Ethics: October 2008 Archives

Along with co-applicants Mark and David Geier, TAP Pharmaceuticals* filed an international patent application (PCT/US2007/082866), "Methods of Treating Autism and Autism Spectrum Disorders," in October of last year for the use of Lupron (leuprolide acetate, a GnRH analog), with or without chelation, in children with autism. (A big discovery hat tip for finding this patent application, along with related US patent applications, goes to Kathleen Seidel of the Neurodiversity blog.) The text of this application was published in August May of this year, and treatment descriptions in 7 children can be found if the reader is willing to wade through a lot of repetitive verbiage—including a seemingly endless string of "need in the art," "known in the art," and "skilled in the art."

Essentially, the treatment "invention" of TAP and the Geiers is intended to lower elevated mercury levels in autistic children by giving the chemical castrator Lupron. The applicants base this idea on a 1968 article, which showed that mercuric chloride complexes with testosterone in a hot benzene solution, a condition not possible in living organisms. The patent idea of TAP and the Geiers is to lower testosterone in autistic children by giving them Lupron, which then supposedly frees up toxic mercury. The idea is that the freed-up mercury can then be eliminated with the aid of chelation therapy, if necessary.

However, TAP and the Geiers don't limit their endocrinologic therapy to Lupron, nor their disease targets to autism. They also include the treatment possibilities of antiandrogen hormones (eg, cyproterone [Androcur; Schering-Plough AG]) and birth control pills and propose that mercury toxicity is implicated in Alzheimer's disease, diabetes, heart disease, obesity, amyotrophic lateral sclerosis, asthma, and immune disorders.

What follows is a summary of the pediatric "examples" of TAP's and the Geiers' so-called invention. In all cases of autism, remarkable improvements in gastrointestinal symptoms (if present) and social/cognitive skills are described, sometimes within days of what are described as well-tolerated injections of Lupron.

Subject ages: Four children were of prepubertal age (two 6-year-old boys; a 7-year-old girl; and an 8-year-old boy), and 3 children were within the age range of puberty or beyond (an 11-year-old girl, an 11-year-old boy, and an 18-year-old boy).

Previous treatments: Two of the children (a 6-year-old boy and the 8-year-old boy) had undergone previous chelation therapy with DMSA for approximately 11 and 15 months, respectively. Clinical improvement is described in the case of the 8-year-old boy; the 6-year-old boy did not demonstrate improvement with chelation, according to the patent application. The 11-year-old girl received prescription amphetamines (Adderall; Shire) for the diagnosis of attention deficit hyperactivity disorder, given at the age of 5 years.

Claims of clinical signs of precocious puberty: In no case of the prepubertal or pubertal children is the Tanner stage noted in the patent application. Signs of precocious puberty in 3 of the prepubertal children are vaguely described as increased body, leg, or facial hair; masturbation; "genital development"; or "early sexual behaviors." The 11-year-old girl showed "mild signs of precocious puberty" (whatever those may be) and "fully developed pubic hair" by 8 years of age. These descriptions were presumably obtained in retrospect by history. The girl also began menstruating at the approximate age of 10 years—which is earlier than average, but not precocious.

The performance of GnRH stimulation tests in the patient examples, as recommended by the Lupron Prescribing Information, is not described by the patent applicants. Other diagnostic criteria for central precocious puberty described in the PI, including the documentation of advanced bone age and a number of baseline tests (to exclude congenital adrenal hyperplasia, a chorionic gonadotropin-secreting tumor, a steroid-secreting testicular tumor, and an intracranial [eg, pituitary] tumor), are also not documented in the application. Addendum: Head MR imaging was performed in 2 individuals; however, the timing of the imaging is not provided by the patent applicants.

Mercury assessment: Mercury levels in the absence of chelation therapy are provided only in the case of the 11-year-old boy, whose blood showed "minimal" levels of mercury (1.5 μg/L; reference range, 0.0-14.9 μg/L) and whose urine did not reveal the presence of mercury. The patent applicants claim that urinary porphyrins (specifically urophorphyrin[sic] and hexacarboxylphorphyrins[sic]) were elevated in the 11-year-old girl. Measurements of urinary porphyrins have been proposed by the Geiers to be surrogate markers for mercury toxicity in autism on the basis of a rat study.

Thiol levels: Given that the Geiers have proposed a "decreased detoxification capacity" in children with autism, defined by certain thiol levels, these metabolites were measured in 2 children. Levels of plasma cysteine and reduced glutathione (GSH) were measured during and after the 6-year-old boy's initial chelation therapy, and selected thiol levels were measured in the 8-year-old boy after his Lupron/chelation therapy. The plasma cysteine levels, although below the reference range contained in the patent application, are within the control ranges of those in the literature. In the case of plasma GSH, the levels (when converted to units of μmol/L) are orders of magnitude greater than those found in relevant medical/science articles.

Plasma Metabolite, μmol/L	8-Year-Old Boy	6-Year-Old Boy	Patent Reference	Literature Reference
Homocysteine	5	—	Not given	6.0 ± 1.3a
Cysteineb	226	212	255-320	207 ± 22a
Sulfateb	302	—	302	369-451c
Reduced GSHb	651	651	>1041	2.2 ± 0.9a

^a From James et al, 2006.
^b Presented by the patent applicants in units of mg/dL.
^c From Chattaraj and Das, 1992. 

Testosterone levels: According to the patent applicants, baseline serum testosterone levels were elevated in 2 of their subjects: a 6-year-old boy (23 ng/dL; reference range, 0-20 ng/dL) and the 7-year-old girl (18 ng/dL; reference range, 0-10 ng/dL). They also emphasize high-normal levels of serum testosterone in the 8-year-old boy (25 ng/dL; reference range, 0-25 ng/dL) and the other 6-year-old boy (20 ng/dL). Follow-up testosterone levels predictably rose and then dropped during the Lupron therapy. (According to the Lupron PI, "During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed.")

Lupron therapy: The Lupron therapy for the 7 pediatric subjects is tabulated. Therapy was not uniform and, in some cases, involved supplementation with the non-depot (subcutaneous) formulation of Lupron. The recommended starting dosage for Lupron Depot-Ped, according to the PI, is 0.3 mg/kg every 4 weeks: 7.5 mg if ≤25 kg (≤55 lb); 11.25 mg if 25-37.5 kg (55-82.5 lb); and 15 mg if >37.5 kg (>82.5 lb). How the doses of 22.5 mg IM in the cases of the 8-year-old boy and a 6-year-old boy were derived is not stated by the patent applicants. The Lupron PI also indicates that, if downregulation is not achieved (via GnRH stimulation testing and Tanner staging), the dose should be titrated upward in increments of 3.75 mg every 4 weeks.

Subject	Lupron Therapy
8-year-old boy	Depot, 22.5 mg IM on 11/24/04, 1/20/05, 3/25/05, 5/25/05, and 7/14/05
6-year-old boy	Depot 22.5 mg IM on 4/2/05, 5/21/05, and 7/9/05
6-year-old boy	Depot 15 mg IM followed immediately by 0.2 mL (55 μg/kg) sq à gradually increased in 0.1-mL increments to final dose of 0.4 mL (83 μg/kg) sq qd
7-year-old girl	0.3 mL (55 μg/kg) sq qd à increased by using Depot 15 mg IM to a final dose of 2.0 mg/d (74 μg/kg)
18-year-old boy	Depot 15 mg IM; augmented with 0.2 mL sq qd à gradually increased in 0.1-mL increments to 0.5 mL (45 μg/kg) sq qd
11-year-old boy	Depot 15 mg IM; augmented with 0.4 mL sq qd à gradually increased in 0.1-mL increments to 0.7 mL (32 μg/kg) sq qd
11-year-old girl	Depot 15 mg IM q 28 d plus 3.5 mg sq qd

The Lupron PI states that therapy should be monitored with a GnRH stimulation test, measurements of sex steroids, and Tanner staging. Bone age for advancement should be assessed every 6-12 months. Confirming GnRH stimulation tests and Tanner staging are not described by the patent applicants, nor is there a discussion of the monitoring of bone age during therapy.

In 5 cases, the total duration of Lupron therapy is not specified in the patent application. In the case of the 18-year-old boy, his serum testosterone level dropped from a baseline of 559 ng/dL (reference range, 241-827 ng/dL) to a follow-up level of 28 ng/dL. The serum testosterone level of the 11-year-old boy dropped from a baseline of 153 ng/dL to 35 ng/dL after "several months of treatment." Essentially both boys were subjected by the applicants to chemical castration with Lupron at the end or beginning of puberty, respectively.

The 11-year-old girl, who began menstruating at the age of 10 years, most likely underwent chemically induced menopause with her Lupron therapy. This girl was also treated with "low dose birth control pills," presumably in conjunction with her Lupron therapy. The rationale for prescribing OCPs with Lupron in the 11-year-old girl is not stated by the applicants. (I'm out of my medical territory here, but I've only heard of prescribing Lupron with OCPs in the setting of infertility therapy.)

The Lupron PI states that discontinuation of the drug, when used for central precocious puberty "should be considered before age 11 for females and age 12 for males." This recommendation is presumably to allow timely puberty to begin. In adults, Lupron is FDA indicated for the treatment of prostate cancer, endometriosis, and uterine fibroids.

Chelation therapy: Only 2 subjects, the 8-year-old boy and a 6-year-old boy underwent chelation therapy. In the case of the 6-year-old boy, chelation preceded Lupron therapy. The 8-year-old boy underwent chelation after the initiation of Lupron therapy. The rationale for starting chelation therapy before Lupron injections is not stated by the applicants.

Other hormonal therapies: In addition to the OCPs prescribed for the 11-year-old girl, the 8-year-old boy began therapy with the antiandrogen cyproterone acetate (Androcur; Schering-Plough AG) 50 mg tid between his 2nd and 3rd doses of Lupron. Cyproterone acetate was prescribed for an unspecified period of time.

TAP's name* on this international patent application, along with the Geiers, is more than just a little troubling, given that pediatric subjects were treated with the company's proprietary drug in a maverick, off-label fashion on the basis of dubious theories about autism. Moreover, this off-label treatment, with TAP's evident involvement or knowledge, was performed without clinical-trial protocols (specifically those for the protection of human subjects) being noted in the patent application. In addition, adherence to on-label treatment guidelines, as recommended by the company's prescribing information, is not described. Clearly 3 autistic pediatric patients, who were at the beginning or end of puberty, received a drug that is known to disrupt reproductive function.

DMSA = dimercaptosuccinic acid; GnRH = gonadotropin-releasing hormone.

* Given the dissolution of TAP, it's unclear whether Abbott or Takeda is now the primary applicant for this international patent. Abbott has apparently taken over the Lupron franchise.

In their recently published study in the Journal of the Neurological Sciences, Geier et al not only presented values for transsulfuration metabolites in children with autism spectrum disorder (ASD); they also measured urinary porphyrins. Their rationale for doing so was to test a pet theory that autism is due to a reduced ability to excrete environmental mercury, as a result of an innate "decreased detoxification capacity"—which is proposed to be characterized by altered levels of transsulfuration metabolites. (The questionable values for some transsulfuration metabolites presented by Geier et al in the JNS article and elsewhere have been discussed here, here, here, and here.) In addition, because investigators have not been able to consistently find elevated mercury levels in children with ASD by direct measurement, Geier et al have turned to the use of "mercury intoxication-associated urinary porphyrins" as markers of mercury toxicity (most notably from thimerosal-containing vaccines) in children with ASD. In the JNS article, they write,

[I]t was previously demonstrated that the transsulfuration pathyway products of glutathione [15] and sulfate [16] were related to mercury excretion rates, and that the heme synthesis pathway products of urinary porphyrins can provide specific profiles that reflect mercury toxicity [17].

The references cited by Geier et al in this statement are worth examining.

First, reference "15" is a 1985 article from Ballatori and Clarkson, with the relatively straightforward (if not bone-dry) title, "Biliary secretion of glutathione and of glutathione-metal complexes." This study is an examination of the excretion of methylmercury in the bile in rats, which was found by the authors to closely parallel the biliary secretion of reduced glutathione (GSH). Important pharmacokinetic differences between methylmercury and ethylmercury (which is in the vaccine preservative thimerosal) have been discussed at this blog and by many others. Also the biochemical/biophysiologic leap from rodents to humans should have been acknowledged by Geier et al.

The same criticism can be applied to the use of reference "16," a 2004 review of organ systems in the American lobster (!) that regulate and detoxify environmental heavy metals.

Reference "17" is a 1996 study by James S. Woods from the University of Washington. In rats, Woods demonstrated changes in urinary porphyrins after prolonged exposure to—again—methylmercury. Specifically levels of 4- and 5-carboxyl porphyrins and the expression of precoproporphyrin were demonstrated in the exposed animals. Woods also conducted a possibly controversial pilot study in Mexican dental workers who were exposed to mercury-containing dental amalgam. Woods showed that the excretion of mercury increased and that levels of these urinary porphyrins decreased with chelation.*

In the JNS study, Geier et al measured urinary porphyrins in their 28 subjects with ASD (age range, 2-16 years), but not in their control children—as they did when assessing transsulfuration metabolites. (The reason for not measuring urinary porphyrins in the control group is not explained by the authors.) So without a true control group, Geier et al compared urinary porphyrin values** in their 14 children with "mild" ASD (CARS score ≤38.5) with those in 14 children with "severe" ASD (CARS score ≥38.5). (It's not clear what the authors did with the kids who hit the 38.5 mark.)

Not too surprising, Geier et al claimed significant differences in urinary levels of pentacarboxyporphyin (ie, 5-carboxyl porphyrins) and precoproporphyrin (Table 2) between the mild and severe ASD groups, which would be consistent with the methylmercury rat data of Woods. The authors also ostensibly monkeyed around with the various ratios of urinary porphyrins and found other significant differences between the 2 ASD groups. Additional fiddling demonstrated relationships between the CARS score and some porphyrin ratios. These data are intended to show that the authors' surrogate markers for mercury intoxication—urinary pentacarboxyporphyin and precoproporphyrin—are associated with the severity of autism.

Last, Geier et al assessed the plasma oxidized glutathione (GSSG) levels—as a "strong indicator of cellular oxidative stress"—among ASD children with low urinary porphyrins or high urinary porphyrins and claimed significantly increased levels of plasma GSSG in subjects with high urinary pentacarboxyporphyin or precoproporphyrin levels. Again, Geier et al intended to demonstrate that their surrogate markers for mercury intoxication are associated with a reduced capacity to excrete mercury, per the GSSG level, in ASD children. The main problem with this particular finding is that the plasma GSSG values presented by Geier et al are considerably different (eg, by 3 orders of magnitude) from those published elsewhere, including references cited by the authors.

Also published data suggest that Geier et al should have controlled for age-related differences in urinary porphyrin excretion—especially given that their subjects ranged in age from 2-16 years. A 1996 study by Minder and Schneider-Yin (Age-dependent reference values of urinary porphyrins in children) found distinctive age-related changes in the urinary excretion of 3 porphyrins, which may be explained—depending on the porphyrin—by age-related changes in the physiologic development of the excretion system and heme synthesis. For instance, their data showed that the urinary excretion of coproporphyrin III decreases steadily from the age of approximately 2 years to late adolescence. In an e-mail response, lead author Elisabeth Minder stated, in reference to the JNS study by Geier et al, that "one should control the data for age."

CARS = Childhood Autism Rating Scale. 

* Curiously enough, Woods is a coauthor of a 2006 JAMA article, which reported no significant differences in urinary mercury levels or neurologic function between Portuguese children who received dental amalgam and those who received a resin-based composite for routine dental work. The study's ethics were criticized in the Petition to Order Mercury Amalgam Withdrawn From Interstate Commerce. According to the JAMA article, "Urinary...porphyrins were monitored as indicators of renal responses to mercury..and will be reported separately."

** Urinary porphyrin levels from the subjects, who were recruited in Dallas, Texas, were shipped to and measured at, for some inexplicable reason, the Laboratoire Philipe Auguste in Paris. A coauthor of the JNS article is Robert Nataf from the same Paris lab. Nataf is the lead author of a retrospective 2006 study, which reported relatively elevated coproporphyrin and precoproporphyrin levels in children with autism.

In their 2005 Medical Hypothesis article, which inspired their questionable 2006 Hormone Research study (background here), Mark and David Geier cited a 1997 French case series (really a letter to the editor by Tordjman et al in the American Journal of Psychiatry) to support their measurement of serum testosterone in children with autism. Geier and Geier wrote...

In addition, Tordjman et al have reported on a case-series of 12 prepubertal autistic children (6-10 years old) in their inpatient child psychiatry department, four of whom the researchers observed to have precocious secondary sexual characteristics (growth of pubic hair, increase of testis volume) that suggest high androgenic activity in autistic disorders.

What Tordjman et al actually did, on the basis of their observation of 4 autistic children with precocious secondary sexual characteristics in their practice, was to measure plasma testosterone and adrenal androgen (presumably DHEA or DHEA-S) in 9 pre- or postpubertal inpatients with autism and 62 matched control children. Because of the possible positive correlation between testosterone and aggression, the investigators divided the 9 autistic children into 3 groups according to their aggressive behaviors. Notably, they observed that autistic children who displayed aggression against others were less likely to demonstrate the typical core symptoms of autism (withdrawal, stereotypy, language dysfunction)—which suggests, perhaps, that these children may actually have an alternative behavioral disorder.

Three of their 9 autistic subjects had abnormally high plasma testosterone levels (Table), given the study's matched reference values. These 3 children all showed aggression against others—meaning, according to the authors, they were less likely to demonstrate typical, core autistic symptoms.

Patient	Serum Testosterone, ng/mL
	Level	Ref Mean ± SD (range)	U Iowa Range
10-year-old boy	0.64	0.06 ± 0.03 (0.01-0.15)	0.18-1.50
17-year-old boy	8.8	5.51 ± 1.27 (0.27-7.50)	3.50-9.70
13-year-old girl	0.5	0.12 ± 0.09 (0.01-0.25)	0.15-0.35

The authors noted that the 10-year-old boy exhibited pubic-hair growth, which is probably not a sign of precocious puberty in boys aged 9 years or older. The 13-year-old girl, whose serum testosterone level exceeded the reference range in the study and that provided by the University of Iowa, also demonstrated a very high level of adrenal androgen, 4.40 ng/mL, at least according to the mean level in the study's control population (mean study reference, 0.88 ng/mL ± 0.39 [range, 0.36-1.70]; U Iowa reference range for DHEA, 1.5-5.7 ng/mL).

What Geier and Geier failed to note, however, in both their Medical Hypothesis and Hormone Research articles, is that a previous study by Tordjman et al (1995) did not find elevated testosterone levels in 31 prepubertal children with autism, when compared with 12 prepubertal subjects who had mental retardation/cognitive impairment* or 10 prepubertal control subjects. The mean levels of plasma testosterone and DHEA-S in 8 postpubertal autistic children were also similar to those in 11 postpubertal normal controls. Tordjman et al concluded from this study that "altered secretion of the androgens is not a common feature of autism."

A PubMed search by this blogger failed to disclose any other studies that assessed testosterone or other androgen levels in pre- or postpubertal children with autism.

DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiandrosterone sulfate.

* The study did find increased plasma DHEA-S levels in prepubertal children with cerebral palsy (among those with mental retardation/cognitive impairment).

The federal court ruling that requires PTC Therapeutics to give its experimental drug to a teenager with muscular dystrophy "could easily destroy" the drug's clinical-trial program. This argument is found in one of 2 amici curiae (friends-of-the-court) briefs, which were recently filed in the appeal of the really bad decision in Gunvalson v. PTC Therapeutics. (Background here.)

One amicus brief is on behalf of a 13-year-old boy with Duchenne muscular dystrophy, and the other is from the disease-advocacy groups Parent Projects for Muscular Dystrophy Research, Inc, and United Parent Projects Muscular Dystrophy. Both are in support of the defendant-appellant, PTC Therapeutics, and are now available at the Drug and Device Law blog, which is operated by 2 lawyers involved in the appeal proceedings.

Among the briefs' arguments:

The court's ruling, which allows one person to access to PTC124 (currently in the middle of phase 2 development), is unfair to others with DMD who must wait for FDA approval of the drug.

The ruling creates a precedent for more drug-access litigation, which will unfairly tax the resources of PTC Therapeutics specifically and those of drug-development companies generally. According to the PPMDR/UPPMD brief, 3 parents contacted the PPMDR founder and president to ask whether litigation is an effective means to obtain PTC124. The close relationship between the Gunvalsons and PTC Therapeutics, cited by the ruling judge as a "unique" factor that should mitigate the risk of similar lawsuits, is actually common in the DMD community.

The ruling impedes the clinical-trial process by 1) undermining communication between companies and families that eases or enables clinical-trial enrollment and 2) creating a disincentive for subjects to enroll in trials in which they may receive placebo. (It should be noted that the subpopulation of DMD patients with a nonsense mutation—the pool of potential enrollees for PTC124 trials—is small, approximately 1700.

The ruling undermines the public interest and informed decisions by Congress and the FDA, which state that publicly available drugs must be proven safe and effective (by means of well-controlled clinical trials). The FDA has declared that expanded access to drugs before approval must not compromise enrollment in clinical trials. One brief goes so far as to indicate that the ruling "could easily destroy the PTC124 clinical trial program and render impossible FDA approval that would permit access to the drug for all patients."

And in a curious side note...

The ruling prompted a recent educational program, "Compassionate Use: Changes You Should Make Following Gunvalson et al v. PTC Therapeutics," which indicates that companies should make changes to their compassionate-use policies on the basis of the decision. (The CD, featuring lawyer Clint Hermes, is available for the bargain [cough] price of $199.00.)

Epi Wonk outs himself in the Atlanta Journal-Constitution by recounting his childhood experience with measles, which included hospitalization and treatment with an oxygen tent. Like many of a certain age, I also acquired measles as a youngster (despite having been vaccinated) and missed 2 weeks (2 weeks!) of junior high. And I didn't stay home because of contagiousness; I stayed home because I felt absolutely terrible.

Epi Wonk is right to chastise Washington for not initiating a progressive public-service campaign (where is our acting Surgeon General anyway?) to urge morbidity-reducing and life-saving vaccination and to counter the spurious claims of an increasingly vocal and attention-hungry antivax crowd.

Photo of child with measles rash from the CDC.

D'oh! Just when you thought you dodged an IOC bullet, the overseer of the Olympic Games announced yesterday that it will further analyze blood and urine samples collected from athletes at this summer's Beijing games. First on the retroactive testing list is Roche's long-acting red-cell booster Mircera.* But the IOC also warns that it will store the Beijing samples for 8 years to enable additional analyses when new drug tests become available.

In Beijing, 4770 doping tests were conducted on blood or urine, covering the period from July 27th to August 24th. But only 6 out of approximately 11,000 athletes suffered sanctions as a result of positive tests, an unexpected, low number (Table). Therefore the IOC will retest samples with a recently validated assay for Mircera. The announcement comes on the heels of news this week that 3 more Tour de France racers tested positively for the substance.

Disqualified Athlete		Country	Sport	Highest Placement	Detected Substance
1	Lyudmila Blonska	Ukraine	Heptathlon	2nd	methyltestosterone
2	Igor Razoronov	Ukraine	Weightlifting	6th	nandrolone
3	Fani Halkia	Greece	Hurdles	—	methyltrienolone
4	Jong Su Kim	North Korea	Shooting	2nd	propanolol
5	Isabel Moreno	Spain	Cycling	—	Epo
6	Thi Ngan Thuong Do	Vietnam	Gymnastics	15th	furosemide

(IOC decisions regarding 3 other alleged Olympic doping cases, Belarussian hammer throwers Vadim Devyatovskiy and Ivan Tiskhan [testosterone] and Polish kayaker Adam Seroczynski [clenbuterol], are pending.)

* A pegylated version of recombinant erythropoietin.

Image of a freakishly bulked-up Lyudmila Blonska from Wikipedia.

Roger Brumback, editor in chief of the Journal of Child Neurology, is not happy. Neurologist Jon Poling, the lead author of the 2006 case report in JCN, "Developmental regression and mitochondrial dysfunction in a child with autism," did not inform Brumback's editorial board that he is the father of the girl described in the report, and moreover, that he petitioned the National Vaccine Injury Compensation Program (VICP) in 2003, claiming his daughter's alleged injury (ie, autism) was due to vaccination.

In a letter published in last month's issue of the JCN (BIG HT to Kathleen Seidel at Neurodiversity), Brumback describes the authors' lack of full disclosure "an appallingly troubling issue." The JCN editors were evidently troubled enough to determine if the case report was used to support the favorable and heavily publicized VICP ruling for the Polings earlier this year (it was not), but Brumback proposes that "media linkage of the published article to the legal outcome implies scientific support from JCN for this legal opinion." He now advises:

Beginning in January 2009, statements from all authors concerning potential conflicts of interest will be published as a part of each article. However, no written statement can substitute for honesty, good faith, and integrity on the part of the authors.

In their defense, the report's coauthors Richard Frye, Andrew Zimmerman, and John Shoffner claim in a separate letter that they did not know of Poling's pending VICP claim at the time of the report's submission to JCN. (However, it is unclear, as Seidel points out, whether the coauthors became aware of Poling's claim sometime later.) The coauthors did know that the report's subject is Poling's daughter.

Poling himself acknowledges, in yet another separate letter to the JCN, that he should have declared his daughter's identity to the JCN editors, but that he withheld her name "to protect a 6-year-old child." Poling confirms that the JCN report was not used to support the VICP claim and characterizes his involvement in the case as minimal—consisting of signing a "short original petition and submitting a required sworn parental affidavit." Poling also reveals that Zimmerman submitted an expert opinion to the VICP court in December 2007 at Poling's request.

Poling further claims, "There are certainly other physicians who have chosen not to publish promising leads or discoveries involving family members, out of respect for privacy or fear of the kind of criticism our article has generated," and suggests that "the JCN explore ways to encourage these helpful contributions, even when the patient is a family member."

An alternative suggestion is to require that any physician-author recuse himself from submitting a case report of a relative to medical journals. Let more objective physicians assess and submit this information for peer review—in an effort to eliminate conflicts of interest and, most important, to ensure the privacy and appropriate care of the patient.

* Poling also presented preliminary findings in his daughter's case in June 2001 at the Johns Hopkins Neurology Grand Rounds.

Way back in June, education expert Robert Cervero and graduate research assistant Jiang He, both of the University of Georgia, published their ACCME-funded examination of professional articles that addressed the relationship between industry support of CME and CME bias. Surprisingly enough, they found no directly relevant, published studies. However, they discovered exactly 2 original research articles, both of which predate the ACCME's 1992 Standards for Commercial Support, that examined the effect of commercially supported CME on physicians' prescribing practices.

In 1988, Bowman and Pearle published before-and-after prescribing patterns of 374 physicians who attended 3 industry-sponsored educational courses on beta blockers or calcium-channel blockers (CCBs). Physicians' prescription data were limited in that they were obtained by mailed self-reports, and before-and-after responses were not matched for 2 of the 3 courses. Also rates of survey returns (6-month "after" responses) were less than robust—from 40% to 60%.

Bowman and Pearle concluded that prescribing patterns generally favored the sponsoring company's drug. However, Cervero and He interpreted these results as mixed. They found that prescriptions for the CME sponsor's drug increased after course 1 (up 12%), but not as much as those for a competitor drug (up 17%). After course 2 (beta blockers), prescriptions for the sponsor's drug increased nonsignificantly, and after course 3, the sponsor's drug became the most frequently prescribed CCB (when compared with 2 other drugs).

Over at The Carlat Psychiatry Blog, Daniel Carlat—fervent critic of industry-supported CME—examined the Bowman-Peale study and, not surprisingly, maligns Cervero and He for not coming to a more emphatic conclusion that industry sponsorship of CME unduly influences prescribing patterns. Curiously enough, though, Carlat proposes that the mixed results seen after course 1—specifically an increase in prescriptions for a competitor drug—are due to the more effective CME efforts of the competitor (eg, course 3 and other CME activities).

This interesting proposal from Carlat actually supports the fact that industry-sponsored CME is not consumed in a vacuum. Carlat (perhaps unwittingly) bolsters the argument that a wide range of industry-sponsored CME, in conjunction with non-industry-sponsored CME and other countless sources of medical information, should be considered (if at all possible) when assessing influences on physicians' prescribing practices.

The other CME study cited by Cervero and He was published in 1992, and the CME activity in question featured a number of perks—for instance, an all-expenses-paid trip to a resort—that would not be compatible with the current standards of the ACCME. The study authors, by assessing hospital pharmacy data, determined that this more blatant marketing activity increased prescriptions for the sponsor's drug.

Cervero and He conclude their report by posing a number of questions to be addressed in the investigation of bias in commercially supported CME. The most important, paraphrased here, is How does the adoption of a sponsor's product (if influenced by CME) affect patient care?

ACCME = Accreditation Council for Continuing Medical Education; CME = continuing medical education.