In re Viagra (Sildenafil Citrate) & Cialis (Tadalafil) Prods. Liab. Litig., Case No. 16-md-02691-RS

424 F.Supp.3d 781

IN RE: VIAGRA (SILDENAFIL CITRATE) AND CIALIS (TADALAFIL) PRODUCTS LIABILITY LITIGATION

This Document Relates to: All Actions

Case No. 16-md-02691-RS

United States District Court, N.D. California.

Signed January 13, 2020

ORDER GRANTING IN PART AND DENYING IN PART MOTIONS TO EXCLUDE EXPERT TESTIMONY

RICHARD SEEBORG, United States District Judge

I. INTRODUCTION

In 2014 the Li study was published in JAMA Internal Medicine, a journal of the American Medical Association, concluding that "[s]ildenafil use may be associated with an increased risk of developing melanoma." The study cautioned its findings were insufficient to require altering clinical recommendations at that time, but acknowledged a need for continued investigation of the observed association between sildenafil use and melanoma. The first of the lawsuits now pending in this Multi District Litigation were filed in response to that study. Plaintiffs allege they have suffered from melanoma exacerbated by their use of sildenafil (sold under the brand name Viagra ) and/or the similar drug tadalafil (sold under the brand name Cialis ). They contend the results of multiple studies following up on Li 2014 are now sufficient to support a scientific conclusion that sildenafil and tadalafil use causes melanoma progression in some instances, and they proffer expert witnesses who are prepared to testify accordingly.

Defendant Pfizer, the maker of Viagra, and defendant Eli Lilly, the maker of Cialis, present experts who dispute the opinions of plaintiffs' experts, and who opine that the body of scientific evidence that has emerged following the Li 2014 study does not support a conclusion that sildenafil or tadalafil causes melanoma progression. Each side now moves to exclude significant portions of the expert opinions offered by the other side, under the standards articulated in Daubert v. Merrell Dow Pharmaceuticals, Inc. , 509 U.S. 579, 113 S.Ct. 2786, 125 L.Ed.2d 469 (1993) and its progeny, and as reflected in Rule 702 of the Federal Rules of Evidence.

Over the course of four days the parties presented live testimony from a subset of their respective expert witnesses. Plaintiffs called four experts, two testifying it is "biologically plausible" that the drugs could cause melanoma progression, and two testifying the epidemiological research shows use of the drugs in fact does cause melanoma progression in some cases. Defendants presented three experts, essentially in rebuttal to the testimony of plaintiffs' experts. For the reasons explained below, while the opinions of plaintiffs' experts regarding "biological plausibility" are admissible, their experts' opinions as to causation are not. The opinions offered by defendants' experts in turn represent admissible rebuttal. Accordingly, defendants' motion to exclude the testimony of plaintiffs' experts will be granted in part, and denied in part. Plaintiffs' motion to exclude the testimony of defendants' witnesses will be denied.

II. BACKGROUND

A. Melanoma

Melanoma is the most serious form of skin cancer, causing the majority of skin cancer deaths. Rates of the disease have been rising in recent decades. Melanoma, however, remains less common than other skin cancers, such as basal cell carcinoma and squamous cell carcinoma. Melanoma arises in melanocytes—cells at the bottom of the epidermis that are present in normal skin. Melanocytes are the cells that produce melanin, the pigment responsible for skin color. Upon undergoing certain genetic mutations, melanocytes gain the ability to grow more rapidly and invade into deeper parts of the skin and beyond. Melanomas are characterized by growth and invasion—they typically begin in nevi (commonly referred to as moles), then grow larger and move (invade) over time.

Melanoma ordinarily takes many years to develop from premalignant nevi into identifiable and diagnosable tumors. Even after a tumor develops, it can lie dormant for decades, or progress only slowly within the skin or in the lymph nodes. There appears to be no dispute that early stage or dormant melanomas may sometimes be reactivated to grow by an environmental trigger or a pharmacologic stimulus. The question is whether tadalafil and sildenafil have that capacity to cause melanoma progression. Because the survival rate for melanoma patients significantly declines as the disease progresses, any agent that promotes rapid progression carries severe consequences.

B. PDE5 inhibitors

Phosphodiesterases (PDEs) are a family of enzymes that play a role in signaling between cells. The particular PDE relevant here is PDE5.¹ Sildenafil and tadalafil both act as "inhibitors" of PDE5, in that they slow or stop the normal activity of the enzyme. Plaintiffs have offered detailed explanations as to how PDE5 inhibitors affect erectile dysfunction. That science, however, does not appear directly relevant to the issue of whether PDE5 inhibitors might contribute to melanoma progression and will not be recounted here. The possible effects of PDE5 inhibitors on a variety of other medical conditions are the subject of ongoing investigation. Indeed, some research is exploring PDE5 inhibitors as a treatment for certain cancers other than melanoma.²

C. The studies

Epidemiology is "the field of public health and medicine that studies the incidence, distribution, and etiology of disease in human populations." Michael D. Green et al., Reference Guide on Epidemiology, in Reference Manual on Scientific Evidence 551, 551 (3d ed. 2011). Epidemiological observational studies compare the risk of disease between patients exposed to a given substance and patients who were not exposed. Such studies may be prospective, identifying patients and then following them for a period of time, or retrospective, identifying patients and then performing a review to determine what took place during the period they did or did not take the drug. There are two types of observational studies: cohort studies and case control studies.

A cohort study identifies patients who are taking the drug and then follows them for a certain amount of time to determine if they experience the alleged negative outcome. The cohort study also identifies people not taking the drug and follows them. The study then compares the rate of the negative outcomes in the first group with the rate in the second group to compute the "relative risk."

A case-control study identifies persons who had a negative outcome (the cases), and reviews their medical records to determine how many of those persons used the studied drug. The study then identifies an equal number of people who did not have the negative event (the controls) and determines how many of them were taking the drug. From those figures an "odds ratio" is computed.

The parties also rely on several meta-analyses, which pool the results of various studies and arrive at a single figure intended to represent the totality of the studies reviewed. Meta-analysis has the advantage of pooling more data so that the results are less likely to be misleading solely due to chance.

When reviewing the results of a study it is important to consider the confidence interval, which, in simple terms, is the "margin of error." For example, a given study could calculate a relative risk of 1.4 (a 40 percent increased risk of adverse events), but show a 95 percent "confidence interval" of .8 to 1.9. That confidence interval means there is 95 percent chance that the true value—the actual relative risk—is between .8 and 1.9. Because the confidence interval includes numbers that do not show any increased risk, and indeed, show the possibility of a decreased risk, such study results do not demonstrate a "statistically significant" increased risk of an adverse outcome. Confidence intervals are calculated, in part, based on the number of people and events included in the study. The larger the sample size in a study, all other things being equal, the narrower the confidence boundaries will be.

All of the experts, on both sides, report that they reviewed all of the available scientific literature on the relationship between PDE5 inhibitors and melanoma, including peer-reviewed articles and "abstracts" submitted in advance of potential future publication of articles describing the results obtained in research studies. The following epidemiological studies feature most prominently in the various expert reports:

(1) The seminal observational study, mentioned above, is known as Li 2014. It found a "significantly elevated risk of invasive melanoma" in patients who had recently used sildenafil. The study reported a risk factor of 1.84, with a confidence interval of 1.04-3.22.

(2) Loeb 2015 found an increased risk of melanoma in men with filled PDE5 prescriptions. The risk factor was 1.21, with a confidence interval of 1.08-1.36.

(3) Matthews 2016 reported a positive association between PDE5 inhibitor use and melanoma, with a risk factor of 1.14 and a confidence interval of 1.01-1.29.

(4) Lian 2016 identified a positive overall association with an increased risk for melanoma among those who had received seven or more prescriptions. The risk factor was 1.3, with a confidence interval of 1.01-1.69. Among those who had greater than twenty-five pills the risk factor was 1.34 with a confidence interval of 1.04-1.72.

(5) Pottegård 2016 observed an association in patients reporting a "high use" of PDE5 inhibitors. The risk factor was 1.28, with a confidence interval of 1.05-1.56.

(6) Shkolyar 2018 found an association between higher volume PDE5 inhibitor use and development of melanoma.

(7) A set of three abstracts presented to the American Academy of Dermatology all found increased risks of melanoma following sildenafil and tadalafil use—the Boor 2016, Ma 2017, and Nardone 2018 studies.

(8) Six meta-analyses have reported an association between PDE5 inhibitor use and an increased risk of melanoma : Loeb 2017; Tang 2017; Wang 2017; Deng 2018; Han 2018; Feng 2018. The risk estimates in...