1. IDRAC 232545
The latest developments from US FDA
drug and biologic advisory committee
meetings.
Today’s
Headline:
Support for
Removing Boxed
Warnings from
Two Smoking
Cessation Aids
September 14, 2016
Meeting Begin Time: 7:59 a.m. | End Time: 4:55 p.m.
IN THIS ISSUE
Joint Meeting of the Psychopharmacologic
Drugs Advisory Committee and the Drug
Safety and Risk Management Advisory
Committee
AdComm Profiles and AdComm Voting
(IDRAC 175864)
Subject: Discussion of EAGLES, a completed
randomized, placebo-controlled trial evaluating
the neuropsychiatric effects of Chantix
(varenicline), Zyban (bupropion hydrochloride),
and nicotine replacement therapy, and of
relevant, published observational studies, to
determine whether findings support changes to
product labeling.
Announced in the Federal Register
July 28, 2016 (IDRAC 230863)
(Volume 81, Number 145)
Decision/Voting
At today’s joint meeting of the Psychopharmacologic Drugs Advisory Committee (PDAC) and
the Drug Safety and Risk Management Advisory Committee (DSRMAC), more than half of
committee members voted to remove boxed warnings from the product labels of 2 smoking
cessation aids: Pfizer, Inc’s Chantix (IDRAC 231526) (varenicline) and GlaxoSmithKline’s
(GSK’s) Zyban (IDRAC 228906) (bupropion hydrochloride). The committees based the
recommendation primarily on the results of a phase 4 randomized, placebo-controlled trial,
EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study), which evaluated
the neuropsychiatric (NPS) effects of the drugs.
FDA Questions to the Committee
Vote
Comments
Yes No
Based on the data presented on the risk of serious NPS adverse events with smoking
cessation products, what would you recommend?
A. Remove the boxed warning statements
regarding risk of serious NPS AE.
10
B. Modify language in the boxed warning. 4
C. Keep the current boxed warning. 5
NOTE: The FDA is not obligated to follow the voting recommendation of the advisory committee, but it
may do so once all information is considered.
Committee discussions stressed the established efficacy of Chantix and Zyban in assisting
smokers attempting to quit. However, while 10 of the 19 committee members supported
removing the boxed warnings, many stated that EAGLES results did not dismiss their concerns
about potential NPS events among certain patients. It was suggested that the Chantix and
Zyban labels should contain EAGLES data, particularly an apparent trend for NPS events
among patients with histories of psychiatric issues.

2. IDRAC 232545
Overall, committee members characterized the design of EAGLES as strong, praising Pfizer and
the FDA for pursuing a randomized control trial and not simply relying on existing
observational data. (Pfizer and GSK collaborated on EAGLES, but Pfizer “took the lead” on
study design and conduct, according to the FDA.) They noted weaknesses in EAGLES,
however, including difficulties stemming from the multicenter design; several expressed
concerns about quality control across multiple sites in multiple countries and identified
problems arising from language differences. There was an underrepresentation of patients with
severe psychiatric illness, they said, and a lack of power in the study for rare NPS events,
including suicide and suicidal ideation. Some stated that Pfizer should have investigated the
potential impact of removing the boxed warnings.
EAGLES studied 2 cohorts of subjects motivated to quit smoking: those with an established
history of major psychiatric disorder (PHx) and those without (non-PHx). In their discussions,
members noted that, numerically, there were more NPS events among PHx patients. Several
stressed that while such evidence suggests a trend for increased risk, it is not statistically
significant. They cautioned against over-interpreting numerical differences, and said that the
impact of a patient’s psychiatric history can be managed by the prescribing physician.
The FDA noted variability in the conduct of EAGLES, particularly in data collection, the coding
of adverse events (AEs), and in case definition on the primary endpoint. In their discussions,
committee members underscored the significance of underreported AEs and the potential
impact on trial outcomes. They also stressed that problems arise when it is left to an
investigator to decide what constitutes an AE. Some members questioned whether EAGLES
was sufficiently powered for meaningful conclusions about the potential for severe NPS events
with Chantix and Zyban use.
The FDA also sought committee feedback on the primary endpoint, a novel, 16-component
composite that was intended to focus on NPS symptoms interfering with normal functioning
and to avoid “noise” by excluding mild events. Several members questioned the use of this
non-validated outcome measure. Some were particularly critical about the use of the
Neuropsychiatric Adverse Event Inventory (NAEI), stating that validity testing must be
conducted to understand its robustness as a tool.
In addition to data from EAGLES, the FDA also asked the committees to consider information
gleaned from published observational studies, and to discuss how to weigh such evidence
when evaluating the risk for serious NPS AEs in patients taking smoking cessation products.
Members agreed with the FDA conclusion that, while valuable, the observational data alone
were insufficient for confirming or refuting increased NPS risk with Chantix or Zyban. Such
results should be considered within the totality of available data.
Background Information
At today’s meeting the Psychopharmacologic Drugs Advisory Committee (PDAC) and the Drug
Safety and Risk Management Advisory Committee (DSRMAC) considered the results of a phase
4, randomized, double-blind, active- and placebo-controlled study evaluating the NPS safety
and efficacy of 3 aids to smoking cessation treatment: Pfizer, Inc’s Chantix (IDRAC 231526)
(varenicline), GlaxoSmithKline’s (GSK’s) Zyban (IDRAC 228906) (bupropion hydrochloride),
and nicotine replacement therapy (NRT). The study, EAGLES, was conducted in 2 patient
cohorts: those with and without a history of psychiatric disorders.
This meeting follows one in October 2014, when the PDAC and DSRMAC discussed safety data
from observational studies and a meta-analysis of randomized controlled trials (RCTs)
conducted since a safety signal emerged associating Chantix use with increased risk for
neuropsychiatric (NPS) adverse events (AEs) [AdComm Bulletin, 16-October-2014 (IDRAC
203644)]. The FDA sought feedback on whether the data (presented by Pfizer) were sufficient
to justify removing a boxed warning (IDRAC 132015) from the Chantix label. Only 1 of 18
voting members supported removal; 6 supported modifying the warning, and 11 voted to
retain the boxed warning and reassess their recommendation following the completion of
EAGLES. The trial began in November 2011 and ended in January 2015. A postmarketing
requirement, EAGLES was sponsored by Pfizer; GSK collaborated. The “Clinical Issues” section
of this AdComm Bulletin contains a detailed description of EAGLES.

3. IDRAC 232545
A partial agonist at the alpha-4 beta-2 nicotinic receptor, Chantix received initial FDA approval
in 2006. The product’s current boxed warning states that 1) serious NPS events have been
reported in patients taking Chantix; 2) patients and caregivers should be advised to stop
treatment and immediately contact the healthcare provider if the patient exhibits unusual
agitation, hostility, depressed mood, or changes in behavior, or develops suicidal ideation or
suicidal behavior while taking Chantix or soon after its discontinuation; and 3) the risks of
Chantix use should be weighed against its benefits in aiding abstinence from smoking.
Zyban is an oral norepinephrine and dopamine reuptake inhibitor. The FDA approved it for
smoking cessation in 1997, but has also approved bupropion for other indications. Bupropion
hydrochloride received initial approval in 1985 for major depressive disorder (MDD). Forfivo XL
(IDRAC 200158), by Edgemont Pharmaceuticals, LLC, and Wellbutrin (IDRAC 206753), by
Valeant Pharmaceuticals North America, LLC, are both bupropion hydrochloride products
approved for MDD; Zyban is not indicated for MDD. Bupropion hydrobromide has been
approved as Aplenzin (IDRAC 206857), by Valeant Pharmaceuticals North America, LLC, for
both MDD and for seasonal affective disorder (SAD).
Zyban also carries a boxed warning. The current warning states that 1) serious NPS events
have been reported in patients taking bupropion for smoking cessation; 2) there is an
increased risk for suicidal thinking and behavior in children, adolescents, and young adults
taking antidepressants; and 3) patients should be monitored for worsening and emergent
suicidal thoughts and behaviors.
Regulatory History
December 30, 1985 Initial FDA approval of new drug application (IDRAC 37900) (NDA)
018644, bupropion hydrochloride (Wellbutrin) for MDD.
May 14, 1997 The FDA approved NDA 20711 (IDRAC 158190) for Zyban.
July 1997 US launch of Zyban.
November 3, 2004 The FDA approved NDA 20711-019/020 (IDRAC 157910), revising
the Warnings and Precautions sections of the Zyban package insert
to state the need for close observation of patients taking
antidepressants for clinical worsening and signs of suicidality.
January 12, 2005 The FDA approved sNDA 20711-021 (IDRAC 158100), adding a
Zyban Medication Guide (IDRAC 121563), a boxed warning (IDRAC
132015), and other label changes regarding the potential increased
risk for pediatric suicidality with antidepressants.
November 2005 Pfizer submitted the varenicline new drug application (IDRAC
37900) (NDA) to the FDA.
December 2005 The FDA granted varenicline priority review (IDRAC 37909).
May 10, 2006 FDA approval of NDA 21928 (IDRAC 58000) for Chantix
(varenicline) for smoking cessation.
August 2006 US launch of Chantix.
May 2007 The European Medicines Agency (EMA) informed the FDA that it
was investigating a signal of suicidal-related AEs with varenicline,
and had asked Pfizer to submit a postmarketing suicidal-event
analysis. The FDA proposed a boxed warning change for all
antidepressants to emphasize increased risk of suicidality in 18- to
24-year-olds in the first 2 months of treatment.
August 2, 2007 The FDA approved sNDA 20711-029 (IDRAC 158113), including
revisions to the Zyban boxed warning
November 20, 2007 An FDA Medwatch Safety Alert (IDRAC 74076) described an
ongoing safety review of Chantix. The FDA recommended that
healthcare providers monitor Chantix patients for behavior and
mood changes [FDA Press Release (IDRAC 74067)].
November 2007 The Adverse Reactions section of the Chantix label was expanded.
January 31, 2008 The FDA approved sNDA 21928-007 (IDRAC 133255). Modifications
to the Chantix label included a warning to observe patients for
serious NPS symptoms, including changes in behavior, agitation,
depressed mood, suicidal ideation, and suicidal behavior.
February 1, 2008 An FDA Medwatch Safety Alert (IDRAC 79452) noted revisions to
the Warnings and Precautions sections of the Chantix prescribing
information [FDA Press Release (IDRAC 79451)].

4. IDRAC 232545
April 2008 An FDA center director briefing discussed varenicline benefits to
help achieve smoking cessation versus the risk for serious NPS AEs.
May 16, 2008 The FDA approved sNDA 21928-008 (IDRAC 133260), including a
risk evaluation and mitigation strategy (IDRAC 177094) (REMS)
with a Medication Guide and communication plan. The FDA issued a
postmarket requirement to assess the risk of NPS symptoms with
Chantix; patients were advised to stop Chantix if symptoms
emerged. The FDA updated the November 2007 Medwatch Safety
Alert (IDRAC 74076), stating an association between Chantix and
serious NPS symptoms “appears increasingly likely.”
May 2008 The Federal Aviation Administration (FAA) banned use of varenicline
by pilots and air traffic controllers.
February 2009 The FDA required a REMS for bupropion and issued a postmarketing
requirement to assess the serious risk for NPS symptoms.
July 1, 2009 In an update to the February 1, 2008 Medwatch, the FDA stated
that the Chantix and Zyban manufacturers must add new label
warnings and develop patient Medication Guides highlighting the
risk for serious NPS symptoms. Chantix received its first boxed
warning; the Zyban boxed warning was updated. The FDA approved
sNDAs 21928-012/013 (IDRAC 133262) (Chantix) and 20711-
032/033 (IDRAC 158122) (Zyban), which included these changes.
February 26, 2010 FDA approval of sNDA 20711-034 (IDRAC 158127), adding a Zyban
REMS to inform patients about potential risk for serious NPS AEs.
March 2010 The FDA formalized the postmarketing requirement description and
milestone dates for both varenicline and bupropion to require a
placebo- and active- controlled RCT to assess the serious risk of
NPS symptoms with treatments for smoking cessation.
October 24, 2011 The FDA updated the May 2008 Medwatch Safety Alert (IDRAC
74076), noting its review of 2 FDA-sponsored epidemiological
studies assessing the risk of NPS AEs with Chantix. While the
studies had “a number of study design limitations,” the FDA found
no difference in the risk of NPS hospitalizations between Chantix
and NRT. The FDA advised professionals and patients to continue
following label recommendations and monitor for NPS symptoms.
November 2011 EAGLES was initiated.
October 15, 2012 Pfizer announced trial results comparing Chantix safety and efficacy
with placebo for smoking cessation in patients with MDD. Chantix
subjects were more likely to quit at weeks 12 and 52. Psychiatric
scales showed no difference between Chantix and placebo.
April 8, 2014 Pfizer submitted a labeling supplement for Chantix; proposals
included removal of the boxed warning. Pfizer asserted that safety
data “do not support an association” with serious NPS events.
May 2014 High-level data from the FDA Adverse Event Reporting System
(FAERS) showed that the FDA continued to receive reports of
serious NPS AEs associated with varenicline.
October 16, 2014 At a joint meeting, the PDAC and DSRMAC voted to retain the
Chantix boxed warning about serious NPS events, but to reassess
after completion of EAGLES [AdComm Bulletin (IDRAC 203644)].
March 2015 An article published in the BMJ (British Medical Journal) suggested
that Chantix NPS AEs may have been exaggerated
Regulatory Issues
The FDA convened the PDAC and DSRMAC to gain input on the results of the EAGLES trial and
whether they support changes to the product labels for Chantix and Zyban, including the
removal of boxed warnings. There are no specific regulations or guidance regarding the
removal of a boxed warning. However, the FDA has stated that “it is reasonable to remove” a
boxed warning if the criteria for including it are no longer met. Section 505(o)(4) of the
Federal Food, Drug, and Cosmetics Act (IDRAC 10364) (FD&C Act) authorizes the FDA to
require application holders of certain drug and biological products to make safety-related
changes to the label based on new safety information [Guidance for Industry: Safety Labeling
Changes - Implementation of Section 505(o)(4) of the FD&C Act (Final), July-2013 (IDRAC
167931); Guidance Bulletin (IDRAC 124131)].

5. IDRAC 232545
According to the FDA’s Guidance for Industry: Warnings and Precautions, Contraindications,
and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products –
Content and Format (Final), October-2011 (IDRAC 132015) [Guidance Bulletin (IDRAC
58828)], a boxed warning “ordinarily” highlights one of these situations:
• There is an adverse reaction (AR) that is so serious in proportion to the drug’s potential
benefit that must be considered when assessing the drug’s risks and benefits (e.g., the
AR is fatal, life-threatening or permanently disabling); or
• Appropriate use of the drug can prevent a serious AR or reduce its frequency or severity
(e.g., through patient selection, careful monitoring, avoiding certain concomitant
therapy, addition of another drug or managing patients in a specific manner, avoiding
use in a specific clinical situation); or
• The FDA concluded that the drug can be safely used only if its distribution or use is
restricted, and thus approved the drug with restrictions to assure safe use (e.g., certain
Elements to Assure Safe Use [ETASU] under a REMS)].
The guidance identified additional situations in which a boxed warning may be used, including:
• Warning information is particularly important for prescribers and should be highlighted.
• A drug poses risk-benefit considerations that are unique among drugs in its class (e.g.,
the drug is the only one in its class to have a particular clinically significant AR or risk
and, for that reason, is indicated as a second-line therapy).
As explained in 21 CFR 201.57(c)(7) (IDRAC 8593), “for purposes of prescription drug labeling,
an adverse reaction is an undesirable effect, reasonably associated with use of a drug, that
may occur as part of the pharmacological action of the drug or may be unpredictable in its
occurrence.” This definition includes only AEs for which there is an apparent causal relationship
between the drug and the occurrence of the AE; it does not does not include all observed AEs.
Clinical Issues
EAGLES was a 24-week, double-blind, NRT- and placebo-controlled, multi-center, parallel
group study. EAGLES was conducted to assess Chantix (IDRAC 231526) (varenicline) and
Zyban (IDRAC 228906) (bupropion hydrochloride) as aids to smoking cessation treatment in 2
cohorts, subjects with and without an established diagnosis of major psychiatric disorder (PHx
and non-PHx), and to characterize the NPS safety profile in both. Table 1 summarizes EAGLES.
Table 1. EAGLES Phase 4 Study
Treatment Dose/Regimen No. Patients Primary Endpoints
Chantix 1 mg BID 2,037 Safety: The occurrence of ≥1 TE SAE of
anxiety, depression, feeling abnormal,
or hostility and/or the occurrence of ≥1
TE moderate AE or SAE of agitation,
aggression, delusions, hallucinations,
homicidal ideation, mania, panic,
paranoia, psychosis, suicidal ideation,
suicidal behavior, or completed suicide.
Efficacy: 4-week CO-confirmed
continuous-abstinence rate (CAR) for
weeks 9-12 and 9-24.
Zyban 150 mg BID 2,034
NRT 21 mg transdermal
patch daily for 7
weeks, then 14 mg
daily for 2 weeks,
then 7 mg daily for
2 weeks.
2,038
Placebo Placebo 2,035
BID = twice daily; CO-confirmed = carbon-monoxide confirmed; SAE = severe AE;
TE = treatment emergent
EAGLES enrolled 8,144 subjects, all of them smokers deemed motivated to quit, at 140 sites
across 16 countries. Subjects were randomized to 12 weeks of treatment with Chantix, Zyban,
or the nicotine patch, followed by 12 weeks of non-treatment follow-up; primary comparisons
were Chantix versus placebo and Zyban versus placebo. EAGLES used a triple-dummy design:
subjects randomized to 1 of the 3 active dosing groups took that active medication and the
other 2 medications in matching placebo form. In each treatment arm, roughly half of patients
had a psychiatric history, and roughly half did not.
The 16 components of the NPS primary endpoint were agreed upon in the EAGLES protocol;
the novel composite endpoint focused on symptoms interfering with normal functioning and
was intended to avoid “noise” by excluding mild events. Subjects made periodic clinic visits for
safety and efficacy assessments and smoking cessation counseling; assessments included

6. IDRAC 232545
volunteered AE reports, clinical rating scales, the Neuropsychiatric Adverse Event Inventory
(NAEI), and the Columbia Suicide Severity Rating Scale.
The FDA Briefing Information (IDRAC 232400) details agency concerns with the conduct of
EAGLES, including issues related to:
• Data quality and reviewability.
• Data reliability.
• The capture of NPS events, including:
o Ineffective use of the NAEI and inconsistent investigator assessment of severity.
o Inconsistent mapping of events to sub-components of the composite endpoint.
o Inconsistent application of coding terms.
o Inconsistent handling of cases involving apparent suicidality.
o Lack of information about circumstances surrounding events.
o Other “miscellaneous” coding errors.
Safety
The FDA reported 10 deaths in EAGLES; 2 occurred post-study. In 1 of the 10, it was not
known whether the patient had taken the study drug; that death is reported as occurring prior
to drug initiation. According to the FDA, this “illustrates the review team’s concerns about lack
of rigor regarding the Sponsor’s data collection, reporting, and coding.” The FDA Briefing
Information (IDRAC 232400) notes additional examples of incomplete documentation by Pfizer.
There were 72 patients with TE SAEs in the non-PHx cohort of patients and 101 in the PHx
cohort. Table 2 summarizes TE SAE incidence.
Table 2: TE SAE Incidence by Treatment and History of Psychiatric Disease
Chantix Zyban NRT Placebo
Non-PHx 16/990 (2%) 19/989 (2%) 21/1,006 (2%) 16/999 (2%)
PHx 23/1,026 (2%) 29/1,017 (3%) 24/1,016 (2%) 25/1,015 (2%)
Each of the 173 patients was reviewed to identify NPS cases of interest. After reviewing the
SAE narratives for potential NPS cases, the FDA identified 30 for which it could not rule out a
relationship to study drug; the FDA Briefing Information (IDRAC 232400) describes each of the
30. The agency found it notable that although 1 of the 30 cases resulted in hospitalization, it
was not included in the NPS endpoint because the investigator rated it, a depression event,
“mild.” The FDA identified cases of both TE and discontinuation-emergent symptoms. NPS
events in the PHx cohort of Zyban patients included cases that appeared to be a precipitation
of mania in bipolar disorder, a labeled risk of Zyban and other antidepressants.
Across sensitivity analyses, the FDA’s conclusions for EAGLES were consistent:
• In the non-PHx cohort, serious or significant NPS AEs occurred in all treatment groups,
with similar incidence across arms.
• In the PHx cohort, serious or significant NPS AEs occurred in all treatment groups; they
were consistently “somewhat more frequent” in the Chantix and Zyban arms.
• While the “vast majority” of events impacted patient functioning, they “were not of a
serious nature and were usually transient.”
• In the PHx cohort, SAEs primarily involved psychiatric decompensation.
The benefit-risk balance for smoking cessation products “appears to differ” based on patient
history of psychiatric history, according to the FDA, “but is favorable for both populations.”
Overall, 115 subjects experienced AEs leading to temporary or permanent discontinuation of
study drug or to dose reduction. Rates of dose reduction or discontinuation in the non-PHx
cohort were Chantix 12%, Zyban 14%, NRT 15%, and placebo 8%. In the PHx cohort, rates
were Chantix 17%, Zyban 15%, NRT 15%, and placebo 14%.
Efficacy
Table 3 summarizes by psychiatric cohort the results of analyses for CAR 9-12 and CAR 9-24.
In addition to the primary analysis group, Table 2 includes data from a patient subset that
excludes 32 study sites. This is because investigators at the 32 sites received payments from
Pfizer between November 2011 and October 2015 in excess of the $25,000 threshold for
reporting to the FDA. The primary comparisons of Chantix versus placebo and Zyban versus

7. IDRAC 232545
placebo for CAR 9-12 and CAR 9-24, and the secondary comparison of NRT versus placebo,
were statistically significant (p<0.001). All other pair-wise comparisons were also considered
statistically significant, except for Zyban versus NRT.
Table 3: NPS Events in Primary Analysis
and in Subset Excluding 32 Sites with Financial Involvement
Patient Cohort Chantix Zyban NRT Placebo
Non-PHx All sites
Excluding 32 sites
13/990
13/804
22/989
18/841
25/1,006
24/864
24/999
20/862
PHx All sites
Excluding 32 sites
67/1,026
65/887
68/1,017
68/896
53/1,016
51/900
50/1,015
49/899
As stated in the FDA Briefing Information (IDRAC 232400), these results were consistent with
Pfizer’s conclusion that Chantix was superior to Zyban, NRT, and placebo with respect to
smoking cessation. Zyban was also considered superior to placebo. Although the observed
rates for CAR 9-12 and CAR 9-24 were numerically lower in the PHx cohort (see Table 4),
there was no statistically significant interaction between treatment and cohort.
An FDA exploratory analysis addressed the possibility that some subjects had tried the study
drugs prior to EAGLES. If randomized to a drug they previously could not tolerate, subjects
would likely drop out and be considered non-responders. To explore the potential impact, the
FDA excluded those subjects and reanalyzed the data (the modified full analysis set [mFAS]).
Table 4 summarizes the primary comparisons (Chantix versus placebo; Zyban versus placebo)
and the secondary comparison (NRT versus placebo) when using the mFAS.
Table 4: Comparison of CAR 9-12 and CAR 9-24 in the mFAS Population
Cohort Chantix Zyban NRT Placebo Odds Ratio
C/P Z/P N/P
Overall:
CAR 9-12
CAR 9-24
31.9%
21.5%
22.8%
15.5%
22.1%
15.4%
12.5%
9.8%
3.39*
2.60*
2.09*
1.70*
1.98*
1.68*
Non-PHx:
CAR 9-12
CAR 9-24
34.9%
23.8%
26.2%
18.3%
26.5%
18.3%
14.3%
11.6%
3.33*
2.42*
2.14*
1.70*
2.16*
1.68**
PHx:
CAR 9-12
CAR 9-24
28.6%
19.0%
19.3%
12.6%
17.5%
12.3%
10.6%
7.8%
3.45*
2.78*
2.04*
1.70**
1.82*
1.68**
*P-value <0.001; **P-value <0.05
C/P = Chantix/placebo; Z/P = Zyban/placebo; N/P = NRT/placebo
Results indicated that Chantix, Zyban, and NRT were all superior to placebo for smoking
cessation, P-value <0.05. There was no statistically significant interaction between treatment
and cohort. Observed rates and estimated odds ratios for CAR 9-24 were lower than for CAR 9-
12. Excluding sites that reported financial involvement with Pfizer did not change conclusions.
Data from Observational Studies
The FDA asked the committees to consider how to weigh evidence from observational studies.
Following a search of the National Library of Medicine’s PubMed database on June 17, 2016,
the FDA reviewed studies that 1) reported the relative risk of NPS events between any of the 3
study treatments, 2) used an adequate design to differentiate temporal relationships between
drug exposure and outcomes, and 3) attempted to account for baseline group differences.
The FDA Briefing Information (IDRAC 232400) summarizes the review and identifies several
limitations to the studies, including concerns about the validity of outcome measures,
channeling bias and residual confounding, and other design/methodological issues. NPS safety
should be assessed base on the totality of data, according to the FDA; existing observational
data alone are insufficient for confirming or refuting increased NPS risk with Chantix or Zyban.
Market Issues
At this meeting the PDAC and DSRMAC considered whether phase 4 trial data and other safety
information sufficed to justify removing boxed warnings from 2 smoking cessation aids: Pfizer’s

8. IDRAC 232545
Chantix (IDRAC 231526) (varenicline) and GSK’s Zyban (IDRAC 228906) (bupropion
hydrochloride). The EAGLES trial compared the efficacy and NPS safety of the 2 drugs versus
NRT and placebo. Varenicline, bupropion hydrochloride, and NRT are the only FDA-approved
prescription products specifically indicated as aids to smoking cessation.
Nicotine replacement products are available in a variety of formulations. There are multiple
brands of over-the-counter (OTC) NRTs, sold in gum, lozenge, and patch formulations.
Prescription-only nicotine replacement products are available only under the brand name
Nicotrol and are available as a nasal spray and an oral inhaler [Nicotrol (IDRAC 151688),
Pharmacia & Upjohn Company].
A phase 3 trial by McGill University (Canada) is investigating the efficacy of e-cigarette use for
smoking cessation. The 3-arm trial is evaluating the efficacy of nicotine e-cigarette use +
counseling, non-nicotine e-cigarette use + counseling, and behavioral counseling alone. The
primary outcome measure is the number of subjects at 52 weeks who self-report smoking
abstinence for the previous 7 days. A phase 3 trial by the University of Auckland (New
Zealand) is also evaluating the efficacy of e-cigarettes, but is combining their use with both
behavioral support and the nicotine patch.
Brainsway is conducting a phase 3 trial evaluating the safety and efficacy of deep transcranial
magnetic stimulation (DTMS) as an aid to smoking cessation. According to Brainsway, the
DTMS coil is designed to enable deeper brain stimulation than standard TMS, without inducing
a significant increase of electric fields in superficial cortical regions. The trial compares DTMS
to treatment with a sham coil that has no treatment effect on the brain. The primary outcome
measure is continuous quit rate, described as abstinence during a consecutive 4-week period.
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