Admitting and excluding general causation expert testimony
Admitting and Excluding
General Causation Expert Testimony:
The Eleventh Circuit Construct
Success in mass toxic tort and product liability cases often turns on theplaintiffs’ ability to present reliable expert evidence of general causationthat can survive
Daubert scrutiny and create a triable issue for a jury. The Eleventh Circuit Court of Appeals has provided litigants with clearguidance on these issues. A litigant’s ability to follow that guidance canmake the difference between winning and losing a major case.
Often multi-plaintiff (or mass) toxic tort and product liability cases
turn on the question of causation. Plaintiffs frequently can prove thatthey have injuries or illnesses and that they used a defendant’s productor were exposed to a chemical compound sold by a defendant—or at thevery least, they can present enough evidence on these elements to survivesummary judgment. Where plaintiffs face a more difficult hurdle is intrying to prove that the defendant’s product or chemical compound cancause the injury or illness the plaintiffs suffered (general causation), and,further, that the product or compound in fact caused each plaintiff’s injuryor illness (specific causation).1
† B.B.A. (1987), Southern M ethodist University; J.D. (1990), University of
Pennsylvania Law School. M r. Pace is a partner in the M iami, Florida office of W eil,Gotshal & Manges, LLP.
Kilpatrick v. Breg, Inc., 613 F.3d 1329, 1334 n.4 (11th Cir. 2010); accord
Howell v. Centric Grp., LLC, 508 F. App’x 834, 836 (10th Cir. 2013) (order denyingmotion for reconsideration) (noting that “courts throughout the country routinelyrequire plaintiffs to show both general and specific causation”); Johnson v. Arkema,Inc., 685 F.3d 452, 468-69 (5th Cir. 2012) (per curiam) (citing Knight v. Kirby InlandM arine, Inc., 482 F.3d 347, 351 (5th Cir. 2007)) (noting that courts can only evaluatespecific causation after finding general causation); Junk v. Terminix Int’l Co., 628 F.3d439, 450 (8th Cir. 2010) (citing Ranes v. Adams Labs., Inc., 778 N.W .2d 677, 688(Iowa 2010)) (“To prevail in a toxic tort case such as this, the plaintiff must show bothgeneral and specific causation.”); In re
M eridia Prods. Liab. Litig., 328 F. Supp. 2d791, 798 (N.D. Ohio 2004), aff’d sub nom
. M eridia Prods. Liab. Litig. v. Abbott Labs.,447 F.3d 861, 869 (6th Cir. 2006) (same); In re
Hanford Nuclear Reservation Litig.,
In such actions, plaintiffs’ likelihood of success is commonly driven
by the admissibility of their experts’ general causation testimony underRule 702 of the Federal Rules of Evidence and Daubert v. Merrell DowPharmaceuticals
.2 If that testimony is not admissible under Daubert
, theaction is dismissed; if it is admissible, a defendant often feels irresistiblepressure to settle the action rather than risk a battle of experts at trial that,if the defendant loses, can cost exponentially more than the settlementcost of the action.3
Given the significant role played by Daubert
challenges to general
causation expert testimony in resolving mass toxic tort and productliability cases, guiding precedent in many United States courts of appealson such challenges is either sparse or, worse, inconsistent.4 The decisions
292 F.3d 1124, 1133 (9th Cir. 2002) (“Causation in toxic tort cases is typically dis-cussed in terms of generic and specific causation.”); Raynor v. M errell Pharms. Inc.,104 F.3d 1371, 1376 (D.C. Cir. 1997) (“testimony on specific causation had legitimacyonly as follow-up to admissible evidence that the drug in question could
in generalcause birth defects”); Rutigliano v. Valley Bus. Forms, 929 F. Supp. 779, 783 (D.N.J.
1996), aff’d sub nom.
Valley Bus. Forms v. Graphic Fine Color, Inc., 118 F.3d 1577(3d Cir. 1997) (granting summary judgment for the defendant as the plaintiff failed toprove general and specific causation). See generally
RESTATEM ENT (THIRD) OF TORTS:LIAB. FOR PHYSICAL & EM OTIONAL HARM § 28 cmt. c (2010) (“The concepts ofgeneral causation and specific causation are widely accepted among courts confrontingcausation issues with toxic agents.”).
2 509 U.S. 579 (1993). References hereinafter to “Daubert
” are shorthand for both
Rule 702 and the Supreme Court’s Daubert
decision and its progeny. Rule 702 wasamended in 2000 to codify the principles of Daubert
and its then-existing progeny. See
FED. R. EVID. 702 advisory committee’s note. Rule 702 permits an expert to testify toopinions if, among other things, the expert’s (1) “knowledge will help the trier of factto understand the evidence or to determine a fact in issue,” (2) “testimony is based onsufficient facts or data,” (3) “testimony is the product of reliable principles andmethods,” and (4) “appli[cation of] principles and methods to the facts of the case” isreliable. FED. R. EVID. 702; see also
Hendrix v. Evenflo Co., 609 F.3d 1183, 1194(11th Cir. 2010) (construing Daubert
3 In all but the rarest of circumstances, a plaintiff cannot prove— or even create a
triable issue of fact as to— general causation without expert testimony. See Hendrix
,609 F.3d at 1203 (affirming summary judgment in favor of defendant after exclusionof experts); see also Kilpatrick
, 613 F.3d at 1334 n.4 (general and specific causationexpert testimony required in products liability cases).
Berry v. City of Detroit, 25 F.3d 1342, 1352-54 (6th Cir. 1996) (excluding
nonscientific expert testimony because it failed to meet the four Daubert
, 115 S. Ct. 902 (1995); M arcel v. Placid Oil Co., 11 F.3d 563, 567-68 (5th Cir.
1994) (excluding testimony of economist because conclusions not based on sufficientdata made the testimony unreliable); Habecker v. Clark Equip. Co., 36 F.3d 278, 289-90 (3d Cir. 1994) (finding testimony of accident simulation expert inadmissible afterassessing expert’s methodology under Daubert
), cert. denied
, 115 S. Ct. 1313 (1995).
of the Eleventh Circuit Court of Appeals, however, are noteworthyexceptions to this. They have established a clear framework for how adistrict court is to determine if expert testimony on general causation isadmissible under Daubert
.5 This Article discusses the framework withwhich every litigator handling a toxic tort or product liability case in theEleventh Circuit—whether representing plaintiffs or defendants—shouldbe familiar.6
I. The Eleventh Circuit’s
Before delving into whether an expert’s general causation opinions
are based on sound and reliable methodologies as required underDaubert
, the threshold issues are whether a district court even needs tosubject those opinions to close Daubert
scrutiny and how tailored dothose opinions need to be to the facts of a given case. The EleventhCircuit has addressed and resolved each of these issues.
In McClain v. Metabolife International, Inc.
,7 the Eleventh Circuit
explained that toxic tort and product liability cases fall within twocategories: (1) “those in which the medical community generallyrecognizes the toxicity of the [substance] at issue,” and (2) “those  inwhich the medical community does not.”8 District courts “need not”conduct an extensive Daubert
general causation analysis for cases in thefirst category, whereas they must for cases in the second category.9 Thus,
McClain v. Metabolife Int’l, Inc., 401 F.3d 1233, 1237-38 (11th Cir.),
, 159 F. App’x 183 (11th Cir. 2005), with In re
Paoli R.R. Yard PCBLitig., 35 F.3d 717, 741 (3d Cir. 1994), cert. denied
, 115 S. Ct. 1253 (1995).
6 In fact, given that the Florida legislature has recently passed a bill to replace the
standard historically used by Florida courts with the Daubert
standard, EleventhCircuit Daubert
precedent is likely to be of great influence in Florida courts, especiallyin the early years before the Florida courts develop their own body of Daubert
interpretations and applications. See
H.B. 7015, 23d Legis., First Reg. Sess. (Fla.
2013) (amending FLA. STAT. § 90.702 (1976)); see also
Frye v. United States, 293 F.
1013 (D.C. Cir. 1923); Daubert
, 509 U.S. 579.
7 401 F.3d 1233 (11th Cir.), reh’g denied
, 159 F. App’x 183 (11th Cir. 2005).
, 401 F.3d at 1239.
while McClain permits
a district court to bypass “an extensive Daubert
analysis” in some circumstances, it never compels
Furthermore, the McClain
court was clear that its first category is very
limited: It applies only in the narrow circumstance “where the reliabilityof the expert’s methods is properly taken for granted.”11 McClain
pro-vided the following examples of agents and illnesses that fall within thefirst category: asbestosis and mesothelioma; cigarette smoke and lungcancer; and silica and silicosis.12 All of these causal connections gainedwidespread acceptance from decades of research and rigorous dataanalysis.13
The Eleventh Circuit, in McClain
and its progeny, also addressed the
need for an expert opinion on general causation to be tied closely to theproduct or chemical compound at issue in a lawsuit.14 It is not enoughfor an expert to opine that (1) similar products, related chemicals, ordrugs within the same class can cause the injury or illness suffered bya plaintiff, or (2) a defendant’s product or chemical compound can causeillnesses or injuries analogous to the injury or illness of the plaintiff.15 Rather, admissible general causation expert testimony must addresswhether the agent in question (be it a product or a chemical compound)can cause the specific injury in question.16 This is required because
1 0 Id.
; see also
Kumho Tire Co. v. Carmichael, 526 U.S. 137, 152-53 (1999) (“The
trial court must have the same kind of latitude in deciding how
to test an expert’sreliability . . . as it enjoys when it decides whether or not
that expert’s relevanttestimony is reliable.”).
1 1 McClain
, 401 F.3d at 1239 n.5 (quoting Kumho
, 526 U.S. at 152).
1 2 Id.
1 3 The McClain
court was clear that its two-category paradigm “is not an effort to
resurrect the test first announced in Frye
, 401 F.3d at 1239 n.5 (referencingFrye
, 293 F. at 1014). Accordingly, the touchstone for admissibility remains whetheran expert’s opinion is based on scientifically reliable methodologies and fits the factsof the case at hand. If this is not true, then the expert’s opinions are inadmissible evenif consistent with what the medical community might generally recognize. SeeDaubert
, 509 U.S. at 592-93.
1 4 See McClain
, 401 F.3d at 1239.
1 5 Id.
1 6 Id.
(“[I]n this case, Plaintiffs’ experts must offer reliable opinions about Metabo-
life’s general toxicity for the harm Plaintiffs allege.”); id
. at 1237 (“Plaintiffs mustprove the toxicity of [M etabolife’s] ephedrine/caffeine combination and that it had atoxic effect on them . . . .”); Kilpatrick v. Breg, Inc., 613 F.3d 1329, 1334 n.4 (11th Cir.
“[e]ven minor deviations in chemical structure can radically change aparticular substance’s properties and propensities,” so extrapolating fromone product to another, or from one type of injury to another, is not easilydone.17
II. Evaluation of
General Causation Methodologies
Just as Eleventh Circuit precedent creates a clear structure for a district
court to assess general causation expert opinions, it also provides clearguidance to district courts on how to evaluate the methodologies that anexpert has employed to form an opinion on general causation. Morespecifically, the Eleventh Circuit has addressed the reliability of variousmethodologies experts use to formulate general causation opinions andexplained why some of the methodologies are simply insufficient towarrant an admissible opinion on general causation.18 In so doing, theEleventh Circuit has not created a strict checklist of required methodolo-gies. Instead, it has developed—consistent with standard practice byscientists researching causation outside the courtroom—a structuredhierarchy of methodologies based on their probative value in demonstrat-ing causation.19 Although experts are not required to employ the most
2010) (“Kilpatrick must offer proof . . . that the device in question can cause harm ofthe type Kilpatrick alleges . . . .”); see also
Goldstein v. Centocor, Inc., 310 F. App’x331, 332-33 (11th Cir. 2009) (per curiam) (involving the issue of whether Remicadecaused pulmonary fibrosis); K ilpatrick v. Breg, Inc., No. 08-10052-CIV, 2009 W L2058384, at *4 (S.D. Fla. June 25, 2009) (“[T]he key issue is . . . whether that[chemical] compound as delivered via a particular medical device inserted in a par-ticular location . . . could and did cause injury.”), aff’d
, 613 F.3d 1329 (11th Cir. 2010);Guinn v. AstraZeneca Pharms. LP, 598 F. Supp. 2d 1239, 1242 (M .D. Fla. 2009) (ordergranting defendant’s motion for summary judgment) (“Guinn must show both thatSeroquel can generally cause diabetes and that Seroquel was a specific cause of herdiabetes.”), aff’d
, 602 F.3d 1245 (11th Cir. 2010) (per curiam).
1 7 McClain
, 401 F.3d at 1246 (alteration in original) (quoting Rider v. Sandoz
Pharms. Corp., 295 F.3d 1194, 1201 (11th Cir. 2002)); see also
W ells v. SmithKlineBeecham Corp., 601 F.3d 375, 380 (5th Cir. 2010); Knight v. Kirby Inland M arine Inc.,482 F.3d 347, 350-53 (5th Cir. 2007).
1 8 See infra
notes 21-55 and accompanying text.
1 9 See Rider
, 295 F.3d at 1202-03 (rejecting the argument that the district court
“requir[ed] a checklist of types of evidence to prove causation,” but rather “washighlighting the plaintiffs’ failure to present evidence in any of several categories that
probative methodologies, the Eleventh Circuit has repeatedly held thatan expert’s general causation testimony that neglects these criticalmethodologies is subject to heightened examination and can rarely, ifever, survive Daubert
A. Most Probative Methodologies
The most probative method for proving that a product causes a specific
injury or illness to humans is controlled human experimentation (suchas randomized clinical trials).21 For obvious reason, however, thatmethod is rarely available (and appropriately so) in situations where aproduct is alleged to cause significant injury or a serious illness. For-tunately, other methodologies exist that have been established as reliablefor demonstrating general causation without the need for direct humantesting. These methodologies share a common trait of being based ondata (not subjective judgment) that can be tested and the results eitherreplicated or refuted.
1. Dose-Response Relationship
“The dose-response relationship is ‘[a] relationship in which a change
in amount, intensity, or duration of exposure to an agent is associatedwith a change—either an increase or decrease—in risk of disease.’”22 It is the “hallmark of basic toxicology” and “the single most importantfactor to consider in evaluating whether an alleged exposure caused aspecific adverse effect.”23 Consequently, in the Eleventh Circuit, the
would have been persuasive”); see also
Hendrix v. Evenflo Co., 609 F.3d 1183, 1196-97 (11th Cir. 2010).
2 0 See, e.g.
, 613 F.3d at 1336-38; Hendrix
, 609 F.3d at 1196-99;
, 401 F.3d at 1240; Rider
, 295 F.3d at 1198, 1202.
2 1 See, e.g.
, 295 F.3d at 1201-02; Kilpatrick
, 613 F.3d at 1338.
2 2 McClain
, 401 F.3d at 1241-42 (alteration in original) (quoting Michael D. Green
et al., Reference Guide on Epidemiology
FED. JUDICIAL CTR., REFERENCE M ANUALO N SCIEN TIFIC EVID EN CE 333, 390 (2d ed., 2000)).
2 3 Id
. at 1242 (quoting David L. Eaton, Scientific Judgment and Toxic Torts—A
Primer in Toxicology for Judges and Lawyers
, 12 J.L. & POL. 5, 11, 15 (2003)). Thisfactor is so significant, in part, because the reality is that most substances— evenwater— can cause adverse effects in high enough quantities, but also can have positive
“expert who avoids or neglects this [dose-response] principle . . . castssuspicion on the reliability of his methodology” and the admissibility ofhis opinions.24
2. Analytic Epidemiological Studies
Analytic epidemiological studies (such as case-control studies, cohort
studies, and cross-sectional studies) have designs and controls that allowan expert to determine whether an agent and a disease occur togethermore frequently than can plausibly be explained by chance.25 TheEleventh Circuit has described analytic epidemiologic studies as “the bestevidence of causation in toxic tort actions.”26 Although “[t]he absenceof such evidence is not fatal,” the absence “makes [the expert’s] task toshow general causation more difficult.”27 Indeed, when expert testimonyis not buttressed by analytic epidemiological studies, the Eleventh Circuithas held the “nature of the other evidence (case reports, animal studies,in vitro
studies) becomes that much more important, and the court’s con-sideration of such evidence and the methodologies used must be thatmuch more searching
3. Background Risk and Additional Risk
The background risk of a disease identifies the chance of someone
acquiring a disease without exposure to the agent in dispute.29 It is the
effects in lower quantities. This is the basis behind perhaps the most quoted adage intoxicology, originally attributed to Paracelsus: “[T]he dose differentiates a poison froma remedy.” E.g.
, David L. Eaton, Scientific Judgment and Toxic Torts— A Primer inToxicology for Judges and Lawyers
, 12 J.L. & POL’Y 5, 11 (2003).
2 4 McClain
401 F.3d at 1241-42; see also Kilpatrick
, 613 F.3d at 1339 (same).
2 5 See
Michael D. Green et al., Reference Guide on Epidemiology
CTR., REFERENCE M ANUAL ON SCIENTIFIC EVIDENCE 549, 555-63, 566 (3d ed., 2011),available at
http://www.au.af.mil/au/awc/awcgate/fjc/manual_sci_evidence.pdf. Gen-erally speaking, analytic epidemiology studies are analyses of health and disease datathat attempt to control for chance, bias, and confounding factors to determine, withsome degree of statistical reliability, the patterns, causes and effects of health anddisease conditions in defined populations.
2 6 Rider
, 295 F.3d at 1198.
2 7 Kilpatrick
, 613 F.3d at 1336-37 (citation omitted).
2 8 Id.
at 1337 n.9 (emphasis added).
2 9 See McClain
, 401 F.3d at 1243.
baseline against which an expert measures whether someone exposed tothe agent has any greater risk of acquiring the disease than individualswithout exposure (what is called the “additional risk”).30 The EleventhCircuit has emphasized that an expert opining on general causation musthave a reliable means of determining both the background risk and theadditional risk. When an expert “offer[s] no evidence of additional risk,”the Eleventh Circuit has directed that a district court “must assume thatit does not exist
.”31 Such an assumption essentially forecloses generalcausation expert testimony that does not account for “background risk”and “additional risk.”
4. Physiological Process
Another critical element of an expert opinion on general causation is
the ability of an expert to identify a credible physiological process (suchas the biological mechanism) by which the product or chemical com-pound being challenged can cause the illness or injury suffered by theplaintiffs. This is one of “[t]he underlying predicates of any cause-and-effect medical testimony.”32 Absent such identification, it is difficult foran expert to opine that an association between an agent and a disease,even a statistically significant association, is actually evidence ofcausation.33
3 0 See id.
Scientists often refer to this as the “relative risk” or the “odds ratio,”
depending on the type of study being conducted. This “additional risk” is assessed atthe level of a relevant population, whereas the toxicology-related dose-responserelationship described earlier is assessed at the level of an individual. See
Green et al.,supra
note 25, at 566-67.
3 1 Id.
(emphasis added). The Eleventh Circuit has not had to address whether the
additional risk/relative risk assessment has to account for confounding factors (otherconditions or events that may explain why a subpopulation exposed to an agentacquired a disease), but it is standard epidemiological practice to account (and adjust)for confounding factors.
3 2 Id.
at 1253 (quoting Black v. Food Lion, Inc., 171 F.3d 308, 314 (5th Cir. 1999)).
3 3 Kilpatrick
, 613 F.3d at 1338 (alteration in original) (“[S]howing [an] association
is far removed from proving causation
.” (quoting Allison v. M cGhan M ed. Corp., 184F.3d 1300, 1315 n.16 (11th Cir. 1999))).
B. Least Probative Methodologies
Eleventh Circuit case law addressing the most reliable methodologies
for an expert to employ to determine general causation is of greatassistance to both litigants and experts attempting to prove or disprovecausation. Equally valuable is the Eleventh Circuit precedent explainingthose methodologies that are least reliable—the ones that may bolstergeneral causation opinions directly supported by other, stronger evidence,but that are too weak themselves to justify an admissible opinion ongeneral causation.
1. In Vitro/Test Tube Studies
How a chemical compound reacts in a test tube is often quite different
from how it reacts in, and impacts, the complex biological system thatis the human body.34 Consistent with this, the Eleventh Circuit hasrecognized that test tube studies alone are unreliable to establish causationand of limited evidentiary value.35 That limited value is diminished evenfurther when an expert is unable to explain how test tube results can beextrapolated to the human body and why such extrapolation is scientifi-cally reliable.
2. Animal Studies
Animal studies have the same basic limitation as in vitro studies: How
a chemical compound affects an animal is not necessarily the same as,and quite often is materially different than, how the compound affects
3 4 See, e.g.
3 5 See, e.g.
at 1340-44; In re
Accutane Prods. Liab., 511 F. Supp. 2d 1288,
1294-95 (M .D. Fla. 2007) (order granting motion to exclude general causationtestimony) (“‘The problem with this approach is also extrapolation— whether one cangeneralize the findings from the artificial setting of tissues in laboratories to wholehuman beings.’ That is, studies such as these necessarily remove the cells from thedynamic metabolic context in which the human body actually processes chemicalcompounds.”); see also
Allen v. Pa. Eng’g Corp., 102 F.3d 194, 198 (5th Cir. 1996)(stating cell biology tests are “the beginning, not the end of the scientific inquiry andprove nothing about causation without other scientific evidence”).
humans.36 Moreover, such studies commonly use high dosages ofcompounds to expedite reactions in animals, which further complicatesextrapolating from animal studies to humans exposed to lower levels ofthe compounds.37 Courts therefore regard animal studies alone as anunreliable means of showing general causation as to humans, though theymay provide support for the interpretation of human epidemiological orclinical data.38
3. Case Reports (and Medical Textbooks Based on Case
A case report is an article discussing the unique symptoms, diagnosis,
and treatment of an individual patient or a small group of patients.39 Itdoes not reflect a controlled clinical trial or a large, statistically signifi-cant sample of patients.40 Case reports frequently hypothesize associa-tions between agents and injuries or illnesses, but those hypotheses, inturn, are frequently invalidated by subsequent analytic epidemiologicalstudies.41 Case reports also lack scientific controls (such as a control
3 6 Kilpatrick
, 613 F.3d at 1338-39 (citations omitted); see also
Johnson v. Arkema,
Inc., 685 F.3d 452, 463 (5th Cir. 2012) (per curiam) (“W e have previously recognizedthe very limited usefulness of animal studies when confronted with questions oftoxicity.”) (citation omitted) (internal quotation marks omitted).
3 7 Arkema
, 685 F.3d at 463-64 (citing Gulf S. Insulation v. U.S. Consumer Prod.
701 F.2d 1137, 1146 (5th Cir. 1983)).
3 8 See, e.g.
, Rider v. Sandoz Pharms. Corp., 295 F.3d 1194, 1202 (11th Cir. 2002);
, 184 F.3d at 1313-14; Allen
, 102 F.3d at 197; W ade-Greaux ex rel.
W hitehall Labs., Inc., 874 F. Supp. 1441, 1445 (D.V.I.), aff’d
, 46 F.3d 1120 (3d Cir.
1994); In re
“Agent Orange” Prod. Liab. Litig., 611 F. Supp. 1223, 1241 (E.D.N.Y.
1985), aff’d sub nom.
, In re
“Agent Orange” Prod. Liab. Litig. MDL No. 381, 818 F.2d187 (2d Cir. 1987); Blum ex rel.
Blum v. M errell Dow Pharms., Inc., 705 A.2d 1314,1323 (Pa. Super. Ct. 1997), abrogated by
Trach v. Fellin, 817 A.2d 1102 (Pa. Super.
3 9 See, e.g.
, Mary Sue Henifin et al., Reference Guide on Medical Testimony
FED. JUDICIAL CTR, REFERENCE M ANUAL O N SCIEN TIFIC EVIDENCE 439, 474 (2d ed.
4 1 See, e.g.
, Ralph R. Cook, Epidemiology for Toxicologists
M ETHODS OF TOXICOLOGY 549, 559 (Hayes ed., 5th ed. 2008) (“Although the theoriesderived from case studies are not always wrong, history teaches that they are seldomright.”); see also
M cClain v. M etabolife Int’l, Inc., 401 F.3d 1233, 1253 (11th Cir.),
group and protections against selection bias).42 Accordingly, the EleventhCircuit has repeatedly held that case reports are simply anecdotal medicalevidence that cannot establish causation.43 The same result holds truefor medical textbooks that opine on a causal connection or associationbetween an agent and an injury or illness when the support they cite forsuch a conclusion are case reports.44 Textbooks that simply rely on casereports have no more authority than the underlying case reports.45
4. FDA Adverse Event Reports
Adverse Event Reports (AERs) are similar to case reports—they
address the unique symptoms, diagnosis, and treatment of an individual
, 159 F. App’x 183 (11th Cir. 2005) (quoting Black v. Food Lion, Inc., 171F.3d 308, 314 (5th Cir. 1999)).
4 2 Hall v. Baxter Healthcare Corp., 947 F. Supp. 1387, 1411 (D. Or. 1996) (“[C]ase
reports and case studies are universally regarded as an insufficient scientific basis fora conclusion regarding causation because case reports lack controls. . . . Therefore,these cannot be the basis of an opinion based on scientific knowledge under Dau-bert
4 3 See, e.g.
, Hendrix v. Evenflo Co., 609 F.3d 1183, 1197 (11th Cir. 2010) (finding
case reports are “insufficient to show general causation”); McClain
, 401 F.3d at 1254(“[C]ase reports raise questions; they do not answer them.”); Allison
, 184 F.3d at 1316(stating “case studies pale in comparison” to epidemiological studies); see also Rider
,295 F.3d at 1199 (finding case reports cannot rule out idiosyncratic or confoundingfactors); In re
Accutane Prods. Liab., 511 F. Supp. 2d 1288, 1298 (M .D. Fla. 2007)(finding case reports cannot rule out coincidence).
4 4 See In re
W elding Fume Prods. Liab. Litig., No. 1:03-CV-17000, 2005 W L
1868046, at *35 (N.D. Ohio Aug. 8, 2005) (citing In re
Phenylpropanolamine (PPA)Prods. Liab. Litig., 289 F. Supp. 2d 1230, 1242 (W .D. W ash. 2003)) (stating thatmedical textbooks are “non-epidemiological lines of evidence of general causation”);Richardson v. Richardson-M errell, Inc., 857 F.2d 823, 830 (D.C. Cir. 1988) (statingthat non-epidimological evidence “[is] not capable of proving causation”), cert. denied
,493 U.S. 882 (1989).
4 5 Glastetter v. Novartis Pharms. Corp., 252 F.3d 986, 990 (8th Cir. 2001) (per
curiam) (noting medical texts did not “present persuasive scientific evidence thatParlodel causes vasoconstriction” because “[s]ome of the texts were largely groundedupon case reports and other anecdotal information”); Siharath v. Sandoz Pharms. Corp.,131 F. Supp. 2d 1347, 1370 (N.D. Ga. 2001) (order granting motion to exclude experttestimony) (“The statements in the treatises are clearly based on case reports and,therefore, provide no more support than the case reports themselves.” (citationomitted)), aff’d sub nom.
Rider v. Sandoz Pharms. Corp., 295 F.3d 1194 (11th Cir.
patient that used an FDA-approved product.46 Based on AERs, the FDAmay issue a Notice and Recommended Action or warning letter to prompta manufacturer to make changes to its product or issue additionalwarnings.47
The Eleventh Circuit has recognized that AERs, even when they lead
to FDA action, are “one of the least reliable sources” to support opinionson general causation.48 This is in part because AERs are a product of avoluntary reporting system that lacks significant controls and “are subjectto a variety of reporting biases” and the underlying “data may be affectedby . . . reporting stimulated by publicity or litigation.”49 Consequently,even the FDA cautions that AERs are only evidence of a safety “signal”indicating “the need for further investigation, which may or may not leadto the conclusion that the product caused the event.”50 Moreover, theFDA uses a lower threshold to decide when it should take action versusthe threshold courts have set for demonstrating causation.51 Thus, AERsmay prompt FDA action (such as issuing a Notice) even though theydemonstrate nothing more than a possible association between a productand an adverse effect.52
4 6 See
21 U.S.C. § 360i(b)(1), (5)-(6) (2006).
4 7 FDA, REGULATORY PROCEDURES MANUAL §§ 4-1-1, 4-1-3, 4-2-1, 10-2-3 (2012).
4 8 McClain
, 401 F.3d at 1250.
4 9 FDA, GUIDANCE FOR INDUSTRY: GOOD PHARMACOVIGILANCE PRACTICES AND
PHARM ACOEPIDEM IOLOGIC ASSESSM ENT 9 (2005) [hereinafter FDA, Guidance for In-dustry
], available at
5 0 Id
. at 4; see also id
. at 7 (“Rigorous pharmacoepidemiologic studies, such as
case-control studies and cohort studies with appropriate follow-up, are usuallyemployed to further examine the potential association between a product and anadverse event.”).
5 1 Rider
, 295 F.3d at 1201 (noting the FDA employs an analysis that “involves a
much lower standard than that which is demanded by a court of law”).
5 2 Id.
(noting the FDA applies a different risk-utility analysis than that employed
by a court, and the FDA’s actions are not scientific proof of causation). The sameapplies to regulatory action by other agencies, which often impose protective orprophylactic limits based on evidence of potential risks or associations as opposed toproof of actual causation. See
Johnson v. Arkema, Inc., 685 F.3d 452, 464 (5th Cir.
2012) (per curiam).
5. Differential Diagnosis and Differential Etiology
The differential diagnosis (or differential etiology) technique is
essentially a process-of-elimination approach. A physician or investiga-tor starts by considering all explanations for a person’s injury or illnessand then eliminates them one-by-one based on tests, examination of theperson or a review of his medical history until the physician or investiga-tor is left (or hopes to be left) with only one possible explanation.53 Thislast explanation is then assumed to be the cause of the injury or illness.54
As this simple description of the technique reflects, advance knowl-
edge by the physician or investigator of the potential causes for an injuryor illness is critical to its effectiveness. The Eleventh Circuit hasaccordingly held that application of the differential diagnosis or etiologytechnique cannot itself demonstrate general causation: “[A] fundamentalassumption underlying [differential diagnosis] is that the final, suspected‘cause’ . . . must actually be capable of causing the injury.”55 Hence, anexpert’s “purported use of the differential [diagnosis] method ‘will notovercome a fundamental failure to lay the scientific groundwork’ for thetheory that [an agent] can, in general, cause [a disease].”56 Stated dif-ferently, a differential diagnosis is inadmissible if there is no independent,reliable evidence to “rule in”—as a matter of general causation—that theagent can cause the medical condition in the first place, even if aphysician or investigator can “rule out” alternative explanations for amedical condition other than the agent in question.57
5 3 See
Hendrix v. Evenflo Co., 609 F.3d 1183, 1194 n.5, 1195 (11th Cir. 2010).
5 5 McClain
, 401 F.3d at 1253 (alteration in original) (citing Clausen v. M/V New
Carissa, 339 F.3d 1049, 1057-58 (9th Cir. 2003)).
5 6 Hendrix
, 609 F.3d at 1195 (quoting McClain
, 401 F.3d at 1252).
5 7 See id.
at 1197-98; Kilpatrick v. Breg, Inc., 613 F.3d 1329, 1342 (11th Cir. 2010)
(stating differential diagnosis “assumes the existence of general causation”); McClain
,401 F.3d at 1253 (“A valid differential diagnosis, however, only satisfies a Daubert
analysis if the expert can show the general toxicity of the drug by reliable methods.”). Other circuits are in accord. See, e.g.
, 685 F.3d at 468 (finding “an expertmay not rely on a differential diagnosis to circumvent the requirement of generalcausation” (citation omitted)); Hollander v. Sandoz Pharms. Corp., 289 F.3d 1193,1211 (10th Cir. 2002) (stating “experts would need to present reliable evidence that thedrug can cause strokes” for differential diagnosis to be admissible); Glastetter v.
Novartis Pharms. Corp., 252 F.3d 986, 989 (8th Cir. 2001) (per curiam) (affirming
6. Combining Evidence from Unreliable Methodologies
A final “methodology” sometimes presented by experts to support
their opinions is what has been described (or misdescribed) as a “weightof the evidence” approach, whereby the expert supports her opinion byapplication of a variety of methodologies, none of which individually isreliable, but all of which in combination are (the expert claims) reliable. The Eleventh Circuit has effectively rejected this method: where eachpiece of evidence upon which an expert relies to form her opinion hasbeen found to be scientifically unreliable, the Eleventh Circuit has heldthe expert’s opinion is properly excluded.58 This is consistent with thestandard application of the scientific method.59 That method allows suchuntestable, judgment-driven assessments to be used either as preliminaryassessments of possible causation (i.e., to identify “signals” meritingfurther investigation)60 or to evaluate the best conclusion to draw from
exclusion of a differential diagnosis because experts could not first “rule in” the agentas a possible cause using an independent, scientifically reliable methodology); Raynorv. M errell Pharms. Inc., 104 F.3d 1371, 1376 (D.C. Cir. 1997) (stating a differentialdiagnosis “had legitimacy only as a follow-up to admissible evidence that the drug inquestion could
in general cause birth defects”).
5 8 See, e.g.
, 613 F.3d at 1337-41; Hendrix
, 609 F.3d at 1202-03;
, 401 F.3d at 1255; Rider
, 295 F.3d at 1202.
6 0 An example of this is the Naranjo Scale, used to evaluate case reports and AERs
involving adverse drug reactions. It consists of ten questions, which examine factorssuch as “previous conclusive
reports” of adverse reactions, the timing of an adversereaction, whether the adverse reaction improved when use of a drug was discontinued(called “dechallenged”), whether it reappeared when the drug was readministered(called “rechallenged”), dosage levels, and the exclusion of alternative causes. C.A.
Naranjo et al., A Method for Estimating the Probability of Adverse Drug Reactions
, 30CLINICAL PHARM ACOL. THER. 239, 240 (1981). Points are assigned or subtracted basedon responses to the questions, with 13 being the highest possible score. Id.
Scientistsdo not use the Naranjo Scale to make conclusions about general causation. Rather, itis used to assess the strength of a case report as a potential “safety signal.” FDA,Guidance for Industry
note 49, at 4-7; Ronald H.B. M eyboom et al., Causal orCasual? The Role of Causality Assessment in Pharmacovigilance
, 17 DRUG SAFETY374, 376-79 (1997). Thus, although the Naranjo Scale yields “provisional” assess-ments that are used to guide further research, conclusions about causation can bedetermined only “through further analytical, or if possible, experimental studies.” Ronald H.B. Meyboom et al., Causal or Casual? The Role of Causality Assessment inPharmacovigilance
, 17 DRUG SAFETY 374, 376, 382 (1997); see
FDA, Guidance forIndustry
note 49, at 7; see also
Rhodes v. Bayer Healthcare Pharms., Inc., No.
testable, analytic data (such as epidemiological studies) that can supportmore than one conclusion on causation.61 The scientific method, how-ever, does not recognize such patchwork, malleable, “weight of theevidence” reasoning as an independent basis to determine that causationexists.62 Hence, an expert cannot aggregate “individual categories ofevidence deemed unreliable by [a] court . . . to form a reliable theory”of general causation, since to do so “would be to abandon ‘the level ofintellectual rigor’ of the expert in the field.”63
10-1695, 2013 W L 1289050, at *6 (W .D. La. M ar. 26, 2013) (“[T]he Naranjoalgorithm/methodology appears, in actuality, to be a classification system, not a methodused to determine actual causal relationships assessments.” (citation omitted)).
6 1 An example of this is a Bradford-Hill analysis. Scientists use a Bradford-Hill
analysis to assess causation only after a statistically significant association has firstbeen established
, normally through analytic epidemiological studies. See
Sir AustinBradford Hill, The Environment and Disease: Association or Causation?
, 58 PROC.
ROYAL SOC’Y M ED. 295 (1965). Thus, Bradford-Hill applies only when an associationhas been established as “perfectly clear cut and beyond what we could care to attributeto the play of chance.” Id.
at 295; see also
Dunn v. Sandoz Pharms. Corp., 275 F.
Supp. 2d 672, 678 (M .D.N.C. 2003) (“Bradford Hill criteria is a method fordetermining whether the results of an epidemiological study can be said to demonstratecausation and not a method for testing an unproven hypothesis.”); Soldo v. SandozPharms. Corp., 244 F. Supp. 2d 434, 569 (W .D. Pa. 2003) (finding the Bradford-Hillanalysis was unwarranted because there were no analytic epidemiological studiesdemonstrating a statistically significant association); Green et al., supra
note 25, at 599n.141 (applying Bradford-Hill factors without an analytic epidemiological study “doesnot reflect accepted epidemiologic methodology”). Two federal appellate cases havebeen cited as permitting experts to use the Bradford-Hill factors to opine on causation,but that is an overstatement of the cases. See
M ilward v. Acuity Specialty Prods. Grp.,Inc., 639 F.3d 11, 23-24 (1st Cir. 2011); In re
Joint E. & S. Dist. Asbestos Litig., 52F.3d 1124, 1128-30, 1134-35 (2d Cir. 1995). In both cases the experts at issue appliedthe Bradford-Hill factors to the evaluation of analytic epidemiological evidence as wellas evidence of a dose-response relationship, an additional risk beyond the backgroundrisk of a disease (described as “relative risk,” “standardized mortality ratio,” or “oddsratio” in the cases) and a plausible biological mechanism. See id.
6 2 See
Sheldon Krimsky, The Weight of Scientific Evidence in Policy and Law
AM . J. PUB. HEALTH S129-130 (2005).
6 3 Hollander v. Sandoz Pharms. Corp., 289 F.3d 1193, 1216 n.21 (10th Cir.) (citing
Kumho Tire Co. v. Carmichael, 526 U.S. 137, 152 (1999)), cert. denied
, 537 U.S. 1088(2002); Glastetter v. Novartis Pharms. Corp., 252 F.3d 986, 992 (8th Cir. 2001) (percuriam) (“[W ]e do not believe that the aggregate of this [unreliable] evidence presentsa stronger scientific basis for Glastetter’s supposition that Parlodel can cause ICHs.”);Soldo v. Sandoz Pharms. Corp., 244 F. Supp. 2d 434, 577 (W .D. Pa. 2003) (stating“plaintiff’s experts ‘cannot lump together lots of hollow evidence’ and reach a reliableconclusion”).
Litigants’ success in mass tort actions is most often determined by
whether plaintiffs can present sufficiently reliable expert evidence ofgeneral causation to survive Daubert
64 scrutiny and create a triable issuefor a jury. By developing an extensive and consistent body of case lawon this issue, the Eleventh Circuit has provided litigants with greatguidance that, in turn, leads to reasonable predictability as to theadmissibility of general causation expert testimony. Every mass tortlitigator needs to be knowledgeable about this guidance or else riskseither losing a winnable case or wasting substantial time, effort, andmoney on an unwinnable case.
The most vocal criticism of the Eleventh Circuit’s general causation
jurisprudence is that it makes it difficult, if not impossible, forplaintiffs to prevail when they are relying on emerging science, even ifleading scholars endorse the new scientific theory and it has not beenrefuted (or at least not yet) by empirical evidence. But “[t]he courtroomis not the place for scientific guesswork, even of the inspired sort. Lawlags science; it does not lead it.”65
Jurors of varying education levels receiving evidence at the speed of
trial are ill-equipped to make judgments about cutting-edge science, butinstead are “more likely . . . to be awestruck by [an] expert’s mystique.”66 This is especially true given the unique flexibility afforded expertstestifying at trial—“no other kind of witness is free to opine about acomplicated matter without any firsthand knowledge of the facts in thecase, and based upon otherwise inadmissible hearsay.”67 All of thismeans that the “importance of Daubert
’s gatekeeping requirement cannotbe overstated.”68 Personal injury statutes of limitations, moreover,
6 4 Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579 (1993).
6 5 Rider
, 295 F.3d at 1197 (quoting Rosen v. Ciba-Geigy Corp., 78 F.3d 316, 319
6 6 Allison v. McGhan Med. Corp., 184 F.3d 1300, 1310 (11th Cir. 1999).
6 7 United States v. Frazier, 387 F.3d 1244, 1260 (11th Cir. 2004) (en banc).
generally afford plaintiffs time to allow empirical evidence to becollected, digested and published, and in the interim regulatory agenciesare empowered to take preemptive or prophylactic action based on alesser standard than actual causation. Finally, of course, there arenumerous examples of “cutting-edge” scientific findings that were provenerroneous with the passage of time.69 For all of these reasons, theEleventh Circuit’s approach, which both counsels caution and fostersclarity and predictability, strikes the proper balance among science, law,and the demands of our legal system.
6 9 W ell-known examples include erroneous preliminary conclusions that silicone
breast implants cause systemic disease, coffee consumption causes pancreatic cancer,and Bendectin causes birth defects. See Allison
, 184 F.3d at 1315; Daubert
, 43 F.3dat 1320-22; John B. W ong et al., Reference Guide on Medical Testimony
REFER-EN C E M AN U AL ON SCIEN TIFIC EVID EN CE 687, 723-24 (3d ed., 2011) (citing B rianM acM ahon et al., Coffee and Cancer of the Pancreas
, 304 NEW ENG. J. M ED. 630-33(1981)), available at
COLONOSCOPY PREPARATION INSTRUCTIONS DULCOLAX TABLETS WITH CO-LYTE, TRI-LYTE, OR NU-LYTELY BOWEL PREP ALL PATIENTS: You should be on a clear liquid diet for the entire day before your scheduled colon examination. This includes bouillon, broth, clear fruit juices, and Jell-O. Please avoid red Jell-O and all milk products, however. Gatorade is a preferred beverage as it contains a good
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