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

398 Pages·2014·14.44 MB·English

FDA Briefing Document

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

October 16, 2014

Chantix and Serious Neuropsychiatric Adverse Events

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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 varenicline and the risk of serious
neuropsychiatric adverse events 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

Chantix and Serious Neuropsychiatric Adverse Events
October 16, 2014

Briefing Materials
Table of Contents

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

DAAAP Integrated Summary Memorandum (Dr. Racoosin) 7

Attachments:
1- Postmarketing Requirement Randomized Controlled Trial: Protocol (Pfizer) 26

2- Drug Utilization Review (Dr. Gill) 143

3- Pharmacovigilance Review: Neuropsychiatric Adverse Events Update -2014 (Dr. 156
Pollock)

4- Provision of Pharmacovigilance Data: Neuropsychiatric Adverse Events -2014 (Dr. 185
Pollock)

5- Pharmacovigilance Review: Smoking Cessation Therapies and Suicidality – 2008 192
(Dr. Pollock)

6- Pharmacovigilance Review: Smoking Cessation Therapies and Psychiatric Events 262
(excluding suicidality) – 2008 (Dr. Pollock)

7- Epidemiology Review (Dr. Chen) 326

8- Statistical Review (Dr. Andraca-Carrera) 345

9- Chantix Proposed Labeling and Medication Guide – Submitted April 8, 2014 (Pfizer) 369

10- Chantix Approved Labeling and Medication Guide – September 19, 2014 (Pfizer) 384

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

MEMORANDUM

Date: September 22, 2014

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

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

To: Chair, Members, and Invited Guests

Re: Overview of the October 16, 2014 Joint Meeting of the Psychopharmacologic
Drugs Advisory Committee and Drug Safety and Risk Management Advisory
Committee Meeting

In April 2014, Pfizer submitted a labeling supplement for varenicline (Chantix, NDA 21-928)
proposing changes to the varenicline labeling relating to the risk of serious neuropsychiatric
adverse events. In the cover letter of this supplement, Pfizer asserted that, “…since 2009, more
reliable data on the NPS [neuropsychiatric] safety of Chantix have become available, including
meta-analyses of placebo-controlled clinical trials and data from observational studies comparing
varenicline to other smoking cessation pharmacotherapies. As presented in this submission, these
data do not support an association between treatment with Chantix and serious NPS
[neuropsychiatric] events.”

Based on Pfizer-conducted meta-analyses of randomized controlled trials of varenicline and a
Pfizer-conducted review of five publications of observational studies of patients treated with
varenicline compared to patients treated with nicotine replacement therapy (NRT) or bupropion,
Pfizer proposed implementing the following major changes to the varenicline labeling (see
Attachment 9 for the specific Pfizer-proposed changes):
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• Highlights of Prescribing Information:
o Remove Boxed Warning on Serious Neuropsychiatric Events
o Under Warnings and Precautions, add a Warning on Serious Neuropsychiatric
Events in bolded font
• BOXED WARNING section of the Full Prescribing Information (FPI):
o Remove the box (i.e., remove the single black line) around the Warning on
Serious Neuropsychiatric Events and add summaries of information from
neuropsychiatric meta-analyses of clinical trial data and observational studies
• WARNINGS AND PRECAUTIONS section of the FPI
o In section 5.1 WARNINGS AND PRECAUTIONS / Neuropsychiatric Symptoms
and Suicidality, add information from neuropsychiatric meta-analyses of clinical
trial data and observational studies

The original signal for serious neuropsychiatric adverse events came from cases reported to the
FDA and described in the medical literature. In this supplement, Pfizer contends that the
information garnered from the meta-analyses they conducted and the published observational
studies they have reviewed is reassuring and trumps the information culled from the case reports
that originally led to the Boxed Warning and Warnings and Precautions statements in varenicline
labeling, and that the sum of this new evidence no longer supports the need for a boxed warning
for serious neuropsychiatric adverse events.

As summarized in the reviews included in this briefing package, the Agency’s review team,
including statisticians and epidemiologists, evaluated the validity of the findings from Pfizer’s
meta-analyses and the published observational studies. The limitations of the findings described
in each of the reviews raise questions as to how to best interpret the findings of the meta-
analyses and observational studies.

Based on FDA’s review of the meta-analyses and observational studies submitted by Pfizer,
FDA has determined that some information about these data could be included in the varenicline
labeling (Attachment 10, section 5.1), in order for prescribers to have a full picture of what
analyses and studies have been conducted to enhance the understanding of varenicline-associated
serious neuropsychiatric adverse events.

However, the determination of whether to remove a boxed warning is a decision for which there
is limited precedent. FDA believes that the randomized controlled trial prospectively designed to
evaluate the risk of serious neuropsychiatric adverse events with varenicline, whose final study
report is expected in a year, should be reviewed and considered as part of such a regulatory
action. However, because Pfizer believes the collection of observational and meta-analytic data
are alone sufficient, we are bringing this issue to the Committee for discussion.

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 effects the understanding of the risk of serious
neuropsychiatric adverse events with varenicline, and how that may be communicated in
labeling.
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Draft Topics for Discussion:

1. What conclusions can be drawn about the risk of serious neuropsychiatric adverse
events with varenicline from the meta-analysis results?

2. What conclusions can be drawn about the risk of serious neuropsychiatric adverse
events with varenicline from the observational studies?

3. How do the meta-analyses and observational studies help in your understanding of the
risk of serious neuropsychiatric adverse events with varenicline?

4. Based on the data presented on the risk of serious neuropsychiatric adverse events with
varenicline, what would you recommend:

a) Removal of the boxed warning?

b) Modification of the language in the boxed warning?

c) Wait until the completion of the postmarketing randomized controlled trial to reassess
the need for the boxed warning?

Please explain the rationale for your answer, and discuss any additional actions you think the
Agency should take regarding the risk of serious neuropsychiatric adverse events with
varenicline.

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Varenicline and the Risk of Serious Neuropsychiatric
Adverse Events

October 16, 2014

Integrated Summary Memorandum

Table of Contents
Introduction ......................................................................................................................... 2
Regulatory History .............................................................................................................. 4
AERS Reviews- 2008 ..................................................................................................... 4
Risk Evaluation and Mitigation Strategy (REMS)/ Postmarketing Requirement (PMR)
Clinical Trial ................................................................................................................... 6
Regulatory Requirements and Guidance Recommendations for the BOXED WARNING
Section and Other Relevant Sections of the Labeling ........................................................ 9
Prescribing Information .................................................................................................. 9
Adverse Reactions .......................................................................................................... 9
Boxed Warning ............................................................................................................... 9
Removal of a Boxed Warning....................................................................................... 10
Warnings and Precautions............................................................................................. 10
Contraindications .......................................................................................................... 11
Usage of Smoking Cessation Prescription Products ......................................................... 12
Update on Reporting of Neuropsychiatric Adverse Events to FAERS ............................ 13
Division of Epidemiology II Summary of Observational Studies Examining the
Relationship Between Varenicline and Neuropsychiatric Adverse Events ...................... 14
Division of Biostatistics VII Summary of Meta-analyses ................................................ 17
Discussion/ Interim actions ............................................................................................... 19

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Introduction

Varenicline, a partial α4β2 acetylcholine nicotinic receptor agonist, was approved in May
2006 in the United States “as an aid to smoking cessation treatment.” Varenicline’s
approval was based on six placebo- and active-controlled trials of 6 to 12 weeks duration
in over 3500 chronic cigarette smokers (average 21 cigarettes per day and average
smoking history of 25 years).

Varenicline’s original approved labeling included a listing of the following
neuropsychiatric adverse events in the ADVERSE REACTIONS section: insomnia,
abnormal dreams, and nightmares. As information about serious neuropsychiatric
adverse events emerged in the postmarketing period, the varenicline labeling evolved to
incorporate this information:

• January 2008: Based on data from spontaneous postmarketing reports of serious
neuropsychiatric adverse events, FDA determined that varenicline was associated
with serious neuropsychiatric adverse events including suicidal ideation, suicidal
behavior, changes in behavior, agitation, depressed mood, and worsening of
preexisting psychiatric illness. A new warning was added to the WARNINGS
section describing these serious neuropsychiatric adverse events; and
recommendations were added for patients, their families, and caregivers to
monitor for these serious neuropsychiatric adverse events during varenicline
treatment.

• May 2008: FDA utilized two postmarketing safety authorities acquired under the
FDA Amendments Act of 2007. FDA required Pfizer to implement a Risk
Evaluation and Mitigation Strategy (REMS) to ensure that the benefits of
varenicline as an aid to smoking cessation outweighed its risk of serious
neuropsychiatric adverse events. The REMS required a Medication Guide to
ensure varenicline-treated patients are aware of the risk of serious
neuropsychiatric adverse events. Additionally, FDA issued a postmarketing
requirement (PMR) to Pfizer to conduct a randomized controlled trial to assess the
risk of serious neuropsychiatric adverse events with varenicline.

• July 2009: A BOXED WARNING section was added to the varenicline labeling
that described information already included in the WARNINGS section
concerning the serious neuropsychiatric adverse events and recommendations to
patients and their caregivers to discontinue varenicline if these serious
neuropsychiatric adverse events occurred. Furthermore, the WARNINGS section
was updated to include additional varenicline-associated serious neuropsychiatric
adverse events including hostility, mania, psychosis, hallucinations, and paranoia.

In April 2014, Pfizer submitted a labeling supplement for varenicline (Chantix, NDA 21-
928) proposing changes to the varenicline labeling relating to the risk of serious
neuropsychiatric adverse events. In the cover letter of this supplement, Pfizer asserts that,
“…since 2009, more reliable data on the NPS [neuropsychiatric] safety of Chantix have
become available, including meta-analyses of placebo-controlled clinical trials and data
2

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from observational studies comparing varenicline to other smoking cessation
pharmacotherapies. As presented in this submission, these data do not support an
association between treatment with Chantix and serious NPS [neuropsychiatric] events.”

Based on Pfizer-conducted meta-analyses of randomized controlled trials of varenicline
and a Pfizer-conducted review of five publications of observational studies of patients
treated with varenicline compared to patients treated with nicotine replacement therapy
(NRT) or bupropion, Pfizer proposed the following major changes to the varenicline
labeling:

• Highlights of Prescribing Information:
o Remove Boxed Warning on Serious Neuropsychiatric Events
o Under Warnings and Precautions, add a Warning on Serious
Neuropsychiatric Events in bolded font
• BOXED WARNING section of the Full Prescribing Information (FPI):
o Remove the box (i.e., remove the single black line) around the Warning on
Serious Neuropsychiatric Events and add summaries of information from
neuropsychiatric meta-analyses of clinical trial data and observational
studies
• WARNINGS AND PRECAUTIONS section of the FPI
o In section 5.1 WARNINGS AND PRECAUTIONS / Neuropsychiatric
Symptoms and Suicidality, add information from neuropsychiatric meta-
analyses of clinical trial data and observational studies

In the subsequent sections of this briefing document, the following is provided:

• Regulatory history leading to the boxed warning, REMS, and PMR for serious
neuropsychiatric adverse events;
• Regulatory requirements and guidance recommendations for BOXED
WARNING section and other relevant sections of the labeling;
• Utilization data for varenicline and other smoking cessation treatments;
• Update on neuropsychiatric adverse events reported to FAERS;
• Summary of FDA review of epidemiological studies cited by Pfizer; and
• Summary of FDA review of RCT meta-analyses submitted by Pfizer

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Regulatory History

Chantix® (varenicline) 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.

In May 2007, the European Medicines Agency (EMA- previously, EMEA) informed
FDA that they were investigating a signal of suicidality-related adverse events. A
chronology of the subsequent regulatory actions and public communications that
followed is shown below.

May 2006 NDA approval for varenicline in the U.S. (trade name “Chantix”)
September 2006 Approval in the European Union (trade name “Champix”)
May 2007 European Medicines Agency informed FDA that they were
investigating a signal of suicidal-related events with varenicline and
had asked Pfizer to submit a postmarketing suicidal-event analysis.
Nov 2007 Information added to ADVERSE REACTIONS section of labeling;
Early communication of an ongoing safety review
Jan 2008 Serious neuropsychiatric adverse events information upgraded to the
WARNINGS AND PRECAUTIONS section of the labeling
Feb 2008 Public health advisory issued
April 2008 Center Director briefing concerning varenicline and serious
neuropsychiatric adverse events: discussed the benefits of varenicline
to help patients achieve smoking cessation vs. the risk of serious
neuropsychiatric adverse events
May 2008 Added MedGuide-only REMS; issued a postmarketing required study/
clinical trial;
Updated public health advisory;
FAA bans use of varenicline by pilots and air traffic controllers
July 2009 Added BOXED WARNING section to varenicline and bupropion
labeling;
Public health advisory issued regarding addition of boxed warning to
both varenicline and bupropion
Oct 2011 Drug Safety Communication issued reporting the results of two FDA-
sponsored epidemiology studies that evaluated the risk of serious
neuropsychiatric adverse events associated with varenicline

AERS Reviews- 2008

Prior to the addition of the boxed warning for serious neuropsychiatric adverse events,
the Division of Adverse Event Analysis II1 completed two reviews of AERS2 cases- one

1 The Division of Adverse Event Analysis II is now called the “Division of Pharmacovigilance II”.
2 The FDA Adverse Events Reporting System was called “Adverse Event Reporting System (AERS)” at
the time these reviews were done.
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