# Presentation: 907680

## Lessons from Vioxx

- DAVID EGILMAN MD, MPH
- 	- Clinical Associate Professor
- 		- Brown University
- Amos Presler
- 	- Consultants to Plaintiffs in Vioxx Litigation
- 		- _[degilman@egilman.com](mailto:degilman@egilman.com)_
- 	- Linked version to actual documents can be found at:
- http://www.vioxxdocuments.com/browse.php?display=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**

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## 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.

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## 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. **MRK-NJ0130089**

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## The Big Picture

**Evaluation MUST consider :**
**Number Needed to Treat**** to Harm/Help**** **

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## 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.)

- 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

*From Merck’s Arcoxia Briefing Document:*

- FDA Arthritis Drug Advisory Committee Meeting, ARCOXIA (Etoricoxib 30 and 60 mg For Symptomatic Treatment of Osteoarthritis.Briefing Document (Background Package) April 12,2007.

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## 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.**

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## More Deaths on COX-2 Treatment

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## 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.
**Pneumonia – Cox-2 is part of response to infection.**
**GI Bleed deaths – Cox-2 needed for ulcer healing. **
**AD patients have increased rates of accidental deaths.**

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## COX-2s Increase Mortality

**Death Warning Needed on Label for Arcoxia**

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## COX-2s may cause  Alzheimer’s Disease

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## 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.

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## 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.**

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

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

- Lots of SOP changes: most are post hoc & follow changes in practice.

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## Unreliable Safety Data:		MANIPULATING THE SOP

-  **CV SOP has No Cut-off Rule for CV Events**

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## 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

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## Unreliable Safety Data:	RETROACTIVE CHANGES OF SOP

**CHF and  PUMONARY EDEMA** **GONE **- **21 DELETIONS 12/1999**

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## 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:
- Serious adverse experiences eligible for adjudication include:
- ...
**All deaths,** including all-cause mortality events and deaths not eligible for inclusion in the all-cause mortality analyses;
**Serious adverse experiences that the clinical monitors feel may potentially be thromboembolic, even though the investigator-reported terms 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.

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**“****Could you confirm that bullet 3 was actually done for the AD studies? If not, **
**	****I’ll simply delete it.”**

## Unreliable Safety Data:	Lots of Post Hoc SOP Changes

**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**

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## Unreliable Safety Data:	CHF under reported

- See Arcoxia transcript page 161. _[MRK-AQZ0039486](file:///../Temporary%20Internet%20Files/Arcoxia%20Docs/MRK-AQZ0039486_CHF%20WHAT%20IS%20SERIOUS.pdf)_

**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.**

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

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## Unreliable Safety Data:CHEATING ON ADJUDICATIONS

-  AN 0158 Alzheimer's Trial

**Reported to FDA as insufficient data **
**to adjudicate: on VIOXX**

- Barr

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## Unreliable Safety Data:CHEATING ON ADJUDICATIONS

**Merck adjudication loses more Vioxx cases than Placebo cases & it happens study after study.**

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## Unreliable Safety Data: Biased adjudication

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**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. **

## The Big Picture: Vioxx Lessons

**Arcoxia Evaluation MUST consider :**
**Number Needed to Treat**** to Harm/Help**
**If approved warnings Must be Explicit**** **

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## 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.

- Merck repeated this “bogus” information in the Arcoxia ACM.
- No evidence Arcoxia reduces hospitalizations for GI bleeds and serious PUBs.

- Out-takes of Merck’s Vioxx 			Video News Release

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- _[AVI1](file:///Egilman/hospitalization.avi)_

## 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.

- 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

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## 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...

- 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

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## Out-takes of Merck’s Vioxx 			Video News Release

- Dr. Laine claims “We were cagey” in how we published the data.

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- _[AVI2](file:///Egilman/cagey.avi)_

## 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.

- 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

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