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Do English Judges Diss Epidemiology?

September 13th, 2013

As noted the other day, Claire McIvor, a senior lecturer, at the Birmingham Law School, has published an interesting U.K. perspective on the use of epidemiologic and statistical evidence in health-outcome litigation. See “Debunking some judicial myths about epidemiology and its relevance to UK tort law,” in 21 Med. Law Rev. (2013), in press.

Ms. McIvor criticizes one case in particular for what she argues is an inappropriate dismissal of epidemiologic evidence as presented by an epidemiologist. Novartis Grimsby Ltd. v. Cookson, [2007] EWCA Civ 1261.

The pursuer, Cookson, worked for Novartis Grimsby, at its factory that manufactured dyes, including azo dyes, from 1964, until 2001, when he developed bladder cancer.  Cookson also chose to be exposed to various carcinogens as a personal lifestyle; he smoked cigarettes, 1/2 to one pack per day, for about 20 years, before quitting around 1980.

Cookson sued Novartis on allegations that he was overexposed to various aromatic amines[1], some of which are known to cause bladder cancer.  Novartis had previously paid such claims, but it contested Mr. Cookson’s case because of its belief that his workplace exposures had not been excessive, and that his past smoking habit more likely explained his cancer.  Both sides called physician expert witnesses, urologists, who both agreed that smoking and the aromatic amines could cause bladder cancer, but disagreed as to what caused Mr. Cookson’s disease.

Given the contest on causation, the two urologists agreed that the input of an epidemiologist, jointly instructed, would be helpful.  Now how quaint is that, for both sides to agree upon an expert witness?  Most lawyers in the United States would think it malpractice to engage in such a practice.

Professor Ray Cartwright, an epidemiologist who had published on the causes of bladder cancer, was the jointly instructed witness. A PubMed search for articles written by Cartwright on bladder cancer is set out below, and suggests that he was an appropriate choice, ex ante, at any rate.

Cartwright reviewed the epidemiologic literature, including some of his own studies. Cartwright’s report disappointed the plaintiff, however, when he opined that the workplace aromatic amine exposure was slight and posed only a low risk compared to the smoking. In assessing Cookson’s workplace exposure, Cartwright relied upon the exposure estimates of the parties’ industrial hygienists, and based his causal attribution upon an assessment that exposures were low.  Later, when plaintiff’s counsel showed that Cartwright misinterpreted some of the exposure data, Cartwright revised his report, but maintained that Cookson’s cancer was caused by smoking.

Professor Cartwright’s misstep on exposure probably diminished the strength of his opinion in the eyes of the trial judge, who ruled for the plaintiff.  Ms. McIvor seems to believe that this ruling improperly elevated clinical testimony over epidemiologic testimony, and credited “personalized probabilities” of the plaintiff’s testifying urologist, who attributed the cancer 20–25% to smoking, versus 70–75% to workplace exposures, and who opined that the workplace more than doubled the risk level that Cookson would have had had he never worked at the Novartis factory.  Novartis Grimsby Ltd. at 48.

Novartis appealed, on grounds that included an allegation of error in equating fact of exposure with causation of the bladder cancer.  Speaking for a unanimous England and Wales Court of Appeal, Lady Justice Smith dismissed the appeal, including its challenge to the medical causation issues.  Contrary to Ms. McIvor, however, the appellate court’s decision gave due weight to the epidemiologist, but found that the epidemiologic evidence was accessible to, and interpretable by, the clinicians. Although neither the appellate decision nor McIvor reviewed the actual epidemiologic evidence, several studies suggest that the relative risks for benzidine-derived dyes are greater than for smoking, and especially the risk for former smokers.  The judicial decision flowed not from improvidently dismissing epidemiologic evidence, or testimony by an epidemiologist, but from relying upon epidemiologic evidence marshaled by the plaintiff, through his urologist.[2]

Both sides agreed that smoking could cause bladder cancer, but they also had to agree that the risk of bladder cancer wanes after smoking cessation. Unfortunately, the Court of Appeal did not review the evidence, but the Surgeon General’s Reports note that cessation reduces risk by half after only a few years.  Wynder and Stellman (1977) and Wynder and Goldsmith (1977) suggest that the risk returns to baseline after 15 years of abstinence.  A study by Cartwright himself suggested the return to baseline in six years, although other studies (by Iscovich; Howe; Vineis; Hartge; and Burch) suggested an initial decline, followed by a persistent increased risk even beyond 15 years of abstinence.

Lady Justice Smith declared herself perplexed by these data, which seemed to be at odds with the notion that bladder cancer develops after 20 or more years latency:

“I myself have found it hard to understand how the passage of time after stopping smoking could result in a reduced risk of developing the disease if the aetiology of the disease is that the cancer begins at the time of exposure but does not manifest itself until later. However, as I have said, this issue was not fully explored in evidence and both experts agreed that the risk of developing bladder cancer from smoking decreased after smoking ceased.”

Novartis Grimsby Ltd. at 45.

Clearly though, it was not helpful to have Cartwright contradicted by the data in his own study.  Although the higher aromatic amine exposures occurred early in the plaintiff’s work career, Cookson continued to have some exposure up until the time of his diagnosis in 2001.  Professor Cartwright may well have been further undermined by the lack of any “time windows” in the occupational epidemiology, which would have supported a similar argument of declining risk from the more intense occupational exposure in the 1960’s.  The absence of such evidence for benzidine, compared with the evidence of latency and post-cessation declining risk for smoking, clearly hurt the employer’s case.  This imbalance in the evidence clearly helps to explain and support the courts’ rejection of Cartwright’s testimony.

Given the epidemiologic evidence, it is not at all clear that the plaintiff’s testifying urologist’s opinion that smoking contributed 25%-30%, whereas aromatic amines contributed 70%-75%, was merely a subjective or personal probability.  Smoking is associated with a two- to three-fold increase in risk in prospective studies, but Cookson was 20 years post-cessation.  His aromatic amine dyestuff exposure, which carries a much higher relative risk for bladder cancer, continued through till the end of his work tenure.  See “Dyes metabolized to benzidine,” in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Volume 100F (WHO 2012).

Cookson’s bladder cancer might have been a “background” case, or a result of both smoking and aromatic amine exposure, or a result of one or the other contested causes.  There appeared to be no serious evidence of synergy.  Given the studies at issue, the plaintiff’s testifying urologist’s opinion may well have been a reasoned analysis of the epidemiologic evidence.  The epidemiologist’s opinion, on the other hand, was clearly undermined by the facts of smoking cessation, and an initial error in exposure estimation.  Novartis’ counsel argued that Cartwright was the “real expert” on the issue of attribution, but Cartwright’s opinion was lacking important foundational facts, and there was no argument that Mr. Barnard, the plaintiff’s urologist, had erred in interpreting the epidemiologic data.  Novartis Grimsby Ltd. at 56.  The real “expert” was in the data, and there was no showing (at least in the published opinion) that the clinician, Mr. Barnard, misunderstood or distorted the epidemiologic data.  In this respect, the Novartis Grimsby case is very different from the Milward case, in which a plaintiff’s toxicologist mistreated, misanalyzed, and misrepresented epidemiologic studies on benzene.

Lady Justice Smith rejected the appellant’s criticism of the trial judge’s weighting Mr. Barnard’s opinion over Professor Cartwright’s:

“The proposition that a clinician is not capable of fully understanding the published epidemiological literature on the causation of a condition within his own specialty seems unsustainable and would, I think, surprise many clinicians and epidemiologists. In my view, it was clear from his detailed reports on causation that Mr. Barnard was familiar with the published work and he was also able to discuss it intelligently when giving evidence. The Recorder was plainly of that view. As for the suggestion that Mr. Barnard was too ready to assume that working for the appellant created an increased risk, this was a good ‘jury point’ but, if it did not appeal to the Recorder, that was an end to it.”

Novartis Grimsby Ltd. at 57.

Although Ms. McIvor is correct to be concerned with the court’s eager over-generalization about the ability of clinicians to understanding of epidemiologic studies, there was little suggestion that Mr. Barnard had tripped up, and there was a good deal to suggest that Professor Cartwright’s opinion was lacking on essential issues.  Admittedly, this impression may have been created by selective reporting by the Court of Appeal.  I have not seen the record or the briefs, but Ms. McIvor has not cited anything from those sources.

Mr. Barnard, the plaintiff’s urologist, further testified that the “occupational exposure had more than doubled the risk due to smoking.”  Novartis Grimsby Ltd. at 53.  The Court of Appeal thus found it easy to affirm the verdict that Cookson had shown that his workplace exposure was the “but for” cause of his cancer.  Of course, the Court of Appeal here accepted evidence of risk and relative risk as showing causation, a dubious proposition. Novartis Grimsby Ltd. at 67. And the Court of Appeal, distinguishing a pneumoconiosis case, further pronounced that the bladder cancer injury was “indivisible,” and thus not capable of an apportionment because neither exposure could be said to make the disease more severe.  The Court could have said, if it yielded to its own risk as causation rationale, that both exposures made the cancer more likely, and the occupational exposure contributed to this overall risk three times as much as the plaintiff’s smoking.  In Justice Lady Smith’s words:

“The natural inference to draw from the finding of fact that the occupational exposure was 70% of the total is that, if it had not been for the occupational exposure, the respondent would not have developed bladder cancer. In terms of risk, if occupational exposure more than doubles the risk due to smoking, it must, as a matter of logic, be probable that the disease was caused by the former.”

Novartis Grimsby Ltd. at 74.

The Court of Appeal’s opinion was thus consistent with its own commitment to the conflation of risk with causation, a conflation that may well be objectionable, but does not seem to be the basis for Ms. McIvor’s objections to the Novartis decision.  Of course, a remand with directions to apportion would have a perfectly logical and consistent result with the insistence that risk be substituted for causation in supporting the verdict below.

Publications of Professor Cartwright on Bladder Cancer from National Library of Medicine Database

1: Subramonian K, Cartwright RA, Harnden P, Harrison SC. Bladder cancer in patients with spinal cord injuries. BJU Int. 2004 Apr;93(6):739-43. PubMed PMID: 15049983.

2: Cartwright RA. Bladder cancer screening in the United Kingdom. J Occup Med. 1990 Sep;32(9):878-80. PubMed PMID: 2074512.

3: Cuzick J, Babiker A, De Stavola BL, McCance D, Cartwright R, Glashan RW. Palmar keratoses in family members of individuals with bladder cancer. J Clin Epidemiol. 1990;43(12):1421-6. PubMed PMID: 2147716.

4: Philip PA, Fitzgerald DL, Cartwright RA, Peake MD, Rogers HJ. Polymorphic N-acetylation capacity in lung cancer. Carcinogenesis. 1988 Mar;9(3):491-3. PubMed PMID: 3345587.

5: Cartwright RA. Screening workers exposed to suspect bladder carcinogens. J Occup Med. 1986 Oct;28(10):1017-9. PubMed PMID: 3772536.

6: Boyko RW, Cartwright RA, Glashan RW. Bladder cancer in dye manufacturing workers. J Occup Med. 1985 Nov;27(11):799-803. PubMed PMID: 4067684.

7: Cartwright RA, Philip PA, Rogers HJ, Glashan RW. Genetically determined debrisoquine oxidation capacity in bladder cancer. Carcinogenesis. 1984 Sep;5(9):1191-2. PubMed PMID: 6467507.

8: Cartwright RA, Glashan RW. Palmar keratoses and bladder cancer. Lancet. 1984 Mar 10;1(8376):563. PubMed PMID: 6142276.

9: Cartwright RA, Adib R, Appleyard I, Glashan RW, Gray B, Hamilton-Stewart PA, Robinson M, Barham-Hall D. Cigarette smoking and bladder cancer: an epidemiological inquiry in West Yorkshire. J Epidemiol Community Health. 1983

Dec;37(4):256-63. PubMed PMID: 6655413; PubMed Central PMCID: PMC1052920.

10: Cartwright RA, Adib R, Appleyard I, Glashan RW, Richards B, Robinson MR, Sunderland E, Barham-Hall D. ABO, MNSs and rhesus blood groups in bladder cancer. Br J Urol. 1983 Aug;55(4):377-81. PubMed PMID: 6411162.

11: Cartwright RA, Adib R, Appleyard I, Coxon JG, Glashan RW, Richards B, Robinson MR, Sunderland E, Barham-Hall D. Ten genetic polymorphisms in bladder cancer. J Med Genet. 1983 Apr;20(2):112-6. PubMed PMID: 6221102; PubMed Central PMCID: PMC1049011.

12: Cartwright RA. Historical and modern epidemiological studies on populations exposed to N-substituted aryl compounds. Environ Health Perspect. 1983 Mar;49:13-9. PubMed PMID: 6339220; PubMed Central PMCID: PMC1569142.

13: Cartwright RA, Robinson MR, Glashan RW, Gray BK, Hamilton-Stewart P, Cartwright SC, Barham-Hall D. Does the use of stained maggots present a risk of bladder cancer to coarse fishermen? Carcinogenesis. 1983;4(1):111-3. PubMed PMID: 6821882.

14: Cartwright RA, Glashan RW, Rogers HJ, Ahmad RA, Barham-Hall D, Higgins E, Kahn MA. Role of N-acetyltransferase phenotypes in bladder carcinogenesis: a pharmacogenetic epidemiological approach to bladder cancer. Lancet. 1982 Oct 16;2(8303):842-5. PubMed PMID: 6126711.

15: Garner RC, Mould AJ, Lindsay-Smith V, Cartwright RA, Richards B. Mutagenic urine from bladder cancer patients. Lancet. 1982 Aug 14;2(8294):389. PubMed PMID: 6124790.

16: Cartwright R. Occupational bladder cancer and cigarette smoking in West Yorkshire. Scand J Work Environ Health. 1982;8 Suppl 1:79-82. PubMed PMID: 7100861.

17: Glashan RW, Cartwright RA. Occupational bladder cancer and cigarette smoking  in West Yorkshire. Br J Urol. 1981 Dec;53(6):602-4. PubMed PMID: 7317749.

18: Cartwright RA, Gadian T, Garland JB, Bernard SM. The influence of malignant cell cytology screening on the survival of industrial bladder cancer cases. J Epidemiol Community Health. 1981 Mar;35(1):35-8. PubMed PMID: 7264531; PubMed Central PMCID: PMC1052117.

19: Cartwright RA, Adib R, Glashan R, Gray BK. The epidemiology of bladder cancer in West Yorkshire. A preliminary report on non-occupational aetiologies. Carcinogenesis. 1981;2(4):343-7. PubMed PMID: 7273315.

20: Cartwright RA, Glashan RW, Gray B. Survival of transitional cell carcinoma cases in 2 Yorkshire centres. Br J Urol. 1980 Dec;52(6):497-9. PubMed PMID: 7459578.

21: Cartwright RA, Bernard SM, Glashan RW, Gray BK. Bladder cancer amongst dye users. Lancet. 1979 Nov 17;2(8151):1073-4. PubMed PMID: 91807.

22: Cartwright RA. Genetic association with bladder cancer. Br Med J. 1979 Sep 29;2(6193):798. PubMed PMID: 519209; PubMed Central PMCID: PMC1596415.

23: Williams DR, Cartwright RA. The esterase D polymorphism in patients with diabetes or carcinoma of the bladder and a matched sample of non-dono. Ann Hum Biol. 1978 May;5(3):281-4. PubMed PMID: 686669.

[1] α-naphthylamine, some of which was contaminated with β-napthylamine, benzidine, dianisidine and o-tolidine

[2] There was a suggestion that the plaintiff’s urologist had invoked his clinical experience in treating men from the factory with bladder cancer, but the courts did not seem to give dispositive weight to this irrelevant argument for causation. Novartis Grimsby Ltd. at 56.

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Daubert Bewigged

September 11th, 2013

Claire McIvor, a senior lecturer, at the Birmingham Law School, has published an interesting U.K. perspective on the use of epidemiologic and statistical evidence in health-outcome litigation. See “Debunking some judicial myths about epidemiology and its relevance to UK tort law,” in 21 Med. Law Rev. (2013), in press.

McIvor argues that British judges have failed to engage with epidemiologic evidence, and have relegated epidemiologic evidence to a status inferior to clinical evidence, even when testifying clinicians have little to offer the fact finder.  If the be-wigged judges have done this shame on them, but McIvor suggests that a pre-trial hearing is necessary to address the proper (and improper) range of methodologies and inferences:

“The very fact that methodologically problematic evidence can end up before a trial court is indicative of the need for a pre-trial admissibility test for scientific evidence in UK civil law. Such a test would afford the court an opportunity to evaluate the scientific reliability of any epidemiological evidence that the parties wish to introduce at trial.”

McIvor at 22.  In advancing this recommendation, McIvor expands upon a recent Law Commission recommendation for what she describes as “a pre-trial admissibility test for scientific evidence in criminal litigation, similar to that which is used in the USA.”  McIvor at 32 (citing Law Commission, Expert Evidence in Criminal Proceedings in England and Wales (Law Comm’n No. 325, 2011)).

This recommendation and discussion, however, are confusing and perhaps confused.  The test in the United States is not a pre-trial test, although a party may ask for a determination in advance, either in conjunction with a motion for summary judgment, or to limit the evidentiary display at trial.   Nonetheless, objections to expert witness opinion testimony can certainly be made at trial.  Indeed, if the pre-trial motion is denied, the moving party may well have to renew its objection at trial in any event.

MacIvor’s recommendation is puzzling for other reasons.  First, most civil cases are tried to the bench, and the need to challenge the expert opinion pre-trial is certainly less pressing.  Lengthy, methodological challenges are virtually impossible before a jury but they would be made in front of the presiding judge, in any event.  Second, having recommended the pre-trial procedure, and the substantive standard for reliability and validity, McIvor proceeds to tell us that it [the Daubert standard] has “proven to be a rather controversial test in practice.”  Id. at 32 n.84 (citing no less of an authority than Carl Cranor, Toxic Torts: Science, Law and the Possibility of Justice 62-90 ( 2006)).  Cranor is hardly an unbiased, reliable source, but if McIvor accepts his pronouncements, her recommendation is hard to understand.  Third, McIvor gives us an example of a class of cases, which at first blush, suggest that judges on the other side of the Atlantic just do not understand science.  In McTear v. Imperial Tobacco, [2005] 2 SC 1, the trial judge, Lord Nimmo Smith, ruled in favor of a tobacco company in a lung cancer personal injury case.  His ruling was largely based upon a rejection of the epidemiologic evidence, which McIvor suggests is unreasonable, but then tells us that the rejection might have resulted from the plaintiffs’ reliance upon reports without the benefit of an epidemiologist to explain and teach the trial judge about the meaning of the evidence.

Indeed, McIvor tells us that Lord Nimmo Smith complained in his opinion that he had not been:

“‘sufficiently instructed by the expert evidence about this discipline’ to be able to form his own judgment of the evidence. This was not an unreasonable point, at least as regards the issue of individual causation.”

McIvor at 32 (quoting Lord Nimmo Smith).  Well, it does suggest that the good Lord may have been a stubborn Scot, who was not going to give any weight to the common wisdom, but rather insist that the plaintiff make his case in court.  Even McIvor goes on to characterize the plaintiff’s counsel’s strategy as “unwise, in hindsight.”  Id.

Rule 702 is an extremely important part of the law of evidence in federal courts, and in many state courts.  The U.K. would do well to adopt it, with allowance for the very different role of judges in civil cases on the other side of the Atlantic.

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Urging Review and Reversal, Scientists File Amicus Brief in the Harkonen Case

September 7th, 2013

Earlier this week, Professors Kenneth Rothman and Timothy Lash, and I, filed our Brief by Scientists And Academics as Amici Curiae, in the case, Harkonen v. United States.  As noted previously, Dr. Harkonen has petitioned the Supreme Court for review of the Ninth Circuit’s affirmance of his conviction for Wire Fraud.  Other amici will likely file on Monday, September 9, 2013.

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Aaron Kesselheim’s Presentation on FDA Regulation of Manufacturer Speech

September 3rd, 2013

On August 5, 2013, Dr. Scott Harkonen filed his petition for a writ of certiorari with the United States Supreme Court. As noted in some previous posts, Dr. Harkonen was acquitted of misbranding, but convicted of wire fraud, for his role in issuing a press release about the results of a clinical trial of interferon gamma 1b, in patients with idiopathic pulmonary fibrosis.  (See Multiplicity versus Duplicity – The Harkonen Conviction; The Matrixx Motion in U.S. v. Harkonen; The (Clinical) Trial by Franz Kafka).

Dr. Harkonen’s petition presents two questions:

“1. Whether a conclusion about the meaning of scientific data, one on which scientists may reasonably disagree, satisfies the element of a “false or fraudulent” statement under the wire fraud statute, 18 U.S.C. § 1343?

2. Whether applying 18 U.S.C. § 1343 to scientific conclusions drawn from accurate data violates the First Amendment’s proscription against viewpoint discrimination, or renders the statute, as applied , unconstitutionally vague.”

Both questions are important given that the government has conceded that Dr. Harkonen’s press release accurately presented the raw data and calculated p-values.  The crime, if crime it be, lay in Dr. Harkonen’s drawing a causal inference from a subgroup, p = 0.004, which was not prespecified, in a specified secondary endpoint of survival (p = 0.08), when the subgroup was clearly based upon the goals of the trials, and there was other corroborative evidence in the form of two previous trials, clinical practice, and strong mechanistic evidence.

The government argued that NO inferences could be drawn from a trial that “failed” on its primary endpoint.  The government’s embrace of this statistical orthodoxy greatly misrepresented scientific practice to the courts below.  The only “failed” trial is one that is not conducted.

There are many who would go to great lengths to distort the facts of the Harkonen case in order to demonize the pharmaceutical industry, or to arm the Justice Department with a weapon that can shut down scientific speech about pharmaceutical interventions.  The expansion of the Wire Fraud Act, seen in the Harkonen case, to achieve these political goals will not only affect pharmaceutical company scientists, but also government and academic scientists.  The standard for falsity, drawn from an out-dated, tendentious, and overly rigid conception of hypothesis testing will apply equally to non-industry scientists in False Claim Act cases.  Perhaps in future posts, I can provide some good examples, on condition that any qui tam relators share their bounty with me.

Back in May, Aaron Kesselheim presented (by video) a paper, written with Michelle Mello, of the Harvard School of Public Health, on “The Prospect of Continued FDA Regulation of Manufacturer Promotion in an Era of Expanding Commercial Speech.”  Kesselheim went out of his way to misrepresent the facts of the Harkonen case, as part of his brief against off-market promotion.

By way of background, Aaron S. Kesselheim is a physician and a lawyer, and an Assistant Professor of Medicine at Harvard Medical School.  He is also a faculty member in the Division of Pharmacoepidemiology and Pharmacoeconomics in the Department of Medicine at Brigham and Women’s Hospital.   Given his position and his training in two professions, as well as the extraordinary stakes involved in allowing the government to prosecute scientists for drawing allegedly false conclusions about facts that the government concedes are accurate, Dr. Kesselheim should have exercised much greater care in checking his own assertions more closely.

Dr. Kesselheim focused primarily on the Second Circuit’s recent decision in United States v. Caronia, 703 F.3d 149 (2d Cir. 2012) , which reversed a judgment of conviction for off-label promotion, on First Amendment grounds.  About nine minutes into his presentation, Kesselheim turned to alternative strategies for the government to use to squelch off-label promotion.  One of his suggestions was to follow the model of the Harkonen prosecution, and to prosecute off-label promotion as false and misleading speech.

In his discussion of his suggested strategy, Kesselheim suggested that Dr. Harkonen had made misleading “conclusory, unsubstantiated claims for efficacy,“ and “without reference to supporting evidence.”  It is Kesselheim, however, who seriously mislead his listeners and readers by stating that Dr. Harkonen had made “conclusory, unsubstantiated claims for efficacy.”  The Press Release that was the subject of the government’s indictment set out accurately actual count data and calculated p-values.  No data were fabricated or falsified.  Within the limited space and the informal context of a Press Release, Dr. Harkonen had provided a substantial account of the data from InterMune’s clinical trial, as well as citing a previous, independent clinical trial and its extension, clinical experience, and mechanism research on the action of interferon γ-1b.  Unfortunately, it is Kesselheim who is speaking in conclusory sound bites when he ignores the context and content of the actual Press Release at issue.

Kesselheim went on to suggest that Harkonen’s statement was refuted by a “company-sponsored clinical trial showing that the drug was not effective.” This statement is not only false, but shows a flagrant disregard for statistical analysis and the data in the Harkonen case.  Kesselheim implies that a clinical trial that fails to show treatment efficacy thereby shows that the treatment was not effective.  His statement commits the fundamental error of equating a failure to reject the null hypothesis at a specified level of attained significance with acceptance of the null hypothesis.  This reasoning is fallacious and fundamentally flawed.

To be sure, the prespecified secondary survival endpoint in InterMune’s clinical trial did not meet the 0.05 cutoff (it was 0.08), although the per-protocol analysis for this endpoint came up at 0.055, on a preliminary analysis of the data. When the clinical trial was fully analyzed and written up for publication in the New England Journal of Medicine, the treatment-adherent analysis for survival in the entire clinical trial was 0.02, with a statistically significant hazard ratio for survival, favoring the therapy:

“Analysis of the treatment-adherent cohort of patients showed an absolute reduction in the risk of death of 9 percent in the interferon gamma-1b group, as compared with the placebo group, and a relative reduction in the risk of 66 percent (5 percent of 126 patients in the interferon gamma-1b group and 14 percent of 143 patients in the placebo group died, P=0.02). The hazard ratio for death in the interferon gamma-1b group, as compared with the placebo group, was 0.3 (95 percent confidence interval, 0.1 to 0.9).”

Ganesh Raghu, Kevin K. Brown, Williamson Z. Bradford, Karen Starko, Paul W. Noble, David A. Schwartz, and Talmadge E. King, Jr., for the Idiopathic Pulmonary Fibrosis Study Group, “A Placebo-Controlled Trial of Interferon Gamma-1b in Patients with Idiopathic Pulmonary Fibrosis,” 350 New Engl. Med. J. 125, 129-30 (2004).

Dr. Harkonen, in his Press Release, did focus on what seems like an eminently sensible subgroup, within the survival secondary endpoint, of mild- and moderate-cases, which, a priori, were believed to be the patients mostly likely to benefit from the interferon γ-1b therapy.  (What was not known before the trial was at what point in disease progression might patients no longer respond with greater survival, and hence the difficulty in setting the boundary between moderate and severe cases.)  Kesselheim might argue that the interferon γ-1b clinical trial, standing alone, was inconclusive, but he certainly cannot argue truthfully that the trial showed that the biological product to be ineffective.  Clinical trials do not neatly divide the world of possible results into demonstrations of efficacy and demonstrations of inefficacy.  Not only does the evidence come in degrees, but there is a range of “inconclusiveness” in between the two extremes. Given his background, training, and experience, Kesselheim certainly should know this, and he should apologize for his inaccurate statements.

Kesselheim might well have stopped there, but he went on to acknowledge that the company-sponsored clinical trial at issue did find, in post-hoc analyses, a non-significant trend of benefit in a subset of patients.  Talk of misleading speech!  The p-value at issue was 0.004, uncorrected for multiple comparisons, but no one, not Kesslheim, not the government or anyone else, has offered any appropriate adjustment for multiple comparisons that would inflate that 0.004 to over 0.05.  Kesselheim has no warrant for branding the subgroup finding “non-significant,” until he shows that the p = 0.004, when appropriately modified (if it can be), exceeds 0.05.

Kesselheim mangles other, less technical facts.  He claims that the company saw a ten-fold increase in sales of interferon γ-1b for idiopathic pulmonary fibrosis.  No such fact was ever, or could ever, be established in the Harkonen case.  Kesselheim claims that Dr. Harkonen admitted, in emails, that he did not really believe that the trial “demonstrated” benefit; no such emails were ever adduced at trial, and this seems to be part of a fictional narrative that Dr. Kesselheim has manufactured.  Finally, Kesselheim harrumphs that FDA declined to approve drug.  The company never filed a new drug application for the idiopathic pulmonary fibrosis indication; there was no application to reject.  Perhaps more important is that the Press Release was issued before InterMune had made any formal submission of data to the FDA, an event that did not take place until the following year.

Kesselheim sighs that the Harkonen prosecution will be a difficult act to follow because it requires a case-by-case showing of falsity, with the necessity of expert testimony, and heavy cognitive demands on lay jurors. How ironic that Kesselheim, a lawyer and a physician, and a Harvard Medical School faculty member, buckled under the cognitive demands of his topic. Indeed, Kesselheim’s confusion is a strong argument for why the Supreme Court should put a stop to the practice of asking jurors to second guess whether a scientist has incorrectly inferred causation from accurately presented facts.

Let’s hope Dr. Harkonen gets a fair hearing in the Supreme Court.

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Woodside & Davis on the Bradford Hill Considerations

August 23rd, 2013

Dr. Frank Woodside and Allison Davis have published an article on the so-called Bradford Hill criteria.  Frank C. Woodside, III & Allison G. Davis, “The Bradford Hill Criteria: The Forgotten Predicate,” 35 Thomas Jefferson L. Rev. 103 (2013).

Their short paper may be of interest to Rule 702 geeks, and students of how the law parses causal factors in litigation.

The authors argue that a “predicate” to applying the Hill criteria consists of:

  • ascertaining a clear-cut association,
  • determining the studies establishing the association are valid, and
  • satisfying the Daubert [1][sic] requirements.

Id. at 107.  Parties contending for a causal association often try to flyblow the need for statistical significance at any level, and argue that Bradford Hill did not insist upon statistical testing.  Woodside and Davis remind us that Bradford Hill was quite firm in insisting upon the need to rule out random variability as an explanation for an association:

“Our observations reveal an association between two variables, perfectly clear-cut and beyond what we would care to attribute to the play of chance.”

Id. at 105; see Hill, Austin Bradford Hill, “The Environment and Disease: Association or Causation?” 58 Proc. Royal Soc’y Med. 295 (1965).  The authors correctly note that the need for study validity is fairly implied by Bradford Hill’s casual expression about “perfectly clear-cut.”

Woodside and Davis appear to acquiesce in the plaintiffs’ tortured interpretation of Bradford Hill’s speech, on which statistical significance supposedly is unimportant.  Woodside & Davis at 105 & n.7 (suggesting that Bradford Hill “seemingly negates the second [the requirement of statistical significance] when he discounts the value of significance testing, citing Bradford Hill at 299).

Woodside and Davis, however, miss the heavy emphasis that Bradford Hill actually placed upon “tests of significance”:

“No formal tests of significance can answer those questions. Such tests can, and should, remind us of the effects that the play of chance can create, and they will instruct us in the likely magnitude of those effects. Beyond that they contribute nothing to the ‘proof’ of our hypothesis.”

Bradford Hill at 299.  Bradford Hill never says that statistical tests contribute nothing to proving an hypothesis; rather, his emphasis is on the insufficiency of statistical tests alone to establish causality.  Bradford Hill’s “beyond that” language clearly stakes out the preliminary, but necessary importance of ruling out the play of chance before proceeding to consider the causal factors.

Passing beyond their exegetical fumble, Woodside and Davis proceed to discuss the individual Bradford Hill considerations and how they have fared in the crucible of Rule 702.  Their discussion may be helpful to lawyers who want to track the individual considerations, and how they have treated, or dismissed, by trial courts charged with gatekeeping expert witness opinion testimony.

There is another serious problem in the Woodside and Davis paper.  The authors describe risk ratios and the notion of “confidence intervals”:

“A confidence interval provides both the relative risk found in the study and a range (interval) within which the risk would likely fall if the study were repeated numerous times.32 … As such, risk measures used in conjunction with confidence intervals are critical in establishing a perfectly clear-cut association when it comes to examining the results of a single study.35”

Woodside & Davis at 110.  The authors cite to the Reference Manual on Scientific Evidence (3d 2011), but they fail to catch important nuances of the definition of a confidence interval.  The obtained interval from a given study is not the interval within which the “risk would likely fall if the study were repeated… .”  Rather it is 95% of the many intervals, from the many repeated studies done on the same population, with the same sample size, which would capture the true risk.  As for the obtained interval, the true risk is either within it, or not, and no probability value attaches to the likelihood that the true value lies within the obtained interval.

It is a mystery why lawyers would bother to define something like the confidence interval, and then do it incorrectly.  Here is how Professors Finkelstein and Levin define the confidence interval in their textbook on statistics:

“A confidence interval for a population proportion P is a range of values around the proportion observed in a sample with the property that no value in the interval would be considered unacceptable as a possible value for P in light of the sample data.”

Michael Finkelstein & Bruce Levin, Statistics for Lawyers 166-67 (2d ed. 2001).   This text explains why and where Woodside and Davis went astray:

“It is the confidence limits PL and PU that are random variables based on the sample data. Thus, a confidence interval (PL, PU) is a random interval, which may or may not contain the population parameter P. The term “confidence” derives from the fundamental property that, whatever the true value of P, the 95% confidence interval will contain P within its limits 95% of the time, or with 95% probability. This statement is made only with reference to the general property of confidence intervals and not to a probabilistic evaluation of its truth in any particular instance with realized values of PL and PU.”

Id. at 167-71.

[1] Surely the time has come to stop referring to the Daubert factors and acknowledge that the Daubert case was just one small step in the maturation of evidence law.  The maturation consisted of three additional Supreme Court cases, many lower court cases, and a statutory revision to Federal Rule of Evidence 702, in 2000.  The Daubert factors hardly give due consideration to the depth and breadth of the law in this area.

Posted in Causation, Rule 702, statistical evidence | Comments Off on Woodside & Davis on the Bradford Hill Considerations

Second Circuit Hands down a Marvel Opinion on Historian Expert Testimony

August 17th, 2013

“What will history say?  History, sir, will tell lies as usual.”
George Bernard Shaw, The Devil’s Disciple (1901)

 * * * * *

Parties to products liability litigation have for some time resorted to the ruse of using historians as rhetoricians and advocates to argue partisan litigation positions to the jury, in the evidentiary phase of trials.  The obvious opening for this ruse has come in advancing party positions on “state of the art” to claim or defend against negligence.  When plaintiffs use this tactic, they seek not only to introduce evidence of pre-sale belief or knowledge of hazards, but also to disparage any challenges to, or doubts about, hazards as unreasonable, biased, or malicious.  When defendants use this tactic, they of course seek to return the favor, by employing their expert witnesses as advocates on crucial issues of historical knowledge.

Two historian gladiators, David Rosner and Gerald Markowitz, have served as capable arguers in silica, asbestos, lead, and vinyl chloride litigation.  Indeed, you might well expect to meet them at the Argument Clinic, although more recently, they starred in an appearance in a California lead paint case, currently on trial.  See CA Lead Paint Trial: Same old Rosner, Markowitz show (Aug. 07, 2013); Howard Mintz, “Hazardous lead paint: Legal battle comes to trial in California” (July 16, 2013) (quoting Rosner’s email exchange with reporter in which he previews his partisan opinions on lead paint in advance of his testimony).

We can find no clearer statement of judicial antipathy to expert witness advocacy than the famous copyright decision by Judge Learned Hand in Nichols v. Universal Pictures Corp., 45 F.2d 119 (2d Cir. 1930).  Both sides in Nichols presented expert testimony on “dramatic writing” in an effort to prove or disprove a claim that one screenplay infringed upon another. Deprecating the lengthy, argumentative testimony from both sides’ experts, Judge Hand declared that

“[i]t ought not be allowed at all. . . .”

Id. at 123. Judge Hand explained with his usual magisterial authority:

“Argument is argument whether in the box or at the bar, and its proper place is the last.”

Id.

Other areas of expertise, besides historical scholarship, fail to satisfy the basic requirements of expert witness testimony. For instance, Judge Hand’s complaints about the “literary critic” expert witnesses in Nichols, have been relodged against “ethics” witnesses. In GST v. Telecommunications, Inc., 192 F.R.D. 109 (S.D.N.Y. 2000), both parties offered expert witness on the ethics of the conduct of corporate officers. Invoking the helpfulness criterion of Federal Rule of Evidence 702, the Court found the proffered testimony would not aid the jury:

“It is evident that the contentious advocacy of the experts – illustrated by conclusions on the credibility of explanations regarding the business judgment of the board of directors . . . in clearly expressed, biased viewpoints – do little to aid the triers of fact on the underlying transactions.”

Id. at 110. The trial court discerned a serious danger that expert testimony on ethics would usurp the jury’s role in applying the law to the facts found in the case. Id. Permitting such testimony would allow expert witnesses to attempt to substitute their judgment for the jury’s. Id.; see, e.g., Pan American World Airways, Inc. v. Aetna Casualty & Surety, 505 F.2d 989, 998 (2d Cir. 1974) (noting disapprovingly that, evidence consisted “largely of hearsay, propaganda, speculation, and conjecture”). See also Imwinkelreid, “Expert Testimony by Ethicists: What Should Be the Norm?” 76 Temple L. Rev. 91, 114, 128 (2003) (noting that normative testimony will virtually always be inadmissible).

Of course, the substitution of an expert witness’s judgment for the jury’s is precisely what many trial lawyers hope to accomplish. Lawyers can select and present expert witnesses based upon their opinions and conclusions, whereas the conclusions of juries are all too unpredictable.  Trial courts must be vigilant to police expert witness opinion testimony in the area of history as much as, if not more than, in the area of scientific testimony. Rule 702’s requirement of knowledge that will assist the trier of fact is designed to prevent expert witnesses from testifying about matters within the common understanding of the jury, and about which the jurors can reason without help from an expert witness. In the Rezulin Multidistrict Litigation (MDL), testimony that was “a narrative of the case which a juror is equally capable of constructing” was precluded.  In re Rezulin Products Liability Litig., 309 F.Supp. 2d 531, 541 (S.D.N.Y. 2004).  Judge Kaplan explained that expert witnesses were not the appropriate conduit for a narrative of events, meetings, regulations, and documents, when they were not percipient witnesses. Such testimony was within the jury’s lay understanding, and the law prohibited the attempt to have expert witnesses “supplant the role of counsel in making argument at trial, and the role of the jury in interpreting the evidence.” Id. at 551.  See generally “Narratives & Historians for Hire”; and “How Testifying Historians Are Like Lawn-Mowing Dogs.”

In Marvel Characters, Inc. v. Kirby, 2013 WL 4016875 (2d Cir. Aug. 8, 2013), the Second Circuit reaffirmed Learned Hand’s jaundiced view of expert witness advocates in the form of historian testimony. Jack Kirby was among the artists responsible for creating comic strip characters of X-Men, the Hulk, Captain America, Thor, and the Fantastic Four. Kirby’s heirs claimed that the intellectual property rights in these characters passed to them.  Marvel Characters, Inc., sought a declaratory judgment that the characters were “works for hire,” now owned by Marvel Entertainment, a subsidiary of corporate oligarch, Walt Disney Co.

The district court rejected the claims of Kirby’s heirs, and the Second Circuit affirmed. Marvel Worldwide, Inc. v. Kirby, 777 F. Supp. 2d 720 (S.D.N.Y. 2011), aff’d, 2013 WL 4016875 (2d Cir. 2013).  In ruling on Marvel’s motion for judgment, the district evaluated and excluded the proffered expert witness testimony of John Morrow and Mark Evanier, who would have testified on the history of the relationship between Marvel and Jack Kirby. 777 F. Supp. 2d 720, 729-30 (S.D.N.Y. 2011). The Second Circuit held that the district court had clearly not abused its discretion in these exclusionary rulings.  Marvel Characters, Inc. v. Kirby, slip op. at 36.

In affirming the rejection of these historians’ proffered opinions, the Circuit waxed  historiosophical:

“We have no doubt that a historian’s ‘specialized knowledge’ could potentially aid a trier of fact in some cases. A historian could, for example, help to identify, gauge the reliability of, and interpret evidence that would otherwise elude, mislead, or remain opaque to a layperson. He or she might helpfully synthesize dense or voluminous historical texts. Or such a witness might offer background knowledge or context that illuminates or places in perspective past events.”

Slip op. at 34 (internal citations omitted).

Morrow and Evanier wandered far outside the permissible boundaries of historian expert testimony.  They sought to marshal opinions based largely upon hearsay statements of various artists, uttered in a variety of settings, about how Marvel treated artists back in the day. From these statements, the aspiring litigation historians speculated about intentions, understandings, and motivations of the historical actors at Marvel, and of Jack Kirby.  Id. at 35.

The appellate court recognized the serious danger of using historian expert witnesses as

“a conduit for introducing hearsay under the guise that the testifying expert used the hearsay as the basis of his testimony.”

Id. (internal citations omitted).  The Circuit recognized that implicit in Rule 703 is something akin to a “best evidence” rule, which relegated the historians to clearly less than best:

“The appropriate way to adduce factual details of specific past events is, where possible, through persons who witnessed those events. And the jobs of judging these witnesses’ credibility and drawing inferences from their testimony belong to the factfinder.”

Id. at 37.  The Circuit also noted that the expert opinion testimony from historians was beset a serious evidentiary challenges. In addition to relevance, legal and logical, and Rule 702, historian opinions raises basic issues about the source of the opinions.

Applying these principles, the appellate court recognized that the heirs’ witnesses were not using specialized knowledge or offering helpful historian insights, but they were marshalling hearsay:

“But Morrow and Evanier do not bring their expertise to bear in any such way. As the district court recognized, their reports are by and large undergirded by hearsay statements, made by freelance artists in both formal and informal settings, concerning Marvel’s general practices towards its artists during the relevant time period.  Drawing from these statements, they then speculate as to the motivations and intentions of certain parties… .”

Id. at 36 (internal citations omitted).

The Second Circuit’s decision is timely.  Perhaps the California trial court pondering the claims against the paint industry will heed the Marvel opinion.  The Marvel Characters opinion should close the door on the use of Rosner and Markowitz’ historical argument, as well as that of other would-be testifying historians in other cases.  In products liability cases, many of the proffered witnesses seek to testify about hearsay statements, and argue inferences about intentions, understandings, and motivations of the historical actors.  Like Morrow and Evanier, they should be excluded from the litigation process.

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The Rhetoric and Challenge of Conflicts of Interest

July 30th, 2013

The Challenge

Critics and anti-industry zealots have argued that industry-sponsored science is vitiated by conflicts of interest.  The critics of industry research have supported their attack with studies that claim to show that industry studies disproportionately report outcomes favorable to their sponsors.

The potential conflicts posed by industry-sponsored research studies are fairly obvious.  Industries that make or sell products, raw materials, or chemicals have an interest in having toxicological and epidemiologic studies support claims of safety.  Research that suggests an industry’s product causes harm may hurt the industry’s financial interests directly by inhibiting sales, or indirectly by undermining the industry’s position in litigation, or by leading to greater regulatory scrutiny and control.  If the harm evidenced by the research is sufficiently severe, the research may lead to product recall or bans, again with serious economic consequences for the industry.  Evidence of harm may require heightened warnings or instructions, which may limit sales or encourage sales of competing, less hazardous products.

The Response.

The answer to the anti-industry challenge lies in a reality more complicated and nuanced that the simplistic views of the critics.  Industry often must conduct or sponsor research to live up to its common law or regulatory duties to test its products.  At other times, industry sponsors research in response to emerging scientific papers that claim that the industry product is harmful in ways not previously known.  While on occasion, industry might be accused of “manufacturing doubt[1],” there are scientists equally intent upon “manufacturing certainty,” whether from dodgy data or iffy inferences.

The motives and interests of scientists intent on manufacturing a faux certainty are harder to discern than the potential conflicts of industry and scientists who are funded by industry.  Many scientists purport to have only the lofty goals of science or the public interest at heart in pursuing their research, but a close look shows that there are several potential conflicts of interest prevalent in the research community, and that these interests help shape science into anti-industry positions.

1.  White Hat Bias

Over 20 years ago, a science journalist published an account of how dire predictions of asbestos deaths had not come to pass.  Tom Reynolds, “Asbestos-Linked Cancer Rates Up Less Than Predicted,” 84 J. Nat’l Cancer Instit. 560 (1992).  In trying to understand why the earlier predictions had been disconfirmed by later data, Reynolds quoted one scientist as saying that:

“the government’s exaggeration of the asbestos danger reflects a 1970s’ Zeitgeist that developed partly in response to revelations of industry misdeeds.  ‘It was sort of the “in” thing to exaggerate … [because] that would be good for the environmental movement’….  ‘At the time it looked like you were wearing a white hat if you made these wild estimates. But I wasn’t sure whoever did that was doing all that much good.”

Id. at 562.  Reynolds captured the essence of “white-hat” bias, a form of political correctness applied to issues that really depend upon scientific method and data for their resolution.

More recently, David Allison and Mark Cope, two public health researchers described[2] white-hat bias as a prevalent cognitive bias in how research is reported and interpreted.  They described white-hat bias as a “bias leading to the distortion of information in the service of what may be perceived to be righteous ends.” Perhaps the temptation to overstate the evidence against a toxic substance is unavoidable, but it diminishes the authority and credibility of regulators entrusted with promulgating and enforcing protective measures.  And error is still error, regardless of its origin.  Allison and Cope give examples of white-hat bias in how papers are cited, with “exonerative” studies cited less often than those than claim harmful outcomes.  And when positive papers were cited, they were often interpreted misleadingly to overstate the harms previously reported.

2. Other “Interested” Actors Who Sponsor and Conduct Scientific Research

The discussion and debate surrounding industry sponsorship of scientific research often ignores the activities of other, intensely interested sponsors and researchers.  Labor unions, for instance, have sponsored research on occupational hazards.  Evidence of harm often becomes potent ammunition in labor-management negotiations over work conditions and wages.  Environmental groups have sponsored studies with sympathetic researchers who are openly eager to embarrass industrial interests and support increasing regulatory restrictions or bans on chemicals or products.  Plaintiffs’ counsel may well be the largest rent-seeking group in the United States, and they have sponsored studies with the implicit or explicit goal of supporting their claims for compensation.  Disease support groups, often aligned with plaintiffs’ counsel, have sponsored research, to support their claims for compensation and fees, the more, the better.  Scientists and physicians who serve as expert witnesses for plaintiffs’ counsel have undertaken research to advance and support their testimonial enterprise in the litigation brought by the counsel who engaged them to testify.

3.  Regulatory Biases

Many scientists are funded by regulatory agencies intent upon showing harm from particularly exposures or industrial processes.  The agencies may be motivated by their desire to expand their regulatory control under their statutory mandate by having scientific evidence that fits their political and regulatory goals.  Some scientists may be politically aligned, or simply believe that the public interest requires the sought after enhanced regulation.

4.  Publication Bias

“Null” studies, studies that do not find a statistical significant increased risk of harm from exposure, do not sell.  More to the point, null studies do not routinely get published.  Spending substantial amounts of time on a study without obtaining an outcome that will make the study publishable is a sure-fire way to sideline one’s academic career.  Publications are the measurable units of success in academic circles.  Publications beget future grants and funding, which further enhance academic reputation and careers.

The pressure on researchers to find some untoward outcome from research on a potential toxic material or product is great.  As John Ioannides and others have shown, prevalent research methods encourage technique that will lead to some findings.  For instance, an epidemiologic cohort study will compare a group with and without exposure, but will look at multiple health outcomes.  Perhaps there was an a priori hunch that lung cancer rates would be increased among the exposed group, but the researchers also looked at a 100 other cancers, and perhaps another 100 other non-malignant diseases, in the study.  Chance alone would have led to several statistically significant findings of increased disease outcomes among the exposed group, and researchers can publish these findings that encourages readers to believe that they were the subject of the research all along.

Similarly, case-control studies can collect cases of a disease of interest and compare them with non-diseased controls in terms of dozens if not hundreds of prior exposures and life-style variables.  Again, the researchers can report the exposures and variables statistically significantly associated with the disease, and neglect to report all those not associated.[3]

5. Biased Studies with Biased Outcomes, Making Biased Claims

The critics of industry-sponsored studies have themselves conducted “studies of studies,” to assess whether sponsorship correlated with outcomes favorable to the sponsor.  These studies of studies claim to find that industry studies invariably or disproportionately favor their sponsors’ interests, but these studies of studies are themselves critically flawed by selection bias.[4]

To understand the selection bias involved, we need only pay attention to the conditions that lead industry to conduct the study.  In connection with potential toxicities of chemicals or products, industry  often is responding to an emerging scientific literature that claims the industrial materials cause harm.  If the studies that claim harm are clearly valid, there is likely to be no counter-study undertaken.  In this scenario, the anti-industry critics will find no industry study for inclusion in their analysis of whether industry studies are correlated with a favorable outcome.

Studies with doubtful data or overstretched conclusions are more likely to provoke an industrial concern into sponsoring research, and given the inciting condition, we should not be surprised that outcome is more favorable to industry than the previously published studies.    Studies ultimately favorable to the defense are thus counted in the “studies of studies,” but given the circumstances that led to the sponsorship, the imbalance in the results is exactly what we should expect to see. Of course, if the study somehow supports the prior findings, the critics of industry will claim that the industry-sponsored study is an “admission” of harm.  Inconclusive or exonerative studies will be dismissed by these critics as uninformative or vitiated by conflicts of interest.

There are many examples of how this selection bias plays out. In the early days of the silicone gel breast implant litigation, ostensibly neutral researchers published papers that claimed an association between silicone implants and scleroderma.  See Harry Spiera, “Scleroderma After Silicone Augmentation Mammoplasty,” 260 J. Am. Med. Ass’n 236 (1988).  These papers led to an FDA-imposed moratorium, which in turn instigated a litigation tsunami.  The then current and former manufacturers of silicone implants sponsored several epidemiologic studies.  Although the companies engaged reputable researchers from the leading medical research centers in the United States, public-interest advocates such as Sidney Wolfe decried the “biased” industry-financed research that came out.  Not surprisingly, the sponsored studies mostly exonerated any causal role of silicone in producing autoimmune diseases.

The biases of the physicians who supported the alleged causal association were much more difficult to ferret out.  Many of the physicians adopted pro-causation views to attract patients from the many support “victim” support groups, and many of the scientists who advocated pro-causation opinions sought to market test kits that would identify biomarkers of a unique silicone-induced disease.  The house of cards created by the support groups and plaintiffs’ counsel ultimately collapsed when court-appointed expert witnesses and the Institute of Medicine examined the evidence closely.  Today, the entire episode can be chalked up mostly to litigation fraud.  See Hon. Judge Jack B. Weinstein, “Preliminary Reflections on Administration of Complex Litigation.” Cardozo Law Review DeNovo 1, 14 (2009) (“[t]he breast implant litigation was largely based on a litigation fraud. …  Claims—supported by medical charlatans—that enormous damages to women’s systems resulted could not be supported.”).

Another example is provided by the welding fume litigation.  In 2001, Dr. Brad Racette published a case series that he erroneously called a case-control study, which purported to find an earlier age of onset for Parkinson’s disease among welders.  In 2005, working in cooperation with plaintiffs’ counsel, Racette transmuted litigation screenings into a cross-sectional study, which purported to find an increased prevalence ratio of “parkinsonism” among welders.  Both studies were seriously flawed, but the plaintiffs’ counsels’ use of Racette’s studies created an incentive for industry to sponsor several studies.  The plaintiffs’ counsel blasted the industry defendants for “manufacturing doubt,” but in fact, the industry-sponsored studies were valid scientific efforts, conducted by respected epidemiologists.  The industry sponsored studies were corroborated several times over by governmentally sponsored studies, conducted in the United States and abroad.  A meta-analysis published last year by well-regarded neuroepidemiologists ultimately vindicated the industry position, as well as the industry-sponsored studies.  See James Mortimer, Amy Borenstein, and Lorene Nelson, “Associations of welding and manganese exposure with Parkinson disease: Review and meta-analysis,” 79 Neurology 1174 (2012) (reporting a statistically significant decreased risk of Parkinson’s disease among welding tradesmen).

In the pharmaceutical industry, publications will invariably show outcomes favorable to drug sponsors.  New drugs that fail to show efficacy in clinical trials will not likely be written about because the sponsor will not file an application for regulatory approval.  Writing up the clinical trials for publication typically is part of the process of seeking regulatory approval, and the publication effort is not undertaken unless there is a reasonable chance of approval.  Unremarkably, the published papers describing these clinical trials disproportionately show efficacy and manageable side effects.

 

6. Hypocrisy Over Conflicts of Interest

The persistence in ignoring non-financial conflict of interests is not innocent.  By elevating financial conflicts of interest, public advocates attempt to silence industry and discount industry-sponsored studies.  The single-minded focus on financial conflicts of interest misdirects attention away from the existence of other sorts of biases, and the distortions they create.[5]

Conflicts of interest have thus largely and incorrectly been reduced to financial conflicts.  For instance, in 2011, the National Institutes of Health (NIH) addressed only financial issues when it promulgated rules for managing conflicts of interest in the field of medical research.[6]  Several commentators advocated regulation of non-financial COI, but the agency refused to include such conflicts within its rules.[7] The Institute of Medicine (IOM), in a monograph on conflicts of interest in medicine, similarly gave almost exclusive priority to financial ties.[8]

The focus on economic conflicts of interest is dangerous because it instills complacency about non-financial interests, and provides a false sense of assurance that the most serious biases are disclosed or eliminated.  One need only consider the many examples of retractions, frauds, and ethical lapses in biomedical research to understand that non-financial interests, such as friendships and alliances, institutional hierarchies, intellectual biases and commitments, beneficence, “white-hat” advocacy, as well as the drive for professional achievement, recognition, and rewards, all have the potential to complicate, distort, and sometimes undermine scientific research in myriad ways. The failure to recognize and regulate non-economic conflicts and biases endangers the validity of science.  Not only are these non-financial threats ignored, but financial interests receive undue attention, resulting in the erosion of public trust in scientific research that is sound.

 

The Cure

1. Push Back Against the Rhetoric of Conflicts of Interest

Industry should not be cowed by the anti-industry attack on industry-sponsored studies.  Twenty years ago, one of the leading epidemiologists, Professor Kenneth Rothman, referred to the anti-industry bias as “new McCarthyism in science.[9]”  This intolerance toward corporate sponsorship has been going on for some time, fueled by one-sided accounts of industry-sponsored studies.  As noted by one of the leading 20th century epidemiologists, “an opinion should be evaluated on the basis of its contents, not on the interests or credentials of the individuals who hold it.[10]”  Courageously, some scientists have fought for science to be judged on its merits.[11]

Professor Stossel and others created an organization, ACRE – The Association of Clinical Researchers and Educators, to defend legitimate interactions between Physicians and Industry. ACRE has spoken out against the lopsided demonization of the pharmaceutical industry, and the lionizing of the industry’s critics.  A few years ago, a scientist working for the pharmaceutical industry, joined Professor Rothman, to cry out against the unfairness and partiality of journals’ conflict-of-interest rules and policies.[12]  Dr. Hirsch published a strongly worded commentary that journals’ concerns are often poorly disguised prejudices against industry.  Many of the journals in question rarely or never fuss over the obvious conflicts of interest created by the “profit motive” of researchers who want to climb the academic ladder, increase their salaries, enlarge their budgets, extend their influence, travel to organizational conferences, bolster their prestige, win more grants, enhance their reputations, or advance their political goals or ideologies.

The medical profession, the courts, and the public are seriously misled by the obsession with conflicts of interest, on either side.  The obsession allows a disclosed or undisclosed conflict of interest to substitute for the much harder work of considering the merits of a study.


[1] David Michaels, Doubt is Their Product (2008).

[2] Mark B. Cope and David B. Allison, “White hat bias: examples of its presence in obesity research and a call for renewed commitment to faithfulness in research reporting,” 34 Internat’l J. Obesity 84 (2010).

[3] The works of John Ioannides explore the problem of false discovery rate and publication practices that encourage error.  See N. S. Young, J. P. Ioannidis and O. Al-Ubaydli, 2008. Why current publication practices may distort science. PLoS Medicine, 5, e20.

[4] Miquel Porta, Sander Greenland, and John M. Last, eds., A Dictionary of Epidemiology 225-26 (5th ed. 2008).

[5] Richard S. Saver, “Is It Really All About The Money? Reconsidering Non-Financial Interests In Medical Research,” 40 J. L. Med. & Ethics 467 (2012).

[6] Department of Health and Human Services, “Responsibility of Applicants for Promoting Objectivity in Research for Which Public Health Service Funding is Sought and Responsible Prospective Contractors,” 76 Fed. Reg. 53256 (Aug. 25, 2011).

[7] Id. at 53258.

[8] Institute of Medicine, Conflict of Interest in Medical Research, Education, and Practice (Washington, D.C.: The National Academies Press, 2009).

[9] Kenneth J. Rothman, “Conflict of interest: the new McCarthyism in science,” 269 J. Am. Med. Ass’n 2782 (1993).

[10] Brian MacMahon, “Epidemiology:  another perspective,” 37 Internat’l J. Epidem. 1192, 1192 (2008).

[11] See Thomas P. Stossel, “Has the hunt for conflicts of interest gone too far?” 336 Brit. Med. J. 476 (2008); Nature Publishing Group, “Nothing to see here: based on one company’s past poor publishing practices, a top-tier medical journal misguidedly stigmatizes any paper from industry,” 26 Nature Biotechnol. 476 (2008); Kenneth J. Rothman & S. Evans, “Extra scrutiny for industry funded trials: JAMA’s demand for an additional hurdle is unfair–and absurd, 331 Brit. Med. J. 1350 (2005), and 332 Brit. Med. J. 151 (2006) (erratum).

[12] Laurence J. Hirsch, “Conflicts of Interest, Authorship, and Disclosures in Industry-Related Scientific Publications: The Tort Bar and Editorial Oversight of Medical Journals,” 84 Mayo Clin. Proc. 811 (2009).

Posted in Conflicts of Interest | Comments Off on The Rhetoric and Challenge of Conflicts of Interest

Securities Fraud vs Wire Fraud

July 29th, 2013

Pharmaceutical manufacturers are particularly vulnerable to securities fraud claims arising from the manufacturers’ pronouncements about safety or efficacy, the evidence for which is often statistical in nature.  Safety claims may involve complex data sets, both from observational studies and clinical trials.  Efficacy claims are typically based upon clinical trial data.

Publicly traded manufacturers may find themselves caught between competing securities regulations.  In evaluating safety or efficacy data, manufacturers will often consult with an outside science advisory board, or report to regulatory agencies.  Securities regulations specify that any disclosure of confidential inside information to an outsider triggers an obligation of prompt public disclosure of that information.[1]  Companies also routinely seek to keep investors informed of research and marketing developments.  Generally, manufacturers will make their public disclosures through widely circulated press releases.[2]  Not surprisingly, disgruntled investors may challenge the accuracy of the press releases, when the product or drug turns out to be less efficacious or more harmful than represented in the press release.  These challenges, brought under the securities laws, often are maintained in parallel to product liability actions, sometimes in the same multi-district litigation.

Securities laws require accurate disclosure of all material information.[3]  Rule 10b-5 of the Securities Exchange Commission (SEC) prohibits any person from making “any untrue statement of material fact” or from omitting “a material fact necessary in order to make the statements made, in light of the circumstances under which they were made, not misleading.”[4]

A prima facie case of securities fraud requires that plaintiff allege and establish, among other things, a material misrepresentation or omission.[5]  The obligations to speak and to speak accurately have opened manufacturers to second guessing in their analyses of safety and efficacy data.  In most securities fraud cases, courts have given manufacturers a wide berth by rejecting differences in opinions about the proper interpretation of studies as demonstrating fraud under the securities regulations.[6]  This latitude has been given both in judgment of what test procedures to use, as well as in how best to interpret data.[7]   In Padnes v. Scios Nova Inc., the manufacturer was testing a drug for treatment of acute kidney failure.  Scios Nova issued a press release after its phase II trial, to announce a statistically significant reduction in patients’ need for dialysis.  When the early phase III results failed to confirm this result, plaintiffs sued Scios Nova for not disclosing the lack of statistically significant outcomes on other measures of kidney function, as well as for its interpretation of dialysis results as statistically significant.[8]  The trial court dismissed the complaint.[9]

Several securities fraud cases have turned on investor dissatisfaction on how companies interpreted clinical trial subgroup data.  In Noble Asset Management v. Allos Therapeutics, Inc.,[10] the company issued a press release, noting no statistically significant increase overall in survival advantage from a drug for breast cancer, but also noting a statistically significant increased survival in a non-prespecified subgroup of patients with metastatic breast cancer.[11] The plaintiff investors claimed that the company should have disclosed that the FDA was unlikely to approve an indication based upon an ad hoc subgroup analysis, but the trial court rejected this claim because FDA policy on drug approvals is public and well known.[12] The plaintiffs also complained that the press release referred to statistically significant results from a Cox multiple regression analysis rather than the log-rank (non-parametric survival) analysis required by FDA. The trial court rejected this claim as well, opining that the analysis was not misleading when the company correctly reported the raw data and the results of the Cox multiple regression analysis.[13]

Two recent appellate decisions emphasize the courts’ unwillingness to scrutinize the contested statistical methodology that underlies plaintiffs’ claims of misrepresentation.  In In re Rigel Pharmaceuticals, Inc. Securities Litigation, the plaintiff investors were dissatisfied, not with reporting of subgroups, but rather with the failure of the company to report geographic subgroup results, as well as its use of allegedly improper statistical tests and its failure to account for multiple comparisons.[14]

The Ninth Circuit affirmed the dismissal of a complaint.  The appellate court held that allegations of “statistically false p-values” were not sufficient; plaintiffs must allege facts that explain why the difference between two statements “is not merely the difference between two permissible judgments, but rather the results of a falsehood.”[15] Alleging that a company should have used a different statistical method to analyze the data from its clinical trial is not sufficient to raise an issue of factual falsity under the securities fraud statute and regulations.[16]  The Court explained that the burden was on plaintiffs to plead and prove that the difference between two statistical statements “is not merely the difference between two permissible judgments, but rather the result of a falsehood.”[17] The Court characterized the plaintiffs’ allegations to be about judgments of which statistical tests or methods are appropriate, and not about false statements.  Furthermore, the Court emphasized that the company’s statistical method was called for in the trial protocol, and was selected before the data were unblinded and provided to the company.[18]

In Kleinman v. Elan Corporation[19], the Second Circuit affirmed the dismissal of a securities fraud class action against two pharmaceutical joint venturers, which issued a challenged press release on interim phase II clinical trial results for bapineuzumab, a drug for mild- to moderate-Alzheimer’s disease.  The press release at issue announced “top line” findings and promised a full review at an upcoming international conference.[20]  According to the release, the clinical trial data did not show a statistically significant benefit on the primary efficacy end point, but “[p]ost-hoc analyses did show statistically significant and clinically meaningful benefits in important subgroups.”[21]

The plaintiffs in Kleinman complained that the clinical trial had started with crucial imbalances between drug and placebo arms, thus indicating a failure in randomization, and that the positive results had come from impermissible post-hoc subgroup analyses.[22]  The appellate court appeared not to take the randomization issue seriously, and rejected the notion that statements can be false when they represent a defendant company’s reasonable interpretation of the data, even when the interpretation later turns out to be shown to be false[23]:

“At bottom, Kleinman simply has a problem with using post-hoc analyses as a methodology in pharmaceutical studies.  Kleinman cites commentators who liken post-hoc analyses to moving the goal posts or shooting an arrow into the wall and then drawing a target around it. Nonetheless, when it is clear that a post-hoc analysis is being used, it is understood that those results are less significant and should have less impact on investors.  Our job is not to evaluate the use of post-hoc analysis in the scientific community; the FDA has already done so.”

In United States v. Harkonen[24], the government turned the law of statistical analyses in securities fraud on its head, when it prosecuted a pharmaceutical company executive for his role in issuing a press release on clinical trial data. The jury acquitted Dr. Harkonen on a charge of misbranding[25], but convicted on a single count of wire fraud.[26] Dr. Harkonen’s crime?  Bad statistical practice.

The government conceded that the data represented in the press release were accurate, as were the calculated p-values.  The chargeable offense lay in Dr. Harkonen’s describing the clinical trial results as “demonstrating a survival benefit” of the biological product (interferon γ-1b) in a clinical trial subgroup of patients with mild- to moderate-idiopathic pulmonary fibrosis.  The p-value for the subgroup was 0.004, with an effect size of 70% reduction in mortality.  The subgroup, however, was not prespecified, and was not clearly labeled as a post-hoc analysis.  The trial had not achieved statistical significant on its primary end point.

In prosecuting Dr. Harkonen, the government offered no expert witness opinion.  Instead, it relied upon a member of the clinical trial’s data safety monitoring board, who advanced a strict, orthodox view that if the primary end point of a trial “failed,” then the data could not be relied upon to infer any meaningful causal connection within secondary end points, let alone non-prespecified end points.  The prespecified survival secondary end point showed a 40 percent reduction in mortality, p = 0.08 (which shrank to 0.055 on an intent-to-treat analysis). The press release also relied upon a previous small clinical trial that showed a benefit in survival at five years, with the therapy group at 77.8%, compared with 16.7% in the control groups, p = 0.009.

The trial court accepted the government’s claim that p-values less than 0.05 were something of “magic numbers,”[27] and rejected post-trial motions for accquittal. Dr. Harkonen’s use of “demonstrate” to describe a therapeutic benefit was, in the trial court’s view, fraudulent, because of the lack of “statistical significance” on the primary end point, and the multiple testing with respect to the secondary survival end point.  The Ninth Circuit affirmed the judgment of conviction in an unpublished per curiam opinion[28].

In contrast to the criminal wire fraud prosecution, the civil fraud actions against Dr. Harkonen and the company were dismissed.[29] The prosecution and the judgment in United States v. Harkonen is at odds with the latitude afforded companies in securities fraud cases.  Furthermore, the case cannot be fairly squared with the position that the government took as an amicus curiae in Matrixx Initiatives, Inc. v. Siracusano[30], where the Solicitor General’s office, along with counsel for the Food and Drug Division of the Department of Health & Human Services, in their zeal to assist plaintiffs on claims against an over-the-counter pharmaceutical manufacturer, disclaimed the necessity, or even the importance, of statistical significance[31]:

“[w]hile statistical significance provides some indication about the validity of a correlation between a product and a harm, a determination that certain data are not statistically significant … does not refute an inference of causation.”

Suddenly, when prosecuting an unpopular pharmaceutical company executive, the government’s flexibility evaporated. Government duplicity was a much greater problem than statistical multiplicity in Harkonen.[32]

[1] Security Exchange Comm’n Regulation FD, 17 C.F.R. § 243.100 (requiring prompt  public disclosure of any confidential, material inside information after disclosed to non-insiders).

[2] Selective Disclosure and Insider Trading, Securities Act Release No. 7881, Fed. Sec. L. Rep. (CCH) ¶ 86,319 (Aug. 15, 2000) (“As a general matter, acceptable methods of public disclosure for purposes of Regulation FD will include press releases distributed through a widely circulated news or wire service . . . .”).

[3] Section 10(b) of the Exchange Act of 1934 prohibits any person “[t]o use or employ, in connection with the purchase or sale of any security . . . any manipulative or deceptive device or contrivance in contravention of such rules and regulations as the [Securities and Exchange Commission] may prescribe.”  15 U.S.C. § 78j(b).

[4] 17 C.F.R. § 240.10b-5.

[5] Stoneridge Inv. Partners LLC v. Scientific-Atlanta, 552 U.S. 148, 157 (2008) (“(1) a material misrepresentation or omission []; (2) scienter; (3) a connection between the misrepresentation or omission and the purchase or sale of a security; (4) reliance upon the misrepresentation or omission; (5) economic loss; and (6) loss causation.”)

[6] In re Medimmune, Inc. Sec. Litig., 873 F.Supp. 953, 965 (D. Md. 1995).  The biological product at issue in this case was Respivir, a polyclonal antibody product, which “significantly” reduced frequency of hospitalization for respiratory syncytial virus (RSV).  Plaintiffs alleged “flaws” in study design, but the trial court appeared to interpret the statistical significance to mean that Respivir was “unquestionably efficacious.” Id. at 967.

[7] See, e.g., Padnes v. Scios Nova Inc., No. C 95-1693 MHP, 1996 WL 539711, at *5 (N.D. Cal. Sept. 18, 1996) (Patel, J.)[cited herein as Padnes].  See also DeMarco v. DePoTech Corp., 149 F.Supp. 2d 1212, 1225 (S.D. Cal. 2001)(“Although plaintiffs have established a legitimate difference in opinion as to the proper statistical analysis, they have hardly stated a securities fraud claim.”); n re Aldor Corp. Sec. Litig., 616 F.Supp. 2d 551, 568 n.15 (E.D. Pa. 2009) (allegations as to how data should have been analyzed do not support claims for false or misleading statements).

[8] Padnes at *2.

[9] Id. at *10.

[10] 2005 WL 4161977 (D. Colo. Oct. 20, 2005).

[11] Id. at *1.

[12] Id. at *6-7.

[13] Id. at *11.

[14] 2010 WL 8816155 (N.D. Cal. Aug. 24, 2010).

[15] 697 F.3d 869, 877 (9th Cir. 2012) (internal citations omitted), aff’g 2010 WL 8816155 (N.D. Cal. Aug. 24, 2010).

[16] Id. at 877-78.

[17] Id. at 878.

[18] Id. (“Because there are many ways to statistically analyze data, it is necessary to choose the statistical methodology before seeing the data that is collected during the trial; otherwise someone can manipulate the unblinded data to obtain a favorable result.”), citing and attempting to distinguish United States v. Harkonen, 2010 WL 2985257, at *4 (N.D. Cal. July 27, 2010).

[19] 706 F.3d 145 (2d Cir. 2013).

[20] Id. at 149.

[21] Id. at 149-50 (also noting that the press release provided a “preliminary analysis,” which might be less favorable upon further analysis).

[22] Id. at 150.

[23] Id. at 154-55 & 155n.11 (citing and quoting FDA Center for Drug Evaluation and Research:  E9 Statistical Principles for Clinical Trials, 63 Fed. Reg. 49583, 49595 (Sept. 16, 1998), that post-hoc analyses are exploratory and “unlikely” to be accepted as support of efficacy.)

[24] United States v. Harkonen, 2010 WL 2985257 (N.D. Calif. 2010) ((Patel, J.) (denying defendant’s post–trial motions to dismiss the indictment, for acquittal, or for a new trial).  Sometimes judges are looking for bright lines in the wrong places).

[25] 21 U.S.C. §§ 331(k), 333(a)(2), 352(a).

[26] 18 U.S.C. § 1343.

[27] United States v. Harkonen, 2010 WL 2985257, at *5 (N.D. Calif. 2010).

[28] United States v. Harkonen, 2013 WL 782354 (9th Cir. 2013).

[29] In re Actimmune Marketing Litig., 2010 WL 3463491 (N.D. Cal. Sept. 1, 2010), aff’d,  464 Fed.Appx. 651 (9th Cir. 2011).

[30] 131 S. Ct. 1309 (2011).

[31] Brief for the United States as Amicus Curiae Supporting Respondents, in Matrixx Initiatives, Inc. v. Siracusano, 2010 WL 4624148, at *14 (Nov. 12, 2010).

[32] Dr. Harkonen is expected to petition the Supreme Court for certiorari on statutory and constitutional grounds.  See Alex Kozinski & Stuart Banner, “Who’s Afraid of Commercial Speech?” 76 VA. L. REV. 627, 635 (1990) (“[T]here are many varieties of noncommercial speech that are just as objective as paradigmatic commercial speech and yet receive full first amendment protection. Scientific speech is the most obvious; much scientific expression can easily be labeled true or false, but we would be shocked at the suggestion that it is therefore entitled to a lesser degree of protection. If you want, you can proclaim that the sun revolves around the earth, that the earth is flat, that there is no such thing as nitrogen, that flounder smoke cigars, that you have fused atomic nuclei in your bathtub — you can spout any nonsense you want, and the government can’t stop you.”).

 

Posted in statistical evidence | Comments Off on Securities Fraud vs Wire Fraud

Using the Rule 45 Subpoena to Obtain Research Data

July 24th, 2013

Back in June, Mr. William Ruskin posted a blog post, “When Should Data Underlying Scientific Studies Be Discoverable?” on his firm’s Toxic Tort Litigation Blog.  Earlier this week, the Defense Research Institute’s blog, dri-today republished the post, and I posted a response, “Research Data from Published Papers Generally Should Be Available,” on the DRI blog.

Mr. Ruskin’s blog post calls attention to the important problem of access to research data in litigation and other contexts.  The effort to obtain Dr. Racette’s underlying data is an interesting case study in these legal discovery battles.  Ruskin notes that there is the potential for “injustice” from such discovery, but he fails to acknowledge that the National Research Council has been urging scientists for decades to have a plan for data sharing as part of their protocol, and that the National Institutes of Health now requires such planning.  Some journals require a commitment to data sharing as a condition to publication.  The Annals of Internal Medicine, which is probably the most rigorously edited internal medicine journal, requires authors to state to what extent they will share data when their articles appear in print. Ultimately, litigants are entitled to “everyman’s” and “every woman’s” evidence, regardless whether they are scientists. If scientists complied with the best practices, guidances, and regulations on planning for data sharing, the receipt of a subpoena for underlying data would not be a particularly disruptive event in their laboratories.

In the case of Dr. Racette, it was clear that the time he needed to spend to respond to defense counsel’s subpoena was largely caused by his failure to comply with NIH guidelines on data sharing.  Racette was represented by university counsel, who refused to negotiate over the subpoena, and raised frivolous objections. Ultimately, the costs of production were visited upon the defendants who paid what seemed like rather exorbitant amounts for Racette and his colleagues to redact individual identifier information.  The MDL court suggested that Racette was operating independently of plaintiffs’ counsel, but the fact was that plaintiffs’ counsel recruited the study participants and brought them to the screenings, where Racette and colleagues videotaped them to make their assessments of Parkinsonism.  Much more could be said but for a protective order that was put in place by the MDL court.  What I can say is that after the defense obtained a good part of the underlying data, the Racette study was no longer actively used by plaintiffs’ counsel in the welding fume cases.

It is not only litigation that gives rise to needs for transparency and openness. Regulation and public policy disputes similarly create need for data access.  As Mr. Ruskin acknowledges, the case of Weitz & Luxenberg v. Georgia-Pacific LLC, 2013 WL 2435565, 2013 NY Slip Op 04127 (June 6, 2013), is very different, but at bottom is the same secrecy and false sense of entitlement to privilege underlying data. The Appellate Division’s invocation of the crime-fraud exception seems to be hyperbolic precisely because no attorney-client privilege attached in the first place. Basic tenets of openness and transparency in science should have guided the Appellate Division.

The Georgia-Pacific effort was misguided on many levels, but we should at least rejoice that science won, and that G-P will be required to share underlying data with plaintiffs’ counsel or whoever wants access. Without reviewing the underlying data and documents, it is hard to say what the studies were designed to do, but saying that they were designed “to cast doubt,” as Mr. Ruskin does, is uncharitable to G-P. After all, G-P may well have found itself responding in court to some rather dodgy data, and thought it could sponsor stronger studies that were likely to refute the published papers.  And the published papers may have been undertaken to “cast certainty,” or even a faux certainty, over issues that were not what they were portrayed to be in the papers.

Earlier this month, Judge Reggie Walton granted a motion to compel a litigant’s motion for underlying research in the denture cream litigation.  Plaintiffs’ counsel contracted with Dr. Salim Shah and his companies Sarfez Pharmaceuticals, Inc. and Sarfez USA, Inc. (“Sarfez”) to conduct human research in India, to support their claims that zinc in denture cream causes neurological damage.  In re Denture Cream Prods. Liab. Litig., Misc. Action 13-384 (RBW), 2013 U.S. Dist. LEXIS 93456, *2 (D.D.C. July 3, 2013).  When defense counsel learned of the Sarfez study, known as the Zinc/077/12 Study, and the plaintiffs’ counsel’s payments of over $300,000, to support the study, they sought discovery of raw data, study protocol, statistical analyses, and other materials from plaintiffs’ counsel.  Plaintiffs’ counsel protested that they did not have all the materials, and directed defense counsel to Sarfez.  Although other courts have made counsel produce similar materials from the scientist independent contractors they engaged, in this case, defense counsel followed the trail of documents to contractor, Sarfez.  Id. at *3-4.

After serving a Rule 45 subpoena on Sarfez, things got interesting.  Raising no objections, and asserting no privileges, Sarfez served about 1,500 pages of responsive documents.  Some of the documents were emails, but crucial attachments were missing, including protocols, analytical reports, and raw data.  Id. at *12-13.  When the defendant, Proctor & Gamble Company (P&G) pressed, Sarfez resisted further production.  P&G filed a motion to compel, and Sarfez objected on various  grounds, including lack of relevancy.

The objections did not go very far.  Plaintiffs’ counsel, who probably should have been tasked with producing the subpoenaed materials in the first instance, had already declared their intent to rely upon the study that they contracted for with Sarfez.  Id. at *9. Judge Walton noted that relevancy did not require that the subpoenaed materials be admissible at trial, but only that they may be relevant to the claim or defense of a party.  Id. at *6.  Judge Walton also upheld the subpoena, which sought underlying data and non-privileged correspondence, to be within the scope of Rules 26(b) and 45, and not unduly burdensome. Id. at *9-10, *20.

Sarfez attempted to suggest that the email attachments might not exist, but Judge Walton branded the suggestion “disingenuous.”  Attachments to emails should be produced along with the emails.  Id. at *12 (citing and collecting cases). Although Judge Walton did not grant a request for forensic recovery of hard-drive data or for sanctions, His Honor warned Sarfez that it might be required to bear the cost of forensic data recovery if it did not comply the district court’s order.  Id. at *15, *22.

The Denture Cream case is a helpful reminder that not only industrial defendants sponsor scientific studies in litigation contexts.  Plaintiffs’ counsel, and sometimes their interest proxies — labor unions, support groups, advocacy groups, zealous scientists, and regulatory agencies — sponsor and conduct studies as well.  Proctor & Gamble should not have been put to the expense and trouble of a Rule 45 subpoena, but it is encouraging to see that Judge Walton cut through the evasions and disingenuous claims, and enforced the research subpoena in this case.

 

Posted in Rule 703, Underlying Data | Comments Off on Using the Rule 45 Subpoena to Obtain Research Data

THE COUNCIL FOR EDUCATION AND RESEARCH ON TOXICS

July 9th, 2013

When the Milward case hit the U.S. Court of Appeals for the First Circuit, it attracted the attentions of an amicus, the Council for Education and Research on Toxics (CERT).  I had never heard of CERT before, and the amicus brief filed by CERT was rather sketchy on the nature of the organization.

A bit of research on CERT revealed the following.  It is a non-profit California corporation, EIN: 42-1571530, founded in 2003.  CERT has a business address at:

401 E Ocean Blvd., Ste. 800, Long Beach, California 90802-4967

And a telephone number:  1-877-TOX-TORT

CERT’s mission statement? Furthering scientific understanding of toxins.

Plaintiffs’ lawyer Ralph Metzger is noted as the contact person for CERT.

Given its phone number and its contact person, one might think that its mission statement was “furthering legal positions on toxins.”

But wait; it gets better.  Ralphael Metzger, at the same Long Beach, California, address is the attorney for CERT on its amicus brief in Milward!

The potential conflicts grow deeper and wider.  Metzger has represented CERT, which shares at least his offices, if not his alter ego, in lawsuits including CERT v. Brad Berry Co., Ltd., No. BC461182 (Cal. Super. Ct., Los Angeles County, Cent. Dist., filed May 9, 2011), and CERT v. Starbucks Corp., BC435759 (L.A. Super. Ct., filed April 13, 2010).

CERT has sued McDonald’s and Burger King over its claim that their french fries contained high levels of acrylamide, a chemical “known” to the State of California to cause cancer. CERT has sued Chemtura on claims that the company’s chemical fire-preventive products, known as PBDEs, cause injuries to wildlife and humans.

Although not definitive, it seems that CERT’s mission is not exactly scientific, and the description of its interests in its Milward brief just a tad misleading.

In addition to the CERT, the other amici joining the brief include:

Nicholas A. Ashford,
Nachman Brautbar,
David C. Christiani,
Richard W. Clapp,
James Dahlgren,
Devra Lee Davis,
Malin Roy Dollinger,
Brian G. Durie,
David A. Eastmond,
Arthur L. Frank,
Frank H. Gardner,
Peter L. Greenberg,
Robert J. Harrison,
Peter F. Infante,
Philip J. Landrigan,
Barry S. Levy,
Melissa A. McDiarmid,
Myron Mehlman,
Ronald L. Melnick,
Mark Nicas,
David Ozonoff,
Stephen M. Rappaport,
David Rosner,
Allan H. Smith,
Daniel Thau Teitelbaum,
Janet Weiss, and
Luoping Zhang

An interesting bunch; eh?  Page two of the amicus brief tells us that:

“None of the amici has any financial or other similar interest in the outcome of this lawsuit. Amici appear on their own behalf to inform this Court of the substantial medical knowledge and understanding of leukemia arising from exposure to benzene.”

That’s probably true for the Milward case itself, but more interesting for what the disclosure does not say.  Many of the amici have testified frequently in toxic tort cases, and several have been excluded by the straightforward application of Rule 702 or its state counterparts.  Some have lost income as a result of judicial gatekeeping, and most have seen their advocacy science curtailed by such gatekeeping.

Appendix I to the brief provides further information on the amici, but there is no mention of their testimonial adventures, their financial stake in expert witnessing, or their political or positional commitments.

I suppose from CERT you get CERT-i-tude, a certain kind of attitude.

Posted in Conflicts of Interest, Rule 702 | Comments Off on THE COUNCIL FOR EDUCATION AND RESEARCH ON TOXICS

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