FDA Briefing Document Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and ...

276 Pages·2012·15.46 MB·English

FDA Briefing Document

Joint Meeting of the Arthritis Advisory Committee and
the Drug Safety and Risk Management Advisory
Committee

April 24 and 25, 2018

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Risk Management Advisory Committee
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 supplemental
new drug application (sNDA) 020998/S-050, Celebrex (celecoxib) capsules, submitted by
Pfizer, Inc., 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 Arthritis Advisory Committee and the Drug Safety and Risk Management
Advisory Committee

April 24-25, 2018

Briefing Materials

Table of Contents

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

Integrated Summary Memorandum – (PRECISION review team) 8

Attachments:

Discipline Reviews
A. Clinical Pharmacology

a. ibuprofen-aspirin and celecoxib-aspirin drug interaction studies
(Dr. Hariharan) 114

b. naproxen-aspirin drug interaction studies (Dr. Dunnmon) 142

B. Epidemiology

a. Division of Epidemiology II – Literature update (Dr. Pratt) 178

b. Division of Epidemiology II – Director memo 2015 (Dr. Staffa) 194

Examples of current labeling

A. Prescription
a. Celebrex (celecoxib) 199
b. naproxen 220
c. ibuprofen-oral formulation 243

B. Over-the-counter (OTC) 262

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FDA CENTER FOR DRUG EVALUATION AND RESEARCH
DIVISION OF ANESTHESIA, ANALGESIA, AND ADDICTION PRODUCTS

Division Director MEMORANDUM

DATE: March 27, 2018

FROM: Sharon Hertz, MD
Director
Division of Anesthesia, Analgesia, and Addiction Products
Office of Drug Evaluation II, CDER, FDA

RE: Overview of the April 24-25, 2018 Joint meeting of FDA’s
Arthritis Advisory Committee and Drug Safety and Risk
Management Advisory Committee

Following emergence of new data about the risk of cardiovascular (CV) thromboembolic
events associated with the cyclooxygenase-2 (COX-2) selective non-steroidal anti-
inflammatory drugs (NSAIDs), rofecoxib and celecoxib, a joint advisory committee
meeting of the Arthritis Advisory Committee (AAC) and the Drug Safety and Risk
Management Advisory Committee (DSaRM) was held in February 2005. During the
2005 meeting, data from clinical outcome trials and epidemiology studies of several
individual NSAIDs were reviewed, and the committee discussed the risk of CV
thromboembolic events associated with the use of both COX-2 selective and nonselective
NSAIDs. Based on the data reviewed and the deliberations of the advisory committee
members, FDA concluded that the risk for CV thromboembolic events was present for
both COX-2 selective NSAIDs and nonselective NSAIDs, and the data available at the
time did not permit rank ordering of the drugs regarding CV risk.1

In 2006, a large randomized controlled trial (RCT) intended to evaluate cardiovascular
(CV) thrombotic risk called “Prospective Randomized Evaluation of Celecoxib
Integrated Safety vs. Ibuprofen or Naproxen” (PRECISION) was initiated after Pfizer
agreed to conduct a postmarketing commitment to evaluate the CV thrombotic risk of
celecoxib requested by the Agency. It was a randomized, double-blind, active-
controlled, parallel-group study of CV safety in osteoarthritis or rheumatoid arthritis
patients with or at high risk for CV disease comparing celecoxib with naproxen and
1http://wwwfda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvid
ers/ucm106201.pdf
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ibuprofen. The trial had originally been anticipated to be completed by December 2013;
however, event accrual occurred more slowly than anticipated.

While the PRECISION trial was under way, numerous epidemiological studies and meta-
analyses of RCTs were conducted examining the relationship between NSAID use and
CV thrombotic risk, including identifying risk factors for the adverse event. In February
2014, a joint meeting of the Arthritis Advisory Committee (AAC) and Drug Safety and
Risk Management Advisory Committee (DSaRMAC) discussed data from the
epidemiological studies and meta-analyses of RCTs examining the risk of cardiovascular
(CV) thromboembolic events associated with the use of NSAIDs published after the
February 2005 joint advisory committee meeting.

Following internal Agency discussion and consideration of the 2014 AC discussion, as
well the revision of a class labeling template for the NSAIDs, a Safety Labeling Change
was required for the NSAID class in July 2015 to incorporate the information drawn from
the published epidemiological studies and meta-analyses, and the AC discussion.

The highlights of the labeling changes related to CV thrombotic risk required for the
NSAID class follow below:

• The risk of heart attack or stroke can occur as early as the first weeks of
using an NSAID. The risk may increase with longer use of the NSAID.
• The risk appears greater at higher doses.
• It was previously thought that all NSAIDs may have a similar risk. Newer
information makes it less clear that the risk for heart attack or stroke is
similar for all NSAIDs; however, this newer information is not sufficient
for FDA to determine that the risk of any particular NSAID is definitely
higher or lower than that of any other particular NSAID.
• NSAIDs can increase the risk of heart attack or stroke in patients with or
without heart disease or risk factors for heart disease. A large number of
studies support this finding, with varying estimates of how much the risk
is increased, depending on the drugs and the doses studied.
• In general, patients with heart disease or risk factors for it have a greater
likelihood of heart attack or stroke following NSAID use than patients
without these risk factors because they have a higher risk at baseline.
• Patients treated with NSAIDs following a first heart attack were more
likely to die in the first year after the heart attack compared to patients
who were not treated with NSAIDs after their first heart attack.
• There is an increased risk of heart failure with NSAID use.

The labeling required in the Safety Labeling Change notification letter was approved in
May 2016 for the entire NSAID class.

The results of the PRECISION trial were published in the New England Journal of
Medicine in November 2016, and the full clinical study report of the trial was submitted
to FDA in June 2017. The primary aim of the PRECISION trial was to assess the CV risk
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of celecoxib compared to naproxen and ibuprofen in a population of osteoarthritis and
rheumatoid arthritis patients with CV disease (CVD) or risk factors for CVD. The
primary Antiplatelet Trialists’ Collaboration (APTC) endpoint of PRECISION was an
independently adjudicated composite of cardiovascular (CV) death, non-fatal myocardial
infarction (MI), or non-fatal stroke. The primary hypothesis tested in PRECISION was
that celecoxib was non-inferior to naproxen for the APTC endpoint. Hypotheses also
tested were whether celecoxib was non-inferior to ibuprofen, and whether ibuprofen was
non-inferior to naproxen for the APTC endpoint.

With the focus on a patient population enriched for CVD, about 45% of the study
population were taking cardioprotective doses of aspirin. Because ibuprofen and
naproxen both act as reversible inhibitors of cyclooxygenase-1 (COX-1), they can
interfere with aspirin’s antiplatelet activity (due to irreversible inhibition of COX-1). The
NSAID interactions with aspirin had potential clinical implications on the occurrence of
the primary study outcome of the APTC composite CV endpoint (non-fatal myocardial
infarction [MI], non-fatal stroke, CV Death). Drug interaction studies conducted for each
of the studied NSAIDs with aspirin will be reviewed as part of the AC meeting, so that
these interactions can be considered during the interpretation of the trial results.

The Committees will be asked to consider the following discussion topics on April 24-25,
2018:

PRECISION trial
1. Discuss evidence from the PRECISION trial that supports cardiovascular safety
for celecoxib.
2. Discuss limitations of the PRECISION trial including, but not limited to, the
comparability of the dosing regimens that may interfere with interpretability of
the cardiovascular outcome results.
3. Has the PRECISION trial demonstrated cardiovascular safety for celecoxib
comparable to naproxen and ibuprofen?
4. Discuss how you interpret the secondary and tertiary endpoints of the trial given
how they were clinically defined and that there was not a pre-specified
hierarchical statistical testing plan.

Aspirin-NSAID interaction
1. Discuss whether there is a clinically significant interaction between aspirin and
celecoxib? Aspirin and ibuprofen? Aspirin and naproxen?
2. Is there a patient population (e.g., patients with recent MI, revascularization, stent
placement) for whom the risks of an aspirin-NSAID interaction outweigh the
benefits of the NSAID?
3. Based on the available data, does the interaction between aspirin and each the
NSAIDs studied warrant a contraindication for vulnerable populations (e.g.,
patients with recent MI, revascularization, stent placement)?
4. For over-the-counter (OTC) naproxen and ibuprofen products, the committees
will be asked to discuss:
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a. Whether the Drug Facts label should warn that naproxen may decrease the
cardiovascular event prevention benefit of aspirin
b. Whether consumers who take aspirin for cardiovascular event prevention
should not concomitantly take naproxen
c. Whether consumers who take aspirin for cardiovascular event prevention
should not concomitantly take ibuprofen

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Integrated Summary Memorandum
Joint meeting of FDA’s Arthritis Advisory Committee and Drug Safety and Risk
Management Advisory Committee – April 24-15, 2018

Division of Anesthesia, Analgesia, and Addiction Products
Office of Drug Evaluation II
Center for Drug Evaluation and Research Food and
Drug Administration

Drug Celebrex (celecoxib)
NDA# 20998, supplement 050
Safety Issue Name Cardiovascular thrombotic risk
PRECISION review team Division of Anesthesia, Analgesia, and Addiction Products
 Drs. Pokrovnichka, Lloyd, Racoosin, Darkwah
Divisio n of Biostatis tics V II
 Drs. Li, Andraca-Carreras
Division of Biostatistics II
 Dr. Petullo
Division of Non-Prescription Products
 Drs. Kelty, V. Pratt
Division of Cardiorenal Products
 Drs. McDowell, Smith, Rose
Division of Clinical Pharmacology I
 Dr. Hariharan
Division of Epidemiology II
 Drs. N. Pratt, Falconer, Mistry, Mathew, Chai
Office of Scientific Investigation
 Drs. Green, Kronstein

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The mechanism of action of NSAIDs is the inhibition of prostaglandin synthesis.1 Prostaglandins
are involved in inflammation, pain, fever, and blood clotting. NSAIDs suppress the production of
prostaglandins by inhibiting enzymes needed for prostaglandin biosynthesis called
cyclooxygenases (COX). The COX enzymes play a key role in the production of prostaglandins
by converting arachidonic acid to prostaglandin H (PGH2), which is metabolized by specific
2
isomerases to tissue-specific prostanoids – prostacyclin (PGI ), thromboxane (TXA ),
2 2
prostaglandin D (PGD ), prostaglandin E (PGE ), and prostaglandin F (PGF ) [Figure 1].
2 2 2 2 2 2
NSAIDs inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) to varying
degrees.2, 3, 4 Inhibition of COX-1 by NSAIDs prevents the formation of thromboxane from the
arachidonic acid derivative prostaglandin H2, and thereby prevents thromboxane-induced
platelet aggregation. The inhibition of COX-2 is thought to mediate the antipyretic, analgesic,
and anti-inflammatory actions of NSAIDs.5 Most NSAIDs are competitive, reversible inhibitors
of the COX enzymes. However, aspirin acetylates the isoenzymes and inhibits them irreversibly.
Figure 1: The Cyclooxygenase Pathway
Source: Profit and Chrisp 2007
1 Vane J, 1971, Inhibition of Prostaglandin Synthesis as a Mechanism of Action for Aspirin-like Drugs, Nat New
Biol, 231(25):232-235.
2 Grosser T, Smyth E, FitzGerald G. Pharmacotherapy of Inflammation, Fever, Pain, and Gout. In: Brunton LL,
Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New
York, NY: McGraw-Hill. http://accessmedicinemhmedical.com/content.aspx?bookid=2189&sectionid=170271972 .
Accessed January 19, 2018.
3 Patrono C, Coller B, FitzGerald G, et al, 2004, Platelet-Active Drugs: The Relationships Among Dose,
Effectiveness, and Side Effects: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy,
Chest, 126(3 Suppl):234S-264S.
4 Renda G, Tacconelli S, Capone M, et al, 2006, Celecoxib, Ibuprofen, and the Antiplatelet Effect of Aspirin in
Patients with Osteoarthritis and Ischemic Heart Disease, Clin Pharmacol Ther, 80:264-74.
5 Grosser T, Smyth E, FitzGerald G. Pharmacotherapy of Inflammation, Fever, Pain, and Gout. In: Brunton LL,
Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New
York, NY: McGraw-Hill. http://accessmedicinemhmedical.com/content.aspx?bookid=2189&sectionid=170271972 .
Accessed January 19, 2018.
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