhancing and not enhancing, respectively,sensitivity to the medication’s efficacy for quitting. Therefore,we concluded that the optimum subject sample for our earlyphase 2 cross-over procedure should comprise smokers highin intrinsic quit interest and that monetary reinforcement forquitting did not matter here. Subsequently, our third study(Perkins et al. 2013b) further validated our refined model,testing only smokers high in intrinsic quit interest, byassessing both its sensitivity with the third FDA-approvedcessation medication, bupropion, as well as its specificity fordetecting failure of an ineffective medication to aid quitting(Glaros and Kline 1988) using modafinil. Modafinil is FDA-approved to improve wakefulness but has been shown to beineffective for smoking cessation (Schnoll et al. 2008) and foracute relief of withdrawal (Schnoll et al. 2008; Sofuoglu et al.2008). The specificity of an early phase 2 medication screen-ing procedure is as important as its sensitivity because anefficient procedure must also be able to determine whether anovel compound does not warrant further evaluation in largerrandomized clinical trials.

To simultaneously assess sensitivity and specificity, weconducted a double cross-over design (e.g., Koch et al.1989; Parodi et al. 1986) with three medication conditions—bupropion, modafinil, and placebo—each phase involving3 weeks for baseline, dose run-up, and quit week assessmenton medication (9 weeks in total). As with our vareniclinestudy (Perkins et al. 2010), medication conditions were pre-sented double-blind and in counter-balanced order acrossweeks (six possible orders). No between-subjects factors werecompared, as all 45 participants were smokers high in intrinsicquit interest, those shown in our prior studies to be moresensitive to medication efficacy in our procedure. (We provid-ed all with $12/day for each quit day to maintain their moti-vation for participation, given the study duration of 9 weeks,but this reinforcement did not differ between subjects oracross the three study phases.) Relative to the placebo condi-tion, bupropion did (p =0.01; effect size of 0.167), butmodafinil did not (p =0.60), increase number of days abstinent(see Fig. 1), both as hypothesized. Also, bupropion (vs. pla-cebo) increased ability to maintain continuous abstinence onall 5 days throughout the quit week (24.4 % vs. 8.9 %, p <

0.05), while modafinil did not (13.3 %). Among those able toinitiate quitting during each week, bupropion prevented anylapses in 45.2 %, compared with 19.2 % for placebo and22.2 % for modafinil. Finally, in follow-up phone contact,post-study quit for at least 24 h was reported in 58 % of thesesubjects, all high in quit interest, while only 4 % reported nochange in their smoking.

Further considerations

Validation of days quit efficacy measure Notably, to furthervalidate the primary outcome measure of efficacy in thiscrossover procedure, data from our prior studies suggest thatnumber of days quit during these week-long assessments maybe clinically meaningful (unpublished data). Specifically, weexamined the association between number of days quit duringthese brief attempts with success or failure in subsequentlybeing able to quit (permanently) in the post-study follow-upassessments. To eliminate the influence ofmonetary reinforce-ment for days quit, we included only non-reinforced subjectshigh in quit interest (N =54) from our first two studies, testingnicotine patch or varenicline. Total days abstinent during thetwo study quit weeks (including placebo) were comparedbetween those able versus those unable to quit for 24 h orlonger in the permanent attempt when contacted several daysafter their target quit date. FTND was included as a covariate,since dependence could explain quit ability during both thestudy quit weeks and the post-study quit attempt. In theANCOVA, we found more days quit during the short-termstudy weeks among those 36 who later quit post-study, com-pared with those 18 who were unable to quit post-study, withrespective means (SE) of 4.1±0.5 versus 0.6±0.7 study daysquit, F (1,51)=14.55, p <0.001. These results suggest thatnumber of days quit during week-long assessments in thiscrossover test is a potentially meaningful clinical measure inpredicting successful initiation of a permanent quit attempt.

These findings are consistent with Ashare et al. (2013), avery recent analysis of three separate randomized clinicaltrials (i.e., not crossovers) of those making a permanent quitattempt on FDA-approved medications (NRT patch or spray,or bupropion). In that analysis, number of quit days during thefirst week of these formal clinical trials very significantlypredicted quit status (seven-day point prevalence) at the endof treatment 8–10 weeks later and at the 6-month follow-upassessment of quit status (with OR’s>1.4, p <0.001; Ashareet al. 2013). Our crossover results are also consistent withother studies showing the first 1–2 weeks of a quit attemptpredict long-term success (e.g., Kenford et al. 1994; Perkinset al. 2001; Wileyto et al. 2004; Ferguson et al. 2009;Romanowich and Lamb 2010b), partly why we chose a

Psychopharmacology (2014) 231:1–11 7

week-long quit period for assessment under each medicationcondition in this cross-over procedure.

Feasibility Our three studies also suggest this crossover de-sign is a feasible approach. The study with varenicline, toreplicate the NRT patch results for high/low intrinsic andextrinsic quit interest, showed some evidence of medicationcarryover effects, in that varenicline resulted in more days quitwhen it preceded rather than followed the placebo condition(Perkins et al. 2010). Yet, varenicline still significantly in-creased quit days over placebo under either medication orderin this crossover procedure. The other medications we tested,NRT patch in study 1 and bupropion in study 3, did not showsignificant order effects in the counter-balancing of activeversus placebo conditions. Among the smokers high in intrin-sic quit interest, who show greater sensitivity to medicationefficacy in our studies, as noted, we also found reasonably lowrates of drop-out after entering the study. Out of the 192 highquit interest smokers entered in all three studies, 43 droppedout (22 % of all entered), with drop-out rates rising as thestudy duration lengthened (15 %, 21 %, and 31 % for the4 weeks of NRT, 6 weeks of varenicline, and 9 weeks ofbupropion/modafinil, respectively). Moreover, despite the re-quirement of daily visits to assess quit status each weekdayduring the quit weeks, fewer than 1% of these visits (15 out of1621 scheduled visits) were missed by the total of 149 highquit interest smokers who completed the three studies(unpublished).

Potential limitations The breadth of our early phase 2procedure across the vast array of potential new medica-tions, or other treatments, for smoking cessation and otheraddictive problems is uncertain and warrants further study.This cross-over design may have less utility in initial testsof efficacy for novel compounds with certain pharmacoki-netic or pharmacodynamic characteristics. For example,our procedure may have practical limitations for earlyassessment of efficacy in medications requiring a longdose run-up period or a long washout period, whichwould also be required for a placebo condition to maintainblinding. Such kinetic factors could exacerbate the chancesof significant carryover effects in a crossover design,which may require procedural alterations in the study tolessen their impact (e.g., Fleiss 1989). Novel drugs withobvious psychoactive or subjective effects would hamperthe attempt to maintain blinding to placebo or other com-parison medication conditions. Among other limitationsmay be the relatively few smokers who truly want to quit“soon” (e.g., within the next 3 months), thus demonstrat-ing high quit interest, relative to the number who expressa general desire to quit but have no time frame formaking a concerted cessation attempt (Wewers et al.2003).

Discussion and conclusions

The greater efficiency of our current early phase 2 crossoverprocedure is such that fewer than 50 smokers were needed inour third study (and fewer than 60 in the subgroups of thosehigh in quit interest in the first two studies) to demonstratemedication effects on aiding cessation. By contrast, abetween-groups early phase 2 test of initial medication effica-cy in a randomized trial with the same statistical power tocompare active (i.e., bupropion) and placebo conditionswould require more than 100 smokers in each of the twomedication conditions (see Fleiss 1986; Perkins and Lerman2011). This is due to the typically high within-subject corre-lation of days quit responses to active medication versusplacebo, which in this third study was r =0.59, both forbupropion and for modafinil, greatly reducing the error vari-ance between conditions. Consequently, the sample size for atwo-group randomized trial of similar power as in our cross-over trial would be 2/(1−r )×the sample size for our within-Sdesign (N =45), or 2/(1−0.59)×45, which (for this study) is220 subjects (Fleiss 1986; see also Perkins and Lerman 2011).

In sum, the consistency of our procedure for sensitivity indetecting cessation efficacy is shown by all three FDA-approved first-line medications (NRT, varenicline, bupropion)increasing “days quit” over placebo. We demonstrated speci-ficity of the procedure for detecting lack of efficacy by show-ing that the negative control of modafinil does not increasedays quit over placebo (Perkins et al. 2013b). Although rep-lication of our results with this innovative early phase 2procedure is needed, we believe these findings provide com-pelling data to support the notion that efficacy of novel med-ications for smoking cessation can be detected in a cross-overstudy in which smokers high in intrinsic quit interest makebrief “practice” quit attempts with each condition (i.e., activeand placebo). Furthermore, this efficacy can be identified witha sample size of smokers high in quit interest that is muchsmaller, and a duration of participation shorter, than those intraditional randomized clinical trials, which by definitiondemonstrates that this procedure has greater efficiency.

The next step is to apply our procedure in the manner forwhich it is ultimately intended, to screen truly novel medica-tions for smoking cessation, in comparison with placebo and/or a known effective medication to provide a comparator. Thedouble crossover design in our most recent study (Perkinset al. 2013b), with two different active medications along witha placebo, could be used to determine superiority (or equiva-lence) of efficacy for a novel drug versus an existing standardtreatment drug (Streiner 2007) or to compare two active dosesof a novel compound to determine the optimum dose forcomparison with placebo in a randomized (and larger) latephase 2 clinical trial. A potentially similar approach that couldbe more practical by reducing subject burden may be toconduct separate cross-over early phase 2 studies comparing

8 Psychopharmacology (2014) 231:1–11

each of two active medications with a placebo, to determinenon-equivalence (e.g., Song et al. 2008). Our procedure mayalso be an efficient method to compare efficacy of combina-tion versus single medications to inform the likely results ofsubsequent randomized trials of combination treatments (Lohet al. 2012; Issa et al. 2013; Mills et al. 2012; Shiltz et al.2011).

Finally, warranting consideration is the possibility a similarprocedure could increase sensitivity and specificity in earlyphase 2 tests of novel compounds to treat other drug abuseproblems, such as alcohol dependence (Jupp and Lawrence2009; Ray et al. 2010) and perhaps others (e.g., Koob et al.2009; Pierce et al. 2012). Findings with such examinationscould thereby increase the efficiency of initial screening ofnew medications for treating these drug dependencies. Con-ceivably, this crossover approach could be further adapted toevaluate efficacy in new behavioral treatments or other non-medication interventions, perhaps to aid development andrefinement of these treatment procedures prior to large, ran-domized trials of their utility.

Acknowledgments This paper, and the research it describes, was sup-ported by NIH Grant CA143187. Dr. Perkins has served as a consultantfor Embera Neurotherapeutics that is unrelated to the current research. Dr.Lerman has served as a consultant for GlaxoSmithKline, Pfizer, and AstraZeneca. She has received research funding, unrelated to the currentresearch, from Pfizer and Astra Zeneca. The authors thank K.N. RoyChengappa, Carolyn Fonte, Joshua Karelitz, and Maxine Stitzer for theirassistance in this research.

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