McNeil v. Wyeth

United States Court of Appeals Fifth Circuit F I L E D In the August 22, 2006 United States Court of Appeals Charles R. Fulbruge III for the Fifth Circuit Clerk _______________ m 05-10509 _______________ SUE C. MCNEIL, Plaintiff-Appellant, VERSUS WYETH, FORMERLY KNOWN AS AMERICAN HOME PRODUCTS CORPORATION, DOING BUSINESS AS A.H. ROBINS COMPANY, INC., Defendant-Appellee. _________________________ Appeal from the United States District Court for the Northern District of Texas _________________________ Before KING, SMITH, and BENAVIDES, scribed Reglan, whose generic name is meto- Circuit Judges. clopramide, manufactured by Wyeth, to treat McNeil’s symptoms of gastroesophagealreflux JERRY E. SMITH, Circuit Judge: disease (“GERD”). The prescription was for six months, though the Food and Drug Sue McNeil appeals a summaryjudgment for Administration had approved the drug only for defendant Wyeth, a pharmaceutical company. use of no more than twelve weeks. There- We reverse and remand. after, McNeil’s prescription was continued by Dr. Roy Ragsdale for six months and then by I. Dr. William Mania for two months. In August 2000, Dr. Eduardo Wilkinson pre- GERD is a disease whose expression ranges In October 2001, about fourteen months af- from infrequent heartburn to frequent heartburn ter she started taking Reglan, McNeil was ad- accompanied by regurgitation. In severe cases mitted to an emergency room complaining of it can lead to a narrowing of the esophagus by shortness of breath, anxiety, and an involun- scarring. tary “chewing motion” of her mouth. The nurse who first treated McNeil noted that she Reglan is a “prokinetic” drug that helps con- was also fidgeting, appeared nervous, and had trol GERD by blocking dopamine receptors in an unsteady gait. The emergency room physi- the brain and throughout the body, thus enhanc- cian who later examined McNeil confirmed ing movement or contractions of the esopha- these observations and diagnosed EPS, likely gus, stomach, and intestines. Dopamine is a occasioned by exposure to Reglan. chemical produced naturally by the human body that sends signals from one nerve to the next. McNeil’s primary care physician confirmed Simple movements of muscles, such as moving this diagnosis, discontinued Reglan, and pre- a finger, are controlled by what is known as the scribed a replacement drug. When McNeil’s pyramidal system. More coordinated muscle EPS symptoms failed to improve with time, movements, such as dancing or talking, require she consulted a neurologist and two medical fine motor control from the extrapyramidal specialists in movement disorder; all three con- system. cluded that McNeil suffers from Reglan-in- duced tardive dyskinesia in addition to Reglan- Byblocking dopamine receptors, Reglan can induced EPS. affect the extrapyramidal system by causing extrapyramidal symptoms (“EPS”), which “are II. a group of adverse drug reactions referred to McNeil sued Wyeth in state court. Her generally as extrapyramidal symptoms because complaint alleged that Wyeth had failed ade- of the involvement of the extrapyramidal ner- quately to warn physicians and consumers of vous system.”1 The clinical pharmacology the increased risk of tardive dyskinesia that section of Reglan’s FDA-approved label ex- accompanies long-term use of Reglan. McNeil plains that, like other “dopamine antagonists” argued that Wyeth’s failure to warn rendered such as phenothiazines, Reglan “may produce the inherently unsafe product unreasonably extrapyramidal reactions, although these are dangerous. Further, McNeil alleged that the comparatively rare.” Reglan label was misleading as to the risk of tardive dyskinesia and failed adequately to Tardive dyskinesia is a particularly severe warn about the increase in risk associated with form of EPS characterized by grotesque invol- exposure to the drug for more than twelve untary movements of the mouth, tongue, lips, weeks. and extremities, involuntary chewing move- ments, and a general sense of agitation. Reg- Wyeth removed to federal court pursuant to lan’s label warned that Reglan may produce 28 U.S.C. § 1332(a)(1). Both parties consent- tardive dyskinesia. ed to decision by a magistrate judge, whom we therefore refer to as the “district court.” 1 Windham v. Wyeth Lab., Inc., 786 F. Supp. Wyeth moved for summary judgment, 607, 612 (S.D. Miss. 1992). 2 which the court granted, concluding that the be viewed in the light most favorable to the Reglan label was “adequate as a matter of law” nonmovant. Minter v. Great Am. Ins. Co., because it “specifically mentions the circum- 423 F.3d 460, 465 (5th Cir. 2005). stances complained of . . . .” More specifically, the court noted that the label IV. Texas, like most jurisdictions, has adopted specifies that the drug is intended for section 402A of the Restatement of Torts for short-term use of 12 weeks or less, warns product liability claims. Nobility Homes, Inc. against the potential risk of tardive dys- v. Shivers, 557 S.W.2d 77, 79-80 (Tex. 1977). kinesia and other movement disorders, Under that section, “[i]f a product is unreason- and discloses that the risk of developing ably or inherently dangerous, a warning is re- tardive dyskinesia is highest among elder- quired.” Gravis v. Parke-Davis & Co., 502 ly women and increases with the duration S.W.2d 863, 870 (Tex. Civ. App.SSCorpus of treatment and the total cumulative Christi 1973, writ ref’d n.r.e.) (citing RE- dose. The label also describes the possi- STATEMENT (SECOND) OF TORTS § 402A ble symptoms associated with movement (1965)). disorders caused by the drugSSthe very symptoms of which plaintiff complains. Texas law generallyholds that the adequacy of a product’s warning is a question of fact to Therefore, the court concluded that Wyeth be determined by the jury. Williams v. Upjohn was entitled to summary judgment on McNeil’s Co., 153 F.R.D. 110, 114 (S.D. Tex. 1994); marketing defect claims. In an additional para- Alm v. Aluminum Co. of Am., 717 S.W.2d graph, the court stated that “Wyeth is entitled 588, 591-92 (Tex. 1986)). In prescription to summary judgment on plaintiff’s design de- drug cases involving the learned intermediary fect claims.” McNeil appeals only the failure- doctrine, however, when “a warning specifi- to-warn claims. cally mentions the circumstances complained of, the warning is adequate as a matter of III. law.” Rolen v. Burroughs Wellcome Co., 856 Summary judgment is proper “if the plead- S.W.2d 607, 609 (Tex. App.SSWaco 1993, ings, depositions, answers to interrogatories, writ denied).2 and admissions on file, together with the affi- davits, if any, show that there is no genuine is- McNeil argues that the district court’s re- sue as to any material fact and that the moving liance on Rolen to find adequacy as a matter of party is entitled to a judgment as a matter of law is inapposite. We agree. Although Reg- law.” FED. R. CIV. P. 56(c). Disputes about lan’s label mentions the conditions of which material facts are genuine “if the evidence is McNeil complains, McNeil’s claim, unlike the such that a reasonable jury could return a ver- dict for the nonmoving party.” Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 248 (1986). 2 In Alm the court also cited with approval de- We review the district court’s decision de novo. cisions from Texas appellate courts that have Skotak v. Tenneco Resins, Inc., 953 F.2d 909, adopted and applied the learned intermediary doc- 912 (5th Cir. 1992). The evidence and infer- trine in cases involving a drug manufacturer’s duty ences from the summary judgment record must to warn about the potential hazards of prescription drugs. 3 claim of the plaintiff in Rolen, is not that the V. warning is inadequate because her condition The issue therefore is whether there is a was not mentioned. Rather, her argument is genuine issue of material fact as to whether the that the label is misleading as to the risk level label was misleading. This must be viewed in for developing the condition. terms of significant differences between the disclosed risk and the actual risk of developing We are aware of no Texas case allowing ad- EPS and tardive dyskinesia, with use longer equacy as a matter of law in such situations, than twelve weeks. and therefore we apply the default Texas rule that adequacy questions go to the jury. Our A. position is consistent with Texas law and the Wyeth argues that it does not have a duty Restatement of Torts, which Texas courts fol- to warn about risks of use longer than twelve low, because, as the district court recognized, weeks because the label clearly states that the even in the context of a learned intermediary, drug is indicated for treatment for no more “‘if the warning to the intermediary is inade- than that duration. Thus, not only would such quate or misleading, the manufacturer remains a warning be superfluous, but it would also be liable for injuries sustained by the ultimate improper, because Wyeth allegedly cannot tell user.’”3 a medical professional how to exercise profes- sional judgment on whether a drug should be Warning the learned intermediary of a much used longer than the period approved by the lower risk than the actual risk could render the FDA. We disagree. warning not just misleading, but ineffective. When the risk described on the label is so low Wyeth was, or should have been, aware as to induce a doctor to undertake the risk, had that Reglan was prescribed routinely for long- he not done so if he were warned of the real term use. Plaintiff’s expert, Dr. Thompson, risk, we cannot say that no reasonable jury testified that by 1988 Wyeth had its “own mar- could conclude that a warning was inadequate. ket data that 84 percent of people” were using Thus, if the manufacturer decides to label a risk Reglan long-term. In 1992, an article by Dr. as “comparatively rare” and also to provide a Ron Stewart and others drew attention to the numerical quantification of that risk, that num- common practice of long-term treatment with ber must be within a certain degree of accur- metoclopramide. The study involved 4,515 acy.4 elderly patients at the Florida Geriatric Re- 3 4 Wyeth-Ayerst Lab. Co. v. Medrano, 28 S.W.3d (...continued) 87 (Tex. App.SSTexarkana 2000, no writ) (citing cant, their potential misleading impact is a question Alm, 717 S.W.2d at 591); see also Bristol-Myers for the jury. Other courts have also recognized that Co. v. Gonzales, 561 S.W.2d 801 (Tex. 1978); warnings that are “unreasonably diluted” may be Crocker v. Winthrop Labs., 514 S.W.2d 429 (Tex. misleading and thus inadequate. See Salmon v. 1974). Parke, Davis & Co., 520 F.2d 1359 (4th Cir. 1975) (deciding that although a specific condition 4 We do not mean to suggest that de minimis dif- was mentioned in the label, “[c]omparing the com- ferences in risk would send the adequacy question to pany’s warning with [that suggested in] the article, the jury, but when the differences in risk are signifi- a jury could infer that Parke, Davis’ version was (continued...) unreasonably diluted”). 4 search Program. Of the patients who reported for longer than twelve weeks was contraindi- using metoclopramide, 32% had used it for cated (absent compelling circumstances). Wy- more than one year. This led the authors to eth’s former medical monitor for Reglan also conclude that long-term treatment with meto- testified similarly by agreeing that “Reglan clopramide is “quite common” and that other should not be prescribed for long-term therapy prescription drugs were effective and safer for for GERD because the side effects are too treating GERD: dangerous and because its efficacy in longer term use has not been established.” The routine use of metoclopramide for gastroesophageal reflux should be ques- In sum, because the widespread long-term tioned in light of the availability of safer, use of Reglan suggests that Wyeth’s indication more effective drugs such as hista- for use for not more than twelve weeks was mine-receptor blocking agents cimetidine widely disregarded, a jury could infer that the and ranitidine, and omeprazole. The warning was ineffective and therefore inade- long-term efficacy and symptomatic ben- quate. It follows that Wyeth had a duty, under efit of metoclopramide have not been Texas law, adequately to warn the learned in- documented. termediary of known risks with long term use and not to be misleading as to that risk. Because the widespread long-term use of Reglan suggests that Wyeth’s indication for use B. for no more than twelve weeks was widely dis- Because Wyeth advertised that the risk of regarded, a jury could infer that Wyeth’s warn- developing EPS is “comparatively rare,” or ing was ineffective and thus inadequate. There- that it is 0.2% for short term use, just noting fore, McNeil’s suggested additional warning that the risk is higher for long-term use may about long-term use would not be superfluous. not put a physician on notice that certain stud- ies have found that the risk could be a hundred times higher.5 That is, because the advertised Moreover, the FDA regulations require a risk is negligibly low, the mere statement that manufacturer to inform a medical professional the risk increases with use does not put a precisely how to exercise his professional judg- ment in certain circumstances. The “Contraindi- 5 cations” regulation requires that ‘[u]nder this An 1989 study by Dr. Lucinda Miller and Dr. section heading, the labeling shall describe Joseph Jankovic looking at 1,031 patients conclud- those situations in which the drug should not be ed that the prevalence of metoclopramide-induced used because the risk of use clearly outweighs movement disorders is probably greater than any possible benefit.’ 21 C.F.R. § 201.57(d) Wyeth’s estimate of 1 in 500. An article published by Dr. Linda Ganzini and others in 1993 described (2000). Thus, the manufacturer must tell the that 29% of the patients in a case-control study physician when the drug should not be used if exposed to metoclopramide met the case definition “the risk of use clearly outweighs any possible of tardive dyskinesia. The average duration of benefit.” exposure to the drug was 2.6 years. Another case-control study conducted by Dr. Daniel Sewell One of McNeil’s experts testified that the in 1994 found that 27% of the patients exposed to label should have indicated that use of Reglan metoclopramide for longer than thirty days met the case definition of tardive dyskinesia. 5 physician on notice that the increase in risk is of the possibility of “acute renal failure.” Jordan, a completely different order of magnitude and 848 S.W.2d at 182. In other words, even if class of risk. Thus, a jury could find that the the clinical studies did not show significant risk of developing EPS from long-term use was renal failure and thus, also did not show acute not just higher, but that it was “significantly” renal failure, there was a genuine issue of higher, and that the label was therefore mislead- material fact on adequacy raised solely by ing and inadequate. association evidence (anecdotal case reports, not clinical trials). Wyeth argues, however, that it was not re- quired to update its label, because the studies McNeil’s expert, Dr. Thompson, also noted indicating that the risk for long-term use could that manufacturers frequently change their la- be a hundred times higher showed mere associ- bels and warn physicians of side effects based ation with a disease, not necessarily causation. on simple case reports, not on actual studies Thus, Wyeth argues, because there could be a showing causation. For example, a pharma- variety of other factors responsible for the “as- ceutical company for which she was working sociation” found in these studies, that associa- at the time (Eli Lily) inserted a warning that a tion does not necessarily require a warning to certain use of the drug Papaverine is contrain- physicians. This argument, however, is contra- dicated based only on a few case reports of its dicted by the FDA regulations that require that apparently causing heart attacks, and no epide- the labeling “be revised to include a warning as miological or other studies showing causation. soon as there is reasonable evidence of an asso- She explained that the contraindication attract- ciation of a serious hazard with a drug; a caus- ed a lot of hate mail from physicians who had al relationship need not have been proved.” 21 practiced the off-label use, but that it had to be C.F.R. § 201.57(e) (emphasis added). done, and it took little time to do. This is not to say that a manufacturer is always required Of course, it does not immediately follow, to change a label based on case reports; we from the fact that Wyeth is required under fed- mention Thompson’s testimony only to coun- eral law to warn physicians of a significant “as- ter Wyeth’s contention that manufacturers sociation” between tardive dyskinezia and long- never change labels based on case reports (as term use of Reglan, that Texas law requires the distinguished from clinical trials) and that they same thing. Texas law, however, does not ab- never tell physicians how to exercise their solve a manufacturer, as a matter of law, of a judgment. duty to warn on grounds that no existing stud- ies or clinical trials prove actual causation. Thus, it is not uncommon for drug compa- nies to do precisely what Wyeth claims it can- In Jordan v. Geigy Pharms., 848 S.W.2d not do: tell physicians that a certain use is con- 176 (Tex. App.—Fort Worth 1992, no writ), traindicated even if no clinical or epidemiologi- the court observed that although the drug cal studies exist that confirm causation or manufacturer warned that cases of “significant degree of risk. Certainly, it is easier for a man- renal failure in patients receiving Voltaren have ufacturer to make an off-label use contraindi- been reported from postmarketing experience, cated when that use provides only a minimal but were not observed in over 4,000 patients in amount of sales from that drug as opposed to controlled clinical trials,” it had not warned of when the off-label use provides the majority of 6 its sales, as allegedly it is with Wyeth and Reg- 730 S.W.2d 19 (Tex. App.—Corpus Christi lan. But it is precisely this factSSthat off-label 1987, writ ref’d n.r.e.). use allegedly provided a majority of Wyeth’s salesSSthat would create Wyeth’s duty to phy- McNeil’s expert, Dr. Thompson, testified sicians not to be misleading about the risk of that the well-known, scientifically established long-term use. pharmacology of dopamine antagonists that block a D2 dopamine receptor such as meto- Admittedly, the physician, in the exercise of clopramide or schizophrenia medications (Hal- professional judgment, can disregard the warn- dol and Thorazine) is to diminish the effects of ings or contraindications provided by the manu- dopamine in the brain. The inability of dopa- facturer. But then he does so at his own risk, mine to produce its effects causes EPS (includ- and most physicians are likely reluctant to do so ing Parkinsonian side effects such as rigidity, absent more concrete evidence about the bene- tremor, and dystonia, and the more severe fits of long-term use, evidence that is absent in side-effect known as tardive dyskinesia), this case. Even Dr. Wilkinson, who initially in- because the extrapyramidal system needs dicated that he would not have changed his dopamine to function. Thompson also testi- long-term prescription of Reglan even if he had fied that these side-effects for metoclopramide read the studies now cited by McNeil, acknowl- are “highly predictable,” given the function it edged that he would not have prescribed performs (blocking dopamine receptors) and Reglan for more than twelve weeks had Wyeth the known effects of other dopamine blockers: provided a contraindication on Reglan’s label. [M]ost of [metoclopramide’s] side effects Therefore, we cannot say as a matter of law are related to its action, which is, in fact, that the peer-reviewed studies cited by McNeil blocking the dopamine effects in the brain do not describe a significant risk about which and elsewhere. And so what it does is to Wyeth should have warned Texas physicians. produce the whole array of side effects that Of course, Wyeth is free to argue, to a jury, its we associate with dopamine blockers. And view of the proper weight to be given to these in this sense, it’s really no different that any studies; it can also challenge (if still timely) the so-called neuroleptics, the drugs that pro- admissibility of these peer-reviewed studies duce the calming effect in schizophrenia. under Daubert v. Merrell Dow Pharms., Inc., So it’s just like Thorazine or Haldol or any 509 U.S. 579 (1993). of the other antipsychotics. It’s highly pre- dictable that this would be its effect . . . . McNeil has also raised a genuine issue of material fact as to whether pharmacologicalevi- Thompson testified that the propensity of dence should have alerted Wyeth about the neuroleptics such as Thorazine and Haldol to significantly increased risk from long-term use. cause tardive dyskinesia was discovered about Under Texas law, causation is generally an is- twenty years after the beginning of the use of sue of fact. Lenger v. Physician’s Gen. Hosp., Thorazine, that is, in the late 1970’s. She fur- Inc., 455 S.W.2d 703, 706 (Tex. 1970). An ther testified that the rate of developing tardive expert opinion is legally sufficient evidence to dyskinesia with long term use of D2 receptor establish a causal relationship between the con- blockers was 25%. Therefore, she found to be dition and the event. See Rodriguez v. Reeves, misleading the label’s claim that like other 7 “dopamine antagonists” such as phenothiazines was “significant,” but would have alerted the (which include Thorazine), Reglan “may pro- plaintiff to that risk. On the other hand, he duce extrapyramidal reactions, although these testified that he would not have prescribed the are comparatively rare. As Thompson testified, drug had its label stated that use for longer than twelve weeks is contraindicated because Most of the papers I’ve seen would give the risks are significant and the benefits have about the same prevalence rate of tardive not been proven. Therefore, McNeil has dyskinesia in Metoclopramide long term and raised a genuine issue of fact as to whether Thorazine long-term. So [the label] would- Wilkinson would have prescribed the drug had n’t be correct in terms of being compara- the label’s warning been adequate. tively rare . . . . 25 percent isn’t rare com- pared to anything. Moreover, because Wilkinson testified that he was never informed of the significant risk of Therefore, we cannot say as a matter of law tardive dyskinesia associated with long-term that Reglan’s label was adequate even if it failed Reglan use and that such information certainly to warn that the risk of developing tardive would have changed the “risk/benefit” analy- dyskinesia was not “comparatively rare,” but sis” and the conversation he would have had increased significantly with long-term use. with McNeil about the risks, the inadequate VI. labeling could be a producing cause of the Under Texas law, a plaintiff who complains injury even if Wilkinson had never testified “that a prescription drug warning is inadequate that he would not have prescribed Reglan had must also show that the alleged inadequacy a contraindication been inserted. Sworn testi- caused her doctor to prescribe the drug for mony from McNeil establishes that she was her.” Porterfield v. Ethicon, Inc., 183 F.3d never told of the significantly increased risk of 464, 468 (5th Cir. 1999); accord Stewart v. tardive dyskinesia with use of Reglan for Jannssen Pharm., 780 S.W.2d 910, 912 (Tex. greater than twelve weeks and that, if she had App.—El Paso 1989, writ denied). In other known of such a risk, she would not have words, a plaintiff must show not only that a taken Reglan for longer than that. warning was inadequate, but that it was a “pro- ducing cause” of his injuries. The doctrine of the “learned intermediary” presupposes that the physician will act as an Wyeth is correct that although the district intermediary. This function includes discuss- court has not addressed this issue, the matter ing the cost-benefit ratio with the patient if was before the court, so we could affirm for necessary. Where the physician would have this reason if we were to find for Wyeth on this adequately informed a plaintiff of the risks of question. We do not so decide, however, be- a disease, had the label been sufficient, but fails cause there is a genuine issue of material fact as to do so on that account, and where the plain- to whether the label’s inadequacy caused Mc- tiff would have rejected the drug if informed, Neil’s doctor to prescribe the drug. the inadequate labeling could be a “producing” cause of the injury, because it effectively sabo- Wilkinson gave conflicting testimony. On the one hand, he stated that he still would have prescribed the drug had he known that the risk 8 tages the function of the intermediary.6 We note that our discussion of “permissible inferences is intended neither to define nor to decide the issues in this case.” Salmon, 520 F.2d at 1364. It serves merely to illustrate our reasons for concluding that summary judgment is inappropriate. Reasonable minds can differ on whether not mentioning that the increase in risk for long-term use was significant would be misleading. But this is precisely why that ques- tion should go to the jury. The summary judg- ment is REVERSED, and this matter is RE- MANDED for further proceedings. 6 “[T]he mere presence of an intermediary does not excuse the manufacturer from warning those whom it should reasonably expect to be endangered by the use of its product.” Alm, 717 S.W.2d at 591. Instead, the issue “in every case is whether the original manufacturer has a reasonable assurance that its warning will reach those endangered by the use of its product.” Id. Although usually the manufacturer can rely on the “learned intermedi- ary,” id., this reliance seems less reasonable where the learned intermediary fails to pass necessary in- formation to the patient because the manufacturer has understated the degree of risk. 9