FDA Briefing Document Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and ...

564 Pages·2016·16.41 MB·English

FDA Briefing Document

Joint Meeting of the Psychopharmacologic Drugs Advisory
Committee and Drug Safety and Risk Management
Advisory Committee

September 14, 2016

Serious Neuropsychiatric Adverse Events with Drugs for Smoking
Cessation

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DISCLAIMER STATEMENT

The attached package contains background information prepared by the Food and Drug
Administration (FDA) for the panel members of the advisory committee. The FDA background
package often contains assessments and/or conclusions and recommendations written by
individual FDA reviewers. Such conclusions and recommendations do not necessarily represent
the final position of the individual reviewers, nor do they necessarily represent the final position
of the Review Division or Office. We have brought the FDA-required postmarketing trial which
evaluated neuropsychiatric adverse effects in patients randomized to Chantix (varenicline),
Zyban (bupropion), nicotine replacement therapy or placebo, along with relevant published
observational studies, to this Advisory Committee in order to gain the Committee’s
insights and opinions, and the background package may not include all issues relevant to the
final regulatory recommendation and instead is intended to focus on issues identified by the
Agency for discussion by the advisory committee. The FDA will not issue a final determination
on the issues at hand until input from the advisory committee process has been considered and all
reviews have been finalized. The final determination may be affected by issues not discussed at
the advisory committee meeting.

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Food and Drug Administration
Center for Drug Evaluation and Research

Joint Meeting of the Psychopharmacologic Drugs Advisory Committee
and Drug Safety and Risk Management Advisory Committee

Serious Neuropsychiatric Adverse Events with Drugs for Smoking Cessation

September 14, 2016

Briefing Materials
Table of Contents

Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) Overview of the Points to
Consider 4

DAAAP Integrated Summary Memorandum 7

Attachments:

1- Epidemiology Review 109
2- Statistical Evaluation of Observational Studies 152
3- Pharmacovigilance Review: Neuropsychiatric Adverse Events Update 2011-2015 163
4- Drug Utilization Review 187
5- Postmarketing Required Randomized Controlled Trial: Protocol 203
6- Chantix Proposed Labeling and Medication Guide – Submitted February 18, 2016 (Pfizer) 442
7- Chantix Approved Labeling and Medication Guide – October 15, 2014 (Pfizer) 460
8- Zyban Approved Labeling and Medication Guide 475
9- Nicotine Patch Drug Facts Labeling 519
10- FDA Background Package from 2014 Advisory Committee Meeting 523
11- Summary Minutes from the 2014 Advisory Committee Meeting 545
12- Guidance for Industry: Warnings and Precautions, Contraindications, and Boxed Warning
Section of Labeling for Human Prescription Drug and Biological Products-Content and Format 550

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Food and Drug Administration
CENTER FOR DRUG EVALUATION AND RESEARCH
Division of Anesthesia, Analgesia, and Addiction Products

MEMORANDUM

Date: August 9, 2016

From: Judith A. Racoosin, MD, MPH
Deputy Director for Safety
Division of Anesthesia, Analgesia, and Addiction Products
Office of Drug Evaluation II, CDER, FDA

Rigoberto Roca, MD
Deputy Division Director
Division of Anesthesia, Analgesia, and Addiction Products
Office of Drug Evaluation II, CDER, FDA

To: Chair, Members, and Invited Guests

Re: Overview of the September 14, 2016 Joint Meeting of the Psychopharmacologic
Drugs Advisory Committee and Drug Safety and Risk Management Advisory
Committee Meeting

Varenicline, marketed by Pfizer as Chantix in the US and Champix globally, is a partial α4β2
acetylcholine nicotinic receptor agonist approved in May 2006 as an aid to smoking cessation.
The treatment regimen is 1 mg twice daily for 12 weeks (with an initial one-week titration). A
second 12-week course may be taken to increase the chance of maintenance of abstinence.

Bupropion HCl is an aminoketone antidepressant originally approved under the proprietary name
Wellbutrin. As an antidepressant, Wellbutrin is thought to act primarily via noradrenergic
mechanisms, but also has some dopaminergic activity. Its mechanism of action as an aid to
smoking cessation is not known. The new drug application (NDA) for Bupropion HCl Sustained
Release Tablets (marketed by GSK under the proprietary name Zyban for this indication) was
approved in May 1997. The treatment regimen is 150 mg twice daily for 7-12 weeks (with an
initial three-day titration).

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Based on postmarketing adverse event reports, both Chantix and Zyban labeling carry boxed
warnings regarding the risk of serious neuropsychiatric events. In 2008, using the postmarketing
safety authorities included in the FDA Amendments Act of 2007, FDA imposed a post marketing
requirement (PMR), which required Pfizer and GSK to conduct a placebo-controlled
postmarketing safety trial to further characterize the risk of neuropsychiatric adverse events and
to evaluate whether a prior history of psychiatric illness was a risk modifier. Because patients
with a history of psychiatric illness did not participate in the initial clinical efficacy trials that
supported approval of the NDA, it was also important to ascertain whether the medications were
effective in these patients, in order to understand the balance of risks and benefits. An active
comparator of transdermal nicotine was included in the clinical trial design to determine whether
nicotine replacement, another pharmacologic option for treating tobacco dependence, offers any
advantage or disadvantage with respect to neuropsychiatric effects.

This PMR trial has now been completed. The background document that accompanies the
background package describes in detail FDA’s review of the study design and results, as well as
sensitivity analyses conducted by FDA review staff. As is conveyed in the background
document, and will be discussed at the advisory committee meeting, FDA has identified
concerns with the ascertainment of the primary neuropsychiatric adverse event outcome that
impacts interpretation of the trial results. In brief, the interview tools that were developed to
optimally capture the neuropsychiatric adverse events of concern were not utilized to the extent
intended to get a nuanced understanding of such adverse events. In some cases, lack of
information about the circumstances of events limited FDA’s ability to determine whether they
were primary outcome events. Additionally, there was substantial variability among investigators
in how the adverse event severity was coded and how the adverse event terms were applied,
leading to variability in the number of neuropsychiatric adverse events included in the primary
outcome. Finally, there was inconsistency in how suicidality cases were handled, with the
Columbia Suicide Severity Rating Scale (C-SSRS) results not being reconciled with the adverse
event reporting. All of these factors likely served to lower the overall number of primary
outcome events, which may result in biasing towards a null finding. FDA conducted some
sensitivity analyses to try and address some of the concerns raised by these ascertainment issues.

The background document and package also include relevant information on observational
studies of neuropsychiatric adverse events with smoking cessation products, pharmacovigilance
information on the smoking cessation products, and drug utilization information.

The Division and Agency are grateful for your participation in this important meeting and for
providing your expertise and insight. We thank you in advance for your advice which will assist
us in determining how the new evidence affects the understanding of the risk of serious
neuropsychiatric adverse events with smoking cessation products, and how that may be
communicated in labeling.

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Draft topics for Discussion

1. Discuss the strengths and weaknesses of the completed randomized controlled trial
(RCT) with regard to the study design including the novel primary endpoint.

2. Discuss the potential impact of the variability in data collection, adverse event coding,
and application of the case definition on ascertainment of the primary endpoint. Because
of this variability, discuss which analysis and results most appropriately describe the
effect of the smoking cessation therapies on neuropsychiatric events.

3. Discuss how you weigh the evidence contributed by the observational studies when
evaluating the risk of serious neuropsychiatric adverse events in patients taking smoking
cessation products.

4. Based on the results of the clinical trial and observational studies, discuss the impact of
psychiatric history on the occurrence of neuropsychiatric adverse events during smoking
cessation therapy.

5. Based on the data presented on the risk of serious neuropsychiatric adverse events with
smoking cessation products, what would you recommend?

a. Remove the boxed warning statements regarding risk of serious neuropsychiatric
adverse events

b. Modify the language in the boxed warning

c. Keep the current boxed warning

6. Explain the rationale for your answer to #5, and discuss any additional labeling actions
you think the Agency should take regarding the risk of serious neuropsychiatric adverse
events with smoking cessation products.
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Serious Neuropsychiatric Adverse Events with Drugs for
Smoking Cessation

September 14, 2016

Integrated Summary Memorandum

1 Introduction and Background ....................................................................................... 5
1.1 Initial Postmarketing Safety Reviews .................................................................. 6
1.2 Risk Evaluation and Mitigation Strategy (REMS)/ Postmarketing Requirement
(PMR) Clinical Trial ........................................................................................................ 8
1.3 October 2014 Joint Meeting of the Psychopharmacologic Drugs Advisory
Committee and the Drug Safety and Risk Management Advisory Committee ............. 10
2 Clinical Pharmacology ............................................................................................... 12
2.1 Varenicline ......................................................................................................... 12
2.2 Bupropion ........................................................................................................... 13
2.3 Nicotine Transdermal System ............................................................................ 14
3 Post-Marketing Requirement Randomized Controlled Trial ..................................... 14
3.1 Overview and Objective ..................................................................................... 15
3.2 Study Design and Endpoints .............................................................................. 15
3.3 Inclusion/Exclusion Criteria ............................................................................... 16
3.4 Procedures .......................................................................................................... 20
3.4.1 Study Treatments .......................................................................................... 21
3.4.2 Behavioral Treatment.................................................................................... 23
3.4.3 Schedule of Study Procedures ...................................................................... 23
3.4.4 Study Endpoints ............................................................................................ 28
3.4.5 Statistical Analysis Plan (SAP) ..................................................................... 29
3.5 Population and Subject Disposition ................................................................... 30
3.6 Study Conduct .................................................................................................... 36
3.6.1 General Issues on Data Quality and Reviewability ...................................... 36
3.6.2 Data Reliability Issues .................................................................................. 38
3.6.3 Issues Related to Capture of NPS Events ..................................................... 40
3.7 Analysis of NPS Primary Endpoint .................................................................... 43
3.7.1 Analysis of the Primary Neuropsychiatric Event.......................................... 44
3.7.2 Composite Neuropsychiatric Event Including Only Severe Adverse Events 47
3.7.3 Composite NPS+ Event ................................................................................ 47
3.7.4 NPS Event by Study Sites ............................................................................. 48
3.7.5 Statistical Models to Account for Extra Binomial Variation between Sites . 50
3.7.6 Analysis of Deaths ........................................................................................ 51
3.7.7 Analysis of the C-SSRS Instrument .............................................................. 52
3.7.8 Effect of Smoking vs Abstinence ................................................................. 53
3.7.9 Impact of Financial Involvement .................................................................. 57
3.8 Analysis of Efficacy ........................................................................................... 60
3.9 Analysis of General Safety Data ........................................................................ 64
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3.10 Deaths ................................................................................................................. 65
3.11 Serious Adverse Events ...................................................................................... 67
3.12 Adverse Events Leading to Dose Reduction or Discontinuation ....................... 75
3.13 Common Adverse Events ................................................................................... 77
4 Observational Studies ................................................................................................. 78
5 Pharmacovigilance Review ........................................................................................ 91
6 Drug Utilization of Smoking Cessation Products ...................................................... 91
7 Discussion and Points for Consideration ................................................................... 91
8 APPENDIX A: Illustrative NPS Cases ...................................................................... 96
9 APPENDIX B: Common Adverse Events ................................................................. 98
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LIST OF TABLES

Table 1 Dosing Schedule (Protocol) ................................................................................. 21
Table 2 Schedule of Activities - Study Treatment Period ................................................ 24
Table 3 Schedule of Activities - Post Treatment Period ................................................... 25
Table 4 Summary of Baseline Characteristics (Non-PHx Cohort) – Safety Population .. 32
Table 5 Summary of Baseline Characteristics (PHx Cohort) – Safety Population... 33
Table 6 Summary of Baseline Psychiatric Characteristics (PHx Cohort) - FAS Population
........................................................................................................................................... 34
Table 7 Disposition in the Non-PHx Cohort..................................................................... 35
Table 8 Disposition in the PHx Cohort ............................................................................. 35
Table 9 Severe Treatment Emergent Neuropsychiatric Events by Cohort ....................... 47
Table 10 Treatment Emergent NPS + Events by Treatment and Cohort .......................... 48
Table 11 Deaths by Cohort and Treatment ....................................................................... 52
Table 12 Results of the C-SSRS in the Non-PHx Cohort – Treatment Emergent Events 53
Table 13 Results of the C-SSRS in the PHx Cohort – Treatment Emergent Events ........ 53
Table 14. NPS Events in Primary Analysis and in Subset Excluding 32 Sites with
Financial Involvement ...................................................................................................... 58
Table 15. NPS Events by Country and Financial Involvement, Pooled Across All
Treatments......................................................................................................................... 58
Table 16. Risk Difference of NPS Events in Primary Analysis and in Subset ................. 59
Table 17. NPS+ Events in All Sites and in Subset Excluding 32 Sites with Financial
Involvement ...................................................................................................................... 59
Table 18. Risk Difference of NPS+ Events in Primary Analysis and in Subset ............... 60
Table 19 Comparison of Continuous Abstinence Rates for Weeks 9-12 and Weeks 9-24 -
FAS Population ................................................................................................................. 61
Table 20 Number of Subjects in FAS and mFAS Datasets .............................................. 62
Table 21 Comparison of Continuous Abstinence Rates for Weeks 9-12 and Weeks 9-24 -
mFAS Population† ............................................................................................................ 62
Table 22. Exposure to Treatment, Non-PHx - Safety Population..................................... 64
Table 23 Exposure to Treatment, PHx - Safety Population .............................................. 65
Table 24 Fatal Adverse Events ......................................................................................... 67
Table 25 Treatment-Emergent SAE incidence by treatment and history of psychiatric
disease ............................................................................................................................... 67
Table 26 Description of 30 NPS SAEs ............................................................................ 69
Table 27 Patients with Treatment-Emergent Adverse Events Leading to Dose Reductions
or Discontinuations ........................................................................................................... 75
Table 28 Adverse Events Leading to Study Drug Reduction or Discontinuation in ≥1% in
Any Arm; Non-Phx Cohort ............................................................................................... 76
Table 29 Adverse Events Leading to Study Drug Reduction or Discontinuation in ≥1% in
Any Arm; PHx Cohort ...................................................................................................... 76
Table 30 Potential channeling bias in the Thomas et al. studya illustrated by their
findings of the all-cause mortality risk among varenicline users and bupropion users .... 90

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LIST OF FIGURES

Figure 1. Study Diagram .................................................................................................. 16
Figure 2. NPS Events in the Non-PHx ............................................................................ 44
Figure 3. NPS Events in the PHx Cohort ......................................................................... 45
Figure 4. Primary Analysis: Risk Difference of NPS Events by Cohort ......................... 46
Figure 5. Site Size and NPS Events in the Non-PHx Cohort........................................... 49
Figure 6. Site Size and NPS Events in the PHx Cohort ................................................... 50
Figure 7. Rate Ratio for NPS Events from a Negative Binomial Model ......................... 51
Figure 8. Primary NPS AE Endpoint – Smoking Status by Week and Onset of AE -
Non-Psychiatric History Cohort, Safety Population ......................................................... 55
Figure 9. Primary NPS AE Endpoint – Smoking Status by Week and Onset of AE -
Psychiatric History Cohort, Safety Population ................................................................. 55
Figure 10. Reviewer-generated forest plot of varenicline-associated neuropsychiatric
(NPS) risk observed in all reviewed studies (reference group: nicotine replacement
therapy,a,b,d,f bupropion,c or person-time that was unexposed to vareniclinee) ................. 88
Figure 11. Reviewer-generated forest plot of neuropsychiatric (NPS) risk observed in all
reviewed studies that examined both varenicline- and bupropion- associated riska,b ....... 89
Figure 12. .......................................................................................................................... 92
Figure 13. Nationally Estimated Number of Unique Patients Who Received Dispensed
Prescriptions for Smoking Cessation Products* from U.S. Outpatient Retail Pharmacies,
2006-2015 ......................................................................................................................... 93

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