[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 139th 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.)
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).
- 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.
[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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[Drug and Device Law] Statistics Are Still Unnecessary for a Label To Be Adequate
We’ve already blogged about Judge Sweet’s decision last November in the Cymbalta litigation and why it was important. McDowell v. Eli Lilly, 2014 WL 5801604 (S.D.N.Y. Nov. 7, 2014). Its most important aspect was Judge Sweet’s holding that the label’s warning of the withdrawal risks associated with discontinuing Cymbalta was sufficient as a matter of law even though it didn’t include the clinical trial statistics that plaintiffs argued should have been included. The language of the warning was sufficient, so the statistics were unnecessary. Another important aspect of the decision was the nurse practitioner’s knowledge of the withdrawal risks of Cymbalta, which eviscerated plaintiff’s warnings causation case.
Judge Sweet had another opportunity to address these same issues just last week. The plaintiff had moved for reconsideration. See McDowell v. Eli Lilly, 2015 U.S. Dist. LEXIS 23445(S.D.N.Y. Feb. 26, 2015). Maybe he shouldn’t have. The court’s opinion reminds us of the ruling that Lieutenant Commander Galloway received from the bench after her follow-up “strenuous objection” in A Few Good Men. That ruling triggered this bit of sarcasm from Lieutenant Weinberg as the court was emptying: “I strenuously object?" Is that how it works? Hmm? ‘Objection.’ ‘Overruled. ‘Oh, no, no, no. I STRENUOUSLY object.’”
The first time around, plaintiff argued that the warning should have laid out the percentage of patients in the “Perahia” study – 44.3% – who had experienced withdrawal symptoms, rather than the descriptive language in the actual label and the list of identified withdrawal symptoms that had occurred in greater than or equal to 1% of the patient population. The study and the argument weren’t new issues for the court. Plaintiff used them in his opposition to summary judgment. This time he simply attached the study to a belatedly filed expert report.
Similar to Lieutenant Commander Galloway’s strenuous objection, this re-argument offered the court one more chance to announce that the label properly characterized the potential withdrawal risks without those statistics:
This was the express theory of McDowell's complaint . . . and the precise point made by McDowell's opposition to Eli Lilly's original motion: . . . The alleged discrepancies between the discussion of discontinuation symptoms in the label and the results of the 2005 Perahia study were considered and it was concluded that, as a matter of law, the label properly characterized the risks. . . . The report by a retained expert does not constitute "new evidence" meeting the high standard warranting reconsideration.
Id. at *7. In fact, the warnings section of the label was loaded with information on withdrawal risks:
Discontinuation: May result in symptoms, including dizziness, nausea, headache, fatigue, paresthesia, vomiting, irritability, nightmares, insomnia, diarrhea, anxiety, hyperhidrosis, and vertigo (5.6). . . .
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms [see Dosage and Administration (2.4) and Warnings and Precautions (5.6) for descriptions of the risks of discontinuation of Cymbalta]. . . .
Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at a rate greater than or equal to 1% and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, fatigue, paresthesia, vomiting, irritability, nightmares, insomnia, diarrhea, anxiety, hyperhidrosis and vertigo.
During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional instability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
It’s not difficult to nit-pick even well-conceived warnings after the fact. We’ve seen plaintiffs’ lawyers do it effectively many times. Si it’s gratifying to see a court reject this approach. Twice.
Plaintiff’s reconsideration motion also lobbed a European label into the case. This is familiar tactic. Labeling in different countries varies. Different countries have different regulatory and medical systems. Plaintiffs almost always try to take advantage of these differences and, for the most part, are rejected by the courts. Trying such a complex issue is more likely to bog down the trial than provide a jury with material information. Judge Sweet rejected the use of the European label outright:
The mere existence of a differently structured and written European label does not establish that the U.S. label is insufficient, misleading, or legally inadequate, nor is foreign regulatory action even appropriate as a subject of expert testimony in pharmaceutical cases.
Id. at *12.
Finally, plaintiff’s reconsideration motion focused on warnings causation and the testimony of the prescriber. This too was one of the main focuses of the court’s summary judgment opinion. But the prescriber, a nurse practitioner, had already testified that she knew that Cymbalta carried a significant withdrawal risk and that she would still have prescribed Cymbalta even if the label included the statistics from the Perahia study. Id. at *14. That’s bad testimony for a plaintiff. In fact, it’s case-ending testimony. So in his reconsideration motion the plaintiff focused on a hypothetical question. Plaintiff’s attorney had asked the prescriber whether she would have continued to prescribe Cymbalta if she had been told that its withdrawal risk was as bad as or worse than that of a particular competitor drug – and the nurse testified that she might then have chosen a different drug. Id. The problem is that there was no support in the record for the hypothetical. Id. The court called it a false hypothetical. Id. When this type of questioning happens, the defense is forced to highlight the lack of support for the question either at the deposition or (more often) afterward in motion practice. A good court will then exclude the question. That’s what Judge Sweet did:
[T]he absence of any basis in the record for this hypothetical was sufficient reason to exclude it. Plaintiffs in pharmaceutical cases may ask doctors what they would have done in the face of a stronger warning . . . but that hypothetical stronger warning must have a factual basis.
Id. at *14-15.
The motion for reconsideration didn’t raise anything new other than an opportunity for the court to explain in more detail why judgment should be entered against plaintiff. The label’s sufficient warning remained sufficient, and the absent warnings causation remained absent. And the court denied plaintiff’s motion for reconsideration, upholding judgment for the defendant.
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Posted By John J. Sullivan to Drug and Device Law at 3/02/2015 10:58:00 AM --
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[DK GreenRoots] Climate Action Hub: Flying Solo
Climate Action Hub: Flying Solo
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