TORTINI

For your delectation and delight, desultory dicta on the law of delicts.

David Madigan’s Graywashed Meta-Analysis in Taxotere MDL

June 12th, 2020

Once again, a meta-analysis is advanced as a basis for an expert witness’s causation opinion, and once again, the opinion is the subject of a Rule 702 challenge. The litigation is In re Taxotere (Docetaxel) Products Liability Litigation, a multi-district litigation (MDL) proceeding before Judge Jane Triche Milazzo, who sits on the United States District Court for the Eastern District of Louisiana.

Taxotere is the brand name for docetaxel, a chemotherapic medication used either alone or in conjunction with another chemotherapy, to treat a number of different cancers. Hair loss is a side effect of Taxotere, but in the MDL, plaintiffs claim that they have experienced permanent hair loss, which was not adequately warned about in their view. The litigation thus involved issues of exactly what “permanent” means, medical causation, adequacy of warnings in the Taxotere package insert, and warnings causation.

Defendant Sanofi challenged plaintiffs’ statistical expert witness, David Madigan, a frequent testifier for the lawsuit industry. In its Rule 702 motion, Sanofi argued that Madigan had relied upon two randomized clinical trials (TAX 316 and GEICAM 9805) that evaluated “ongoing alopecia” to reach conclusions about “permanent alopecia.” Sanofi made the point that “ongoing” is not “permanent,” and that trial participants who had ongoing alopecia may have had their hair grow back. Madigan’s reliance upon an end point different from what plaintiffs complained about made his analysis irrelevant. The MDL court rejected Sanofi’s argument, with the observation that Madigan’s analysis was not irrelevant for using the wrong end point, only less persuasive, and that Sanofi’s criticism was one that “Sanofi can highlight for the jury on cross-examination.”[1]

Did Judge Milazzo engage in judicial dodging with rejecting the relevancy argument and emphasizing the truism that Sanofi could highlight the discrepancy on cross-examination?  In the sense that the disconnect can be easily shown by highlight the different event rates for the alopecia differently defined, the Sanofi argument seems like one that a jury could easily grasp and refute. The judicial shrug, however, begs the question why the defendant should have to address a data analysis that does not support the plaintiffs’ contention about “permanence.” The federal rules are supposed to advance the finding of the truth and the fair, speedy resolution of cases.

Sanofi’s more interesting argument, from the perspective of Rule 702 case law, was its claim that Madigan had relied upon a flawed methodology in analyzing the two clinical trials:

“Sanofi emphasizes that the results of each study individually produced no statistically significant results. Sanofi argues that Dr. Madigan cannot now combine the results of the studies to achieve statistical significance. The Court rejects Sanofi’s argument and finds that Sanofi’s concern goes to the weight of Dr. Madigan’s testimony, not to its admissibility.34”[2]

There seems to be a lot going on in the Rule 702 challenge that is not revealed in the cryptic language of the MDL district court. First, the court deployed the jurisprudentially horrific, conclusory language to dismiss a challenge that “goes to the weight …, not to … admissibility.” As discussed elsewhere, this judicial locution is rarely true, fails to explain the decision, and shows a lack of engagement with the actual challenge.[3] Of course, aside from the inanity of the expression, and the failure to explain or justify the denial of the Rule 702 challenge, the MDL court may have been able to provide a perfectly adequately explanation.

Second, the footnote in the quoted language, number 34, was to the infamous Milward case,[4] with the explanatory parenthetical that the First Circuit had reversed a district court for excluding testimony of an expert witness who had sought to “draw conclusions based on combination of studies, finding that alleged flaws identified by district court go to weight of testimony not admissibility.”[5] As discussed previously, the widespread use of the “weight not admissibility” locution, even by the Court of Appeals, does not justify it. More important, however, the invocation of Milward suggests that any alleged flaws in combining study results in a meta-analysis are always matters for the jury, no matter how arcane, technical, or threatening to validity they may be.

So was Judge Milazzo engaged in judicial dodging in Her Honor’s opinion in Taxotere? Although the citation to Milward tends to inculpate, the cursory description of the challenge raises questions whether the challenge itself was valid in the first place. Fortunately, in this era of electronic dockets, finding the actual Rule 702 motion is not very difficult, and we can inspect the challenge to see whether it was dodged or given short shrift. Remarkably, the reality is much more complicated than the simple, simplistic rejection by the MDL court would suggest.

Sanofi’s brief attacks three separate analyses proffered by David Madigan, and not surprisingly, the MDL court did not address every point made by Sanofi.[6] Sanofi’s point about the inappropriateness of conducting the meta-analysis was its third in its supporting brief:

“Third, Dr. Madigan conducted a statistical analysis on the TAX316 and GEICAM9805/TAX301 clinical trials separately and combined them to do a ‘meta-analysis’. But Dr. Madigan based his analysis on unproven assumptions, rendering his methodology unreliable. Even without those assumptions, Dr. Madigan did not find statistical significance for either of the clinical trials independently, making this analysis unhelpful to the trier of fact.”[7]

This introductory statement of the issue is itself not particularly helpful because it fails to explain why combining two individual clinical trials (“RCTs”), each not having “statistically significant” results, by meta-analysis would be unhelpful. Sanofi’s brief identified other problems with Madigan’s analyses, but eventually returned to the meta-analysis issue, with the heading:

“Dr. Madigan’s analysis of the individual clinical trials did not result in statistical significance, thus is unhelpful to the jury and will unfairly prejudice Sanofi.”[8]

After a discussion of some of the case law about statistical significance, Sanofi pressed its case against Madigan. Madigan’s statistical analysis of each of two RCTs apparently did not reach statistical significance, and Sanofi complained that permitting Madigan to present these two analyses with results that were “not statistically very impressive,” would confuse and mislead the jury.[9]

“Dr. Madigan tried to avoid that result here [of having two statistically non-significant results] by conducting a ‘meta-analysis’ — a greywashed term meaning that he combined two statistically insignificant results to try to achieve statistical significance. Madigan Report at 20 ¶ 53. Courts have held that meta-analyses are admissible, but only when used to reduce the numerical instability on existing statistically significant differences, not as a means to achieve statistical significance where it does not exist. RMSE at 361–362, fn76.”

Now the claims here are quite unsettling, especially considering that they were lodged in a defense brief, in an MDL, with many cases at stake, made on behalf of an important pharmaceutical company, represented by two large, capable national or international law firms.

First, what does the defense brief signify by placing ‘meta-analysis’ in quotes. Are these scare quotes to suggest that Madigan was passing off something as a meta-analysis that failed to be one? If so, there is nothing in the remainder of the brief that explains such an interpretation. Meta-analysis has been around for decades, and reporting meta-analyses of observational or of experimental studies has been the subject of numerous consensus and standard-setting papers over the last two decades. Furthermore, the FDA has now issued a draft guidance for the use of meta-analyses in pharmacoepidemiology. Scare quotes are at best unexplained, at worst, inappropriate. If the authors had something else in mind, they did not explain the meaning of using quotes around meta-analysis.

Second, the defense lawyers referred to meta-analysis as a “greywashed” term. I am always eager to expand my vocabulary, and so I looked up the word in various dictionaries of statistical and epidemiologic terms. Nothing there. Perhaps it was not a technical term, so I checked with the venerable Oxford English Dictionary. No relevant entries.

Pushed to the wall, I checked the font of all knowledge – the internet. To be sure, I found definitions, but nothing that could explain this odd locution in a brief filed in an important motion:

gray-washing: “noun In calico-bleaching, an operation following the singeing, consisting of washing in pure water in order to wet out the cloth and render it more absorbent, and also to remove some of the weavers’ dressing.”

graywashed: “adj. adopting all the world’s cultures but not really belonging to any of them; in essence, liking a little bit of everything but not everything of a little bit.”

Those definitions do not appear pertinent.

Another website offered a definition based upon the “blogsphere”:

Graywash: “A fairly new term in the blogsphere, this means an investigation that deals with an offense strongly, but not strongly enough in the eyes of the speaker.”

Hmmm. Still not on point.

Another one from “Urban Dictionary” might capture something of what was being implied:

Graywashing: “The deliberate, malicious act of making art having characters appear much older and uglier than they are in the book, television, or video game series.”

Still, I am not sure how this is an argument that a federal judge can respond to in a motion affecting many cases.

Perhaps, you say, I am quibbling with word choices, and I am not sufficiently in tune with the way people talk in the Eastern District of Louisiana. I plead guilty to both counts. But the third, and most important point, is the defense assertion that meta-analyses are only admissible “when used to reduce the numerical instability on existing statistically significant differences, not as a means to achieve statistical significance where it does not exist.”

This assertion is truly puzzling. Meta-analyses involve so many layers of hearsay that they will virtually never be admissible. Admissibility of the meta-analyses is virtually never the issue. When an expert witness has conducted a meta-analysis, or has relied upon one, the important legal question is whether the witness may reasonably rely upon the meta-analysis (under Rule 703) for an inference that satisfies Rule 702. The meta-analysis itself does not come into evidence, and does not go out to the jury for its deliberations.

But what about the defense brief’s “only when” language that clearly implies that courts have held that expert witnesses may rely upon meta-analyses only to reduce “numerical instability on existing statistically significant differences”? This seems clearly wrong because achieving statistical significance from studies that have no “instability” for their point estimates but individually lack statistical significance is a perfectly legitimate and valid goal. Consider a situation in which, for some reason, sample size in each study is limited by the available observations, but we have 10 studies, each with a point estimate of 1.5, and each with a 95% confidence interval of (0.88, 2.5). This hypothetical situation presents no instability of point estimates, and the meta-analytical summary point estimate would shrink the confidence interval so that the lower bound would exclude 1.0, in a perfectly valid analysis. In the real world, meta-analyses are conducted on studies with point estimates of risk that vary, because of random and non-random error, but there is no reason that meta-analyses cannot reduce random error to show that the summary point estimate is statistically significant at a pre-specified alpha, even though no constituent study was statistically significant.

Sanofi’s lawyers did not cite to any case for the remarkable proposition they advanced, but they did cite the Reference Manual for Scientific Evidence (RMSE). Earlier in the brief, the defense cited to this work in its third edition (2011), and so I turned to the cited page (“RMSE at 361–362, fn76”) only to find the introduction to the chapter on survey research, with footnotes 1 through 6.

After a diligent search through the third edition, I could not find any other language remotely supportive of the assertion by Sanofi’s counsel. There are important discussions about how a poorly conducted meta-analysis, or a meta-analysis that was heavily weighted in a direction by a methodologically flawed study, could render an expert witness’s opinion inadmissible under Rule 702.[10] Indeed, the third edition has a more sustained discussion of meta-analysis under the heading “VI. What Methods Exist for Combining the Results of Multiple Studies,”[11] but nothing in that discussion comes close to supporting the remarkable assertion by defense counsel.

On a hunch, I checked the second edition of RMSE, published in the year 2000. There was indeed a footnote 76, on page 361, which discussed meta-analysis. The discussion comes in the midst of the superseded edition’s chapter on epidemiology. Nothing, however, in the text or in the cited footnote appears to support the defense’s contention about meta-analyses are appropriate only when each included clinical trial has independently reported a statistically significant result.

If this analysis is correct, the MDL court was fully justified in rejecting the defense argument that combining two statistically non-significant clinical trials to yield a statistically significant result was methodologically infirm. No cases were cited, and the Reference Manual does not support the contention. Furthermore, no statistical text or treatise on meta-analysis supports the Sanofi claim. Sanofi did not support its motion with any affidavits of experts on meta-analysis.

Now there were other arguments advanced in support of excluding David Madigan’s testimony. Indeed, there was a very strong methodological challenge to Madigan’s decision to include the two RCTs in his meta-analysis, other than those RCTs lack of statistical significance on the end point at issue. In the words of the Sanofi brief:

“Both TAX clinical trials examined two different treatment regimens, TAC (docetaxel in combination with doxorubicin and cyclophosphamide) versus FAC (5-fluorouracil in combination with doxorubicin and cyclophosphamide). Madigan Report at 18–19 ¶¶ 47–48. Dr. Madigan admitted that TAC is not Taxotere alone, Madigan Dep. 305:21–23 (Ex. B); however, he did not rule out doxorubicin or cyclophosphamide in his analysis. Madigan Dep. 284:4–12 (“Q. You can’t rule out other chemotherapies as causes of irreversible alopecia? … A. I can’t rule out — I do not know, one way or another, whether other chemotherapy agents cause irreversible alopecia.”).”[12]

Now unlike the statistical significance argument, this argument is rather straightforward and turns on the clinical heterogeneity of the two trials that seems to clearly point to the invalidity of a meta-analysis of them. Sanofi’s lawyers could have easily supported this point with statements from standard textbooks and non-testifying experts (but alas did not). Sanofi did support their challenge, however, with citations to an important litigation and Fifth Circuit precedent.[13]

This closer look at the actual challenge to David Madigan’s opinions suggests that Sanofi’s counsel may have diluted very strong arguments about heterogeneity in exposure variable, and in the outcome variable, by advancing what seems a very doubtful argument based upon the lack of statistical significance of the individual studies in the Madigan meta-analysis.

Sanofi advanced two very strong points, first about the irrelevant outcome variable definitions used by Madigan, and second about the complexity of Taxotere’s being used with other, and different, chemotherapeutic agents in each of the two trials that Madigan combined.[14] The MDL court addressed the first point in a perfunctory and ultimately unsatisfactory fashion, but did not address the second point at all.

Ultimately, the result was that Madigan was given a pass to offer extremely tenuous opinions in an MDL on causation. Given that Madigan has proffered tendentious opinions in the past, and has been characterized as “an expert on a mission,” whose opinions are “conclusion driven,”[15] the missteps in the briefing, and the MDL court’s abridgement of the gatekeeping process are regrettable. Also regrettable is that the merits or demerits of a Rule 702 challenge cannot be fairly evaluated from cursory, conclusory judicial decisions riddled with meaningless verbiage such as “the challenge goes to the weight and not the admissibility of the witness.” Access to the actual Rule 702 motion helped shed important light on the inadequacy of one point in the motion but also the complexity and fullness of the challenge that was not fully addressed in the MDL court’s decision. It is possible that a Reply or a Supplemental brief, or oral argument, may have filled in gaps, corrected errors, or modified the motion, and the above analysis missed some important aspect of what happened in the Taxotere MDL. If so, all the more reason that we need better judicial gatekeeping, especially when a decision can affect thousands of pending cases.[16]


[1]  In re Taxotere (Docetaxel) Prods. Liab. Litig., 2019 U.S. Dist. LEXIS 143642, at *13 (E.D. La. Aug. 23, 2019) [Op.]

[2]  Op. at *13-14.

[3]  “Judicial Dodgers – Weight not Admissibility” (May 28, 2020).

[4]  Milward v. Acuity Specialty Prods. Grp., Inc., 639 F.3d 11, 17-22 (1st Cir. 2011).

[5]  Op. at *13-14 (quoting and citing Milward, 639 F.3d at 17-22).

[6]  Memorandum in Support of Sanofi Defendants’ Motion to Exclude Expert Testimony of David Madigan, Ph.D., Document 6144, in In re Taxotere (Docetaxel) Prods. Liab. Litig. (E.D. La. Feb. 8, 2019) [Brief].

[7]  Brief at 2; see also Brief at 14 (restating without initially explaining why combining two statistically non-significant RCTs by meta-analysis would be unhelpful).

[8]  Brief at 16.

[9]  Brief at 17 (quoting from Madigan Dep. 256:14–15).

[10]  Michael D. Green, Michael Freedman, and Leon Gordis, “Reference Guide on Epidemiology,” at 581n.89, in Fed. Jud. Center, Reference Manual on Scientific Evidence (3d ed. 2011).

[11]  Id. at 606.

[12]  Brief at 14.

[13]  Brief at 14, citing Burst v. Shell Oil Co., C. A. No. 14–109, 2015 WL 3755953, at *7 (E.D. La. June 16, 2015) (Vance, J.) (quoting LeBlanc v. Chevron USA, Inc., 396 F. App’x 94, 99 (5th Cir. 2010)) (“[A] study that notes ‘that the subjects were exposed to a range of substances and then nonspecifically note[s] increases in disease incidence’ can be disregarded.”), aff’d, 650 F. App’x 170 (5th Cir. 2016). SeeThe One Percent Non-solution – Infante Fuels His Own Exclusion in Gasoline Leukemia Case” (June 25, 2015).

[14]  Brief at 14-16.

[15]  In re Accutane Litig., 2015 WL 753674, at *19 (N.J.L.Div., Atlantic Cty., Feb. 20, 2015), aff’d, 234 N.J. 340, 191 A.3d 560 (2018). SeeJohnson of Accutane – Keeping the Gate in the Garden State” (Mar. 28, 2015); “N.J. Supreme Court Uproots Weeds in Garden State’s Law of Expert Witnesses” (Aug. 8, 2018).

[16]  Cara Salvatore, “Sanofi Beats First Bellwether In Chemo Drug Hair Loss MDL,” Law360 (Sept. 27, 2019).

April Fool – Zambelli-Weiner Must Disclose

April 2nd, 2020

Back in the summer of 2019, Judge Saylor, the MDL judge presiding over the Zofran birth defect cases, ordered epidemiologist, Dr. Zambelli-Weiner to produce documents relating to an epidemiologic study of Zofran,[1] as well as her claimed confidential consulting relationship with plaintiffs’ counsel.[2]

This previous round of motion practice and discovery established that Zambelli-Weiner was a paid consultant in advance of litigation, that her Zofran study was funded by plaintiffs’ counsel, and that she presented at a Las Vegas conference, for plaintiffs’ counsel only, on [sic] how to make mass torts perfect. Furthermore, she had made false statements to the court about her activities.[3]

Zambelli-Weiner ultimately responded to the discovery requests but she and plaintiffs’ counsel withheld several documents as confidential, pursuant to the MDL’s procedure for protective orders. Yesterday, April 1, 2020, Judge Saylor entered granted GlaxoSmithKline’s motion to de-designate four documents that plaintiffs claimed to be confidential.[4]

Zambelli-Weiner sought to resist GSK’s motion to compel disclosure of the documents on a claim that GSK was seeking the documents to advance its own litigation strategy. Judge Saylor acknowledged that Zambelli-Weiner’s psycho-analysis might be correct, but that GSK’s motive was not the critical issue. According to Judge Saylor, the proper inquiry was whether the claim of confidentiality was proper in the first place, and whether removing the cloak of secrecy was appropriate under the facts and circumstances of the case. Indeed, the court found “persuasive public-interest reasons” to support disclosure, including providing the FDA and the EMA a complete, unvarnished view of Zambelli-Weiner’s research.[5] Of course, the plaintiffs’ counsel, in close concert with Zambelli-Weiner, had created GSK’s need for the documents.

This discovery battle has no doubt been fought because plaintiffs and their testifying expert witnesses rely heavily upon the Zambelli-Weiner study to support their claim that Zofran causes birth defects. The present issue is whether four of the documents produced by Dr. Zambelli-Weiner pursuant to subpoena should continue to enjoy confidential status under the court’s protective order. GSK argued that the documents were never properly designated as confidential, and alternatively, the court should de-designate the documents because, among other things, the documents would disclose information important to medical researchers and regulators.

Judge Saylor’s Order considered GSK’s objections to plaintiffs’ and Zambelli-Weiner’s withholding four documents:

(1) Zambelli-Weiner’s Zofran study protocol;

(2) Undisclosed, hidden analyses that compared birth defects rates for children born to mothers who used Zofran with the rates seen with the use of other anti-emetic medications;

(3) An earlier draft Zambelli-Weiner’s Zofran study, which she had prepared to submit to the New England Journal of Medicine; and

(4) Zambelli-Weiner’s advocacy document, a “Causation Briefing Document,” which she prepared for plaintiffs’ lawyers.

Judge Saylor noted that none of the withheld documents would typically be viewed as confidential. None contained “sensitive personal, financial, or medical information.”[6]  The court dismissed Zambelli-Weiner’s contention that the documents all contained “business and proprietary information,” as conclusory and meritless. Neither she nor plaintiffs’ counsel explained how the requested documents implicated proprietary information when Zambelli-Weiner’s only business at issue is to assist in making lawsuits. The court observed that she is not “engaged in the business of conducting research to develop a pharmaceutical drug or other proprietary medical product or device,” and is related solely to her paid consultancy to plaintiffs’ lawyers. Neither she nor the plaintiffs’ lawyers showed how public disclosure would hurt her proprietary or business interests. Of course, if Zambelli-Weiner had been dishonest in carrying out the Zofran study, as reflected in study deviations from its protocol, her professional credibility and her business of conducting such studies might well suffer. Zambelli-Weiner, however, was not prepared to affirm the antecedent of that hypothetical. In any event, the court found that whatever right Zambelli-Weiner might have enjoyed to avoid discovery evaporated with her previous dishonest representations to the MDL court.[7]

The Zofran Study Protocol

GSK sought production of the Zofran study protocol, which in theory contained the research plan for the Zofran study and the analyses the researchers intended to conduct. Zambelli-Weiner attempted to resist production on the specious theory that she had not published the protocol, but the court found this “non-publication” irrelevant to the claim of confidentiality. Most professional organizations, such as the International Society of Pharmacoepidemiology (“ISPE”), which ultimately published Zambelli-Weiner’s study, encourage the publication and sharing of study protocols.[8] Disclosure of protocols helps ensure the integrity of studies by allowing readers to assess whether the researchers have adhered to their study plan, or have engaged in ad hoc data dredging in search for a desired result.[9]

The Secret, Undisclosed Analyses

Perhaps even more egregious than withholding the study protocol was the refusal to disclose unpublished analyses comparing the rate of birth defects among children born to mothers who used Zofran with the birth defect rates of children with in utero exposure to other anti-emetic medications.  In ruling that Zambelli-Weiner must produce the unpublished analyses, the court expressed its skepticism over whether these analyses could ever have been confidential. Under ISPE guidelines, researchers must report findings that significantly affect public health, and the relative safety of Zofran is essential to its evaluation by regulators and prescribing physicians.

Not only was Zambelli-Weiner’s failure to include these analyses in her published article ethically problematic, but she apparently hid these analyses from the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency, which specifically inquired of Zambelli-Weiner whether she had performed such analyses. As a result, the PRAC recommended a label change based upon Zambelli-Weiner’s failure to disclosure material information. Furthermore, the plaintiffs’ counsel represented they intended to oppose GSK’s citizen petition to the FDA, based upon the Zambelli-Weiner study. The apparently fraudulent non-disclosure of relevant analyses could not have been more fraught for public health significance. The MDL court found that the public health need trumped any (doubtful) claim to confidentiality.[10] Against the obvious public interest, Zambelli-Weiner offered no “compelling countervailing interest” in keeping her secret analyses confidential.

There were other aspects to the data-dredging rationale not discussed in the court’s order. Without seeing the secret analyses of other anti-emetics, readers were deprive of an important opportunity to assess actual and potential confounding in her study. Perhaps even more important, the statistical tools that Zambelli-Weiner used, including any measurements of p-values and confidence intervals, and any declarations of “statistical significance,” were rendered meaningless by her secret, undisclosed, multiple testing. As noted by the American Statistical Association (ASA) in its 2016 position statement, “4. Proper inference requires full reporting and transparency.”

The ASA explains that the proper inference from a p-value can be completely undermined by “multiple analyses” of study data, with selective reporting of sample statistics that have attractively low p-values, or cherry picking of suggestive study findings. The ASA points out that common practices of selective reporting compromises valid interpretation. Hence the correlative recommendation:

“Researchers should disclose the number of hypotheses explored during the study, all data collection decisions, all statistical analyses conducted and all p-values computed. Valid scientific conclusions based on p-values and related statistics cannot be drawn without at least knowing how many and which analyses were conducted, and how those analyses (including p-values) were selected for reporting.”[11]

The Draft Manuscript for the New England Journal of Medicine

The MDL court wasted little time and ink in dispatching Zambelli-Weiner’s claim of confidentiality for her draft New England Journal of Medicine manuscript. The court found that she failed to explain how any differences in content between this manuscript and the published version constituted “proprietary business information,” or how disclosure would cause her any actual prejudice.

Zambelli-Weiner’s Litigation Road Map

In a world where social justice warriors complain about organizations such as Exponent, for its litigation support of defense efforts, the revelation that Zambelli-Weiner was helping to quarterback the plaintiffs’ offense deserves greater recognition. Zambelli-Weiner’s litigation road map was clearly created to help Grant & Eisenhofer, P.A., the plaintiffs’ lawyers,, create a causation strategy (to which she would add her Zofran study). Such a document from a consulting expert witness is typically the sort of document that enjoys confidentiality and protection from litigation discovery. The MDL court, however, looked beyond Zambelli-Weiner’s role as a “consulting witness” to her involvement in designing and conducting research. The broader extent of her involvement in producing studies and communicating with regulators made her litigation “strategery” “almost certainly relevant to scientists and regulatory authorities” charged with evaluating her study.”[12]

Despite Zambelli-Weiner’s protestations that she had made a disclosure of conflict of interest, the MDL court found her disclosure anemic and the public interest in knowing the full extent of her involvement in advising plaintiffs’ counsel, long before the study was conducted, great.[13]

The legal media has been uncommonly quiet about the rulings on April Zambelli-Weiner, in the Zofran litigation. From the Union of Concerned Scientists, and other industry scolds such as David Egilman, David Michaels, and Carl Cranor – crickets. Meanwhile, while the appeal over the admissibility of her testimony is pending before the Pennsylvania Supreme Court,[14] Zambelli-Weiner continues to create an unenviable record in Zofran, Accutane,[15] Mirena,[16] and other litigations.


[1]  April Zambelli‐Weiner, Christina Via, Matt Yuen, Daniel Weiner, and Russell S. Kirby, “First Trimester Pregnancy Exposure to Ondansetron and Risk of Structural Birth Defects,” 83 Reproductive Toxicology 14 (2019).

[2]  See In re Zofran (Ondansetron) Prod. Liab. Litig., 392 F. Supp. 3d 179, 182-84 (D. Mass. 2019) (MDL 2657) [cited as In re Zofran].

[3]  “Litigation Science – In re Zambelli-Weiner” (April 8, 2019); “Mass Torts Made Less Bad – The Zambelli-Weiner Affair in the Zofran MDL” (July 30, 2019). See also Nate Raymond, “GSK accuses Zofran plaintiffs’ law firms of funding academic study,” Reuters (Mar. 5, 2019).

[4]  In re Zofran Prods. Liab. Litig., MDL No. 1:15-md-2657-FDS, Order on Defendant’s Motion to De-Designate Certain Documents as Confidential Under the Protective Order (D.Mass. Apr. 1, 2020) [Order].

[5]  Order at n.3

[6]  Order at 3.

[7]  See In re Zofran, 392 F. Supp. 3d at 186.

[8]  Order at 4. See also Xavier Kurz, Susana Perez-Gutthann, the ENCePP Steering Group, “Strengthening standards, transparency, and collaboration to support medicine evaluation: Ten years of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP),” 27 Pharmacoepidemiology & Drug Safety 245 (2018).

[9]  Order at note 2 (citing Charles J. Walsh & Marc S. Klein, “From Dog Food to Prescription Drug Advertising: Litigating False Scientific Establishment Claims Under the Lanham Act,” 22 Seton Hall L. Rev. 389, 431 (1992) (noting that adherence to study protocol “is essential to avoid ‘data dredging’—looking through results without a predetermined plan until one finds data to support a claim”).

[10]  Order at 5, citing Anderson v. Cryovac, Inc., 805 F.2d 1, 8 (1st Cir. 1986) (describing public-health concerns as “compelling justification” for requiring disclosing of confidential information).

[11]  Ronald L. Wasserstein & Nicole A. Lazar, “The ASA’s Statement on p-Values: Context, Process, and Purpose,” 70 The American Statistician 129 (2016)

See alsoThe American Statistical Association’s Statement on and of Significance” (March 17, 2016).“Courts Can and Must Acknowledge Multiple Comparisons in Statistical Analyses (Oct. 14, 2014).

[12]  Order at 6.

[13]  Cf. Elizabeth J. Cabraser, Fabrice Vincent & Alexandra Foote, “Ethics and Admissibility: Failure to Disclose Conflicts of Interest in and/or Funding of Scientific Studies and/or Data May Warrant Evidentiary Exclusions,” Mealey’s Emerging Drugs Reporter (Dec. 2002) (arguing that failure to disclose conflicts of interest and study funding should result in evidentiary exclusions).

[14]  Walsh v. BASF Corp., GD #10-018588 (Oct. 5, 2016, Pa. Ct. C.P. Allegheny Cty., Pa.) (finding that Zambelli-Weiner’s and Nachman Brautbar’s opinions that pesticides generally cause acute myelogenous leukemia, that even the smallest exposure to benzene increases the risk of leukemia offended generally accepted scientific methodology), rev’d, 2018 Pa. Super. 174, 191 A.3d 838, 842-43 (Pa. Super. 2018), appeal granted, 203 A.3d 976 (Pa. 2019).

[15]  In re Accutane Litig., No. A-4952-16T1, (Jan. 17, 2020 N.J. App. Div.) (affirming exclusion of Zambelli-Weiner as an expert witness).

[16]  In re Mirena IUD Prods. Liab. Litig., 169 F. Supp. 3d 396 (S.D.N.Y. 2016) (excluding Zambelli-Weiner in part).

Practical Solutions for the Irreproducibility Crisis

March 3rd, 2020

I have previously praised the efforts of the National Association of Scholars (NAS) for its efforts to sponsor a conference on “Fixing Science: Practical Solutions for the Irreproducibility Crisis.” The conference was a remarkable event, with a good deal of diverse view points, civil discussion and debate, and collegiality.

The NAS has now posted a follow up to its conference, with a link to slide presentations, and to a You Tube page with videos of the presentations. The NAS, along with The Independent Institute, should be commended for their organizational efforts, and their transparency in making the conference contents available now to a wider audience.

The conference took place on February 7th and 8th, and I had the privilege of starting the event with my presentation, “Not Just an Academic Dispute: Irreproducible Scientific Evidence Renders Legal Judgments Unsafe”.

Some, but not all, of the interesting presentations that followed:

Tim Edgell, “Stylistic Bias, Selective Reporting, and Climate Science” (Feb. 7, 2020)

Patrick J. Michaels, “Biased Climate Science” (Feb. 7, 2020)

Daniele Fanelli, “Reproducibility Reforms if there is no Irreproducibility Crisis” (Feb. 8, 2020)

On Saturday, I had the additional privilege of moderating a panel on “Group Think” in science, and its potential for skewing research focus and publication:

Lee Jussim, “Intellectual Diversity Limits Groupthink in Scientific Psychology” (Feb. 8, 2020)

Mark Regnerus, “Groupthink in Sociology” (Feb. 8, 2020)

Michael Shermer, “Giving the Devil His Due” (Feb. 8, 2020)

Later on Saturday, the presenters turned to methodological issues, many of which are key to understanding ongoing scientific and legal controversies:

Stanley Young, “Prevention and Management of Acute and Late Toxicities in Radiation Oncology

James E. Enstrom, “Reproducibility is Essential to Combating Environmental Lysenkoism

Deborah Mayo, “P-Value ‘Reforms’: Fixing Science or Threats to Replication and Falsification?” (Feb. 8, 2020)

Ronald L. Wasserstein, “What Professional Organizations Can Do To Fix The Irreproducibility Crisis” (Feb. 8, 2020)

Louis Anthony Cox, Jr., “Causality, Reproducibility, and Scientific Generalization in Public Health” (Feb. 8, 2020)

David Trafimow, “What Journals Can Do To Fix The Irreproducibility Crisis” (Feb. 8, 2020)

David Randall, “Regulatory Science and the Irreproducibility Crisis” (Feb. 8, 2020)

Counter Cancel Culture – The NAS Conference on Irreproducibility

February 9th, 2020

The meaning of the world is the separation of wish and fact.”  Kurt Gödel

Back in October 2019, David Randall, the Director of Research, of the National Association of Scholars, contacted me to ask whether I would be interested in presenting at a conference, to be titled “Fixing Science: Practical Solutions for the Irreproducibility Crisis.” David explained that the conference would be aimed at a high level consideration of whether such a crisis existed, and if so, what salutary reforms might be implemented.

As for the character and commitments of the sponsoring organizations, David was candid and forthcoming. I will quote him, without his permission, and ask his forgiveness later:

The National Association of Scholars is taken to be conservative by many scholars; the Independent Institute is (broadly speaking) in the libertarian camp. The NAS is open to but currently agnostic about the degree of human involvement in climate change. The Independent Institute I take to be institutionally skeptical of consensus climate change theory–e.g., they recently hosted Willie Soon for lecture. A certain number of speakers prefer not to participate in events hosted by institutions with these commitments.”

To me, the ask was for a presentation on how the so-called replication crisis, or the irreproducibility crisis, affected the law. This issue was certainly one I have had much occasion to consider. Although I am aware of the “adjacency” arguments made by some that people should be mindful of whom they align with, I felt that nothing in my participation would compromise my own views or unduly accredit institutional positions of the sponsors.

I was flattered by the invitation, but I did some due diligence on the sponsoring organizations. I vaguely recalled the Independent Institute from my more libertarian days, but the National Association of Scholars (NAS, not to be confused with Nathan A. Schachtman) was relatively unknown to me. A little bit of research showed that the NAS had a legitimate interest in the irreproducibility crisis. David Randall had written a monograph for the organization, which was a nice summary of some of the key problems. The Irreproducibility Crisis of Modern Science: Causes, Consequences,and the Road to Reform (2018).

On other issues, the NAS seemed to live up to its description as “an organization of scholars committed to higher education as the catalyst of American freedom.” I listened to some of the group’s podcasts, Curriculum Vitae, and browsed through its publications. I found myself agreeing with many positions articulated by or through the NAS, and disagreeing with a few positions very strongly.

In looking over the list of other invited speakers, I saw great diversity of view points and approaches, One distinguished speaker, Daniele Fanelli, had criticized the very notion that there was a reproducibility crisis. In the world of statistics, there were strong defenders of statistical tests, and vociferous critics. I decided to accept the invitation, not because I was flattered, but because the replication issue was important, and I believed that I could add something to the discussion before an audience of professional scientists, statisticians, and educated lay persons. In writing to David Randall to accept the invitation, I told him that with respect to the climate change issues, I was not at all put off by healthy skepticism in the face all dogmas. Every dogma will have its day.

I did not give any further consideration to the political aspect of the conference until early January, when I received an email from a scientist, Lenny Teytelman, Ph.D., the C.E.O. of a company protocols.io, which addresses reproducibility issues. Dr Teytelman’s interest in improving reproducibility seemed quite genuine, but he wrote to express his deep concern about the conference and the organizations that were sponsoring it.

Perhaps a bit pedantically, he cautioned me that the NAS was not the National Academy of Sciences, a confusion that never occurred to me because the National Academies has been known as the National Academies of Science, Engineering and Medicine for several years now. Dr. Teytelman’s real concern seemed to be that the NAS is a “‘politically conservative advocacy group’.” (The internal scare quotes were Teytelman’s, but I was not afraid.) According to Dr. Teytelman, the NAS sought to undermine climate science and environmental protection by advancing a call for more reproducible science. He pointed me to what he characterized as an exposé on NAS, in Undark,1 and he cautioned me that the National Association of Scholars’ work is “dangerous.” Finally, Dr. Teytelman urged me to reconsider my decision to participate in the conference.

I did reconsider my decision, but reaffirmed it in an email I sent back to Dr. Teytelman. I realized that I could be wrong, in which case, I would eat my words, confident that they would be most digestible:

Dear Dr Teytelman,

Thank you for your note. I was aware of the piece on Undark’s website, as well as the difference between the NAS and the NASEM. I don’t believe anyone involved in science education would likely to be confused between the two organizations. A couple of years ago, I wrote a teaching module on biomedical causation for the National Academies. This is my first presentation at the request of the NAS, and frankly I am honored by the organization’s request that I present at its conference.

I have read other materials that have been critical of the NAS and its publications on climate change and other issues. I know that there are views of the organization from which I would dissent, but I do not see my disagreement on some issues as a reason not to attend, and present at a conference on an issue of great importance to the legal system.

I am hardly an expert on climate change issues, and that is my failing. Most of my professional work involves health effects regulation and litigation. If the NAS has advanced sophistical arguments against a scientific claim, then the proper antidote will be to demonstrate its fallacious reasoning and misleading marshaling of evidence. I should think, however, as someone interested in improving the reproducibility of scientific research, you will agree that there is much common ground for discussion and reform of scientific practice, on a broader arrange [sic] of issues than climate change.

As for the political ‘conservatism’, of the organization, I am not sure why that is a reason to eschew participation in a conference that should be of great importance to people of all political views. My own politics probably owe much to the influence of Michael Oakeshott, which puts me in perhaps the smallest political tribe of any in the United States. If conservatism means antipathy to post-modernism, identity politics, political orthodoxies, and assaults on Enlightenment values and the Rule of Law, then count me in.

In any event, thanks for your solicitude. I think I can participate and return with my soul intact.

All the best.

Nathan

To his credit, Dr. Teytelman tenaciously continued. He acknowledged that the political leanings of the organizers were not a reason to boycott, but he politely pressed his case. We were now on a first name basis:

Dear Nathan,

I very much applaud all efforts to improve the rigour of our science. The problem here is that this NAS organization has a specific goal – undermining the environmental protection and denying climate change. This is why 7 out of the 21 speakers at the event are climate change deniers. [https://docs.google.com/spreadsheets/d/136FNLtJzACc6_JbbOxjy2urbkDK7GefRZ/edit?usp=sharing] And this isn’t some small fringe effort to be ignored. Efforts of this organization and others like them have now gotten us to the brink of a regulatory change at the United States Environmental Protection Agency which can gut the entire EPA (see a recent editorial against this I co-authored). This conference is not a genuine effort to talk about reproducibility. The reproducibility part is a clever disguise for pushing a climate change denialism agenda.

Best,

Lenny

I looked more carefully at Lenny’s spreadsheet, and considered the issue afresh. We were both pretty stubborn:

Dear Lenny,

Thank you for this information. I will review with interest.

I do not see that the conference is primarily or even secondarily about climate change vel non. There are two scientists, Trafimow and Wasserstein with whom I have some disagreements about statistical methodology. Tony Cox and Stan Young, whatever their political commitments or views on climate change may be, are both very capable statisticians, from whom I have learned a great deal. The conference should be a lively conversation about reproducibility, not about climate change. Given your interests and background, you should go.

I believe that your efforts here are really quite illiberal, although they are in line with the ‘cancel culture’, so popular on campuses these days.

Forty three years ago, I entered a Roman Catholic Church to marry the woman I love. There were no lightning bolts or temblors, even though I was then and I am now an atheist. Yes, I am still married to my first wife. Although I share the late Christopher Hitchins’ low view of the Catholic Church, somehow I managed to overcome my antipathy to being married in what some would call a house of ill repute. I even manage to agree with some Papist opinions, although not for the superstitious reasons’ Papists embrace.

If I could tolerate the RC Church’s dogma for a morning, perhaps you could put aside the dichotomous ‘us and them’ view of the world and participate in what promises to be an interesting conference on reproducibility?

All the best.

Nathan

Lenny kindly acknowledged my having considered his issues, and wrote back a nice note, which I will quote again in full without permission, but with the hope that he will forgive me and even acknowledge that I have given his views an airing in this forum.

Hi Nathan,

We’ll have to agree to disagree. I don’t want to give a veneer of legitimacy to an organization whose goal is not improving reproducibility but derailing EPA and climate science.

Warmly,

Lenny

The business of psychoanalyzing motives and disparaging speakers and conference organizers is a dangerous business for several reasons. First motives can be inscrutable. Second, they can be misinterpreted. And third, they can be mixed. When speaking of organizations, there is the further complication of discerning a corporate motive among the constituent members.

The conference was an exciting, intellectually challenging event, which took place in Oakland, California, on February 7 and 8. I can report back to Lenny that his characterizations of and fears about the conference were unwarranted. While there were some assertions of climate change skepticism made with little or no evidence, the evidence-based presentations essentially affirmed climate change and sought to understand its causes and future course in a scientific way. But climate change was not why I went to this conference. On the more general issue of reform of scientific procedures and methods, we had open debates, some agreement on important principles, and robust and reasoned disagreement.

Lenny, you were correct that the NAS should not be ignored, but you should have gone to the meeting and participated in the conversation.


1 Michael Schulson, “A Remedy for Broken Science, Or an Attempt to Undercut It?Undark (April 18, 2018).