Ethics: May 2009 Archives

Parents who refuse pertussis (whooping cough) vaccination for their child increase the child's risk of infection by about 20-fold. This conclusion is derived from a first-of-its-kind study of medical records within the huge Kaiser Permanente Colorado health plan (N > 430,000 members). Results of the study were published in the latest issue of Pediatrics.

Investigators extracted individual-level data from the medical charts of children (age 2 months-18 years) about documented vaccine refusal and pertussis infection during a 12-year-period (1996-2007). A total of 156 laboratory-confirmed cases of pertussis were discovered; 9 (6%) required hospitalization.* Among these 156 cases, the parents of 18 children (~12%) had refused all or nearly all of the recommended pertussis vaccinations.** Among a randomly selected, matched control population (n = 595), the vaccine refusal rate was 0.5%.

Two case-control analyses (primary and secondary) were used to determine the odds of pertussis infection as a function of vaccine refusal. (In the secondary analysis, subjects were continuously enrolled in the health plan between the ages of 2 and 20 months.)

Case-Control Analysis	Odds Ratio (95% CI)
Primary (all ages)	22.8 (6.7, 77.5)
Secondary (2-20 months of age)	19.3 (3.5, 104.5)

Assessments of attributable risk suggested that all 18 cases of pertussis in unvaccinated children were due to vaccine refusal.

The investigators acknowledged that a potential bias in the study was the fact that physicians were 3 times more likely to test for pertussis in unvaccinated children who presented with a respiratory infection. But this bias was probably offset by the fact that unvaccinated children with a respiratory infection were less likely to present for evaluation than vaccinated children. 

* Notably the annual incidence of confirmed pertussis cases increased over time; more than three quarters occurred after 2001.

** The parents of 14 children had refused all routine immunizations. Most of these parents were white, older than 30 years of age, and of higher socioeconomic status.

Photo of symptomatic child with pertussis from pertussis.com.

And not to flattering effect.

The Chicago Tribune, a high-profile newspaper with a generally less-than-stellar reputation, nevertheless gets it right with its recent coverage of the father-and-son duo Mark and David Geier and their horrifying Lupron treatment for autism.

'Miracle drug' called junk science by Trine Tsouderos

Physician team's crusade shows cracks by Steve Mills and Tom Jones

In a noteworthy side bar (A flawed rationale for treatment), data from one published study by the Geiers (which they use repeatedly to support Lupron treatment in autistic children) are found to be specious by 3 nationally recognized pediatric endrocrinologists: Paul Kaplowitz, Alan Rogol, and Peter Lee.* Specifically Dr. Rogol labels the Geiers' FSH levels "irrelevant," and states that any conclusions based on the testosterone reference range of 0-10 ng/dL are "worse than meaningless." He also concludes that some of the Geiers' pediatric subjects were too old to be diagnosed with precocious puberty.

Mark and David Geier respond that these pediatric endocrinologists are "not qualified to discuss hormone disorders in autistic children." This forehead-slapping rebuttal is made despite the fact that 1) Mark Geier has no specialized training in pediatric endocrinology and 2) David Geier possesses no more than a BA degree.

* The Geiers' 2006 Hormone Research article was scrutinized at this blog in October of 2008.

(For important background on this story, please see Tuesday's initial post).

According to Insmed's website, Tercica (comarketer of Increlex) and Insmed (sole manufacturer of Iplex) "plan to enter into negotiations concerning the development of IPLEX™ for the treatment of ALS." Insmed writes that clinical development is contingent on data from Italian ALS patients who received (or are receiving) Iplex on a compassionate basis, as well as FDA requirements. At present, there are no clinical trials of Iplex in patients with ALS at the NIH database website.

Insmed also provides a summary of the first 2 years of the "Italian experience" with Iplex. According to the pdf, more than 500 patients, with various disorders, have been exposed to Iplex, most often at dosages ranging from 0.5-2 mg/kg/day. Insmed reports, "Positive effects on statural growth, insulin sensitivity, glycemic control, dyslipidemia, muscle strength, endurance, and functional abilities have been demonstrated [emphasis added]."*

In the Italian Expanded Access Program, subcutaneous Iplex (typically 1 vial or 36 mg) is being taken daily. Of 110 ALS patients (most of whom have advanced disease), 53 remain on treatment (at least at the time of the pdf draft—the date of which is not provided).

A total of 57 discontinued Iplex treatment (52% dropout rate): 34 died; 10 withdrew consent (1 due to an adverse effect, described as "muscle twitching")**; for 6, the court order was annulled or expired or there was "logistic difficulty" with the program; 5 experienced an "unsatisfactory" therapeutic effect; and 2 were lost to follow-up.

Disease progression is being measured by the ALS Functional Rating Scale. Because there is no control population, the deterioration of the functional score can only be assessed and possibly compared to historical/natural-history data (although such a comparison is incredibly problematic, probably to the point of being useless). For what they're worth, mean longitudinal scores are provided for 24 patients who completed 12 months of expanded-access nonblinded treatment (possible score range, 0-48).

Pretreatment	6 Months	12 Months
30.2 ± 7.9	27.8 ± 8.2	25.2 ± 7.8

Five patients discontinued Iplex as a result of possible treatment-related adverse effects: 1 case of nonserious "muscle twitching"; 1 case of fatal cholelithiasis and infection (patient had a history of gallbladder disease); and 3 cases of fatal cardiopulmonary arrest (1 patient had a history of hypertension and silent MI). The fatalities that were believed to be due to ALS (33) occurred at a time frame consistent with the known progression of the disease.

Insmed indicates that it is "working diligently" with the FDA to "make the necessary preparations" for the US clinical trial of Iplex. The company's share price has risen sharply since the FDA provided expanded access to Iplex in March and okayed a clinical trial of the drug in ALS.

* Presumably Insmed means "or" instead of "and" in its description, unless all of the effects were demonstrated in each condition studied--which is highly doubtful.

** Which may well be a manifestation of ALS.

Last weekend's NYT featured a lengthy story on ALS victim Joshua Thompson ("Fighting for a Last Chance at Life") and his struggle to obtain access to the investigational drug Iplex (from Insmed) on a compassionate basis. Like most patient-centered articles in the mainstream press, the feature is heart breaking...and arguably irresponsible.

In what turns out to be really a very cloying piece, writer Amy Harmon takes the usual easy, uninformed (or perhaps just uninformative) road in pharma journalism by 1) stressing the ostensibly cruel indifference of corporate America and FDA bureaucracy; 2) downplaying the total absence of clinical data to support the use of Iplex in ALS; and 3) completely sidestepping the issue of poor medical policy as bullied into existence by an Internet-fueled public.

So here's the...

Necessary Background

Iplex, a synthetic insulin-like growth factor (IGF-1) that is linked to a binding protein (IGFBP-3), was FDA approved in December 2005 for the treatment of growth failure in children with severe, primary IGF-1 deficiency. The drug received a priority review and was designated an orphan drug, because of the rarity of its indication. But Iplex was removed from the market in early 2007 after Insmed settled a patent dispute with Tercica and Genentech. These companies held the patent on a similar rival drug, Increlex, a synthetic IGF-1 without the binding protein. Increlex was FDA approved in August 2005 for the same rare condition.

In its defense, Insmed pleaded that Iplex should be made available and its development continued, given the drug's other potential indications, including ALS and multiple sclerosis. Proponents also argued that the drug's distinctive binding protein (in contradistinction to Increlex) facilitates entry of IGF-1 into the central nervous system—a purely theoretical proposition. Bolstering Insmed's argument was the fact that the Italian Ministry of Health had asked Insmed to make Iplex available to the country's ALS patients, despite the fact that no clinical (or even published preclinical) data existed to support the drug's efficacy or safety in the condition. Through several court rulings, Insmed then worked out a deal with Cephalon, the European patent owner of IGF-1, to provide Iplex to about 100 Italian citizens in an expanded access program (which the government paid for, to the tune of $100,000 USD per patient per year).

In the United States, some ALS patients had acquired Iplex off label before the drug was pulled. In online testimonials, these patients crowed about the drug's benefits—thereby prompting individuals like Joshua Thompson and their families to invest tremendous hope, time, and effort in acquiring Iplex by whatever means necessary. Thompson even contemplated moving to Italy, until he discovered that Iplex was only available to Italian citizens.

Harmon chronicles the crusade of Joshua's mother, Kathy, to get compassionate access to the unproven drug for her son. Perhaps most disturbing is Harmon's unwitting example of the insidiousness of the online testimonial: Because of a single forum post maligning the effect of Increlex, when compared with Iplex, Kathy Thompson believed that only Iplex would help her son. 

IGF-1 Clinical Data Disappoint

Up until recently, results of well-controlled clinical studies of subcutaneous IGF-1 (Increlex) were mixed. In a double-blind, placebo-controlled, randomized trial of 266 North American ALS patients, IGF-1 significantly slowed the progression of functional impairment in an apparent dose-dependent fashion. However, a similarly designed European study (N = 183) showed no benefits with IGF-1 treatment in ALS. Then last year, results of a definitive, phase 3 trial (N = 330) revealed no difference in the primary or secondary outcomes between IGF-1- and placebo-treated ALS patients at 2 years.*

The negative clinical-trial results with IGF-1 in ALS apparently eased the way for compassionate access to Iplex in the United States, since Tercica and Genentech could not hold a competitive position in this therapeutic area. More important, safety data provided to the FDA by the Italian Ministry informed the agency's decision to grant restricted access to Iplex. So in March of this year, the FDA—bowing to the grass-roots demand for Iplex from Kathy Thompson and others—decided to allow access to the drug under an IND application. This decision was made to the consternation of several ALS experts (for excellent and more detailed coverage of this story angle, see the May 4th issue of Neurology Today). The 2 methods by which American ALS patients could (or can) obtain Iplex: 1) a single-patient IND application to the FDA that had to be received by March 6, 2009,** and 2) a randomized clinical trial.

Through his single-patient IND, Joshua Thompson received his first dose of Iplex on March 25th. An NYT epilogue reveals that Joshua reported subjective improvement in his swallowing with treatment; however, on April 12th, he was hospitalized with pneumonia and placed on mechanical ventilation, where he evidently remains.

ALS = amyotrophic lateral sclerosis; IND = investigation new drug.

* A small, double-blind trial of 2 doses of intrathecal IGF-1 in Japan (N = 9) provided mixed, but largely disappointing, results.

** Harmon writes that it's unclear who's paying for the drug.

The 50-game suspension handed down yesterday to the LA Dodgers' power hitter Manny Ramirez brings another performance-enhancing drug to public attention: human chorionic gonadotropin, or hCG. Best known as the hormone assayed in urine or serum to confirm early pregnancy, hCG is used to treat infertility in women by stimulating ovulation (eg, Pregnyl; Organon). In men, the substance is also injected to treat infertility or to reverse hypogonadism; the hormone stimulates the testicular Leydig cells to produce testosterone.

But because hCG is less efficient than anabolic steroids for increasing muscle mass,* it is most likely injected by power athletes to treat androgen-induced hypogonadism, either during or after a course of anabolic steroids. The substance, consequently, is an indirect indicator of steroid abuse.

In healthy males, hCG normally occurs at low, but measurable, levels in serum or urine, and serum assays are sensitive. However, most doping surveillance tests are performed on urine, and the suitability of the assay in this context has not been defined, according to a recent report. No matter for Manny. His penalty for hCG doping was reportedly based on evidence in his medical files, not on a positive drug test, according to the NYT.

* hCG is also more expensive than anabolic steroids, but what does that matter to an MLB player.

Image of chorionic gonadotropin preparation from APP Pharmaceuticals.