As I have previously discussed, a risk ratio (RR) ≤ 2 is a strong practical argument against specific causation. See Courts and Commentators on Relative Risks to Infer Specific Causation; Relative Risks and Individual Causal Attribution; and Risk and Causation in the Law. But a relative risk greater than 2 threshold has little to do with general causation. There are any number of well-established causal relationships, where the magnitude of the ex ante risk in an exposed population is > 1, but ≤ 2. The magnitude of risk for cardiovascular disease and smoking is one such well-known example.
When assessing general causation from only observational epidemiologic studies, where residual confounding and bias may be lurking, it is prudent to require a RR > 2, as a measure of strength of the association that can help us rule out the role of systemic error. As the cardiovascular disease/smoking example illustrates, however, there is clearly no scientific requirement that the RR be greater than 2 to establish general causation. Much will depend upon the entire body of evidence. If the other important Bradford Hill factors are present – dose-response, consistent, coherence, etc. – then risk ratios ≤ 2, from observational studies, may suffice to show general causation. So the requirement of a RR > 2, for the showing of general causation, is a much weaker consideration than it is for specific causation.
Randomization and double blinding are major steps in controlling confounding and bias, but they are not complete guarantees that systematic bias has been eliminated. A double-blinded, placebo-controlled, randomized clinical trial (RCT) will usually have less opportunity for bias and confounding to play a role. Imposing a RR > 2 requirement for general causation thus makes less sense in the context of trying to infer general causation from the results of RCTs.
Somehow the Texas Supreme Court managed to confuse these concepts in an important decision this week, Merck & Co. v. Garza (August 26, 2011).
Mr. Garza had a long history of heart disease, at least two decades long, including a heart attack, and quadruple bypass and stent surgeries. Garza’s physician prescribed 25 mg Vioxx for pain relief. Garza died less than a month later, at the age of 71, of an acute myocardial infarction. The plaintiffs (Mr. Garza’s survivors) were thus faced with a problem of showing the magnitude of the risk experienced by Mr. Garza, which risk would allow them to infer that his fatal heart attack was caused by his having taken Vioxx. The studies relied upon by plaintiffs did show increased risk, consistently, for larger doses (50 mg.) taken over longer periods of time. The trial court entered judgment upon a jury verdict in favor of the plaintiffs.
The Texas Supreme Court reversed, and rendered the judgment for Merck. The Court’s judgment was based largely upon its view that the studies relied upon did not apply to the plaintiff. Here the Court was on pretty solid ground. The plaintiffs also argued that Mr. Garza had a higher pre-medication, baseline risk, and that he therefore would have sustained a greater increased risk from short-term, low-dose use of Vioxx. The Court saw through this speculative argument, and cautioned that the “absence of evidence cannot substitute for evidence.” Slip op. at 17. The greater baseline does not mean that the medication imposed a greater relative risk on people like Mr. Garza, although it would mean that we would expect to see more cases from any subgroup that looked like him. The attributable fraction and the difficulty in using risk to infer individual attribution, however, would remain the same.
The problematic aspect of the Garza case arises from the Texas Supreme Court’s conflating and confusing general with specific causation. There was no real doubt that Vioxx at high-doses, for prolonged use, can cause heart attacks. General causation was not at issue. The attribution of Mr. Garza’s heart attack to his short-term, low-dose use of Vioxx, however, was at issue, and was a rather dubious claim.
The Texas Supreme Court proceeded to rely heavily upon its holding and language in Merrell Dow Pharmaceuticals, Inc. v. Havner, 953 S.W.2d 706 (Tex. 1997). Havner was a Bendectin case, in which plaintiffs claimed that the medication caused specific birth defects. Both general and specific causation were contested by the parties. The epidemiologic evidence in Havner came from observational studies, either case-control or cohort studies, and not RCTs.
The Havner decision insightfully recognized that risk does not equal causation, but RR > 2 is a practical compromise for allowing courts and juries to make the plaintiff-specific attribution in the face of uncertainty. Havner, 953 S.W.2d at 717 . Merck latched on to this and other language, arguing that “Havner requires a plaintiff who claims injury from taking a drug to produce two independent epidemiological studies showing a statistically significant doubling of the relative risk of the injury for patients taking the drug under conditions substantially similar to the plaintiff’s (dose and duration, for example) as compared to patients taking a placebo.” Slip op. at 7.
The plaintiffs in Garza responded by arguing that their reliance upon RCTs relieved them of Havner‘s requirement of showing a RR > 2.
The Texas Supreme Court correctly rejected the plaintiffs’ argument and followed its earlier decision in Havner on specific causation:
“But while the controlled, experimental, and prospective nature of clinical trials undoubtedly make them more reliable than retroactive, observational studies, both must show a statistically significant doubling of the risk in order to be some evidence that a drug more likely than not caused a particular injury.”
Slip op. at 10.
The Garza Court, however, went a dictum too far by expressing some of the Havner requirements as applying to general causation:
“Havner holds, and we reiterate, that when parties attempt to prove general causation using epidemiological evidence, a threshold requirement of reliability is that the evidence demonstrate a statistically significant doubling of the risk. In addition, Havner requires that a plaintiff show ‘that he or she is similar to [the subjects] in the studies’ and that ‘other plausible causes of the injury or condition that could be negated [are excluded] with reasonable certainty’.40“
Slip op. at 13-14 (quoting from Havner at 953 S.W.2d at 720).
General causation was not the dispositive issue in Garza, and so this language must be treated as dictum. The sloppiness in confusing the requisites of general and specific causation is regrettable.
The plaintiffs also advanced another argument, which is becoming a commonplace in health-effects litigation. They threw all their evidence into a pile, and claimed that the “totality of the evidence” supported their claims. This argument is somehow supposed to supplant a reasoned approach to the issue of what specific inferences can be drawn from what kind of evidence. The Texas Supreme Court saw through the pile, and dismissed the hand waving:
“The totality of the evidence cannot prove general causation if it does not meet the standards for scientific reliability established by Havner. A plaintiff cannot prove causation by presenting different types of unreliable evidence.”
Slip op. at 17.
All in all, the Garza Court did better than many federal courts that have consistently confused risk with cause, as well as general with specific causation.
