Mass Tort – Proton Pump Inhibitor Litigation (is it likely to fail?)

Since the introduction of omeprazole in 1989, proton pump inhibitors (PPIs) have steadily become the mainstay in the treatment of acid-related disorders. The general clinical uses of PPIs include – healing of peptic ulcer disease, peptic ulcer-related gastrointestinal bleeding, prevention of NSAID (Motrin-type medications) induced gastroduodenal ulcers, treatment of Zollinger-Ellison syndrome, treatment of erosive gastritis, treatment of functional dyspepsia, and eradication of H. pylori infection. There are currently six FDA approved PPIs – omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), dexlansoprazole (Dexilant), pantoprazole (Protonix), and rabeprazole (AciPHex). Despite an excellent safety profile throughout their first two decades of use, the nearly universal popularity of PPIs has prompted several concerns about both their short- and long-term effects Since their inception, long-term use of PPIs have been known to have potential side effects, including: decreased absorption of certain vitamins, increased susceptibility to a multitude of enteric infections such as C. difficile. However, most of the published evidence is inadequate to establish a definite association between PPI use and the risk for development of serious adverse effects. After 25 years of use, it has become increasingly apparent that PPIs cause certain types of kidney disease – namely acute interstitial nephritis (AIN) and more recently, chronic kidney disease (CKD). More recently, a series of class actions have been brought against the drug manufacturers based on strict liability. The basis of the suit is that PPIs cause certain types of kidney problems, that the manufacturer was aware of this and failed to warn consumers. Failure to warn is a marketing defect cause of action. Manufacturers are required to issue warnings about any serious side effects associated with pharmaceuticals and provide appropriate instructions. Failure to warn may be based on strict liability or negligence. If a negligence cause of action is asserted, plaintiffs will need to establish that the manufacturer failed to use reasonable care to provide appropriate information about a foreseeable risk significant enough to justify the cost of giving the information. However, in a strict liability cause of action, plaintiffs need to prove that there was a defective warning and that it caused the injuries suffered by the plaintiff. The primary issue in either case is whether the warning was adequate. Currently, all claims are pending in court. There are more than 4200. The federal cases are being consolidated. Other lawsuits are pending in state and local courts, but I found none that have been set for trial. These cases appear to me to be most likely than not destined for ultimate failure. Some background first. The Science One of the alleged types of injury – acute interstitial nephritis (AIN) is a type of acute kidney damage that is very specific. It is characterized by the presence of inflammatory cells, including eosinophils (a type of white blood cell) in the urine and blood. It is readily identifiable on kidney biopsy. It is caused predominantly by certain drugs (the classic of which is methicillin), but many other drugs are implicated. In fact, virtually any drug can cause AIN. A few known drugs and classes include: 1,2

• • Nonsteroidal anti-inflammatory agents (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors (i.e. motrin, naproxyn, Celebrex)

• • Penicillins and cephalosporins (related antibiotics)

• • Rifampin (anti-tubercular drug)

• • Bactrim

• • Ciprofloxacin (a common antibiotic used for urinary track infections)

• • Diuretics

• • Cimetidine (another type of antacid)

• Allopurinol (used to treat gout)

AIN can also has other causes:3

• • Infections: multiple organisms have been associated with AIN, some of which are indolent (you never know you have it). Some are Legionella, Leptospira, cytomegalovirus, Streptococcus, tuberculosis, Epstein-Barr and others.

• Systemic diseases: these primarily include SLE, sarcoidosis, and Sjögren’s syndrome.

AIN is a very specific type of kidney injury. It’s pathogenesis (how it progresses) has been well described, as is it’s histologic characterization. 4 This would appear to favor plaintiffs. Acute interstitial nephritis (AIN) is characterized by the presence of inflammatory infiltrates and edema within the interstitium, usually associated with an acute deterioration in renal function.5,6 The development of drug-induced AIN is not dose dependent, and recurrence or exacerbation can occur with a second exposure to the same or a related drug.4 This would seem to work against plaintiffs. The actual incidence of AIN is reported to be less than 1% of the total population. This does not indicate the actual number of those affected since 1% represents a larger number than 0.01%. Moreover, most studies report the incidence as a percentage of kidney biopsies taken. When the analysis was restricted to patients with acute kidney failure, AIN accounted for 15–27% of lesions.7,8,9. This type of reporting makes it very difficult to extrapolate to the actual incidence amongst the general population. There have been a number of observational studies that have linked proton pump inhibitors (as a class) with AIN. To date, the best study comes out of John Hopkins and was published in 2016. Based on two large collections of patient, the authors report proton pump inhibitors (PPIs) as an independent risk factor, not only for AIN, but also for chronic kidney disease disease (CKD). https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2481157 This study was observational. An observational study is a great way of isolating adverse effects of drugs as they exist in the real world. On the other hand, they are not the “gold standard” study – which is a double blind, placebo-controlled study. Observational studies have significant limitations. For instance, all in the cohort from Hopkins were likely to be taking multiple medications, have obesity and hypertension. Consider that, in both groups, there was a statistically significant increase in concomitant use of NSAIDs (which are much more likely to cause kidney injury) among PPI users, which is a confounding variable. They report that PPI’s were associated with a 20-50% greater risk of developing CKD when compared to nonusers, with a 10-year absolute risk increase of 3.3%. The proper interpretation of this study is that it identified a small, but significant increase in kidney injury from PPIs. In other words, there is a small potential risk that is applied to a large number of people who take these drugs. The association is probably real and demands that physicians and patients be cautious. Using the Department of Veterans Affairs national databases, Xie et al also assessed kidney outcomes in patients using PPI’s and another antacid medication. In this study, there was a significant association discovered between duration of exposure and worsening outcomes. This tidbit probably favors the defense. The connection between AIN and CKD The study in JAMA unveiled another variable – that PPIs are associated with chronic kidney disease. In fact, this makes sense and is not confounding at all. The mechanism for the development of CKD is likely the result of AIN, which if untreated progresses to the more permanent injury. We should note, all of the studies to date are retrospective observational studies. Aside from intrinsic biases, are incapable of demonstrating a definite causal relationship. With adverse effects being uncommon, the absolute risk to patients remains quite small. The cases that I’ve looked at are misusing and misquoting the studies. In any event, the fact that they are observational would seem to favor the drug manufacturers. A complaint alleging that a manufacturer failed to provide adequate warning of a product’s dangers may be brought under at least three legal doctrines: strict liability, implied warranty, and negligence. 10 Failure to warn of a product’s dangerous propensities may, under appropriate circumstances, constitute a breach of duty upon which an action for negligence might be predicated, and may also serve as the basis for holding a defendant liable under a strict products liability theory. Lewis v. Lead Industries Ass’n, Inc., 342 Ill. App. 3d 95, 276; Generally speaking, a prima facie claim that a product was defective due to a failure to warn consists of three elements in addition to those in a state’s defective product statute: (1) the defendants had a duty to warn; (2) the lack of an adequate warning made the product unreasonably dangerous, and therefore defective; and (3) the lack of an adequate warning was a proximate cause of the injury. Kellogg v. Wyeth, 762 F. Supp. 2d 694 (D. Vt. 2010) (applying Vermont law); Surre v. Foster Wheeler LLC, 831 F. Supp. 2d 797 (S.D. N.Y. 2011) (applying New York law). FDA standard: In area of advertising of pharmaceuticals, rebuttable presumption exists that when manufacturer complies with Food and Drug Administration (FDA) advertising, labeling, and warning requirements, the manufacturer has satisfied its duty to warn consumer about potentially harmful side effects of its product. Perez v. Wyeth Laboratories Inc., 161 N.J. 1, 734 A.2d 1245 (1999). Case Analysis I located a complaint against PPI manufacturer, Astra Zeneca, recently filed in federal court. My purpose was to examine and evaluate their evidence. Evidence – in the form of medical studies – would have to exist and establish that Astra Zeneca was aware of the risk. For the plaintiffs to prevail, there had to exist the predicate medical knowledge that PPIs caused kidney damage. If the science exists, this would establish a duty to warn. I was able to locate one case that had been filed. The original complaint is telling, in that it spells out all of the evidence that the plaintiffs have. What I found was surprising. In Re: Proton-Pump Inhibitor Products Liability Litigation (No. II), Clarice Armstrong v. Astra Zeneca Pharmaceuticals LP – the complaint was filed in New Jersey District Court on September 22, 2017. In the section entitled “Factual Allegations,” the plaintiffs allege that the manufacturer was aware that PPIs cause renal injury. In support of this, they cite and discuss a number of publications. In fact, as I reviewed each of the studies, I found their evidence to be largely insufficient to support their claim. Below is a synopsis of their evidence. I noticed that there were three occasions where the plaintiffs double quoted the same study, referencing them differently. In other words, the same study was re-packaged and presented separately. This gave the appearance (at least to me) of there being more data than there actually was.

1. Simpson, I, et al., Proton pump inhibitors and acute interstitial nephritis: Report and analysis of 15 cases, Nephrology (2006)11: 381-85

• • This publication was a case report, based out of the largest referral center in Austria.

• • Note that in all cases, withdrawal of the PPI resulted in resolution.

• • This particular case report was limited in being a small sample size without comparator groups.

• • As a result, no estimate of the effect size was available.

• • Determining if an association between PPI use and AIN requires studies using larger sizes and control groups.

• At best, this study is inconclusive.

2. Geevasinga, N, Coleman PL, Webster AC. Proton pump inhibitors and acute interstitial nephritis, Clin Gastroenterol Hepatol. 2006 May, 4(5): 597-604

• • This was a retrospective case review based on thousands of potential cases at multiple teaching hospitals extracted from the Therapeutic Goods Administration of Australia (TGA).

• • From this, 18 cases were identified.

• • Withdrawal of the PPI resulted in resolution in all cases.

• • Given the volume of PPI prescribed, no credible conclusion can be reach.

• Again, there is no comparator groups.

3. Klepser, D., Collier, D., Cochran, G., Proton pump inhibitors and acute kidney injury: a nested case control study. BMC Nephrology 2013, 14:150

• • This study was another retrospective case-control study looking a privately insured population in a single (undisclosed) Midwestern state of 185,000 patients which identified 195 patients who developed AIN and were taking PPIs.

• • To identify AIN, multiple ICD-9 codes (medicare diagnostic codes) were used to capture unrecognized cases.

• • PPI exposure status was obtained through prescription claims.

• • This analysis, like the first two studies, has certain limitations.

• • They include misclassification bias (including instances of renal injury not associated with PPI exposure, thus overestimating the true relationship between PPI use and renal disease).

• • On the other hand, this study did not capture OTC PPI utilization – therefore potentially underreporting prevalence.

• Surveillance bias is another source of overestimation, a potential erroneous estimate of relative risk and odds ratio

4. Brewster, UC, Perazella, MA, Acute kidney injury following proton pump inhibitor therapy, Kidney International, 2007:71, 589-93

• • This publication was a single case presented by a student followed by a discussion.

• It is not a persuasive argument.

5. Blank, ML, et al. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use Kidney International, 2014: 86, 837-44

• • According to this study out of New Zealand, “The magnitude of the suspected increase in risk of acute interstitial nephritis among proton pump inhibitor users is uncertain.”

• • The cohort identified 572,661 patients retrospectively.

• • From this, 72 validated cases of which 46 were definite.

• Aside from the potential sources of error described previously for case control studies, the conclusion was “absolute risks were very low.”

Finally, the previously mentioned JAMA publication was referenced in the case. Recall the JAMA article was published in 2016 and this case was published in 2017. Conclusion PPIs were clinically introduced more than 25 years ago. They have since proven invaluable, safe and highly effective.9 Given the prevalence of acid related GI disorders, the PPIs are considered life-saving by the medical community. They came into existence at a time when little else outside of surgery to remove affected portions of the upper GI system were available. Consider that by 2009, more than 119 million PPI prescriptions were filled in the United States, accounting for nearly $14 billion dollars in prescription PPI sales, in addition to billions more in over-the-counter (OTC) sales. This according to IMS health, US Sales and Prescription Information.http://www.imshealth.com/portal/site/ims/menuitem.d248e29c86589c9c30e81c033208c22a/?vgnextoid=9c61ba440c900310VgnVCM10000071812ca2RCRD&cpsextcurrchannel=1, The case that I analyze above is based on no evidence based data. In short, the scientific articles did not raise an objectively reasonable safety concern. In my view, they did not trigger a duty to warn. The most influential research to date which makes a causal connection is from JAMA. I realize that my inexperience in the law renders me naïve. Yet the above case lacked evidence. Double quoting and re-identifying the same data differently gives the impression that there is more data than there actually is. Using the study from Yale – which was a mere “poster presentation” by a student – appears deceptive. In short, without a tobacco industry type smoking gun, there does not appear to be adequate evidence that the manufacturers knew of a defective drug. Even against a preponderance standard, the evidence will not survive. It makes more sense that after an extended period of time – after acquiring data based on the consumption of billions of tablets, we have only recently learned of the potential for kidney damage. The evidential value of the epidemiological studies is difficult to determine. Over a period of years, there was little evidence that PPIs cause renal injury. Knowledge of harm has occurred temporally. Twenty years ago, the evidence was sparse. Over time, the evidence began to accrue in the form of case studies, followed by observational studies. Only recently – due to the JAMA report, do we have a clearer picture, sufficient to create a causal link. Even with the JAMA report, causation is not necessarily established. The primary issue in these cases is whether the epidemiological evidence submitted by the plaintiffs clearly proves the causal relationship between PPI use and disease. Epidemiology studies the distribution and determinants of diseases in a defined population group. Hence, epidemiological evidence tends to have statistical and stochastic characteristics. The plaintiffs use epidemiological evidence to demonstrate a causal relationship between a risk factor and a disease by showing that there is a substantial probability of a certain disease developing in a certain group of people exposed to a risk factor, and that the plaintiffs themselves belong to that group and have developed the disease after being exposed to the risk factor. In the present case, defendants will successfully argue that statistical and stochastic epidemiological evidence is not sufficient to prove proximate or factual causation. Proving “but for” causation is difficult. Renal disease can be caused by many different levels of insult. Even AIN, which is a more specific disease has hundreds of causes. It is tenuous at best to make the causal connection at the individual level. This was seen in tobacco lawsuits – factors other than smoking are involved in the development of a disease, and also because of the lapse of time between smoking and the manifestation of the disease. On the other hand, the epidemiological evidence in the tobacco lawsuits was absolute and rock solid. The epidemiological association between the disease and the risk factor was proven to be significant. However, even in tobacco litigation, the epidemiological evidence was group-level and not individual-level, a hurdle that was overcome on a theory of “probability of causation.” From tobacco litigation, we observe the presence of flawless scientific studies. These were relentlessly attacked and withstood the challenge. The link between science/statistics and harm could be made to a preponderance standard, only because the science was not disputable. In fact, the data was well established by the early 1970s. In the present case, the evidence was sparse from beginning up until the present day. The best evidence (the VA and Hopkins studies) only recently came about. It is unclear whether these will be sufficient to create a causal link by a preponderance standard. The reason the plaintiffs attempted to prove causation with epidemiological evidence is because the types of evidence presented in other tort lawsuits were not useful in proving the causal relationship in tobacco lawsuits. Most compensatory damages in traditional tort lawsuits, e.g., an injury caused by a fistfight, result from a relatively recent event and have relatively simple causal links, usually explained by a basic understanding of physics. However, proving the causal relationship in the case presented was much more complicated. It appears likely that PPI users are progressively more vulnerable to injury as a function of time – manifesting perhaps 10 or more years after their initial exposure. Even this statement is ambiguous in that the data is unclear. During this period, various other factors (i.e. consuming NSAIDs, antibiotics, the presence of certain systemic diseases) may all play a part in the development of the disease. In many cases, more than one exposure is likely. Over a ten year period, it would be challenging to find an individual who has not consumed a Motrin (a known nephrotoxic drug) and an antibiotic. Of course, the issue, a complex one, has many sides – including numerous that are competing. At one point, prescription PPIs began to include a suitable warning in their package insert. When PPIs were made available OTC, a similar warning on the product insert was not included. It’s hard to imagine why such a warning was excluded. Although the OTC formulations were not identical, they were sufficiently similar. Whatever the reason ($$), it makes the entirety of a complex issue much simpler. It makes no sense, on one hand, to include a similar warning on the OTC product, since I doubt that most who are in need of the medication are able to read the small print contained on package inserts.

1. 1. Michel DM, Kelly CJ, Acute interstitial nephritis. J Am Soc Nephrol. 1998; 9(3):506.

1. 1. Schubert C, Bates WD, Moosa MR. Acute tubulointerstitial nephritis related to antituberculous drug therapy. Clin Nephrol 2010; 73:413.

1. 1. Neilson EG, Pathogenesis and therapy of interstitial nephritis. Kidney Int. 1989; 35(5):1257.

1. 1. Cameron, J.S. Allergic interstitial nephritis: clinical features and pathogenesis.Q J Med. 1998; 66: 97–115

1. 1. Rossert JA, Fischer EA. Acute interstitial nephritis. In: Comprehensive Clinical Nephrology, 2, Johnson RJ, Feehally J (Eds), Elsevier Limited, Philadelphia 2003. Vol 1, p.769.

1. 1. Ten RM, Torres VE, Milliner DS, Schwab TR, Holley KE, Gleich GJ. Acute interstitial nephritis: immunologic and clinical aspects. Mayo Clin Proc. 1988; 63(9):921.

1. 1. Haas, M., et al., Etiologies and outcome of acute renal insufficiency in older adults: a renal biopsy study of 259 case. Am J Kidney Dis. 2000; 35: 433-47.

1. 1. Farrington, K., Levison, D.A. et al. Renal biopsy in patients with unexplained renal impairment and normal kidney size. Q J Med. 1989; 70: 221-33.

1. 1. Baker, R.J. and Pusey, C.D. The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant. 2004; 19: 8-11.

1. 1. See, for example, McNeal v Hi-Lo Powered Scaffolding, Inc. (1988) 266 App DC 473, 836; Petree v Victor Fluid Power, Inc. 831 F2d 1191; Payne v Soft Sheen Products, Inc. (1985, Dist Col App) 486 A2d 712; Sprankle v Bower Ammonia & Chemical Co. (1987, CA5 Miss) 824 F2d 409.

1. Strand, D., Kim, D., Peura, D., 25 Years of Proton Pump Inhibitors: A Comprehensive Review Gut Liver. 2017 Jan; 11(1): 27–37.