Recently in Legal Category
As just about everyone knows by now, the Special Masters of the US Court of Federal Claims handed down their decisions on Friday, which deny a causative link between the vaccine preservative thimerosal and autism in 3 test cases.
Among the many opinions rendered in the decisions from the Special Masters (see here, here, and here) are discussions of the autism studies published by Mark and David Geier—whose work has been criticized sharply and at length at this blog and in my 2009 letter to the Journal of the Neurological Sciences.
The court's Special Master George Hastings, for instance, writes in his decision re King v Secretary of Health and Human Services:
[M]ost of the epidemiologic studies that have addressed the thimerosal/autism causation issue have failed to find any association between thimerosal-containing vaccines and autism, but there have been certain exceptions. Those exceptions were studies published by the research team of Dr. Mark Geier and his son David Geier[*]...To be sure, the petitioners in this case have not cited or relied upon those Geier studies in their post-hearing briefs, because, as I will discuss below...the petitioners argue that all of the epidemiologic studies done to date are irrelevant to the petitioners' causation theory in this case. However, since I find that the epidemiologic studies are of relevance, I have found it reasonable to examine those Geier studies, to see if they afford any significant counterweight to the many contrary studies...
After careful consideration, I conclude that the Geiers' studies cannot be given any weight. A number of those studies were considered by the Institute of Medicine (IOM) committee that fully studied the entire thimerosal/autism causation issue in 2004. That committee concluded that the studies were so flawed as to be "uninterpretable," and that the studies contributed nothing meaningful ("noncontributory") concerning the causation issue...The committee noted that the studies were based on databases that themselves had "significant limitations"...and that the studies had "serious methodological problems"...or "serious methodological limitations"...The committee added that the Geiers' articles describing their analytical methods were "not transparent" and omitted "important details," so that it was impossible to evaluate the studies...Other specific deficiencies in the studies were also discussed, including the fact that the Geiers incorrectly used several epidemiologic terms and measures.
In addition, Dr. Fombonne [respondent's expert] agreed with the IOM's criticisms of the Geier studies, and testified that the Geier studies in general failed to use accepted epidemiologic methods...Dr. Rutter [respondent's expert] was critical of the Geier studies as well...Further, petitioners' own expert witness concerning epidemiology, Dr. Greenland, agreed with the criticisms of the Geier articles, acknowledging that those studies are "deficient in methodology"...And none of the expert witnesses for the petitioners vouched for the reliability of the Geier studies.
I have reviewed the published Geier studies discussed in the 2004 IOM report, and I agree with the analysis of those studies set forth in that IOM report. Further, I have reviewed the additional studies published by the Geiers since the 2004 IOM report, and find that those studies suffer from the same type of flaws as the earlier Geier studies. That view includes a study published in 2008 by the Geiers, along with Young as the third author. Two of respondent's experts, Drs. Fombonne and Rutter, testified that that 2008 study was again deeply flawed, and those experts provided a number of specific examples of deficiencies in the study...And, again, none of the petitioners' experts testified in support of that 2008 Young, Geier, and Geier study.
In summary, I conclude that all of the Geier epidemiologic studies are not reliable, and cannot be accorded any weight.
In a lengthy footnote from the decision handed down in the case of Mead v Secretary of HHS, Special Master Patricia Campbell-Smith writes,
Although the studies conducted by Dr. Mark Geier and his son purport to find an association between thimerosal-containing vaccines and autism, their studies have been criticized consistently by various reviewers, including petitioners' own expert epidemiologist, as methodologically deficient...(Dr. Rutter [characterized] the 2008 Young study—that was conducted in part by Dr. Geier and his son...as a poorly designed study for the following reasons: (1) the researchers used a "strange" study design that is both a cohort study [a controlled study] and a time-trend analysis of the available database information [an ecological study] and (2) the researchers included emotional disturbance as one of the neurodevelopmental disorders observed following exposure to thimerosal-containing vaccines even though emotional disorders are not included in any of the official psychiatric classifications systems for neurodevelopmental disorders). The undersigned has reviewed carefully the presented studies conducted by the Geiers and has considered the criticisms leveled against the Geiers' studies. Persuaded that the studies are flawed methodologically in critical respects, the undersigned, without addressing the studies in extensive detail here, declines to accord any evidentiary weight to the studies. The undersigned notes that other researchers have been unable to verify the validity of the Geiers' statistical analysis on a number of occasions and a number of courts have expressed concerns about the reliability of their work.
Campbell-Smith goes on to cite 8 court cases in which the Geiers' work was called, among other things, "unintelligible," or in which Dr. Geier's testimony was described as "not reliable."
In her decision for the third test case, Special Master Denise Vowell affords special attention to the Young, Geier, and Geier study of 2008—which was specifically pulled apart at this blog and by Epi Wonk.
The only studies demonstrating a relationship between TCVs [thimerosal-containing vaccines] and ASD [autism spectrum disorder] are those in which Dr. and Mr. Geier appear as co-authors, including the Young study published in May, 2008, and funded by the OAP PSC [Omnibus Autism Proceeding Petitioners' Steering Committee]...Because petitioners’ own expert commented that the Geier studies were not reliable as evidence... and they were thus not addressed by respondent’s experts, I do not discuss the earlier Geier studies any further. In view of the numerous criticisms of the earlier Geier studies and petitioners' own expert’s dismissal of them, I have placed no reliance on them.
The Young study was an ecological analysis using the VSD database...Doctor Greenland [petitioners' expert] did not comment on this study during his testimony, as the article was introduced after his appearance and excusal. The study found an increased risk of ASD, based on increasing exposure to TCVs. Doctor Fombonne offered several criticisms of this study. In a critique common to many of the studies performed by Dr. and Mr. Geier, Dr. Fombonne commented that the Young article did not provide the data that would allow others to verify the calculations performed.
Doctor Fombonne reproduced one chart from the article...Using the chart, he explained that the birth cohorts used in the study did not all contain the same number of individuals, with most representing 40,000 children...One birth cohort, that of children born in 1990, contains only 2,000 children...When this "outlier" is removed, the purported statistical relationship between ASD and TCVs during the first four years of the sample disappears.
Doctor Fombonne was also highly critical of the authors' addition of invented numbers to the 1995 and 1996 data from the VSD...If the adjustments are removed, there is no correlation at all between the increase in thimerosal exposure and increase in autism cases per 10,000...Doctor Fombonne commented: "It’s dishonest to impute like 45 new cases which are just invented to top up the prevalence in a way which is supportive of their hypothesis. It’s clear that these investigators have a clear track record to do with the data that supports their hypothesis. And I’ve seen that in their previous papers."
Doctor Rutter offered similar criticisms of the Young study...calling it "a poor study for several different reasons"...It began with a cohort design, but ended up being analyzed as a time trend study. That required the authors to make adjustments to the first and last cohorts. Doctor Rutter described this as "putting together chalk and cheese in the hope of gazpacho soup coming out"...The "analytic design and strategy was not a satisfactory one."
He pointed to Table 3 as a striking example of the poor design...Table 3 compares "neurodevelopmental disorders" to several control disorders, measuring the difference in rates of the disorder developing in the cohorts that received 100 micrograms more mercury. The table shows higher rate ratios for autism, ASD, ADD/ADHD, developmental or learning disorders, disturbance of emotions, and tics...Doctor Rutter called this table an example of demonstrating a statistical effect without showing a causal effect...If the neuroinflammation hypothesis is correct, it is difficult to explain how neuroinflammation causes tics or disturbance of emotions. The study reported TCV effects across a very broad range of unconnected disorders having different ages of onset, different genetic factors, and different disease courses...The broad range of effects in these diverse disorders caused Dr. Rutter to be "immediately skeptical as to what [the study] shows."
He also questioned why "disturbance of emotions" was listed in the category of neurodevelopmental disorders, noting that anyone knowledgeable about the field of neurodevelopmental disorders would not have categorized it as one, and would have placed it with the control disorders...To prove their hypothesis that increased mercury exposure causes increases in neurodevelopmental disorders but not control disorders, the authors have to demonstrate that mercury is associated with increased rates of one but not the other. If "disturbance of emotions" was properly placed with the list of control disorders, it would undercut the authors' hypothesis. Their comparison between the two groups is therefore invalid.
Vowell also comments on a reanalysis of the Young et al data by Young herself, who found no association between birth year (which was purported to be associated with exposure to TCVs) and ASD when the imputed cases were removed.
Doctor Young’s subsequently-filed letter indicated that she reanalyzed the data to respond to Dr. Fombonne's criticisms. After she removed the 1990 birth cohort (the one containing only 2,000 cases) and the notional cases for 1995 and 1996, the results for autism, ASD, and unspecified developmental disorders lost statistical significance...She nevertheless defended the use of the 1990 birth cohort and her adjustments to the numbers for 1995 and 1996.
Vowell also dismisses the study of Young et al on the basis of its funding source.
For the reasons indicated in the criticisms proffered by Drs. Fombonne and Rutter, I have accorded the Young study little weight. An additional reason for viewing this study as unreliable is the conflict of interest generated by the PSC’s funding of the study. In its opinion on remand in Daubert, the Ninth Circuit considered whether the matters an expert proposed to testify about flowed from research conducted independently of involvement in the litigation in question, noting that this factor provides objective proof that the research was conducted for scientific purposes.
Yet, despite these unequivocal, disparaging opinions on the work of Geier and Geier, they continue to find sympathetic medical publishers. Their latest article (pdf here) can be found in the Journal of Toxicology and Environmental Health, Part A, which has now published the Geiers' work on 5 occasions.
In their latest article, the Geiers (along with Janet Kern of the Genetic Consultants of Dallas) again try to link the excretion of some urinary porphyrins (their dubious pet marker for mercury toxicity) with ASD severity. The study is very similar to their previously published work in the JNS, and one wonders if there isn't substantial overlap in the study subjects (26 vs 28 children).
Despite the suspicion, the tabulated presentation of the Geiers' urinary porphyrin data in JNS (nanomoles per gram of creatinine) makes it virtually impossible to compare these numbers with their urinary porphyrin values in the latest article (which are presented in "normalized" uP levels). Similar objections can be raised of their graphed data, primarily because of differences in the presentations of the x-axes.
N.B.--The Geier studies reviewed by Special Master Hastings included the following:
Yesterday the FDA approved Botox (onabotulinumtoxin A; Allergan) to treat distal arm spasticity in adults.* The approval was based on results from at least 3 trials in a total of 305 people with arm spasticity after stroke. Two of the 3 studies have been published in peer-reviewed journals (see here and here).
While the FDA's new approval partially mitigates the legal issue that Allergan has had with the agency's mandate to disseminate off-label safety information about Botox (for necessary background, go here, here, here, and here), it does not resolve the problem with respect to the use of Botox for limb spasticity in children—a still unapproved indication.
The case of Allergan v the United States of America et al was scheduled for a motion hearing in the US District Court for the District of Columbia on March 2nd. However, the docket has evidently been altered. According to the current court calendar, a status conference is scheduled for March 25th in the chambers of Judge John D. Bates, and a motion hearing is scheduled for April 26th.
* Specifically the flexor muscles of the elbow (eg, biceps), wrist (eg, flexor carpi radialis), and fingers (eg, flexor digitorum profundus).
Image of deep muscles of the ventral forearm from Gray's Anatomy (1918).
Recently I wrote that "plaintiff-sponsored research is disturbing and represents a potentially significant conflict of interest for the investigator who accepts plaintiff funds to perform related studies—particularly studies that may be used to the advantage of the plaintiff in ongoing litigation." This statement was in response to a recent court opinion that dismissed the plaintiff-funded study of Bremner et al, who attempted to associate altered brain metabolism with Accutane exposure. The study was published in a 2005 issue of the peer-reviewed American Journal of Psychiatry, which acknowledged the study's funding source.
The reflexive "ick" to plaintiff-sponsored research or, more broadly, litigation-driven research is undoubtedly related to the fact that the outcome is intended to support one side of an argument. This inherent bias in litigation-driven research is, therefore, completely contrary to the fundamental tenet of scientific endeavor, which is to investigate the universe with as much objectivity as possible.
By comparison, there is generally less disgust when considering industry-funded, and in particular, pharma-funded, research—although agendas certainly exist among the financial supporters of these clinical studies. The reasons for the relatively ease with which we accept pharma-funded research, despite the fact that these studies are designed and performed to sell prescription drugs, are threefold: 1) there is a longtime precedent of reviewing and accepting pharma-funded research; 2) the intended outcome of pharma-funded research is less overt than that of litigation-driven research; and 3) the drug industry is government regulated. Specifically much of the clinical research supported by pharma, including raw data, is subject to the scrutiny of FDA officials (which is why reasons 1 and 2 exist, for the most part).
But law professor William Childs, in a 2006 paper, argues that litigation-driven research should not be dismissed out of hand by the scientific community. Moreover, litigation-driven research may add importantly to the foundation of science by funding studies that would not have been performed otherwise. And the validity of litigation-driven research, especially if it has been published in a peer-reviewed journal, will likely be subjected to a lengthy Daubert hearing—which is used by many courts to determine the admissibility of expert testimony.
This legal scrutiny of scientific research, Childs argues, goes beyond peer review*—the parameters of which are limited and vary widely from journal to journal—to examine researchers' methodologies and, importantly, their raw data. For instance, in the case of Bremner's Accutane-PET study, a lengthy pretrial court hearing revealed that the authors did not follow their methodology as described, and that there were outcome-altering errors in data entry. Without the hearing and the resulting court opinion, these shortcomings of the peer-reviewed study would not have been known.
It therefore goes to reason that researchers who perform litigation-funded research, knowing that their research will likely be subjected to cross-examining attorneys and the scrutiny of opposing expert witnesses, should be sufficiently motivated to perform their research with irreproachable standards. These standards should certainly include avoiding dishonesty or the appearance of it.
Childs writes that, while "it is highly unusual for a party's retained expert to testify contrary to the party's litigation position,"** checks exist to ensure the integrity of litigation-driven research through the possibility of subpoenas and depositions and any consequent risk to a researcher's reputation—"the coin of the realm in academia."
* In fact, Daubert hearings reveal the shortcomings of peer review to reliably ferret out scientific fraud.
** And the plaintiffs' retention of an expert "is dependent on whether the results support the plaintiffs' argument." Recently Bremner emphasized that he was retained as an expert witness by the Accutane litigation plaintiffs after the PET study was completed--which means that his retention as an expert witness by the plaintiffs was dependent on the results of his study.
Image of vintage Pepto-Bismol ad from Flickr.
