[Drug and Device Law] A Pleasant Surprise from the Accutane MCL

A couple of weeks ago, we talked about Westminster Kennel Club Dog Show.  We were eagerly anticipating the Best in Show competition, which was slated to feature a Standard Poodle – the breed of our heart – along with a Portuguese Water Dog whose record of wins was unprecedented in dog show history.  Based on this past record, the “PWD” was heavily favored to “take the Garden.”   The Best in Show judge (few assignments in dogdom carry more prestige) built the tension in the sold-out stadium to a fever pitch.  The dogs submitted to painstaking “hands on” examinations, they “free-stacked,” they gaited.   And they gaited again.  Finally, the judge, flanked by AKC officials, strode purposefully to the table to “sign the book,” then returned to the center of the ring, microphone turned on, purple and gold rosette and trophy in hand.   He made a moving speech about the history of the event, and he praised the lineup of seven gorgeous group winners.   Pausing one more time for effect, he announced, “Best in Show at the 139^th Westminster Kennel Club Dog Show is . . .  the Beagle!”  The Beagle?   Make no mistake – “Miss P” is a spectacular show dog, with many Best in Show wins to her credit.  She is a striking example of her breed.  And she is very, very cute.   But it just wasn’t what we expected. 

We also thought we knew what to expect when we began reading the recent decision of the Superior Court of New Jersey – Atlantic County -- in the Accutane Multicounty Litigation.   This litigation, in which plaintiffs allege that Isotretinoin (Accutane’s chemical name) causes Inflammatory Bowel Disease (“IBD”) and Crohn’s Disease (“CD”), has been pending since 2003, and we have been troubled, at times, about an apparent plaintiff bias. Appellate courts have agreed with us, overturning a number of plantiffs' verdicts.  (See here and here, for example.)  But we were most pleasantly surprised this time. 

In In re Accutane Litigation, 2015 WL 753674 (N. J. Super. Law. Feb. 20, 2015), the Court considered defendant’s motion to exclude plaintiffs’ general causation and biostatistics experts.  The Court explained that New Jersey applies a standard less stringent than Frye’s “general acceptance” standard, in determining whether expert testimony is admissible.  Under the guiding Rubanick decision of the New Jersey Supreme Court (125 N.J. 421 (1991)), “if the methodology by which the expert reached a conclusion is sound, the conclusion may be introduced into evidence.”  Accutane, 2015 WL 753674 at *4 (citation to Rubanick omitted).  Later, in Kemp v. The State of New Jersey,  174 N.J. 412 (2002), the Supreme Court held that the trial court was obligated to conduct an evidentiary hearing “any time an expert’s theory has not attained ‘general acceptance,’” and that the failure to do so is “plain error.”  Accutane, 2015 WL 753674 at * 6 (citations to Kemp omitted).  Hence the moniker “Kemp hearing” to describe hearings such as the one that was the subject of the Court’s decision.

To prepare for the hearing, the Court “solicited from counsel all such reports, abstracts, peer-reviewed studies, etc.. . . relied upon by the witnesses in formulating their opinions; said items total in excess of 400 treatises . . . .”  Id. at *2.  Aided by the reports and testimony of defendants’ experts, the Court began its analysis by discrediting the key sources on which plaintiffs’ experts relied.   Based on defendants’ expert’s meta-analysis, the Court stated that “there appears to be little-to-no consensus in the medical/scientific community as to [Accutane’s] correlation to CD and IBD generally.”  Id. at *8.  Corroborating this conclusion were two “extensive review articles” on risk factors for IBD and CD.  The Court commented, “Interestingly, after 30+ years following FDA approval of Accutane, neither of these extensive studies even mentions Isotretinoin as a risk factor.”  Id. at *10.  The Court also noted that plaintiffs’ gastroenterology expert had declined to include comments about Isotretinoin as a possible cause of IBD in a peer-reviewed article he had prepared; however,  before the Court, he was “prepared to say that Isotretinoin is a cause of IBD, yet to a more limited and less informed audience than his peer-reviewed article would have reached.”  Id.   The Court cautioned, “Expert opinions generated as a result of litigation have less credibility than opinions generated as a result of academic research or other forms of “pure” research.”  Id. at *11 (citation omitted).   Against this backdrop, with inevitable skepticism, the Court continued its analysis of the sources relied upon by plaintiffs’ experts.

Epidemiology Studies  

The Court explained that epidemiologic studies “provide the primary accepted methodology for determining a causal relationship between a chemical compound and a set of symptoms or disease.”  Id. (citation omitted), noting that the Reference Manual for Scientific Evidence deems large epidemiological studies to be “some of the strongest medical/scientific evidence.”  Id. (citations omitted).  

We have blogged about the pitfalls of reliance on weak or statistically insignificant associations, in the name of epidemiology, to prove general causation.   Here, the Court wasted little time in discrediting this reliance by plaintiffs’ experts.  After listing the key data produced by nine risk assessment studies and a meta-analysis, the Court concluded,

As discussed in greater detail herein, the information learned from the aforementioned studies together with the testimony of [defendant’s experts] at the Kemp Hearing leads the court to conclude that there is no epidemiologic evidence to justify a reasonable inference that there is a causal link between Isotretinoin and CD. Nor is there any rational basis for Plaintiffs to resist the findings of all the epidemiological studies before the court except for [a single study] comprised of 509 patients. Plaintiffs' criticism of the studies relied upon by Defendant served to highlight the serious weakness of the single study upon which Plaintiffs rely; namely, insufficient numbers to warrant respect by the scientific community. (NOTE: [Plaintiffs’ experts ignore the [study] authors' own conclusions.)   

Id. at *13. 

Reliance on Adverse Event Reports

Noting that, throughout their testimony, plaintiffs’ experts had made reference to spontaneous adverse event reports filed with the FDA, the Court emphasized that the “FDA Adverse Event Reporting System (FAERS) typically yields information that is not evidentiary in a court of law, As the FDA itself notes, there are serious limitations to such information.”  Id., at *14.  In particular, because “FDA does not require that a causal relationship between a product and an event be proven,” “there is no certainty that the reported event . . . was actually due to the product.”  Id.  Further, “FDA does not require reports for every adverse event or medication error that occurs with a product.  Many factors can influence whether or not an event will be reported, such as the time a product has been marketed and publicity about an event.  Therefore, FAERS data cannot be used to calculate the incidence” of an adverse event in the U.S. population.  Id.   In addition, “voluntary reporting suffers from chronic underreporting and other biases, and the unknown nature of the underlying population makes true reporting rates difficult to obtain and use for comparisons.”  Id. at *15. 

 

We confess that we snickered at the Court’s final point about adverse event reports, which included a swipe at the plaintiffs' bar.  The Court cited an article describing disproportionate FAERS reporting of IBD cases by attorneys -- of 3.3 million IBD cases reported between 2003 and 2011, attorneys reported a whopping 87.8 %, while physicians reported only 6.0%.  Id. (citation omitted). .  The Court concluded, “The legal profession is a bulwark of our society, yet the courts should never underestimate the resourcefulness of some attorneys.”   (You can read more about the limits of Adverse Event Reports here.)

 Other Criticisms of Plaintiff’s Sources

 Noting that the Reference Manual for Scientific Evidence “ranks case reports at the bottom of the medical evidence hierarchy,” id. (citation omitted), the Court denounced “Plaintiffs’ efforts to characterize case reports as inherently valuable evidence. . . .” Id.  Similarly, the Court discounted studies linking Isotretinoin to intestinal damage in dogs, holding “. . . [T]here are limited occasions in which the information derived from animal studies may be used as an integral link in a chain of evidence in support of a novel hypothesis of a causal relationship, but . . . not in this instance.”  Id. at *16.  

Deficiencies in Plaintiffs' Experts' Methodologies

Having made short work of the sources on which plaintiffs’ experts relied, the Court turned next to criticisms of the experts’ methodologies.  The Court began its attack by commenting, “While both Plaintiffs’ experts are eminently qualified, their reasoning and methodology is slanted away from objective science and in the direction of advocacy.   It is this court’s conclusion that the opinions expressed by Plaintiffs’ experts are motivated by preconceived conclusions, and that they have failed to demonstrate that the data or information they used were soundly and reliably generated and are of a type reasonably relied upon by comparable experts.” Id. at *17 (internal punctuation and citation omitted).  

 Ouch.   And it was downhill from there.   The Court attacked the experts’ reliance on a single risk-assessment study, noting, inter alia: 

• The study data were collected by questionnaire, which are subject to recall bias and poor recollection;
• The report of the “study” was published as an abstract in a quarter-page of text, without footnotes.  Neither expert sought to learn any more than was published in the abstract.
• The number of subjects was small enough to be of little or no epidemiological significance.

 Id.   Most importantly, the study’s authors had concluded that “after adjusting for antibiotic exposure, the risk for IBD following Isotretinoin exposure lost any statistical significance.”  As the Court queried, “If it had lost “statistical significance,” how/why do Plaintiff’s believe it is of any value as a risk assessment? Clearly, it is not.”  Id.  The Court concluded, “The unsound nature of Plaintiffs’ methodology in relying upon such a study becomes readily apparent when compared with the population studies, involving hundreds of thousands of subjects, presented to the court. . . .Yet here again, Plaintiffs’ experts engage in their finely-tuned selectivity of the evidence by disregarding eight of the nine . . . studies.”  Id. at *18.  

 Taking the experts individually, the Court proclaimed that, “[Plaintiffs’ biostatistics expert]’s opinions aren’t methodology based, but are conclusion-driven.  This is an expert on a mission.  As cautioned by our Supreme Court, trial courts must attend to the “hired gun phenomenon.”  Id. at *19.   The Court was even less kind to plaintiffs’ gastroenterology expert: 

 

[He] wants to have it both ways.  First, he wants the Court to reject the best evidence available because he says it is flawed.  Second, he wants the court to accept inferior evidence at the bottom of the medical evidence hierarchy because it is all that he can find to support his hypothesis of causation.  [His] written report itself confirms that his hypothesis is a muddle of ambiguities and that his report camouflages mere speculation as true science. . . . In short, [his] reasoning is a string of ambiguities held together by two insignificant and misused studies, plus convenient assumptions to bridge any analytical gaps that might arise along the way. Such contrived reasoning is not supported by the scientific community as a reliable basis for making causal determinations. 

Id.  at *19-21. 

It is worth one more block quote to include the Court’s lyrical conclusion: 

It is one thing to stand alone in the world of science, advancing a hypothesis that others do not accept. It is quite another thing to advance a hypothesis that can only be supported by disregarding valid scientific research.. . .  [C]oursing through Plaintiffs' presentation is a refrain that is a ruse. . . .  Counsels' sophistry is belied by the fact that the examination of the “lines of evidence” by Plaintiffs' experts was highly selective, looking no further than they wanted to - cherry picking the evidence - in order to find support for their conclusion-driven testimony in support of a hypothesis made of disparate pieces, all at the bottom of the medical evidence hierarchy. This crafty stratagem cannot bridge the analytical gaps inherent in Plaintiffs' hypothesis. 

Id. at *21.   Clearly, New Jersey did not provide a “day at the beach” (or “down the shore,” as we say in Philadelphia) for plaintiffs’ experts.  The Court articulated the relevant legal standards, scrutinized the evidence, applied the law to the evidence with rigor, and reached a conclusion of uncommon correctness and enviable literacy.  It is a shame that we find ourselves surprised by this.  But, every now and then, there is a Beagle. 

 

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Posted By Rachel B. Weil to Drug and Device Law at 3/03/2015 04:09:00 PM

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