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More Antic Proposals for Expert Witness Testimony – Including My Own Antic Proposals

December 30th, 2014

The late Professor Margaret Berger epitomized a person you could like and even admire, while finding many of her ideas erroneous, incoherent, and even dangerous. Berger was frequently on the losing side of expert witness admissibility issues, and she fell under the influence of the plaintiffs’ bar, holding conferences with their walking-around money, laundered through SKAPP, The Project on Scientific Knowledge and Public Policy.[1] In appellate cases, Berger often lent the credibility of her scholarship to support plaintiffs’ efforts to strip away admissibility criteria for expert witness causation opinion.[2] Still, she was always polite and respectful in debate. When Judge Weinstein appointed her to chair a committee to search for appropriate court-appointed expert witnesses in the silicone gel breast implant litigation, Professor Berger proved a careful, impartial listener to all the parties involved.

In 2009, before the publication of the Third Edition of the Reference Manual on Scientific Evidence, Professor Berger gave a presentation for an American Law Institute continuing legal education program, in which she aired her antipathy toward gatekeeping.[3] With her sights set primarily on defense expert witnesses, Berger opined that a monetary relationship between an expert witness and the defendant could be grounds for a Rule 702 exclusion. While the jingle of coin doth soothe the hurt that conscience must feel (for some expert witnesses), the focus of the Rule 702 inquiry is properly on relevance, reliability, and validity. Judge Shira Scheindlin, who sat on the same panel as Professor Berger, diplomatically pointed out that employee expert witnesses are offered all the time, and any bias is a subject for cross-examination, not disqualification. Remarkably, neither Professor Berger nor Judge Scheindlin acknowledged that conflicts of interest, actual or potential, are not relevant to the Daubert or Rule 702 factors that guide admissibility. If Berger’s radical position of identifying conflict of interest with unreliability were correct, we might dismiss her views without any consideration[4], given her conflicts of interest from her association with SKAPP, and her several amicus briefs filed on behalf of plaintiffs, seeking to avoid the exacting requirements of expert witness evidence gatekeeping.

In her ALI-CLE lecture, Professor Berger waxed enthusiastically about what was then a recent federal trial court decision in Allen v. Martin Surfacing, 263 F.R.D. 47 (D. Mass. 2009). Berger asserted that the case was unpublished and that the case, like many other “Daubert” cases was hidden from view. Berger thought that Allen’s obscurity was unfortunate because the decision was “fabulous” and was based upon astute opinions of “outstanding” experts[5]. Berger was wrong on every point, from the chemical involved, to the unavailability of the opinion, to the quality of the expert witnesses (who were not ALS experts, but frequent, willing testifiers), and to the carefulness of the exposure and causation opinions offered.[6] See James L. Bernat & Richard Beresford, Ethical and Legal Issues in Neurology 59-60 (Amsterdam 2013) (discussing Allen and characterizing the court’s decision to admit plaintiffs’ expert witnesses’ opinions as based upon plausibility without more).

Implicit in Berger’s errors, however, may be the beginnings of some concrete suggestions for improving the gatekeeping process. After all, Berger thought that no one would likely find and read the Allen decision.  She may have thus believed that she had some freedom from scrutiny when she praised the decision and the expert witnesses involved. Just as there is a groundswell of support for greater disclosure of underlying data to accompany scientific publications, there should be support for wide dissemination of the underlying materials behind Rule 702 opinions. Most judges cannot or will not write sufficiently comprehensive opinions describing and supporting their decisions to admit or exclude expert witness opinion to permit vigorous public scrutiny. Some judges fail to cite to the underlying studies or data that are the bases of the challenged opinions. As a result, the “Daubert” scholarship suffers because it frequently lacks access to the actual reports, testimony, studies, and data themselves. Often the methodological flaws discussed in judicial opinions are just the tip of the iceberg, with flaws running all the way to the bottom.

And while I am on “antic proposals” of my own, courts should consider requiring all parties to file proposed findings of fact and conclusions of law, with record cites, to support their litigation positions. Lawyers on both sides of the “v.” have proven themselves cavalier and careless in their descriptions and characterizations of scientific evidence, inference, and analysis. Proposed findings would permit reviewing courts, scientists, and scholars to identify errors for the benefit of appellate courts and later trial courts.

 

[1] SKAPP claimed to have aimed at promoting transparent decision making, but deceived the public with its disclosure of having been supported by the “Common Benefit Trust, a fund established pursuant to a court order in the Silicone Gel Breast Implant Products Liability litigation.” Somehow SKAPP forgot to disclose that this court order simply created a common-benefit fund for plaintiffs’ lawyers to pursue their litigation goals. How money from the silicone gel breast implant MDL was diverted for advocated anti-Daubert policies is a mystery that no amount of transparent decision making has to date uncovered. Fortunately, for the commonweal, SKAPP appears to have been dissolved. The SKAPP website lists those who guided and supported SKAPP’s attempts to subvert expert witness validity requirements; not surprisingly, the SKAPP supporters were mostly plaintiffs’ expert witnesses:

Eula Bingham, PhD
Les Boden, PhD
Richard Clapp, DSc, MPH
Polly Hoppin, ScD
Sheldon Krimsky, PhD
David Michaels, PhD, MPH
David Ozonoff, MD, MPH
Anthony Robbins, MD, MPA

[2] See, e.g., Parker v. Mobil Oil Corp., N.Y. Ct. App., Brief Amicus Curiae of Profs. Margaret A. Berger, Edward J. Imwinkelried, Sheila Jasanoff, and Stephen A. Saltzburg (July 28, 2006) (represented by Anthony Z. Roisman, of the National Legal Scholars Law Firm).

[3] Berger, “Evidence, Procedure, and Trial Update: How You Can Win (Or Lose) Your Case (Expert Witnesses, Sanctions, Spoliation, Daubert, and More)” (Mar. 27, 2009).

Berger, “Evidence, Procedure, and Trial Update: How You Can Win (Or Lose) Your Case (Expert Witnesses, Sanctions, Spoliation, Daubert, and More)” (Mar. 27, 2009).

[4] We can see this position carried to its natural, probable, and extreme endpoint in Elizabeth Laposata, Richard Barnes, and Stanton Glantz, “Tobacco Industry Influence on the American Law Institute’s Restatements of Torts and Implications for Its Conflict of Interest Policies,” 98 Iowa Law Rev. 1 (2012), where the sanctimonious authors, all anti-tobacco advocates criticize the American Law Institute for permitting the participation of lawyers who represent tobacco industry. The authors fail to recognize that ALI members include lawyers representing plaintiffs in tobacco litigation, and that it is possible, contrary to their ideological worldview, to discuss and debate an issue without reference to ad hominem “conflicts” issues. The authors might be surprised by the degree to which the plaintiffs’ bar has lobbied (successfully) for many provisions in various Restatements.

[5] Including Richard Clapp, who served as an advisor to SKAPP, which lavished money on Professor Berger’s conferences.

[6] See “Bad Gatekeeping or Missed Opportunity – Allen v. Martin Surfacing” (Nov. 30, 2012); “Gatekeeping in Allen v. Martin Surfacing — Postscript” (April 11, 2013).

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New Standard for Scientific Evidence – The Mob

December 27th, 2014

A few years ago, a law student published a Note that argued for the dismantling of judicial gatekeeping.  Note, “Admitting Doubt: A New Standards for Scientific Evidence,” 123 Harvard Law Review 2021 (2010).  The anonymous Harvard law student asserted that juries are at least as good, if not better, at handling technical questions than are “gatekeeping” federal trial judges. The empirical evidence for such a suggestion is slim, and ignores the geographic variability in jury pools.

To be sure, some jurors have much greater scientific and mathematical aptitude than some judges, but the law student’s run at Rule 702 ignores some important institutional differences between judges and juries, including that judicial errors are subject to scrutiny and review, and public comment based upon written judicial opinions. Most judges have 20 years of schooling and 10 years of job experience, which should account for some superiority.

Misplaced Sovereignty

Another student this year has published a much more sophisticated version of the Harvard student’s Note, an antic proposal with a similar policy agenda that would overthrow the regime of judicial scrutiny and gatekeeping of expert witness opinion testimony. Krista M. Pikus, “We the People: Juries, Not Judges, Should be the Gatekeepers of Expert Evidence,” 90 Notre Dame L. Rev. 453 (2014). This more recent publication, while conceding that judges may be no better than juries at evaluating scientific evidence, asserts that jury involvement is required by a political commitment to popular sovereignty. Ms. Pikus begins with the simplistic notion that:

“[o]ur system of government is based on the idea that the people are sovereign.”

Id. at 470. Since juries are made up of people, jury determinations are required to implement popular sovereignty.

This notion of sovereignty is really quite foreign to our Constitution and our system of government. “We, the People” generally do not make laws or apply them, with the exception of grand and petit jury factual determinations. The vast legislative and decision making processes are entrusted to Congress, the Executive, and the ever-expanding system of administrative agencies. The Constitution was indeed motivated to prevent governmental tyranny, but mob rule was not an acceptable alternative. For the founders, juries were a bulwark of liberty, and a shield against an overbearing Crown. Jurors were white men who owned property.

Pikus argues that judges somehow lack the political authority to serve as fact finders because they are not elected, but in some states judges are elected, and in other states and in the federal system, judges are appointed and confirmed by elected officials. Juries are, of course, not elected, and with many jurisdictions permitting juries of six persons or fewer, juries are hardly representative of the “popular sovereign.” The systematic exclusion of intelligent and well-educated jurors by plaintiffs’ counsel, along with the aversion to jury service by self-employed and busy citizens, helps ensure that juries fail to represent a fair cross-section of the population. Curiously, Pikus asserts that the “right to a trial by one’s peers is an integral part of our legal system,” but the peerage concept is nowhere in the Constitution. If it were, defendants in complicated tort cases might well have a right to juries composed of scientists or engineers.

The Right to Trial by Jury

There is, of course, a federal constitutional right to trial by jury, guaranteed by the Seventh Amendment:

“In Suits at common law … the right of trial by jury shall be preserved, and no fact tried by a jury shall be otherwise reexamined in any Court of the United States, than according to the rules of the common law.”

A strict textualist might hold that federal courts could dispense with juries in cases brought under statutory tort legislation, such as the New Jersey Products Liability Act, or for claims or defenses that were not available at the time the Seventh Amendment was enacted. Even the textualist might hold that the change in complexity of fact-finding endeavors, over two centuries, might mean that both the language and the spirit of the Seventh Amendment point away from maintaining the jury in cases of sufficient complexity.

Judges versus Juries

The fact is that judges and juries can, and do, act tyrannically, in deciding factual issues, including scientific and technical issues. Ms. Pikus would push the entire responsibility for ensuring accuracy in scientific fact finding to the least reviewable entity, the petit jury. Juries can ignore facts, decide emotively or irrationally, without fear of personal scrutiny or criticism. Pikus worries that judges “insert their policy opinions into their decisions,” which they have been known to do, but she fails to explain why we should tolerate the same from unelected, unreviewable juries. Id. at 472.

Inconsistently, Pikus acknowledges that “many can agree that some cases might be better suited for a judge instead of a jury,” such as “patent, bankruptcy, or tax” cases that “typically require additional expertise.” Id. at 471 & n. 185. To this list, we could add family law, probate, and equity matters, but the real question is what is it about a tax case that makes it more intractable to a jury than a products case. State power is much more likely to be abused or at issue in a tax case than in a modern products liability case, with a greater need for a “bulwark of liberty”. And the products liability case is much more likely to require scientific and technical expertise than a tax case.

The law of evidence, in federal and in most state courts, permits expert witnesses to present conclusory opinions, without having to account for the methodological correctness of their relied-upon studies, data, and analyses. Jurors, who are poorly paid, and pulled away from their occupations and professions, do not have the aptitude, patience, time, or interest to explore the full range of inferences and analyses performed by expert witnesses. Without some form of gatekeeping, trial outcomes are reduced to juror assessment of weak, inaccurate proxies for scientific determinations.

Pikus claims that juries, and only juries, should assess the reliability of an expert witness’s testimony. Id. at 455. As incompetent as some judges may be in adjudicating scientific issues, their errors are on display for all to see, whereas the jury’s determinations are opaque and devoid of public explanation. Judges can be singled out for technical competency, with appropriate case assignments, and they can be required to participate in professional legal education, including training in statistics, epidemiology, toxicology, genetics, and other subjects. It is difficult to imagine a world in which the jurors are sent home with the Reference Manual on Scientific Evidence, before being allowed to sit on a case. Nor is it feasible to have lay jurors serve on an extended trial that includes a close assessment of the expert witnesses’ opinions, as well as all the facts and data underlying those opinions.

Pikus criticizes the so-called “Daubert” regime as a manifestation of judicial activism, but she ignores that Daubert has been subsumed into an Act of Congress, in the form of a revised and expanded Federal Rules of Evidence.

In the end, this Note, like so much of the anti-Daubert law review literature is a complaint against removing popular, political, and emotive fact finding from technical and scientific issues in litigation. To the critics, science has no criteria of validity which the law is bound to respect. And yet, as John Adams argued before the Revolution:

“Facts are stubborn things; and whatever may be our wishes, our inclinations, or the dictates of our passion, they cannot alter the state of facts and evidence[1].”

Due process requires more than the enemies of Daubert would allow.

[1] John Adams, “Argument in Defense of the Soldiers in the Boston Massacre Trials” (Dec. 1770)

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When is a Treating Physician Not a Treating Physician?

December 25th, 2014

When the so-called treating physician is handpicked by an attorney to advance his client’s lawsuit. See Daniel E. Cummins, “Did Your Attorney Refer You to that Doctor?” (Dec. 17, 2014).

Treating physicians are a powerful weapon in health-effects litigation because they can deliver what appears to opinions untainted by “litigation bias.” Jurors and judges, challenged by difficult medical causation issues, find the caring attitude of treating physicians as a powerful proxy for the truth, which alleviates the need to think critically and carefully about epidemiology, statistics, toxicology, and the like. Of course, some treating physicians are biased by their care and treatment of the patient, especially when their treatment did not go so well. Physicians who were not able to cure or ameliorate their patients’ conditions may welcome the opportunity to advocate for their patients to give them, or their survivors, to make up for their failure to help through the healing arts. Patient-advocacy bias, however, is more difficult to appreciate than hired-expert witness bias.

Plaintiffs’ counsel often base their litigation strategy upon using treating physicians on causation or damages issues to take advantage of jurors’ and judges’ perceptions of treating physicians as motivated by beneficence rather than lucre[1]. Of course, there are dangers in these tactics. For one thing, the treating physicians, as in Tamraz v. Lincoln Elec. Co., may not really be up to the task of delivering a causation opinion, and the plaintiffs’ counsel’s cynical tactic will make a weaker case weaker still in the eyes of the jury. And then the treating physician may not subscribe fully to the plaintiffs’ lawyer’s litigation goals and theories[2]. See “Politics of Expert Witnesses – The Treating Physician” (June 7, 2012).

Plaintiffs’ counsel may attempt to avoid the weaknesses of their treating physician strategy by selecting a carefully screened physician, ready to endorse plaintiffs’ litigation theories, and then to refer the claimant to this physician under cover of an asserted attorney-client privilege. A recent trial court in Pennsylvania, however, dealt a serious blow to this covert strategy by holding that the lawyer’s directing of his client’s medical care is not within the scope of the attorney-client relationship, and thus not a privileged communication. English v. Stepchin, No. CP-23-CV-786-2014, 101 Del. 424 (C.P. Del. Cty. Nov. 12, 2014 Kenney, P.J.). In English, plaintiff’s counsel asserted the privilege and objected to defense counsel’s deposition question whether plaintiff’s counsel had referred plaintiff to her treating physician.

On motion to compel discovery, Delaware County President Judge Chad F. Kenney overruled the objection, and held that “whether counsel referred Plaintiff to her treating physicians does not constitute legal assistance so as to justify properly invoking the attorney-client privilege.” As Judge Kenney explained:

“Clearly, whether counsel referred Plaintiff to her treating physicians is not a communication involved in either rendering a legal opinion or securing legal services. Furthermore, we conclude that the communication of such information does not constitute assistance in a legal matter so as to properly invoke the attorney-client privilege.

* * *

The disclosure of such information is not of a nature as would discourage trust or candid communication between a lawyer and a client and we are of the opinion that it does not outweigh the interest in the accessibility of material evidence to further the truth determining process.”

Id. at 425. The assertion of the attorney-client privilege was thus rejected, and the plaintiff was required to provide details as to how she came to go to her so-called treating physician.

The English decision represents a symmetrical paring of the attorney-client privilege to match the limitations imposed by other recent decisions on defense counsel. See, e.g., In re Vioxx Prods. Liab. Litig., 501 F. Supp. 2d 789, 800, 802 (E.D.La. 2007)(“We could not see the legal significance of these comments…” by in-house counsel on “scientific reports, articles accepted for publication in noted journals, and research proposals”); Weitz & Luxenberg P.C. v. Georgia-Pacific LLC, 2013 WL 2435565, 2013 NY Slip Op 04127 (June 6, 2013).

[1] See, e.g., Simmons v. Novartis Pharm. Corp., 2012 WL 2016246, *2, *7 (6th Cir. 2012) (affirming exclusion of retained expert witness, as well as a treating physician who relied solely upon a limited selection of medical studies given to him by plaintiffs’ counsel); Tamraz v. BOC Group Inc., No. 1:04-CV-18948, 2008 WL 2796726 (N.D.Ohio July 18, 2008)(denying Rule 702 challenge to treating physician’s causation opinion), rev’d sub nom. Tamraz v. Lincoln Elec. Co., 620 F.3d 665 (6th Cir. 2010) (carefully reviewing record of trial testimony of plaintiffs’ treating physician; reversing judgment for plaintiff based in substantial part upon treating physician’s speculative causal assessment created by plaintiffs’ counsel), cert. denied, 131 S. Ct. 2454 (2011).  See generally Robert Ambrogi, “A ‘Masterly’ Opinion on Expert Testimony,” Bullseye: October 2010; David Walk, “A masterly Daubert opinion” (Sept. 15, 2010);  Ellen Melville, “Comment, Gating the Gatekeeper: Tamraz v. Lincoln Electric Co. and the Expansion of Daubert Reviewing Authority,” 53 B.C. L. Rev. 195 (2012) (student review that mistakenly equates current Rule 702 law with the Supreme Court’s 1993 Daubert decision, while ignoring subsequent precedent and revision of Rule 702).

[2] In the welding fume litigation, inspired by the money and tactics of ex-convict Richard Scruggs, plaintiffs’ counsel adopted a dual strategy of co-opting a local treating physician, and alternatively, having their ready, willing, and able retained expert witness, Dr. Paul Nausieda, claim that he had created a physician-patient relationship with the claimant.

 

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First Amendment Rights of the Litigation Industry

December 21st, 2014

When a Wall Street Journal opinion piece stated that “the plaintiffs bar is all but running the Senate[1],” Frederick Martin (“Fred”) Baron, former president of the litigation industry’s Association of Trial Lawyers of America (ATLA), reportedly quipped that “I really, strongly disagree with that. Particularly the ‘all but’.” Baron, affectionately known as “Robber Baron” for his aggressive advocacy for uninjured asbestos claimants and questionable deposition coaching tactics, was the ultimate Democratic party insider. He was the finance chair of John Edwards’ ill-fated presidential campaign, and the sugar daddy for Rielle Hunter, the mother of Edwards’ out-of-wedlock child. You cannot get more “inside” than that.

Robber Baron died in 2008, but his legacy is a reminder of the hypocrisy of those who decry the Citizens United[2] opinion, which held that corporations and unions have first amendment rights to speak in ways that might influence the outcomes of elections. While many fuss over “corporate” speech, the litigation industry has operated largely without constraint. Last year, for example, plaintiffs’ counsel, Edward F. Blizzard, and representatives of the litigation industry’s ATLA, now operating under the self-serving name, American Association for Justice (AAJ), met with Food and Drug Administration officials to influence agency policy on generic medication warnings. This week, the Times featured front-page coverage of how the litigation industry has co-opted the policies and agendas of the States’ attorneys general, and directed their targeting of corporations. See Eric Lipton, “Lawyers Create Big Paydays by Coaxing Attorneys General to Sue,” New York Times (Dec. 18, 2014).

The litigation industry makes its presence felt in many ways, sometimes as an omnipresent threat that influences business and professional judgments. President Obama criticized Sony’s decision to pull down The Interview, as an undue concession to terrorists. See “Sony’s Decision to Pull Movie Is a ‘Mistake,’ Obama Says.” Obama went so far as to express his wish that “they’d spoken to me first.” But would Obama, or anyone, have been able to control the litigation industry’s second-guessing of Sony’s or any individual theater owner’s decision to show the movie?

Lipton’s article is a vivid reminder that the plaintiffs’ trial bar remains the largest rent-seeking lobby in the United States.

[1] John Fund, “Have You Registered to Sue?” Wall Street Journal (Nov. 6, 2002).

[2] Citizens United v. Federal Election Comm’n, 558 U.S. 310 (2010).

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Showing Causation in the Absence of Controlled Studies

December 17th, 2014

The Federal Judicial Center’s Reference Manual on Scientific Evidence has avoided any clear, consistent guidance on the issue of case reports. The Second Edition waffled:

“Case reports lack controls and thus do not provide as much information as controlled epidemiological studies do. However, case reports are often all that is available on a particular subject because they usually do not require substantial, if any, funding to accomplish, and human exposure may be rare and difficult to study. Causal attribution based on case studies must be regarded with caution. However, such studies may be carefully considered in light of other information available, including toxicological data.”

F.J.C. Reference Manual on Scientific Evidence at 474-75 (2d ed. 2000). Note the complete lack of discussion of base-line risk, prevalence of exposure, and external validity of the “toxicological data.”

The second edition’s more analytically acute and rigorous chapter on statistics generally acknowledged the unreliability of anecdotal evidence of causation. See David Kaye & David Freedman, “Reference Guide on Statistics,” in F.J.C. Reference Manual on Scientific Evidence 91 – 92 (2d ed. 2000).

The Third Edition of the Reference Manual is even less coherent. Professor Berger’s introductory chapter[1] begrudgingly acknowledges, without approval, that:

“[s]ome courts have explicitly stated that certain types of evidence proffered to prove causation have no probative value and therefore cannot be reliable.59”

The chapter on statistical evidence, which had been relatively clear in the second edition, now states that controlled studies may be better but case reports can be helpful:

“When causation is the issue, anecdotal evidence can be brought to bear. So can observational studies or controlled experiments. Anecdotal reports may be of value, but they are ordinarily more helpful in generating lines of inquiry than in proving causation.14”

Reference Manual at 217 (3d ed. 2011). The “generally” is given no context or contour for readers. These authors fail to provide any guidance on what will come from anecdotal evidence, or when and why anecdotal reports may do more than merely generating “lines of inquiry.”

In Matrixx Initiatives Inc. v. Siracusano, 131 S. Ct. 1309 (2011), the Supreme Court went out of its way, way out of its way, to suggest that statistical significance was not always necessary to support conclusions of causation in medicine. Id. at 1319. The Court cited three Circuit court decisions to support its suggestion, but two of three involved specific causation inferences from so-called differential etiologies. General causation was assumed in those two cases, and not at issue[2]. The third case, the notorious Wells v. Ortho Pharmaceutical Corp., 788 F. 2d 741, 744–745 (11th Cir. 1986), was also cited in support of the suggestion that statistical significance was not necessary, but in Wells, the plaintiffs’ expert witnesses actually relied upon studies that claimed at least nominal statistical significance. Wells was and remains representative of what is possible and results when trial judges ignore the constraints of study validity. The Supreme Court, in any event, abjured any intent to specify “whether the expert testimony was properly admitted in those cases [Wells and others],” and the Court made no “attempt to define here what constitutes reliable evidence of causation.” 131 S. Ct. at 1319.

The causal claim in Siracusano involved anosmia, loss of the sense of smell, from the use of Zicam, zinc gluconate. The case arose from a motion to dismiss the complaint; no evidence was ever presented or admitted. No baseline risk of anosmia was pleaded; nor did plaintiffs allege that any controlled study demonstrated an increased risk of anosmia from nasal instillation of zinc gluconate. There were, however, clinical trials conducted in the 1930s, with zinc sulfate for poliomyelitis prophylaxis, which showed a substantial incidence of anosmia in the treated children[3]. Matrixx tried to argue that this evidence was unreliable, in part because it involved a different compound, but this argument (1) in turn demonstrated a factual issue that required discovery and perhaps a trial, and (2) traded on a clear error in asserting that the zinc in zinc sulfate and zinc gluconate were different, when in fact they are both ionic compounds that result in zinc ion exposure, as the active constituent.

The position stridently staked out in Matrixx Initiatives is not uncommon among defense counsel in tort cases. Certainly, similar, unqualified statements, rejecting the use of case reports for supporting causal conclusions, can be found in the medical literature[4].

When the disease outcome has an expected value, a baseline rate, in the exposed population, then case reports simply confirm what we already know: cases of the disease happen in people regardless of their exposure status. For this reason, medical societies, such as the Teratology Society, have issued guidances that generally downplay or dismiss the role that case reports may have in the assessment and determination of causality for birth defects:

“5. A single case report by itself is not evidence of a causal relationship between an exposure and an outcome.  Combinations of both exposures and adverse developmental outcomes frequently occur by chance. Common exposures and developmental abnormalities often occur together when there is no causal link at all. Multiple case reports may be appropriate as evidence of causation if the exposures and outcomes are both well-defined and low in incidence in the general population. The use of multiple case reports as evidence of causation is analogous to the use of historical population controls: the co-occurrence of thalidomide ingestion in pregnancy and phocomelia in the offspring was evidence of causation because both thalidomide use and phocomelia were highly unusual in the population prior to the period of interest. Given how common exposures may be, and how common adverse pregnancy outcome is, reliance on multiple case reports as the sole evidence for causation is unsatisfactory.”

The Public Affairs Committee of the Teratology Society, “Teratology Society Public Affairs Committee Position Paper Causation in Teratology-Related Litigation,” 73 Birth Defects Research (Part A) 421, 423 (2005).

When the base rate for the outcome is near zero, and other circumstantial evidence is present, some commentators insist that causality may be inferred from well-documented case reports:

“However, we propose that some adverse drug reactions are so convincing, even without traditional chronological causal criteria such as challenge tests, that a well documented anecdotal report can provide convincing evidence of a causal association and further verification is not needed.”

Jeffrey K. Aronson & Manfred Hauben, “Drug safety: Anecdotes that provide definitive evidence,” 333 Brit. Med. J. 1267, 1267 (2006) (Dr. Hauben was medical director of risk management strategy for Pfizer, in New York, at the time of publication). But which ones are convincing, and why?

        *        *        *        *        *        *        *        *        *

Dr. David Schwartz, in a recent blog post, picked up on some of my discussion of the gadolinium case reports (see here and there), and posited the ultimate question: when are case reports sufficient to show causation? David Schwartz, “8 Examples of Causal Inference Without Data from Controlled Studies” (Dec. 14, 2014).

Dr. Schwartz discusses several causal claims, all of which gave rise to litigation at some point, in which case reports or case series played an important, if not dispositive, role:

  1.      Gadolinium-based contrast agents and NSF
  2.      Amphibole asbestos and malignant mesothelioma
  3.      Ionizing radiation and multiple cancers
  4.      Thalidomide and teratogenicity
  5.      Rezulin and acute liver failure
  6.      DES and clear cell vaginal adenocarcinoma
  7.      Vinyl chloride and angiosarcoma
  8.      Manganese exposure and manganism

Dr. Schwartz’s discussion is well worth reading in its entirety, but I wanted to emphasize some of Dr. Schwartz’s caveats. Most of the exposures are rare, as are the outcomes. In some cases, the outcomes occur almost exclusively with the identified exposures. All eight examples pose some danger of misinterpretation. Gadolinium-based contrast agents appear to create a risk of NSF only in the presence of chronic renal failure. Amphibole asbestos, and most importantly, crocidolite causes malignant mesothelioma after a very lengthy latency period. Ionizing radiation causes some cancers that are all-too common, but the presence of multiple cancers in the same person, after a suitable latency period, is distinctly uncommon, as is the level of radiation needed to overwhelm bodily defenses and induce cancers. Thalidomide was associated by case reports fairly quickly with phocomelia, which has an extremely low baseline risk. Other birth defects were not convincingly demonstrated by the case series. Rezulin, an oral antidiabetic medication, was undoubtedly causally responsible for rare cases of acute liver failure. Chronic liver disease, however, which is common among type 2 diabetic patients, required epidemiologic evidence, which never materialized[5].

Manganism, by definition, is the cause of manganism, but extremely high levels of manganese exposure, and specific speciation of the manganese, are essential to the causal connection. Manganism raises another issue often seen in so-called signature diseases: diagnostic accuracy. Unless the diagnostic criteria have perfect (100%) specificity, with no false-positive diagnoses, then once again, we expect false-positive cases to appear when the criteria are applied to large numbers of people. In the welding fume litigation, where plaintiffs’ counsel and physicians engaged in widespread, if not wanton, medico-legal screenings, it was not surprising that they might find occasional cases that appeared to satisfy their criteria. Of course, the more the criteria are diluted to accommodate litigation goals, the more likely there will be false positive cases.[6]

Dr. Schwartz identifies some common themes and important factors in identifying the bases for inferring causality from uncontrolled evidence:

“(a) low or no background rate of the disease condition;

(b) low background rate of the exposure;

(c) a clear understanding of the mechanism of action.”

These factors and perhaps others should not be confused with strict criteria here. The exemplar cases suggest a family resemblance of overlapping factors that help support the inference, even against the most robust skepticism.

In litigation, defense counsel typically argue that analytical epidemiology is always necessary, and plaintiffs’ counsel claim epidemiology is never needed. The truth is more nuanced and conditional, but the great majority of litigated cases do require epidemiology for health effects because the claimed harms are outcomes that have an expected incidence or prevalence in the exposed population irrespective of exposure.

[1] Reference Manual on Scientific Evidence at 23 (3d ed. 2011) (citing “Cloud v. Pfizer Inc., 198 F. Supp. 2d 1118, 1133 (D. Ariz. 2001) (stating that case reports were merely compilations of occurrences and have been rejected as reliable scientific evidence supporting an expert opinion that Daubert requires); Haggerty v. Upjohn Co., 950 F. Supp. 1160, 1164 (S.D. Fla. 1996), aff’d, 158 F.3d 588 (11th Cir. 1998) (“scientifically valid cause and effect determinations depend on controlled clinical trials and epidemiological studies”); Wade-Greaux v. Whitehall Labs., Inc., 874 F. Supp. 1441, 1454 (D.V.I. 1994), aff’d, 46 F.3d 1120 (3d Cir. 1994) (stating there is a need for consistent epidemiological studies showing statistically significant increased risks).”)

[2] Best v. Lowe’s Home Centers, Inc., 563 F. 3d 171, 178 (6th Cir 2009); Westberry v. Gislaved Gummi AB, 178 F. 3d 257, 263–264 (4th Cir. 1999).

[3] There may have been a better argument for Matrixx in distinguishing the method and place of delivery of the zinc sulfate in the polio trials of the 1930s, but when Matrixx’s counsel was challenged at oral argument, he asserted simply, and wrongly, that the two compounds were different.

[4] Johnston & Hauser, “The value of a case report,” 62 Ann. Neurology A11 (2007) (“No matter how compelling a vignette may seem, one must always be concerned about the reliability of inference from an “n of one.” No statistics are possible in case reports. Inference is entirely dependent, then, on subjective judgment. For a case meant to suggest that agent A leads to event B, the association of these two occurrences in the case must be compared to the likelihood that the two conditions could co-occur by chance alone …. Such a subjective judgment is further complicated by the fact that case reports are selected from a vast universe of cases.”); David A. Grimes & Kenneth F. Schulz, “Descriptive studies: what they can and cannot do,” 359 Lancet 145, 145, 148 (2002) (“A frequent error in reports of descriptive studies is overstepping the data: studies without a comparison group allow no inferences to be drawn about associations, causal or otherwise.”) (“Common pitfalls of descriptive reports include an absence of a clear, specific, and reproducible case definition, and interpretations that overstep the data. Studies without a comparison group do not allow conclusions about cause and disease.”); Troyen A. Brennan, “Untangling Causation Issues in Law and Medicine: Hazardous Substance Litigation,” 107 Ann. Intern. Med. 741, 746 (1987) (recommending that testifying physicans “[a]void anecdotal evidence; clearly state the opposing side is relying on anecdotal evidence and why that is not good science.”).

[5] See In re Rezulin, 2004 WL 2884327, at *3 (S.D.N.Y. 2004).

[6] This gaming of diagnostic criteria has been a major invitation to diagnostic invalidity in litigation over asbestosis and silicosis in the United States.

Posted in Causation, Rule 702 | Comments Off on Showing Causation in the Absence of Controlled Studies

Power at the FDA

December 11th, 2014

For six years, the Food and Drug Administration (FDA) has been pondering a proposed rule to abandon the current system of pregnancy warning categories for prescription drugs. Last week, the agency finally published its final rule for pregnancy and lactation labeling[1]. The rule, effective in June 2015, will require removal of the current category labeling, A, B, C, D, or X, in favor of risk statements and narrative summaries of the human, animal, and pharmacologic data for adverse maternal and embryo/fetal outcomes.

The labeling system, which will be phased out, discouraged or prohibited inclusion of actual epidemiologic data results for teratogenicity. With sponsors required to present actual data, the agency voiced a concern whether prescribing physicians, who are the intended readers of the labeling, interpret a statistically non-significant result as showing a lack of association:

“We note that it is difficult to be certain that a lack of findings equates to a lack of risk because the failure of a study to detect an association between a drug exposure and an adverse outcome may be related to many factors, including a true lack of an association between exposure and outcome, a study of the wrong population, failure to collect or analyze the right data endpoints, and/or inadequate power. The intent of this final rule is to require accurate descriptions of available data and facilitate the determination of whether the data demonstrate potential associations between drug exposure and an increased risk for developmental toxicities.[2]”

When human epidemiologic data are available, the agency had proposed the following for inclusion in drug labeling[3]:

“Narrative description of risk(s) based on human data. FDA proposed that when there are human data, the risk conclusion must be followed by a brief description of the risks of developmental abnormalities as well as other relevant risks associated with the drug. To the extent possible, this description must include the specific developmental abnormality (e.g., neural tube defects); the incidence, seriousness, reversibility, and correctability of the abnormality; and the effect on the risk of dose, duration of exposure, and gestational timing of exposure. When appropriate, the description must include the risk above the background risk attributed to drug exposure and confidence limits and power calculations to establish the statistical power of the study to identify or rule out a specified level of risk (proposed [21 C.F.R.] § 201.57(c)(9)(i)(C)(4)).”

The agency rebuffed comments that physicians would be unable to interpret confidence intervals, and confused by actual data and the need to interpret study results. The agency’s responses to comments to the proposed rule note that the final rule requires a description of the data, and its limitations, in approved labeling[4]:

‘‘Confidence intervals and power calculations are important for the review and interpretation of the data. As noted in the draft guidance on pregnancy and lactation labeling, which is being published concurrently with the final rule, the confidence intervals and power calculation, when available, should be part of that description of limitations.’’

The agency’s insistence upon power calculations is surprising. The proposed rule talked about requiring ‘‘confidence limits and power calculations to establish the statistical power of the study to identify or rule out a specified level of risk (proposed § 201.57(c)(9)(i)(C)(4)).” The agency’s failure to retain the qualification of power, at some specified level of risk, makes the requirement meaningless. A study with ample power to find a doubling of risk may have low power to find a 20% increase in risk. Power is dependent upon the specified alternative to the null hypothesis, as well as the level of alpha, or statistical significance.

The final rule omits all references to power and power calculations, with or without the qualifier of at some specified level of risk, from the revised sections of part 201; indeed the statistical concepts of power and confidence interval do not show up at all, other than a vague requirement that the limitation of data from epidemiologic studies be described[5]:

‘‘(3) Description of human data. For human data, the labeling must describe adverse developmental outcomes, adverse reactions, and other adverse effects. To the extent applicable, the labeling must describe the types of studies or reports, number of subjects and the duration of each study, exposure information, and limitations of the data. Both positive and negative study findings must be included.”

Presumably, the proposed rule’s requirement of providing power calculations and confidence intervals is part of the future requirement to describe data limitations. The agency, however, omitted this level of detail from the revised regulation.

The same day that the FDA issued the final rule, it also issued a draft guidance on pregnancy and lactation labeling, for public comment[6].

The guidance recommends what the regulation, in its final form, does not require specifically. First, the guidance recommends omission of individual case reports from the human data section, because:

‘‘Individual case reports are rarely sufficient to characterize risk and therefore ordinarily should not be included in this section.[7]”

And for actual controlled epidemiologic studies, the guidance suggests that:

‘‘If available, data from the comparator or control group, and data confidence intervals and power calculations should also be included.[8]”

Statistically, this guidance is no guidance at all. Power calculations can never be presented without a specified alternative hypothesis to the null hypothesis of no increased risk of birth defects. Furthermore, virtually no study provides power calculations of data already acquired and analyzed for point estimates and confidence intervals. The guidance is unclear as to whether sponsors should attempt to calculate power from the data in a study, and try to anticipate what level of specified risk is of interest to the agency and to prescribing physicians. More disturbing yet is the agency’s failure to explain why it is recommending both confidence intervals and power calculations, in the face of many leading groups’ recommendations to abandon power calculations when confidence intervals are available for the analyzed data.[9]

[1] Dep’t of Health & Human Services, Food & Drug Admin., 21 CFR Part 201, Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling; Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products—Content and Format; Draft Guidance for Industry; Availability; Final Rule and Notice, 79 Fed. Reg. 72064 (Dec. 4, 2014) [Docket No. FDA–2006–N–0515 (formerly Docket No. 2006N–0467)]

[2] Id. at 72082a.

[3] Id. at 72082c-083a.

[4] Id. at 72083c.

[5] Id. at 72102a (§ 201.57(c)(9)(i)(D)(3)).

[6] U.S. Department of Health and Human Services, Food and Drug Administration, Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products — Content and Format DRAFT GUIDANCE (Dec. 2014).

[7] Id. at 12.

[8] Id.

[9] See, e.g., Vandenbroucke, et al., “Strengthening the reporting of observational studies in epidemiology (STROBE):  Explanation and elaboration,” 18 Epidemiology 805, 815 (2007) (Section 10, sample size) (“Do not bother readers with post hoc justifications for study size or retrospective power calculations. From the point of view of the reader, confidence intervals indicate the statistical precision that was ultimately obtained. It should be realized that confidence intervals reflect statistical uncertainty only, and not all uncertainty that may be present in a study (see item 20).”); Douglas Altman, et al., “The Revised CONSORT Statement for Reporting Randomized Trials:  Explanation and Elaboration,” 134 Ann. Intern. Med. 663, 670 (2001) (“There is little merit in calculating the statistical power once the results of the trial are known, the power is then appropriately indicated by confidence intervals.”).

Posted in Risk and Risk Factor, statistical evidence | Comments Off on Power at the FDA