Ethics: May 2008 Archives

This post represents the fourth (and god willing, final) installment of my review of the study by Young et al, which links exposure to Thimerosal-containing vaccines with autism. Previous posts on the subject can be found here (IRB approval), here (IRB follow-up), here (article Introduction), here (Materials and Methods), and here (Results). The current post provides commentary on statements made in the article's Discussion.

The authors begin by pointing out the favorable aspects of their study.

[T]he study design...helps to strengthen the observed results. The medical conditions examined were selected a priori as biologically or not biologically plausibly linked to Hg exposure from Thimerosal-containing vaccines administered during specific exposure windows.

Not to be too snide here, but when was it decided that foregone conclusions are study strengths?

Additionally the study design also allowed us to be certain that virtually all exposures to Hg preceded the diagnoses of the diseases examined (ie, allowing for a potential cause-effect relationship between exposure and disease). This was ensured because only children receiving a vaccine by age 3 months were examined, and as Table 2 shows the median age of initial diagnosis for the conditions examined in the present study ranged from 1.7 to 6.4 years-old.

The diagnoses in question may follow vaccine exposures, but that doesn't necessarily mean their existence does. For instance, the presence of congenital anomalies (which, by definition, exist at birth) should not be affected by subsequent exposure to vaccine-related ethylmercury. However, if Young et al were consistent in their thinking, they would propose that a 100-µg increase in ethylmercury exposure somehow confers a retroactive, protective effect against congenital anomalies (with a risk reduction of ~40%).*

[T]he methods of ensuring capture of Hg exposure from Thimerosal-containing vaccines and outcomes appear to have yielded results consistent with previous studies. For example, the US CDC previously published that the overall prevalence of ASD [autism spectrum disorder] in children, born for similar birth years as examined in the present study, was 3.4 per 1000 children in the metropolitan Atlanta, Georgia area [13]. The adjusted overall prevalence of ASDs (3.67 per 1000) in the present assessment of the VSD was consistent with the previous observation made by the US CDC.

The CDC investigators examined multiple medical or educational records from 5 Atlanta-area counties and calculated a 0.34% prevalence rate for autistic disorder, pervasive developmental disorder (NOS), or Asperger disorder (per DSM-IV criteria) among children 3-10 years of age in 1996. Young et al's overall (unadjusted) prevalence rate for ASD in the VSD was 0.293%, and the adjusted prevalence rate was 0.367%, after adding approximately 206 cases (see explanation here). Calculations for the year 1996 indicate an unadjusted rate of autism (ASD data for 1996 were not provided) of 0.17% and an adjusted rate of 0.33%, after Young et al added 80 cases. So Young et al's prevalence rates are "consistent" with the CDC's (circa 1996), after their liberal imputation of autism cases.

[T]he birth cohort years examined in the VSD help to strengthen the results observed. The birth cohort years examined from 1990 through 1996 occurred many years prior to the raising of concern about potential problems with Thimerosal in childhood vaccines by the American Academy of Pediatrics and the US Public Health Service, so that their announcement to remove Thimerosal from childhood vaccines in July of 1999 should have had virtually no impact on physicians' thoughts about Thimerosal in childhood vaccines.

While the above statement is not entirely unreasonable, it doesn't acknowledge the groundswell of anti-Thimerosal sentiment from lay and fringe medical groups during the 1990s. Therefore it is possible, as suggested in a prior post, that parents within the Kaiser system requested, or even demanded, the administration of some newly available, Thimerosal-free vaccines to their children during 1997 or later. 

Additionally, the years examined in the VSD help to ensure that changes in diagnostic criteria for outcomes such as autism that came into effect in 1994 would have minimally impacted the present study since most children examined were diagnosed post-1994 with autistic disorder.

"Minimally impacted" is a disingenuous conclusion, in my opinion. According to a recent post by EpiWonk, studies indicate that the rise in autism rates during the last 3 decades is an artifact due to broadened diagnostic criteria, diagnostic substitution, and the diagnosis of autism at a younger age. Moreover, there's no reason to assume that the rate of recognizing autism would have leveled off after 1994. In fact, the increasing prevalence of autism depicted by Young et al in Figure 1 is probably due to a continuing uptick in diagnostic acuity.

[A]nother significant strength of the present study stems from the trends in birth cohort Hg exposure and outcomes. As shown in Fig. 1 for autism, it was observed there were increasing/decreasing trends in exposure and outcomes across the birth cohort years examined, and that for the neurodevelopmental disorders there were significant associations between birth cohort mean Hg exposure and disease prevalence rates. It is important to note that the increasing/decreasing trends in Hg exposure were not simply the result of random yearly fluctuations in vaccine uptake rates or even simply the result of increasing exposure to vaccine antigens, but instead reflect known changes in the Hg content of the US childhood vaccine schedule...

It's difficult to understand how Young et al can so easily dismiss the idea that "the increasing/decreasing trends in Hg exposure were not simply the result of random yearly fluctations." Note that the largest difference in the average per-person ethylmercury exposure is pretty small, approximately 35 µg according to Figure 1 (~110 µg for the 1990 birth cohort and ~145 µg for 1992), which equals a little more than 1 vaccine dose. Also note that there are many ways to represent the data in Figure 1, so that the putative association between ethylmercury exposure and the prevalence of autism is less graphically compelling (see examples below).

[B]ecause of the ecological nature of the study design, we were not able to link vaccine exposures across individual patient records...

EpiWonk explains the important distinctions between an ecological, or group-level, study and an individual-level study. He argues that Young et al have committed the "ecological fallacy."

Another possible limitation of the present study was the potential for under ascertainment of a child's total Hg exposure...Other potential sources of Hg such as fish consumption or environmental exposure, while potentially significant to the risk of a child being diagnosed with a neurodevelopmental disorder, could not be examined...We believe that these other exposures to Hg should not have biased the effects observed. In actuality, such sources of Hg exposure would potentially minimize the significance of the effects observed.

Here Young et al appear to contradict themselves. If I'm reading correctly, they first state that non-vaccine sources of mercury "should not have biased" their results, but they follow with the conclusion that non-vaccine mercury would "potentially minimize" their results.

This study was also limited to a maximum of 4 years of follow-up time for the latest birth cohorts...

Young et al's highly dubious imputation of cases for later birth cohorts, owing to shorter follow-up periods, has been discussed by EpiWonk and myself.

Finally, the present study was not able to adjust for potential factors that might have resulted in vaccine avoidance but may have predisposed one towards neurodevelopmental disorders under study. Specifically, Fine and Chen reported that there are several social and medical attributes associated with avoidance or delay of vaccination and an increased risk of neurological adverse events, and that confounding of this sort is a general problem for studies of adverse reactions to prophylactic interventions, as they may be withheld from some individuals precisely because they are already at high risk of the adverse event [14]...As a result, the effects observed in the present study may represent an underestimate of the true effects of Hg exposure from Thimerosal-containing vaccines on the risk of neurodevelopmental disorders.

Not to sound like a broken record, but What the—? Young et al cite a 1992 CDC article on confounding (an issue discussed by EpiWonk here). But as far as I can tell, Young et al have taken the article's conclusion—that is, putative vaccine benefits may be observed because fewer high-risk children are vaccinated—and turned it on its head. (BTW, this phenonmenon may well explain the observed low rate ratio for congenital anomalies and increased ethylmercury exposure.)

Young et al then go on to support their findings by citing themselves (Geier and Geier) on 3 occasions, a "neutral" 2003 study by Verstraeten et al (who ultimately concluded that further study was needed), and a 2003 study by Stehr-Green et al, who concluded that the data do not support an association between Thimerosal exposure and autism.

Young et al also attempt to undermine the applicability of studies from the United Kingdom, Canada, Sweden, and Denmark (which did not find an association between Thimerosal exposure and autism) to the United States. They write, "In many of these countries, alternate vaccines in different vaccine schedules and different diagnostic measures were used, and many countries apparently had very different neurodevelopmental disorder prevalence rates than in the US." However, Young et al fail to note that WHO found these studies convincing and dismissed 2 US studies (at least one of which was by Geier and Geier) as "unconvincing."

Mercury exposure was also observed to be significantly associated with neurodevelopmental disorders and autism in a series of epidemiological studies...

As in their introduction, Young et al conclude by attempting to link Thimerosal (ethylmercury) exposure to environmental methylmercury from a number of sources including seafood (for instance, in the Faroe Islands) and Ecuadorian gold mines. They also cite one California Department of Public Health study, which found associations between autism spectrum disorder and a number of airborne substances, including elemental mercury.

Young et al continue to cherry-pick or outrightly misrepresent data (again, in my opinion) from other sources, including 1) a primate study, which concluded that methylmercury "is not a suitable reference for risk assessment from exposure to thimerosal-derived Hg"; 2) mouse models, which suggested that Thimerosal-induced neurotoxicity is breed dependent; and 3) a rat study, which examined the perinatal neurotoxic effects of methylmercury.

Other studies are cited, including 3 more by Geier and Geier, which attempt to link elevations in mercury concentrations and "potential biochemical and genomic susceptibility factors to Hg poisoning" with autism. One of the Geiers' articles alleges that urinary porphyrins are a marker for heavy metal exposure, a favorite hypothesis featured on YouTube.

Summarizing the drawbacks of Young et al's study and write-up is a considerable challenge, frankly because there are so many. Nevetheless, I'll attempt to list the most salient here:

• The a priori association between microgram doses of ethylmercury and autism. This association really isn't anymore biologically plausible than an association between any trace substance and autism.
• The loose association between methylmercury and ethylmercury, two substances with considerably different pharmacokinetic properties.
• The liberal addition of neurodevelopmental cases, particularly for the later birth cohorts of 1995 and 1996.
• The absence of controlling for confounders, such as birthdate, and the alleged commission of "ecological fallacy" (per EpiWonk). Controlling for birthdate in a study of autism is essential, because of time-sensitive changes in the diagnosis of autism.
• The possible overestimation of ethylmercury exposure from vaccines, particularly among later birth cohorts.
• The presentation of astonishingly high rate ratios (which have to be taken on faith) that have very wide confidence intervals, for neurodevelopmental disorders. These rate ratios suggest, in some cases, several-hundred-fold increased risks of disorders due to very small increases in ethylmercury exposure—a dubious proposition, in my opinion.
• A rate ratio that suggests (although this is not addressed by the authors) that ethylmercury exposure actually reduces the risk of congenital anomalies by approximately 40%.*
• The use of the authors' previous questionable studies to support the current study.
• The authors' cherry-picking or outright mispresentation, in my opinion, of other references to support their beliefs.

*This observation may well be the result of confounding, as discussed by Fine and Chen (which Young et al ironically cite for other reasons, later in their Discussion).

Photo: iStockPhoto.

This post represents the third installment of my review of the study by Young et al, which links exposure to Thimerosal-containing vaccines with autism. Previous posts on the subject can be found here, here, here, and here.

Results

Table 3 presents the rate ratios and 95% confidence intervals for each diagnosis assuming a µg increase in mercury exposure from Thimerosal-containing vaccines administered from birth to 7 months and birth to 13 months. It was observed that there were significantly increased rate ratios for the neurodevelopmental disorders of autism, autism spectrum disorder (ASD), hyperkinetic syndrome of childhood (attention deficity disorder/attention deficity hyperactivity disorder), developmental disorder/learning disorder—not otherwise specificied, disturbance of emotions specific to childhood and adolescence, and tics following additional Hg exposure from Thimerosal-containing childhood vaccines...By contrast, no significantly increased rate ratios for the control disorders of pneumonia, congenital anomalies, and failure to thrive were observed with increasing Hg exposure from Thimerosal containing vaccines.

The rate ratios, given a 100-µg increase in vaccine-related ethylmercury exposure, are reproduced below from Young et al's Table 3:

Condition	Rate Ratio (95% CI), Birth-7 Months	Rate Ratio (95% CI),  Birth-13 Months
Neurodevelopmental
Autism	2.87 (1.19, 6.94)	2.62 (1.15, 6.01)
Autism spectrum	2.44 (1.16, 5.10)	2.20 (1.10, 4.40)
Hyperkinetic syndrome	3.15 (2.38, 4.17)	4.51 (3.48, 5.84)
Developmental disorder/ learning disorder—not otherwise specified	1.73 (1.08, 2.75)	1.81 (1.17, 2.80)
Disturbance of emotions	2.27 (1.36, 3.80)	2.91 (1.81, 4.68)
Tics	3.39 (1.64, 6.79)	4.11 (2.12, 7.94)
Control
Pneumonia	0.98 (0.86, 1.11)	0.92 (0.82, 1.04)
Congenital anomalies	0.62 (0.34, 1.14)	0.57 (0.33, 1.00)
Failure to thrive (FTT)	1.05 (0.74, 1.47)	0.92 (0.67, 1.27)

There's little to say about these numbers, other than they have to be taken on faith, which is a dubious proposition in my opinion. The rate (or risk) ratios for the neurodevelopmental disorders are very high, suggesting (in some cases) a several-hundred-fold increased risk for a neurodevelopmental disorder with what is really a very small (ie, 100-µg) increase in ethylmercury exposure. The 95% confidence intervals for the neurodevelopmental disorders are also exceptionally wide, especially when compared with those for the control conditions. The following graphs of the rate ratios and 95% CIs illustrate this point.

Birth-7 Months

Birth-13 Months

Also, given these data, couldn't it be concluded (although a P value is not provided) that a 100-ug increase in vaccine-related ethylmercury exposure reduces the risk of congenital anomalies by approximately 40%?

Next: Discussion.

The following is the second installment of a review of "Thimerosal exposure in infants and neurodevelopmental disorders," by Young et al, which links thimerosal exposure to autism. Statements from the materials and methods section are discussed, with otherwise heavy deferrals to EpiWonk.

The study protocol employed was approved by the US [CDC], the Institutional Review Board (IRB) of Kaiser North-West, and the IRB of Kaiser Northern California. The data were analyzed at the secure Research Data Center of the National Center for Health Statistics in Hyattsville, MD.

Alleged violations of this study's protocol by the Geiers (father-and-son duo) are discussed here and here. According to an 05/21/08 e-mail from the Kaiser IRB office, the objections stated in 2004 by the CDC and Kaiser were resolved, and the study was ultimately approved by the IRB. However, Kaiser did not specify how the objections were resolved. At the time of this post, a statement from the CDC regarding the alleged protocol violations is pending.

The study was conducted based upon a retrospective ecological [emphasis added] assessment of neurodevelopment disorders that were identified a priori as possibly related to Hg exposure.

There are several uses of the term "ecological" in the article to describe this study and others. Perhaps EpiWonk can provide some insight into the word's meaning in this context; the distinction's lost on me. The authors acknowledge the preselection of a list of neurodevelopmental disorders (eg, autism) that are presumptively (ie, "a priori") related to mercury exposure.

Only those individuals who had a non-missing date of birth and were born before January 1, 1997 were examined. This date was chosen to allow for at least 4 years of follow-up for each member of the cohort which was believed to be an adequate amount of time to observe the outcomes of interest.

Here the authors acknowledge that a minimum 4-year time frame should be sufficient to assess the occurrence of preselected neurodevelopmental disorders in the VSD, which was created in 1991 and updated through the year 2000. However, the authors later contend that the time frame is not sufficient, to justify their addition of presumptive cases. (An aside: Data from Kaiser North-West, Kaiser Northern California, and Kaiser Colorado were examined by Young et al; however, an IRB nod from Kaiser Colorado was not mentioned in the previous, relevant paragraph.) 

All children who received an oral polio vaccine within 3 months of their birth date and who were born before January 1, 1997 were used as the denominator or population at risk for this study.

The time period for the study is from 1990 (0.6% of the study population) to 1996, inclusive. A total of 278,624 children were identified. (Another aside: Because of the very rare incidence of vaccine-induced polio associated with the administration of the oral vaccine [1 case in 2.4 million doses], it was recommended in 2000 that all US children should receive only inactivated polio vaccine).

The outcome files (inpatient and outpatient diagnoses) from this population were then reviewed to find the first instance of diagnosis of the disorders of interest. If there were multiple instances of the same diagnosis in a child, only the first instance of diagnosis was counted. Then the total numbers of each diagnosis for each disorder of interest were determined by birth cohort. The counts of each diagnosis of interest represented the numerator or outcomes for this study.

Okay, I'm still following along at this point. The authors tallied the first instance of each preselected ICD-9 code and divvied the total counts by birth cohort (ie, year). Referral to Table 2 reveals, for instance, that there were 583 identified cases of autistic disorder, current or residual (ICD-9 codes 299.00, 299.01), among the 278,624 children (ages 4-10 years) who received oral polio vaccine within 3 months of birth, to produce an overall 0.21% frequency of autistic disorder. However, note in Table 2 that the authors' adjusted overall prevalence rate for autism is 25.4/10,000, or 0.254%. More on this later.

The prevalence of each diagnosis was then calculated by birth cohort by dividing the count of a diagnosis in that birth year by the total number of children from the study population that were born in that same year.

The number of children per birth cohort (year) can be calculated by using percentage data in Table 1; however, the raw numbers of autism (and other) cases by birth year are not provided. (Figure 1 does provide graphically the number of autism cases per 10,000 per year [with imputed data for 1995 and 1996 presumably included—as indicated, more on added cases later]). EpiWonk talks extensively about birth year as a confounder in this study.

Because of concern that the cohorts from 1995-1996 had only 4-6 years of follow-up, frequency distributions of age at diagnosis were examined for all years. This revealed that for some of the disorders a sizable proportion of children were diagnosed after 4.5 years. Adjustments were made for counts of cases as needed for birth cohorts depending upon the disorders examined to correct for under ascertainment that occurred due to shorter follow-up times. These adjustments were made for all disorders including the control disorders as appropriate based on the age distribution.

Although the authors originally proposed that 4 years of follow-up would be sufficient, they now conclude that more follow-up time is needed. This conclusion is presumably based on their discovery in earlier birth cohorts that, for some of the ICD-9 codes (essentially all of the neurodevelopmental conditions, except 315.9), the median (not mean) age at diagnosis was 4.5 years or older (Table 2). Therefore, the authors made "adjustments" to "correct for under ascertainment" by adding cases "as appropriate." EpiWonk talks about this "extremely dubious" imputation of data here. Also, although the authors say that "adjustments were made for all disorders including the control disorders," Table 2 reveals that the median ages for these conditions (pneumonia, congenital anomalies, failure to thrive) were below the 4-year time frame, suggesting that "adjustments" may not have been necessary for these particular control conditions.

For example, 37% of autism cases in the study were diagnosed after 5 years old with about 50% diagnosed after 4.5 years old. This is a conservative estimate since it includes the 2 years (1995-1996) that had shorter follow-up times. Examination of the distribution of age of diagnosis by birth year for autism revealed that only about 15% of cases were diagnosed after 5 years of age in the 1995 birth cohort while the 1996 cohort had no cases diagnosed after 5 years of age and only 3.5% of cases diagnosed between 4.5 and 5 years of age.

So among the 583 total number of autism cases identified in the VSD (which presumably do not include the imputed cases), a little more than 200 (~37%) were diagnosed after 5 years of age. The authors argue that this is an underestimate because of the relatively shorter follow-up times for the 1995 and 1996 cohorts. For the 1995 cohorts (with presumably 6 years of follow-up, 1995-2000 inclusive), 15% of cases (not 37%) were diagnosed after 5 years of age. Because the follow-up for the 1996 cohort was 1 year less, no cases of autism were detected after 5 years of age.

Based on the average age at diagnosis for all cohorts, the 1995 count of autism cases was increased by 45 cases with the assumption that all of these would have been added in the 5 year+ age group (bringing this percentage close to the overall average of 37% diagnosed after 5 years of age). The same was done for 1996, but the number of cases was augmented by 80 because it was assumed that these would be diagnosed in the 4.5 to 5 and 5+ groups essentially bringing the percentage diagnosed after age 4.5 close to the overall average of 50% diagnosed after 4.5 years of age. The new augmented frequency counts of cases in 1995 and 1996 birth cohorts were then used as the new case counts in the analysis. 

Here's where my head starts to rotate on its axis. The number of autism cases for the 1995 cohort were increased by 45 to increase the rate of autism cases diagnosed after the age of 5 years from 15% to 37%. Therefore, we can conclude that 22% (37% – 15%) of the imputed autism cases for 1995 equals 45 cases. Working backwards, we can actually estimate raw data from the later birth cohorts. There were approximately 160 autism cases orginally identified in the 1995 cohort (45/22 x 100 = 205; 205 – 45 = 160). Therefore, the original rate of autism for the 1995 cohort (using data from Table 1) was 0.31%; the imputed rate is 0.39%. Similar calculations can be performed for the 1996 cohort. Eighty cases of autism were originally identified in the 1996 cohort, for a rate of 0.17%; the imputed rate is double that, or 0.33%. (Also note that the authors now refer to the "average age at diagnosis," not the median age. It's unclear if the lack of the distinction between median and average age is an oversight or an intentional slide.)

For the entire "autism" cohort (all birth years), 125 cases were added. By using data from Table 2, we can calculate how many cases were added overall for each diagnosis, with the presumption that most (if not all) cases were added to the birth cohort data for 1995 and 1996.

Condition	n	Prevalence Rate, %	Adjusted Prevalence Rate, %	Calculated No. Added Cases
Neurodevelopmental
Autism	583	0.209	0.254	125
Autism spectrum	817	0.293	0.367	206
Hyperkinetic syndrome	5712	2.05	2.51	1281
Developmental disorder/ learning disorder—not otherwise specified	2248	0.807	0.948	393
Disturbance of emotions	1694	0.608	0.762	429
Tics	804	0.289	0.389	280
Control
Pneumonia	33,648	12.1	13.2	3130
Congenital anomalies	1643	0.59	6.32	15,966
Failure to thrive	4754	1.71	1.85	401

For the neurodevelopmental disorders, the number of cases overall were typically increased by approximately 20%-25%, with the exception of tic cases, which were increased by approximately 35%. The control cases (excepting congenital anomalies) were increased by much less, approximately 10%. (It is assumed that the adjusted prevalence rate for congenital anomalies [63.2/1000] is almost certainly a typo and should be 63.2/10,000. It is also assumed that ~1597 cases were added to the database, not 15,966 as calculated by the numbers given.)

In analyzing the adjustments made for follow-up corrections, varying levels of imputing additional cases were modeled to assess the sensitivity of the results to the assumptions made when imputing additional cases in specific birth cohorts. Sensitivity analyses revealed that point estimates were similar even when imputing 50% fewer cases than would be expected using the average age distributions as noted above. In addition, confidence intervals showed little variation and maintained statistical significance when imputing as low as 25% fewer cases than would be expected using the average age distributions.

Head now spinning like Michael Keaton's in Beetlejuice. How I read the above: the authors extensively monkeyed with the outcome data to determine how much "imputation" the data (or we) could possibly stand.

Because the study protocol did not permit us to match data across vaccine files, exposure was determined in aggregate by birth cohort for each vaccine and then summed across birth cohorts. The routine childhood vaccines of interest were Haemophilus influenza type b (Hib), hepatitis B vaccine, [DTaP], and [DTP] vaccines.

Young et al assumed that the mercury content from Thimerosal provided by each vaccine dose would be 25 µg, with the exception of hepatitis B vaccine (12.5 µg per dose). The authors cite the FDA study by Ball et al from 1999, which indicates that Thimerosal-free vaccines were available for Hib (FDA approved September and November 1996), DTaP (January 1997), and a combination Hib-hepatitis B vaccine (October 1996). So it is possible that children in the VSD, specifically those in the later birth cohorts, may have received some Thimerosal-free vaccines (Hib at 2, 4-6, and ≥12 months; DTaP at 2, 4, 6, and 15-18 months; and the combination Hib-hepatitis B at times of Hib administration). Nevertheless, Young et al assumed the mercury content per vaccine dose as described.

Within each vaccine file, the cumulative Hg dose for each individual was calculated based on the number of each type of vaccine received...This calculation resulted in an average Hg dose per person for each birth cohort which served as the exposure variable. Because of interest in particular windows of exposure, Hg doses from vaccine exposure were calculated for the following periods: 1) birth to 7 months; and 2) birth to 13 months. 

In other words, the authors tallied up the number of Hib, hepatitis B, DTaP, and DTP vaccines received from birth to 7 months or birth to 13 months for each birth-year cohort. So for every dose of Hib, DTaP, or DTP vaccine dose, 25 µg of mercury was added; for every hepatitis B vaccine dose, 12.5 µg was added. Young et al then divided that cumulative mercury dose for each birth-year cohort by the number of children in the cohort—for instance, approximately 51,267 for 1995. This number, the average mercury dose per person per birth cohort, was designated the "exposure variable."

Logic would dictate that the cited cases in the VSD could have received no vaccines (other than oral polio) between birth and 7 months or a maximum of 3 Hib, 3 DTaP, and 4 hepatitis B vaccines (including one at birth) during that time frame, for an ethylmercury dose ranging from 0 to 200 µg. Figure 1 bears out this thinking, with the exposure variable ranging from ~110 µg (for 1990) to ~145 µg (for 1992). 

Graphs plotting the Hg dose by birth cohort as well as prevalence of a particular disorder by birth cohort were constructed. Poisson regression analysis was used to model the association between prevalence of event of interest and Hg dose...Parameter estimates from Poisson regression models were used to obtain rate ratios. Hg dose was modeled as a continuous variable and rate ratio estimates and 95% confidence intervals were calculated to determine the change in prevalence rate of each diagnosis per unit increase in Hg dose from Thimerosal-containing vaccines.

So after all the aforementioned maneuvers, Young et al estimated a rate (or risk) ratio for each diagnosis per each 100-µg change in mercury exposure by using Poisson regression models, which is about as useful to me as saying, "Presto Change-o." It's now a deep-field punt to EpiWonk to discuss (further) the use and validity of a Poisson regression to estimate these ratios; but before I do, I ask 2 questions in particular: 1) Is it appropriate to assume a linear regression between ethylmercury and the ICD-9 codes, especially when considering such miniscule doses of ethylmercury? 2) Given that the average ethylmercury exposure per birth cohort is somewhere between 100 and 150 µg, does it make sense to stratify disease risk on the basis of 100-µg changes in ethylmercury exposure?

---

Conclusions: The most concerning methodologic issue in the study by Young et al is the liberal imputation of cases, which the authors justify on the basis of shorter follow-up times for later birth-year cohorts. The practice challenges credulity, in part because the percentage increases for neurodevelopmental diagnoses are so much higher than those for control cases (discounting congenital anomaly data). But also, the authors do not provide enough raw data (eg, prevalence rates per birth cohort) to enable the confirmation of data. The authors also make assumptions about the amount of ethylmercury delivered from vaccines, particularly in later years, which may not be accurate. Some Thimerosal-free vaccines were available in late 1996 and may have been administered to children in the 1995 or 1996 birth cohorts.

Last, the estimated rate ratios per change in mercury exposure demand a considerable amount of trust from the (nonstatistician) reader, which is sharply limited in this writer after the authors' imputation of cases.

Next: Results.

Like Orac, I'm perfectly happy to let EpiWonk (who appears far more qualified than I am) to dissect the methods of the recently published study by Heather Young and Mark and David Geier, which links thimerosal exposure to autism. However, given that the study is published in the Journal of the Neurological Sciences, I should be able to understand and critique it. I am, after all, a member of the journal's intended readership.

So here goes—although, like EpiWonk, I'm posting in installments, beginning with the article's introduction.

Thimerosal is an organic mercury-containing compound that is 49.55% mercury (Hg) by weight, and initially metabolized to ethylmercury compounds and thiosalicylate [3].

The mercury in thimerosal, a bacteriocidal vaccine preservation, exists in the form of ethylmercury that is bound to thiosalicylate. In an excellent historical review, Duke epidemiologist Jeffrey Baker, writes, "Much in the thimerosal debate hinges on the alleged similarity, or dissimilarity, of ethylmercury to methylmercury," and "[T]he chemical distinction is not trivial; it may be compared with that between ethanol (in the form of alcohol in wine) and its highly lethal counterpart methanol." The FDA concurs that ethylmercury should be distinguished from methylmercury.

In a 2002 statement, WHO wrote that the half-lives of methylmercury and ethylmercury are 1.5 months and less than 1 week, respectively, and concluded, "Thus, exposure to ethyl mercury in blood is relatively brief. Ethyl mercury is actively excreted via the gut, whereas methyl mercury accumulates in the body." These conclusions were reiterated by WHO in a 2006 statement.

The American Academy of Pediatrics and the US Public Health Service in 1999 [4] published a joint statement that urged "all government agencies to work rapidly toward reducing children's exposure to mercury from all sources." The statement recommended that Thimerosal be removed from vaccines as soon as possible as part of this overall process.

While the above statements by Young et al are true, the joint statement also reads: "[T]here are no data or evidence of any harm caused by the level of exposure that some children may have encountered in following the existing immunization schedule. Infants and children who have received thimerosal-containing vaccines do not need to be tested for mercury exposure," and, "The large risks of not vaccinating children far outweigh the unknown and probably much smaller risk, if any, of cumulative exposure to thimerosal-containing vaccines over the first 6 months of life."

Exposures to Thimerosal through pediatric vaccines, however, still occur in the US and worldwide. Thimerosal continues to remain in most formulations of influenza vaccine recommended for administration to pregnant women and infants in the US, and in many of the childhood vaccines used in other countries where multiple-dose vaccine vials are utilized [6].

In the United States, thimerosal has not been used as a preservative in routinely recommended childhood vaccines since 2001, with the exception of some influenza vaccines (containing ~25 μg of ethylmercury per 0.5-mL dose); these vaccines are also available in thimerosal-free formulations. Young et al cite a 2002 statement from WHO, which concluded in 2006 that findings from 4 independently conducted epidemiological studies in the United Kingdom, Northern Ireland, and Denmark "do not challenge the safety of existing thiomersal-containing vaccines in infants."

WHO added, "Recently two studies were published alleging reduction of neurodevelopmental disorders in the United States of America following discontinuation of thiomersal-containing vaccines in the national immunization programme. The Committee found the conclusions made by the authors unconvincing due to the study design, and the data source...The Committee concluded, and advises accordingly, that there is no reason on grounds of safety to change current immunization practices with thiomersal-containing vaccines, as the risks are unproven."

The authors of at least one of the studies dismissed by WHO are (you guessed it) Mark and David Geier. The other study dismissed by WHO is presumed to be a 2006 Geier study published in the same dubious journal, the Journal of American Physicians and Surgeons (which is not included in the PubMed database).

Hg exposure from Thimerosal-containing vaccines administered to American infants in the 1990s, in conjunction with environmental Hg exposure, resulted in some infants receiving cumulative Hg doses for the first 6 to 12 months of life that were in excess of the US [EPA], the US [FDA], and the US Agency for Toxic Substances and Disease Registry (ATSDR) safety guidelines established for methylmercury, a closely related chemical compound to the ethylmercury found in Thimerosal [7].

This statement deserves further explanation, and Baker provides important context. In response to a rider to the FDA Modernization Act, which was concerned with environmental mercury exposure, the FDA's CBER performed a risk assessment of thimerosal in vaccines. The study was completed in 1999, and as Baker writes, "The actual cumulative exposure varied considerably, given that not all manufacturers used the preservative." He continues, "[B]ut the CBER scientists calculated that a minority of infants could receive as much as 187.5 [μg] of ethylmercury during the first 6 months of life. Lacking any standard for ethylmercury, the CBER team compared this exposure to standards for methylmercury and discovered that it exceeded that set by the [EPA]."

For their support, Young et al cite, curiously enough, a 2005 Canadian reference that concludes, "The guidelines for long-term mercury exposure should not be used for evaluating risk from intermittent single day exposures, such as immunisation using thiomersal-containing vaccines...Because of the contribution to overall mercury exposure from breast milk and diet in later life, the removal of thiomersal from vaccines would produce no more than a 50% reduction of mercury exposure in infancy and <1% reduction over a lifetime." The Canadian authors did not advocate the use of thimerosal-free vaccines over current thimerosal-containing vaccines, particularly in developing countries.

It is important to note that the National Research Council of the US National Academy of Science in 2000 determined that there is a causal relationship between childhood methylmercury exposure and neurodevelopmental disorders [8].

This report concerned itself exclusively with methylmercury (the major source of which for Americans is contaminated fish) and found epidemiologic associations between high and/or chronic, environmental methylmercury exposure and developmental neurotoxic effects—nothing particularly new. There is scant mention of ethylmercury, and the Council makes no conclusions regarding any relationship between ethylmercury exposure and neurodevelopmental disorders (at least, not that I could find). 

Parenthetically the report did cite (among many references) a 1979 case report (Table 5-7) from Romania, in which a mother and her 3 children suffered neurologic, muscular, and cardiologic effects after consuming the meat of a sick hog that had eaten ethylmercury-tainted seed. Two of the children died, presumably due to cardiac arrest. Mercury poisoning was confirmed by very high levels in blood, hair, and 24-hour urine samples. This study was questionably cited in a 2007 review article by Geier, Sykes, and Geier to support their claim that "further incidents of mercury poisonings by ethylmercury compounds continued to offer substantial evidence and disclose a pattern of extreme toxicity produced by ethylmercury in humans."

Geier et al's brief discussion of the Romanian case report is accompanied by citations of the accidential ingestion of fungicide-tainted food in China (1984) and Ghana (1974). According to the EPA, methyl- and ethylmercury were used in fungicides for crop seeds up until the 1970s, but their use was banned in the United States and is "subject to severe regulatory restriction worldwide." In the Romanian case studies, the implicated fungicides contained 1%-2.5% ethylmercury, in which case 100 g (~3.5 oz) of fungicide would contain up to 2.5 g of ethylmercury (100,000 times more ethylmercury than that delivered in a dose of influenza vaccine).

---

 

The introduction to Young et al's article suggests a heavy reliance on a proposed link between methylmercury and ethylmercury, which isn't justified on the basis of known pharmacokinetic properties. Specifically the half-life of ethylmercury is much shorter than that of its methyl counterpart, and microgram doses of ethylmercury do not appear to bioaccumulate. In other articles, Geier et al have cited epidemiologic reports, which suggest that very high doses of ethylmercury are toxic to humans (like just about every substance, including essential ones, on planet Earth). Clearly microgram doses of ethylmercury are bactericidal, which is why thimerosal was in vaccines in the first place; however, it is misleading (in my constitutionally protected opinion) to generalize adverse effects associated with very high-volume ingestion of ethylmercury in fungicides to potential adverse effects associated with miniscule amounts in a vaccine preservative.

 

Moreover, the examination of the vaccine data (with the exclusion of the questionable studies by Geier and Geier) doesn't support the generalization. In fact, the authoritative sources cited by Young et al in their introduction (specifically WHO and the AAP/US Public Health Service) conclude that there is no evidence of harm from thimerosal-containing vaccines. It is particularly curious that Young et al cite a 2002 statement from WHO, which specifically dismissed a study from Geier and Geier in 2006, calling the authors' conclusions "unconvincing."

Coming up: "Materials and methods," with probably heavy deferrals to EpiWonk.

HT to neurodiversity for providing EpiWonk link.

Image: iStockPhoto

And it's BEAU-TI-FUL.

After Monday's post, which questioned the IRB approval of the Geier study, "Thimerosal exposure in infants and neurodevelopmental disorders," I was notified of a link to the Geiers' 2004 response letter that addressed their alleged confidentiality breaches of the VSD.

Several excerpts from the Geiers' (father and son) response letter to the Kaiser IRB office merit comment, and I admittedly draw on relevant insights made Wednesday by "Emily" at AutismVox.

In their 2004 letter, the Geiers acknowledge the 2 questions stipulated by the IRB-approved protocol: 1) Does acellular DTaP increase the risk for acute adverse event (list of 15 [ICD-9 codes]) within 30 days following vaccination? And 2) Does acellular DTaP increase the risk for chronic adverse event (same list of 15) within 1 year following vaccination?

The Geiers then respond to the alleged deviation from the IRB-approved protocol as follows:

In the brief time we were able to access the VSD data on October 9-10, 2003 CDC allowed us to access datasets with the following information per patient identifier number: specific vaccine and brand name [emphasis added], ICD-9 code and date of diagnosis assigned, maternal age, APGAR score at birth, birthweight, gestation and race.

Here the Geiers seem to imply that identification of the vaccine brand name was part of the IRB-approved protocol, because the CDC allowed access to this information.

The ICD-9 codes were limited to 15 set forth in the approved IRB protocol. We are currently in the process of analyzing the temporal relationship between the administration of the vaccine and these 15 ICD-9 codes. Therefore, for the CDC to allege that we have violated the protocol is disingenuous since we have not even been allowed to finish our analysis.

Interesting. If I'm reading this correctly, the Geiers claim that they did not violate protocol, because they were prevented from doing so in January 2004 after being caught in flagrante delicto by VSD monitors. (See CDC warning letter: "[T]he researchers...on the second visit attempted to carry out unapproved analyses but did not complete this attempt.")

Further, since different brand name vaccines are used, it is not violative of the protocol to examine whether or not an acute or chronic condition is associated with a specific vaccine and not accellular[sic] DtaP vaccines in general.

Now the Geiers appear to contradict their first claim (ie, identification of the vaccine brand was part of the IRB-approved protocol) by asserting their interpretation that the protocol should really allow identification of vaccine brands. Perhaps the Geiers' assertion is based on their reading of the "spirit" of the protocol and not on the literal wording of the protocol. In any event, it seems a very loose interpretation, if not an outright violation. 

If a statistically significant relationship is found based upon the brand of vaccine administered this information should be vitally important to you as well as the CDC.

So the Geiers add, in head-spinning fashion, that Kaiser and the CDC should really be interested in this information anyway, regardless of what the protocol says—an argument that, of course, doesn't defend an alleged violation (or attempted violation) of protocol.*

In the second half of the letter, the Geiers recite a litany of VSD security measures to rebut the claim that they tried to merge VSD datasets in violation of protocol. However, the section reads more like a tirade against draconian government security than a defense against their alleged violation of protocol. The Geiers further imply that the VSD data are being kept from the public in conspiratorial fashion.

They then write:

It is impossible for the datasets given to us by CDC to be merged...It is impossible therefore to construct a dataset that contains any information on one patient that links the vaccines administered to the ICD-9 diagnosis.

As Emily at AutismVox suggests, wouldn't this conclusion have to be drawn empirically, after first attempting to merge the datasets (in violation of protocol)?

It should be pointed out that CDC and its approved external researchers have full access to this type of information, not us.

The Geiers again suggest a government conspiracy to keep the VSD data from the public, and more specifically from themselves.

They then conclude:

[W]e were asked by members of Congress to investigate the VSD, especially with regards to the thimerosal and neurodevelopmental disorder issue. Therefore, we were only doing the study which the Congress asked us to do...

It does appear that certain sympathetic members of Congress facilitated the Geiers' study of the VSD and perhaps even the study's ultimate IRB approval, despite the alleged protocol violations. For instance, in February 2006, 8 congressional members (Senators Joe Lieberman and Debbie Stabenow and Reps. Dan Burton, Dave Weldon, Carolyn Maloney, Joseph Crawley, Chris Smith, and Maurice Henchey) signed a letter to the head of the National Institute of Environmental Sciences, urging the use of the VSD data to examine a potential link between thimerosal and autism (despite the acknowledged conclusion of the IOM in May 2004). Moreover, the congressional members advised the NIES to work with the CDC and external researchers, because "a CDC-led study would be viewed with much skepticism." Now that's a shocking and unmerited slap in the face (and even an implied allegation of corruption) against a government organization that's charged to monitor and guide public health. 

Well the congressional leverage appears to have worked, and perhaps then some. The protocol in the Geiers' published study is considerably broader than that described in 2004. For instance, the original protocol stipulated the examination of 15 ICD-9 codes; however, the published study (Table 2) describes 26 ICD-9 codes for neuro-developmental disorders and 6 codes for "control disorders." Likewise the vaccine database appears to have been broadened to include oral polio, Haemophilus influenza type b, hepatitis B, and whole-cell DTP vaccine data—as well as DTaP data.

*It's interesting that the Geiers focus so heavily in their letter on the identification of vaccine brands in the VSD, an issue not mentioned by the CDC in its warning letter. Of course, the ultimate concern is that identification of individual patients or vaccine brands might be used to inform plaintiff litigation (which is how Dr. Geier earns his keep) against particular companies.

Image: iStockPhoto

The idea that thimerosal-containing vaccines are associated with the development of autism has been broadly and compellingly refuted (see, for instance, authoritative conclusions rendered by the Institute of Medicine and the CDC). Moreover, autism rates have continued to climb, despite the removal of the ethylmercury preservative from routine childhood vaccines since 2001.* Nevertheless, the editorial board of the Journal of the Neurological Sciences, a self-described peer-review journal, finds it necessary to revive the debate in arguably unnecessary fashion by publishing a study that was funded by the Autism Petitioners' Steering Committee and written by plaintiffs' consultants in vaccine litigation.

Talk about your potential conflicts of interest. Given the well-known positions of the study's coauthors—in particular, those of Mark R. Geier, MD, PhD, and his son David Geier (see, for instance, a 2005 profile of the duo by the NYT and a considerable amount of research conducted by Kathleen Seidel at the neurodiversity blog)—it is not surprising that the authors concluded an "association between increased Hg exposure from Thimerosal-containing vaccine and neurodevelopmental disorders."

But the article and additional investigation raise several questions that go beyond the merits of the study itself (which will be discussed in another post). For instance:

1. Was the study protocol, which drew on Kaiser HMO data from the CDC's Vaccine Safety Datalink (VSD), in fact, approved by Kaiser's institutional review board (IRB) as described?
2. What was the decision process among the editorial members of the Journal of the Neurological Sciences that led to the publication of such a questionable study?
3. What exactly is the nature of the body of work conducted by Geier and Geier?

For now, I will address (in as much as I can) the first and second questions.

In the article's Materials and Methods section, the authors claim, "The study protocol employed was approved by the US Centers for Disease Control and Prevention (CDC), the Institutional Review Board (IRB) of Kaiser North-West, and the IRB of Kaiser Northern California." However, an online source suggests that this may not be so, or that there was at least a hitch in the approval of the study given the conduct of its researchers.

In a February 2004 letter to the IRB administrator of Kaiser of Northern California, the then Acting Associate Director for Science of the National Immunization Program at the CDC, Jeanne Santoli, MD, warned Kaiser of "potential breaches in confidentiality and execution of analyses that were not approved in advance," when Mark and David Geier visited the CDC Research Center in Hyattsville, MD, in October 2003 and in January 2004 to collect data from the VSD.

Kaiser's IRB administrator, Leigh Pruneau, RN, PhD, then wrote a letter the following week, informing Mark Geier that his research project was suspended pending his response to the CDC allegations. The letter advised Geier that "you and your co-investigator are prohibited, until notified otherwise, from accessing VSD data derived from Colorado Kaiser Permanente and Northern California Kaiser Permanente institutional officials," and continued:

Federal regulations and KPNC/IRB policy prohibit conduct of research that has been suspended by the IRB. The IRB is required to report, and will proceed to report, the suspension of this study to the CDC and Kaiser Permanente institutional officials.

The following actions are required:

• You must immediately cease all activities which involve Kaiser Permanente data, as it is required by federal regulations and KPNC IRB policy.
• You must inform the IRB of any research-related activity continued beyond this notification of study suspension, providing the reason(s) for continuation.
• You must provide written notification of study suspension and the required cessation of all research activities to the co- and sub- investigators, if any, participating in this research within five business days of receiving this notification.

The IRB requires that you provide your response to the CDC's letter to KFRI via e-mail to KPNC IRB on Lotus Notes, or KPNC.IRB@kp.org, or by U.S. Mail by noon on March 8, 2004, for review at the March 18, 2004 IRM meeting.

It is currently unknown to me if the CDC's allegations were resolved or even addressed by Geier and his coinvestigator or if Kaiser ever gave the go-ahead to continue the study. An inquiry to the CDC reveals that the current Acting Director of the CDC's Immunization Safety Office, John Iskander, is aware of the published study, and that the CDC is preparing a response. E-mails sent to Kaiser's public relations office and its IRB office regarding Kaiser's approval of the study are, so far, unanswered.

On the flip side, Ed Silverman at Pharmalot published yesterday a less-than-thoughtful piece on the study's publication, which frankly reads like a press release from the study's researchers and/or the Autism Petitioners' Steering Committee. Beginning with Silverman's graf 7, the steering committee chides the Federal government, the vaccine makers, and the HMOs for not conducting any studies in the VSD database, and claims that the study's investigators were hampered in their mining of the VSD data: 

First, the government refused to produce the automated data in a way that would have allowed the investigators to link vaccine-mercury exposure to outcome data in individuals...

Second, the government and the HMO’s refused to permit access to any data entered after the year 2000, which meant that the maximum follow up period of the neurodevelopmental disorders for some children was only to four years of age. Specifically, for children born in 1997 or later, this restriction to access prevented any examination of true prevalence rates for those later birth cohorts.

Third, only three of the eight HMO’s participating in the taxpayer funded database permitted even this limited access (Northern California, Colorado, and Oregon Kaiser plans). Other HMO’s blocked access to the data on hundreds of thousands of additional children.

The steering committee then alleges that plaintiffs' families have been denied access to the "taxpayer-funded" VSD by the government and the courts. Regardless of what the steering committee believes, their statements do not address the IRB approval of the study and, in fact, suggest unresolved issues with respect to the use of the VSD data by the study's authors.

Nevertheless, it is certainly possible that the CDC's alleged confidentiality breaches from 2004 were resolved by Geier and that the study protocol as published in the Journal of the Neurological Sciences was, in fact, ultimately approved by the CDC and the respective Kaiser IRBs; however, if this is not the case, the study's claim of IRB approval would be seriously undermined and suggest poor judgment on the part of the journal's editorial board to publish the work.

To that end, I e-mailed Robert Lisak, MD, the journal's editor (as well as chair of the Department of Neurology at Wayne State University and a highly regarded neurologist), asking for any comments on the study's publication. His response was disappointing and of ultimate brevity: "None."

05/21/08 update: An e-mail reply from the Kaiser IRB office provides the following information. "The objections stated in the referenced letter were resolved and the study was ultimately approved by the IRB—as is stated in the published article." How the objections were resolved is not described.

*Thimerosal has not been used as a preservative in routinely recommended childhood vaccines since 2001, with the exception of some influenza vaccines.

So who can use the emblematic red cross?

Evidently the American Red Cross still can, but I found it a bit challenging to determine from the media and press releases the prevailing decisions that came down Wednesday in the case of Johnson & Johnson and Johnson & Johnson Consumer Companies, Inc. v. The American National Red Cross. So here's a tabulated form of the remaining or dismissed (struck-out) claims and counterclaims from US District Court Judge Rakoff.*

JNJ Claims	ARC Counterclaims	Counterclaims of Codefendents Water-Jel, Magla, Learning Curve, and FAO
Tortious interference by all defendants with plaintiffs' prospective economic advantage† Tortious interference by ARC with plaintiffs' existing contractual relations Unfair competition by all defendants Promissory estoppel against ARC‡ Unlawful dilution by all defendants of plaintiffs' federally protected trademark rights Unlawful dilution by all defendants of plaintiffs' trademark rights under New York law Breach of contract by FAO Breach of contract by Water-Jel	Violation by JNJ of 18 U.S.C. § 706 Cancellation of JNJ's trademark Unfair competition by JNJ	Invalidity of JNJ's trademark Cancellation of JNJ's trademark

*From the Annals of Neither Here Nor There, Judge Rakoff was the judge who ruled in 1997, just hours before a Knicks play-off game, that the NBA had the right to suspend Patrick Ewing and 4 teammates for joining an on-court brawl against the Miami Heat.

†In a prior ruling, the claim was limited to interference with JNJ's business relationships with retailers Target, Wal-Mart, Walgreens, and CVS.

‡Dismissed in a prior ruling.

What's harder to get than a drug prescription from your doctor? Answer: an implanted stent from your doctor.

Nevertheless, there's much ado about a DTC television ad for the Cypher stent from Cordis (a JNJ subsidiary), which aired nationally last fall but can now only be viewed in the Baltimore area, according to the WSJ Health Blog. Today both the NYT and the WSJ report on an NEJM editorial against the ad, which was published online yesterday.

In the NEJM perspective, cardiologists William Boden, MD, and George Diamond, MD, question the propriety of airing a medical-device ad to "millions of people who are ill-equipped to make judgments about the many clinically relevant but subtle and complex therapeutic issues that even specialists continue to debate." Despite acknowledged benefits of DTC advertising to both the public and industry, the authors write that they are troubled by the limits of TV ads generally to disclose risks and find the Cypher ad, in particular, overpromising with respect to depicted functional outcomes.*

The curious aspect of the editorial, however, is Boden's and Diamond's objection to promoting a medical device that "can be selected and implanted only by someone with a very sophisticated medical understanding." They write, "It seems almost unimaginable that a patient would challenge an interventional cardiologist's judgment about the use of a particular stent or that a cardiologist would accede to a patient's request for a particular stent on the basis of the information gleaned from a television ad."

So at this point, I'm not sure what their objection is to the Cypher ad: Is the Cypher ad objectionable because it is misleading and therefore potentially harmful, or is the ad objectionable because it is useless, even absurd?

*Last year, Boden et al published "Optimal medical therapy with or without PCI for stable coronary disease," in which the rates of a number of vascular outcomes were no different between patients who underwent percutaneous coronary intervention and those who received optimal medical therapy alone. For what it's worth, Boden reports consulting fees from CV Therapeutics and PDL BioPharma; lecture fees from CV Therapeutics, sanofi-aventis, BMS, and Abbott; and grant support from Abbott.

Photo of Cypher (sirolimus-eluting coronary stent) from http://www.cypherusa.com/cypher-j2ee/cypherjsp/main_splash/stent.jsp.

China's not the world's only source of counterfeit drugs. Perhaps 20% of pharmaceuticals in India may be fake, according to a story in today's Times of India. Moreover, 75% of fake medications distributed throughout the world may come from India, claims the Organisation for Economic Cooperation and Development. To clarify the extent of the problem, India's drug controller general is initiating a 5-million-rupee (~$118,000-USD) 6-month study, in which inspectors will anonymously pick up 31,000 drug samples—representing a wide range of therapeutic classes—for testing.

India's health ministry and others, however, dispute the estimated magnitude of the problem and suggest that 5% or less of Indian drugs are counterfeit. One drug expert doubted the wide extent of counterfeiting in India, because legitimate drugs can already be made there at rock-bottom prices. "India is the only country where tableting, packaging, and carton costs are more than the cost of the actual active medicine," quotes the paper.

Nevertheless, India's health secretary agrees that the extent of counterfeiting should be determined, and the controller general's study design is evidently awaiting financial approval from the health ministry. 

HT: WSJ Health Blog.

Photo: iStockPhoto.

Peter Libby, MD, now refuses pharma fees for his consulting services not because of impropriety, but because of the growing perception of impropriety. The chief cardiologist at Brigham and Women's Hospital in Boston told NPR's Madeline Brand last week that his decision was motivated by negative comments in the blogosphere after he appeared in a public-service documentary on PBS.

The documentary, "The Hidden Epidemic: Heart Disease in America," was a 4-year, unpaid labor for the doctor, according to a recent mini-profile in the NYT. However, shortly after the show's airing in October, Roy Poses, MD, at the Health Care Renewal blog raised conflict-of-interest (COI) issues, given that the show was funded by pacemaker-producer Medtronic and statin-maker AstraZeneca and that Libby, in particular, had an undisclosed relationship with AstraZeneca (although that relationship was not specified by Poses, other than in the form of grant support, consulting services, or participation on a speakers' bureau—which are important to distinguish [see below]).

Poses also discovered that another program participant, Douglas Zipes, MD, of Indiana University, had an undisclosed relationship with Medtronic. However, Poses did not identify particular instances in the documentary in which undue influence appeared to be exerted by the funding companies or by the participating experts themselves—other than to cite the unbranded claim that some cardiac arrhythmias are treated with implantable pacemakers (ho hum).

Yet despite the lack of specific examples suggesting commercial influence on the documentary's content, Pharmalot's Ed Silverman posted the story, arguably fomenting the unfounded perception that the program or its physician participants were biased, solely on the basis of their undefined relationships with the 2 supporting companies. Silverman (and Poses) also neglected to call out other documentary participants, including outspoken pharma critic Steven Nissen, MD, of the Cleveland Clinic.

In a moment of needed clarity, one Pharmalot commenter ("Reality") wrote:

Oh dear, another case of the COI vapors! Overall, I'd say this ranks around an 8 out of 10 on the conflict-of-interest overreaction scale...[F]rom what I've read, this was a simple, layman's educational series. No specific products were mentioned and what they reported in terms of treatments was straigh[t]forward and followed expert guidelines...

Should the advisors' ties to AZ and Medtronics...been noted? Probably. But I think the level of criticism here goes far beyond the seriousness of the infraction, or lack thereof. Look, there are some very real and very troubling COI issues out there, but to me, this is not one of them. This is a case of someone looking for a problem.

When Libby was asked by NPR last week if he could have been unconsciously* biased given his relationships with pharma, he denied influence. Because he has worked with "virtually every company that has produced, manufactured, sold, or even thought about producing, manufacturing, or selling" any cardiovascular product, he could claim no particular commercial allegiance.

Libby believes that academic investigators should be involved with pharma to ensure the integrity of clinical trials and, ultimately, the public good. Unfortunately Libby's decision to now refuse pharma money may confirm to a suspect crowd that his previous choice to do so was, somehow, improper.

N.B. In the 5-minute segment featuring Libby, NPR made a disingenuous, if not inaccurate, segue from the discussion of Robert Jarvik^† appearing in Lipitor's DTC ads to physicians consulting for or receiving grant support from commercial interests. In doing so, NPR failed to make important distinctions among 1) the appearance of physicians in advertisements, 2) their participation in speakers' bureaus, 3) their participation in advisory boards, and 4) the receipt of grant support.

*Of course, consciously assessing unconscious influence is really difficult, given that the influence, by definition, hasn't bubbled up to consciousness. So it's a very difficult question to answer, other than to ensure that there are conditions (such as consulting for everybody) that make unconscious bias toward one company unlikely.

†NPR also falsely stated that Jarvik is not a medical doctor. Jarvik evidently earned his MD from the University of Utah; however, to my knowledge, he does not hold an active license to practice medicine.

Progress in the study of stem cells for neurologic conditions is outpacing ethical oversight in the United States, according to a multiauthored "review-itorial" in last week's online version of Neurology. At least 6 stem-cell products are currently under investigation for neurologic disorders (tabulated below), one of which is in phase 1 development, despite the fact that no review is required at the national level for their study.* Like any other human clinical trial, the study of stem cells is currently relegated to institutional review boards (IRBs) and the FDA, in addition to local embryonic stem-cell research oversight committees (ESCROs).

Condition	Status	Stem Cell Line	Sponsor
Batten disease (infantile or late infantile neuronal ceroid lipofuscinosis)	Phase 1	HuCNS-SC (human fetal brain) (n = 6)	StemCells (study location: Oregon Health and Science University)
Post-stroke	Preclinical	MultiStem (adult bone marrow)	Athersys
Post-stroke	Preclinical	NurOwn (human autologous bone marrow–derived neural-like cells)	BrainStorm Cell Therapeutics
Spinal cord injury	Preclinical	GRNOPC1 (human oligodendrocytes and dopaminergic neurons)	Geron
Post-stroke, Huntington's disease	Preclinical	NtCell (porcine choroid plexus)	Living Cell Technologies
Post-stroke	Preclinical	ReN001 (human cortical brain)	ReNeuron

The authors acknowledge that many of the ethical issues raised by the clinical study of stem cells are similar to those in any clinical endeavor; however, there are ethical challenges which are specific to something as novel as stem-cell clinical trials, particularly when they involve the central nervous system. These include heightened risks related to the development of abnormal brain function, which may be difficult to discern and the timing of which is unclear, and the possible transmission of genetic disease (which is not necessarily peculiar to the stem-cell treatment of neurologic conditions).

*National review of stem-cell study is, for instance, required in the UK by the Human Fertilisation and Embryology Authority.

The only really intesting piece of information that came out of yesterday's House Subcommittee Hearing (Direct-to-Consumer Advertising: Marketing, Education, or Deception?) is how many documents Pfizer and Schering-Plough have supplied separately to Representative Dingell's panel to date. James Sage, senior director of Pfizer's Lipitor team, unequivocally stated 290,000 pages, and Merck/Schering-Plough's Deepak Khanna echoed the number.*

So what does that mean in terms of the number of trees sacrified (assuming that the paper supplied was not recycled)? Well if you buy into the idea that an average pine tree produces 80,500 sheets of paper, then just over 7 trees were required to produce the amount of paper sent by the 2 companies together to Congress.

*Ortho Biotech's Kim Taylor said that she believed her company had supplied something considerably less than 290,000 pages but didn't know the exact number.

Thanks be to Pharmalot for providing the live feed of the hearing.

2008 is becoming the year of reckoning, thanks in part to the anti-vax movement. Today's MMWR reveals that 64 cases of measles—a disease declared eliminated in the United States in 2000—have occurred so far this year in the country.* Compare that number with the average 62 cases annually during the last 8 years, and you've got the expectation for a dubious record in 2008.

According to the MMWR, most reported measles cases (84%) this year were due to imported disease from other countries (59 patients were US residents), and the overwhelming majority occurred in persons who were unvaccinated or whose vaccination status was unknown. Exactly half of the patients were younger than 5 years; 14 were younger than 1 year and therefore not eligible for immunization. Among the 21 US residents aged 16 months to 19 years, two thirds claimed exemption from vaccination because of religious or personal beliefs. Twenty-one measles patients were adults (including 1 US resident born before 1957). 

Although 14 (22%) of those affected were hospitalized, there were no fatalities. Possibly the most shocking revelation is that 1 patient was an unvaccinated health care worker who acquired the disease in hospital. Another 17 individuals were infected while visiting a health care facility, including a 12-month-old child who, ironically, was exposed to the virus in the physician's office while receiving a routine MMR vaccine.

Details of the 2008 measles cases are tabulated below, and the MMWR provides a very nice annotated map:

Location	No. Cases	Date of Cases/ Outbreak	Source
San Diego, CA	11	01/25-02/16	Switzerland; genotype D5 (Index pt = unvaccinated child who traveled to Switzerland)
Honolulu, HI	3	02/05-02/25	California outbreak (1), Italy (2)
NY, NY	22	02/07-04/20	Israel (2), Belgium (2), Unknown (8); genotype D4
Pima Co, AZ	15	02/13-04/23	Switzerland; genotype D5 (Index pt = unvaccinated adult from Switzerland)
Missaukee Co, MI	4	02/19-04/08	Unknown; genotype D5 (Index pt = unvaccinated 13-year-old)
Fairfax, VA	1	02/25	India
Milwaukee Co, WI	4	03/19-04/09	China (likely); genotype H1 (Index pt = 37-year-old with unknown vaccination status; likely exposed to Chinese visitor with disease)
Los Angeles, CA	1	03/23	Unknown
Pittsburgh, PA	1	04/12	Unknown
Nassau Co, NY	1	04/12	Unknown
Chicago, IL	1	04/17	Switzerland

Although US vaccination levels are high, reports the MMWR, unvaccinated children tend to be clustered geographically or socially, which increases the risk of outbreaks. The article undermines the belief of some vaccine rejectionists that they can coast on the vaccine-provided immunity of other US residents. Cases to date show that the risk of imported disease remains high, and that unvaccinated individuals can propagate the spread of foreign-born infection. It is notable that a substantial measles outbreak occurred earlier this year in San Diego, CA, home of 3 vaccine-rejecting moms who were recently profiled by the NYT. The index patient in the San Diego outbreak was an unvaccinated child, who brought the infection back from Switzerland.

And California receives more negative attention today because of a pertussis outbreak that has closed a private school near San Francisco.  

*Up until April 25.

Chinese health officials continue to claim that the artificial contaminant, oversulfated chondroitin sulfate, in lots of Baxter's recalled heparin was not the cause of the 81 associated deaths and hundreds of allergic reactions that occurred in the United States, reports Reuters. The Chinese assertion comes in the wake of reports in the NEJM and Nature Biotechnology, which described the contaminant as structurally identical to a withdrawn intramuscular drug, Arteparon, and the contaminant's actions on the kinin-kallekrein pathway.

The Chinese food and drug agency points to the fact that only patients in the United States or Germany experienced adverse reactions to the tainted heparin, whereas the contaminant has been found in heparin products in other countries. The Chinese agency also claims that adverse reactions have occurred with some batches that did not contain the contaminant. Both of these assertions, however, have already been rebutted by the US FDA, which cited the relatively common practice of heparin bolusing in the United States and Germany and the initial use of an insufficiently sensitive test for the heparin contaminant.

In what appears to be a digressive move, Chinese officials accuse Baxter of obstructing their investigation of the company's tainted heparin, a charge that Baxter denies. A Chinese regulator is quoted by Reuters: "Baxter failed to provide necessary cooperation in the process of the investigation, which is not conducive to further identifying the reasons for the adverse reactions to heparin." Baxter is also accused of destroying some drug samples and relevant production records—an allegation also denied by the company. Chinese officials also point a finger at Baxter's Chinese heparin supplier Changzhou SPL, implying that the company avoided registration with China's food and drug administration because the company was considered a chemical manufacturer, not a drug maker.

Most important, however, Chinese health officials have yet to explain how the artificial contaminant made its way into heparin. Information to date suggests that the contaminant, which is considerably cheaper than crude heparin, was intentionally introduced into supplies at the workshop level, before processing at Changzhou SPL. 

Spheramine brain implants improve mobility in moderate-to-advanced Parkinson's disease, according to a phase 1/2 open-label pilot study in 6 patients. A 4-year follow-up report* of the study was presented April 29 at the annual meeting of the American Association of Neurological Surgeons in Chicago and through a press release from Titan Pharmaceuticals, codeveloper of the therapy.

According to Titan, Spheramine improved mobility (per UPDRS motor scores) by an average of 44% and patient-reported quality-of-life scores by 23% at 48 months. Titan also claims that there were no Spheramine-related serious adverse events. One-year data from the open-label study justified the initiation of a double-blind, randomized, sham-surgery-controlled trial of Spheramine (STEPS). Information regarding the design of this study was also presented at the AANS meeting, and Titan CEO Mark Rubin, MD, expects results in the third quarter of this year.

Enrollment in STEPS (N = 71) was completed last year and included retired teacher Suzanne Davenport, who experienced a precipitous decline in her clinical status after Spheramine implantation in January 2005. Ms. Davenport's family is currently seeking compensation from Titan and Spheramine codeveloper Bayer Healthcare for her study-related injury.