VIOXX

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VIOXX Gastrointestinal Outcome
Research(VIGOR)Arthritis Advisory Committee
Meeting February 8, 2001

• Lourdes Villalba, M.D.
• DAAODP, CDER, FDA

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Rofecoxib Overall Safety

• VIGOR - General safety
• CV safety in other databases
• Risk/benefit assessment - Co-use of ASA
• Post-marketing safety
• Conclusions

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VIGOR General Safety

• Evaluation of routine safety parameters
• Deaths
• Serious Clinical AEs
• Dropouts due to Clinical AEs
• Laboratory AEs
• Number of Hospitalizations
• Pre-specified NSAID-related AEs

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VIGOR General Safety Deaths

• Rofecoxib (N4047)
• 22 (0.5)
• 9 cardiovascular
• 5 pneumonia
• 4 worsening ILD
• 2 GI bleeding
• 1 gastric malignancy
• 1 unknown (CHF?)

• Naproxen (N4029)
• 15 (0.4 )
• 7 cardiovascular
• 3 pneumonia
• 1 worsening ILD
• 1 GI bleeding
• 1 hepatic necrosis
• 2 malignant neoplasm

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Definition of Serious AEs

• Death
• Life threatening
• Results in persistent or significant
  disability/incapacity
• Results in or prolongs patient hospitalization
• Is a congenital anomaly/birth defect
• Cancer
• The result of an overdose
• Or event may jeopardize the patient and require
  medical or surgical intervention to prevent one
  of the outcomes listed above

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VIGOR General Safety Serious AEs (?gt1)

• Rofecoxib Naproxen
• N4047 () N4029 ()
• Any 378 (9.3) 315 (7.8)
• CV 101 (2.5) 46 (1.1)
• Digestive 48 (1.2)
  97 (2.4 )
• MS1 83 (2.1) 70
  (1.7)
• Resp 52 (1.3)
  39 (1.0)
• p lt 0.05 1MS musculo-skeletal

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VIGOR General Safety Dropouts due to AEs (?gt1)

• Rofecoxib Naproxen
• N4047 () N4029 ()
• Any 643 (15.9) 635 (15.8)
• CV 109 (2.7) 33 (0.8)
• Digestive 292 (7.2) 392 (9.7)
• Nervous 44 (1.1) 24 (0.6)
• Body1 100 (2.5) 107
  (2.7)
• p lt 0.05 1Body body as a whole

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VIGOR General Safety Lab AEs

• Rofecoxib Naproxen
  N4047 () N4029 ()
• Any 418 (10.4) 368 (9.2)
• Dropouts 22 (0.6) 12 (0.3)
• Serious 3 (lt0.1) 0

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VIGOR General Safety Hospitalizations

• Rofecoxib Naproxen
  N4047 N4029
• Any 338 265
• CV 65 24
  
• GI 29 49
• Hematologic 7 6
• Hepatobiliary 12 8
• Renal 6 6
• Other

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VIGOR General Safety Pre-specified
NSAID-related AEs

• Rofecoxib Naproxen
  p-value N4047 N4029
• Dropouts
• GI abdom. pain 307 416
  lt0.001
• Edema-related 25 13 0.057
• HTN-related 28 6 lt0.001
• Liver-related 10 3 0.067
• Renal-related 8 7
  0.796
• CHF-related 19 9
  0.065

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VIGOR General Safety Summary

• GI safety favored rofecoxib
• Overall, general safety parameters trended in
  favor of naproxen, particularly due to the excess
  in serious cardiovascular events in the rofecoxib
  group.

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Rofecoxib Overall Safety

• VIGOR - General Safety
• CV safety in other databases
• Risk/benefit assessment - Co-use of ASA
• Post-marketing safety
• Conclusions

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Time to event plot. Adjudicated serious CV
thrombotic events in VIGOR
RR 2.37 (R vs. N)
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Serious CV/thrombotic EventsDefinitions

• 1) Investigator reported
• 2) Adjudicated confirmed by the CV Case Review
  Committees (Pre-specified analysis in
  SOP)(excludes hemorrhagic stroke)
• 3) APTC Anti-platelet Trialists Collaboration
  composite endpoint cardiac death, non-fatal MI
  and stroke (includes hemorrhagic stroke and
  excludes peripheral events)

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VIGORAdjudicated Serious CV thrombotic Events
Included for Analyses

• Cardiac Event
• Acute myocardial infarction
• Unstable angina
• Sudden cardiac death
• Cerebrovascular Event
• Ischemic CVA stroke with documentation
• Transient ischemic attack (TIA)
• Peripheral Vascular Event
• Peripheral arterial thrombosis
• Peripheral venous thrombosis

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VIGORSerious CV thrombotic eventsThree
Different Endpoints
rofecoxib
naproxen
64
80
45
60
35
32
patients with events

40
19
18
20
0
Investigator
Adjudicated
APTC 1
APTC 1 Anti-platelet Trialists Collaboration
composite
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VIGOR CV SafetyHypotheses

• Pro-thrombotic effect with rofecoxib? (biological
  plausibility)
• Cardio-protective effect of naproxen? (biological
  plausibility)
• Unknown factors?

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VIGOR CV SafetyHypotheses (2)

• Cardio-protective effect of naproxen?
• Adjudication criteria RR 0.42 N vs. R
• APTC combined endpoint RR 0.51 N vs. R
• (8,000 patients, median f.u. 9 months,
  population of patients with no recent
  CV/thrombotic event)
• No controlled studies of naproxen vs. placebo for
  CV prophylaxis.

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Rofecoxib CV SafetyImportant Limitations to
Sponsors Meta-analysis

• Studies of different length (4 - 86 weeks)
• Most patients exposed lt 6 months
• Different doses (rofecoxib 12.5, 25 and 50 mg)
• Most patients exposed ?25 mg
• Multiple comparators which may be associated with
  different risk of CV events.
• Different diseases that may be associated with
  different risk of CV events.

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Rofecoxib Exposure Data from Meta Analysis Data
Sets

• Total number included in sponsors meta-analysis
• 28,349 patients
• Exposure to rofecoxib 50 mg/day for at least 6
  months in studies other than VIGOR
• 638 patients

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Rofecoxib CV Safety Summary

• Cardiovascular Safety in VIGOR favored naproxen
  (CV/thrombotic, HTN and CHF)
• HTN/fluid retention/edema for rofecoxib dose
  dependent (signal present in original NDA)
• CV/thrombotic events
• Original NDA small database
• Sponsors meta-analysis has serious
  methodological limitations to answer the question
  

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Rofecoxib Overall Safety

• VIGOR - General Safety
• CV safety in other studies
• Risk/benefit assessment - Co-use of ASA
• Post-marketing safety
• Conclusions

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Rofecoxib Risk/benefit Assessment

• Patients at increased risk of certain CV
  thrombotic events should be on concomitant low
  dose ASA
• The effect of concomitant use of rofecoxib with
  low dose ASA on GI and CV risk is unknown.
• Studies that allowed ASA from the start were
  small and short in duration, except for study 102
  (Advantage study)

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Study 1021 Preliminary safety data

• Rofecoxib Naproxen
• 25 mg 1000 mg
• N2785 N2771
• Serious CV2 10
  7
• Cardiac 7 1
• MI 5
  1
• Sudden death 2
  0
• Ischemic CVA 0
  6
• Other events3 3
  0
• Confirmed UGI 6 12
• 1 12- week 2 APTC terms 3 Arterial rupture,
  hemorrhagic CVA, unknown cause of death 12
  low dose ASA

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Rofecoxib Risk/benefit AssessmentCo-use with low
dose ASASummary

• Insufficient data on concomitant ASA use.

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Rofecoxib Overall Safety

• VIGOR - General Safety
• CV safety in other studies
• Risk/benefit assessment - Co-use of ASA
• Post-marketing safety
• Conclusions

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Rofecoxib Overall SafetyPost-marketing
Surveillance

• Post-marketing reports include
• GI
• Renal
• Liver
• Anaphylactoid reactions
• Prothrombin time prolongation with coumadin co-use

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Rofecoxib Overall Safety

• VIGOR - General Safety
• CV Safety in other studies
• Risk/benefit assessment - Co-use of ASA
• Post-marketing safety
• Conclusions

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Rofecoxib Overall Safety Conclusions (1)

• VIGOR GI Safety favored rofecoxib vs. naproxen
  (in a population of patients not taking ASA)
• VIGOR Overall, no safety superiority of
  rofecoxib over naproxen due to an excess of
  serious CV events in the rofecoxib group compared
  to the naproxen group
• Rofecoxib 50 mg is twice the upper dose labeled
  for chronic use in OA. The chronic use of the 50
  mg dose is not recommended.

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Rofecoxib Overall Safety Conclusions (2)

• Post-marketing safety risk of serious GI events
  still a concern in high risk population
• Questions raised in VIGOR
• Is there a pro-thrombotic effect of rofecoxib?
• What would be the impact of chronic co-use of low
  dose ASA in GI and CV events?

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