JPML Takes a Second Look at Proton Pump Inhibitor MDL 2757 at July 27, 2017 Hearings in Los Angeles
The Judicial Panel on Multidistrict Litigation (JPML) has decided to revisit a possible Proton Pump Inhibitor (PPI) MDL consolidation (Nexium, Prevacid, et al) and will hear arguments July 27, 2017 at the Los Angeles Federal court on a new motion to centralize (PPI) drugs in a multidistrict litigation. The case is In Re: Proton-Pump Inhibitor Products Liability Litigation [No. II], MDL Docket No. 2757, JPML, where the case filings have significantly increased since the initial JPML hearing January 26, 2017 in Miami when U.S. District Judge Sarah Vance said at one point during the oral arguments “It just seems to me to be nightmarishly complex” as the primary defense counsel raised concern over the generic makers and related defense issues with so many co-defendants. The JPML ultimately denied the MDL 10 days later to the view that consolidation would be to cumbersome, however due to the large numbers of new suits and the refiling of a Motion to Consolidate, the Los Angeles hearings may have a different outcome.
The drugs at issue include Prilosec, Nexium, Protonix and Dexilant as well as potential the numerous generic manufacturers. The hearing order lists over 163 cases in 28 federal district courts and a decision will likely come in mid-August. Nevertheless, the judges may try to come up with ways to split up the cases into structures that might be simpler and more efficient or combine all parties. Ideas included single-product or single-defendant MDLs, separating out prescription-only users, or separating out patients who had only used products made and sold by AstraZeneca, which its attorney said is currently named in 100 cases.
The plaintiffs allege that PPIs cause kidney injuries including acute interstitial nephritis, chronic kidney disease and end-stage renal disease. Concerns that these drugs have harmful side effects for users’ kidneys were brought to the U.S. Food and Drug Administration by consumer advocacy group Public Citizen in 2011, and the agency required warnings about risks of acute interstitial nephritis on labels in 2014, according to the patients’ MDL brief.
More recent research led to stronger findings of a connection, including a scientific study published in January 2016 that said PPI use was independently linked to a 20 to 50 percent higher risk of chronic kidney disease. Plaintiffs have also brought allegations of renal failure being caused by the drugs. To date, more than 5,000 PPI cases are under investigation by Plaintiff’s counsel, and more could be added to that number as awareness of the association between PPI use and kidney damage continues to increase. While the drug class first received FDA approval in 1989, serious side effects prompted the FDA in 2014 to require all PPIs to display a warning label that called out the connection to acute interstitial nephritis. The Plaintiff’s brief also mentions several studies that have made a correlation between PPI use and kidney damage during the past 25 years, including a 1992 study by the University of Arizona Health Sciences Center, a 2006 study conducted at the Yale School of Medicine and a 2016 study from John Hopkins published in the Journal of the American Medical Association (JAMA).
The plaintiffs note that in January, the JPML denied centralization of PPI cases, but say later significant developments “warrant a second look at consolidation.”
The defendants are AstraZeneca Pharmaceuticals LP, Proctor & Gamble Co., McKesson Corp., Takeda Pharmaceuticals USA Inc., Novartis Pharmaceuticals Corp., Pfizer Inc. and Pfizer subsidiary Wyeth. The defendants’ responses are due June 27.
The plaintiff attorneys are Christopher A. Seeger and Jeffrey Grand of Seeger Weiss in New York.
There is much uncertainty throughout the pharmaceutical industry as a new U.S. Food and Drug Administration (FDA) Commissioner is chosen and steps are taken to deregulate government agencies.
President Donald Trump has stated one of his goals is to speed up the drug approval process to lower drug prices, promote competition, benefit small start-ups and bring innovative new treatments to market faster.
However, many industry leaders are concerned that dramatically speeding up the current approval process could put patients at risk. This, in turn, could subject manufacturers to costly litigations.
CEO of Pfizer favors deregulation
The high cost of obtaining approval for a new drug, estimated at $2.6 billion, has been blamed for hindering pharmaceutical start-ups from entering the market. As a result, certain pharmaceutical executives, like the CEO of Pfizer Inc., have publicly favored deregulation, claiming it will help create more competition and lower drug prices.
Others in the pharmaceutical industry disagree, opining that current FDA rules and regulations provide a level playing field for both small and large companies. Lowering the bar for drug approvals, they contend, would allow the wealthiest pharmaceutical companies to inundate the market with countless new drugs and associated advertising, eclipsing any potential advances of smaller companies.
President Trump, who has stated that 75% to 80% of all governmental regulations are unnecessary, issued an executive order on January 30, 2017, aimed at significantly reducing them. The order requires all executive government agencies identify at least two regulations to be repealed for each newly-proposed regulation.
There are 40 MDLS where plaintiffs allege the drug companies engaged in false and misleading marketing and sales practices, including Vioxx, Tylenol, Celexa, Lipitor, Avandia and Plavix.
FDA may not be affected
While not immune to the executive order, the FDA, which regulates food, drugs, medical devices, blood donations, vaccines, biologic products, animal and veterinary products, cosmetics and tobacco products, may not be markedly affected by it. Many FDA regulations deal with process and merely codify or interpret the law. Accordingly, even if certain agency regulations were repealed, congressional mandates, including statutory safety and efficacy standards under the Food, Drug and Cosmetic Act (FDCA), would not change.
Further, a number of regulations are no longer applicable and could be repealed without consequence. Arguably, some existing regulations could even increase protection and transparency for the public if rescinded.
It is not the executive order that has the industry buzzing, however, but rather the potential actions of the new FDA commissioner under the Trump administration, who is likely to share the President’s goal of streamlining the FDA’s drug approval process to decrease the amount of time it takes for new drugs and medical devices to get to market. In an attempt to restructure and quicken the process, the commissioner may choose to institute various levels of approvals, focusing on biomarkers and short-term surrogate endpoints.
Although legislation is in place that requires substantial evidence of a drug’s efficacy prior to it being sold in the marketplace, some suggest if the new commissioner were so inclined, the commissioner need only to interpret existing regulations loosely to weaken the efficacy standard.
12 years from lab to patient
Under the current system, it takes a new drug, on average, 12 years to make it from a research lab to the patient. The FDA’s role is minimal throughout the preclinical research stage, which can take one to six years, but increases if the drug is successful and the FDA approves the commencement of human trials.
Phase one allows researchers to test the drug for the first time in a small group of healthy volunteers, identifying side effects and basic product characteristics, adjusting dosages and evaluating safety. Phase two involves evaluating
Phase two involves evaluating efficacy and short-term side effects for different dosages within a larger randomized or controlled group of people, often measuring biomarkers or laboratory results rather than clinical outcomes. Phase three, a large clinical trial, uses a group of people more similar to those to whom the product would be marketed to determine a risk/benefit ratio. Each phase takes about one to two-and-a-half years.
Ninety percent of the drugs and biologics that proceed through clinical trials fail, whether it’s due to safety or efficacy. If a drug completes phase three of the trials, the manufacturer will file a New Drug Application with the FDA, getting a response, on average, in about 12 months for standard review and eight months for priority review.
Nevertheless, according to 2016 data, the majority of new drugs are approved through an expedited approval process. The approval process has also already been shortened for certain drugs and medical devices by the 21st Century Cures Act, which was signed by President Barack Obama last year.
Safety and efficacy
Some experts argue that safety and efficacy go hand-in-hand; side effects that would never be approved for an over-the-counter drug may be approved for a drug that treats a life-threatening illness if it were proven to be an effective treatment. The type, nature, length and size of clinical trials are already becoming increasingly flexible, allowing deviations from the typical structure on a case-by-case basis in consideration of factors such as whether the condition is widespread, rare, chronic, short-term or life-threatening, the frequency of the symptoms, and the toxicity of the drug on test subjects.
For instance, the FDA may approve orphan drugs, which treat diseases that typically affect less than 200,000 people, based on only one positive clinical trial and/or on surrogate endpoints, while mass-market drugs typically require two to three trials to prove safety and efficacy. In doing so, the FDA provides patients access to a drug, often where there was a previously unmet medical need, while the company continues to study its clinical benefits.
Even so, the FDA maintains that “a randomized, controlled, clinical trial… of a size and duration that reflect the product and target condition remains the gold standard for determining whether there is an acceptable benefit/ risk profile for drugs and biologics.” A neurologist at the Mayo Clinic told Business Insider he commends the idea of speeding up the development of new treatments, but worries that in doing so patients could be exposed to “costly, ineffective and potentially dangerous drugs.” Likewise, the CEO of Ovid Therapeutics Inc., a pharmaceutical company that develops drugs for rare diseases, told Reuters, “any change at the FDA that allows drugs to be tried out on patients without clinical evidence is a damaging approach.”
In a January 2017 FDA evaluation of 22 case studies with divergent results, early clinical studies were promising. Should the commissioner decide to base approval on initial safety reports or on surrogate endpoints, these drugs could have been approved. However, “[p]hase 3 studies did not confirm phase 2 findings of effectiveness in 14 cases, safety in 1 case, and both safety and effectiveness in 7 cases… In two cases, the phase 3 studies showed that the experimental product increased the frequency of the problem it intended to prevent.” The side effects of these drugs in phase three trials ranged from mere uselessness to serious adverse events, including death.
Further, removing the requirement of extensive clinical testing could mean that courts will see more lawsuits and multidistrict litigations similar to those currently filed against 3M involving its Bair Hugger Forced Air Warming device. In that litigation, it is alleged that the company knew of the threat of contaminants due to the device, and the risk of infection, but failed to warn of the risk. The plaintiffs further allege that 3M continued to market its product as safe for use during surgeries and attempted to “conceal and discredit peer-reviewed scientific studies that undermined their ability to market the Bair Hugger.” Notably, the FDA approved the Bair Hugger device for use in 1987 under Section 510(k) of the FDCA, which is an expedited process that allows for less clinical testing if a substantially similar device is already on the market.
It is also unclear how rules and regulations that promote a quicker approval process will affect the doctrine of federal preemption. Just like Bayer Corp. has done with some success in suits alleging injuries sustained from the implantation of Essure Permanent Birth Control, a manufacturer’s defense often rests on the fact that the FDA approved the drug or device’s design, manufacturing method, labels, warnings and instructions for use prior to its release into the market.
This defense has held up in the past, especially for devices approved in the premarket approval process, based on the FDCA’s statutory requirements for safety and effectiveness, with defendants arguing the FDA subjected their product to the “highest level of scrutiny that exists in the federal regulatory system.” If the statutory requirements for a new drug’s approval are weakened, this defense may prove futile for pharmaceutical companies in future litigations to the advantage of plaintiffs.
Congruently, there are currently 40 multidistrict litigations pending with the Judicial Panel on Multidistrict Litigation in which plaintiffs allege the defendants engaged in false and misleading marketing and sales practices, including those for Vioxx, Tylenol, Celexa, Lipitor, Avandia and Plavix, to name a few. Allowing a pharmaceutical company to advertise a drug for potentially ineffective uses without proper testing could open the floodgates of similar litigation should the drug fail to work, or worse, cause fatalities, while costing patients hundreds of thousands of dollars per year. For example, Sarepta Therapeutic’s orphan drug, Exondys 51, which the FDA approved for use in September 2016 based on surrogate endpoints, runs patients about $300,000 per year with little to no insurance coverage, but it has not yet been proven effective.
Industry heads such as the CEO of Alnylam Pharma and the head of research and development at Merck and Co Inc. have also expressed concern about how a manufacturer must be able to show insurers and physicians alike through a risk/benefit profile that their drug has value, rather than leaving them to make such a determination on their own. Further, even if deregulation lowers costs to pharmaceutical companies, there have been no assurances that these reduced costs will be passed on to patients. A first-to-market advantage will not do pharmaceutical companies much good if the product is too expensive for patients to afford and insurance companies are not willing to cover the cost.
If current pre-market clinical requirements are reduced, it could arguably endanger patients, who are often the most vulnerable. It may also make it more difficult for pharmaceutical companies to differentiate effective products from new, less effective — or ineffective — treatments flooding an easy-to-enter market. On the other hand, greater flexibility could allow for innovative new products to enter the market faster and reach those waiting on new therapies or a cure. Until the right balance has been struck, the industry may be in for a bumpy, litigation-filled ride.
Will Nicholas Jewell, a renowned Ph.D. biostatistician, get his chance to testify in In re Zoloft Products Liability Litigation? More than 300 mothers in 45 states who charge that the antidepressant caused heart defects in their newborns hope he will.
It’s up to the Third US Circuit Court of Appeals, which will decide whether US District Judge Cynthia M. Rufe of the Eastern District of Pennsylvania erroneously excluded him as a causation expert last April. The judge also granted summary judgment to defendant Pfizer and effectively wiped out the caseload in MDL 2342.
Judge is “armchair scientist”
Calling the judge an “armchair scientist,” the plaintiffs argue that the court “superimposed its own standard of sound science,” and disregarded Jewell’s 40 years of experience.
The case is Jennifer Adams v. Wolters Kluwer, No. 16-2247 in the Third Circuit. Leading the effort to revive the litigation are plaintiff attorneys Mark P. Robinson, Jr. of Robinson Calcagnie, Inc. in Newport Beach, CA, Dianne M. Nast of Nastlaw LLC in Philadelphia, PA, and David C. Frederick, Derek T. Ho and Hilary P. Gerzhoy of Kellogg, Huber, Hansen, Todd, Evans & Figel, PLLC in Washington, D.C.
Jewell is highly qualified:
He has been a professor of biostatistics (the statistical design and analysis of studies that investigate risk factors for disease) for nearly four decades, first at Princeton University.
For the last 33 years, he has been a professor at the University of California (Berkeley).
He authored a widely used textbook, Statistics for Epidemiology, and 160 peer-reviewed articles on biostatistics.
He is also the editor of the Journal of the American Statistical Association, the country’s preeminent peer-reviewed statistics journal.
Zoloft triples the risk
Jewell reviewed multiple peer-reviewed epidemiological studies involving hundreds of thousands of women, and concluded that taking Zoloft (sertraline) during pregnancy can as much as triple the risk for having babies with serious, life-altering heart defects.
He employed a “weight of the evidence” methodology using established criteria developed by English epidemiologist Sir Austin Bradford Hill. This methodology has been generally accepted in the scientific community for decades.
However Judge Rufe ruled that a causation opinion must be supported by “repeated, consistent, statistically significant human epidemiological findings.”
In fact, four published peer-reviewed studies did find a statistically significant increased risk of cardiac birth defects with Zoloft use during pregnancy.
Further, the plaintiffs argue that the judge’s doubt about Jewell’s methodology usurps the role of the jury, and that questions about his analysis are properly left to cross-examination and trial.
For 30 years, the scientific community has been aware that serotonin reuptake inhibitiors (SSRIs), including Zoloft, are potential teratogens (i.e., agents that affect the development of eggs, sperm, or embryos and therefore increase the risk of birth defects).
In 1988, a Pfizer report warned that “[s]ertraline should not be administered to pregnant or lactating females.” In 1995, the Food and Drug Administration sent a letter to Pfizer that it was “necessary to change the pregnancy category of Zoloft® from B to C” (drugs that have caused or may be suspected of causing, harmful effects on the human fetus).
The four studies that the court disregarded include:
Colvin (2011). Lyn Colvin, et al., Dispensing Patterns and Pregnancy Outcomes for Women Dispensed Selective Serotonin Reuptake Inhibitors in Pregnancy, 91 Birth Defects Res. A Clin. Mol. Teratol. 142 (2011), a study including 123,405 pregnancies from 2002 to 2005 in Western Australia, found a positive association between Zoloft exposure and cardiovascular defects.
Ban (2014). Lu Ban, et al., Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study, 121 BJOG 1471 (2014), a study including 349,127 births from 1990 to 2009 in the U.K., found a positive association between Zoloft exposure and cardiovascular defects.
Huybrechts (2014). Krista F. Huybrechts, et al., Antidepressant Use in Pregnancy and the Risk of Cardiac Defects, 370 N. Engl. J. Med. 2397 (2014), a study that included 949,504 U.S. pregnancies from 2000 to 2007, found a positive association between Zoloft exposure and cardiac malformations.
Furu (2015). Kari Furu, et al., Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design, 350 British Med. J. 1798 (2015), a study that included 2.3 million births in Denmark, Finland, Iceland, Norway, and Sweden from 1996 to 2010, found a positive association between Zoloft exposure and all cardiac defects.
“Under the correct legal standard, Dr. Jewell’s analysis easily clears Rule 702’s bar for admissibility,” the plaintiffs argue.
Bristol-Myers Squibb and Pfizer have filed a motion to create a new MDL 2754 consolidating mass tort litigation in US District Court for the Southern District of New York concerning bleeding-related injuries allegedly caused by Eliquis blood thinner.
The companies are facing 34 related actions filed in 13 different federal courts. Plaintiffs’ counsel have promised that they intend to file many more cases in the near future.
Starting in 2015, plaintiffs began filing lawsuits alleging the defendants failed to warn adequately about the risk of bleeding, and that the defendants should not have sold Eliquis without precautions for blood monitoring or an additional drug to reverse its anticoagulant effect.
Eliquis (also known by its molecular name apixaban) is an anticoagulant medication that thins the blood, prevents the formation of blood clots, and decreases the risk of stroke in patients with atrial fibrillation and certain other conditions. Atrial fibrillation is a common arrhythmia (abnormal heart beat) that causes blood clots to form in the heart, and that is known to be associated with a very high risk of stroke.
The companies claim that the drug is “no less safe than a daily aspirin.” It was approved by the FDA in 2012 and carries a warning that it increases the risk of bleeding that there is no antidote for Eliquis.
The companies requested the New York federal court because they have headquarters there and because half of the actions have been filed there. The court has previously handled 158 MDLs and now is handling 27 MDLs including product liability cases against prescription drugs Rezulin (MDL 1348) and Fosamax (MDL 1789).
Bogus Aristotle Study
Plaintiffs allege that approval of Eliquis was based in large part on clinical trials known as Aristotle, which was conducted under the supervision and control of the defendants, in various countries, including China.
“Defendants, as a means of cutting costs, chose incompetent and untrustworthy agents in China to conduct the Aristotle study Defendants’ agents committed fraud in their conduct of the Aristotle study, by concealing side effects which occurred in test users of Eliquis; a death which went unreported (whereas one purpose of the study was to study the rate of death in Eliquis users compared to others in Coumadin); loss of subjects to follow-up; major dispensing errors including indicating that certain subjects were getting Eliquis when they were not; poor overall quality control; and changing and falsifying records, including records disappearing just before the FDA made a site visit, reportedly on the order of an employee of BMS,” states the complaint in Charlie Utts and Ciara Utts v. Bristol-Myers Squibb Company and Pfizer Inc., Case 1:16-cv-05668-DLC (S.D.N.Y).
According to the complaint, the companies:
Failed to provide adequate warnings about the increased risk of gastrointestinal bleeds in those taking Eliquis, especially, in those patients with a history of gastrointestinal issues and upset;
Failed to provide adequate warnings about the increased risk of suffering a bleeding event, requiring blood transfusions in those taking Eliquis;
Failed to provide adequate warnings about the need to assess renal functioning before starting a patient on Eliquis and to continue testing and monitoring of renal functioning periodically while the patient is on Eliquis.
Failed to provide adequate warnings about the need to assess hepaticfunctioning prior to starting a patient on Eliquis and to continue testing and monitoring of hepatic functioning periodically while the patient is on Eliquis.
A drug commonly used to treat pain, epilepsy, anxiety and other brain health disorders may be associated with an increased risk of major birth defects, according to a study published in the May 18, 2016, online issue of Neurology®, the medical journal of the American Academy of Neurology.
The drug pregabalin is approved by the FDA to treat epilepsy, fibromyalgia and neuropathic pain, such as pain from diabetic neuropathy or pain after shingles or spinal cord injury. It is also used for generalized anxiety disorder and other mental health issues. This is called off-label prescribing.
Lyrica, made by Pfizer, has been the target of extensive litigation. In 2009, for example, parent company Pfizer agreed to pay $2.3 billion to the Department of Justice for illegally promoting sales of a Lyrica dosage. This charge revolved around the fact that manufacturers urged doctors to prescribe Lyrica for so-called “off-label” use.
The study collected information in seven countries from 164 women who took pregabalin during a pregnancy and 656 pregnant women who were not taking any anti-seizure drugs. The women or their practitioners were then contacted again after their expected date of delivery.
Birth defects 3X more likely
Pregnancies of the women who took pregabalin during the first trimester of pregnancy were three times more likely to result in major birth defects than those of the women who did not take anti-seizure drugs. Seven of the 116 pregnancies in women taking anti-seizure drugs, or 6 percent, had major birth defects, compared to 12 of 580 pregnancies, or 2 percent, in women who did not take the drug. Birth defects due to chromosomal abnormalities were not included in these results.
The major birth defects included heart defects and structural problems with the central nervous system (CNS) or other organs. The women taking pregabalin were six times more likely to have a pregnancy with a major defect in the central nervous system than women who were not taking the drug, with four CNS defects out of 125 pregnancies, or 3.2 percent, compared to three CNS defects out of 570 pregnancies, or 0.5 percent.
Of the women taking pregabalin, 115 were taking it to treat neuropathic pain, 39 were taking it for psychiatric disorders, including depression, anxiety, bipolar disorder and psychosis, five were taking it for epilepsy and one was taking it for restless leg syndrome.
A total of 77 percent of the women started taking pregabalin before they became pregnant. The women in the study stopped taking the drug at an average of six weeks into their pregnancies. Of the women taking pregabalin, 22, or 13 percent, were also taking another anti-seizure drug.
“We can’t draw any definitive conclusions from this study, since many of the women were taking other drugs that could have played a role in the birth defects and because the study was small and the results need to be confirmed with larger studies, but these results do signal that there may be an increased risk for major birth defects after taking pregabalin during the first trimester of pregnancy,” said study author Ursula Winterfeld, PhD, of the Swiss Teratogen Information Service and Lausanne University Hospital in Lausanne, Switzerland.
Winterfeld said, “Pregabalin should be prescribed for women of child-bearing age only after making sure that the benefits of the drug outweigh the risks and after counseling them about using effective birth control. In cases where women have taken pregabalin during pregnancy, extra fetal monitoring may be warranted.”