1. Association Versus Causation: Epidemiology Versus the Law
Association Versus Causation: Epidemiology Versus the Law? Perspective From the States
Little bit about myself .. Work on complex lit cases for which Epi is always a consideration in every case. Just finished the epidemiological battle in Zofran.. Still waiting on the judge’s ruling. 90% of my caseload is pharma or device, or some kind of products lit, so about 90% of my cases involve some showing and weighing of epidemiology.
What I’ve been asked to do today is give a glimpse Going to do that by FIRST explaining the structure through which we evaluate epi and other expert evidence, then discuss some of the larger – some recent some a few years old – cases that have had important rulings on epidemiology in the US. Hopefully show a RANGE of scenarios.
I think you’ll see that in the US… it cerintaly HELPS your case to have good epi in ANY juris, although you might be able to get away WIHTOUT IT in a couple.
NEXT..
Mike Daly - Pogust Millrood, LLC Philadelphia, PA

2. The US Approach to Expert Testimony and Evidence
General v. Specific Causation
Standard Complex Products Liability Approach
The Multidistrict Litigation (MDL) Approach
First Prove the Product Can Cause X Injury (Generally), then Prove it Did Cause X Injury in the Plaintiff (Specifically)
Typically Broached at the End of Discovery, unless Bifurcated
Epidemiology Only One Factor in Admissibility
Multiple Pieces of Evidence Upon Which Experts Rely
Biological Mechanism, Animal (Preclinical) Studies, and Epi
SO just to sort of start at Square In the US, a plaintiff in a civil – non-crim – case will have to establish that the product both CAN CAUSE the TYPE of injury or disease complained of, AND THEN once satisfied that the product caused a particular Plaintiff’s injury. This is the dynamic of GENERAL (can Zofran cause heart defects) Versus SPECIFIC (Did Zofran cause Mary’s birth defect) CAUSATION.
In terms of sequence in a case, I’ll use a MASS TORT as an example. Mass torts = dozens, hundreds, or thousands of individuals bring claims against the same company for INJURIES caused by the same product. Any one of these could continue on its own –a nd many often do – but the US has CONSOLIDATION mechanisms that can come into effect when a critical mass of the cases are filed throughout the country.
In a typical mass tort, we’ll do liability discovery first – what did company know, when Then expert discovery close to last. Typically, you’ll have REPORTS submitted by your experts that speak first to whether the drug … let’s say Zofran for example Can cause certain types of birth defects. THe judge will then rule on whether you’ve provided sufficient evidence in support of your claim. WE’LL GET INTO THAT IN MORE DETAIL later, but the GIST is that you use a VARIETY OF proofs in order to establish general causation ---- EPI IS ONLY ONE OF THE FACTORS … BIO mechanism, preclinical studies, case reports.
If the judge agrees you have satisified general causation.. And the judge isn’t saying DRUG DOES CAUSE DISEASE X .. Just that you’ve shown enough evidence to suggest it CAN… THEN you move forward and submit an ADDITIONAL REPORT on an individual plaintiff’s case. This is the SPEC CAUSE report… in this report, you’re basically rehashing everything you asid in the general cause report, then turning attnetino to the specific facts of this plaintiff. This is where things like comorbriditeis, timing of drug ingestion, dosage, come into consideration.
Now this can become quite complicated Judges aren’t asked to do this without any support A primary source of authority for this brief is the Reference Manual on Scientific Evidence, published by the Federal Judicial Center
And more than that, there is a BODY OF CASE LAW that has been built over decades – mostly since the 1990s, that judges and lawyers turn to ASCERTAIN whether the evidence – AND EPI – in their budding case is going to pass in a PARTICULAR JURISDICTION. The most notable of those cases…
NEXT

3. The Daubert Standard: Judge as the Gatekeeper
Daubert v. Merrell Dow, 509 U.S 579 (1993) (Bendectin Litigation)
The “requisite review for reliability includes consideration of several factors,” including:
(1) whether an expert’s theory or technique can and has been tested;
(2) the error rate of such a technique;
(3) whether a such theory or technique has been published or peer reviewed; and
(4) the theory or technique’s acceptance in the scientific community.
Daubert Takeaways
Reliable Experts, Reliable Methodology
Trial Judge Serves as the Gatekeeper
Not necessarily a Doubling of the Risk
Daubert is a case known by every products lawyer in the US Daubert involved the drug Bendectin ..used for NVP in pregnancy from the 1950s-80s. Litigation arose suggesting it caused congenital birth defects in babies. The defendant pharma company challenged the plaintiff’s cases and experts ….. Mainly, and the reason why Daubert is so largely affiliated with epi, is that the plaintiffs experts had ZERO EPI in the case. There was epi that existed, but it all suggested Bendectin did not cause the birth defects at issue. So Plts experts recalculated the stats in those epi studies – to their benefit – and relied on in vitro (test tube) and in vivo (animal) studies. But their recalculations weren’t published, so they weren’t trustworthy.
Now both the DC and App Court kicked out the cases and it made its way to the SC. The SC laid out the 4 points for guidance above, and they’ve been added to some in the 3 decades since the opinion, but they are: (READ)
This opinion put A LOT OF ONUS on the trial judge – as the SC often does – by holding that the trial judge should serve in the role as GATEKEEPER with the task of ensuring that an expert’s testimony both rests on a reliable foundation and is relevant to the task at hand.” Thi was a new more flex standard.
“It demands only that the proponent of the evidence show that the expert’s conclusion has been arrived at in a scientifically sound and methodologically reliable fashion.” Ruiz-Troche, 161 F.3d at 85. “The focus, of course, must be solely on principles and methodology, not on the conclusions that they generate.”
Now there was some reference in the opinion to a doubling of the risk, but it is not conclusive. Certainly not mandatory. The court held that one can establish causation with something less than a doubling IN CONCERT with other forms of evidence (like animal studies, biological mech, etxc). As you’ll see in some of the cases we look at today, the reality in US complex products litigation is that most of them don’t rely on epi that has a doubling of the risk
In the US, the standard of epi required to pass SJ can very much turn on the location of the lit . .. The jurisdiction…
NEXT

4. United States Federal Circuit Courts
Our most important epi cases are largely decided in federal court. Now in the US we have state law and we have federal law. If you bring a complex products lit and are able to keep it in state court, you will likely be bound by that state’s precendet on expert testimony & epi standards. THE REALITY is that most of the caselaw on epi is built up in the country’s fed courts. That is because most complex products cases involve a Citizen from STATE X suing a company from STATE Y, and therefore there is a diversity of citizenship which means the case goes to fed court.
Our federal courts are split as above. REALLY only looking at the far left side of this image. SC at the top, then beneath it we have 12 courts of appeals, beneath that we have Dist Courts.
You see from the image to the right how these CIRCUITS are split up geographically. While we have at least 1 DC in each state, Circ Courts can and do cover several states. I practice in …
This is important because the law very much develops via the individual 12 Circuits.. What may be sufficient in the 9th Circ very well might not past muster in the 3rd, as we’ll see… .

5. s The Relationship Between the Daubert Standard & Epi in the US
3rd Circuit: Statistical Significance Important; Not Determinative
(In re Zoloft)
9th Circuit: From Daubert to Roundup A Loosening
The Relationship Between the Daubert Standard & Epi in the US
In re Accutane… State Courts’ Slow Embrace of Daubert
1st Circuit: Epi Not Necessary (Milward)
So today I though I’d give you some examples of how the US courts have interepreted the Duabert standard of review over the past 3 decades. I selected 4 cases, each one representing a different jurisdiction … 3 in the fed CIRC COURTS and 1 in a STATE court. To the extent you all ever want to advocate a policy change in UK that trends towards the more lax standard for EPI in the US, just know that we’re a MESS too…
AN example of a fairly lax juris when it comes to EPI is the 1st Circ, Milward… we’ll also discuss a decision from a few years ago in the 3rd circ, where I practice, which eliminated a litigation … and 2 very recnet opinions – 1 in the 9th Circ .. And 1 in state court in NJ, also where I practice a bit.
I think you’ll see that whilet he outcome may vary in each of these, there are some similarities in how US courts –r egardless of location – look at epi & expert evidence.. 1 of the largest similarities being THE ABSOLUTELY NEED TO HAVE CREDIBLE EXPERT WITNESS TO PRESENT AND INTERPRET THE DATA, AND A DEMAND THAT THOSE WITNESSES UTILIZE A CREDIBLE AND RECOGNIZED METHODOLOGY
NEXT

6. Milward: No Epi; No Problem
Milward (1st Circuit) – Epi is not required; One must consider all the evidence.
In the First Circuit, “no single factor disposes of a reliability inquiry.” Instead, the First Circuit has embraced the “weight of the evidence” methodology used by general causation experts in products liability cases.
The weight of the evidence approach “involves a mode of logical reasoning often described as ‘inference to the best explanation’
The First Circuit recognizes that reasonable scientists may come to different opinions. Id. at 18.
In Milward, supra, the First Circuit stated: “the absence of peer-reviewed epidemiological studies does not, as defendants contend, make it ‘almost impossible’ for Dr. Smith’s opinion to be admissible Epidemiological studies are not per se required as a condition of admissibility regardless of context.”
Weight of the Evidence wins the day: the “sum of [the expert’s] testimony was that a weighing of the Hill factors, including biological plausibility, supported the inference that the association between benzene exposure and APL is genuine and causal.”
So the first case I wanted to discuss with you all is Milward … and I realize I didn’t put up pin cites for most of these matters so please feel free to reach out to me for citations afterwards.
Milward is esp important and relevant to me BC it ws decided in the 1st Circuit, where my firm is currently leading a large birth defect litigation against GSK . As many of you may know, epi in birth defect lit can be very tricky. Can’t do studies on pregnant WOMEN in the US, and the defects are so rare that they’re difficult ot track..
Milward recognized this….
In Milward, supra, the First Circuit stated: “the rarity of [the disease] and difficulties of data collection in the United States ma[d]e it very difficult to perform an epidemiological study of the causes of [the disease] that would yield statistically significant results.” 639 F.3d at 24. Plaintiffs’ expert there offered that to obtain statistically significant results, “one would need hundreds of thousands of highly exposed workers, the same number of controls, and millions of dollars in funding.” Id
Milward, fortunately, in a case that didn’t have to do with birth defects, says you DON’T NECESSARILY NEED epi… LOOK UP .. ‘NO SINGLE FACTOR …”
(Read through the first 2 large bullets)… So where DOES that leave US in the 1st Circ… the WEIGHT OF THE EVIDNECE WINS.. The DAY..
NEXT .. It doesn’t get easier than this WHEN YOU HAVE BAD EPI in the STATES…
….. Extra….
- In Milward, the plaintiffs’ expert toxicologist opined that exposure to benzene is generally
capable of causing Acute Promyelocytic Leukemia (APL) based on a weight of the evidence5 analysis. 639 F.3d at 13. The district court excluded the expert’s testimony. Id. In reversing, the Court of Appeals noted that “[t]here is an important difference between what is unreliable support and what a trier of fact may conclude is insufficient support for an expert’s conclusion.” Id. So long as an expert’s scientific testimony rests upon “good grounds based on What is known,” - QUOTING DAUBERT - it should be tested by the adversarial process, rather than excluded for fear that jurors will be unable to handle the scientific complexities. Id. at 596. Instead, “[v]igorous cross-examination, presentation of contrary evidence, and careful instruction on the burden of proof” are the appropriate means of attacking admissible evidence. Id.

7. In re Zoloft: No Epi; Might Have a Problem
3rd Circuit refused to establish a “bright-line rule” requiring statistical significance.
A causal connection may exist despite the lack of significant findings, due to issues such as random misclassification or insufficient power. Conversely, a causal connection may not exist despite the presence of significant findings.
Given this, the requisite proof necessary to establish causation will vary greatly case by case.
Although Daubert wasn’t severely limited here, the experts were in fact disqualified due to methodology.
In re Zoloft.. Another birth defect case Is an example of a case, and a CIRCUIT, that VALUES Strong Epi. BUT won’t kick you out if the epi is lacking in statistical significance. LOOK AT BULLET 1 .. THEY REFUSED..
- This is because, as the Court acknowledged… The SO CALLED bedrock principles of “p ≤ 0.05” and “95% confidence interval” are hardly “scientific.” Instead, they were pulled out of thin air decades ago by a eugenicist.
BULLET 2 and 3 ….
The 3rd Circ had a great line…. Despite the problems with treating statistical significance as a MAGIC criterion, it remains an important metric to distinguish between results supporting a true association and those resulting from mere chance. Discussions of statistical significance should thus not understate or overstate its importance.
AND MOREOVER, THE COURT HAD A VERY SOLID THEME – CONSISTENCY…. The critical part for Daubert purposes isn’t whether or not an expert applied a general methodology in a particular way, but whether they applied the methodology they chose consistently. Whether the PTLS expert ASSESSED PLTs favorable data THE SAME WAY he assessed DEFS contradictory data…
Here’s the bad news for the EXPERT in Zoloft : the expert hadn’t followed that roadmap. He “did not 1) reliably apply the ‘techniques’ to the body of evidence or 2) adequately explain how this analysis supports specified Bradford Hill criteria.” Id.
Add note about how one of the problems was lack of specificity of birth defects … claimed Zoloft caused a bunch. We avoided that in Zofran, and have epi that speaks both generally to heart defects and spec to ASD/VSD.
NEXT….

8. ‘ ‘ Roundup Weed Killer – Shaky, but Sufficient
Therefore, it's a close question whether to grant or deny Monsanto's motion for summary judgment. But the Court concludes that the opinions of these experts, while shaky, are admissible. They have surveyed the significant body of epidemiological literature relevant to this question; identified at least a few statistically significant elevated odds ratios from case-control studies and meta-analyses; identified what they deem to be a pattern of odds ratios above 1.0 from the case- control studies, even if not all are statistically significant; emphasized that studies of glyphosate have focused on many different types of cancer but found a link only between glyphosate and NHL; given legitimate reasons to question the results of the primary study on which Monsanto relies; and concluded, in light of all the available evidence, that a causal interpretation is appropriate
In re Monsanto Roundup Herbicide Litigation involving over 11,000 plaintiffs; Venued in 4 Separate Jurisdictions in the US
The MDL judge – sitting in the same Circuit as the Daubert Appellate Judge – commented that epidemiology was “loosey-goosey” and highly subjective.
Despite the “skaky” opinions of the experts, unanimous verdicts in 3 trials amounting to over $2,200,000,000
RDP is a very large case in the US THAT INVOLVES A PRODUCT very much in use all over the world. It was actually spurred by a report from the INTL AGENCY FOR RESEARCH ON CANCER ( IARC ), a European agency.
RDP is a good example of a case where DIRECT EPI is lacking.. RoundUP is a herb made up of glypho & surfactants… It’s also a GOOD EXAMPLE of how a US JUDGE IS SUPPOSED TO ASSESS EPI … DOESN’T MATTER IF YOU DON’T LIKE IT, OR IF ITS HEAVILY WEIGHTED ON ONE SIDE – AS IS THE CASE HERE, GIVEN THE PROLIFIC # OF STUDIES COMPLETED AND PRESENTED BY MONSANTO – cough, ghostwritten, cough – over the YEARs..
HERE, the judge REFERRED TO PTLS EPI and BODY OF EVIDENCE – IN COMPARISON TO MONSANTO’S .. As LOOSEY GOOSEY AND SHAKY. BUT, If the METHODOLOGY IS SOUND AND THE EXPERTS RELIABLE, THE CASE GOES TO JURY.
I THINK THE QUOTE IS WORTH READING…
Then read this…
…… “Epidemiology studies examine whether an association exists between an agent like glyphosate and an outcome like NHL. Whether that agent causes the outcome, however, cannot be proven by epidemiological studies alone; an evaluation of causation requires epidemiologists to exercise judgment about the import of those studies and to consider them in context.”
Last bullet, then NEXT (below is extra)…
The second problem with the plaintiffs' presentation is that the evidence of a causal link between glyphosate exposure and NHL in the human population seems rather weak. Some epidemiological studies suggest that glyphosate exposure is slightly or moderately associated with increased odds of developing NHL. Other studies, including the largest and most recent, suggest there is no link at all. All the studies leave certain questions unanswered, and every study has its flaws. The evidence, viewed in its totality, seems too equivocal to support any firm conclusion that glyphosate causes NHL. This calls into question the credibility of some of the plaintiffs' experts, who have confidently identified a causal link.

9. In re Accutane: the Tightening of State Expert Standards
Plaintiffs faced the daunting task of establishing causation in the face of no supportive epidemiology
The New Jersey State Supreme Court found fault with the experts’ methodology, thereby moving New Jersey state law requirements closer to the federal Daubert standard
The lack of viable epi here was fatal to plaintiffs’ claims ‘ ‘
Thus, we do not mean to suggest that animal studies and case reports can never be relied upon for forming an opinion on causation, but we find ample support for the trial court's determination that it was not proper to do so here in light of the uniform body of epidemiological evidence.”
And last but not least, we have our ONLY state court opinion, In re Accutane. A giant case.
Plaintiffs claim that a causal connection exists between Accutane, a prescription drug used in the treatment of nodular acne, and Crohn's disease, a chronic gastrointestinal illness. Litigation in New Jersey over Accutane's side effects has spanned more than a decade. This action is a continuation in that series of litigated matters. Since those actions first commenced in New Jersey in 2005, a number of epidemiological studies have been published, all concluding that there is no causal relationship between Accutane and Crohn's disease.
The fatal flaw in Accutane was 2fold – 1, the epi was very bad for them. 2 – the court found fault with the experts’ methodology.. THIS IS WHAT CAN GET YOU IN TROUBLE IN THE US The court pointed out that:
Both Doctors Madigan and Kornbluth employed a methodology whereby they disregarded eight of nine epidemiological studies and relied on case reports and animal studies to support their opinion.
The Court found case reports to be fairly unreilable as a LEADING source of evidence, and “at the bottom of the *393 evidence hierarchy,” ..citing the REF MANUAL we discussed earlier Reference Manual at 724,
Read the quote…
AND IN LIEU OF A CONCLUSIONS SLIDE, I’LL JUST SUM UP THE STATE OF EPI ANALYSIS AND RELIANCE IN THE US - There is no requirement that a DOUBLING of the RISK be demonstrated, and I think that’s in part b/c reliable scientific resoruces have agreed that you don’t need it in order to prove causation. AND COURTS have adopted that standard, and it certainly helps when the brightest minds in a particular field can reach a causation opinion despite the lack of a doubling.
Our approach is to only go in cases where the epi is good, but if it’s not, have other liens of evidence upon which to rely (bio mech, animal studies).. And KNOW YOUR JURISDICTION!
NEXT

10. Any questions? Mike Daly mdaly@pogustmillrood.com
THANKS!
Any questions?
Mike Daly
SO THAT’S MY SHOW.. I TRULY HOPE IT WAS HELPFUL IN ASSESSING A POTENTIAL NEW APPROACH TO EPI IN THE LAW IN THE UK…