We await with anticipation the outcome of Bartlett v. Mutual Pharmaceutical, the generic drug design-defect case recently heard by the Supreme Court, and for which a decision is expected in the next few months. Rather than focus on the important legal and regulatory ramifications of the pending decision (ramifications that have been getting a lot of press), in this post we decided to discuss some of the underlying science – i.e.
We await with anticipation the outcome of Bartlett v. Mutual Pharmaceutical, the generic drug design-defect case recently heard by the Supreme Court, and for which a decision is expected in the next few months. Rather than focus on the important legal and regulatory ramifications of the pending decision (ramifications that have been getting a lot of press), in this post we decided to discuss some of the underlying science – i.e., how drugs are thought to be associated with Steven’s Johnson Syndrome (SJS) and Toxic Epidemeral Necrolysis (TEN), the disease that plaintiff Bartlett suffered.
The Legal Arguments
By way of brief background, a central argument of Mutual Pharmaceutical is that the Food, Drug, and Cosmetic Act (FDCA) preempts state “design-defect” laws because the Act requires generic drug makers to manufacture drugs that are equivalent to the corresponding brand-name drug. It follows that the state law (New Hampshire in this case) on defective design makes it impossible to comply with the requirements of the FDCA.
Further, Mutual argued that this case fell under the Supreme Court’s decision in PLIVA, Inc. v. Mensing, which held that the FDCA and the Hatch-Waxman Act (which permits generic drug makers to sell their drugs following an abbreviated FDA approval pathway) preempted a state-created “failure-to-warn” claim. The outcome was clear: since generic drug makers do not have control of warnings on a drug label, they cannot be sued for not warning patients to the risks of taking the drug. Mutual contends that the holding also applies to claims alleging a product’s defective design.
Plaintiff lawyers argued that the NH design-defect state law does not conflict with federal law, since the state law does not impose a duty on generic manufacturers to modify their products. Further, plaintiffs contend that federal laws governing the design of generic drugs can be avoided if the generic manufacturers stopped producing the drug.
Plaintiff prevailed in the NH case and was awarded over $21 million for her injuries based on a NH products liability claim for defective design. The case is now before the Supreme Court on appeal. Obviously, from a legal perspective, a clear focus will be whether generic drug manufacturers can be held liable for design defect claims (given the fact that generic manufacturers don’t have control over the product label). Nevertheless, we believe that there is another interesting question specific to the disease claims at issue here: is there solid evidence for causation independent of liability?
What is SJS/TEN?
From a scientific and medical perspective, Bartlett v. Mutual Pharmaceutical was initiated based on allegations that Ms. Bartlett suffered a rare adverse skin reaction SJS, which progressed to TEN after being prescribed and taking the generic version of an anti-inflammatory drug (sulindac).
SJS is a devastating skin condition characterized by widespread detachment of epidermis and erosion of mucous membranes. The main distinguishing feature between the two is the extent of skin detachment, which is more limited in SJS, and more extensive in TEN.
Leading experts around the world concur that the incidence of these diseases remains very low (making them difficult to study epidemiologically), and the mechanism through which SJS/TEN occurs continues to elude scientists. Like many diseases, the etiology of SJS/TEN is poorly understood, likely complex, and can potentially be caused by many agents, including infection, drugs, genetics, environmental exposures, and likely other risk factors not yet identified.
Failure to Meet Causation Criteria
The key to making a reliable determination that sulindac is capable of causing SJS/TEN or that sulindac caused SJS in this particular plaintiff (specific causation) rests on a set of criteria and a methodology that we have described and discussed in previous posts (e.g., see here and here). ISS has repeatedly focused on helping litigators understand whether any agent (drug, environmental exposure, etc.) can be considered causative for some outcome. This involves compiling all of the available evidence and applying a set of systematic rules to evaluate that evidence and determine whether it meets reliable standards of causation.
We decided to perform a preliminary systematic review [for an example of a published systematic review, this is one by Repacholi et al. assessed the link between cell phone exposure and brain cancer] of the evidence relevant to sulindac and SJS/TEN.
The following search terms were used in the National Library of Medicine database using the Pubmed web portal:
(sulindac) AND ((stevens johnson syndrome) OR (toxic epidermal necrolysis))
Of the seventeen articles that were returned (12 articles in English and 7 in foreign language journals), only one reasonably controlled study was identified. The other articles were all reviews, case reports/case series, or editorials/commentaries. The single analytical studied identified, while it did report statistically elevated risk ratios for sulindac and SJS, utilized a somewhat unconventional approach by combining an analysis of a case control study, a drug registry, and a spontaneous reporting system. While this technique is perfectly reasonable for hypothesis generation, it should not be considered as reliable evidence of causation.
There has also been much discussion in the scientific literature regarding the mechanism through which a drug (such as sulindac), or any other agent, may be associated with SJS/TEN. Overall, the mechanism, if any, remains unknown, and many leading experts agree with this view.
Thus, if we don’t know how a given drug can cause a condition, and if we don’t have solid epidemiological evidence that there is an increased risk of that condition associated with that drug, in our view causation cannot be readily established. These limitations certainly make it difficult to draw any definitive conclusions about causation, regardless of the responsibility of generic drug manufacturers.
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