Ethics: December 2008 Archives

In separate tampering conspiracies, Chinese manufacturers spiked crude heparin and infant formula with artificial contaminants. The respective contaminants, oversulfated chondroitin sulfate (OSCS) and melamine, were most likely known to dissemble the products' key ingredients, heparin and milk protein, respectively, in routine testing. The presumed motive behind the acts is economic, given that both contaminants are cheap additives that reduce the costs of the manufacturing processes. At least 81 Americans died who received the tainted heparin, and the contaminated formula killed at least 4 Chinese infants.

Heparin Scandal

At the end of 2007 and escalating into 2008, an increasing number of allergic-type reactions and deaths in the United States were associated with the intravenous administration (particularly bolus administration) of Baxter's heparin products. Consequently Baxter recalled a number of its heparin products in February, and in April, the FDA reported that a heparin contaminant, OSCS, was the likely cause of 81 American deaths and hundreds of adverse reactions to the suspect product.

With nearly unprecedented speed, 2 international groups of scientists simultaneously published their investigations of the contaminated heparin in the NEJM and Nature Biotechnology in April. It was determined that OSCS, a synthetic product,* which exhibits antithrombin activity in vitro, had triggered hypotension and other adverse reactions by activating the kinin-kallikrein pathway and by generating anaphylactoid complement proteins. Animal studies suggested that some individuals, like those undergoing dialysis, were more vulnerable to the contaminant's hypotensive effects—which may explain the varied reactions to the tainted product.

Baxter's heparin was traced to its Chinese supplier, Scientific Protein Labs, which apparently bought its crude material from a number of Chinese heparin "workshops." In February, the plant was cited by the FDA for several "significant deviations" from good manufacturing processes; however, when and where OSCS was introduced into the heparin remains a mystery. For its part, Baxter got out of the heparin business entirely, and Chinese officials, not surprisingly, have been less than conciliatory in the FDA's investigation.

* Chondroitin sulfate, an essential component of animal cartilage that is marketed as a nutritional supplement for joint pain, was intentionally altered with additional sulfate groups to confer anticoagulant properties to the molecule. The contaminant is structurally identical to Arteparon, an intramuscular drug that was marketed in Europe for the treatment of individuals with degenerative joint disease. Arteparon has been shown to induce an allergic-type response and was withdrawn from the market because of patient deaths, most likely due to thromboembolic complications.

For more on heparin production and the heparin scandal, visit...

• Where Does Heparin Come From?
• WSJ: Product Variations Found in Baxter's Chinese-Made Heparin
• APP: Aiming for a Heparin Monopoly?
• The WSJ Has Gordon Fairclough in China
• APP's Soon-Shiong: No Stranger to Suspect Chinese Suppliers
• More on Heparin Extraction: Zzzzzz
• Heparin Supplier Changzhou SPL: FDA Inspection Form Now Available
• "Contaminant" in Baxter's Recalled Heparin
• Japanese Companies Recall SPL Heparin
• Baxter: No Endotoxins in Recalled Heparin
• NYT: Counterfeit Heparin Likely Altered Chondroitin Sulfate
• More on Faux Heparin Contaminant
• FDA Updates Likely Heparin Death Toll
• Chinese Official: Heparin Contaminant Not Cause of Adverse Reactions
• FDA to China: Prime Suspect Is Heparin Contaminant
• Actions of Heparin Contaminant Revealed
• Heparin Contaminant Not Naturally Produced
• China Is Being, Well, China in the Investigation of Tainted Heparin
• Synthetic Heparin on the Distant Horizon

Also the WSJ provided terrific gross-out pictures of crude heparin production in China, which may or may not have been a part of SPL's pipeline.

Melamine Returns

After melamine was found last year in Chinese-imported wheat gluten, which was used to make domestic pet food, the ersatz protein and renal toxin returned in Chinese-made infant formula. According to news reports, workers at a Chinese baby-formula company, Sanlu, and several milk-collection agencies conspired to spike diluted milk with melamine, which artificially raises the protein level of the product.

WHO reported that Sanlu received related complaints of illness associated with its formula as early as March of this year and was urged in early August by its majority owner, New Zealand's Fonterra Cooperative Group, to initiate a product recall. However, Sanlu (in possible collusion with Chinese government officials) reportedly delayed the recall to avoid a PR scandal during the upcoming Olympic Games in Beijing.

At last count, melamine-tainted baby formula is believed to have sickened more than 53,000 Chinese infants and caused at least 4 infant deaths over the course of this year (see update below). Melamine is known to form poorly soluble crystals in renal tubules, when combined with its byproduct, cyanuric acid.

This year's melamine scandal widened, following concerns that tainted milk was incorporated into other food products like ice cream and chocolate, some of which were exported. In response, the FDA assured consumers that domestically made formula was safe and issued its guidance for acceptable (miniscule) melamine levels in certain products.

According to some reports, eliminating melamine from the Chinese food supply may be next to impossible, because of the difficulty of ensuring the purity of livestock feed in the country. Chinese authorities issued a standard for melamine levels in feed last year; however, melamine was recently discovered in eggs and fish feed in Hong Kong.

For more melamine reading, visit...

• The Return of Melamine
• Cobbled Update of Melamine in Chinese Baby Formula
• Melamine Contamination Expands
• Update on Melamine in Chinese Food Supply

01/01/09 update: Yesterday's NYT reported that the former chairwoman of Sanlu pleaded guilty to selling tainted baby formula. The paper indicates that "consumer complaints about Sanlu’s milk came in as early as December 2007." In court, Sanlu's chairwoman admitted that she knew her company was selling contaminated formula by May 2008 but did not report the problem to local officials until August. Sanlu's formula reportedly sickened nearly 300,000 Chinese children and caused the deaths of 6.

Readers are also referred to "Melamine and the Global Implications of Food Contamination" in the December 25th issue of the NEJM and the FDA's periodically updated web page, "Melamine Contamination in China."  

In 2008, the United States experienced the largest measles outbreak in more than 10 years, due to pockets of imported or importation-associated disease in unvaccinated individuals.* An August report in the MMWR indicated that more than 80% of these 131 cases were related to 7 outbreaks (≥3 cases). Fifteen individuals, including 4 children younger than 15 months of age, were hospitalized for disease. 

Most important, however, is the fact that a whopping 91% of cases occurred in individuals who had not received vaccination or whose vaccination status was unknown. Among these 112 patients, 85% were eligible to receive vaccination, but 66% had declined because of "philosophical or religious beliefs." In many cases, elected exemptions are based on parents' disproven fears of the risk of autism.

In England, measles was declared endemic this year for the first time since the mid-1990s, because a critical number of parents declined vaccinations for their children. Gibraltar also experienced an unprecedented measles outbreak, which affected 1% of the population. The outbreak was blamed on the poor uptake of measles vaccination and a subsequent shortage of the vaccine.

Those most affected by the deferral of measles vaccination are immunocompromised children and children younger than 12 months of age, who rely on adequate herd immunity. It appears to be a matter of time before a measles outbreak will cause a known, severe complication of the disease, like encephalitis or death, in the United States. Such an event occurred in April in the United Kingdom.

By way of contrast, worldwide deaths due to measles dropped dramatically, according to the World Health Organisation. The plunge in measles-related deaths, from 750,000 in the year 2000 to 197,000 last year, is due to a massive, coordinated vaccination effort, the Measles Initiative. In Africa and countries of the Eastern Mediterranean region specifically, the effort resulted in a fall in measles deaths by approximately 90% during the same time period. The goal of the Measles Initiative—which is led by the American Red Cross, the CDC, the UN Foundation, UNICEF, and WHO—is to reduce the number of measles deaths worldwide by at least 90% by the year 2010.

Because the majority of measles-related deaths no longer occur in Africa, vaccination efforts are now being intensified in other regions—particularly India, where 8.5 million children do not receive their first dose of measles vaccine by 1 year of age. According to a spokesperson for the UN Foundation, the success of the campaign depends on urgently needed funds for the next 2 years.

More details can be found at the following Pathophilia links (and at links through these links):

• And the Air-Travel Risks Just Keep on Comin': This Time, Measles
• Looming Large: The Cost of Not Vaccinating
• Measles Outbreak in DuPage County, IL
• Biggest US Measles Outbreak in 10 Years
• Boo, Boo, Boo: US Measles Cases Increase
• Most US Parents Remain Sane, Vaccinate Children
• Measles Hits Gibraltar, Hard
• Global Measles Initiative a Success, but Funding Needed

* The percentage of US toddlers who received at least 1 dose of MMR vaccine (from 91.5% to 93.0%) has remained stable since 2004. Still nearly 8% of American toddlers did not receive vaccination for the disease in 2007, and geographic clusters of unimmunized children appear to account for this year's record number of cases of the highly contagious disease.

Photo of child with measles rash from the CDC.

The comarketers of the cholesterol-lowering combo pill Vytorin (ezetimibe/simvastatin) received a protracted and very public comeuppance in 2008—primarily for delaying the negative and controversial results of a relatively small study of the drug in patients with familial hypercholesterolemia.

Unfortunately for Merck and Schering-Plough, most medical reporters and bloggers viewed the delayed publication of the ENHANCE trial results—which failed to show a reduction in carotid plaque with Vytorin use—as highly suspect. Moreover, the negative results were taken as an indicator of the drug's inability to reduce cardiovascular events in a general at-risk population, and prescriptions plummeted.

The companies' explanation for the delay—namely, that missing or implausible carotid ultrasound data* in the ENHANCE trial had to be accommodated—was viewed as unfair to the trial's principal investigator, John Kastelein. With respect to the trial's clinical implications, little was settled in the professional or public arena when the ENHANCE data were simultaneously presented at the annual meeting of the American College of Cardiology and published in the NEJM in the spring.

In April, Senator Chuck Grassley fired off inquiries to the company CEOs, which instigated a kind of journalistic pile-on from the likes of Matthew Herper at Forbes, Ed Silverman at Pharmalot, and the WSJ Health Blog gang. And the schadenfreude ante was upped when, in September, the industry-sponsored SEAS trial failed to show that Vytorin reduced major cardiovascular events in patients with aortic valve or atherosclerotic disease. To add insult to injury, the data suggested an increased risk of cancer with Vytorin treatment. (However, this latter finding was not supported by a meta-analysis of cancer data from 2 other, ongoing Vytorin studies.)

While the primary endpoint in the ENHANCE trial rests entirely on the validity of the ultrasound measurement of carotid intima-media thickness (CIMT), some investigators question the usefulness of CIMT to assess cholesterol-lowering drugs. In the placebo-controlled CASHMERE trial, Pfizer's Lipitor (atorvastatin) failed to significantly alter CIMT in postmenopausal women, despite that fact that Lipitor undeniably reduces the risk of cardiac events and stroke.

These facts may portend a positive outcome in IMPROVE-IT, a comparison of Vytorin with simvastatin alone to reduce the primary composite endpoint of major coronary events, stroke, or cardiovascular death. However, IMPROVE-IT won't be completed until July 2012.

It is with some embarrassment that an inordinate number of Vytorin posts at this blog were dug up for background reading:

• ENHANCE Study: Basically, the Ultrasound Images Were Crap
• ENHANCE Study: More Much Ado About Suboptimal Data
• ENHANCE Study: Frustration With Trial and Coverage of It
• SP Share Price, Insider Trading, and the ENHANCE Timeline: Now in Fancy Graphs
• ENHANCE E-Mail Exchange: Dear John, John, and...Rick
• ENHANCE Study: The Thing That Wouldn't Leave...the Blogosphere
• Pfizer Attempts to Capitalize on Vytorin's Limited Indications: Oh, the Irony
• Another ENHANCE Panel: Still No Discussion of "Missing" or "Implausible" Data
• Independent Reviewer: ENHANCE Data "Not Acceptable"
• Then and Now: Quality Differences in ENHANCE Data
• Media Retain Big Anti-Jones for ENHANCE, Schering-Plough, and Fred Hassan
• Negative Lipitor Data Raise Doubt About CIMT
• Statins and Aortic Stenosis: Retrospective vs Prospective Study
• Vytorin Is Beaten Up Some More
• Need a Negative Vytorin Quote? Call Dr. Nissen
• Pols Piss Off Peto

* Specifically the carotid intima-media thickness (CIMT).

CASHMERE = Carotid Atorvastatin Study in Hyperlipidemic Postmenopausal Women; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis.

The popular and continuing backlash against the pharmaceutical industry and its potential influence on the practice of medicine (and the practice of academic medicine, in particular) led to a number of notable events this year.

The most tangible is legislation dictating pharma and physician conduct—specifically, the Massachusetts Health Code Bill, which bans pharma gifts and meals to Massachusetts physicians and requires them to report pharma payments for their consulting and speaking services. The legislation is in the spirit of the updated PhRMA Interaction Code, which goes into effect January 1 and bans non-educational gifts—like branded pens, notepads, and stress balls—from pharma or medical-device companies to healthcare professionals.

A prime issue informing these actions is whether pharma money biases the treatment recommendations of key opinion leaders in academia. Notable academic psychiatrists specifically* were caught in the crosshairs of anti-pharma bulldog Senator Chuck Grassley, the national press, and interested bloggers, who charged that these influential physicians failed to report the payment of hundreds of thousands of dollars from pharma.

Another important factor is whether pharma currently holds undue influence over the content of continuing medical education (CME) that it supports financially. Some pharma companies (eg, Lilly), without withdrawing CME support altogether, have agreed to publicly disclose their CME funding to outside groups in a show of conscientiousness and in response to a request from Senator Grassley. Others (ie, Pfizer) cut off direct CME grants to medical education communications companies (MECCs), a probable PR move that is based on the perception of (and not so much actual) bias in MECC-produced CME specifically.

And if academic isolation from pharma is not possible (or very smart), then transparency is next to godliness. This year, the web site of The Cleveland Clinic began disclosing information about its physicians' financial ties to industry; although specific dollar amounts and research funding from pharma are not currently provided. In addition, the University of Pennsylvania recently reported that it will create a searchable web site that discloses the industry relationships of its physicians.

Straggling behind in this anti-pharma zeitgeist is the nearly toothless Accreditation Council for CME (ACCME), the accreditor of CME providers and, like many a bureaucracy, an apparent fan of abstruse verbiage. This year, the ACCME promised to enhance its monitoring and surveillance of CME production (by increasing its fees) and proposed harsh limits on CME production that demonstrated little practical forethought.

* Namely Joseph Biederman of Harvard, Alan Schatzberg of Stanford, and Charles Nemeroff of Emory.

The ill-known procedure of cardiac-death organ donation was raised in the public consciousness by the criminal case of California v. Roozrokh.

On the night of February 3, 2006, a transplant team, including surgeon Hootan Roozrokh, MD, was dispatched by the California Transplant Donor Network to the Sierra Vista Medical Center to harvest the organs of Ruben Navarro, a 25-year-old man with adrenoleukodystrophy and minimal brain function after cardiopulmonary arrest. What happened next is a function of the Rashomon effect, in which the involved medical professionals told differing accounts of a procedure gone wrong.*

What isn't disputed is that Roozrokh took over the end-of-life care of Navarro, in clear violation of general transplant procedures and Sierra Vista policy, and that Navarro didn't die within the required window of time to allow organ harvesting after being withdrawn from life support. An ensuing inquiry into the failed procedure led to an ongoing investigation by the Medical Board of California, civil suits filed by Navarro's mother, and 3 felony counts against Roozrokh: dependent-adult abuse; administering a harmful substance (oral Betadine); and the unlawful prescription of a controlled substance.

At the preliminary hearing in March for Roozrokh's criminal case, the judge dismissed 2 charges against the physician. First, conflicting or vague testimony could not establish that Roozrokh was the physician who administered Betadine to Navarro in the operating room. Second, the judge determined that the unlawful prescription of a controlled substance did not apply in this case, because the relevant California statute exempts drug orders for a patient in a licensed hospital.

At his criminal trial, Roozrokh testified that he stepped in to fill a void in physician care, while others characterized his actions as those of a callous and impatient surgeon, who ordered massive doses of morphine and Ativan (lorazepam) to hasten Navarro's death. Nevertheless, Roozrokh was acquitted of dependent-adult abuse by a 12-person jury last week. Defense attorney M. Gerald Schwartzbach (who successfully defended actor Robert Blake in his murder trial) had contended that his client "could not have violated the standard of care to merit [the charge]...because no such standard applies to the extraordinary circumstances of this case."

Indeed Schwartzbach's statement highlights the absence of a universal protocol for cardiac-death donation at the time of Navarro's death (despite Roozrokh's clear violation of standard transplant procedure). The California Transplant Donor Network did not require physicians or nurses to undergo specific training in cardiac-death donation until 1 year after Navarro's death, and, in fact, the criminal investigation prompted the adoption of training standards for the procedure by the Network. Roozrokh himself had assisted only one such procedure before the night of February 3, 2006.

The use of cardiac death (as opposed to brain death) to obtain organs for transplantation has been accepted practice for more than a decade in the United States, but hospital-based protocols can vary—thereby creating confusion among medical practitioners. In a prepared statement, the jury members in Roozrokh's criminal case expressed their desire for a uniform protocol, reported the San Luis Obispo Tribune:

"Ruben's case had identified that donation by cardiac death is in desperate need" of having a national refined protocol. "Refining the nationwide protocol of DCD organ procurements will be an important part of Ruben's legacy and for that we pay him our respect and owe him our thanks."

In August, ethicist Robert Veatch argued in the NEJM that heart donation after cardiac death raises a logical paradox. He proposed that, if the heart can be restarted in the graft recipient, then the donor could not have been dead in the first place on the basis of cardiac death. Moreover, the very act of removing the "restartable" heart from the donor is equivalent to killing the donor by means of organ removal. Veatch concluded that it is therefore impossible to legally harvest a heart in the setting of cardiac death and wrote that this paradox can only be resolved by either redefining brain death or altering laws to permit heart removal from living donors.

Veatch's argument was printed in the same NEJM issue that included a report of 3 heart transplantations in infants after the cardiac deaths of pediatric donors. 

For more details on the attempted organ donation of Ruben Navarro and a discussion of cardiac-death donation, check out...

• NYT Discovers California (and Roozrokh Case)
• More on Roozrokh Case: Lubarsky Testimony
• Continuing Coverage of Roozrokh Preliminary Hearing: Transplant Expert Testimony
• Roozrokh Prelim Hearing Continues: Conflicting Accounts and Neuro Testimony
• Roozrokh Prelim Hearing: See One, Botch One
• Roozrokh Prelim Hearing: Who Ordered What When?
• Roozrokh Prelim Hearing: Final Testimony
• Surgeon Roozrokh to Face 1 Charge; 2 Dismissed
• The Transplant Paradox: Heart Donation After Cardiac Death
• Transplant Surgeon Acquitted of Dependent-Adult Abuse

Also visit the web site of the San Luis Obispo Tribune for its excellent and complete coverage of the Roozrokh case.  

* Compounding the Rashomon effect in this case is the fact that, during the attempted procedure, no one recorded the administration of medications, and the vital-sign records were lost.

It's the 1-year birthday of the Pathophilia blog, which means it's time to count down the top 10 medical stories of the year (in what is now a venerable 2-year tradition). Cue the drumroll.

No. 10: Gunvalson v. PTC Therapeutics

A teenage boy with an X-linked muscular dystrophy, Jacob Gunvalson, and a small biopharmaceutical company, PTC Therapeutics, locked legal horns over access to the company's investigational agent, PTC124. Jacob and his parents claimed that key PTC employees had promised access to the agent, while discouraging clinical-trial enrollment, and PTC denied the charges.

The case highlighted a number of important considerations in the development of pharmaceutical products, particularly by small companies. Namely...

• The advisability of close communications between company representatives and patients;
• The nontrivial nature of a company's application for a single-patient (ie, compassionate-use) investigational new drug application (IND) to the FDA; and
• The maintenance of the integrity of the clinical-trial process (on which evidence-based medicine rests).

With respect to this last and vital issue, it is paramount that investigators maintain the general uniformity of trial enrollees and the fairness of drug access in the form of trial randomization, if at all possible. Moreover, they should not create a disincentive for individuals to enroll in clinical trials by providing medication to a particular individual outside of trial enrollment,* especially when trial subjects may be assigned to placebo, and others must wait for FDA approval to access the drug.

In August, a NJ federal judge ordered PTC to provide its drug to Jacob,** but that decision was reversed by a US appeals court last week. The appeals court determined that Jacob and his parents had failed to plead the requirements of an alleged promissory estoppel. Specifically PTC's "clear and definite promise" of access to PTC124 was not demonstrated and, perhaps most important, Jacob did not forgo enrollment in a key PTC124 trial (which would have provided PTC124 to Jacob in an extension phase) on the advice of a PTC employee. He was denied enrollment, because he did not meet the trial requirements.

For more details on Gunvalson v PTC Therapeutics, go here, here, here, here, and here and check out relevant posts of the more-than-passively interested lawyers at the Drug and Device Law blog.

* A prime example of privileged, and arguable unfair, drug access is provided by prominent personal injury lawyer Fred Baron's treatment with Tysabri (natalizumab; Biogen Idec/Elan) through the lobbying efforts of none other than Lance Armstrong and Hillary Clinton.

** In the form of submitting a single-patient IND to the FDA on behalf of Jacob, and, if the FDA denied the IND, by asking for a protocol exception so that he could enroll in a phase 2a extension trial of PTC124.

Hootan Roozrokh, the transplant surgeon who was charged with the dependent-adult abuse of Ruben Navarro, was acquitted by a 12-person jury yesterday in San Luis Obispo, California. The charge stemmed from the failed attempt to harvest Navarro's organs on February 3, 2006, in a case of cardiac-death donation. (For essential background on the story, start here.)

According to the San Luis Obispo Tribune, Roozrokh still faces a civil suit filed by Navarro's mother and an accusation filed with the Medical Board of California. The latter involves a "formal, public charge by the Board alleging a physician violated the Medical Practice Act. This is the result of a fully investigated complaint that has been referred to the Attorney General's Office for prosecution. Practice is permitted unless otherwise specified," reports the MBC web site.

At his trial, Roozrokh testified that he was trying to care for "Ruben," not hasten his death, when others failed to perform their jobs. The testimony is a thinly veiled accusation against Navarro's covering attending physician at the Sierra Vista Medical Center, Laura Lubarsky. Roozrokh claimed that, when he and another transplant surgeon, Arturo Martinez, arrived at the Sierra Vista Medical Center to harvest Navarro's organs, no one had ordered pain medications to be used during Navarro's attempted organ donation, and Navarro's covering physician was either not present or not responding to inquiries regarding the patient's end-of-life care. Roozrokh reported that he consequently stepped in.

Roozrokh also called his referral to Navarro's pain medications as "candy" in the operating room "dumb." According to the Tribune, Roozrokh testified, "It was an unconscious statement...It just came out."

During cross-examination, prosecutor Karen Gray asked Roozrokh if the California Transplant Donor Network had revoked the doctor's privileges to harvest organs after cardiac death, which prompted a dramatic call for a mistrial by defense attorney M. Gerald Schwartzbach. The Tribune reported:

"I can't believe it," Schwartzbach yelled, raising his hands in exasperation after jurors had been removed from the courtroom. "The beginning of that question was so outrageous. This is an experienced prosecutor. She obviously knows she should not have filed this case...The prosecution is beyond me. The fact that they filed it is beyond me."

Gray was referring to a letter that Roozrokh had received from the California Transplant Donor Network, which temporarily halted his privilege to perform cardiac-death donation until he had observed the procedure. The judge instructed the jurors to disregard Gray's question.

So far the jurors have declined to comment publicly on their verdict; however, they issued the following statement, as provided by the Tribune.

"We the jury...would like to thank the family of Ruben Navarro, and especially to Ruben, for bringing to light the issues brought forth in this matter...Ruben's case had identified that donation by cardiac death is in desperate need" of having a national refined protocol. "Refining the nationwide protocol of DCD organ procurements will be an important part of Ruben's legacy and for that we pay him our respect and owe him our thanks."

DCD = donation after cardiopulmonary death.

The Drug and Device Law Blog posteth, and I posteth on the post.

The decision that a teenage boy with muscular dystrophy,* Jacob Gunvalson, should have access to a proprietary, experimental drug has been reversed by the US Appeals Court for the Third District in Philadelphia. The original decision, made by a NJ federal judge, had ordered PTC Therapeutics, the owner of the experimental agent PTC124, to submit a single-patient investigational new drug application (IND) to the FDA on behalf of Jacob, and, if the FDA denied the IND, to ask for a protocol exception so that he could enroll in a phase 2a extension trial of PTC124. The decision had rested on alleged promises made by PTC employees to Jacob's mother about drug access.

(For a lot of important blog-type background on this case, Gunvalson v PTC Therapeutics, go here, here, here, and here. Also browse through the DDL Blog, the WSJ Health Blog, and Pharmalot.)

The appeals court determined that the Gunvalsons had failed to demonstrate a reasonable probability of success of their claim on the merits of a something called a promissory estoppel. In this case, a promissory estoppel would have prevented PTC Therapeutics from withdrawing its alleged promise to the Gunvalsons to access PTC124, if the Gunvalsons has reasonably relied on this promise and had acted on it to their detriment (meaning that Jacob had foregone enrollment in the phase 2a trial voluntarily).

The appeals court noted that the claim of a promissory estoppel requires a "clear and definite promise" and "a reasonable reliance on the promise." However, the appeals court found that the Gunvalsons failed to adequately plead these 2 requirements. With respect to the second requirement, the NJ court failed to recognize that Jacob did not enroll in the phase 2a trial (which was required for enrollment in the extension phase) because he was ineligible, not because he was promised access to PTC124 by some other means.

Gunvalson v PTC Therapeutics is now remanded to the NJ court for further claims. According to an AP story, the Gunvalsons and their attorney are assessing their legal options. 

* Whether Jacob Gunvalson has Becker or Duchenne muscular dystrophy remains unclear.

Five months before Patrick Magoon, the CEO of Chicago's Children's Memorial Hospital, wouldn't return the phone calls of the governor's fund raiser, Magoon was praising the governor for approving $650 million in tax-exempt bonds to the hospital. The bonds, from the Illinois Finance Authority, are intended to construct a new replacement hospital, the Ann and Robert H. Lurie Children's Hospital of Chicago, and to refund hospital debt, according to a March press release from IFA.

Governor Blagojevich and Magoon exchanged the usual platitudes in the press release, and there is presently no indication that the finance approval was anything but above board. However, given the pervasive, corrupt nature of state business that was revealed in the recent federal complaint against the Illinois governor (particularly as it pertains to Magoon, the Planning Board, and the construction of Mercy Hospital*), it is hard to imagine Blago approving a $650-million something for nothing—especially when he was ready to squeeze Magoon in exchange for a mere $8 million in state Medicaid funds.

* Admittedly old news in Illinois.

Among the many charges in the federal complaint against IL governor Rod Blagojevich—which are astounding even by Chicago standards—is the allegation that he tried to extort $50,000 from the CEO of Children's Memorial Hospital in Chicago, Patrick Magoon, in exchange for state funds for pediatric care performed at the hospital. The alleged extortion attempt happened as recently as last month.

According to an FBI informant ("Individual A"*), Blago discussed his attempt to gain a sizeable campaign contribution from Magoon on October 8 of this year with words like, "I'm going to do $8 million for them. I want to get [Magoon] for 50." The $8 million was understood to mean $8 million in state Medicaid reimbursement to the hospital [see addendum below].

In a November 12 phone call recorded by the FBI, the chairman of the governor's campaign fund, Friends of Blagojevich (possibly Steve Witek; identified as the governor's brother by the WSJ), expressed his frustration to the governor after not hearing from Magoon. The chairman said, "I've left three messages there, so I'm gonna quit calling. I feel stupid now." Blago learned from the chairman that the most recent call to Magoon was on November 10 and responded, "[If] they don't get back to you, then, then, last resort is, I'll call."

During that afternoon, Blago spoke by phone with a Deputy Governor (possibly Bob Greenlee, who resigned today), and the following exchange was recorded, according to the complaint:

Blago: The pediatric doctors—the reimbursement. Has that gone out yet, or is that still on hold?

Deputy gov: The rate increase?

Blago: Yeah.

Deputy gov: It's January 1 [2009].

Blago: And we have total discretion over it?

Deputy gov: Yep.

Blago: We could pull it back if we needed to—budgetary concerns, right?

Deputy gov: We sure could. Yep.

Blago: Okay, that's good to know.

[12/12/08 addendum: According to the Chicago Tribune, the $8 million in state funds was intended for a pediatric-care intiative, We Care for Illinois Kids, a coalition that promotes increased state reimbursement rates for specialized pediatric care. The coalition supports Illinois HB5331, which stipulates that physician fee rates for the All Kids Insurance Program (the state's Medicaid program for children) must increase to competitive levels on January 1, 2009. The coalition indicates that pediatric specialists in Illinois currently receive only 33 cents for every dollar spent on Medicaid patients, one of the lowest Medicaid reimbursement rates in the country. The Children's Hospital of Chicago is the state's largest provider of inpatient, outpatient, and physician Medicaid services.] 

That evening, the governor instructed his fund chairman to contact a lobbyist (possibly Alonzo Monk) and to ask him what to do about Magoon not returning the phone calls. Blago also told the chairman to ask the lobbyist whether it was possible that Individual A (the FBI informant) had instructed Magoon to not call the fundraiser back. The governor was recorded saying, "What do we do with this guy, [Magoon]?" 

The next day, the fundraiser reported to Blago that he "had a call into" Individual A to talk about Magoon.

On November 14, the fundraiser told the governor that he had spoken with Individual A and that the governor needed to call Magoon. Blago indicated that he would do so. The complaint does not provide additional information regarding the governor's attempt to contact Magoon, and there is no indication that the hospital CEO was receptive to the contribution scheme.

In a statement released December 9, Children's Memorial Hospital indicated that it had "worked diligently to obtain funding from the State of Illinois...for the costs of providing much needed services to children covered by Medicaid." The statement continued, "Children's Memorial is very disappointed that the $8 million in Illinois funding...has been tied to an alleged pay-to-play scheme. Neither Children's Memorial nor any of its personnel participated in such a scheme." The hospital also indicated that it is cooperating fully with federal authorities.

An online source, campaignmoney.com, provides the following information regarding Magoon's contributions for the last several years—none of which appear to have gone to Blagojevich. (12/18/08 addendum: According to the Illinois Board of Elections, Magoon contributed the following to the Friends of Blagojevich: $500 on 9/18/02; $1000 on 7/24/03; $1000 on 6/09/04; $1000 on 6/29/06; and $1000 on 10/12/07—for a total of $4500.)

$	Date	Primary or General	Contributed To
1000	03/31/2008	P	Citizens for Harkin - D
1000	03/27/2008	G	Jesse Jackson Jr. For Congress - D
800	12/28/2007	P	American Hospital Association PAC
1000	11/08/2007	P	Friends of Dick Durbin Committee - D
1000	09/14/2007	P	A Lot of People for Dave Obey - D
1000	06/27/2007	P	A Lot of People for Dave Obey - D
2300	03/10/2007	P	Jesse Jackson Jr for Congress - D
200	03/10/2007	G	Jesse Jackson Jr for Congress - D
1000	08/13/2006	G	Mike Dewine for US Senate - R
500	05/09/2006	G	Kirk for Congress - R
1000	12/01/2005	P	Friends of Dick Durbin Committee - D
1000	05/28/2005	P	Mike Dewine for US Senate - R
1500	03/05/2005	P	Jesse Jackson Jr for Congress - D
250	02/20/2004	P	Mckenna for Senate - R
250	11/17/2003	P	Hynes for Senate - D
1000	11/17/2003	P	Hastert for Congress Committee - R
500	06/27/2003	P	Obama for Illinois Inc - D
500	03/31/2003	P	Committee to Re-Elect Loretta Sanchez - D
500	03/04/2003	P	Jesse Jackson Jr for Congress Committee - D
1000	09/30/2002	G	Nussle for Congress Committee - R
1000	06/20/2002	G	Hastert for Congress Committee - R
1000	04/22/2002	P	Democratic Congressional Campaign Committee
500	02/27/2002	P	Friends of Dick Durbin Committee - D
500	12/20/2001	P	Illinois Senate 2002 - D
200	10/26/2001	P	Friends of Max Baucus - D
500	08/16/2001	P	Friends of Ray Lahood - R
250	08/13/2001	P	Jesse Jackson Jr for Congress Committee - D
250	05/14/2001	P	American Hospital Association PAC
5000	10/31/2000	P	Keep Our Majority PAC
500	04/07/2000	P	American Hospital Association PAC

According to a Google-cached web page (curiously the link is not currently active at the Children's Memorial website), Magoon is chair-elect of the IL Hospital Association's board of trustees. The September press release also indicates that Magoon has been a member of the IHA's Policy Council, the Medicaid Reimbursement Task Force, and the All Kids Task Force. 

* According to the complaint, Individual A is an "associate" of Blagojevich and has assisted in campaign fundraising for the governor. The informant is hoping for immunity in exchange for his cooperation with the investigation. Notably the complaint indicates that the informant refused to wear a wire or participate in recorded phone calls with the governor. The informant is speculated by the Sun-Times to be John Wyma.

In the spirit of the transparency zeitgeist, the University of Pennsylvania health system (my postgrad alma mater) will create a searchable web site that discloses the industry relationships of its physicians. The web site is scheduled to launch in the spring of 2009, according to the Philly Inquirer, and follows the example of the Cleveland Clinic, which most recently began providing information about its physicians' financial ties to industry.

The types of potential conflicts to be posted by Penn are not specified; however, the institution has a longstanding reputation for being relatively pristine, providing few (if any) opportunities for its residents and faculty to interact with pharma.* My estimation, if history is any guide, is that there will be little to disclose. Penn already bans its staff from accepting industry gifts, meals, and even drug samples, and the institution does not allow its name to be posted on pharma-supported CME.

Although the Cleveland Clinic discloses pharma-related royalties, equity interest holdings, and speaker or consulting fees (>$5000) received by its physicians, it fails to provide other, potentially relevant information like research grant support or actual dollar amounts received by faculty. For instance, the web page for Steven Nissen—head of cardiology, harsh critic of Vytorin (ezetimibe/simvastatin; Merck/Schering-Plough), and apparent lover of Crestor (rosuvastatin; AstraZeneca)—discloses no "applicable" financial relationships and reports that he donates all honoraria or consulting fees directly to nonprofit organizations. But other sources (eg, here) indicate that Nissen has received research support—life's blood for any academician—from a number of companies, including AstraZeneca.

* From 1986-1991, I never saw a drug rep in the Department of Medicine or Neurology, and I knew of noone who collaborated with industry on research at the time.

Workers at the Chinese baby-formula company, Sanlu, and several milk-collection agencies conspired to spike diluted milk with the ersatz protein and renal toxin melamine, according to a report in the latest issue of Science. Melamine-tainted baby formula is believed to have sickened more than 53,000 Chinese infants and caused at least 4 infant deaths over the course of this year.

In addition, Chinese workers added an emulsifier, which suspends melamine in solution, to elevate the apparent fat content of the formula. According to Science, Sanlu baby formula contained an astounding amount of melamine, 2563 mg/kg.* However, investigators found only trace amounts of a melamine byproduct, cyanuric acid, in the formula. Cyanuric acid, when combined with melamine, forms poorly soluble crystals in renal tubules.

The investigators concluded that melamine alone caused the tens of thousands of cases of renal dysfunction in Chinese infants. However, others doubt this conclusion and suspect that cyanuric acid has eluded detection because it is so tightly bound up with melamine. In last year's case of contaminated pet food, initial assays failed to detect cyanuric acid, but follow-up attempts revealed substantial amounts of the byproduct.

Eliminating melamine from the Chinese food supply may be difficult, reports Science, because of the difficulty of ensuring the purity of livestock feed in the country. Chinese authorities issued a standard for melamine levels in feed last year; however, melamine was recently discovered in eggs and fish feed in Hong Kong.

Chinese bloggers are in on the investigation of melamine, writes reporter Hao Xin at ScienceInsider. According to yesterday's post, bloggers found evidence that researchers from the Chinese Academy of Sciences offered technology for making high-protein feed with its dan bai jing ("protein essence"), which may have included melamine or its byproducts. Hao Xin writes that the Academy absolved itself of any connection to China's melamine scandal after an internal investigation in October; but the Academy also declined to report the ingredients of its dan bai jing.

In an effort to capitalize on the melamine scandal, one Chinese company is offering melamine-free dan bai jing; however, the product contains the additive isobutylidene diurea, a lawn fertilizer, writes Xin. Isobutylidene urea is not approved by the FDA for inclusion in animal feed, but it is apparently allowed by the Chinese agriculture ministry.

* On November 28, the FDA concluded that levels of melamine or cyanuric acid of 1 part per million (1 mg/kg) or less in infant formula do not pose a public health risk.

Depiction of melamine chemical structure from Wikipedia.

12/4/08 update on update: More melamine-tainted Chinese eggs have been found in Hong Kong, according to yesterday's NYT. The discovery of the contaminated eggs, the fourth discovery in less than 2 months, is the result of the random testing of Chinese foods in the territory. The level of melamine in the eggs was 4.7 ppm, which is nearly 90% higher than the acceptable melamine level in foods (other than infant formula) set by the FDA, 2.5 ppm.

Three Generations, No Imbeciles: Eugenics, the Supreme Court, and

Buck v. Bell

By Paul A. Lombardo

365 pages

If generations of illegitimacy and limited intellect can be used to justify mass sterilization, then count on wiping out most of the southeastern United States, white or black or otherwise. But the consequence would not be merely the intended elimination of welfare-sucking trash—if such an outcome could be predicted. Say goodbye to the works of Tennessee Williams, Faulkner, Capote, and any other writer whose work draws on the freewheeling peccadilloes or horrors, depending on your viewpoint, of the extended Southern family. And say goodbye to anybody like yours truly, whose ancestral history in The Volunteer State contains its share of illiteracy, illegitimacy, and "imbecility" (thank you, US Census Bureau).

But unintended consequences were not considered by proponents of eugenics and sterilization laws in the early 20th century. In their conceit to claim an understanding of inheritance and Darwinian theory, eugenicists believed that the road to public health and lower taxes was paved with the legally mandated sterilization of society's feebleminded and promiscuous citizens—which, in their minds, meant men and women (but mostly women) of the lower classes.

At the center of this sorry time in American history is the legal case of Buck v. Bell, the end-result of Virginia's carefully crafted sterilization law, enacted in 1924. In comprehensive fashion, Georgia lawyer Paul Lombardo lays out this sad case, which was argued before the US Supreme Court, in Three Generations, No Imbeciles, the most detailed account to date of Buck v. Bell and its aftermath.

The Buck in this case was Carrie Buck, a young pregnant woman committed to the Virginia Colony for Epileptics and Feebleminded in 1924 under dubious circumstances. Carrie's mother, Emma, was already a member of the Colony under allegations of mental deficiency and moral turpitude, and Carrie's soon-to-be daughter would be placed in the foster care of the couple who arranged for Carrie's residence at the Colony. Among the 15 of so residents at the state institution selected as candidates by the Colony's Board for sterilization, on the basis of the newly enacted Virginia law, Carrie was chosen as the hapless test case. The argument for Carrie's sterilization would rest on flimsy evidence that 3 generations of the Buck family—including Carrie's infant daughter—constituted inherited imbecility.

Lombardo describes Carrie's legal defense, both at the state and federal levels, as a charade. Buck's anemic appeal before members of the Supreme Court, most of whom sympathized with the eugenics movement, led to a terse ruling in 1927, written by associate justice Oliver Wendell Holmes, Jr, which upheld the Virginia law. In his 3-page opinion, Holmes wrote the famous, cutting phrase, "Three generations of imbeciles are enough," which in fact had no foundation in the Buck family.

On the basis of the Supreme Court decision in Buck v. Bell, many other states (which already had sterilization laws in place) proceeded in relatively unfettered mode to conduct mass sterilization on their less fortunate citizens, and Lombardo writes that the US eugenics movement, bolstered by Buck v. Bell, informed a like-minded program in Socialist Germany, with known consequences.

Remarkably the Supreme Court decision of Buck v. Bell remains intact, although enduring sterilization laws in most states were repealed at the height of the civil-rights movement. (Laws in Washington state and Mississippi remain.) And while the general conceit of today's Americans may be that the constitutionality of legal sterilization won't be tested again before the high court, Lombardo reminds us that the same incentives to improve public health and lower tax burdens exist today and are manifest in selective reproduction methods and judge-mandated orders to not procreate.