From: Colin Taylor [colin.taylor@verizon.net]
Sent: Monday, February 07, 2005 2:44 PM
To: Dockets, FDA
Subject: Cardiovascular Safety of Celebrex

I attach a PDF file: “TMT Review of Cardiovascular Safety of Celebrex”. 



Comparable information is available on the TMT website at www.masterdocs.com (e.g., http://masterdocs.com/cardiovascular_safety_cox-2s.htm and http://masterdocs.com/tmt_safety_review.htm).



The TMT position on Celebrex is:

  a.. Celebrex has received more extensive evaluation of cardiovascular safety than any other non-aspirin drug for chronic pain. 
  b.. There is no evidence of cardiovascular toxicity at Celebrex dosage up to 200 mg/day. 
  c.. The present data, overall, neither confirms nor excludes an increased risk of major cardiovascular events at doses in excess of 200 mg/day. There is no sound basis for supposing that any such toxicity is not shared by conventional NSAIDs. 
  d.. All drugs for chronic pain should be used in as low dosage and for as limited duration as is consistent with effective pain relief. 
  e.. Celebrex should remain on the market with appropriately revised labeling and a restriction of the maximum dose to 200 mg/day. 


TMT has reviewed the Pfizer Briefing Book made available on the FDA website and has the following comments:

  a.. META-ANALYSIS: 
    a.. Dosage and Duration of Therapy: 
      a.. The average duration of therapy in those receiving >200 mg/day was only 2 months and Celebrex dosage may not have exceeded 200 mg/day in most patients. 
      b.. Additional analyses should be provided to clarify the dose-response and time-response relationships for cardiovascular events. 
      c.. As far as possible, the analysis should avoid confounding of time and dose. 
    b.. Definitions of Cardiovascular Endpoints: 
      a.. The primary cardiovascular endpoint is a composite index based on a modification of the APTC index. It includes 19 event types, some of which are debatable in the COX-2 context (e.g., all five peripheral vascular terms dealing with venous rather than arterial thrombosis, and inclusion of "cerebrovascular disorder" and "cerebral hemorrhage"). 
      b.. It is stated that "Stroke comprised the individual adverse events cerebrovascular accident, cerebrovascular disorder, and cerebral hemorrhage." Including "cerebrovascular disorder" as a "stroke" is debatable, particularly in patients with Alzheimer's disease. It would be useful to have event rates separately for cerebrovascular accident and cerebral hemorrhage, since the thromboxane/prostacyclin hypothesis would suggest that thrombotic cerebrovascular events might be increased with Celebrex whereas cerebral hemorrhage could be reduced. 
      c.. Assurance is required that inclusion of many terms in the APTC and stroke definitions did not dilute a true drug effect on events related purely to arterial thrombosis. 
      d.. Separate Kaplan-Meier plots for myocardial infarction and/or stroke, myocardial infarction alone, and stroke alone (based only on the term “cerebrovascular accident”) would be useful. 
      e.. It should be stated whether the decision to use the modified APTC composite index and other defined endpoints was made before or after the safety results had been examined. 
    c.. One-Sided or Two-Sided Testing: It is not stated whether p values in the meta-analysis were based on one-sided or two-sided testing. 
    d.. Inclusion of Non-Pfizer-Sponsored Studies in Meta-Analysis or Comparable Tables: To the extent possible from the data available to Pfizer, tabulations of cardiovascular safety should include both Pfizer-sponsored and non-Pfizer-sponsored studies. 
    e.. Kaplan-Meier Plot (Figure 1): This plot is visually misleading and difficult to interpret (closed circles for Celebrex, and NSAIDs plotted on top of Celebrex data). Additional analysis of the 6-month-to-1-year data would be useful. 
    f.. Typographical-Type Errors: There are some scattered minor errors in the Pfizer Briefing Book (e.g., Page 25 says “3 of the 10 patients in the celecoxib treatment group” whereas it should say “3 of the 10 patients in the placebo treatment group”). TMT can provide a listing of these errors if Pfizer wishes. 
  b.. ADDITIONAL DATA ON THREE KEY INDIVIDUAL TRIALS: 
    a.. Three trials of particular importance are the APC trial, the ADAPT trial and Study IQ5-97-02-001. 
    b.. The APC and ADAPT trials were not Pfizer-sponsored, and only preliminary results are available. However, in so far as these preliminary results can be combined with the appropriate long-term studies in the Pfizer database, an overall assessment of risk should be made. 
    c.. Study IQ5-97-02-001 is a Pfizer-sponsored study and was completed several years ago. However, the Study Report for IQ5-97-02-001  posted on the Internet does not reach Pfizer’s normal high standards. The statement is made that “A statistically significant difference favoring placebo in adverse events was observed for certain CV-related body system terms (Cardiovascular Disorders, General; Heart Rate and Rhythm Disorders; Myo, Endo, Pericardial & Valve Disorders). These differences were primarily driven by the individual terms cardiac failure, fibrillation atrial, and angina pectoris.” However the raw tabulations, statistical rationale, and detailed results underlying this statement are not provided in the study report. 


I have provided copies of these TMT comments to Pfizer which has thanked me for the information.



Sincerely yours,



Colin R. Taylor, President, TMT Inc.