Lessons from Vioxx
DAVID EGILMAN MD, MPH
- Clinical Associate Professor
- Brown University
Amos Presler
- Consultants to Plaintiffs in Vioxx Litigation
- degilman@egilman.com
- Linked version to actual documents can be found at:
http://www.vioxxdocuments.com/browse.php?disp
lay=list&dir=egilman_arcoxia/
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
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.
1. Huskisson EC, Berry H, Gishen P, Jubb RW, Whitehead J. Effects of anti-inflammatory drugs on the
progression of osteoarthritis of the knee. J Rheumatol 1995;22:1941-6.
4
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
Arthritis Rheum. 1999 Sep;42(9):1870-8. Comment in: Arthritis Rheum. 2000 Nov;43(11):2615-6. Function and health-related quality of life:
results from a randomized controlled trial of leflunomide versus methotrexate or placebo in patients with active rheumatoid arthritis. Leflunomide
Rheumatoid Arthritis Investigators Group. Strand V, Tugwell P, Bombardier C, Maetzel A, Crawford B, Dorrier C, Thompson A, Wells G. 19
MRK-NJ0130089
The Big Picture
Evaluation MUST
consider :
Number Needed to Treat
to Harm/Help
22
Arcoxia: Less Safe than Comparators
From Merck’s Arcoxia Briefing Document:
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.)
FDA Arthritis Drug Advisory Committee Meeting, ARCOXIA (Etoricoxib 30
and 60 mg For Symptomatic Treatment of Osteoarthritis.Briefing Document
(Background Package) April 12,2007.
5
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.
17
More Deaths on
COX-2 Treatment
23
COX-2 Increase Mortality:
Effects are complex
Merck claims AD deaths should be
ignored because there’s ―no pattern.‖
Pattern: excess deaths were a result of selective
Cox-2 blocking and accidents due to AD
conversion.
1. Pneumonia – Cox-2 is part of response to
infection.
2. GI Bleed deaths – Cox-2 needed for ulcer healing.
3. AD patients have increased rates of accidental
deaths.
24
COX-2s Increase Mortality
Death Warning Needed
on Label for Arcoxia
26
COX-2s may
cause
Alzheimer’s
Disease
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
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
Unreliable Safety Data:
Manipulating the Standard
Operating Procedure (SOP)
44
Unreliable Safety Data:
Manipulating the Standard
Operating Procedure (SOP)
Lots of SOP
changes:
most are post
hoc & follow
changes in
practice.
45
Unreliable Safety Data:
MANIPULATING THE SOP
CV SOP has No Cut-
off Rule for CV Events
46
Unreliable Safety Data:
MANIPULATING THE SOP
Study was un-blinded and results were
distributed 3-9-2000. Bad CV data.
SOP 14 Day CV cut off Rule comes later.
MRK-NJ0121088 47
Unreliable Safety Data:
RETROACTIVE CHANGES OF SOP
CHF and PUMONARY EDEMA GONE - 21 DELETIONS 12/1999
51
Unreliable Safety Data:
MANIPULATING THE SOP
SOP re-written to match procedures:
2003 Chen memo:
―regarding serious AEs eligible for adjudication, I used the following wording in my
DAP:
“Could you confirm that bullet 3
Serious adverse experiences eligible for adjudication include:
…
was actually done for the AD
All deaths, including all-cause mortality events and deaths not eligible for inclusion
studies? If not,
in the all-cause mortality analyses;
I’ll though the delete it.”
be thromboembolic, evensimplyinvestigator-reported terms
Serious adverse experiences that the clinical monitors feel may potentially
would not normally be eligible for adjudication (e.g., a case with a term of
"neurological disorder").
[…]
Could you confirm that bullet 3 was actually done for the AD studies? If not, I’ll
simply delete it.‖ [Emphasis added]
Chen, J. Email communication, Examples of spreadsheets for internally adjudicated confirmed safety
endpoints for Vioxx ad. MRK-AFV0210573. May 28, 2003. 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
Unreliable Safety Data:
CHF under reported
CHF is serious by definition if it was a diagnosis that
was “Eligible for Adjudication.” Catch 22
Merck deleted CHF post hoc from list of eligible events.
See Arcoxia transcript page 161. MRK-AQZ0039486
55
Unreliable Safety Data:
CHEATING ON ADJUDICATIONS
and MANIPULATION OF
INDIVIDUAL CASES
56
Unreliable Safety Data:
CHEATING ON ADJUDICATIONS
AN 0158 Alzheimer's Trial
Barr
Reported to FDA as insufficient data
to adjudicate: on VIOXX
58
Unreliable Safety Data:
CHEATING ON ADJUDICATIONS
Merck adjudication
loses more Vioxx
cases than Placebo
cases & it happens
study after study.
59
Unreliable Safety Data: Biased adjudication
•Vioxx cases confirmed less often than
placebo cases ss 1998-2000.
•Vioxx label only included data
through March 16, 2001.
•Study 078 was not supposed to be
adjudicated.
60
The Big Picture: Vioxx Lessons
Arcoxia Evaluation
MUST consider :
Number Needed to Treat to
Harm/Help
If approved warnings
Must be Explicit
22
Out-takes of Merck’s Vioxx
Video News Release
Dr. Laine claims
Merck broadcasted
―bogus‖ information
Merck repeated this
―bogus‖ information
in the Arcoxia ACM.
No evidence Arcoxia
reduces
hospitalizations for
GI bleeds and
serious PUBs.
AVI1
135
Out-takes of Merck’s Vioxx
Video News Release
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.
136
Out-takes of Merck’s Vioxx
Video News Release
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…
137
Out-takes of Merck’s Vioxx
Video News Release
Dr. Laine claims
―We were cagey‖ in
how we published
the data.
AVI2
139
Out-takes of Merck’s Vioxx
Video News Release
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.
140