The Zantac Rule 702 Order: TLBR (Too Long, But Read)

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On opening an opinion, lawyers habitually roll their eyes when they see a table of contents.  Even more so when they learn the opinion is over 300 pages.  The MDL order granting defense motions to exclude experts and for summary judgment in In re Zantac (Ranitidine) Products Liability Litig. (S.D. Fla. Dec. 6, 2022), however, is a worthwhile read.  The court’s analysis and prose is thorough, clearly reasoned, well-supported, … and highly readable.  It reveals a court willing to roll up its judicial sleeves, tackle and explain the fundamental science in detail, and rigorously apply Rule 702 to perform its essential gatekeeping function – to insulate the jury, and the defendants, from flawed advocacy masquerading as scientific evidence and holding retained experts to reasonable standards of intellectual rigor.

The Zantac litigation involves claims that the active ingredient in popular heartburn medication ranitidine breaks down to produce excessive levels of NDMA, a probable human carcinogen, under certain storage and biological conditions.  That sounds scary.  FDA has set a low daily intake limit of NDMA, a byproduct of, among other things, a common diet.

But looking a little deeper, the FDA limit, like other regulatory precautionary exposure limits, incorporates a sizable safety margin.  Meeting that limit every day over the course of a lifetime is estimated to create a one-in-one-hundred-thousand cancer risk (.001%).  And despite a great deal of study, there seems to be little or no scientific evidence causally associating ranitidine exposure with the several cancers at issue in the litigation.

So how did these claims wind up in an MDL?  A pharmaceutical testing company filed a Citizen’s Petition with FDA claiming high levels of NDMA were in various popular ranitidine heartburn drugs.  That testing lacked scientific credibility, but FDA performed independent testing and found variable levels of NDMA that, while nowhere near the levels reported by the testing company, sometimes slightly exceeded the precautionary regulatory limits.  Testing by the manufacturers concurred.  Though the cancer risk at these levels was vanishingly infinitesimal, FDA and the manufacturers agreed to a voluntary recall.  Predictably, plaintiffs’ firms were off to the races, resulting in enough claims to ultimately justify an MDL.

Plaintiffs retained a chemist, Dr. Ramin Najafi, and his lab.  Pre-retention, he had tested the products at issue and found NDMA at levels similar to the harmless but excessive level found by FDA.  Post-retention, however, he changed testing protocols and recorded more alarming levels.  Plaintiffs also retained multiple epidemiologists and toxicologists, and other causation experts, and the defendants filed several complex motions to exclude their testimony and for summary judgment.

The court’s opinion exposes many common Rule 702 flaws:  Unreliable and unreasonably opaque methodologies; analytical gaps and inconsistencies; excessive reliance on statistically insignificant data and inapposite, irreconcilably confounded studies based on ill-fitting exposures far different in type and magnitude; and overly subjective and result-oriented weighing methodologies bearing multiple indicia of biased thumbs firmly placed on the scientific scales.

At the outset, plaintiffs tried to avoid their obligation to prove general causation, arguing that doing so was unnecessary under Eleventh Circuit law because NDMA is an acknowledged human carcinogen.  The court recognized this argument operated at too high a level of generality – the issue was whether ranitidine was capable of causing the cancers at issue at reasonably attainable exposure levels, not the toxicity of NDMA in the abstract.

Plaintiffs also argued they did not need to establish a toxic threshold, i.e., how much exposure to ranitidine is needed to cause the cancers.  The Eleventh Circuit requires a plaintiff to prove how much is too much as part of their general causation burden, to at least demonstrate a toxic threshold range.  And plaintiffs also need to demonstrate that they could reasonably have been exposed to that toxic level or more.  Thus, the court rejected the position that any exposure sufficiently increases the risk and supports general causation.

The court then turned to the question at hand, whether plaintiffs had produced reliable evidence that ranitidine can cause the cancers at the highest realistic level to which plaintiffs could have been exposed.  To establish exposure to a toxic dose, the plaintiffs proffered Dr. Najafi’s post-retention testing of the amount of NDMA generated by ranitidine consumption.  But the court took apart Dr. Najafi’s testing, piece-by-piece, and thoroughly (and at length) exposed numerous reliability flaws.  Dr. Najafi had deviated from FDA-validated methods, failed to validate the testing equipment and protocol, and inadequately documented the procedures and results, thereby evading replication.  The methodology lacked peer review and general acceptance, and it failed to address error rate.  The tests were plagued by excessive manual manipulation pursuant to subjective “judgment calls” by the individual analysts.  These irregularities were exacerbated because Dr. Najafi was “a mere conduit” for these opaque analyses; he could neither explain the manual inputs nor articulate any guiding principles controlling their application.  Various simulated tests involving different storage scenarios were also struck because the testing conditions were not shown to be substantially similar to real world conditions.

Most of this testing focused on the exogenous sources of NDMA, from ranitidine in the drugs, but plaintiffs also tried to boost the exposure levels by claiming that the NDMA content of the products was supplemented by endogenous formation of additional NDMA through the digestive process, a mechanism known as nitrosation.  But Dr. Najafi’s simulated testing was also struck for lack of foundation, and the in vitro and in vivo studies relied on by the experts failed to reliably support the theory.

Having stricken Dr. Najafi’s data, the court excluded another expert’s statistical analysis of that data.  Garbage-in is garbage-out.  This also eliminated the foundation for various causation opinions to the extent the experts relied on Dr. Najafi’s data.

Other general causation experts evaluated the epidemiological literature, relying on a weight-of-the-evidence approach to the data.  The court found their analyses flawed because they had not sufficiently explained their methodology and how they weighed the evidence.  They had also engaged in impermissible cherry-picking in selecting what evidence to credit and what evidence to reject, applying inconsistent standards and reasoning (characterized as “situational science”).  Plaintiffs also failed to demonstrate that individual studies were reliable, physiologically relevant, and reasonably extrapolatable to human experience.  For example, the court found proffered studies on cancer risk from dietary NDMA exposure through processed meats and occupational exposures in the rubber industry to lack relevance to ranitidine drug exposures.

Independently assessed, the relevant epidemiology evidence failed to find any causal association, and often any association at all, between ranitidine and the cancers at issue. The court also found the experts’ approach to the studies and conclusions drawn from them to be unreliable, including insufficient regard for the reliability standard of statistical significance analysis.

341 pages is a long way to go to reap the rewards of a well-reasoned vindication of Rule 702, but the experts were many, the science complex, and the grounds for exclusion were bountiful, and thoroughly considered and explained.  However readable, perhaps any opinion over 300 pages should earn the conscientious reader something like a Croix de Candlestick.  Back when the San Francisco Giants called Candlestick Park home, fans exiting after an extra inning night game in the summer cold and fog were given the Croix, an award pin, to memorialize their feat of endurance, inscribed “Veni, Vidi, Vixi.”  Translation:  “I came, I saw, I survived.”

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About the Author: Alan Lazarus

Alan J. Lazarus is a Products Liability Partner residing in our San Francisco, California, office. Alan is an experienced trial and appellate attorney with a focus on products liability, consumer protection, toxic substances and environmental litigation. Alan writes and lectures frequently on products liability and appellate practice topics.