Recently in Ethics Category

In a 3-part criminal and civil agreement with the Department of Justice, Allergan, the maker of Botox, has dropped its free-speech suit against the FDA—which had the potential to be a pivotal case on the rights of commercial free speech. In addition, the company has pleaded guilty to a single misdemeanor "misbranding" charge, stemming from the off-label promotion of Botox during 2000-2005, and will pay $375 million. Last Allergan will fork over another $225 million to resolve civil claims made by the DOJ under the False Claims Act (concerning qui tam or whistleblower complaints). The plea agreement was announced yesterday in a company press release and also by the DOJ.

According to the government, Allergan, during the described time period, "exploited" an approved indication for cervical dystonia (obtained in 2000) to expand the off-label use of Botox for headache. Company reps were also instructed to call on doctors who typically treat off-label conditions (like pediatric spasticity), and Allergan held workshops to inform healthcare providers on how to be reimbused for injecting Botox off label.

The civil settlement resolved 3 qui tam lawsuits, with whistleblowers Dr. Amy Lang (a former Allergan consultant), Charles Rushin (a former Botox sales rep), Cher Beilfuss (a former Regional Healthcare Policy Manager for Allergan), Kathleen O'Conner-Masse (a former Payor Reimbursement Account Manager for Allergan), and Edward Hallivis (a former I-don't-know-what). They will split $37.8 million.

The current, FDA-approved indications for Botox (not Botox Cosmetic) in adults are the following:

• Cervical dystonia
• Primary axillary hyperhidrosis
• Blepharospasm and strabismus
• Upper limb spasticity (approval obtained March 2010)

In an effort to better understand the legal issues surrounding the use of human embryonic stem cells (hESCs) for research, the following timeline is provided. It is is mostly informed by Judge Royce C. Lamberth's August 23rd decision, which blindsided many researchers who work with hESCs; however, it is also supplemented (and confirmed) by other linked sources.

1960s: Researchers discover, isolate, and begin to work with human stem cells, which are derived directly from bone marrow, peripheral blood, or discarded tissues, like the umbilical cord and placenta. These cells are multipotent, meaning that they can differentiate into a limited number of cell types. Their most notable therapeutic use during the next decades is the reconstitution of bone marrow during bone marrow transplantation.

1996: Congress passes and President Bill Clinton signs the Balanced Budget Downpayment Act, which contains the Dickey-Wicker Amendment. The amendment, or really rider, prohibits the use of federal funds to support research "in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury of death greater than that allowed for research on fetuses in utero." Since 1996, Congress includes the Dickey-Wicker Amendment in every iteration of its appropriations bill for the DHHS.

November 1998: James Thomson, VMD, PhD, of the University of Wisconsin, and colleagues report their process of creating stem cells from human embryos. The hESCs are pluripotent, meaning that they can differentiate into any of the 200 or so cell types found in the human body. They can also be maintained indefinitely. The potential of hESC-based research surpasses that of work on traditional stem cells, because the latter are only multipotent, not pluripotent. Creation of the hESCs, however, requires destruction of a human embryo (or really its potential to develop into a human being), which produces a moral/ethical dilemma.

July 7, 1999: The Clinton administration circumvents the Dickey-Wicker Amendment by arguing that hESCs are not embryos as defined by the statute and that research on existing hESC lines should not be prohibited, because it does not destroy embryos. Congress subsequently fails to alter the Dickey-Wicker Amendment.

August 9, 2001: President George W. Bush publicly addresses the use of federal funds to conduct research on hESCs. Informed by his conservative beliefs, he reports to the nation,

As a result of private research, more than 60 genetically diverse stem cell lines already exist. They were created from embryos that have already been destroyed, and they have the ability to regenerate themselves indefinitely, creating ongoing opportunities for research. I have concluded that we should allow federal funds to be used for research on these existing stem cell lines, where the life and death decision has already been made.

June 20, 2007: President Bush issues Executive Order 13435, which expands on his statement from August 2001. The order stipulates,

The Secretary of Health and Human Services (Secretary) shall conduct and support research on the isolation, derivation, production, and testing of stem cells that are capable of producing all or almost all of the cell types of the developing body and may result in improved understanding of or treatments for diseases and other adverse health conditions, but are derived without creating a human embryo for research purposes or destroying, discarding, or subjecting to harm a human embryo or fetus [emphasis added].

And

...[T]he destruction of nascent life for research violates the principle that no life should be used as a mere means for achieving the medical benefit of another...human embryos and fetuses, as living members of the human species, are not raw materials to be exploited or commodities to be bought and sold...

December 2007: Thomson et al report their success in genetically reprogramming some specialized adult human cells to assume a stem cell-like state. Through the use of viral vectors, these induced pluripotent stem cells (iPSCs) are forced to express genes that confer the defining properties of ESCs. The NIH later warns, however, that, although iPSCs meet the defining criteria for pluripotent stem cells, it is not known if iPSCs and ESCs differ in clinically significant ways. Moreover, in animal studies, the virus that is used to introduce stem cell factors sometimes causes cancers. According to the NIH, researchers are investigating nonviral delivery methods. If iPSCs become, for all practical purposes, equivalent to ESCs, their use cannot be objected to on the basis of the destruction of human embryos.

March 9, 2009: President Barak Obama issues Executive Order 13505 (Removing Barriers to Responsible Scientific Research Involving Human Stem Cells), which states that the DHHS Secretary (Kathleen Sebelius), through the NIH Director (Francis Collins, MD, PhD), "may support and conduct responsible, scientifically worthy human stem cell research, including human embryonic stem cell (hESC) research, to the extent permitted by law." The executive order pertains to extramural NIH-funded stem cell research. The executive order revokes the President Bush's statement of August 9, 2001 and his follow-up Executive Order 13435 of June 20, 2007.

April 23, 2009: In response to Executive Order 13505, the NIH publishes draft guidelines, "National Institutes of Health Guidelines for Human Stem Cell Research," which allow for the funding of research with hESCs "that were derived from human embryos created by in vitro fertilization (IVF) for reproductive purposes and were no longer needed for that purpose." The NIH receives approximately 49,000 comments on the draft guidelines.

July 7, 2009: The NIH publishes its final guidelines for scientific work on hESCs, with a number of stipulated conditions for their use. The guidelines also acknowledge,

Since 1999, the Department of Health and Human Services (HHS) has consistently interpreted this provision as not applicable to research using hESCs, because hESCs are not embryos as defined by Section 509. This long-standing interpretation has been left unchanged by Congress, which has annually reenacted the Dickey Amendment with full knowledge that HHS has been funding hESC research since 2001. These guidelines therefore recognize the distinction, accepted by Congress, between the derivation of stem cells from an embryo that results in the embryo’s destruction, for which federal funding is prohibited, and research involving hESCs that does not involve an embryo nor result in an embryo’s destruction, for which federal funding is permitted.

August 19, 2009: Plaintiffs James L. Sherley, MD, PhD, Theresa Deisher, PhD, Nightlight Christian Adoptions (“Nightlight”), Embryos, Shayne and Tina Nelson, William and Patricia Flynn, and Christian Medical Association (“CMA”) file suit in the US District Court for the District of Columbia against Kathleen Sebelius et al. The plaintiffs seek declaratory and injunctive relief to prevent the NIH's Guidelines for Human Stem Cell Research from taking effect. Specifically plaintiffs argue that the NIH guidelines violate the Dickey-Wicker Amendment.

October 27, 2009: Judge Lamberth dismisses the plaintiffs' suit, finding that the plaintiffs lack standing. Lamberth also denies the plaintiffs' motion for a preliminary injunction as moot. The plaintiffs appeal.

June 25, 2010: The Court of Appeals reverses, concluding that Drs. Sherley and Deisher, who work with adult stem cells, had standing under the competitor-standing doctrine. Because the other plaintiffs did not contest the Court’s prior finding, the Court of Appeals treats "their lack of standing as conceded." The Court of Appeals then remands the matter back to the US District Court for the District of Columbia to consider the plaintiffs’ motion for a preliminary injunction.

August 23, 2010: Judge Lamberth rules "that the likelihood of success on the merits, irreparable harm to plaintiffs, the balance of hardships, and public interest considerations each weigh in favor of a preliminary injunction." Lamberth agrees that federal funding of hESC research increases competition for limited NIH funds, thereby causing an "actual, imminent injury" to Drs. Sherley and Deisher. "Accordingly, plaintiffs would suffer irreparable injury in the absence of the injunction," Lamberth writes. Moreover, Lambert concludes that the imminent injury to Drs. Sherley and Deisher outweighs any potential harm to individuals who may otherwise benefit from hESC research. He concludes, "It is not certain whether ESC research will result in new and successful treatments for diseases such as Alzheimer’s and Parkinson’s disease." Lamberth did not agree with the defendants that the Dickey-Wicker Amendment is ambiguous (thus allowing for the distinction between the creation of hESC lines—which necessarily destroy an embryo's potential to develop into a human being—and subsequent research on extant hESC lines). On the contrary, he ruled that adherence to the amendment is in the public interest.

Here, the will of Congress, as expressed in the Dickey-Wicker Amendment, is to prohibit federal funding of research in which human embryos are destroyed. Accordingly, it is in the public interest to enjoin defendants from implementing the Guidelines because the Guidelines allow federal funding of ESC research, which involves the destruction of embryos.

August 31, 2010: The Justice Department files an emergency motion, asking Judge Lamberth to temporarily stay his ruling, while the government appeals.

Image of undifferentiated hESCs from http://www.nih.gov/catalyst/2007/07.01.01/page1.html.

Released yesterday, the FDA's inspection report of facilities at Wright Company and Quality Egg, ground zero for the recent egg-borne salmonella outbreak, is either an outing of a filthy outlier in the business of mass agriculture or a revelation of the filthy business of mass agriculture. How much chicken shit is acceptable in and around hen houses is virtually unknowable for the 99% of Americans who don't farm. But 4-to-8-feet piles seem excessive.

According to the FDA, the laying facilities in north-central Iowa, managed by Austin "Jack" DeCoster's son, Peter, were plagued with the following:

• Massive and escalating amounts of chicken excrement.

Inspectors reported that "outside access to the manure pits...had been pushed out by the weight of the manure, leaving open access to wildlife or domesticated animals." Manure, aka "dark liquid," was also observed to be seeping through the concrete foundation of the outside of the laying houses. Uncaged birds were seen using the piled-up manure to access laying areas.

• Standing water near manure pits.
• Live rodents, namely mice, who evidently had free access into and out of the laying houses.
• And lots and lots of flies and maggots. "The live flies were on and around egg belts, feed, shell eggs and walkways in different sections of each egg laying area," the inspectors wrote. "In addition, live and dead maggots too numerous to count were observed on the manure pit floor..."

Most important, perhaps, was the fact that the FDA found evidence of Salmonella enteritidis in multiple locations, including in manure and chicken feed.

The FDA's inspection took place from August 12 to August 30, longer than 2 weeks. Given the duration of the inspection (and the possibility that facility managers knew that the FDA was coming), it seems that officers at Wright County and Quality Egg actually had the opportunity to clean up their facilities. If so, the conditions of these businesses may have been, in reality, considerably worse.

Former Duke med classmate Chuck Murry, co-director of U Washington's Institute for Stem Cell and Regenerative Medicine, was featured last night in an NBC Nightly News piece on embryonic cell research (video here). Veteran science reporter Robert Bazell said that what Murry has done, converting embryonic cells to beating cardiac tissue, is "remarkable."

But Murry's work and others' like it are now threatened by Monday's decision from a federal judge, Royce C. Lamberth, which blocks President Obama's 2009 order to expand funding for embryonic cell research. Lamberth ruled that the executive order conflicts with a legislated ban on using federal funds to destroy embryos (first contained in the Dickey-Wicker Amendment to the Balanced Budget Downpayment Act of 1996).

According to NIH director Francis Collins, by way of USA Today, the effects of Lamberth's ruling are chilling. A total of 167 grants, representing $149 million, will be frozen in the very near future. However, another 131 awarded grants, which are already "out the door," will not be affected until they're up for renewal next year.

Yesterday the US Department of Justice announced that it will appeal Lamberth's ruling. A profile of the judge, a Reagan appointee, is provided by the Washington Post.

The NYT and the WSJ are also, predictably, all over the story. According to the NYT, a Clinton* administration lawyer tried to circumvent the Dickey-Wicker Amendment in 1999, by arguing that federal money could support research on stem cell colonies, or lines, that had already been produced with private funding. (The idea being: use private funds to destroy the embryonic cell as it differentiates; then use federal funding to support research on the created stem-cell line.) The Bush administration adopted the lawyer's argument "with severe restrictions," and Obama attempted to lift the Bush restrictions last year. 

* BTW, Clinton signed the Balanced Budget Downpayment Act of 1996 with the Dickey-Wicker Amendment. 

P.S. Go Chuck.

Gird yer loins, Austin "Jack" DeCoster. You're about to receive uncompromising media and Congressional attention. And the metaphoric (and partially ironic) tarring and feathering may long be overdue, if archived news stories are any indication.

The growing recall of Salmonella-tainted eggs is focusing widespread attention on DeCoster (photos here and here), who is the owner of Wright County Egg in Galt, Iowa, and Quality Egg, a supplier of chicks and feed to Hillendale Farms in New Hampton, Iowa. On August 13, Wright County recalled 380 million eggs that it had shipped since May 19. Hillandale recalled 170 million eggs on Friday, according to USA Today.

The FDA says that the Wright County eggs had been distributed to "food wholesalers, distribution centers and food service companies in California, Illinois, Missouri, Colorado, Nebraska, Minnesota, Wisconsin and Iowa." These companies distribute eggs nationwide. The recalled eggs were packaged under the brand names of Lucerne, Albertson, Mountain Dairy, Ralph’s, Boomsma’s, Sunshine, Hillandale, Trafficanda, Farm Fresh, Shoreland, Lund, Dutch Farms  and Kemps. [Writer's note: Because Lucerne consistently provides the least expensive dairy products in Chicago-area Dominick's stores, I've always been skeptical of their origin. BTW, Lucerne's cheese is absolutely tasteless.]

DeCoster, who also has a history in hog farming, is reportedly no stranger to alleged health, safety, or labor violations, which date back to at least the mid-1990s.

Reports USA Today,

• In 1997, DeCoster Egg Farms of Turner, Maine, agreed to pay $2 million to settle health and safety citations. Employment conditions at DeCoster's farm were publicly denounced by Labor secretaries Robert Reich (he called them "dangerous and oppressive") and Alexis Herman (who said they were "simply atrocious"). See the NYT's "In Maine, Egg Empire Is Under Fire."
• In 2000, Iowa (as in the state of) called DeCoster a "habitual violator" of environmental regulations. One infraction: allowing hog manure to run off into waterways. DeCoster was prohibited from building new farms. See a 2000 statement from the Iowa Attorney General.
• In 2002, DeCoster paid more than $1.5 million in a settlement with the EEOC regarding sexual harassment claims (including rape) from Mexican women who worked at Wright County.

Other violations, including those of animal mistreatment, are reported by the Washington Post and detailed by Mercy for Animals here and here. DeCoster's heavy use of battery cages to house chickens has been linked to the spread of Salmonella on egg farms.

More than 1000 Americans have been sickened by Salmonella-tainted eggs in the current recall, according to the latest news reports, and the obligatory litigation is in the works. This may be one case in which it is reasonable to root for personal-injury attorneys. 

The original source of Baxter's contaminated heparin, which killed scores of Americans in 2007 and 2008, has still not been identified, according to letters sent between the FDA and Congressmen Joe Barton (R-TX), who is investigating the matter. The heparin, which was intentionally spiked with oversulfated chondroitin sulfate (OCSC), was traced early to Baxter's Chinese supplier of crude heparin, Changzhou SPL, but the FDA has apparently not been able to get beyond the company to implicate any of Changzhou's suppliers. (A colorful expose by the WSJ in 2008 about the unregulated production of raw heparin in China showed just how hard it might be to identify the perpetrator.)

According to the agency's response letter of June 16, officials of China's State Food and Drug Administration (SFDA) have stifled the FDA's investigation beyond Changzhou SPL, and "repeated" follow-up requests to the SFDA have yielded only "general information." The latest from Chinese officials to the agency: There have been no breakthroughs in the case. However, Congressman Barton, in his latest volley with the FDA, suggests that the US agency has been lax in its follow-up and specifically in its investigation of several suspect Chinese firms, including transparently bogus "front companies." (For more on these suspect firms, read the letter.)

In its efforts to protect the American public, the FDA posted testing methods for OSCS and initiated a "sampling program" to examine products on entry to the country. In addition, specific Chinese firms, like Changzhou, have been given an "import alert" status, in which products can be confiscated without inspection.

Leading the search for a synthetic version of heparin, which would entirely circumvent any reliance on the crude harvesting process (in China or elsewhere), are investigators at Rensselaer.

SPL = Scientific Protein Labs.

Just as an astronomical white count is not an entity unto itself but a marker of a serious underlying disorder, like leukemia, so a big lie on a CV is an indicator of a grave underlying problem, like sociopathy.

Faculty members at the Duke Institute for Genome Sciences and Policy are learning this lesson the hard way thanks to the failure of someone at Duke to perform the basic HR duty of vetting Anil Potti's curriculum vitae 7 years ago. Potti, who was hired in 2003 as a physician-researcher by Duke, falsely claimed that he was a Rhodes Scholar on scientific grant proposals, according to a recent expose by Paul Goldberg in The Cancer Letter. That's a big lie and one suggesting that other big lies are possible, if not probable. Taking this very cue, Goldberg then questioned the integrity of Potti's research at Duke and found that 2 biostatisticians at M. D. Anderson discovered "a series of errors," including mislabeling errors, in a seminal article by Potti and others.

Consequently the biggest victim of Duke's remote HR lapse: cancer patients who enrolled in clinical trials, which were based on Potti's questionable work. According to the NYT, these trials have now been suspended (after stuttering efforts by Duke officials to reopen them, reported Goldberg). News coverage can also be found at NPR's Shots blog.

For yucks or groans, I performed a quick PubMed search: "A Potti" is the coauthor of 48 articles that were published within the last 5 years. Potti's articles appeared in, for example, PNAS, JAMA, JCO, PLoS One, Lancet Oncology, Nature Medicine, and the NEJM.

Photo of Anil Potti from Duke Institute for Genome Sciences and Policy.

10/24/10 addendum: As the AP reported yesterday, Lancet Oncology editor David Collingridge relayed an "expression of concern" from 15 European investigators who were coauthors with Potti and 3 other Duke researchers on a 2007 article in the journal. (The article validated the use of gene signatures to predict the response of breast cancers to neoadjuvant [perioperative] chemotherapy.) After the damning report from biostatisticians at M. D. Anderson about Potti's alleged errors in another article, the Lancet Oncology coauthors repeatedly attempted to contact their Duke colleagues, but they were ignored, wrote Collingridge.

The editor also revealed that "a large group of scientists" wrote to NCI director Harold Varmus on July 19th, expressing their concerns about the validity of a) Potti's cancer-treatment prediction models and b) 3 clinical trials that were based on these prediction models. Collingridge expressed his own concerns about the Lancet Oncology article given recent developments surrounding Potti. The journal has contacted the Duke coauthors—Anil Potti, Chaitanya Acharya, Sayan Mukherjee, and Joseph Nevins—and awaits their responses. 

Two studies* have now documented that Medicare spending per beneficiary varies widely on the basis of geographic location. The latest study, published in today's NEJM, indicates a difference of up to 52% between the highest- and lowest-spending areas in the United States. But reasons for a big portion of this spending difference remain a mystery.

While the authors conclude that some regionally based differences in Medicare spending per beneficiary can be explained by baseline health and demographic characteristics (like age, sex, and race), explanations for 60% of the spending difference are unknown. The researchers speculate that differences in Medicare spending might be influenced by a number of factors, including what boils down to fraudulent Medicare billing (eg, "providers' profit-seeking behavior" and "rates of inappropriate Medicare payment").

My own view, given a recent hospitalization, is that rampant billing fraud by in-hospital physicians (whether targeting Medicare, insurance companies, or patients) plays a substantial role. If my experience is any indication, it seems the rule,** rather than the exception, for physicians to greatly exaggerate their services—both in terms of level of care provided and time spent. Unfortunately this type of billing fraud is difficult, if not impossible, to detect, unless a very granular survey of physician billing can be compared with a reliable account of services actually rendered. And a reliable account probably requires the input of an unusually savvy patient—like a hospitalized physician.

* The first is Sutherland et al. NEJM. 2009;361:1227-1230.

** At least in my neck of the woods.

The recuperating blogger's method of easy blogging: Link to another story.

For today: A report from the NY Times, which revisits the dubious idea of stenting jugular veins in patients with multiple sclerosis. According to the paper, interest in the unproven procedure remains fueled by unknown numbers of desperate, logged-on MS patients and a few rogue physicians—some of whom market, in cringe-inducing fashion, a "liberation package."

Oh my ugh.

But neurologist Stephen Hauser of UCSF correctly tells the NYT that evidence for the procedure "is quite scanty" and that its "biological plausibility is low."

Previous posts at this blog highlight 1) a conclusion from US neurologist John Corboy that the small drop in pressure provided by these jugular-vein procedures is unlikely to be pathologically significant; and 2) the correct decision by Stanford to shut down the jugular-stent program of a vascular surgeon until well-controlled data are available to support the treatment.

Image of neck veins from Gray's Anatomy (1918).

Okay, maybe it's a cloying move by Pfizer to protest the absurdity of government oversight. But it's also kind of funny.

The world's largest drug company is advising US physicians who visit its exhibit booth at the ongoing ASCO meeting that they will have to swipe their registration cards if they want a freebie latte, reports Reuters. And oh no, you di'int: MDs from Minnesota and Vermont can't have one at all, thanks to their state laws that prohibit all swag—no matter how trivial.

Moreover, if you do accept a latte from Pfizer, the company may provide your name to US regulators and post the fact that you received caffeinated remuneration at its disclosure website. God knows, you could end up scribbling scores of prescriptions for Aromasin during your 20-minute Pfizer-propagated caffeine buzz.

At least the oversight measures are keeping somebody employed...and amused.

ASCO = American Society of Clinical Oncology.

"angry latte" by Chris Barkeley at Flickr.

06/10/10 addendum: It's hard to keep up, but Vermont recently amended its existing, relevant law to allow the "provision of coffee and other snacks or refreshments at a booth at a conference or seminar." The bill became effective on March 27th (without the governor's signature, according to the FDA Law Blog).