COX-2 FDA Advisory Committee Meeting February 16-18, 2005 Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee

TMT distributed full papers from the February, 2005 FDA COX-2 Advisory Committee meeting, together with an extensive analysis of the meeting and a set of recommendations.  Subsequently, in April, 2005, TMT also distributed an analysis and recommendations document (COX-2 Analysis & Recommendations) that described several novel approaches to safety evaluation of NSAIDs (and by implication to safety evaluation of other drugs used in long-term therapy). The main themes of this analysis and recommendations document are:

TOT Meta-Trial: A meta-trial to address NSAID issues within a common design architecture. Patients would proceed through: a) 6-week DB trial with individual sub-trials, b) 2-year open randomized trial, c) 8-week DB withdrawal/switch trial. 

Collaborative Database: Drug company sponsors would provide NSAID data from clinical trials in a common format for combined data analysis, using highly specific criteria for data selection and categorization of events and efficacy/safety variables.  

Analysis of Existing NSAID Database: A collaborative effort for systematic exploration of unanswered NSAID questions. Central clearing house with analyses/meta-analyses by academicians, drug companies, and other researchers.  

Medical Issues on Coxibs and other NSAIDs: Pain-relief-induced reduction in CV risk, naproxen and the heart, the blood pressure/CV risk relationship as a function of the magnitude of each effect, aspirin-induced mitigation of NSAID-induced CV risk, dose-response, time-response, and review of the APC trial analysis. 

Standards Setting: Clinical Study Design & Analysis: Need for clear standards for statistical analyses, statistical meta-analyses, Data Safety Management Board (DSMB) procedures, clinical trial stopping rules, observational study design, and bias reduction in integrated clinical summaries. Statistical issues include clarification and implementation of well-established statistical approaches, and identification of some new problems. 

Structured Meeting Information Processing: Systematic, computer-assisted approach to categorize, analyze and display information from sources such as the COX-2 meeting.  

Top Twenty Issues from COX-2 Meeting: An outsider’s view of the consensus views of the committee. 

Highlights of Presentations and Discussion Sections: A detailed analysis with over 2,000 highlights identified.

 The following PDF files contain 1) Highlights from the COX-2 meeting, 2) a TMT Analysis with Recommendations, 3) Full text as well as slides from each of the presentations and discussion periods, and 4) Miscellaneous other reports and analyses of the COX-2 meeting. Click on an item to open it in Acrobat Reader. To navigate through the document, click View | Navigation Tabs | Pages -- thumbnails of the pages will appear in the left-hand panel. Check the Table of Contents at the beginning of the document and then navigate to the page you want.

Highlights  Key points from each of the presentations, discussion periods and voting sessions.

Analysis & Recommendations  Pain-Relief-Induced Reduction in Cardiovascular Risk.  Can BP Effect explain CV Risk? Mitigation by Aspirin? Dose & Time Response Relationships. Naproxen & the Heart. Problems in Statistical Analysis & Interpretation. A New Meta-Trial design. And Much More........

Presentations, Discussions & Voting (Click to go to document):

A.  Start of Meeting:   GI Toxicity of NSAIDs:  COX-2 & Prostacyclin.

A1 COX-2 Meeting Participants	A6 Gastrointestinal Effects of NSAIDs and COX-2 Specific Inhibitors - Byron Cryer MD
A2 Call to Order - Day 1	A7 Committee Questions to Dr Cryer
A3 Conflict of Interest Statement, Day 1	A8 Mechanism Based Adverse Cardiovascular Events and Specific Inhibitors of COX-2 - Garrett Fitzgerald MD
A4 Welcome - Steven Galson MD	A9 Committee Questions to Dr Fitzgerald.pdf
A5 Regulatory History FDA - Jonca Bull MD

B. Rofecoxib (Vioxx)

B1 Sponsor Presentation (Merck) Rofecoxib Introduction, Peter Kim MD	B3 FDA Presentation - Vioxx (Rofecoxib) - Lourdes Villalba MD
B2 Sponsor Presentation (Merck) Rofecoxib Safety, Ned Braunstein MD	B4 Committee Questions on Rofecoxib to Dr Braunstein & Dr Villalba

C. Celecoxib (Celebrex)

C1 Sponsor Presentation (Pfizer) Celecoxib Introduction, Joseph Feczko MD	C5 Committee Questions to Dr Witter on Celecoxib
C2 Sponsor Presentation (Pfizer) Cardiovascular Safety and the Risk_Benefit Assessment of Celecoxib, Kenneth Verburg PhD	C6 The APC Trial (Prevention of Sporadic Colorectal Adenomas with Celecoxib) - Ernest Hawk MD.
C3 Committee Questions to Dr Verburg on Celecoxib	C7 The PreSAP Trial (Prevention of Colorectal Sporadic Adenomatous Polyps) - Bernard Levin MD
C4 FDA Presentation - COX-2 CV Safety - Celecoxib - James Witter MD	C8 Committee Questions to Dr Hawk and Dr Levin on APC and PreSAP

D. Valdecoxib (Bextra) and Parecoxib

D1 Sponsor Presentation (Pfizer) Cardiovascular Safety and Risk-Benefit Assessment of Valdecoxib and Parecoxib, Kenneth Verburg PhD	D4 FDA Presentation - COX-2 CV Safety - Valdecoxib-Naproxen - James Witter MD
D2 Sponsor Presentation (Pfizer) Concluding Remarks, Joseph Feczko MD	D5 Valdecoxib Discussions between Dr Furberg and Pfizer
D3 Committee Questions to Dr Verburg on Valdecoxib and Parecoxib

E. Naproxen

E1 Sponsor Presentation (Bayer & Roche)  Naproxen Introduction, Leonard Baum MD	E3 Committee Questions to Naproxen Speakers
E2 Sponsor Presentation (Bayer & Roche) Naproxen Safety Data, Martin Huber MD

F. Observational Studies

F1 Conflict of Interest Statement, Day 2	F4 Questions to Dr Graham
F2 Interpretation of Observational Studies of Cardiovascular Risk of Nonsteroidal Drugs - Richard Platt MD	F5 Committee Questions to Dr Platt and Dr Graham
F3 FDA Presentation - Review of Epidemiologic Studies on Cardiovascular Risk with Selected NSAIDs, David Graham MD

G. Etoricoxib (Arcoxia) and Lumiracoxib (Prexige)

G1 Sponsor Presentation (Merck) Arcoxia (etoricoxib), Sean Curtis MD	G4 Sponsor Presentation (Novartis) Gastrointestinal and Cardiovascular Safety of Lumiracoxib, Ibuprofen, and Naproxen, Patrice Matchaba MD
G2 FDA Presentation - Analysis of Cardiovascular Thromboembolic Events with Etoricoxib, Joel Schiffenbauer MD	G5 FDA Presentation - Lumiracoxib, Lourdes Villalba MD
G3 Sponsor Presentation (Novartis) Lumiracoxib Introduction, Mathias Hukkelhoven PhD	G6 Committee Questions to Merck (Etoricoxib), Novartis (Lumiracoxib) and Dr Villalba (FDA)

H. Open Public Hearing

H Open Public Hearing

I. Administrative Matters - Beginning of Day 3

I1 Call to Order, Shortening of Presentations, Request for Sponsor 2-Minute Summaries, Day 3

I2 Conflict of Interest Statement, Day 3

J. The ADAPT Study: Celecoxib, Naproxen & Placebo.

J1 Investigator Presentation - Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) - Constantine Lyketsos MD

J2 Committee Questions to Dr Lyketsos

K. Difficulties in Interpreting Infrequent Adverse Events.

K1 Interpretation of Observed Differences in the Frequency of Events When the Number of Events is Small - Milton Packer MD

K2 Committee Questions to Dr. Packer

L. FDA Presentations Prior to Questions to Committee

L1 Clinical Trial Design and Patient Safety: Future Directions for COX-2 selective NSAIDs, Robert Temple MD (FDA)	L3 Issues in Projecting Increased Risk of Cardiovascular Events to the Exposed Population, Robert O'Neill PhD (FDA)
L2 Committee Questions to Dr Temple	L4 Summary of Meeting Presentations (FDA), Sharon Hertz MD

M. Sponsor Closing Statements.

M Sponsor Two-Minute Statements

N. FDA's Regulatory Armamentarium, Discussion of & Voting on Questions to Committee.

N1 FDA   Regulatory Armamentarium, Anne Trontell (FDA) & Committee Discussion	N7 Question 4 - Low Dose ASA and CV Events
N2 Preliminary Committee Discussion of Questions 1-3 -End of Day 2	N8 Question 5 - Future Trials for Coxibs
N3 Questions to Advisory Committee -Introduction, General Discussion & Committee Statements	N9 Question 6  - Labeling for Approved NSAIDs
N4 Question 1 - Celecoxib	N10 Question 7 - Trials for CV Effects of Non-Selective NSAIDs
N5 Question 2 - Valdecoxib	N11 Question 8 - CV Evaluation of New NSAIDs
N6 Question 3 - Rofecoxib	N12 Announcements of Voting Results

Links to additional materials related to the COX-2 meeting made available by FDA or others are shown below:

Sponsor Briefing Books posted by FDA prior to COX-2 Meeting

COX-2 Presentation Slides

Additional Summaries and Analyses of the COX-2 meeting made available by TMT are shown below:

FDA Dockets Copy of TMT Pre-COX-2 Meeting 2-7-05 Cover Letter	Analysis of Committee Voting Patterns:
Latest News from the World of Medicine	FDA Dockets Copy of TMT Pre-COX-2 Meeting Submission: Review 2-7-05 of Celebrex Cardiovascular Safety
Documents posted by TMT on Celebrex safety prior to COX-2 Meeting	Key Audio Recordings from COX-2 Meeting
Sponsor Briefing Books posted by FDA prior to COX-2 Meeting

Disclosure: TMT received consulting fees from Pfizer in 2003 and 2004 related to computerized pain diagram analysis and neuropathic pain. No consulting fees were received for work relating to Pfizer COX-2 inhibitor drugs. Dr. Taylor, President of TMT , was employed by Pfizer from 1970-1993 as a research physician.