Background Analysis: US FDA Advisory Committee Seeks Input on Safety Data from the Cardiovascular Outcomes Trial for Pfizer’s Celebrex – APR 24-25, 2018 (AAC/DSRM)

Announcement

The US FDA has scheduled a joint meeting of the Arthritis Advisory Committee (AAC) and the Drug Safety and Risk Management (DSRM) Advisory Committee for Tuesday to Wednesday, April 24-25, 2018. The Committees will review and provide input on safety data that were submitted by Pfizer, Inc. (Pfizer) in a supplemental new drug application (sNDA) for Celebrex (celecoxib) capsules. Celebrex is a nonsteroidal anti-inflammatory drug (NSAID) indicated for osteoarthritis (OA), rheumatoid arthritis (RA), juvenile rheumatoid arthritis in patients 2 years and older, ankylosing spondylitis, acute pain, and primary dysmenorrhea (label version dated May 2016).

Agenda

The Committees will review data from the PRECISION trial, a cardiovascular outcomes trial that compared celecoxib to ibuprofen and naproxen. The FDA is seeking input on whether the findings of the trial should change the Agency’s current understanding of the safety of these three NSAIDs, including interpreting drug interactions between the three drugs and aspirin in patients taking aspirin for secondary prevention of cardiovascular (CV) disease.

Clinical Trials of Proposed Indication

PRECISION was a non-inferiority trial of 24,081 patients, designed to assess the CV safety of celecoxib versus ibuprofen and naproxen in patients with chronic pain from OA or RA who were at high risk for CV disease. Results were announced by Pfizer in November 2016, Pfizer believes that the trial demonstrated similar rates of CV risk in patients treated with celecoxib, ibuprofen, and naproxen. The company also reported that patients treated with celecoxib experienced significantly fewer gastrointestinal (GI) events as compared with those receiving ibuprofen or naproxen. Pfizer has emphasized that it is important to note that the trial studied prescription doses and chronic use; therefore, no inferences are possible regarding the safety of intermittent use of low-dose, over-the-counter NSAIDs.

Results of the PRECISION trial were presented at an annual meeting of the American Heart Association by Dr. Steven Nissen, the principal investigator of the trial, and published in The New England Journal of Medicine (Dated November 13, 2016, Updated on December 2, 2016 at NEJM.org) and at ClinicalTrials.gov (ClinicalTrials.gov ID: NCT00346216).

Detailed safety results from the trial, including a review of data pertaining to drug interactions with aspirin, will be provided in FDA and company briefing materials that are post ahead of the meeting. These materials will be summarized on the day they are posted in our subsequent report, the Briefing Summary.

Regulatory Background

US Regulatory Background

NSAIDs: CV Safety and Drug Interactions with Aspirin

Starting in the year 2000, data emerged suggesting a potential CV risk for Vioxx (rofecoxib) and Celebrex (celecoxib), two cyclooxygenase-2 selective-type NSAIDs (COX-2 NSAIDs). In February 2005, the FDA convened a joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee (AAC/DSRM). At this meeting, data from clinical outcome trials and epidemiology studies of several non-aspirin NSAIDs were reviewed. The Committees 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 on the Committees’ deliberations, the FDA concluded that the risk for CV thromboembolic events was present for both COX-2 selective NSAIDs and nonselective NSAIDs, excluding aspirin. The FDA concluded that the available data did not permit rank-ordering of the drugs with regard to CV risk.

Subsequent to this meeting, in June 2005, the FDA sent a letter to all non-aspirin NSAID sponsors requesting that a Boxed Warning be added to labeling describing CV risk, as well as GI risks.

In October 2006, the PRECISION trial was initiated in response to a request by the FDA for Pfizer to obtain additional data describing the CV risk associated with celecoxib.

In February 2014, the FDA reconvened the AAC/DSRM to discuss data and analyses published in 2006 or later that were relevant to further understanding the relationship between NSAIDs and the CV thrombotic risk as described in non-aspirin NSAID class labeling. Subsequent to this meeting, in July 2015, the FDA requested  for sponsors of non-aspirin NSAIDs to again revise labeling, this time to include additional language that was intended strengthen the current warnings pertaining to CV risk.

In addition, at the February 2014 AAC/DSRM meeting, the Committees were asked to discuss if changes should be made to the ongoing PRECISION trial. The Committees did not suggest any changes. Furthermore, the Committees agreed that there is still clinical equipoise for the trial population targeted in PRECISION and stated there did not appear to be a need for re-consenting the participants. One Committee member stated that the risks for the PRECISION population are not limited to CV thrombotic events and the trial should help to provide insights into all of the different adverse events related to NSAIDs, and from this it may be possible to come up with some kind of composite risk and benefit profile in totality.

Regarding drug interactions for NSAIDS taken concomitantly with aspirin, current labeling (May 2016) for Celebrex states the following:

·      “There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as celecoxib, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)].” “NSAIDs, including CELEBREX, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

·      Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].

·      In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200–400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100–325 mg).

·      When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known

·      Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].

·      Concomitant use of CELEBREX and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].

·      Inform patients not to use low-dose aspirin concomitantly with CELEBREX until they talk to their healthcare provider [see Drug Interactions (7)].

In addition, the FDA has posted information at their website to inform consumers who are taking aspirin for heart attack prevention while also taking ibuprofen for pain relief that ibuprofen may interfere with the benefits of aspirin for the heart. The FDA states, “It is all right to use them together, but the FDA recommends that you contact your doctor for more information on the timing of when to take these two medicines, so that both medicines can be effective.”

sNDA Filing

Unknown – PDUFA date

Unknown –The sNDA was submitted to NDA20998

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Pfizer, Inc., Drug Name: celecoxib Drug Class: non-steroidal anti-inflammatory drug Indication: pain, arthritis

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.