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T.M. v. Janssen Pharmaceuticals Inc.

Superior Court of Pennsylvania

July 16, 2019


          Appeal from the Judgment Entered December 4, 2017 In the Court of Common Pleas of Philadelphia County Civil Division at No(s): 1076 May Term, 2013



          BOWES, J.

         T.M. and his mother, Brenda Tinkham, ("Plaintiffs") appeal from the December 4, 2017 judgment entered in favor of Janssen Pharmaceuticals, Inc., Johnson & Johnson, Janssen Research & Development, LLC ("Janssen"), [1]following entry of a compulsory nonsuit in their action seeking damages for the drug manufacturer's failure to adequately warn of the risk of gynecomastia associated with Risperdal use in children.[2] We vacate the judgment, reverse the order entering a compulsory nonsuit, and remand for a new trial.

         We glean the following from the evidence offered by Plaintiffs at trial. In 2004, T.M. was seven years old and living with his family in Wichita Falls, Texas.[3] When he began acting out in school, his parents arranged for a mental health evaluation at the Rose Street Mental Health Clinic. Physician Assistant John Dewar diagnosed him with attention deficit hyperactivity disorder ("ADHD"), oppositional defiant disorder ("ODD"), and depression, and under the supervision of pediatric psychiatrists Harvey Martin, M.D. and Brian Wieck, M.D., prescribed Risperdal for T.M. Risperdal was not approved by the Food and Drug Administration ("FDA") for use in children, or for the indication for which it was prescribed. As approved, the drug was indicated only for adults with schizophrenia. Thus, Risperdal was prescribed for T.M. for an off-label use.[4] At the time, Risperdal was known to cause increased prolactin levels associated with gynecomastia and other endocrine disorders. T.M. remained on Risperdal for three and one-half years. In 2006, T.M. developed breasts.

         In May 2013, Plaintiffs filed the instant case against Janssen, the manufacturer and distributor of Risperdal, alleging negligent failure to provide adequate warnings of the known risk of gynecomastia associated with its drug, [5] and fraud. A jury trial commenced on November 28, 2016.

         At trial, Plaintiffs offered the testimony of David Kessler, M.D, a physician specializing in pediatric medicine and public health, who served as the Commissioner of the FDA from 1990 through 1997, and who was formerly a biostatistics professor at the University of California and Dean of the Yale Medical School. Dr. Kessler provided expert testimony establishing that Janssen had a duty to warn of the known risks of gynecomastia with Risperdal use, and that it breached that duty. Dr. Kessler traced the history of Risperdal, explaining that it was a second-generation antipsychotic drug manufactured and marketed by Janssen. It was first approved by the FDA in 1993 for the treatment of adults with psychotic disorders such as schizophrenia. In 1996, Janssen asked the FDA for permission to include dosing information for children on the label as it was "aware that Risperdal was being utilized in children in adolescence" for off-label uses such as ADHD. Videotaped Deposition of David Kessler, M.D. 12/2/16, at 36.[6] The FDA refused the request, citing "inadequate support for the changes sought." Id. at 40. Specifically, the FDA cited the "meager safety data" for Risperdal's pediatric use, and it feared that the proposed labeling would promote use in pediatric patients without justification. Id. at 41-42; see also Plaintiffs' Exhibit 8 (letter from Paul Leber, M.D. to Janssen, 9/17/97).

         Plaintiffs offered into evidence the 2002 package insert for Risperdal, often referred to as the "label." Plaintiffs' Exhibit 2. Dr. Kessler pointed to language therein that the drug's "[s]afety and effectiveness in children have not been established." Id. Under "Precautions," the label listed "hyperprolactinemia," a condition in which one has higher than normal serum levels of the hormone prolactin, the main function of which is to stimulate breast milk production after childbirth. The label also provided that "[a]s with other drugs that antagonize dopamine D receptors," elevated prolactin levels persisted "during chronic administration." Id. at 42. The label acknowledged that although disturbances such as galactorrhea (the expression of breast milk), amenorrhea (absence of menstrual period), impotence, and gynecomastia (feminization of the male breast) had been reported with prolactin-elevating compounds, it stated that, "the clinical significance of elevated prolactin levels is unknown for most patients." Id. at 18, 21. The contents of the Risperdal label remained the same until 2006.

         Dr. Kessler testified that, in 2004, when Risperdal was prescribed off-label for T.M., Janssen was actively marketing the drug to physicians for off-label use in children. Janssen's July 29, 2002 business plan listed strategic initiatives associated with gaining acceptance of the usage of antipsychotics in child and adolescent psychology. Plaintiffs' Exhibit 19. This included "establishing Risperdal as having a favorable risk/benefit ratio" and "neutralizing] safety and tolerability concerns." Id.) Videotaped Deposition of David Kessler, M.D., supra at 82.

         In 2006, the Risperdal label was changed. Pediatric use fell under the "Precautions" section of the 2006 label. The label indicated that Risperdal was approved by the FDA for use in children to treat irritability associated with autism, and that its safety and efficacy in treating children with schizophrenia and bipolar mania had not been established. It reported that Risperdal's safety and efficacy had been established in short-term clinical trials in autistic children ages five to sixteen; longer term studies in autistic children; and other short-term and long-term studies of children with other psychiatric disorders. For the first time, the label disclosed that Risperdal was associated with higher prolactin levels than other antipsychotic drugs in the same class. Again, it warned of hyperprolactinemia, and the conditions associated with it, including gynecomastia, but stated that the risk of such side effects was "rare."[7]Plaintiffs' Exhibit 3 (2006 Label). In 2007, the label was updated to warn that the incidence of gynecomastia with the use of Risperdal was 2.3 percent.

         Dr. Kessler then surveyed the studies and clinical trials Janssen had undertaken to test the safety and efficacy of Risperdal in young children and adolescents. Janssen carried out two short-term double-blind studies of children and adolescents ages five to seventeen years of age, completed in 2000, which demonstrated that forty-nine percent of the children who received Risperdal had elevated prolactin levels as compared to two percent of children who received a placebo. From the foregoing, the expert concluded that the results showed a statistically significant association between ingestion of Risperdal and higher prolactin levels and, further, that higher prolactin levels were known to be associated with certain conditions, including gynecomastia.

         Dr. Kessler explained that, in 2000, Janssen initiated an international study known as RIS-INT-41, which was intended to pay special attention to gynecomastia in boys and other prolactin-related events in children taking Risperdal. Risperdal was administered in two different doses to children with various levels of mental retardation and conduct disorder. The interim results showed that of the 266 males, ten were diagnosed with gynecomastia, an incidence rate of 3.75 percent. Sixteen of 319 patients had a prolactin-related adverse effect, a rate of 5 percent. In Dr. Kessler's opinion, this finding was a "red flag." Videotaped Deposition of David Kessler, M.D., supra at 56.

         The RIS-INT-41 study continued for another year. As of August 2001, there were twenty-six documented cases of prolactin-related adverse events in 504 children, an incidence of 5.15 percent. Twenty-four of the twenty-six children with prolactin-related adverse events had gynecomastia, and twenty-three of them were male. Dr. Kessler opined that there was an obligation on the part of Janssen "certainly by July 2001" to convey this information to physicians who were prescribing the drug off-label to children. Id. at 65.

         Janssen initiated a second study, RIS-INT-70, which was an extension of RIS-INT-41. Dr. Kessler reported that there were four additional cases of gynecomastia in children who participated in both studies, a risk of 8.3 percent. The children who participated only in RIS-INT-70 had an incidence of gynecomastia of 12.5 percent.[8] Id. at 70.

         During the early 2000s, Janssen conducted eighteen clinical studies with pediatric patients, some of which were double-blind, i.e., involved a placebo, and others that were open-lab studies. Six of the studies lasted up to six months. RIS-INT-41 and RIS-INT-70 were the only long-term studies, and the only studies that paid special attention to prolactin-related adverse events such as gynecomastia. The eighteen studies encompassed 1, 885 subjects from five to eighteen years of age. In the double-blind studies, no children who received a placebo were diagnosed with gynecomastia. Eight of nine cases of gynecomastia reported were related to the long-term studies. Dr. Kessler testified that the studies indicated that gynecomastia was manifested over time after exposure and that short-term studies did not capture the actual number of related cases. Id. at 72-79; Plaintiffs' Exhibit 17. Dr. Kessler informed the jury that, in January 2002, Janssen's own studies showed a significant association of 4.4% between hyperprolactinemia and gynecomastia in young males.

         In May 2002, Janssen conducted a post hoc analysis of data from five of the eighteen earlier studies. RIS-INT-41 data was included; RIS-INT-70 data was not. Dr. Kessler opined that Janssen was attempting to prove that Risperdal was not related to elevated prolactin levels, but the data proved otherwise. Analysis of the data showed a rate of 4.4% of gynecomastia. Plaintiffs' Exhibit 22. More importantly, he focused on one particular item of Janssen's supporting documentation, Table 21, which revealed that there were more prolactin-related side effects in Risperdal patients whose prolactin levels were higher. Dr. Kessler explained that Table 21 demonstrated a causal correlation between high prolactin levels and "prolactin related adverse effects," called PRAE, one of which was gynecomastia. He opined that the correlation was statistically significant, as there was a 98.5% likelihood that the side effects did not occur randomly. Internal Janssen emails confirmed, according to Dr. Kessler, that Janssen was aware of the significance of the findings. Based on the foregoing evidence of a causal connection between Risperdal and elevated levels of prolactin, and higher levels of prolactin and gynecomastia, Dr. Kessler opined that Janssen had a duty to warn physicians who were prescribing the drug off-label to children and to notify the FDA. Id. at 121.

         According to Dr. Kessler, Janssen breached its duty to disclose Table 21 to the FDA, and withheld data showing the correlation between elevated prolactin levels and prolactin related adverse effects such as gynecomastia from its own endocrinologist and psychiatrist consultants. The expert demonstrated how Janssen manipulated the study data in such a way as to reduce the statistical significance of the association between Risperdal and boys with gynecomastia, and alleged that Janssen funded the publishing of a misleading article in the Journal of Clinical Psychiatry.[9] Id. at 149.

         Plaintiffs also offered the expert testimony of Mark Solomon, M.D., a plastic surgeon with expertise in gynecomastia and diseases of the breast. He examined T.M., who was at the time was twenty-one years of age, and confirmed that T.M. suffered from true gynecomastia. After reviewing the medical literature about Risperdal, T.M.'s family history, his medical records, and ruling out other possible causes of T.M.'s gynecomastia, Dr. Solomon concluded, with a reasonable degree of medical certainty, that Risperdal was the cause of T.M.'s gynecomastia. N.T. Trial (Jury), 12/7/16, at 71. He explained that, although T.M.'s family physician in Nebraska only diagnosed him with gynecomastia on May 19, 2010, his breasts had started to develop in 2006. Dr. Solomon opined that the timing was consistent with the development of breast tissue generally, and that T.M.'s early breast development could be seen in photographs from 2007.

         When Plaintiffs attempted to elicit additional testimony from Dr. Solomon about two studies he had reviewed and relied upon in reaching his opinions, Janssen objected to the testimony on the ground that Dr. Solomon had not identified them in his expert report.[10] N.T. Trial (Jury), 12/7/16, at 53. Janssen maintained that it lacked fair notice of Dr. Solomon's testimony in this regard. Plaintiffs countered that since Janssen had cross-examined Dr. Solomon in other trials and depositions regarding the same articles, there was no surprise and no prejudice. Moreover, Plaintiffs argued that Janssen had been afforded the opportunity to depose Dr. Solomon in this case, but had declined. The trial court sustained Janssen's objection under Pa.R.C.P. 4003.5, finding that the expert's testimony regarding the literature and studies he relied upon was beyond the fair scope of his expert report, and precluded the expert's testimony in this regard. However, on cross-examination, Dr. Solomon testified that his opinion that Risperdal caused elevated prolactin levels was informed by his review of the literature, the package inserts, and Janssen's documents. N.T. Trial (Jury), 12/7/16, at 91.

         In addition to the foregoing proof regarding the inadequacy of the Risperdal label, Janssen's failure to accurately report the drug's role in elevating prolactin levels and gynecomastia, and ingestion of Risperdal as the cause of T.M.'s gynecomastia, Plaintiffs offered the following proof to rebut the presumption under the TPLA that the label was adequate. The prescribed use in T.M., a child, was off-label and not approved by the FDA. Furthermore, it was not FDA-approved for ADHD or conduct disorders. Dr. Martin, Dr. Wieck, and Physician Assistant Dewar testified that Janssen had actively promoted the use of Risperdal in children, and that the marketing had influenced them to prescribe Risperdal for T.M. for an off-label use. Dr. Wieck, the psychiatrist who supervised the prescribing of Risperdal for T.M., attended a Janssen meeting, all expenses paid, in Miami Beach. In addition, just days before Dr. Wieck prescribed Risperdal for T.M., he had a visit from a Janssen representative, who talked about the use of Risperdal to treat younger children with agitation and anxiety and conduct disorders generally. The prescribers testified that if they had been aware that the real risk of gynecomastia with Risperdal was frequent rather than rare, and that Risperdal was linked to a greater elevation of prolactin levels than other antipsychotic drugs in the same class, they would have prescribed another medication instead. Brenda Tinkham testified that she was not told of the risk of gynecomastia or breast development when Risperdal was recommended for T.M. N.T. Trial (Jury), 12/8/16, at 60. Had she known, she stated she would not have agreed to its administration to T.M. Id. at 44, 60.

         On December 9, 2016, at the close of Plaintiffs' case, Janssen orally moved for a nonsuit. It alleged first that Plaintiffs failed to produce sufficient evidence to rebut the presumption under the TPLA that the FDA-approved warning was adequate. Specifically, Janssen maintained that Plaintiffs failed to prove that Janssen promoted or advertised Risperdal for an indication not approved by the FDA, or that plaintiff used it for an off-label use, and that Janssen's off-label promotion caused the prescriber to prescribe it for the off-label use.

         Second, Janssen argued that Dr. Solomon's opinions did not meet the general or specific causation requirements for scientific reliability under Texas law, including proof of two epidemiological studies demonstrating a statistically significant doubling of the relative risk. Janssen maintained that the 2007 photographs of T.M. that Dr. Solomon testified showed budding breasts could not overcome the fact that T.M. stopped the medication in 2008 and was first diagnosed with gynecomastia in 2010. Finally, Janssen argued that there was a complete failure of proof as to fraud.[11]

         Plaintiffs countered that they could maintain the action as they had rebutted the presumption under Texas's Products Liability Act that the warnings were adequate by introducing proof that Janssen promoted Risperdal for an indication that was not approved by the FDA; that the drug was used as promoted; and that T.M.'s gynecomastia was causally related to the promoted off-label use of Risperdal. See Tex. Civ. Prac. & Rem. Code § 82.OO7(b)(3)(A-C).

         Plaintiffs argued that Texas law did not require proof of epidemiological studies to prove general or specific causation. Furthermore, they maintained that Texas's standards governing the reliability of scientific evidence of general or specific causation under Texas law were not substantive. They maintained that Pennsylvania adheres to Frye v. United States, 293 F. 1013 (D.C. Cir. 1923), and that the issue was one of procedure and not a question governed by Texas substantive law.

         The trial court granted the nonsuit, finding that Texas law as enunciated in MerrellDow Pharm. v. Havner, 953 S.W.2d 706 (Tex. 1997), and Merck & Co. v. Garza, 347 S.W.3d 256, 266 (Tex. 2011), governed the issue of the sufficiency of expert scientific testimony regarding medical causation. It then construed Havner and Garza as strictly requiring Plaintiffs to introduce the following proof of causation: 1) two epidemiological studies[12] proving general causation, i.e., that exposure to a particular agent causes or increases the risk of the injury sustained; 2) that those studies demonstrated a doubling of the relative risk; and 3) that the plaintiff is similarly situated to the study participants. The trial court ruled that Dr. Solomon failed to introduce at least two epidemiological studies demonstrating a doubling of the risk for purposes of general causation and testify that T.M.'s circumstances were similar to those of the study subjects. The court reasoned that Plaintiffs could not rely upon Janssen's clinical trials, RIS-INT-41 and RIS-INT-70, to meet the requirement set forth in Havner because the studies did not show a doubling of the risk for gynecomastia or demonstrate that the subjects of those studies were similar to T.M. Thus, the court concluded that Plaintiffs' evidence was insufficient under Texas law to make out a prima facie failure to warn claim as it lacked the scientific reliability to prove that exposure to Risperdal caused gynecomastia, and that T.M. developed gynecomastia due to his ingestion of Risperdal.

         Plaintiffs filed a post-trial motion, which the trial court denied. Plaintiffs appealed, both Plaintiffs and the trial court complied with Pa.R.A.P. 1925, and the matter is ripe for our review.

1. Did the trial court improperly enter nonsuit given the evidence introduced at trial ...

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