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