Lessons from Vioxx

1. Lessons from Vioxx DAVID EGILMAN MD, MPH - Clinical Associate Professor - Brown University - Consultant to Plaintiffs in Vioxx Litigation - degilman@egilman.com A copy of the presentation with hyperlinks to most of the documents cited can be found at: http://www.vioxxdocuments.com/browse.php?display=list&dir=egilman_arcoxia/

2. 2 Lessons from Vioxx COX-2s increase Mortality COX-2s may cause Alzheimer's Safety Data Unreliable Anti-Platelet Trial Collaborative (APTC) Strategy Standard Operating Procedure (SOP) was not standard Adjudications often ad hoc Delayed Key Data Submission

3. 3 The Big Picture(Things the Public Thinks the FDA Considers but it Doesn�t) What is the best way to treat RA & OA? RA: There is no evidence that NSAIDs do anything but treat pain. NSAIDs do not �treat� the underlying disease process. OA: There is evidence NSAIDs makes OA worse (not including Cox-2 effects on fracture). 1 Worried about GI bleeds and CV/T ? (Think whole patients here.) NSAIDs combination with PPI or H2 blocker is safer and cheaper than Cox-2.

4. 4 More Hypertension Pg 155-63 More Renal complications Pg 162 More CHF Pg 142 More Strokes Pg 163 More MIs Pg 164 More Arrhythmias Pg 93 (Despite the fact that Arrhythmias were retroactively deleted from adjudication event list.) Arcoxia: Less Safe than Comparators

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12. 12 Based on observational data, we know Arcoxia can cause stroke:

13. 13 Some NSAIDS take away the pain but make the disease worse: Arcoxia never evaluated for this.

14. 14 Arcoxia studies did not evaluate efficacy relative to the disease process (joint space deterioration):

15. 15 Arcoxia studies did not evaluate efficacy relative to the disease process (joint space deterioration):

16. 16 Arcoxia in no better for patients than Tylenol, naproxen or Celebrex. The burden is on Merck & the FDA to assure that it is as safe prior to approval. Arcoxia: Less Safe than Comparators

17. 17 CHF: Adjudicated Post Hoc & for EDGE after Freezing (Un-blinding) FDA says: �Development of Congestive Heart Failure (CHF) � CHF was handled similarly to the CV and GI events with an adjudication committee.� NOT TRUE Merck deleted CHF & (atrial Fib) from list of events to be adjudicated Dec 1999 (post dated Oct 3). Merck added CHF to ADJ event list around 12/2006 This data is unreliable since the CHF data was not collected systematically throughout the trials.

18. 18 Placebo/Tylenol/methotrexate Long-term Trials are Ethical Bombardier - 1 year placebo trial in 1999 On the other hand, VIGOR WAS unethical 50% of the patients in VIGOR were on steroids. Scolnick wrote, this is ��like testing Mevacor for liver safety in patients with hepatitis.� Long term placebo trials are necessary to establish safety & there is no excuse for not doing them

19. 19 Little understood: A caused case is a case that occurs before it would �normally� occur. For example, if you expect 3 cancer cases in patients who are over 80 and the exposed group has just 3 cases, but they occur in patients who are under 30, these are all caused cases.

20. 20 Reviewers comments: �Of note, there are 11 cardiac events in the etoricoxib group vs. 2 in the non-naproxen combined group which is made up of diclofenac events only (there were no events in the ibuprofen treatment arm). Three of the 4 events in the non-naproxen group occurred at greater than 3 years of exposure (as noted in a review of the KM plots). All but one of the events in etoricoxib occurred within the first 2 years. There are also 5 MIs in the etoricoxib group vs. 1 in the diclofenac group. Although there is no difference in the absolute numbers of CNS events the rates are higher in the diclofenac group because of the fewer patient-years of exposure. Numbers are small and firm conclusions are difficult.�

21. 21 The Big Picture Evaluation MUST consider : Number Needed to Treat to Harm/Help

22. 22 More Deaths on COX-2 Treatment

23. 23 COX-2 Increase Mortality: Effects are complex Merck claims AD deaths should be ignored because there�s �no pattern.�

24. 24 COX-2 Increase Mortality :Deaths in Arcoxia Trials Too �For CV related deaths there appears to be an excess of cases due to etoricoxib compared to placebo although the exposure to placebo is limited. However, the data related to naproxen clearly shows an excess of CV mortality related to etoricoxib (and this is consistent with comparisons of naproxen to rofecoxib in other studies). The explanation for these results is not clear and may or may not be related to a protective effect of naproxen (not demonstrated).� - Schiffenbauer - February 2005 ACM

25. 25 COX-2s Increase Mortality Death Warning Needed on Label for Arcoxia

26. 26 COX-2s may cause Alzheimer�s Disease

27. 27 COX-2s may cause Alzheimer�s (AD) Relative Risk of AD Conversion: Vioxx/Placebo Trial would have been stopped by a DSMB, but Merck eliminated the DSMB from the protocol.

28. 28 COX-2s may cause AD: AD Conversion and Evidence of Dose Response Patients who were more compliant on Vioxx had a greater risk of developing AD than those who were less compliant. ITT (includes all patients regardless of compliance) AD conversion RR = 1.46 p=0.01 For those 80% compliant: RR 1.72 ss This evidence for dose response was removed from published paper.

29. 29 COX-2s may cause Alzheimer�s Disease AD Warning Needed on Label for Arcoxia �Class Effect� Cox-2 drugs should have a warning that states that studies have found a relationship between use and conversion to AD.

30. 30 Unreliable Safety Data:  Anti-Platelet Trial Collaborative (APTC) Strategy

31. 31 Unreliable Safety Data: APTC STRATEGY In October 2000, cardiology consultants review VIGOR & meta-analysis. Dr. Gertz Notes:

32. 32 Unreliable Safety Data:APTC STRATEGY The Original Endpoints in SOP: Primary Event Type MI (fatal and non-fatal) Unstable angina pectoris Ischemic stroke (fatal and non-fatal) Secondary Event Type Arterial thrombo-embolism (fatal and non-fatal) Sudden cardiac death Resuscitated cardiac arrest Transient Ischemic attack

33. 33 Unreliable Safety Data:APTC STRATEGY Rationale for Changing Endpoints from Dr. Reicin�s Power point:

34. 34 Unreliable Safety Data:APTC STRATEGY Actually there is no APTC �endpoint�

35. 35 Unreliable Safety Data:APTC STRATEGY APTC mixes strokes, MIs & bleeding. So when Merck changed the endpoint from MI related events (in the SOP) to APTC, they did this to hide the MIs.�

36. 36 Unreliable Safety Data: Merck knew MI was the only �meaningful� endpoint One Merck physician stated: �I would have thought we would see some difference in the totality of non-MI events, even with these small numbers. Apart from the ever-present possibility of small-number artifact, another possibility is that the ''thromboembolic'' terms other than MI were so non-specifically used that they represent "noise", making "MI" the only category defined specifically enough to be meaningful.�

37. 37 Unreliable Safety Data:Deaths adjudicated but if CV/T not analyzed �

38. 38 Unreliable Safety Data:APTC STRATEGY �Causes of death were subdivided into "non-vascular" (that is, definitely non-vascular) and "vascular" (that is, definitely or possibly vascular, which includes all deaths attributed to cardiac, cerebral, hemorrhagic, embolic, other vascular, or unknown causes).

39. 39 Unreliable Safety Data:APTC altered to hide GI bleeds

40. 40 Unreliable Safety Data: APTC �We�re never going to be consistent�

41. 41 Unreliable Safety Data: APTC STRATEGY

42. 42 Unreliable Safety Data:APTC STRATEGY Where is the MI/SD only analysis?

43. 43 Unreliable Safety Data:  Manipulating the Standard Operating Procedure (SOP)

44. 44 Unreliable Safety Data: Manipulating the Standard Operating Procedure (SOP)

45. 45 Unreliable Safety Data: MANIPULATING THE SOP CV SOP has No Cut-off Rule for CV Events

46. 46 Unreliable Safety Data: MANIPULATING THE RESULTS Study was un-blinded and results were distributed 3-9-2000. Bad CV data.

47. 47 Unreliable Safety Data: MANIPULATING THE SOP

48. 48 Unreliable Safety Data: MANIPULATING THE SOP

49. 49 Unreliable Safety Data: 14 Day Rule

50. 50 Unreliable Safety Data:RETROACTIVE CHANGES to events to be adjudicated after unblinding (unblinded Oct 3 changed Dec 29)

51. 51 Unreliable Safety Data:

52. 52 Unreliable Safety Data: MANIPULATING THE SOP SOP re-written to post hoc to match procedures:

53. 53 Unreliable Safety Data: Lots of Post Hoc SOP Changes Standard Operating Procedure for the Surveillance, Monitoring, and Adjudication of Acute Thrombotic and Embolic Vascular Events and Deaths in Clinical Trials of COX-2 Specific Inhibitors Revised 16-February-1999 Revised: 30-August-1999 Revised: 17-September-2003 Revised: 22-August-2005 Revised: 22-February-2006

54. 54 Unreliable Safety Data: CHF under reported

55. 55 Unreliable Safety Data:CHEATING ON ADJUDICATIONS and MANIPULATION OF INDIVIDUAL CASES

56. 56 Unreliable Safety Data:CHEATING ON ADJUDICATIONS

57. 57 Unreliable Safety Data:CHEATING ON ADJUDICATIONS

58. 58 Unreliable Safety Data:CHEATING ON ADJUDICATIONS Merck adjudication loses more Vioxx cases than Placebo cases & it happens study after study.

59. 59 Unreliable Safety Data: Biased adjudication

60. 60 Unreliable Safety Data:Why the different rate of Adj success? What Happened 1999-2000? 078 began in April 1998 & the �CV SOP" only applied to studies that started after 6/98. The SOP was not written until 7/99 & it was constantly revised after that. Although the SOP called for adjudication of all deaths, this was not done until sometime in 2001 under the outside adjudication process. Deaths were "internally adjudicated" before & after this date.� Merck did not include adjudicated death (other case) diagnosis in analyses if they did not have a term that indicated that they should be sent for adjudication in the first place (initially CRISP, later ad hoc changed to MedDRA with numerous ad hoc deletions). This in not in DAP or SOP but was used to justify exclusion of case 5005 & others, including all deaths without proper terms even if they were adjudicated to MI or other endpoint.

61. 61 Unreliable Safety Data: Rush to Adjudicate AD cases for Label

62. 62 Unreliable Safety Data: Arcoxia: Medal Trial Reviewer�s comments: �Of note, there are 9 events in the etoricoxib group that had �insufficient� information vs. only 1 in the naproxen group.� - Schiffenbauer - February 2005 ACM

63. 63 Unreliable Safety Data:Arcoxia:CT/T Adjudicated cases missing from analysis

64. 64 Is the safety data reliable? Considerations: Same players: Dr. Reicin Dr. Laine History of Bad Conduct: VIGOR: ASA/Non-ASA lie Approve 18 month �error� Hiding the AD ITT analysis

65. 65 Is the safety data reliable?

66. 66 Giving the MI Data the �Best Face� Possible

67. 67 Giving the MI Data the �Best Face� Possible

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72. 72 Data Hidden from the FDA

73. 73 Hiding Data from the FDA Goal: Keeping the AD death data off the label.

74. 74 Hiding Data from the FDA:  AD Deaths & CV/T

75. 75 Hiding Data from the FDA:  AD deaths & CV/T Dec. 7, 2001: Merck email and spreadsheet of additional Alzheimer�s data collected since March 15 shows 39 additional CV/T including 13 additional deaths. At least 5 of the 13 deaths were CV/T. At least 6 of the 13 deaths were adjudicated.

76. 76 Other Lessons from Vioxx Advantage Trial Secret �Internal Adjudications� process Missing Data Safety Monitoring Board (DSMB) Hiding the ITT Data VACT Studies Misrepresentations in Published Literature, Thal et al. How Merck really feels about the FDA�. Other Hidden Analyses

77. 77 ADVANTAGE TRIAL

78. 78 Advantage: A Seeding Trial Key issues: Study did not support �Naproxen defense theory� Study did not support �high dose defense� ASA allowed (25 mg); short term (3 month). Reported results: 7 MI/SD on Vioxx to 1 on Naproxen Reported results as not statistically significant.

79. 79 �INTERNAL ADJUDICATIONS�

80. 80 Unreliable Safety Data:CHEATING ON ADJUDICATIONS

81. 81 Case 5005 is unblinded on 11/3/2000, making the MI/SD statistically significant. Dr. Reicin asks Barr to change the diagnosis on Nov 8, 2000. �Since the APTC analysis does not change whether we call it [case 5005] unknown cause of death or sudden death I would prefer unknown cause of death so that we don�t raise concerns. I still strongly feel that this should not be an MI - how do you know it wasn�t a massive stroke, primary arrhythmia? Pulmonary embolus etc. I am not sure the adjudication process can be changed going forward but it is worth discussing with Doug�but that does not help us for ADVANTAGE OR VIGOR.� [Emphasis added]

82. 82 Case 5005 is classified as �Unknown Cause of Death� in published literature.

83. 83 Merck�s excuse for not counting Case 5005 as MI/SD:  �� the term hypertensive heart disease did not trigger adjudication in the existing standard operating procedure.� Counting Case 5005 would have made Vioxx/placebo difference statistically significant.

84. 84 SOP called for external adjudication of all unknown deaths. �Internal adjudication� not mentioned.

85. 85 Missing Data Safety Monitoring Board (DSMB)

86. 86 Missing Alzheimer�s Data Safety Monitoring Board (DSMB)

87. 87 FDA missed the DSMB removal � no surprise given Merck�s disclosure:

88. 88 FDA missed the DSMB removal � no surprise given Merck�s disclosure:

89. 89 Merck knew they needed a DSMB:

90. 90 Nov. 6, 2001: Merck amends 10/15/01 FDA- LABEL proposed label, adding favorable language that CV/T events occurred in 25 Vioxx patients and 39 placebo patients. Merck proposal omits CV deaths.

91. 91 December 18, 2001: Silverman responds to FDA. Data not given. FDA is told that there is no DSMB despite the fact that the protocol called for one. FDA does NOT respond. Merck Response appears to be lost!

92. 92 Hiding the ITT Data

93. 93 Alzheimer�s Data Analysis Plan (DAP) called for ITT Analysis:

94. 94 Alzheimer�s ITT was Pre-Specified Analysis:

95. 95 Merck had it but you never saw it:

96. 96 Published study: �A total of 39 deaths occurred in patients who were taking study treatment or from fatal adverse events that started within 14 days of the last dose (24 or 3.3% for rofecoxib and 15 or 2.1% for placebo).� ITT mortality analysis: All cause: 41 vs 20 CVT: 17 vs 4

97. 97 CV/T deaths placed on 4/2002 label used 3/16/2001 cut off: 8 events on Vioxx/asa  vs. 3 on Placebo/asa

98. 98 Vioxx vs. Comparator Drugs

99. 99 Merck argues that Arcoxia should be approved because it MAY work better for patients who fail on other drugs. Although Vioxx has shown efficacy in some patients, population, data does not show superiority of Vioxx over other NSAIDS.

100. 100 Protocol 906 evaluated Vioxx in Celebrex failures:

101. 101 June 22, 2001: FDA requests All studies (105, 150, 112, 116, 905, and 906), including complete analyses of CV events.

102. 102 Protocol 906: Keep Alarming Results tight

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104. 104 Merck did not Give the FDA Key  Adverse Event Data:

105. 105 Lessons Learned from Vioxx: Are there similar crossover studies on Arcoxia? Is there evidence that Arcoxia works when others fail? Approval should be not be based on unsubstantiated anecdotal theory.

106. 106 Unpublished Placebo Data

107. 107 CV Events and Outcomes: Rofecoxib v. Placebo  Merck had 5-2002 Given to FDA 3-2004

108. 108 Analysis was cut from final Merck slides for 2005 Advisory Comm. Meeting Merck�s pooled, placebo-controlled data for approved uses showed a 3.29 RR (1.27,8.47) for TCVSAEs on Vioxx

109. 109 Hidden evidence that Cox-2s cause AD

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112. 112 In the draft paper Merck makes the lack of dose response a central argument against the proposition that that Cox-2s causes Alzheimer�s.

113. 113 From Draft: �Since the above analyses all included patients whether or not they were taking study medication, we also performed a post hoc analysis excluding subjects who were less than 80% compliant with taking treatment, as well as those who were protocol violators, in order to determine whether the effect of rofecoxib was increased in this group with greater time-adjusted exposure to rofecoxib (as would be expected if the primary findings represented a true effect of rofecoxib). There was no evidence for an increased effect of rofecoxib in this analysis (hazard ratio = 1.45, P =0.052)."

114. 114 Merck performed the analysis wrong:

115. 115 Merck deletes this analysis from published paper & never tells the FDA. They substitute an ITT analysis that helps them:

116. 116 Aisen et al. also publish that COX-2 makes AD Worse

117. 117 How Merck Really Feels about the FDA�.

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127. 127 Other Hidden Analyses

128. 128 Hiding the MI-only Meta-Analysis In October 2000, Merck performed an MI-only meta-analysis. Never given to FDA or MCA, who asked for it specifically. Vioxx vs. all comparators: 1.66 (1.05, 2.63)

129. 129 Hiding the MI-only Meta-Analysis Dr. Scolnick says it should have been given to the FDA. Merck claims it was withheld because it failed test for Homogeneity but Merck gave FDA other data from the same set of meta-analyses that also failed the test for homogeneity. Even if it failed Merck could have used random effects model meta-analysis.

130. 130 Hiding the MI-only Meta-Analysis They also performed analysis wrong. Sander Greenland, author of Modern Epidemiology, comments:

131. 131 PLANNED ANALYSIS:COMBINE 0-12 MONTH 091 AND 078

132. 132 Merck Compares the Data they had to the Data they Gave the FDA:

133. 133 CV/T Deaths in Alzheimer�s Studies 091 & 078 (March 30, 2002):

134. 134 Dr. Laine claims Merck broadcasted �bogus� information. Arcoxia does not reduce hospitalizations for GI bleeds and serious PUBs. Out-takes of Merck�s Vioxx  Video News Release

135. 135 Transcript: Interviewer: You know, let�s just take another quick crack at the hospitalizations for the VNR, alright? Dr. Laine: And the reason I actually think is because those numbers, by the way, that people use are totally incorrect, and they�re based on just extreme, totally incorrect umm data. Interviewer: But we keep using them. Dr. Laine: No. Everybody uses them because they sound good. [Indistinct Comment from Interviewer] Dr. Laine: No, they sound good, but I mean, well it�s the same person who keeps putting them out. Interviewer: Oh, I see. Dr. Laine: But I mean I have recalculated also, so the only way you can do it is subtract those who do from those who don�t, and that number doesn�t take it into account. So to say it�s due to NSAIDs is also incorrect. So there�s about five different reasons why those numbers are totally bogus, but umm, I agree, it�s in the, it�s out there in the umm common realm and everybody uses those numbers. Yeah, I know, because it�s a very impressive sound-byte. Out-takes of Merck�s Vioxx  Video News Release

136. 136 Transcript: Interviewer: Does it help that we�re using the word �associated� with NSAIDs? Does that sort of, water it down a little bit? Dr. Laine: No, I mean because the issue is umm part of the issue is the umm you just don�t have any idea. I�m not saying it�s actually wrong. The death-rate is probably wrong. The hospitalizations prob-, may be right. Umm, just the death rate�s probably wrong, but umm anyway. Interviewer: Alright, let�s, let�s� Dr. Laine: But as long as we say it�s estimated, or reported it�s, it�s not me saying it, so� Out-takes of Merck�s Vioxx  Video News Release

137. 137 Merck keeps repeating �bogus� numbers in Arcoxia ACM document:

138. 138 Out-takes of Merck�s Vioxx  Video News Release Dr. Laine claims �We were cagey� in how we published the data.

139. 139 Transcript: Interviewer: What were the renal findings in the study? Dr. Laine: Well, umm, that�s actually not going to be, I mean the only thing that�s in the New England journal article, says there�s no difference in renal failure, or renal dysfunction. So I don�t think you really want to go there, do you? Because, there are no data on blood pressure or hypert�excuse me, blood pressure or edema in the study. And the only thing it says specifically, and we were cagey about this, was related to renal failure, renal dysfunction. And that�s not what you�re looking at, so, I mean I would actually take that out, because I think you don�t, no I mean I would just suggest that anything you do, just as an aside, I�m gonna talk to Alise in about an hour, but you don�t wanna talk about that because if you start bringing up hypertension [and] edema it�s nowhere in the study, so if you bring it up it�s not what�s in the article. Interviewer: I agree, I agree. Dr. Laine: Okay. Out-takes of Merck�s Vioxx  Video News Release

140. 140 What data did Merck omit when Dr. Laine said they were being �cagey� ?