This post is an attempt to provide a snapshot of the multidistrict litigation (MDL) in the US concerning ranitidine, marketed under the name of Zantac.
Most of the information for this post comes from the 341 page ruling1 of December 2022 which includes the defendants summary judgement. You have the option reading an abbreviated version of the case here or here, a more detailed version in this post or a very detailed version in the ruling1 here.
About ranitidine
Ranitidine an H2 receptor blocker (“H2 blocker”) was commonly sold under the brand name Zantac. Cimetidine, commonly known as Tagamet, famotidine, commonly known as Pepcid, and nizatidine, commonly known as Axid, are also H2-blockers. H2-blockers decrease the amount of acid produced in the lining of the stomach. Because of this property, H2-blockers treated heartburn and many other gastro-intestinal disorders, including duodenal ulcers, gastroesophageal reflux disease (“GERD”), and oesophagitis.
Products with the active ingredient ranitidine are no longer sold in the United States because, in the spring of 2020, the U.S. FDA requested that the manufacturers of ranitidine voluntarily recall their products and cease all future sales. All manufacturers complied. The same applies in other parts of the world1.
Zantac – a brief history1,3,4
| Year | Event |
|---|---|
| 1983 | Glaxo Holdings Ltd, now a part of GlaxoSmithKline PLC, receives its first U.S. FDA approval for Zantac as a short-term treatment of a common form of ulcers. The drug was already approved in 31 different countries. |
| 1997 | Glaxo’s U.S. patent for ranitidine expires and competitors launch generic alternatives to the drug. |
| 1988 | Zantac becomes the world’s best selling drug and one of the first-ever drugs to top $1 billion in annual sales. |
| 1993 | GSK entered a joint venture with Warner-Lambert to develop an over-the-counter (“OTC”) form of Zantac, which the FDA approved in various forms in 1995 |
| 1998 | The joint venture between GSK and Warner-Lambert ended. Moving forward, Warner-Lambert controlled the sale of OTC Zantac in the United States and GSK controlled the sale of prescription Zantac. |
| 2000 | Pfizer merged with Warner-Lambert, along with the right to control the sale of OTC Zantac in the US. |
| 2004 | Pfizer gained FDA approval to sell over-the-counter versions of Zantac in the United States. |
| 2006 | Pfizer transferred the right to control the sale of OTC Zantac in the US, to Boehringer Ingelheim Pharmaceuticals. |
| 2017 | Boehringer Ingelheim ultimately sold the right to Sanofi. |
About N-Nitrosodimethylamine (NDMA)1
The FDA considers NDMA to be a carcinogenic impurity. The U.S. Environmental Protection Agency (EPA) and the International Agency for Research on Cancer (“IARC”) consider NDMA to be a probable human carcinogen and the U.S. Department of Health and Human Services considers NDMA to be a reasonably anticipated human carcinogen.
Studies have also shown that NDMA increases the risk of cancer in humans and animals. As a result of findings like these, the FDA set an acceptable daily intake (“ADI”) limit for NDMA at 96 nanograms.
Zantac (Ranitidine) Products Liability Litigation or the Zantac MDL
Zantac (more specifically the active ingredient, ranitidine), came under scrutiny after being linked to several forms of cancer. In 2019, some manufacturers and pharmacies6 halted sales of the drug over concerns that its active ingredient, ranitidine, degraded over time to form a chemical called NDMA5 which the FDA considers to be a carcinogenic impurity.
Lawsuits began piling up soon after the recalls began from people who said they developed cancer after taking Zantac. Plaintiffs said the companies knew, or should have known, that ranitidine posed a cancer risk and that they failed to warn consumers5.
GSK Plc, Sanofi SA, Pfizer Inc and Boehringer Ingelheim, the manufacturers of Zantac, are facing thousands of lawsuits that have been consolidated in various jurisdictions due to the large number of Zantac lawsuits and the similar fact patterns common to the cases.
Most Zantac lawsuits were consolidated in a federal multidistrict litigation (MDL) created on 6 February 2020 by the United States Judicial Panel on Multidistrict Litigation.
Note that this happened before the FDA requested voluntary withdrawal of all ranitidine containing products from the market on 1 April 2020.
The federal Zantac MDL was captioned 20-MD-2924-Rosenberg – In Re: Zantac (Ranitidine) Products Liability Litigation.
What were the plaintiffs claims against the brand name defendants?1
The plaintiffs claims were that the brand name defendants are liable for failing to warn consumers of the dangers of ranitidine through proper precautions and expiration dates, failing to test ranitidine for NDMA, negligently packaging and storing ranitidine, unjustly enriching themselves, defrauding consumers, and tortiously causing the plaintiffs to require medical monitoring. Significantly, the lynchpin of all of these claims was the proposition that ranitidine causes cancer, namely bladder, esophageal, gastric, liver, and pancreatic cancers as opposed to all other cancers.
Valisure and its citizen petition2
In order to understand what led to the MDL, we have to start with the company called Valisure an online pharmacy (licensed in a number of states in the US) and an analytical laboratory.
Valisure discovered the link between ranitidine and NDMA formation during its routine analysis of drug products in its pharmacy.
On 9 September 2019, Valisure submitted a citizen petition to request the FDA Commissioner to issue a regulation, revise industry guidance, and request a recall and suspend sales of ranitidine from the US market and take such other actions detailed in the petition.
What did Valisure hypothesise and how did it test the hypothesis?1
Valisure hypothesised that ranitidine has the potential to degrade into a carcinogen known as NDMA. Valisure tests all batches of all its medications for quality and consistency issues and through such tests detected extremely high levels of N-Nitrososdimethylamine (“NDMA”), a probable human carcinogen, in every lot tested, across multiple manufacturers and dosage forms of the drug ranitidine.
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 detected NDMA in excess of 3,000,000 ng per tablet when analysing ranitidine products, likely due to an inherent instability of the ranitidine molecule
Why did Valisure’s tests find such a large amount of NDMA in ranitidine?1
To achieve a test result of 3,000,000 ng per tablet however, Valisure had to heat the ranitidine to a temperature well above the 98 degrees Fahrenheit (36.7 degrees Celsius) found in the human body. In fact, Valisure used a temperature of 266 degrees Fahrenheit (130 degrees Celsius). When Valisure tested ranitidine with a temperature of 98 degrees Fahrenheit, it detected no NDMA.
Did Valisure’s testing extend beyond temperatre based testing?1
Yes it did. 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.
Did the FDA take immediate action based upon Valisure’s citizen petition?1
No, the FDA did not immediately act on Valisure’s information for at least two reasons which are:
- First, the FDA concluded that the laboratory equipment that Valisure used to test for NDMA actually created NDMA i.e. 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.
What testing did the FDA conduct and what were the findings?1
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. On 1 November 2019 FDA announced that it had found levels of NDMA that exceeded its acceptable daily intake (ADI) limit, in some ranitidine products.
Why did the FDA decide to initiate a voluntary recall of all ranitidine containing products in spite of the findings from the tests that it conducted?1
Although the FDA’s tests revealed NDMA levels far below Valisure’s and 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.
Important key facts to understand how the FDAs prior actions impact this case1
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. The FDA’s limit of 96 ng per day 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%.
- Second, one must consider 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— 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.
Much of the ranitidine-based science that predated this MDL did not further the Plaintiffs’ case.
Did the Plaintiffs rely upon Valisure’s test results to prove their case?1
Consistent with the FDA’s findings about 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.
What happened to the Stanford study?1
The Stanford University study was retracted by the study authors because, like Valisure, the Stanford laboratory equipment had created NDMA as part of the testing process.
The ranitidine based science during the pendency of the MDL1
The ranitidine-based science that developed during the pendency of this MDL, 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.
So, if the Plaintiffs could not use the Valisure citizen petition or the Stanford study or the ranitidine based science to try and prove their case, what evidence did they use?1
The Plaintiffs elected to prove their case via the following two avenues:
- First, the Plaintiffs retained a chemist to test ranitidine for NDMA. This chemist 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. For the reasons outlined in the summary judgement, the methods used by the Plaintiffs’ chemist were unreliable and resembled (in many respects) the testing conducted by Valisure.
- 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 analysed NDMA rich food and NDMA-rich air. Those studies focused on the consumption of processed meats and the inhalation of fumes in rubber factories. Processed meats contain other carcinogens besides NDMA, and people struggle to accurately remember what they have eaten the prior day, let alone what they have eaten throughout the entire course of their lifetime and the inhalation of rubber factory fumes (which also contain many carcinogens in addition to NDMA) is too far removed from the ingestion of ranitidine to be reliably applied in this MDL.
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.
The summary judgement
The simple version
U.S. District Judge Robin Rosenberg of West Palm Beach, Florida, held in a 341-page ruling that the plaintiffs lawyers failed to offer credible scientific evidence that the heartburn drug Zantac causes liver, bladder, pancreatic, esophageal or stomach cancer. Based on that conclusion, the judge granted summary judgment to the defendants, which include GSK Plc, Pfizer Inc, Sanofi SA and Boehringer Ingelheim.3
The legal version1
Federal Rule of Civil Procedure 56 requires a court to grant summary judgment for a moving party when the party proves that there is no genuine dispute of material fact and that the party is entitled to judgment as a matter of law. In a products liability MDL, the plaintiff must have admissible primary evidence with which to establish general causation. As a result, if the plaintiff does not have this evidence, then there is no genuine dispute of material fact, and the defendant is entitled to judgment as a matter of law.
In this case, as explained in the omnibus order and defendants summary judgement, the Plaintiffs failed to produce admissible primary evidence of general causation. Accordingly, it is hereby ORDERED AND ADJUDGED that:
The Defendants:
- Daubert Motions on general causation were GRANTED
- Motion for Summary Judgment was GRANTED
- miscellaneous expert-related motions are DENIED AS MOOT.
The Plaintiffs’ Daubert Motions to strike the Defendants’ general causation experts were DENIED without prejudice as moot.
What happens next?
The ruling by U.S. District Judge Robin Rosenberg in West Palm Beach, Florida, knocks out about 50,000 claims in federal court, though it does not directly affect tens of thousands of similar cases pending in state courts around the country.5
“We are extremely surprised by this miscarriage of justice,” and “fully expect” the ruling will be reversed on appeal, lawyers for the plaintiffs said in a joint statement.5
References:
- Omnibus order on all pending Daubert motions and defendants summary judgement. The order is over 300 pages long because the Court endeavoured to carefully explain each reason why the Plaintiffs’ experts have utilised unreliable methodologies to reach their conclusions.
- Valisure citizen petition on ranitidine – September 9 2019
- Drugmakers’ huge win in consolidated Zantac case shows process can work for defendants (December 7 2022) –Reuters
- Arnold & Itkin website
- GSK, Pfizer, Sanofi fend off thousands of U.S. lawsuits over alleged Zantac cancer link (December 6 2022) –Reuters
- Why Pharmacies Are Suspending Sales Of Zantac (October 1 2019) – Forbes
- Zantac Lawsuit Update January 2023: What You Need To Know About The Heartburn Medication (January 10 2023) – Forbes