Every pharmaceutical and medical device lawyer knows that the heart of the general causation defense lies in insisting on the need for controlled scientific studies linking the exposure to the disease entity. Indeed, controlled epidemiological studies are the tools required to meet many of the Hill criteria (e.g., strength and consistency of association must be demonstrated using these types of studies).
Every pharmaceutical and medical device lawyer knows that the heart of the general causation defense lies in insisting on the need for controlled scientific studies linking the exposure to the disease entity. Indeed, controlled epidemiological studies are the tools required to meet many of the Hill criteria (e.g., strength and consistency of association must be demonstrated using these types of studies). In a perfect world, the evidence goes beyond the observational realm and the relationship is established using the gold standard: randomized controlled trials (RCTs).
The need for controlled scientific studies to infer general causation in product liability and toxic tort litigation goes back decades. Clearly, this argument was made in the Bendectin litigation, the very cases that led to the Daubert decision. This laid the groundwork for strong pro-defense rulings in many subsequent cases, including litigation involving Prozac, breast implants, phen-fen, welding rods, and cellular telephones. In each of these cases, the Defense crafted strong arguments requiring the demonstration of statistical associations using controlled scientific studies (mostly analytical epidemiological study designs but also RCTs). We have written about the process for inferring causation in a pharmaceutical or medical case.
But are controlled studies always necessary to establish a causal inference? Of course the key to answering this question is to determine whether exceptions to the rule exist.
After reading and discussing two recent blog posts by Nathan Schachtman relating to recent rulings in the gadolinium litigation (see here and here), I began to question the inviolability of this rule. By way of brief background, gadolinium is a paramagnetic chemical ion used as a contrast agent in MRI scans to improve the results from imaging studies. The problem is that, in its ionic form, gadolinium is known to be highly toxic. Since the late 1970s, gadolinium has been causally linked to a rare condition known as nephrogenic systemic fibrosis (NSF). And it turns out (and as Nathan points out in his posts), the basis for the causal inference in this situation is entirely due to evidence from case reports.
To be sure, there are extenuating circumstances making a causal inference in this situation reasonable. Most notably, NSF is an exceedingly rare condition that has rarely been observed outside exposure to gadolinium. This type of disease entity is often referred to as a “signature disease.” In addition, because gadolinium exposure is rare (it is only seen in the context of this contrast agent), the signal is easier to detect than more commonly observed exposures. Furthermore, gadolinium’s toxicity is well characterized and the mechanism underlying its ability to cause NSF is reasonably well understood. Finally, because gadolinium-based contrast agents are intravenous drugs, the NSF case reports are well characterized with lots of medical detail.
So is the basis for concluding that gadolinium can cause NSF an anomaly? Is this the only situation where we can rely on a series of case reports to establish a causal inference? Stepping back, it appears that it may not be.
We were able to come up with the following additional examples where an exposure has been readily accepted to cause an adverse health effect without the benefit of controlled scientific data:
Each of these cases appear to represent examples where causation was reasonably well accepted by the medical community before data from controlled epidemiogical studies were documented. In some cases, the inference was later confirmed by controlled epidemiological studies; but only after causation was well accepted (e.g., amphibole asbestos and malignant mesothelioma). In the case of thalidomide, the risk of teratogenicity was so high it literally jumped off the page from a study of spontaneous, anecdotal case reports.
Looking for commonalities, one could argue that the following factors are important: (a) low or no background rate of the disease condition; (b) low background rate of the exposure; (c) a clear understanding of the mechanism of action. However, none of these factors is essential, as there appear to be exceptions to each factor.
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