The Vioxx Story McDarby v.

Merck
401 N.J. Super 10 (App. Div. 2008)

Vioxx ® May 20, 1999-September 30, 2004

McDarby v. Merck

1

Standards of review on appeal
   


Questions of law - de novo review Questions of fact: - defer to jury if there is more than a scintilla of evidence - review facts in light most favorable to prevailing party below Questions of admissibility of evidence - abuse of discretion
McDarby v. Merck 2

Elements of a failure to warn claim


Plaintiff was a foreseeable user Product was not being misused by plaintiff Product defect: Seller/mfr failed to provide adequate warning of risks Product defect was a proximate cause of harm

McDarby v. Merck

3

Framing the counterfactual hypothetical

What was Merck’s tortious conduct? If Merck’s conduct had not been tortious what harm would have been avoided?

McDarby v. Merck

4

Did Merck behave reasonably toward three constituencies?

FDA - with which the seller contends for the widest possible marketing range Physicians - the primary targets of intensive marketing campaigns, and Patients - the object of push-marketing to create demand for the drug

McDarby v. Merck

5

Stating the theme

“The record discloses the tension that existed between Merck's scientists and its marketers and, in plaintiffs' view, the pressure on Merck's employees to preserve market share and concomitant profits arising from the sale of Vioxx -- a drug envisioned as re-establishing Merck as preeminent in the field of pharmaceutical development and manufacture -- regardless of the cardiovascular risks posed by the drug.”
McDarby v. Merck 6

Dr. Scolnick‟s lament

The pain is truly awful. Not financial but personal.... The Times said this was marketing triumphing over science. When science dominated in the past we won over and over again. It will take a new CEO … to help Merck become reborn...

McDarby v. Merck

7

Product launch – a superstar

At the 3 day June 1999 launch party David Anstice, Merck's President for Human Health Products in North America, described Vioxx as a "superstar" that would make Merck "own" the rheumatology market "once again.“ McDarby v. Merck (NJAD 2008)
McDarby v. Merck 8

Vioxx for lunch -Targeting MD‟s
 

 

The largest sales force ever deployed Sales incentives targeting over 10,000 physicians – MD’s pitching VIOXX "Health Education Liaison" - $ 3 million/month 17 million free samples in 1st 6 months D’s who resisted Vioxx sales entreaties were to be “neutralized” or “discredited”
McDarby v. Merck 9

A blockbuster

Merck SEC 8 K filing January 23, 2001
"Our five key products - VIOXX. ZOCOR. COZAAR, FOSAMAX and SINGULAIR drove Merck's performance for the year and created a powerful platform for growth."
“VlOXX has become the world’s fastest growing branded prescription arthritis medicine.” “VIOXX achieved $2.2 billion in sales for the year 2000”
McDarby v. Merck 10

Hard sell

Mass marketing to the elderly

McDarby v. Merck

11

Targeting Dr. Braun

Vioxx sales rep’s visited “ at least twice a week” “One acknowledged, the doctor was targeted because of the high volume of his prescriptions for pain relievers” Braun relied on sales reps for information, as well as on label itself Would this affect your view of the case?
McDarby v. Merck 12

Post-VIGOR – Safer than Placebo

Dr. Braun was also shown Merck's "CV Card," entitled Chemical Profile, Osteoarthritis Studies" that indicated no elevated risk of heart attack and, according to Dr. Braun, showed Vioxx to be safer than a placebo.
McDarby v. Merck 13

Dr. Braun

  

Q. If you had been told by Merck that Vioxx could increase the risk of a heart attack, would you have prescribed Vioxx to Mr. McDarby? THE WITNESS: Of course not. Q. Why not? A. My . . . job as a doctor is to try to prevent things from happening, try to prevent strokes, try to prevent heart attacks.
Ch. 5 Cause in fact 14

Fighting the FDA

McDarby v. Merck

15

Ugly cubed
October 15 2001 e-mail Dr. Scolnick to Anstice: David. Be assured we will not accept this label. If we need to we will ask to go to an advisory committee meeting.  Anstice replied:  . . . We knew it would be UGLY and it is. We'll fight back and see where we get.  Scolnick responded:  It is ugly cubed. They are bastards.

McDarby v. Merck 16

Risks to Sales – strength of label

McDarby v. Merck

17

Dilution: Burying the bad news
The FDA-Merck Compromise of 2002 – revised labeling

McDarby v. Merck

18

2002 FDA-Approved post-VIGOR Vioxx Label
 

Precautions Cardiovascular Effects The information below should be taken into consideration and caution should be exercised when VIOXX is used in patients with a medical history of ischemic heart disease.
McDarby v. Merck 19

2002 FDA Approved post-VIGOR Vioxx Label
 

Precautions Because of its lack of platelet effects, VIOXX is not a substitute for aspirin for cardiovascular prophylaxis.

McDarby v. Merck

20

Is Naprosyn really better than aspirin? Or is Vioxx the problem?
The need for study post-VIGOR

McDarby v. Merck

21

Science vs. marketing

March 9, 2000, Dr. Edward Scolnick, the President of Merck's Research Division, in an e-mail about the VIGOR data stated: "The CV events are clearly there…It is a shame but it is a low incidence and it is mechanism based as we worried it was."
McDarby v. Merck (N.J.A.D. 2008)

McDarby v. Merck

22

I‟m in minor agony

April 12, 2000 e-mail to Dr. Alise Reicin from Dr. Scolnick re CV safety post-VIGOR I will tell you my worry quotient is high. I actually am in minor agony. What I really want to do is a 10,000 vs. 10,000 patient study… safety first primary endpoint and efficacy secondary or coprimary.
McDarby v. Merck 23

Vioxx – the business climate
Blockbuster drug patent expirations on the horizon

McDarby v. Merck

24

Who’s in charge here?
  

David Anstice, direct By Mark Lanier 185

    

12 You're a salesman? 13 A. Yes. I have been involved at Merck for 32 years. 14 Q. So in 1994, Merck makes you their new 15 president of health, you, David Anstice, the marketing sales guru, right? 17 A. Yes.
McDarby v. Merck 25

Storm clouds
  

David Anstice, Direct By Mr. Lanier 15 the storm cloud that's


 

16 developing is y'all have these six blockbuster drugs,
17 and by that we mean drugs that are bringing in each 18 over a billion dollars in sales a year, that you see


19 that these drugs are coming off patent and that you
20 know that other companies are going to be able to

make generics and drive the price down, true?

22 A. That's right.

McDarby v. Merck

26

Rush to market

Q. Sir, do you recall in your own speech saying that VIOXX was important because it was through products like VIOXX that you got your replacement revenue that y'all would desperately need?

A. I may have used the term….
McDarby v. Merck 27

Compressed and accelerated

Q. This is the same page where earlier y'all said that "the development of VIOXX must proceed aggressively to meet the challenge of Celebrex." "The clinical program has, thus, been compressed and accelerated.”
Direct examination of David Anstice, Pres., Merck Human Health
McDarby v. Merck 28

FDA – Expedited Approval

May 20, 1999

McDarby v. Merck

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Phase IV – Mass marketing
The scarcely controlled human experiment stage of product development

McDarby v. Merck

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Changes may be needed
If additional information relating to the safety or effectiveness of this drug becomes available, revision of the labeling may be required. Sincerely, Robert J. DeLap, M.D., Ph.D., Director Office of Drug Evaluation Food & Drug Administration Center for Drug Evaluation and Research May 20, 1999

McDarby v. Merck 31

Superior to Placebo

Initial label “VIOXX has demonstrated significant

reduction in joint pain compared to
placebo” for treatment of

osteoarthritis….
McDarby v. Merck 32

The scarcely controlled human experiment

FDA medical officer Maria Villalba, MD, May 20, 1999:

“With the available data, it is impossible to answer with complete certainty whether the risk of cardiovascular and thromboembolic events is increased in patients on [Vioxx].
“A larger database will be needed to answer this and other safety comparison questions.”
McDarby v. Merck (N.J. App.Div. 2008)
McDarby v. Merck 33

Hard sell

Mass marketing to the elderly

McDarby v. Merck

34

DTC Advertising

Throughout the period Vioxx was on the market Merck ran magazine advertisements and television spots featuring ice skater Dorothy Hamill touting the drug and persons able to engage in leisure activities because of their use of Vioxx McDarby v. Merck (NJAD 2008)

McDarby v. Merck

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Persuading the jury
McDarby v. Merck

McDarby v. Merck

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12/13/2003
John McDarby‟s 75th Birthday

Only 4 Months Before Heart Attack

It didn’t have to happen. What obstacles did McDarby face in proving Vioxx caused his heart attack?

VIGOR
THE BEGINNING OF THE END

McDarby v. Merck

39

Merck failed to tell the whole truth
And nothing but the truth

McDarby v. Merck

40

McDarby v. Merck

41

Diabetics
• Vioxx= 6.1 x increased risk of heart attack

7 6 5

Heart Attack Risk

4 3 2 1 0 Placebo Vioxx

Diabetics

McDarby v. Merck

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Valley Hospital Consultation
“HISTORY OF PRESENT ILLNESS: The patient is a 75- year-old male with a past history of diabetes mellitus who was in his normal state of health when he was in his house and experienced some weakness. The patient denies any chest pain… when he had felt weak and possibly had some vertigo, fell on his right side and sustained a fracture.”
April 15, 2004
McDarby v. Merck 43

“MEDICATIONS: Micronase and Vioxx”

It didn’t have to happen

McDarby v. Merck

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You should have known
In fact, you did

McDarby v. Merck

45

9 September „98 Merck & Co., Inc.

Letter to Merck & Co., Inc. “…patient groups where this hypothesis could be tested … patients with diabetes mellitus…”

“… Potential cardiovascular implications of COX-2…”

“… I suggest that it would be in the best interest of Merck to look into these issues as quickly and thoroughly as possible.”
McDarby v. Merck 46

Cox-2 Inhibitors - imbalance in the bloodstream?


Garret Fitzgerald, the [Merck] study's chief investigator … hypothesized - if COX-2 inhibitors suppressed prostacyclin generated within blood vessels without suppressing thromboxane, increased clotting, leading to heart attacks and strokes, would result. October 19, 1998
McDarby v. Merck (N.J.A.D.2008) McDarby v. Merck
47

Unblinding the VIGOR Data
March 2000

McDarby v. Merck

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2000-03-09

Dr. Edward Scolnick
Head of Merck Research Labs\March 9, 2000

“The CV events are clearly there.”

12 days later Dr. Braun prescribed John McDarby his first dose of Vioxx
McDarby v. Merck 49

Merck Blames
Diabetes

No Excuses
Why didn‟t Merck warn? Why didn‟t Merck warn?

Age

Low good cholesterol

Why didn‟t Merck warn?

McDarby v. Merck

50

Is Naprosyn really better than aspirin? Or is Vioxx the problem?
The need for study post-VIGOR

McDarby v. Merck

51

Science vs. marketing

March 9, 2000, Dr. Edward Scolnick, the President of Merck's Research Division, in an e-mail about the VIGOR data stated: "The CV events are clearly there…It is a shame but it is a low incidence and it is mechanism based as we worried it was."
McDarby v. Merck (N.J.A.D. 2008)

McDarby v. Merck

52

I‟m in minor agony

April 12, 2000 e-mail to Dr. Alise Reicin from Dr. Scolnick re CV safety post-VIGOR I will tell you my worry quotient is high. I actually am in minor agony. What I really want to do is a 10,000 vs. 10,000 patient study… safety first primary endpoint and efficacy secondary or coprimary.
McDarby v. Merck 53

In the Spin Zone
Selling Vioxx to patients, regulators, physicians, investors after VIGOR

McDarby v. Merck

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Preaching to the profession
The New England Journal of Medicine COMPARISON OF UPPER GASTROINTESTINAL TOXICITY OF ROFECOXIB AND NAPROXEN IN PATIENTS WITH RHEUMATOID ARTHRITIS

McDarby v. Merck

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Pitching naproxen as cardioprotective

Testimony of Dr. Braun –

I was told … Vioxx was a safe drug, but it was not cardioprotective as Naprosyn is.
And I was told …to just make sure they don't stop taking their aspirin. (DaC 43414342)
McDarby v. Merck 57

SNDA – spinning VIGOR to the FDA

On June 29, 2000, Merck submitted a

supplemental new drug application to
add the VIGOR results to the Vioxx

label.

McDarby v. Merck (N.J.A.D. 2008)

McDarby v. Merck

58

SNDA – spinning VIGOR to the FDA

“Primarily, Merck sought to disclose that

the results of the VIGOR study provided
"conclusive evidence of the improved GI safety of [Vioxx] compared [Naprosyn]”

McDarby v. Merck (N.J.A.D. 2008)

McDarby v. Merck

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Good news about Naprosyn

McDarby v. Merck

60

Naprosyn is better than aspirin? an implausible hypothesis

Eric Topol, MD, Case-Western, Cleveland Clinic


you have a randomized trial and
an experimental, a new drug which hasn’t

been studied extensively – Vioxx and

an anchor drug, naproxen, that had been

available for 20 years

McDarby v. Merck

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Naprosyn is better than aspirin? an implausible hypothesis

A comparison shows there’s more than five-fold heart attacks and two-fold excess of cardiovascular serious events

How could you possibly conclude that it’s the naproxen being beneficial?

Eric Topol
McDarby v. Merck 62

Sullied study

Editorial – December 29, 2005 Expression of Concern: Bombardier et al., “Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis,” N Engl J Med 2000;343:1520-8. Gregory D. Curfman, M.D., Stephen Morrissey, Ph.D., and Jeffrey M. Drazen, M.D.
McDarby v. Merck 63

Sullied Study
 

Harlan Krumholz, Yale Cardiologist: … a strong concern being raised by this study. The additional three heart attacks would have increased the intensity of that concern, increased the level of risk associated with VIOXX in the results

McDarby v. Merck

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Sell, Sell, Sell

2001- 2002

McDarby v. Merck

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Selling the sales staff: It‟s the Naprosyn, stupid!

Anstice – vmm to sales staff 9/13/2001

To understand VIGOR you must
understand Naproxen is cardioprotective.

McDarby v. Merck

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Gung-ho marketing
 

David Anstice, direct By Mark Lanier

16 In fact, there's this whole training video. It is called "Be the Power" where two Merck salesmen 18 are dressed up like superheroes 23 There's a woman who is acting kind of whiny, “I'm afraid I'm going to get hurt if I take VIOXX”... And in the video… the VIOXX superheroes, the Merck superheroes are trained to take this card and use it like a ray gun.
McDarby v. Merck 67

 

Post-VIGOR – Safer than Placebo

Dr. Braun was also shown Merck's "CV Card," entitled Chemical Profile, Osteoarthritis Studies" that indicated no elevated risk of heart attack and, according to Dr. Braun, showed Vioxx to be safer than a placebo.
McDarby v. Merck 68

The CV Card – Omitting the Naproxen Comparator

McDarby v. Merck

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FDA v. Merck - the Inside Story
Turmoil and doubt – Is science or marketing in command?

McDarby v. Merck

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The only Essential study

Dr. Scolnick - September 13, 2001 memo: I want to give you a list of the only studies that I regard as ESSENTIAL. Essential means just that ESSENTIAL. Not preferred, not useful, not helpful; ESSENTIAL. . . . 1. For Vioxx: Only the CV outcome study ONLY ESSENTIAL STUDY!
McDarby v. Merck 71

Your marketing is misleading

FDA to Merck Warning letter 9/17/2001: Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to… Naprosyn (naproxen).
McDarby v. Merck 72

FDA Warning Letter to Merck
 

9/17/2001 You fail to disclose that your explanation is hypothetical has not been demonstrated by substantial evidence, and there is another reasonable explanation, that Vioxx may have pro-thrombotic properties.
McDarby v. Merck 73

Stonewalling

October 1, 2001 Anstice to sales staff: “Merck continues to stand behind the overall and cardiovascular safety of Vioxx." if you are asked any other questions about VIGOR by a health care professional or a customer, you may not answer the question.
McDarby v. Merck 74

The FDA Draft Label
UGLY CUBED

McDarby v. Merck

75

FDA’s draft label for Vioxx. October 15, 2001


Warnings Cardiovascular Disease VIOXX should be used with caution in

patients at risk of developing
cardiovascular thrombotic events

McDarby v. Merck

76

FDA’s draft label for Vioxx. October 15, 2001

The risk of developing myocardial infarction in the VIGOR study was five-fold higher in patients treated with VIOXX 50-mg (0.5%) as compared to patients treated with naproxen (0.1%)
McDarby v. Merck 77

FDA’s draft label for Vioxx. October 15, 2001

Prospective, well-powered, long term studies required to compare the incidence of serious CV events in patients taking VIOXX versus NSAID comparators other than naproxen have not been performed.
McDarby v. Merck 78

The CV Safety Study‟s Fate

By February 13, 2002, a letter of intent was sent by Dr. Alan Nies, Senior Vice-President for Clinical Sciences at Merck Research Laboratories to the Harvard Medical School with respect to the study. Despite Dr. Scolnick's urging, the study was never performed. McDarby v. Merck (N.J.A.D. 2008)
McDarby v. Merck 79

Fighting the FDA

McDarby v. Merck

80

Ugly cubed
October 15 2001 e-mail Dr. Scolnick to Anstice: David. Be assured we will not accept this label. If we need to we will ask to go to an advisory committee meeting.  Anstice replied:  . . . We knew it would be UGLY and it is. We'll fight back and see where we get.  Scolnick responded:  It is ugly cubed. They are bastards.

McDarby v. Merck 81

Risks to Sales – strength of label

McDarby v. Merck

82

Dilution: Burying the bad news
The FDA-Merck Compromise of 2002 – revised labeling

McDarby v. Merck

83

2002 FDA-Approved post-VIGOR Vioxx Label
 

Precautions Cardiovascular Effects The information below should be taken into consideration and caution should be exercised when VIOXX is used in patients with a medical history of ischemic heart disease.
McDarby v. Merck 84

2002 FDA Approved post-VIGOR Vioxx Label
 

Precautions Because of its lack of platelet effects, VIOXX is not a substitute for aspirin for cardiovascular prophylaxis.

McDarby v. Merck

85

The charge to the jury

McDarby v. Merck

86

The relevant period of time

When deciding whether plaintiff has

proven Merck failed to warn of
potential cardiovascular risks of

VIOXX®, that it knew or should have
known, the time frame to consider is

the time before Mr. McDarby’s heart
attack.
McDarby v. Merck 87

The burden of proof

To establish a claim of failure to

warn, plaintiff must prove all of the
following elements by a

preponderance (greater weight) of
the credible evidence:

McDarby v. Merck

88

Failure to provide adequate warning

l. That Merck failed to provide an adequate warning to prescribing doctors based on what Merck knew or should have known about the risks of VIOXX® in sufficient time before it was prescribed to the plaintiff to allow for an effective warning to be given to his prescribing physician.

McDarby v. Merck

89

Adequate warning (statutory)

In the case of a prescription drug, the warning must be one that a reasonably prudent manufacturer would have provided to adequately communicate information on the risks of the product to the prescriber, taking into account the characteristics of, and the ordinary knowledge common to, such prescribing physicians.
McDarby v. Merck 90

Adequate warning

You should look at the totality of the information given to the physicians about the drug and its risks, including information given in the package insert, in the published articles, in the promotional materials and the information provided by Merck’s sales representatives to doctors.
McDarby v. Merck 91

The learned intermediary doctrine and the extent of the duty

Why the emphasis on Doctors? Why not direct warning to the consumer? Should Merck have compared the risks and benefits of Vioxx to each of its competitors? Should a drug company’s duty differ from that of doctors as stated in Mastromonaco?
McDarby v. Merck 92

Elements – misuse and alteration

93

2. That when the injury happened VIOXX® was not being misused, or it had not been substantially altered in a way that was not reasonably foreseeable. There is no evidence in this case the product was misused by the plaintiff or altered in a way not reasonably foreseeable.
McDarby v. Merck 93

Elements – reasonably foreseeable user (or bystander)

94

3. That the plaintiff was a reasonably foreseeable user, or a person who might reasonably be expected to come in contact with VIOXX®.

There is no issue as to this fact.

McDarby v. Merck

94

95

Proximate cause

4. That VIOXX® was a proximate cause of Mr. McDarby’s injury and damages.

On what aspect of proximate cause was the jury’s finding directed by the court?
McDarby v. Merck 95

Proximate cause

By proximate cause is meant that the defect in the product was a substantial factor which singly, or in combination with another cause, brought about the illness. If the product in question, however, does not add to the risk of the occurrence of the particular illness and hence was not a contributing factor in the happening of the illness then plaintiff has failed to establish that a particular product defect was a proximate cause of the accident
McDarby v. Merck 96

The heeding presumption

If you find that Merck failed to provide an adequate warning, then the law requires you to presume that plaintiffs' doctors would have heeded that adequate warning and not have prescribed VIOXX to [plaintiffs]. However, to recover damages for their heart attacks, [plaintiffs] must still prove that their taking VIOXX was a proximate cause of their heart attacks. Why take this from the jury?
McDarby v. Merck 97

The Effect of FDA Approval Judge Higbee’s charge to the jury

We start with the presumption that if the FDA approved a drug label, then the warnings on the label are adequate. However, if plaintiff produces substantial evidence that the approved label is not an adequate warning, then the presumption can be overcome.
McDarby v. Merck 98

Overcoming the presumption Judging Merck

You, the jury, must …decide if plaintiff has met its burden of proving that Merck failed to provide an adequate warning to physicians.

McDarby v. Merck

99

Overcoming the presumption Judging Merck

If you find that plaintiff has proven by a preponderance of the evidence that after a label was approved there was new information that changed the known or knowable cardiovascular risks of VIOXX®
McDarby v. Merck 100

Overcoming the presumption Judging Merck

Then under FDA regulations, Merck had a duty to warn

physicians of any newly
discovered risks of the drug.

McDarby v. Merck

101

Overcoming the presumption Judging Merck

The FDA requires a drug manufacturer to warn the medical community as soon as there is reasonable evidence of

an association of a serious
hazard with a drug.
McDarby v. Merck 102

Overcoming the presumption Judging Merck

Merck could, if it chooses to without prior FDA approval, send letters to physicians, take out ads, publish in journals, or send out sales representatives in order to advise physicians of newly known risks of VIOXX®.
McDarby v. Merck 103

104

Overcoming the presumption
It is up to you to decide what Merck knew or should have known about whether there were potential cardiovascular risks of VIOXX® based upon reasonable evidence and when.
McDarby v. Merck 104

How did plaintiffs overcome the 105 presumption?

It is up to you to then determine

whether… Merck… acted
reasonably and adequately

warned physicians of any serous
cardiovascular risks…before the plaintiff was prescribed VIOXX®.
McDarby v. Merck 105