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Embracing risk factors in pharmaceutical litigation: plaintiff lawyers tend to be reluctant to take on a drug injury case unless the client has few or no risk factors for the injury alleged. But attorneys who take the road less traveled may discover it's the quickest path to success.

I never realized that there was a similarity between being a successful professional golfer and being a successful trial lawyer until I heard former professional golfer David Feherty say these words: "Successful people want to place themselves in a spot where they are uncomfortable." It is easy for either professional to become complacent and seek to operate solely within a "comfort zone." The young golfer to whom Feherty was referring had never won a golf tournament before, and judging by the way his knees quivered as he stood over a short putt to win the tournament, he was definitely in an uncomfortable place.

Lawyers representing plaintiffs in pharmaceutical products cases could take a lesson from that young golfer. The strategy among attorneys representing individuals injured by unreasonably dangerous drugs has typically been to seek out and litigate only the "clean cases"--those in which the injured person has few or no underlying risk factors such as diabetes, hypertension, hypercholesterolemia, and a history of smoking.

To be truly successful in the representation of our clients, we must embrace these seemingly uncomfortable cases and handle them professionally and competently. Not doing this constitutes a tragic disservice to the multitude of individuals who have been seriously wronged.

Many of the trials involving Cox-2 inhibitors that resulted in successful plaintiff verdicts have strategically incorporated the injured party's known risk factors into the case presentation. (1) The tactics used in these cases may be useful in other pharmaceutical cases.

Relative risk

General causation tends to be the linchpin of a pharmaceutical company's defense of a claim alleging that a drug was defective or unreasonably dangerous. In the Cox-2 litigation, however, a plethora of clinical, epidemiological, and animal studies have helped shift the focus in individual cases to specific causation.

Jurors in these cases have a conceptual causation hurdle to overcome because no specific "signature injury" is associated with Cox-2 inhibitor use. A plaintiff attorney must convince jurors that even in the absence of a signature injury, the drug was the cause of, or at least a substantial contributing factor to, the plaintiff's injury.

This may seem onerous considering that Cox-2 inhibitors have typically been prescribed for the treatment of osteoarthritis and rheumatoid arthritis and are mainly used by the elderly, a population exhibiting risk factors for injuries attributed to Cox-2 inhibitor use: heart attacks and strokes. These cardiovascular problems--often a result of atherosclerosis--are among the most common injuries and causes of death within the elderly population in this country. (2)

The pharmaceutical companies' primary defense in this litigation has been that, since 300,000 to 400,000 people die of heart attacks each year in the United States alone, no one can prove that a Cox-2 inhibitor caused or contributed to any one person's heart attack or stroke. (3)

Not surprisingly, the cases have been a prime breeding ground for Daubert motions. (4) The key to slaying the Daubert beast and proving specific causation lies within the field of epidemiology and the Cox-2 inhibitor clinical trials conducted by the pharmaceutical companies. The data from Merck's and Pfizer's internal clinical trials, for example, establishes the increased risk of adverse cardiovascular events associated with using Cox-2 inhibiting drugs. (5)

Epidemiologists study populations to determine the frequency and distribution of disease and measure the related risks. Pharmacoepidemiology, a more specialized area of epidemiology, examines drug use in society and the process of identifying and responding to safety issues associated with drugs.

With even a cursory study of epidemiology, a lawyer quickly becomes familiar with the term "relative risk"--a quantitative measure used to describe the increase (or decrease) in the risk associated with a specific risk factor. Relative risk is the ratio of two absolute risks: The numerator is the absolute risk among those people with the risk factor (for example, the risk of heart attack among people who are 50 or older, with the risk factor being advanced age), and the denominator is the absolute risk among those without the risk factor (the risk of heart attack in people younger than 50). (6)

A plethora of published medical and scientific literature establishes a statistically significant increased relative risk for adverse cardiovascular events associated with Vioxx use. Internal Merck studies prove that this elevated relative risk exists for all dosages taken for any duration. (7) Merck-sponsored and independent studies also indicate that the hazard associated with Vioxx is immediate. (8)

Attorneys need look no further than the Federal Judicial Center's Reference Manual on Scientific Evidence to discover how to use this information effectively. (9) The section entitled "What Role Does Epidemiology Play in Proving Specific Causation?" is particularly helpful:
 The threshold for concluding that an agent
 was more likely than not the cause of an individual's
 disease is a relative risk greater
 than 2.0. Recall that a relative risk of 1.0
 means that the agent has no effect on the incidence
 of disease. When the relative risk
 reaches 2.0, the agent is responsible for an
 equal number of cases of disease as all other
 background causes. Thus, a relative risk
 of 2.0 (with certain qualifications noted below)
 implies a 50% likelihood that an exposed
 individual's disease was caused by the
 agent. A relative risk greater than 2.0 would
 permit an inference that an individual
 plaintiff's disease was more likely than not
 caused by the implicated agent. (10)


In any case where a pharmaceutical agent creates an increased relative risk of an adverse event greater than 2, the plaintiff's attorney can definitively state from a scientific and epidemiological standpoint that the event was more likely than not caused by the agent. An increased relative risk of greater than 2 substantiates the plaintiff's 51 percent burden of proof.

Merck's large randomized controlled clinical trials unequivocally do this, and plaintiff attorneys representing clients who took Vioxx can use that evidence to establish not only that the drug more likely than not caused an adverse cardiovascular event but also that with certain users--those with a history of symptomatic atherosclerotic disease--Vioxx was much more likely than any preexisting risk factor to have caused the event.

Yet plaintiff attorneys shouldn't abandon a particular study simply because it does not meet the statistical definition of significance--a relative risk greater than 2. For example, many studies of Cox-2 inhibitors have revealed an increased relative risk of cardiovascular injury, albeit at a rate less than the twofold level. Plaintiff lawyers should encourage the jury to examine the available literature in its totality. In the case of Cox-2 inhibitors, the evidence as a whole reveals not only that there are clear, immediate hazards associated with the drugs, but also that the industry has known about these dangers for years.

Attributable risk ratio

A plaintiff attorney, through his or her experts, must also become familiar with the concept of the attributable risk ratio--"a measurement of the excess risk that can be attributed to an agent, above and beyond the background risk due to other causes." (11)

An attributable risk ratio is the calculation of the percentage contribution to the particular adverse event that can be conclusively assigned to the pharmaceutical agent. It can be easily calculated using the following formula: Attributable risk ratio equals the relative risk minus 1 divided by the relative risk (ARR= (RR- 1)/RR). (12)

For example, in the Vioxx context, the attributable risk ratio can be calculated by plugging in the increased relative risk of heart attack (5) observed in one of the published studies of subjects taking the drug: (13)

Attributable Risk Ratio (ARR) = (5-1)/5, or 4/5, or 80 percent

With this calculation, an expert or trial attorney could state from a scientifically reliable and a Daubert-defensible standpoint that Vioxx contributed at least 80 percent to the plaintiff's heart attack--independent of any underlying risk factors the defense may attribute to the plaintiff. It also highlights the true hazards associated with this dangerously defective drug.

The concepts of relative risk and attributable risk ratio are indispensable for an attorney who accepts a client's risk factors as a beneficial aspect of a pharmaceutical case and actively pursues the issue at trial. Merck's own clinical study, for example, reveals a much greater hazard associated with Vioxx for users who have preexisting risk factors. Its APPROVe trim revealed that diabetics were exposed to a 6.1-fold increase in the relative risk of suffering an adverse cardiovascular event. (14)

The same study revealed that patients with a history of symptomatic atherosclerotic cardiovascular disease were exposed to a 9.59-fold increase in relative risk. Thus, Merck's APPROVe trial revealed that patients who took Vioxx and had either diabetes or a history of symptomatic atherosclerotic cardiovascular disease were exposed to an increased risk of suffering adverse cardiovascular events of 610 percent and 959 percent, respectively.

An attorney handling a case, for example, of a diabetic man who suffered a heart attack while taking Vioxx could use his history of diabetes--coupled with Vioxx usage--as a powerful tool of persuasion. The increased relative risk of 6.1 for a diabetic Vioxx user results in an attributable risk ratio of 83.6 percent (ARR = (6.1 - 1)/6.1, or 5.1/6.1, or 83.6 percent). This type of scientifically reliable information can be compelling to a jury in search of a method by which to connect a plaintiff's Vioxx use to a heart attack or stroke.

The same principles apply to other individual risk factors for which Cox-2-related clinical trials have demonstrated an increased risk. In the APPROVe trial, researchers examined the potential increased relative risk of adverse cardiovascular events in high-risk populations. They noted that "a high cardiovascular risk was defined by a history of symptomatic atherosclerotic cardiovascular disease or the presence of at least two of the following risk factors for coronary artery disease: a history of hypertension, a history of hypercholesterolemia, a history of diabetes, or current cigarette use." (15)

In one of my firm's Vioxx cases, we used forms designed by researchers for the Framingham Heart Study to establish the plaintiff's predisposition--based on his risk factors--for a heart attack. (16) The analysis served as the foundation for a pharmacoepidemiologist to calculate Vioxx's contribution to the heart attack based on the increased relative risks revealed in Merck's various clinical trials. Using the scientifically reliable principles discussed above, the pharmacoepidemiologist concluded that given the plaintiff's risk factors and family history, the quantifiable contribution of Vioxx to the plaintiff's heart attack was 56 percent.

There is one potential drawback to using epidemiologic and pharmacoepidemiologic calculations to prove causation. The calculations can be both difficult for some jurors to understand and, if not effectively presented, mind-numbingly dull. To avoid losing jurors' attention, keep the concepts as simple as possible and ensure that the information is presented in an understandable manner.

Also, as clearly presented as the information may be, plaintiff counsel cannot predicate his or her entire specific causation case on epidemiology and pharmacoepidemiology. A medical practitioner will be needed, too.

Counsel should educate the practitioner about relevant clinical trials. The doctor can then review the plaintiff's medical history--and any predisposing risk factors--and note that based on the results of the relevant clinical trials, the plaintiff was the type of person to whom doctors should have never given the dangerously defective drug.

Risk factor or injury?

The plaintiff attorney who is considering taking a pharmaceutical injury case should also consider that sometimes a potential client's risk factor may actually be a drug injury. For example, atherosclerosis, or coronary artery disease, is a risk factor for heart attack but also can be caused by Cox-2 inhibitor drugs.

Atherosclerosis is one of the most common ailments in Western society. It was once deemed a disease associated primarily with the elderly, but postmortem examinations of young men who died in the Korean War revealed that soldiers as young as 17 had atherosclerotic plaques, a buildup of fat and other debris on the inner walls of blood vessels. (17)

It is well established in medical literature that heart attacks are often caused when plaques rupture or break open within the coronary arteries and cause blood clots that obstruct blood flow to the heart. (18) Consequently, many attorneys have rejected cases of potential clients who had a history of atherosclerosis and who suffered a heart attack after taking a Cox-2 inhibitor.

Yet medical and clinical literature unequivocally establishes that Cox-2 inhibitors increase atherosclerosis progression and initiate atherogenesis--the development of atherosclerosis. A Merck-sponsored study involving a genetically altered mouse model came to this conclusion: "Lesion analysis showed that selective Cox-2 inhibition ... increases atherosclerotic lesion area." (19)

This finding has been replicated in other published studies. (20) Recently released follow-up data from the APPROVe trial further establishes that Cox-2 inhibition contributes to atherosclerotic progression and atherogenesis, and that the hazard continues even after the drug is discontinued. (21)

These findings may warrant a reevaluation of Cox-2 cases involving a client with a history of atherosclerosis. The very preexisting risk factor that may have prompted declining the case in the past may now, in fact, encourage its pursuit. What was previously presumed to be a preexisting risk factor--atherosclerosis or atherogenesis--may be the actual injury caused by the Cox-2 inhibitor. This strategy passed Daubert scrutiny and was effectively applied at the recent Barnett Vioxx trial. (22)

Embracing an uncomfortable position

The pharmaceutical industry failed to disseminate data about the hazards associated with its Cox-2 inhibitor drugs. (23) Consequently, patients and their prescribing physicians were never afforded an opportunity to examine the true risks associated with these medications before using them.

Had doctors or consumers been adequately informed that individuals with specific underlying risk factors were many times more likely to suffer a heart attack or stroke if they consumed Vioxx or another Cox-2 inhibitor, the drugs never would been prescribed in such magnitude. The 38,000 Vioxx-related deaths and the 88,000 to 144,000 Vioxx-related heart attacks and strokes that have occurred in the United States alone may have been prevented. (24)

Some lawyers may be reluctant to accept these cases and other pharmaceutical liability cases if a potential client is not "clean." But I would encourage them to remember that golfer who had the courage to move out of his comfort zone. We should not turn our backs on elderly or infirm individuals, who are specifically targeted by pharmaceutical companies because they are not healthy. Incentives abound to enter this potentially uncomfortable place and actively pursue a trial strategy that uses preexisting risk factors to defeat Daubert motions and defense arguments.

Notes

(1.) Beasley, Allen, Crow, Methvin, Portis & Miles and Robinson Calcagnie Robinson successfully used this strategy in the recent federal Vioxx consolidated proceedings. Mark Lanier and Rob Gordon effectively applied this theory in New Jersey proceedings. Kathy Snapka and Mark Lanier both used it in their Texas state court cases. Barnett v. Merck & Co., No. 06-CV-0485-L, MDL No. 1657 (E.D. La. Aug. 17, 2006); Cona v. Merck & Co., No. ATL-L-3553-05MT (N.J. Super.Apr. 11, 2006); McDarby v. Merck & Co., No. ATL-L-1296-05MT (N.J. Super. Apr. 11, 2006); Garza v. Evans, No. DC-03-84 (Tex., Star Co. 229th Jud. Dist. Apr. 21,2006); Ernst v. Merck & Co., No. 19961*BH02 (Tex., Brazoria Co. 23rd Jud. Dist. Apr. 19, 2005).

(2.) Goran K. Hansson et al., Inflammation, Atherosclerosis, and Coronary Artery Disease, 352 New Eng. J. Med. 1685, 1686 (2005).

(3.) Michael Rubart & Douglas Zipes, Mechanisms of Sudden Cardiac Death, 115 J. Clinical Investigation 2305, 2305-15 (2005).

(4.) See Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579 (1993); see also Gen. Elec. Co. v. Joiner, 522 U.S. 136 (1997); Kumho Tire Co. v. Carmichael, 536 U.S. 137 (1999).

(5.) The studies are known as VIGOR, ADVANTAGE, 090, APPROVe, VICTOR, and 203. See e.g. Claire Bombardier et al., Comparison of upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis, 343 New Eng. J. Med. 1520, 1520-28 (2000); Debabraka Mukherjee et al., Risk of Cardiovascular Events Associated with Selective Cox-2 Inhibitors, 286 JAMA 954, 954-59 (2001). See also Fred E. Silverstein et al., Gastrointestinal Toxicity with Celecoxib Versus Nonsteroidal Anti-Inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis: The CLASS Study, 284 JAMA 1247 (2000).

(6.) Definition available at http://en.wikipedia. org/wiki/Relative_risk, (last accessed Oct. 3, 2006).

(7.) Bombardier et al., supra n. 5; Jeffrey R. Lisse et al., Gastrointestinal Tolerability and Effectiveness of Rofecoxib Versus Naproxen in the Treatment of Osteoarthritis, 139 Annals Internal Med. 539 (2003); Peter Juni et al., Risk of Cardiovascular Events and Rofecoxib: Cumulative Meta-Analysis, 364 Lancet 2021 (2004); Daniel H. Solomon et al., Relationship Between Selective Cyclooxygenase-2 Inhibitors and Acute Myocardial Infarction in Older Adults, 109 Circulation 2068, 2068-73 (2004); Julia Hippisley-Cox & Carol Coupland, Risk of Myocardial Infarction in Patients Taking Cyclo-Oxygenase-2 Inhibitors or Conventional Nonsteroidal Anti-Inflammatory Drugs: Population Based Nested Case-Control Analysis, 330 Brit. Med. J. 1366, 1366-73 (2005); Tilo Grosser et al., Biological Basis for the Cardiovascular Consequences of Cox-2 Inhibition: Therapeutic Challenges and opportunities, 116 J. Clinical Investigation 4 (2006).

(8.) Linda E. Levesque et al., Time Variations in the Risk of Myocardial Infarctions Among Elderly Users of Cox-2 Inhibitors, 174 Can. Med. Assn. J. 1563 (2006); see Solomon et al., supra n. 7.

(9.) Fed. Jud. Ctr., Reference Manual on Scientific Evidence 381-84 (2d ed., Matthew Bender 2000).

(10.) Michael D. Green et al., Reference Guide on Epidemiolgy, in Fed. Jud. Ctr., Reference Manual on Scientific Evidence, 333, 384, 384 n. 140 (2d ed., Matthew Bender 2000).

(11.) Id. at 385.

(12.) Id.

(13.) Bombardier et al., supra n. 5.

(14.) Robert S. Bresalier et al., Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial, 352 New Eng. J. Med. 1092, 1097 (2005).

(15.) Id.

(16.) The Framingham study is a decades-long cardiovascular analysis of the inhabitants of a small town. Study subjects filled out forms designed to assess their potential risk for an adverse cardiovascular event based on their medical history and risk factors. See Framingham Heart Study: 50 Years of Research Success, www.nhlbi.nih.gov/ about/framingham (last accessed Oct. 3, 2006); see also Scott M. Grundy et al., Assessment of Cardiovascular Risk by Use of Multiple-Risk-Factor Assessment Equations: A Statement for Healthcare Professionals from the American Heart Association and the American College of Cardiology, 100 Circulation 1481, 1481-92 (1999), http://circ.ahajournals. org/cgi/content/full/100/13/1481 (last accessed Oct. 3, 2006).

(17.) William F. Enos et al., Landmark Article, July 18, 1953: Coronary Disease Among United States Soldiers Killed in Action in Korea, 256 JAMA 2863 (1986).

(18.) Hansson et al., supra n. 2, at 1686.

(19.) David Rott et al., Effects of MF-Tricyclic, a Selective Cyclooxygenase-2 Inhibitor, on Atherosclerosis Progression and Susceptibility to Cytomegalovirus Replication in Apolipoprotein-E Knockout Mice, 41 J. Am. College Cardiology 1812, 1816 (2003) (emphasis in original).

(20.) Takuya Kobayashi et al., Roles of Thromboxane A2 and Prostacyclin in the Development of Atherosclerosis in ApoE-Deficient Mice, 114 J. Clinical Investigation 784, 784-94 (2004).

(21.) See www.merck.com/newsroom/vioxx/ Pdf/APPROVe_Extension_Statistical_Package. pdf (last accessed Oct. 3, 2006).

(22.) Barnett, No. 06-CV-0485-L, MDL No. 1657.

(23.) Gregory D. Curfman et al., Expression of Concern: Bombardier et al., "Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis, "353 New Eng. J. Med. 2813, 2813-14 (2005); Gregory D. Curfman et al., Expression of Concern Reaffirmed, 354 New Eng. J. Med. 1193 (2006); Correction: Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial, 355 New Eng. J. Med. 221 (2006).

(24.) David J. Graham et al., Risk of Acute Myocardial Infarction and Sudden Cardiac Death in Patients Treated with Cyclo-Oxygenase 2 Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs: Nested Case-Control Study, 365 Lancet 475 (2005); Eric J. Topol, Failing the Public Health--Rofecoxib, Merck, and the FDA, 351 New Eng. J. Med. 1707 (2004).

J. PAUL SIZEMORE practices law at Beasley, Allen, Crow, Methvin, Portis & Miles in Montgomery, Alabama.
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