In re Zantac (Ranitidine) Prods. Liab. Litig.
| Docket Number | MDL NO. 2924 20-MD-2924 |
| Decision Date | 06 December 2022 |
| Citation | 644 F.Supp.3d 1075 |
| Parties | IN RE: ZANTAC (RANITIDINE) PRODUCTS LIABILITY LITIGATION. |
| Court | U.S. District Court — Southern District of Florida |
OMNIBUS ORDER ON ALL PENDING DAUBERT MOTIONS AND DEFENDANTS' SUMMARY JUDGMENT MOTION
1. Creation of this MDL ... 1096
2. Plaintiffs' Master Complaints ... 1096
3. Discovery ... 1098
4. Designated Cancers ... 1098
1. Expert Reports ... 1099
2. Daubert and Summary Judgment Briefing ... 1100
1. Qualification ... 1102
2. Reliability ... 1102
3. Helpfulness ... 1103
1. Definition of General Causation ... 1103
2. General Causation Inquiry in this MDL ... 1104
1. Dr. Najafi and Emery Pharma's Testing ... 1112
2. Experts Relying on Dr. Najafi and Emery Pharma's Testing ... 1159
3. Final Ruling on Plaintiffs' Internal Testing ... 1161
1. In Vivo Studies ... 1162
2. In Vitro Studies ... 1173
1. Summary of Epidemiological Concepts ... 1182
2. Summary of Parties' Arguments ... 1186
3. Defendants' Generalized Challenges to Plaintiffs' Epidemiology Experts ... 1187
4. Defendants' Specific Challenges to Plaintiffs' Epidemiology Experts ... 1221
5. Final Ruling on Epidemiology Motion ... 1264
1. Dr. Salmon's Dose-Response Relationship and Threshold Dose Opinions ... 1266
2. Remaining Experts' Dose-Response Relationship Opinions ... 1271
3. Drs. Panigrahy, Michaels, McTiernan, and Moorman's Threshold Dose Opinions ... 1273
1. Species and Dose Extrapolation ... 1279
2. Cancer Diagnosis Extrapolation ... 1283
1. Parties' Arguments ... 1285
2. Analysis ... 11285
This multidistrict litigation ("MDL") is about Zantac heartburn medication or, more particularly, the molecule marketed under the label name of Zantac: ranitidine. Ranitidine is no longer sold in the United States and many other parts of the world because, in the spring of 2020, the U.S. Food and Drug Administration requested that the manufacturers of ranitidine voluntarily recall their products and cease all future sales. All manufacturers complied. The voluntary recall of ranitidine is a logical starting point for the facts underlying this MDL, but it is not the best starting point.
The best starting point involves a private company known as Valisure. Valisure theorized that ranitidine has the potential to degrade into a carcinogen known as NDMA. To evaluate this theory, Valisure tested batches of ranitidine in various conditions and found NDMA—lots of it. To put the Valisure test results into proper context, the FDA's self-determined daily limit for NDMA in a drug is 96 nanograms, or 96 ng. Valisure's tests found NDMA in ranitidine in excess of 3,000,000 ng.
To achieve a test result of 3,000,000 ng, however, Valisure had to heat the ranitidine to a temperature well above the 98 degrees Fahrenheit found in the human body; Valisure used a temperature of 266 degrees Fahrenheit. When Valisure tested ranitidine with a temperature of 98 degrees Fahrenheit, Valisure detected no NDMA.
Valisure's testing, however, extended beyond just temperature-based tests. Using the human body's base temperature, Valisure tested ranitidine's reaction with salt in an artificial stomach. Once ranitidine was mixed with salt, Valisure detected NDMA in excess of 300,000 ng. The amount of salt Valisure used, however, is worth noting. According to a Plaintiffs' expert in this MDL, the amount of salt Valisure used to generate 300,000 ng of NDMA was so great that it was close to the level where, upon consumption, the salt intake would cause death. When Valisure tested ranitidine with salt concentrations more closely approximating what a human could safely ingest, Valisure detected no NDMA.
Valisure presented its findings to the FDA. The FDA did not immediately act on Valisure's information, however, for at least two reasons. First, the FDA concluded that the laboratory equipment that Valisure used to test for NDMA actually created NDMA. In other words, Valisure's laboratory equipment created the very substance for which it was testing. Second, the FDA wanted to conduct its own tests using laboratory equipment that did not create NDMA. Using its own laboratory equipment, the FDA tested ranitidine pills from several different manufacturers. Some of the ranitidine pills tested showed no NDMA or almost no NDMA. Others showed NDMA, but the NDMA was below the FDA's limit of 96 ng. Some ranitidine pills did show NDMA above 96 ng, but even the highest-tested pill showed NDMA at a tiny fraction of the level reported by Valisure.
Why then did the FDA initiate a voluntary recall of ranitidine? Although the FDA's tests revealed NDMA levels far below Valisure's, and although many of the FDA's tests showed NDMA levels that were acceptable, the fact remained that some of the FDA's tests showed ranitidine samples that eclipsed the 96 ng daily limit. Based upon the potential of some ranitidine pills to eclipse the 96 ng limit, the FDA initiated its voluntary recall of ranitidine.
Two key facts are important to an understanding of how the FDA's prior actions interplay with this case. First, one must consider what risk, if any, is posed by eclipsing the FDA's daily limit of 96 ng of NDMA. Second, one must consider the state of the science when this MDL was initiated. As for the FDA's daily limit, 96 ng per day (a nanogram is a billionth of a gram) is a conservative, protective limit.
According to the FDA, one could expect to consume this much NDMA from eating a meal of grilled or smoked meats, yet those foods are lawful to sell. Also, according to the FDA, if one were to consume 96 ng of NDMA every day, for 70 years in succession, the risk of cancer would be 1 in 100,000, or .001%.
As for the state of the science when this MDL was initiated, the first of the Plaintiffs' lawsuits were filed simultaneously with the Valisure petition to the FDA. Those lawsuits—and the first master complaint filed in this MDL—relied heavily upon Valisure's science. For example, the first master complaint in this MDL referred to Valisure's 266-degree heat as "modest" and the salt levels used by Valisure as "biologically relevant." Additionally, the Plaintiffs initially highlighted and relied upon a study overseen by Stanford University, which reported NDMA levels in ranitidine in excess of 47,000 ng.
Consistent with the FDA's findings as to the lack of validity of Valisure's laboratory equipment, the Plaintiffs ultimately elected not to rely upon Valisure's test results to prove their case. Relatedly, the Stanford University study was retracted by the study authors since, like Valisure, the Stanford laboratory equipment had created NDMA as part of the testing process. Much of the ranitidine-based science that predated this MDL, then, no longer furthered the Plaintiffs' case. As for ranitidine-based science that developed during the pendency of this MDL, that science also did not assist the Plaintiffs.
By way of example, the FDA commissioned a human clinical trial to determine whether ranitidine degrades into NDMA in the human body. That trial was completed in the summer of 2021 (a year after the voluntary recall and initiation of this MDL) and was conducted by FDA scientists. The FDA scientists concluded that they had found no evidence that ranitidine degrades into NDMA, even when the subjects in the study ate a diet rich with salt. Additionally, many epidemiological studies that focused on ranitidine were initiated and completed in 2020 and 2021, after the voluntary recall. None of the ranitidine-focused epidemiological studies concluded that ranitidine causes cancer, and most of the studies concluded that there was not even an association (a far lesser standard than causation) between ranitidine and cancer.
In light of this evidence, the Plaintiffs elected to prove their case through two avenues. First, the Plaintiffs retained a chemist to test ranitidine for NDMA. Second, the Plaintiffs retained epidemiologists who based their opinions, not on the conclusions of any ranitidine-based study author, but instead (for the most part) upon the raw data found in studies that analyzed NDMA-rich food and NDMA-rich air.
The chemist that the Plaintiffs retained to test ranitidine for NDMA used laboratory equipment that differed from the laboratory equipment used by the FDA. Using his equipment, he found NDMA levels in ranitidine far, far higher than those found by any governmental body in the world.1 For the reasons outlined in this Order, the methods used by the Plaintiffs' chemist were unreliable and resembled (in many respects) the testing conducted by Valisure. As the Court's ruling reflects, the only reliable testing of ranitidine puts the average amount of NDMA in ranitidine at roughly equivalent or slightly higher than the FDA's daily limit which, as discussed, equates to an infinitesimal, unprovable risk of cancer.
As for the Plaintiffs' reliance on studies of...
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