TERRY v. MCNEIL-PPC, INC. et al
MEMORANDUM AND/OR OPINION. SIGNED BY HONORABLE LAWRENCE F. STENGEL ON 7/26/2016. 7/26/2016 ENTERED AND COPIES E-MAILED TO LIAISON COUNSEL. (SEE PAPER # 378 IN 13-MD-2436) (ems)
UNITED STATES DISTRICT COURT
EASTERN DISTRICT OF PENNSYLVANIA
IN RE: TYLENOL
SALES PRACTICES, AND
MDL NO. 2436
HON. LAWRENCE F. STENGEL
This Document Relates to:
Rana Terry, as Personal Representative
and Administrator of the Estate of Denice
McNEIL-PPC, Inc., McNeil Consumer
Healthcare, and Johnson & Johnson, Inc.,
Civil Action No. 2:12-cv-07263
July 26, 2016
This case is part of a Multidistrict Litigation (MDL) involving claims of liver
damage from the use of Tylenol at or just above the recommended dosage.1 The first
See Master Compl., 13-md-2436, Doc. No. 32. There are over two hundred other cases included in this MDL,
along with several similar cases in New Jersey state court.
“bellwether” case is scheduled for trial.2 The plaintiff plans to offer Dr. Timothy Davern,
M.D. as a general and specific causation expert. Dr. Davern contends that recommended
doses of acetaminophen, the main ingredient in Tylenol, can cause acute liver failure
(ALF). He is of the opinion that the decedent, Denice Hayes, died of acetaminopheninduced ALF after taking recommended doses. The defendants move to exclude his
testimony under Daubert. For the reasons stated below, I will deny their motion.3
The admissibility of expert testimony is governed by Federal Rules of Evidence
702 and 703 as well as by Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579 (1993),
and its progeny.4 See In re Paoli RR Yard PCB Litigation (Paoli II), 35 F.3d 717, 735 (3d
Cir. 1994). “Under the Federal Rules of Evidence, a trial judge acts as a ‘gatekeeper’ to
ensure that ‘any and all expert testimony or evidence is not only relevant, but also
reliable.’” Pineda v. Ford Motor Co., 520 F.3d 237, 243 (3d Cir. 2008)(quoting
Kannankeril v. Terminix Int'l, Inc., 128 F.3d 802, 806 (3d Cir. 1997)). The Third Circuit
recognizes a “liberal policy of admissibility” regarding Rule 702. Pineda, 520 F.3d at 243
A “bellwether” case is a test case. “Bellwether” trials should produce representative verdicts and settlements. The
parties can use these verdicts and settlements to gauge the strength of the common MDL claims to determine if a
global resolution of the MDL is possible. See FEDERAL JUDICIAL CENTER, MANUAL FOR COMPLEX LITIGATION,
FOURTH EDITION 360 (2004); DUKE LAW CENTER FOR JUDICIAL STUDIES, MDL STANDARDS AND BEST PRACTICES
In making my decision, I have reviewed all of the materials submitted as attachments to the parties’ briefs,
including those submitted during oral argument.
Daubert held that the Federal Rules of Evidence, specifically Rule 702, controlled the issue of when experts were
qualified. Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579, 587-88 (1993). It found that Rule 702 superseded the
Court’s prior precedent on the subject found in Frye v. United States, 54 App.D.C. 46, 47, 293 F. 1013, 1014 (1923).
Id. at 587. Daubert went on to clarify what was required under Rule 702, as compared to Frye. See id. at 589-598.
(quoting Kannankeril, 128 F.3d at 806); United States v. Schiff, 602 F.3d 152, 173 (3d
“[B]ecause expert evidence is often more misleading than other evidence,
Rule 403 gives a judge more power over experts than over lay witnesses.” In re
Paoli RR Yard PCB Litigation (Paoli II), 35 F.3d 717, 747 (3d Cir. 1994).
However, “in order for a district court to exclude scientific evidence, there must be
something particularly confusing about the scientific evidence at issue—
something other than the general complexity of scientific evidence.” Id.
a. Rule 702
Federal Rule of Evidence 702 has three major requirements: 1) the expert must be
qualified; 2) the expert must testify about matters requiring scientific, technical, or
specialized knowledge; and 3) the testimony must assist the trier of fact.6 Pineda, 520
F.3d at 243 (citing Kannankeril, 128 F.3d at 806). 702’s inquiry should be a “flexible
one.” Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579, 594 (1993).
See also Holbrook v. Lykes Brothers Steamship Company, Inc., 80 F.3d 777, 780 (3d Cir. 1996); Zaprala v. USI
Servs. Gp., Inc., No. 09–1238, 2013 WL 1148335, at *6 (E.D. Pa. Mar. 20, 2013)(quoting Pineda, 520 F.3d at 243).
Federal Rule of Evidence 702 states:
A witness who is qualified as an expert by knowledge, skill, experience, training, or education
may testify in the form of an opinion or otherwise if:
(a) the expert's scientific, technical, or other specialized knowledge will help the trier of fact to
understand the evidence or to determine a fact in issue;
(b) the testimony is based on sufficient facts or data;
(c) the testimony is the product of reliable principles and methods; and
(d) the expert has reliably applied the principles and methods to the facts of the case.
FED. R. EVID. 702.
Expert Must Be Qualified
An expert’s qualifications may include education, provided it is in a field
related to the one in which the expert intends to testify. Fedor v. Freightliner, Inc.,
193 F. Supp. 2d 820, 827 (E.D. Pa. 2002). Overall, the court will consider both
academic training and practical experience to determine if the expert has “more
knowledge than the average lay person” on the subject. Id. at 827-28 (citing
Waldorf v. Shuta, 142 F.3d 601, 627 (3d Cir. 1998)). “An expert may be generally
qualified but may lack qualifications to testify outside his area of expertise.”
Calhoun v. Yamaha Motor Corp., U.S.A., 350 F.3d 316, 322 (3d Cir. 2003).
However, this does not mean that the “best qualified” expert must testify.
“[W]itnesses may be competent to testify as experts even though they may not, in
the court's eyes, be the ‘best’ qualified.” Holbrook v. Lykes Bros. S.S. Co., Inc.,
80 F.3d 777, 782 (3d Cir. 1995).7 “Rule 702 and Daubert put their faith in an
adversary system designed to expose flawed expertise.” U.S. v. Mitchell, 365 F.3d
215, 244-45 (3d Cir. 2004)(citations omitted). “As long as an expert's scientific
testimony rests upon ‘good grounds, based on what is known,’ it should be tested
by the adversary process—competing expert testimony and active cross–
examination—rather than excluded from jurors' scrutiny for fear that they will not
grasp its complexities or satisfactorily weigh its inadequacies.” Id. at 244
See also Keller v. Feasterville Family Health Care, 557 F. Supp. 2d 671, 675 (E.D. Pa. 2008)(Rice, J.).
Expert’s Methods Must be Reliable
This Circuit interprets the second factor as one of “reliability,” i.e., the testimony
is admissible so long as the process or technique the expert used in formulating the
opinion is reliable. Pineda, 520 F.3d at 244. An expert’s opinion need not be correct, only
reliable. See In re Paoli RR Yard PCB Litigation (Paoli II), 35 F.3d 717, 744 (3d Cir.
1994)(“This does not mean that plaintiffs have to prove their case twice—they do not
have to demonstrate to the judge by a preponderance of the evidence that the assessments
of their experts are correct, they only have to demonstrate by a preponderance of
evidence that their opinions are reliable.” (emphasis in original)). “[A]n expert is
permitted wide latitude to offer opinions, including those that are not based on firsthand
knowledge or observation.” Daubert, 509 U.S. at 592. “[I]t is the burden of the party
offering the expert scientific testimony to demonstrate reliability by a preponderance of
the evidence.” In re TMI Litig., 193 F.3d 613, 705 (3d Cir. 1999)(citing Paoli II, 35 F.3d
“Rule 702 grants the district judge the discretionary authority, reviewable for its
abuse, to determine reliability in light of the particular facts and circumstances of the
particular case.” Kumho Tire Co., Ltd. v. Carmichael, 526 U.S. 137, 158 (1999). Judges
considering this factor should look to whether a theory, technique, or opinion can be
tested or has been subject to peer review or publication. Daubert, 509 U.S. at 593. “The
fact of publication (or lack thereof) in a peer reviewed journal thus will be a relevant,
See also FED. R. EVID. 702, Advisory Committee Note (2000 Amendments)(“Under that Rule, the proponent has
the burden of establishing that the pertinent admissibility requirements are met by a preponderance of the evidence.”
(citing Bourjaily v. United States, 483 U.S. 171 (1987)).
though not dispositive, consideration in assessing the scientific validity of a particular
technique or methodology on which an opinion is premised.” Id. at 594. A court should
also consider the known or potential rate of error involved in a scientific method. Id.
“Reliability” does not require that a technique or methodology be generally accepted by a
scientific community. Id. See also id. at 597-98. However, “[w]idespread acceptance can
be an important factor in ruling particular evidence admissible” while a minimally
supported technique “may properly be viewed with skepticism.” Id.
Expert Must be Helpful
The third factor “is typically understood in terms of whether there is a sufficient
‘fit’ between the expert's testimony and the facts that the jury is being asked to consider.”
United States v. Schiff, 602 F.3d 152, 172-73 (3d Cir. 2010)(citing Daubert, 509 U.S. at
591). See also In re: TMI Litigation, 193 F.3d 613, 670 (3d Cir. 1999). This factor is
about relevance. “Expert testimony which does not relate to any issue in the case is not
relevant and, ergo, non-helpful.” Daubert, 509 U.S. at 591 (quoting 3 Weinstein & Berger
¶ 702, p. 702–18). “Rule 702's ‘helpfulness’ standard requires a valid scientific
connection to the pertinent inquiry as a precondition to admissibility.” Id. at 591-92.
b. Rule 703
Under Federal Rule of Evidence 703, the data underlying the expert's opinion is
the central focus. Rule 703 states:
An expert may base an opinion on facts or data in the case that the expert
has been made aware of or personally observed. If experts in the particular
field would reasonably rely on those kinds of facts or data in forming an
opinion on the subject, they need not be admissible for the opinion to be
admitted. But if the facts or data would otherwise be inadmissible, the
proponent of the opinion may disclose them to the jury only if their
probative value in helping the jury evaluate the opinion substantially
outweighs their prejudicial effect.
FED. R. EVID. 703. The trial court must evaluate whether the data used by an
expert is reasonably relied upon by experts in the field. See In re Paoli RR Yard
PCB Litigation (Paoli II), 35 F.3d 717, 747-49 (3d Cir. 1994).
Dr. Davern is a Leading Expert in DILI9
Timothy Davern, M.D. is a board-certified gastroenterologist and hepatologist,
specializing in liver transplants. He is the Director of the Acute Liver Failure Program at
California Pacific Medical Center (CPMC) in San Francisco, California. Prior to joining
CPMC, he held several academic positions at University of California, San Francisco
(UCSF), including Associate Professor of Medicine.
Dr. Davern is an active investigator for the Acute Liver Failure Study Group
(ALFSG). He has been involved with the ALFSG for almost 15 years. He has personally
enrolled nearly 300 ALFSG cases, most of which were due to acetaminophen toxicity. He
represented the American Association for the Study of Liver Disease (AASLD) at the
joint meeting of three Food and Drug Administration (FDA) Advisory Committees, held
in June 2009. He presented data from the ALFSG on unintentional acetaminophen
poisoning at that joint meeting. He was also the principal investigator for the National
Though the defendants do not challenge Dr. Davern’s qualifications, an overview of his credentials is helpful to
understanding their challenge to his methodology. Information about Dr. Davern’s credentials can be found in his
Curriculum Vitae (Doc. No. 155, Ex. 6) and his expert report (Doc. No. 155, Ex. 1) unless noted otherwise. See also
T. Davern Dep., Mar. 28, 2015 at 73-78 (Doc. No. 155, Ex. 3).
Institutes of Health (NIH)-funded Drug-Induced Liver Injury Network (DILIN) Study
from its inception in 2004 until 2014.
Dr. Davern is a national-recognized expert in drug-induced liver injury (DILI).10
He has published close to 100 articles, including peer-reviewed research, book chapters
and abstracts—almost all of which have to do with acute liver failure (ALF), druginduced liver disease, and acetaminophen-induced ALF.11 He has conducted research
related to acetaminophen-induced liver injury. In addition, he has written about the DILI
Defendants’ hepatology experts acknowledge Dr. Davern as a national-recognized expert in DILI. See R. Brown
Dep., Apr. 30, 2015 at 41-43 (Doc. No. 155, Ex. 8); S. Flamm Dep., May 5, 2015 at 29-36 (Doc. No. 155, Ex. 9).
See, e.g., Murphy, E.J., Davern, T.J., et al., Troglitazone Induced Fulminant Hepatic Failure: A Report of Three
Case, Digestive Diseases and Sciences, 2000, 45(3):549-553; Ostapowicz, G., Davern, T.J., et al., Results of a
Prospective Study of Acute Liver Failure at 17 Tertiary Care Centers in the United States, Annals of Internal
Medicine, 2002, 137(12):947-954; Davern, T.J., Fulminant Hepatic Failure, in Advanced Therapy in
Gastroenterology and Liver Disease, TM Bayless and AM Diehl, Eds., Fifth Edition, BC Decker, Inc., Ontario, at
629-637; Schiodt, F.V., Davern, T., et al., Viral Hepatitis Related Acute Liver Failure, Am. J. Gastroenterol., 2003,
98(2):448-453; Davern, T.J., Acetaminophen hepatotoxicity, Hepatology, 2004, 40(4): 1021-1022; Wai, C.T.,
Davern, T.J., et al., Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the
United States, J. Viral. Hepat., 2005 Mar: 12(2):192-198; Vaquero, J., Davern, T.J., et al., Blei AT Complications
and use of intracranial pressure monitoring in patients with acute liver failure and severe Encephalopathy, Liver
Transpl., 2005 Dec; 11(12):1581-1589; Larson, A.M., Davern, T.J., et al., Acetaminophen-induced acute liver
failure: results of a United States multicenter, prospective study, Hepatology, 2005 Dec: 42(6): 1364-1372; Davern,
T.J., et al., Measurement of serum acetaminophen protein adducts in patients with acute liver failure,
Gastroenterology, 2006 Mar.: 130(3):687-694; Rutherford, A., Davern, T.J., et al., High Body Mass Index Predicts
Poor Outcome in Acute Liver Failure, Clin. Gastroenterol. & Hepatology, 2006 Sep 2; [Epub ahead of print]; Lee,
W.M., Davern, T., et al., Brief Report: No Evidence for Parvovirus B19 or Hepatitis E Virus as Cause of Acute
Liver Failure, Dig. Dis. Sci., 2006 Sep. 9 [Epub ahead of print]; James, L.P., Davern, T.J., et al., Detection of
acetaminophen protein adducts in children with acute liver failure of indeterminate etiology, Pediatrics, 2006
Sep.: 118(3): e676-81; Stravitz, R.T., Davern, T., et al., Intensive care of patients with acute liver failure:
Recommendations of the U.S. Acute Liver Failure Study Group, Crit. Care Med. 2007 Sep. 25, [Epub ahead of
print]; Davern, T.J., Predicting prognosis in acute liver failure: ammonia and the risk of cerebral edema, Hepatology,
2007 Dec.: 46(6): 1679-1681; Chalasani, N., Davern, T.J., et al., Clinical Advances in Liver, Pancreas and Biliary
Tract: Causes, Clinical Features and Outcomes from a Prospective Study of Drug-Induced Injury in the United
States, Gastroenterology, 2008; 135:1924-1934; Davern, T.J., et al., Drug-induced liver injury in clinical trials: as
rare as hens’ teeth, Am. J. Gastroenterol., 2009; 104(5):1159-1161; Lee, W.M., Davern, T.J., et al., Intravenous
NAcetylcysteine Improves Transplant-Free Survival in Early State Non-Acetaminophen Acute Liver Failure,
Gastroenterology, 2009, 137:856-864; Davern, T.J., Drug-Induced Liver Disease, Clin. Liver Dis., 2012, 16:231245; Davern, T.J., Concepts in Drug-Induced Liver Disease, AGA Perspectives, 2012 May 23; Holt, E.W., Davern,
T.J., et al., Acute Liver Failure Due to Acetaminophen Poisoning in Patients with Prior Weight Loss
Surgery: A Case Series, J. Clin. Gastroenterol., 2014 Dec. 30 [Epub ahead of print]. See also T. Davern Dep., Mar.
28, 2015 at 31-35 (Doc. No. 155, Ex. 3).
“causation assessment methodology” he uses in this case. He wrote a book chapter called
“Drug-Induced Liver Disease” at the request of McNeil’s expert, Steven Flamm, M.D.12
Dr. Davern’s General Causation Methodology is Reliable13
Dr. Davern opines that acetaminophen-induced livery injury can occur at or near 4
grams—the daily recommended dose of acetaminophen at the time of the decedent’s
death.14 Dr. Davern was of this opinion prior to this litigation; he has routinely limited his
patients to only 2 grams of acetaminophen a day.15 He explained that certain factors
enhance susceptibility to acetaminophen poisoning: chronic alcohol use, female gender,
chronic ingestion of certain drugs, fasting/malnutrition, and/or gastric bypass surgery.16
See S. Flamm Dep., May 5, 2015 at 32-34 (Doc. No. 155, Ex. 9); T. Davern Dep., Mar. 28, 2015 at 37-39 (Doc.
No. 155, Ex. 3).
The defendants claim Dr. Davern’s supplemental report was untimely. This report was served in response to their
expert reports, which were given to Dr. Davern only hours before his deposition (as shown by the deposition
testimony). See T. Davern Dep., Mar. 28, 2015 at 18-22 (Doc. No. 155, Ex. 3). The defendants’ point is of no
See T. Davern Expert Report, Feb. 16, 2015 at 5-6 (Doc. No. 155, Ex. 1).
See T. Davern Addendum to Expert Report, Apr. 27, 2015 at 2 (Doc. No. 155, Ex. 2)(“I have long limited the
exposure of my patients to no more than 2 grams a day…”); T. Davern Dep., Mar. 28, 2015 at 105-09 (Doc. No.
155, Ex. 3).
Defendants’ experts, Drs. Brown and Flamm also limit their patients to 2-4 grams a day. See R. Brown Dep., Apr.
30, 2015 at 72-73 (Doc. No. 155, Ex. 8)(“I tell them to take no more than six or eight regular-strength tablets in a
day, knowing that they’ll take more….It’s neigh on 2 grams [daily].”); S. Flamm Dep., May 5, 2015 at 168-69 (Doc.
No. 155, Ex. 9)(explaining why he only recommends that patients take a maximum of 3 or 4 grams of Tylenol a day
but advises them that this is the upper limit on what should be taken because he recognizes the likely risk of patients
taking too much).
See also T. Davern Dep., Mar. 28, 2015 at 330-31, 388-89 (Doc. No. 155, Ex. 3).
The defendant argue that Dr. Davern’s opinion regarding malnutrition as a risk factor of acetaminophen-induced
liver failure is scientifically unsound because he did not consider one article which contradicts his point. See
Lauterburg, Bernhard, Analgesics and Glutathione, Am. J. Therapeutics, 9, 225-231 (2002)(Doc. No. 126, Ex. E).
The article written in 2002 is a review of available literature on analgesics and glutathione. The author concludes
from his review of the literature on fasting that “there is no convincing evidence that fasting enhances the toxicity of
paracetamol [acetaminophen] in humans as reviewed by Prescott.” Id. at 228-29. This article is not a study or a peerreviewed case series. The fact that Dr. Davern does not address it and was not aware of it does not require his
opinion to be excluded.
He also noted that not all the risk factors which could cause acetaminophen-induced liver
injury are known, making a “wide margin of safety” (i.e., the difference between a safe
dose and a toxic dose) important for everyone.17 In making his determination, he relied
on the available information on this subject area—case series, case reports, clinical trials,
FDA documents, animal studies—and his own clinical experience.18
a. Lack of Epidemiological and Case-controlled Studies Does Not Render
The defendants argue that Dr. Davern’s general causation opinion about the
risk of acetaminophen-induced ALF at recommended doses is flawed because it is
not supported by statistically-significant data.20
See T. Davern Expert Report, Feb. 16, 2015 at 5-6 (Doc. No. 155, Ex. 1); T. Davern Addendum to Expert Report,
Apr. 27, 2015 at 3 (Doc. No. 155, Ex. 2).
The defendants also make an implicit Rule 403 argument, claiming testimony about fasting, malnutrition, and
gastric bypass as risk factors will be a waste of time. I see nothing in the record to support this argument. The
information being presented by the experts on this point is highly probative and relevant to this case.
See T. Davern Dep., Mar. 28, 2015 at 53-57 (Doc. No. 155, Ex. 3).
The defendants also claim Dr. Davern’s reliance on a memorandum issued in 2007 by the American Association
for the Study of Liver Disease (AASLD) is inappropriate because the memorandum was not peer-reviewed and
some of its recommendations were rejected by the FDA. The AASLD is the leading organization of doctors and
specialists on the study of liver disease in the United States. The information contained in this document is entirely
relevant to Dr. Davern’s opinion. I see no problem with Dr. Davern relying on the 2007 document—along with other
available information—in forming his opinions. See Heller v. Shaw Industries, 167 F.3d 146, 155 (3d Cir.
1999)(“Given the liberal thrust of the Federal Rules of Evidence, the flexible nature of the Daubert inquiry, and the
proper roles of the judge and the jury in evaluating the ultimate credibility of an expert's opinion, we do not believe
that a medical expert must always cite published studies on general causation in order to reliably conclude that a
particular object caused a particular illness…. To so hold would doom from the outset all cases in which the state of
research on the specific ailment or on the alleged causal agent was in its early stages, and would effectively resurrect
a Frye-like bright-line standard, not by requiring that a methodology be ‘generally accepted,’ but by excluding
expert testimony not backed by published (and presumably peer-reviewed) studies. We have held that the reliability
analysis applies to all aspects of an expert's testimony: the methodology, the facts underlying the expert's opinion,
the link between the facts and the conclusion, et alia.”).
The defendants argue that Dr. Davern’s methodology is flawed because he did not look for statistically significant
associations between substance exposure and injury and then apply the Bradford-Hill method—a set of nine
guidelines to evaluate scientific data to determine causation. The Bradford-Hill methods, enunciated by Sir Austin
Bradford Hill in a 1965 speech before the Royal Society of Medicine, includes a collection of “nine different
The Fourth Circuit addressed this exact same argument by the defendants in a
similar case decided over twenty years ago. In Benedi v. McNeil, a jury found that the
defendants failed to warn consumers about the risk of liver damage when acetaminophen
was taken with alcohol. Benedi v. McNeil-P.P.C., Inc., 66 F.3d 1378, 1381 (4th Cir.
1995).21 On appeal, McNeil argued that Benedi's experts should have been excluded
because they “did not rely upon epidemiological data in formulating their opinions.” Id.
at 1384. The Fourth Circuit rejected this argument:
[W]e do not read Daubert as restricting expert testimony to opinions that
are based solely upon epidemiological data. Daubert merely requires that
the expert testimony be both relevant and reliable; and Daubert clearly vests
viewpoints” from which to “study association before we cry causation.” Hill, A.B., The Environment and Disease:
Association or Causation?, PROC. R. SOC. MED., 58(5):295–99 (May, 1965). These nine guidelines are: 1) the
strength of the association; 2) consistency of the association; 3) specificity or whether there are multiple causes of a
condition; 4) the temporal relationship between a condition followed the exposure to the agent; 5) biological
gradient or the existence of a dose-response relationship; 6) how plausible the association is biologically; 7) whether
the association is “coherent” with (i.e., does not seriously conflict with) generally known facts of the natural history
and biology of the disease; 8) does experimentation—removing the causative agent—improve the condition; and 9)
analogy. Id. See also In re Seroquel Products Liability Litigation, No. 6:06–md–1769–Orl–22DAB, 2009 WL
3806435, at *5, n. 5 (M.D. Fla. Jun. 23, 2009).
The defendants’ interpretation of the type of association needed before using Bradford-Hill appears to be overstated.
There is nothing to say that a statistically-significant association must be found before applying the methodology.
See In re: Lipitor (Atorvastatin Calcium) Marketing, Sales Practices and Products Liability Litigation, --- F.Supp.3d
----, MDL No. 2:14–mn–02502–RMG, 2016 WL 1251828, at *2 (D.S.C. Mar. 30, 2016)(“Randomized, doubleblind, clinical trials are the ‘gold standard’ for determining whether an association exists. However, the Reference
Manual on Scientific Evidence recognizes that observational studies can be sufficient to establish an
association.”)(citation omitted); Federal Judicial Center, Reference Manual on Scientific Evidence, at 598-99 (3d
ed. 2011)(recognizing that an association is needed first to apply Bradford-Hill but not a statistically significant
one); id. at 217-18 (recognizing the role of observational studies in establishing causation). The case the defendants
cite for this argument is unpersuasive and/or distinguishable from this case. See In re Zoloft (Sertraline
Hydrocholoride) Products Liability Litig., 26 F. Supp. 3d 449, 456 (E.D. Pa. 2014)(excluding expert opinion on
teratogenicity, not drug-induced liver injury, because expert failed to follow generally accepted method in that
field). I find nothing that requires the plaintiff’s expert to use the methodology, as prescribed by the defendants.
The defendants argue that reliance on Benedi v. McNeil-P.P.C., Inc., 66 F.3d 1378 (4th Cir. 1995), is misplaced
because case reports in that action were only admissible to show notice, not proof of causation. It is the defendants’
argument that is misplaced. In Benedi, the Fourth Circuit found that the district court did not err in admitting the
case reports themselves into evidence, though they may be considered hearsay, because they were used to show
notice. Id. at 1385-86. The court did not address whether reliance on case reports by experts in forming causation
opinions was appropriate. Whether an expert can rely on case reports or whether a court can admit the case reports
themselves into evidence are two entirely different questions. See FED. R. EVID. 703.
the district courts with discretion to determine the admissibility of expert
testimony. Under the Daubert standard, epidemiological studies are not
necessarily required to prove causation, as long as the methodology
employed by the expert in reaching his or her conclusion is sound.
Id. See also id. at 1384-85. While epidemiological studies can be valuable evidence of
causation, they are not a pre-requisite for products liability causation expert testimony in
this Circuit.22 The defense experts admit that having case-controlled epidemiological data
is not a requirement in finding causation for drug-induced liver injuries.23
In this case especially, epidemiological studies and/or statisticallysignificant clinical evidence would be difficult to obtain. Drug-induced ALF and
severe liver injury are rare.24 Case-controlled epidemiologic studies of rare
diseases, such as ALF, with control groups are difficult to perform. Drug-induced
See Wolfe v. McNeil-PPC, Inc., No. 07–348, 2011 WL 1673805, at *15 (E.D. Pa. May 4, 2011)(rejecting similar
argument from McNeil in Motrin products liability action); Lanzilotti by Lanzilotti v. Merrell Dow Pharmaceuticals
Inc., No. 82–0183, 1986 WL 7832, at *2 (E.D. Pa. Jul 10, 1986)(“We note also that it has not been declared in this
circuit that epidemiological studies are an indispensable element in the presentation of a prima facie drug product
liability case, or that such studies must be the sole basis for expert opinion.”); Mazur v. Merck & Co., Inc., 742
F.Supp. 239, 264 (E.D. Pa. 1990)(same). See also Soldo v. Sandoz Pharms. Corp., 244 F. Supp. 2d 434, 449 (W.D.
Pa. 2003)(discussing the value of epidemiological studies).
See R. Brown Dep., Apr. 30, 2015 at 106-07 (Doc. No. 154, Ex. 3)(“Q. My question is very specific, sir. My
question is, is there a requirement in any of the peer-reviewed medical literature that before a drug can be ruled in as
a potential hepatotoxic drug that there must be a case-controlled epidemiologic study?…A. The answer is, you have
to have some data. What form that data takes varies, based upon the drug you're studying and what you're trying to
assess. You have to have reliable data. And that reliable data can come from a number of sources. If you have
randomized controlled clinical trial data, you don't have need much else. If you're requiring lower -- the way we
grade data is you have a quality of the data and a confidence in the data, and then you come up with a strength of the
recommendation. And that's a -- that was not a standard process in 1990 and 2000 when many of these articles were
done, but it is the standard now. And so the higher the quality of the evidence, the fewer studies you need. The lower
the quality of the evidence, the -- either you need stronger data or more research.”) and at 107-109; S. Flamm Dep.,
May 5, 2015 at 97 (Doc. No. 154, Ex. 4)(“Q. Okay. And there is no requirement in the causation algorithm that there
be an epidemiologic study that would demonstrate a statistically significant 2.0 relative risk to a P-value of .05
standard epidemiologic association in order to rule in a drug as a potential cause for acute liver failure or DILI.
True? A. Yes. Again, it's not a requirement, but for you to make a very good clinical decision and really understand
an interaction with a particular patient and a product, you have to have some level of comfort in the data that are
behind it.”) and at 98.
Dr. Davern also explained that death resulting from ALF is rare because patients often receive transplants. See T.
Davern Dep., Mar. 28, 2015 at 324-25 (Doc. No. 155, Ex. 3).
ALF is unlikely to ever be seen in a human prospective placebo-controlled clinical trial,
which studies a small number of patients.25 Because of the rarity of drug-induced ALF,
randomized placebo-controlled clinical trials would not necessarily establish a connection
between acetaminophen and ALF.26
The experts in this case recognize that the types of studies the defendants claim are
needed to make an opinion reliable—human prospective placebo-controlled clinical
trials—are not feasible or ethical.27 During his deposition, Dr. Anthony Temple, former
Vice President of Medical Affairs at McNeil, admitted that McNeil consulted with
epidemiologists to design a statistically-significant controlled study which would prove
or disprove acetaminophen-induced ALF; they found such a study was not feasible and/or
was too expensive to conduct.28
See Davern, T.J., et al, Drug-Induced Liver Injury in Clinical Trials: As Rare as Hen’s Teeth (editorial), Am. J.
Gastroenterol., 2009: 104: 1159-1161 (Doc. No. 154, Ex. 8); T. Davern Dep., Mar. 28, 2015 at 115-16, 119-26, 141,
144 (Doc. No. 155, Ex. 3).
See T. Davern Addendum to Expert Report, Apr. 27, 2015 at 3 (Doc. No. 155, Ex. 2). See also A. Temple Dep.,
Mar. 20, 2014 at 91, 100, 185-86 (Doc. No. 154, Ex. 10).
See T. Davern Addendum to Expert Report, Apr. 27, 2015 at 3-4 (Doc. No. 155, Ex. 2); T. Davern Dep., Mar. 28,
2015 at 121 (Doc. No. 155, Ex. 3).
See also N. Kaplowitz Dep., Jun. 3, 2014 at 138-42, 164, 214-15 (Doc. No. 154, Ex. 9)(Lyles Deposition) and at 139
(“I mean, there's no -- first of all, there is no scientific evidence that it does not because the studies are not powered
to exclude it. And so, as one always has to do in the setting of rare events, is you have to see an accumulation of rare
events. If this happened once in history, you know, one case report in the world's literature, obviously -- or two,
even – we wouldn't be sitting here. But there are -- there's enough smoke here, enough case reports, coupled with all
the other things that I've just been talking about that I won't repeat that I don't agree with.”); S. Flamm Dep., May 5,
2015 at 94, 96-98 (Doc. No. 155, Ex. 9)(admitting that he cannot name one hepatotoxic drug which has statistically
significant proof to show liver injury causation); R. Brown Dep., Apr. 30, 2015 at 105-09 (Doc. No. 154, Ex.
3)(same) and at 209-230 (Doc. No. 155, Ex. 8); A. Temple Dep., Mar. 20, 2014 at 84-85 (Doc. No. 154, Ex. 10)(“Q.
And because it would be inappropriate and unethical to prospectively expose a patient to a drug with the intent of
trying to measure harm? A. Well, yeah. That's been an issue with giving overdoses of acetaminophen, yes. You
wouldn't do it -- if you knew that giving a drug in a certain dose produced harm, then you wouldn't want to give it to
See A. Temple Dep., Mar. 20, 2014 at 91 (Doc. No. 154, Ex. 10)(under seal)(“I don't think there was an easy way
or even a way to look retrospectively. I mean, we just did another case series with -- he admitted that it's very hard
Like the Fourth Circuit, I find the defendants’ argument unpersuasive.29 Dr.
Davern has extensive clinical experience treating patients with acetaminophen-induced
liver injury. He has enrolled 300 patients in ALFSG studies. Most of them suffered from
acetaminophen poisoning.30 He has presented to the FDA Advisory Committees about
unintentional acetaminophen-induced liver injury. As a leading expert in acetaminopheninduced liver injury, he relies on his own clinical experience and available research in
rendering his opinions.31 He weighs the “totality of the evidence”—acetaminophen
to define ingestion of alcohol or fasting during this period of time. So his case series was what it was. So doing the
kind of epidemiology series I think you're describing, we determined wasn't a feasible study, but we have evaluated
whether to do that or not, yes.”), at 100 (“[W]e talked -- we had talked with epidemiologists, and we had looked at
that issue, and I don't know that they -- I don't recall them ever giving us an adequate proposal, but the answer is yes,
we did talk to them about the dosing issues and about ways to conduct epidemiology studies.”), and at 185-86
(“McNeil has not done an epidemiology study that way because we couldn't find a way to conduct that trial.”).
I also note that two different databases (the ALFSG and FDA databases) showed a risk in some people at 4 grams
and that the median daily dose for liver injury was 5-7 grams a day. FDA Working Group Report (2008) at 11, n. 41
(Doc. No. 155, Ex. 24).
I note that the way acetaminophen has been regulated—having been on the market, grandfathered in under the
monograph system, and never issued a final monograph—may also explain why this type of research has never been
conducted. Unlike other drugs, no pre-marketing research was conducted on acetaminophen to determine its adverse
effects. In addition, while acetaminophen manufacturers are encouraged to explore reports of adverse events, they
were not necessarily required to perform post-marketing research by regulation. See 21 C.F.R. § 330.12(c)
(explaining how manufacturers of drugs with a Tentative Final Monograph are “encouraged to perform studies to
obtain adequate evidence of effectiveness” and make appropriate changes in labels and formulations “to bring the
products into conformity with current medical knowledge and experience”). This unique regulatory scheme is one
reason why expert opinions without epidemiological or statistically-significant data may also be appropriate in this
Among these references, Dr. Davern’s cites Larson, A.M., Davern, T.J., et al., Acetaminophen-induced acute liver
failure: results of a United States multicenter, prospective study, Hepatology, 2005 Dec: 42(6): 1364-1372 (Doc. No.
154, Ex. 22). The defendants filed a separate motion to exclude the use of this article. See Motion to Exclude
Opinion Testimony of Timothy Davern based on Supplemental Data, Jan. 29, 2016 (Doc. No. 193). I denied that
motion. See Memorandum and Order Denying Defendants’ Motion to Exclude Plaintiff’s Expert Testimony Based
on Larson Article/ALFSG Data, Jul. 14, 2016 (Doc. No. 224, 225). I see nothing improper with how Dr. Davern has
used the Larson article—along with his other evidence—in rendering his opinion.
See, e.g., T. Davern Addendum to Expert Report, Apr. 27, 2015 at 4-9 (Doc. No. 155, Ex. 2); Watkins, P., et al.,
“Aminotransferase Elevations in Healthy Adults Receiving 4 grams of Acetaminophen Daily: A Randomized
Controlled Trial,” JAMA, 296:87-93, 2006 (Doc. No. 155, Ex. 14); Sabate, M., et al., Paracetamol in therapeutic
dosages and acute liver injury: causality assessment in a prospective case series, BMC Gastroenterology, 2011,
11:80 (Doc. No. 155, Ex. 16); Kurtovic, J. and Riordan, S.M., Paracetamol-Induced Hepatoxicity at Recommended
Doses, J. Internal Med., 2003 Feb.: 253(2):240-3 (Doc. No. 155, Ex. 19); Forget, P., et al., Therapeutic dose of
clinical trials, animal studies, numerous case reports and case series, and his own clinical
experience—in rendering his opinion.32 I see nothing wrong with his general causation
b. Reliance on the Watkins study is Appropriate
The defendants argue the Dr. Davern’s reliance on a study from 2006 authored by
Dr. Paul Watkins is not appropriate because the article discusses elevated
acetaminophen may induce fulminant hepatitis in the presence of risk factors: A report of two cases, B. J.
Anesthesia, Vol. 103, Issue 6; 899-900, 2009 (Doc. No. 155, Ex. 20); FDA Working Group Report (2008)(Doc. No.
155, Ex. 24).
See T. Davern Addendum to Expert Report, Apr. 27, 2015 at 2-7 (Doc. No. 155, Ex. 2). See also In re Levaquin
Products Liab. Litig., No. MDL 08-1943 JRT, 2010 WL 8400514, at *4 (D. Minn. Nov. 8, 2010)(“When courts
allow expert testimony premised on animal studies, it is because human studies cannot be done for ethical reasons,
or there is a reasonable basis to believe that the results from the animal studies can be reliably extrapolated to
humans….Though courts should be cautious in presuming that findings derived from animal studies are applicable
to humans, the applicability of animal studies is often appropriately explored during cross-examination.”)(citations
The defendants argue that Dr. Davern cannot rely upon information contained in a 2008 report from the FDA’s
Acetaminophen Hepatotoxicity Working Group because it is not peer-reviewed and does not offer information to
support Dr. Davern’s opinions. See FDA Working Group Report (2008)(Doc. No. 155, Ex. 24). This is a weak
argument. See Heller v. Shaw Industries, 167 F.3d 146, 155 (3d Cir. 1999)(“Given the liberal thrust of the Federal
Rules of Evidence, the flexible nature of the Daubert inquiry, and the proper roles of the judge and the jury in
evaluating the ultimate credibility of an expert's opinion, we do not believe that a medical expert must always cite
published studies on general causation in order to reliably conclude that a particular object caused a particular
illness…. To so hold would doom from the outset all cases in which the state of research on the specific ailment or
on the alleged causal agent was in its early stages, and would effectively resurrect a Frye-like bright-line standard,
not by requiring that a methodology be ‘generally accepted,’ but by excluding expert testimony not backed by
published (and presumably peer-reviewed) studies. We have held that the reliability analysis applies to all aspects of
an expert's testimony: the methodology, the facts underlying the expert's opinion, the link between the facts and the
conclusion, et alia.”).
I see nothing inherently unreliable in a report prepared by a group of scientists, who are experts in this area of study,
coming together to discuss, discern, and analyze possible concerns on this topic. Not only was the document
produced with input from experts on the topic of acetaminophen-induced liver injury, including ones working for the
defendants, but it was also sponsored by the FDA. The fact that the national regulatory agency convened a group of
experts to discuss the issue of acetaminophen-induced liver injury, to collectively present and analyze the available
information about acetaminophen-induced liver injury, provides the document with the indicia of reliability required
The Working Group report stated that acetaminophen has a narrow therapeutic margin. It discussed cases of liver
injury caused by acetaminophen at or near recommended doses. The Working Group considered ways to reduce the
risk of unintentional overdose and liver injury to consumers, including decreasing the maximum daily dose from
4000 milligrams to 3250 milligrams. This information would be relevant to Dr. Davern’s opinions.
aminotransferase levels, not ALF.34 See Watkins, P., et al., “Aminotransferase Elevations
in Healthy Adults Receiving 4 grams of Acetaminophen Daily: A Randomized
Controlled Trial,” JAMA, 296:87-93, 2006 (Doc. No. 155, Ex. 14).
The Watkins article found that some adults had developed abnormalities in liver
enzymes (e.g., aminotransferases or ALTs) after taking recommended doses of
acetaminophen.35 ALF occurs when the liver is severely damaged. Elevated ALTs are
markers of liver damage (i.e., liver cell death).36 Increased ALTs do not necessarily lead
They also point out the Watkins article’s statements that “acetaminophen clearly has a remarkable safety record
when taken as directed, and chronic treatment with 4 g daily has been confirmed to be safe.” Watkins, P., et al.,
“Aminotransferase Elevations in Healthy Adults Receiving 4 grams of Acetaminophen Daily: A Randomized
Controlled Trial,” JAMA, 296:87-93, 93 (2006)(Doc. No. 155, Ex. 14). The mere fact that the article acknowledges
that acetaminophen is typically safe at recommended doses does not mean that other findings in the article should be
negated or reliance on the article is inappropriate.
The defendants claim that Dr. Davern’s general causation opinion is unreliable because he “cherry picked”
evidence that would support his findings, while disregarding evidence that contradicted them. The defendants argue
that Dr. Davern did not address studies conducted by McNeil and others, which contradicted the findings in
Watkins. See Kuffner, E.K., et al., Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients:
a randomized, double-blind, placebo-controlled trial, Arch. Intern. Med., 2001, 161:2247-52 (Doc. No. 126, Ex. J);
Kuffner, E.K., et al., The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in
alcoholic patients – a multicenter randomized study, BMC Medicine, 2007; 5:13 at 4. (Doc. No. 126, Ex. K);
Temple, A. et al., Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel-Group Trial of the Long
Term (6-12 Months) Safety of Acetaminophen in Adult Patients with Osteoarthritis, Clinical Therapeutics
(2006)(Doc. No. 126, Ex. M). See also Heard at el., A randomized trial to determine the change in alanine
aminotransferase during 10 days of paracetamol (acetaminophen) administration in subjects who consume moderate
amounts of alcohol, Alimentary Pharmacology & Therapeutics (2007)(Doc. No. 126, Ex. L). This point goes to
weight, not admissibility.
See Davern, T., Book Chapter: “Drug Induced Liver Disease” In Approach To Consultations For Patients With
Liver Disease, Flamm, S.L. guest editor, May 2012, Vol. 16, No. 2, 231-244, 232 (Doc. No. 155, Ex. 4)(“Acute
hepatocellular injury is caused by injury primarily to the hepatocytes and is characterized be elevated levels of [liver
chemistries reflecting injury].Severe hepatocellular injury may evolve into acute liver failure with hepatic synthetic
dysfunction and hepatic encephalopathy, which carries a very poor prognosis and often requires a liver
transplantation for survival.”); T. Davern Dep., Mar. 28, 2015 at 101 (Doc. No. 155, Ex. 3)(“The injury caused by
acetaminophen is a spectrum. Some patients have mild, asymptomatic elevations of the serum aminotransferases
with absolutely no symptoms or sequela, but there are other patients who have more severe liver injury. And, again,
it is a continuum, with the far end being acute liver failure, the syndrome where there is not only severe injury, but
liver failure with coagulopathy and mental status changes, hepatic encephalopathy.”)
See also R. Brown Dep., Apr. 30, 2015 at 15 (Doc. No. 155, Ex. 8)(“Q. Okay. Well, for acute liver disease, the
range of liver disease is typically from asymptomatic elevations in liver enzymes all the way through acute liver
failure and death. True? A. Well, asymptomatic elevations of liver enzymes may or may not be related to drug
induced liver injury. And that's where many of these issues arise because patients who are ill can have injuries in the
to ALF.37 However, elevated ALTs are one early indicator that ALF might occur.38 The
defendants fail to acknowledge the fact that the Watkins study was stopped early because
the authors were concerned about the harm being caused to study participants. 39 It would
not have found ALF because inducing ALF—a life threatening condition—would have
been unethical. I see no problem with Dr. Davern’s use of the Watkins data to support his
opinions, along with the many other sources he cites.40
c. Dr. Davern’s Use of Case Reports is Appropriate in this Case
The defendants argue that Dr. Davern cannot use case reports to establish
causation.41 It is true that case reports and anecdotal evidence alone may not be sufficient
liver enzymes and they may or may not have drug induced liver injury. But drug induced liver injury does have a
spectrum from mild to severe, including acute liver failure.”).
See T. Davern Dep., Mar. 28, 2015 at 132 (Doc. No. 155, Ex. 3).
See T. Davern Dep., Mar. 28, 2015 at 132, 159-61 (Doc. No. 155, Ex. 3).
Dr. Temple also admitted that looking at elevated ALTs is one way to study the risk of ALF. See A. Temple Dep.,
Mar. 20, 2014 at 85 (Doc. No. 154, Ex. 10)(“Q. Right. So the way in which you study risk in clinical trials is to look
for surrogates for risk. Oftentimes you look for laboratory abnormalities. If there happens to be a patient reaction
during the clinical trial, you look for measurements of blood pressure, liver function tests, those kinds of things as a
predictor, potential predictor of clinical problems when a drug is more widely used, true? A. You can do that, yes.”).
The defendants also do not recognize McNeil’s own research using elevated ALTs and ASTs in patients taking 4
grams. See McNeil chart, Summary of Peak Lab Values Post-Baseline, Jul. 6, 2012 (Doc. No. 155, Ex. 15); T.
Davern Addendum to Expert Report, Apr. 27, 2015 at 5 (Doc. No. 155, Ex. 2)(citing Ex. 15).
The defendants also claim Dr. Davern’s reliance on data from the Acute Liver Failure Study Group (ALFSG),
including Larson, A.M., Davern, T.J., et al., Acetaminophen-induced acute liver failure: results of a United States
multicenter, prospective study, Hepatology, 2005 Dec: 42(6): 1364-1372 (Doc. No. 154, Ex. 22)(i.e., the “Larson
article”), is not appropriate because this data is nothing more than case reports. The defendants filed a separate
motion regarding the admissibility and validity of the ALFSG data. See Doc. No. 193. I explain in my decision on
that motion why the ALFSG data is admissible and can be relied upon by experts in the field. See Memorandum and
Order Denying Defendants’ Motion to Exclude Plaintiff’s Expert Testimony Based on Larson Article/ALFSG Data,
Jul. 14, 2016 (Doc. No. 224, 225). I see no problems with the way Dr. Davern has used this data in forming his
opinions. See T. Davern Dep., Mar. 28, 2015 at 119-121 (Doc. No. 155, Ex. 3).
Along the same lines, the defendants argue that Dr. Davern’s opinion that acetaminophen-induced ALF can occur
at 4 grams is not admissible because it relies on data from the Acute Liver Failure Study Group (ALFSG)—an
“uncontrolled” registry of case reports. To support this opinion, the defendants cite Ratner v. McNEIL-PPC, Inc., 91
A.D.3d 63 (N.Y. App. Div. Nov. 22, 2011). This precedent is non-binding and unpersuasive. I further address why
support for a causation opinion. See, e.g., Wade-Greaux v. Whitehall Labs., Inc., 874 F.
Supp. 1441, 1483 (D.V.I. 1994)(“…anecdotal human data, whether from published case
reports, DERs or other litigation, have inherent biases that make them unreliable.”).
However, case reports considered in conjunction with other evidence may be an
appropriate basis for an expert’s causation opinion.42 Dr. Davern does not rely solely on
case reports in rendering his opinion. The case reports and case series he does cite also
include controls on the information analyzed, which enhance their reliability.43
In addition, case reports and case series are the types of information on which
DILI experts rely. See FED. R. EVID. 703; Wolfe v. McNeil-PPC, Inc., No. 07–348, 2012
the ALFSG data is more than an “uncontrolled” registry of case reports in my decision on the admissibility of that
data. See generally Memorandum and Order Denying Defendants’ Motion to Exclude Plaintiff’s Expert Testimony
Based on Larson Article/ALFSG Data, Jul. 14, 2016 (Doc. No. 224, 225).
See Wolfe v. McNeil-PPC, Inc., No. 07–348, 2012 WL 38694, at *3 (E.D. Pa. Jan. 9, 2012)(“As for the use of
AERs as bases for expert testimony, this Court has previously ruled that expert testimony that relies, in part, on case
reports to establish causation satisfies the requirements of Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S.
579, 113 S.Ct. 2786, 125 L.Ed.2d 469 (1993). See Wolfe v. McNeil–PPC, Inc., No. 07–348, 2011 WL 1673805, at
*5 (E.D. Pa. May 4, 2011). The Court reiterates its conclusion that, because plaintiff's experts ‘did not solely rely on
case reports in forming their opinions on causation but used them to supplement their extensive review” of other
evidence, such testimony is admissible.”); Wolfe v. McNeil–PPC, Inc., No. 07–348, 2011 WL 1673805, at *5 (E.D.
Pa. May 4, 2011)(“In this case, the three doctors did not solely rely on case reports in forming their opinions on
causation but used them to supplement their extensive review of plaintiff's medical records and deposition testimony
of plaintiff's treating physicians. As with defendants' other objections, the three doctors' use of case studies in
reaching their conclusion affects only the weight to be given their testimony, not its admissibility. Thus, the
proposed testimony of the three doctors is based on sufficiently reliable methods.”); Schedin v. Ortho–McNeil–
Janssen Pharm., Inc., 808 F.Supp.2d 1125, 1139 (D. Minn. 2011)(explaining that AERs are commonly used by
experts to determine causation in conjunction with other evidence), rev'd in part on other grounds, In re Levaquin
Prods. Liab. Litig., 700 F.3d 1161 (8th Cir. 2012).
See Caraker v. Sandoz Pharm. Corp., 172 F.Supp.2d 1046, 1050 (S.D. Ill. 2001)(explaining how “an
overwhelming amount” of case reports/series with appropriate controls, analysis of alternative causes, temporal
proximity may be a reliable basis for expert opinion). See also Soldo v. Sandoz Pharms. Corp., 244 F. Supp. 2d 434,
537-44 (W.D. Pa. 2003)(finding case reports to be unreliable and “unscientific” bases for causation opinion because
are unpublished, not peer-reviewed, did not consider alternative causes, patients’ medical history, etc.); McClain v.
Metabolife Int’l, Inc., 401 F.3d 1233, 1250 (11th Cir. 2005)(explaining that anecdotal information “without any
medical controls or scientific assessment” is unreliable basis for expert opinion); Hollander v. Sandoz Pharms.
Corp., 289 F.3d 1193, 1211 (10th Cir. 2002)(finding that exclusion of opinions based on case reports with little
information about medical history appropriate but that case reports with more detailed information may be reliable
source of expert opinion).
WL 38694, at *3 (E.D. Pa. Jan. 9, 2012); FDA Working Group Report (2008) at p. 11, n.
41 (Doc. No. 154, Ex. 30)(explaining how members of the working group looked at two
different databases of case reports/adverse event reports (AERs) in finding that there is a
risk of liver injury for some people at 4 grams).44 As explained above, epidemiological or
case-controlled studies for acetaminophen-induced liver injuries are not available. In the
absence of epidemiological data, case reports and case series may be valuable sources of
information for DILI experts, doctors, and scientists in determining causation.45
Dr. Davern’s Specific Causation Opinion is Reliable46
After reviewing Ms. Hayes’ medical records, Dr. Davern opined that Ms. Hayes
died of acetaminophen-induced ALF after taking recommended doses of Tylenol. He
ruled out alternative causes and noted that Ms. Hayes’ biochemical patterns were
consistent with acetaminophen-induced ALF.47 He noted that her prior gastric bypass
surgery was a risk factor.
Whether the case reports themselves may be admissible or disclosed to the jury is a separate question, which I will
defer until I see how they may be used at trial. See FED. R. EVID. 703 (“An expert may base an opinion on facts or
data in the case that the expert has been made aware of or personally observed. If experts in the particular field
would reasonably rely on those kinds of facts or data in forming an opinion on the subject, they need not be
admissible for the opinion to be admitted. But if the facts or data would otherwise be inadmissible, the proponent of
the opinion may disclose them to the jury only if their probative value in helping the jury evaluate the opinion
substantially outweighs their prejudicial effect.”); Wolfe v. McNeil-PPC, Inc., No. 07–348, 2012 WL 38694, at *3
(E.D. Pa. Jan. 9, 2012).
See, e.g., T. Davern Addendum to Expert Report, Apr. 27, 2015 at 4 (Doc. No. 155, Ex. 2)(explaining the
usefulness of case reports in DILI causation analysis); N. Kaplowitz Dep., Jun. 3, 2014 at 134-136, 139, 158, 194,
213 (Doc. No. 154, Ex. 9)(Lyles Deposition); Davern, T.J., et al., Drug-Induced Liver Injury in Clinical Trials: As
Rare as Hen’s Teeth (editorial), Am. J. Gastroenterol., 2009: 104: 1159-1161 (Doc. No. 154, Ex. 8)(explaining how
multi-center reporting is important to understanding DILI); FDA Working Group Report (2008) at 3-5, 11, n. 41
(Doc. No. 154, Ex. 30).
See T. Davern Expert Report, Feb. 16, 2015 at 6-9 (Doc. No. 155, Ex. 1); T. Davern Addendum to Expert Report,
Apr. 27, 2015 at 8-11 (Doc. No. 155, Ex. 2). See also T. Davern Dep., Mar. 28, 2015 at 82-92, 179-309, 378-80
(Doc. No. 155, Ex. 3).
See T. Davern Dep., Mar. 28, 2015 at 195-234, 239-271 (Doc. No. 155, Ex. 3).
Dr. Davern uses a “causality assessment methodology” (CAM) in rendering his
specific causation opinion.48 This is the same methodology Dr. Davern uses when
treating patients. While there are variations among CAM tools, at the core of this
methodology is a “differential assessment.” DILI causality assessments consider a
combination of factors, including: temporal associations, the rate of improvement after
cessation of the drug, the definitive exclusion of alternative causes, and the “signature” of
the drug as revealed in clinical trials and experience.49 This “science of [DILI] causality
assessment” has been published by DILI experts in various forms since the 1980s.50
See T. Davern Addendum to Expert Report, Apr. 27, 2015 at 2-3 (Doc. No. 155, Ex. 2)
The defendants do not dispute that CAM is a reliable methodology. Defendants’ Reply, Doc. No. 172 at 11. They
argue that Dr. Davern has applied the methodology incorrectly. How he misapplied the CAM, in their view, is
unclear. I see nothing in Dr. Davern’s reports to indicate a misapplication of this methodology.
See T. Davern Addendum to Expert Report, Apr. 27, 2015 at 2-3 (Doc. No. 155, Ex. 2); Davern, T., Book
Chapter: “Drug Induced Liver Disease” In Approach To Consultations For Patients With Liver Disease, Flamm,
S.L. guest editor, May 2012, Vol. 16, No. 2, 231-244, 237-39 (Doc. No. 155, Ex. 4). See also Kaplowitz N.,
Causality Assessment verses Guilt by Association in Drug Hepatoxicity, Editorial, Hepatology, 33:308-310, 2001
(Doc. No. 154, Ex. 11); R. Brown Dep., Apr. 30, 2015 at 103-05 (Doc. No. 154, Ex. 3); S. Flamm Dep., May 5,
2015 at 69, 138-140 (Doc. No. 155, Ex. 9).
See, e.g., Maria, V. & Victorino, R., Development and Validation of a Clinical Scale for the Diagnosis of Drug
Induced Hepatitis, Hepatology, Vol. 26; 664-669, 1997; Aithal, G., et al., Clinical Diagnostic Scale: A Useful Tool
in the Evaluation of Suspected Hepatotoxic Adverse Drug Reactions, J. Hepatology, 2000:33; 949-953; Danan G., et
al., Causality Assessment of Adverse Reactions to Drugs – I. A Novel Method Based on the Conclusions of the
International Consensus Meetings: Application to Drug Induced Liver Injuries [RUCAM], J. Clin. Epidemiol., 1993;
46:1323-1330; Benichou, C., et al., Criteria of Drug Induced Liver Disorders: Report of an International Consensus
Meeting [CIOMS], J. Hepatol.,1990:11:272-276; Lucena, M., et al., Comparison of Two Clinical Scales for
Causality Assessment in Hepatotoxicity, Hepatology, 2001: 33:123-130; Lee, W.M., Assessing Causality in Drug
Induced Liver Injury, J. Hepatology, 2000, 33:1003-1005; Kaplowitz, N., Causality assessment versus guilt-byassociation in drug hepatotoxicity, Hepatology, Vol. 33, No. 1, 308-10, 2001; Davern, T., Drug-Induced Liver
Disease, in Clinics in Liver Disease, Vol. 13, No. 2, May 2012, 231-239 (“Diagnosis of DILI: Causality
Assessment”]; Causality Assessment in Drug Induced Liver Injury, Presentation at the FDA, PhRMA, ASSLD
Symposium by Robert J. Fontana, M.D. (Jan. 28, 2005).
a. Use of the Holt Study in Rendering his Specific Causation Opinion
The defendants argue that Dr. Davern’s general causation opinion that
gastric bypass surgery may be a risk factor for acetaminophen-induced acute liver
failure (ALF) is not reliable because Dr. Davern only cites one study he published
in 2014. See E. Holt, et al., “Acute Liver Failure Due to Acetaminophen Poisoning
in Patients With Prior Weight Loss Surgery: A Case Series,” J. Clin.
Gastroenterol., Vol. 00, No. 00, 1-4 (2014)(Doc. No. 154, Ex. 29). This study was
published several years after the decedent’s death. Dr. Davern’s deposition
testimony, however, makes clear that his opinion about gastric bypass surgery ties
into his opinions about fasting and malnutrition.51 He bases his opinions not
simply on the findings in the Holt study, but also his understanding of how fasting
and malnutrition—and, in turn, gastric bypass surgery—can affect glutathione
levels.52 Glutathione is necessary to neutralize toxins caused by acetaminophen.
The defendants also claim the Holt study cannot be relied on because it
does not report dosing. Dr. Davern offers other evidence to support his opinion
See T. Davern Dep., Mar. 28, 2015 at 100-03, 185-85, 235-37, 343-45 (Doc. No. 155, Ex. 3).
The defendants claim that Dr. Davern offers no evidence that Ms. Hayes was malnourished. Dr. Davern indicates
that Ms. Hayes was vomiting, dehydrated, and experiencing hypoglycemia. See T. Davern Addendum to Expert
Report, Apr. 27, 2015 at 2-7 (Doc. No. 155, Ex. 2). See also T. Davern Dep., Mar. 28, 2015 at 393 (Doc. No. 155,
Ex. 3). This information is enough for him to opine about Ms. Hayes’ nutritional state. Any flaws in his reasoning
can be brought out on cross-examination.
See T. Davern Addendum to Expert Report, Apr. 27, 2015 at 6-7 (Doc. No. 155, Ex. 2); T. Davern Expert Report,
Feb. 16, 2015 at 5-6 (Doc. No. 155, Ex. 1). See also Kurtovic, J. and Riordan, S.M., Paracetamol-Induced
Hepatoxicity at Recommended Doses, J. Internal Med., 2003 Feb; 253(2):240-3 (Doc. No. 155, Ex. 19)(as support
for liver injury with fasting and recommended doses); Forget, P., et al., Therapeutic dose of acetaminophen may
induce fulminant hepatitis in the presence of risk factors: A report of two cases, B. J. Anesthesia, Vol. 103, Issue 6;
899-900, 2009 (Doc. No. 155, Ex. 20)(as support for liver injury with recommended doses and gastric bypass).
that acetaminophen-induced ALF can occur at recommended doses.53 That
evidence is enough to support that part of his opinion.
b. Dr. Davern’s Discussion of Sepsis was Appropriate
The defendants argue that Dr. Davern’s specific causation opinion is flawed
because he didn’t specifically note that he ruled out sepsis as an alternative cause. Only
after he was served the defendants’ expert reports did he address sepsis. Dr. Davern
explained during his deposition why he did not even consider sepsis as an alternative
cause before reading the defendants’ expert reports—because it was “a far reach.”54 Dr.
Davern has had considerable experience with sepsis, treating many patients with it during
his career.55 He explained in his response to defendants’ expert reports that he “did not
include sepsis in [his] initial report because there was no evidence [Ms. Hayes] had any
type of significant infection at presentation, much less an infectious process that
progressed or developed into sepsis.”56 He explained how her blood cultures and urine
tests were negative, none of her treating physicians considered sepsis as a cause of death,
that she did not present with an infection when she was in the hospital the week before
See T. Davern Addendum to Expert Report, Apr. 27, 2015 at 6-7 (Doc. No. 155, Ex. 2)(noting a hospital case
from 2009 of acetaminophen poisoning related to gastric bypass).
See T. Davern Dep., Mar. 28, 2015 at 21-22 (Doc. No. 155, Ex. 3), at 351 (“Again, most patients with
acetaminophen poisoning that die, die from multiorgan failure. And most of those patients have a positive blood
culture before -- or many of them have positive blood cultures or other cultures before death. The diagnosis on the
death certificate is still acute liver failure from acetaminophen poisoning, but they had sepsis as well. Again, the two
-- the two aren't mutually exclusive, and sepsis complicates acute liver failure frequently. I just don't think in this
case sepsis explains her presentation, and I think that, despite a fairly intensive investigation with cultures and
imaging, et cetera, that there wasn't convincing evidence in this patient of sepsis.”), and at 195-217, 257-58, 266-67,
271, 284, 305-06, 351.
T. Davern Addendum to Expert Report, Apr. 27, 2015 at 7 (Doc. No. 155, Ex. 2).
her death, and that she did not show other signs of sepsis (i.e., deeply jaundiced skin,
elevated ammonia, etc.).57 The defendants’ argument is unpersuasive.
c. Use of McNeil’s CAM Instrument
Lastly, the defendants argue that Dr. Davern’s causality assessment of Ms. Hayes’
case is flawed because he “relies upon a causality assessment form that is not generally
accepted in the scientific community.” In fact, the form Dr. Davern uses is the one
McNeil uses in determining causality, as confirmed by Dr. Anthony Temple (former Vice
President of Medical Affairs at McNeil) during his deposition.58 This form was created
with the assistance of Dr. Neil Kaplowitz, a leading DILI expert.59 This argument borders
on ridiculous. McNeil criticizes Dr. Davern for using a form McNeil has approved.
McNeil’s CAM assessment instrument—developed by a leading DILI expert for a
leading producer of acetaminophen—shows all signs of being a reliable methodological
tool for determining causation in this case.
Overall, I find that Dr. Davern’s opinions are reliable and appropriate under
Daubert and the Federal Rules of Evidence. I will DENY the defendants’ motion.
An appropriate Order follows.
Id. at 7-8.
See A. Temple Dep., Mar. 20, 2014 at 310-13 (Doc. No. 155, Ex. 12).
See N. Kaplowitz Dep., Apr. 21, 2015, at 310-312 (Doc. No. 154, Ex. 5)(Hayes Deposition); Doc. No. 154, Ex. 1
(under seal)(McNeil CAM assessment with emails between Kaplowitz and Temple).
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