bmartin: July 2010 Archives

On Saturday. No good excuses.

To watch The Heiress (1949), based on the play of the same name, which is based on the Henry James novel Washington Square, is to engage in an exercise of contrasts. To wit:

• Contrast the dowdy Catherine (Olivia de Havilland) with her father's ideal of womanhood: Catherine's socially accomplished, dead mother.
• Contrast the overt contempt of Catherine's father for Catherine with the cloaked abuse of Catherine's suitor, Morris Townsend (Montgomery Clift).
• Contrast de Havilland's old-school mugging with Clift's subtler method acting.*
• Contrast Catherine's restrictive 19th-century bun with Morris's bon-vivant locks.
• And so on...

It's also worth noting that more contrasts are possible by watching the deftly filmed Washington Square of 1997, starring Jennifer Jason Leigh as Catherine, Albert Finney as Catherine's father, and Ben Chaplin as Morris. Leigh, in particular, adds several effective layers to Catherine's developing character that are absent from de Havilland's two- or three-note execution.

* de Havilland wins, if only because mugging is so hard to ignore.

A big HT to the WSJ Health Blog for showcasing this intriguing study in Health Affairs. Against the otherwise commonsensical preference for screening colonoscopy (to prevent and detect colorectal cancer), researchers at RTI International showed that yearly testing for fecal occult-blood leads to more life years saved. The result held even when adherence to CRC screening guidelines dropped to 40% and follow-up compliance was only 65%.

The context of the study was a fixed budget for a CRC-screening program ($1 million), and the assumed costs for guaiac testing and colonoscopy were $23 and $699, respectively. (Although the Healthcare Blue Book price for colonoscopy [no biopsy] is much higher, at $1658.) Consequently fecal occult-blood tests allowed the hypothetical program to screen more individuals and lead to a greater number of life-years gained.

The authors warned that the study only assessed life-years gained, not quality-adjusted life years (QALY), and that the test selection was made in the context of a fixed budget. "If there were no budget constraints," they wrote, "a different screening test might be preferable."

But really: When are there no budget constraints?

Addendum: At the WSJ Health Blog, one commenter raised the issue that the authors only assessed a hypothetical population-based screening program. The results do not necessarily indicate that fecal occult-blood tests are preferable screening tools for individuals who are at high risk for CRC (eg, people with Crohn disease or a family history of CRC).

Photo of Olympus standard video colonoscope: price, $3500. (Avoiding Olympus standard video colonoscope: priceless.)

Nearly 8 months after the FDA refused to file Merck Serono's application for oral cladribine as an MS treatment, the company says the drug has now received priority review.* Merck Serono resubmitted its application to the agency in June. Related coverage from the WSJ indicates that the company expects an FDA decision in the fourth quarter, although the goal for a priority review is a bit longer, at 6 months.

With cladribine, Merck Serono has been in a nose-to-nose horse race with Novartis, which is developing fingolimod (Gilenia). One of these companies is very likely to be the first to offer an FDA-approved, orally administered disease-modifying drug for the relapsing-remitting form of the disease. (Current, approved, disease-modifying medications for RRMS, like interferon beta, are injected subcutaneously or intramuscularly.)

According to the WSJ and Reuters, oral cladribine for RRMS was approved in Russia earlier this month and is awaiting a nod in Europe. In June, an FDA panel voted overwhelmingly in favor of fingolimod's approval—at least with respect to its efficacy. Safety issues with Novartis's agent include opportunistic infections, and analysts have speculated that the FDA will institute some kind of access-limiting REMS program for the drug, if/once it is approved.

A new survey analysis indicates that US neurologists are considerably more aware of cladribine than fingolimod—probably because the former has been available as an injectable anticancer drug since the Stone Age (ie, the early 1990s), and fingolimod is a new molecular entity (NME).

MS = multiple sclerosis; REMS = Risk Evaluation and Mitigation Strategies.

* According to the FDA, a "Priority Review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. A Priority Review means that the time it takes FDA to review a new drug application is reduced. The goal for completing a Priority Review is six months."

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 OSCS), 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.

The White Ribbon

(2009): Oh those Germans. Or Austrians. Whatever. And their frivolity. Not.

In austere and exquisitely still frames of retrofitted black and white, director Michael Haneke unfolds his story of anonymous evil deeds in a farm village on the cusp of World War I. Cryptically narrated in retrospect by the town's sympathetic, if ineffectual, schoolteacher (who's not even sure he's remembering correctly), the story reveals the stark brutality of paternal figures, suggesting that the perpetrator is an adult. But the innocence of the town's oppressed children cannot be assumed. Brutal adults can bear brutal children.

Advice for those fearful and fear-mongering parents who space out or delay vaccinations for their children: Don't.

The "too many, too soon" rant, which is predicated on the convoluted idea that multiple vaccinations overwhelm the immune system and thereby cause autism, has been thoroughly shot down by logical argument and now by a recent study in the journal Pediatrics.

Mining the Vaccine Safety Datalink, physicians at the University of Louisville in Kentucky compared the long-term neuropsychological outcomes of children who received on-time vaccinations during their first year with those who didn't. The cut-to-the-chase result: children who received timely vaccinations generally performed better and certainly no worse than less vaccinated kids. The study was based on a previous CDC study, which showed no association between exposure to thimerosal, a long-time vaccine preservative containing microgram amounts of ethylmercury, and autism.

At Medscape, CHOP pediatrician Paul Offit (Satan incarnate to antivaccinationists) offers his predictable and correct perspective on the study, saying,

I think parents can be reassured here that a choice to delay vaccines or to not give vaccines does not in any sense decrease the risk of a neurological outcome or autism. All it does is increase the period of time during which children are susceptible to vaccine-preventable diseases.

CDC = Centers for Disease Control and Prevention; CHOP = Children's Hospital of Philadelphia.

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. 

Dr. George Lundberg, MedPage's Editor at Large, is really excited about an article that was published in March in the Journal of Clinical Investigation. And he predicts big things for the article's authors, like a Nobel Prize.

The article, by California academicians and an employee at AntiCancer, Inc., describes how vasculogenesis* of irradiated tumors can be inhibited by an already approved drug, AMD3100, in a mouse model of glioblastoma multiforme—the deadliest of brain cancers.

AMD3100 is also known as plerixafor or Mozobil, which is owned by Genzyme. The injectable drug is currently indicated, in combination with G-CSF, to mobilize hematopoietic stem cells for autologous transplantation in patients with non-Hodgkin lymphoma or multiple myeloma. So human trials of the drug and uncontrolled case studies can begin, Lundberg argues, more or less immediately.

G-CSF = granulocyte-colony stimulating factor (eg, filgrastim [Neupogen; Amgen]).

* Which is distinguished from angiogenesis or "the sprouting and proliferation of endothelial cell from local vessels. The authors posit that tumor recurrence after radiation is largely mediated by vasculogenesis, the "colonization of circulating endothelial or other cells primarily from the bone marrow."

Photo of Ted Kennedy, who died last year of glioblastoma: Biographical Directory of the United States Congress.

As predicted

, more or less, by Yale's Jack Balkin in January's NEJM, the T word is hauled out to defend the constitutionality of ObamaCare's health-insurance mandate.

In fact, in one of the many legal cases protesting the insurance mandate (and the associated penalty for not having insurance), Balkin and others rebutted with an amicus brief that argues the T point. The NYT has the story.

To celebrate BP's sealing of the Macondo well,* jump into the big, black tarry pit of oil-company litigation by watching Crude. The 2009 documentary by Joe Berlinger is an account of a the sticky, interminable class-action suit brought by Ecuadorians against Texaco (now owned by Chevron). Predictably, and primarily because we're considering a documentary here, it is a very plaintiff-friendly account of the protracted and ongoing legal proceedings that are anything but clear-cut. Just perform a search of the Google News archives with "Chevron" and "Ecuador," and you'll get an idea of how really, really complicated things are.

The story relayed in Crude, however, is comparatively straightforward—and deceptively simple. It begins when Texaco discovered oil in the area of Nueva Loja in northeastern Ecuador in the 1960s. In conjunction with Ecuador's national oil company, Petroecuador, Texaco launched full-scale production in the 1970s by thoroughly mining the area. As was oil business as usual, the massive amounts of drilling waste were disposed in superficial pits—which the resident Ecuadorians claim tainted their drinking and bathing water (obtained from nearby streams and rivers) and caused multiple ailments, including cancer. The plaintiffs are asking for $27 billion.

The corporate side of the story, which Berlinger does reveal, however impersonally, is that Texaco transferred ownership of the oil field and its production to Petroecuador in 1990 and spent millions cleaning up the waste pits under the direction of the Ecuadorian government. According to Chevron, which bought Texaco in 2001, the Ecuadorian government released Texaco of any liability once the waste pits were cleaned up to the government's satisfaction. Chevron also denies that there is an increased risk of cancer or cancer-related death in Nueva Loja residents, when compared with their countrymen.

Featured in the plaintiffs' David-versus-Goliath cause (as it is billed repeatedly in the movie) is a young, modest Ecuadorian lawyer, Pablo Fajardo, who is aided by a tenacious or insufferable (depending on your viewpoint) American lawyer, Steven Donziger. Donziger is a world-class grandstander (at least when the camera's rolling) and a seeker of high-level publicity (either for himself or the suit, it's not always clear). On a few occasions, Berlinger shows the frustration or outright umbrage that Donziger's constant 8-cylinder attitude produces in his adversaries and, at least on one occasion, his Ecuadorian allies.

Donziger becomes the means by which Fajardo is featured in a very sympathetic Vanity Fair article, which becomes the springboard for introducing Fajardo and his cause to the new Ecuadorian president, Rafeal Correra, and Trudy Styler, wife of Sting. Berlinger does gets a nod for including a segment in which Styler visits an unidentifed Ecuadorian tar pit (the reponsibility of which, mind you—Texaco or Petroecuador—is completely unclear). In the segment, the publicity-minded Donziger pulls Styler aside and tells her to mention "Texaco" as much as possible on film. Whether it is the intention of Berlinger (and what does that matter anyway?), the viewer hopes that Donziger will not pollute the simple Fajardo with Western celebrity. Thanks to Donziger's publicity efforts, Fajardo ended up hanging out with Sting at the 2007 Live Earth concert and was honored with CNN's Hero Award and the Goldman Prize.**  

What Crude ultimately prompts (besides repugnance for Donziger) are a number of questions that attempt to flush out a more even-handed and accurate account of the events that led to and inform this litigation. Namely...

• Do Ecuadorian residents of Nuevo Lajo, in fact, have an increased incidence of disease generally and cancer specifically? The pathetic, heart-wrenching cases presented in Crude shouldn't be sufficient for evidentiary purposes (but they probably will be). According to a PubMed search, there are a number of medical articles suggesting that the Nuevo Lajo Ecuadorians are at greater risk of certain diseases, but these positive studies are also authored by the same Ecuadorian investigators and apparently haven't been replicated by independent sources.
• If Neuvo Lajo citizens have an increased incidence of certain diseases, can they be linked to chemicals leaching from the remaining, uncleaned waste pits?
• If so, who created or has responsibility for these waste pits? Chevron or Petroecuador? (It is undisputed in Crude that Petroecuador has a dismal environmental record.)
• Can a fair trial be conducted in Ecuador, where judicial and political corruption seems to be the norm instead of the exception? While judicial corruption is highlighted briefly in Crude (and to the plaintiffs' advantage), more widespread charges have been made by Chevron against a court-appointed expert, the formerly presiding judge, and Donziger himself. (Although Crude revealed that the presiding judge was removed from the case, Berlinger did not explain why.)
• If the plaintiffs prevail in their suit, who gets the money? Crude hints that much of the cash will go to attorneys (eg, the Philadelophia firm of Kohn Swift and Graft, which is funding the plaintiffs) and the Ecuadorian government.

N.B.--No matter how unduly influenced Styler may have been by the bulldozing Donziger to believe that Texaco/Chevron is responsible for the current mess in Nuevo Lajo, it is to her (and Sting's) credit that their organization supplied local families with rain-water cisterns--which the Ecuadorian government is apparently unwilling or unable to do.

* However temporary.

** It should be noted that Donziger approached Berlinger to make Crude, although this fact is only revealed in recent news coverage of the suit.

While most of us are consumed with the Avandia vote or diverted by the umpteenth procedure on Dick Cheney's failing heart, Wayne Koff and Seth Berkley of the International AIDS Vaccine Initiative promise the existence of an effective HIV vaccine...in the not-too-distant future. Their perspective on vaccine development, in the context of the upcoming International AIDS Conference in Vienna, is available in this week's NEJM.

The reasons for their enthusiasm:

• Encouraging results from the large vaccine trial (RV144) in Thailand, which was reported last year.
• The prevention or control of infection with simian immunodefiency virus (a monkey correlate of HIV) in preclinical studies by using "new vaccine approaches."
• The identification of "vulnerable" HIV targets by using broadly neutralizing mAbs.

Data from these investigations can and/or will be used to tweak (for lack of a better word) candidate vaccine regimens against HIV. Specifically in the short term, investigators will attempt to define the immune mechanisms that conferred protection in the Thai trial and then create a vaccine regimen (eg, multiple prime and boost shots) to maximize those responses. Koff and Berkley predict follow-up clinical trials to be under way by 2013. (That's sooner that the legislated kick-off of ObamaCare.)

Successful vaccine development will necessitate the cooperation of government, academia, and industry and will demand, of course, lots of money. Koff and Berkley advise that the global financial crisis should not thwart the forward movement of vaccine development at this promising stage. One visible backer is Bill Gates, who recognizes the big hurdles to a successful HIV vaccine and is scheduled to speak at the Conference, says the WSJ Health Blog.

If you're looking for a break from the FDA's much-covered review of Avandia,* try the refreshing In Vivo Blog. The latest from the armchair bloggers (talk about redundant phrasing, and heh, takes one to know one) is their follow-up of biomarker data from JNJ and Pfizer on bapineuzumab, the anti-amyloid mAb in phase 3 development for Alzheimer disease.

Presented at the Alzheimer's Association International Conference on Alzheimer's Disease 2010 in Honolulu (Altoona wasn't available?), the biomarker data don't concern a reduction of amyloid with bapineuzumab treatment. Instead the data (and they're phase 2 clinical data) show a drop in CSF levels of P-tau, at least when they're pooled.

The examination of P-tau, as a "downstream" biomarker, may be scientifically valid in studies of anti-amyloid therapies. P-tau is certainly an important marker of AD pathology generally, and investigators seem to be more enthusiastic about direct, anti-tau therapies than anti-amyloid therapies. But the tau angle is also commercially savvy. It's a way of bolstering interest in the continued investigation of the leading anti-amyloid drug, which has provided underwhelming clinical results to date.

* heartwire.org provides the most detailed description of yesterday's contentious agency meeting, IMO--just short of live blogging it.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

CSF = cerebrospinal fluid; mAb = monoclonal antibody.

On the cusp of the FDA's safety review of Avandia, a couple of indeterminately sized bombshells:

One from Dr. Rosemary Johann-Liang, vis-a-vis Business Week. Johann-Liang, a former manager in the FDA's drug-safety office, said by way of a legal deposition that GSK withheld results of a 2001 Avandia study from the agency. The study reportedly showed that Avandia increased the risk of heart attack.

And another from Gardiner Harris of the NYT, who reported on the buried results of a 1999 GSK-sponsored trial that pitted Avandia against its competitor Actos and an older OAD, glyburide. The results, which have evidently been cloistered at GSK for more than 10 years, were "disastrous," Harris wrote, with respect to Avandia's cardiac risks. According to Harris, Dr. Martin I. Freed, who was in charge of Avandia's development at SmithKline Beechem in 2001 (ie, before the Glaxo merger), wrote that "these data should not see the light of day..."

Unfortunately Harris didn't or wasn't able to track down Freed for the doctor's updated perspective—that is, Harris did not even write something like "Dr. Freed declined to comment" in his NYT report.

According to a 2007 press release from Adnexus Therapeutics (an R&D arm of BMS), Freed was appointed to the newly created role of Chief Medical Officer; however, at the company's web site, Freed is not currently mentioned among the company's current top management.

The 2007 Adnexus press release described Freed's background, including his pharma experience:

Dr. Freed was Vice President of Clinical Development at GlaxoSmithKline. During his tenure he led [the] clinical development of Avandia, a leading drug in the treatment of type 2 diabetes from preclinical to market. Dr. Freed was also involved in the clinical development of drugs across a broad range of therapeutic areas including metabolic diseases, cardiovascular disease and diseases of inflammation, with experiences ranging from Phase 1 through Phase 4 clinical trials. He participated or directed more than 100 clinical and clinical pharmacology studies, involving thousands of patients, for multiple products. Prior to joining Adnexus, Dr. Freed was Chief Medical Officer at a privately-held biotechnology company Vitae Pharmaceuticals, which has programs across a range of therapeutic areas including hypertension, diabetes, cancer and inflammation. A Fellow of the American College of Physicians, Dr. Freed received his Doctor of Medicine from Pennsylvania State University College of Medicine and graduate magna cum laude with a Bachelor of Arts with Distinction in Biology from the University of Delaware. Dr. Freed is Board Certified in Internal Medicine, Nephrology and Clinical Pharmacology. He performed his internal medicine residency and nephrology post-doctoral training at Temple University Hospital and Yale New Haven Hospital, respectively.

Other web-based searches suggest that Freed is now in Wellesley, Mass. It's unclear if the 50-ish doctor is retired or working.

OAD = oral antidiabetic drug. 

In what amounts to the best brief analysis of the Avandia controversy—that is, whether to keep the antidiabetic drug on the market—Daniel Carpenter, professor of government at Harvard, defines the major divisive issues that inform the FDA's upcoming review of the product. His BEST GUEST PHARMA BLOG POST PROBABLY EVER can be found at today's Pharmalot.

The battles, as defined by the prof:

• "The War Over Method"—meaning, should we continue to overwhelmingly favor the results of randomized controlled trials, which have generally downplayed Avandia's cardiac risks, or should we cling to the findings of less rigorous and inherently problematic observational studies (eg, meta-analyses), which emphasize the drug's cardiac risks? Inextricably tied to this debate is the fact that the Avandia RCTs are uniformly funded by GlaxoSmithKline, the maker of Avandia, while the most press-worthy observational studies have been conducted by an attention-loving academic (Steve Nissen) and an FDA maverick (David Graham)—both of whom may have their own axes to grind with GSK and the FDA, respectively.
• A complicating subissue in The War Over Method (although Carpenter defines this as a separate issue) is what to do with a new report from FDA reviewer Thomas Marciniak, who publicly maligned the design and analysis of GSK's RECORD trial (a trial that was intended to assess Avandia's cardiac risks). With his report, Marciniak cast a very long shadow over the integrity of all GSK-sponsored RCTs.
• The third issue that Carpenter defines is Reputation and Power—which, in my mind, is so strong an undercurrent in the Avandia debate that it merits upfront discussion. And while Carpenter primarily directs this topic at the FDA (an emphasis, not coincidentally, that markets his new book, Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA), the issue can also be applied to the motives and integrity of individual parties—like Steve Nissen and David Graham.

I'll forgo this week's obvious recommendation: The Girl with the Dragon Tattoo (2009), which was just released on DVD. The movie is undeniably engaging. (What serial-killer tale isn't?) But the story, at least as executed on film, simply isn't good enough or clever enough or sufficiently well executed to justify or sustain several explicitly violent scenes and images, most of which are sexually brutal.

Instead this week's KBF is Panic in the Streets (1950) from director Elia Kazan.

After an unidentified murder victim shows up in the coroner's office with pneumonic plague, a government health officer (Richard Widmark) and a police captain (Paul Douglas) reluctantly pair up to thwart an epidemic. Their ultimate task: to find the victim's killer (or killers), who might spread the disease or die of it.

Because this is an Elia Kazan joint, character dynamics approach the importance of plot, and several new actors—namely Walter Jack Palance, Zero Mostel, and Barbara Bel Geddes—get to flaunt their emotive talents.

One brief, callous and self-serving act in particular (which is perpetrated by Palance's character) is all the more shocking and effective because the movie (unlike The Girl...) doesn't repeatedly assault the viewer with technicolor carnage.

Just like in 2008, total income to produce all certified continuing medical education (CME) programs dropped by another 7% last year, from about $2.37 billion in 2008 to $2.18 billion, according to the latest data from the Accreditation Council for CME. But commercial support to publishing/ educational companies, or MECCs, fell even more dramatically—by greater than 20% (which is comparable to the drop observed between 2007 and 2008). Consequently total income to MECCs (which are down from a total number of 144 in 2008 to 135) declined by about 10% (companies evidently made up some of their losses with modest increases in advertising income, money from other sources,* and a slight reduction in expenses).

Here's the cut-up year-to-year table, which provides not only cumulative data, but average total and net incomes per MECC. The cumulative net income (total income minus total expense) and the average net income per MECC in 2009 were about half of what they were in 2007. The explanations: a general reduction in support from commercial sources to all CME providers (down 30% from 2007) and a directed reduction in support to MECCs (down nearly 40% from 2007).

Year	Total Income	Total Commercial Support	Advertising and Exhibits Income	Other Income	Total Expense
2005 (N = 148)	$780,783,394	$594,864,588	$18,757,802	$167,161,004	$598,727,647
2006 (N = 154)	$818,772,623	$620,657,405	$15,431,546	$182,683,672	$607,961,083
2007 (N = 150)	$830,811,192	$594,419,878	$10,831,027	$225,560,282	$615,705,205
2008 (N = 144)	$667,419,787	$463,382,991	$10,054,745	$193,982,051	$509,811,733
2009 (N = 135)	$604,024,888	$365,315,693	$11,406,679	$227,302,516	$500,057,330

Year (No. MECCs)	Net Income	Average Total Income per MECC	Average Net Income per MECC
2005 (N = 148)	$182,055,747	$5,275,563	$1,230,106
2006 (N = 154)	$210,811,540	$5,316,705	$1,368,906
2007 (N = 150)	$215,105,987	$5,538,741	$1,434,040
2008 (N = 144)	$157,608,054	$4,634,860	$1,094,500
2009 (N = 135)	$103,967,558	$4,474,258	$770,130

MECCs = medical education-communications companies.

* Like, for example, participant registration fees and "allocations from a provider's parent organization or other internal departments." 

When it comes enforcing or repealing the SGR formula, the legal fix that was designed to reduce Medicare growth way back in 1998, don't look for decisive action from Congress any time soon. So says Henry Aaron of the Brookings Institute* in this week's NEJM. 

Congressional enforcement of the SGR formula is untenable because it means making increasingly draconian cuts in physician reimbursement (~21% this year). But the abomination (as Aaron calls it) won't be repealed because the Congressional Budget Office will view the act as an increase in spending. So for now, Congress repeatedly suspends the formula, while keeping the law "on the books" to avoid a monstrous increase in the already monstrous deficit.

However, Aaron offers hope—albeit faint hope. The Patient Protection and Affordable Care Act (aka ObamaCare) offers several provisions that allow for the study of pilot programs (eg, accountable-care organizations) that may [yeesh—tugging at neckline] streamline healthcare and cut costs. Physicians could someday be sufficiently motivated to participate in one or more of these programs, Aaron argues, if the alternative is sustaining a very-deep SGR-defined gash in Medicare reimbursement. Aaron evokes the near-future image of Congress as Vito Corleone ("make physicians offers they can't refuse), but I've got a more vivid picture: Luca Brasi and the Johnny Fontane contract.

SGR = sustainable growth formula.

* Not Henry Aaron of the MLB.

Photo of weathered can from magannie at Flickr.

Last year, Merck, Sharp, and Dohme, Ltd—the UK subsidiary of Merck & Co in the United States—warned the Association of British Neurologists of an impending shortage of Sinemet and Sinemet CR,* long-term mainstays of Parkinson's treatment. The anticipated shortage was "related to a change in the source of supply for the drug and the necessary timelines needed to obtain regulatory approvals for this supply change," wrote MSD's Medical Director, Paul Robinson. The temporary "supply interruption," as he described it, was expected to continue into 2011.

Robinson also advised that MSD and its parent company, Merck, would manage the available supply of Sinemet by taking into account "patient needs," the availability of "alternative treatments" (presumably other dopaminergic drugs or generic versions of Sinemet), and "contractual obligations." However, many markets would "not get any supply of these products," Robinson cautioned. He did not name the at-risk areas.

The carbidopa/levodopa supply for US Parkinson's patients is not endangered, according to a BNET story in March. BNET implied that this is primarily because a CR equivalent (from Mylan) was approved by the FDA in 2009. In the United States, Sinemet CR is manufactured by Merck and marketed by BMS, and nonbranded versions of standard-release carbidopa/levodopa have been available for several years.

Also according to BNET, Sinemet-deficient areas throughout the world include not only the United Kingdom, but Canada, Spain, and Australia. Each of these countries appears to have specific manufacturing and marketing arrangements for the drug—which likely inform the product's regional availability.

Yesterday a UK patient-support group "called for action" on the Sinemet shortage. Specifically the group urged visitors to use an online form to "demand clear communication and effective management of the shortage" from Merck. The MSD website for UK professionals currently advises a shortage of Sinemet Plus (125 mg), Sinemet (62.5 mg), and Sinemet CR (250 mg). In Canada, the product is evidently licensed to Merck Frosst Canada and BMS Canada. But the website does not advise of any supply problems, as far as I can tell. The MSD website for Australia reports that Sinemet CR (200/50 mg) is out of stock and will be in very short supply until early 2011. This shortage, however, does not affect the supply of standard Sinemet (100/25 mg and 250/25 mg).

At the time of this post, inquiries to clarify the Sinemet shortage have been sent to the American Academy of Neurology, BMS, and Merck. Responses are pending.

CR = controlled release.

* Combination pills of carbidopa/levodopa (or co-careldopa in the United Kingdom).

Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers at Wikimedia Commons.

Addendum #1: According to an e-mail from Merck, the shortage of branded Sinemet and Sinemet CR is a global problem. However, the fallout for patients seems to be regionally dependent and based on the availability of generic equivalents—particularly a CR version. So for American patients, the shortage doesn't appear to be as acutely felt as it is by UK patients.  

Here's the company's undated PR output, which was sent to me today:

A temporary global supply shortage of SINEMET and SINEMET CR, Merck's/ MSD's Parkinson's disease products, will begin in late 2009 and affect most markets. The supply shortage is related to a change in the source of supply and the necessary time needed to obtain regulatory approvals for the change. It is not related to any product safety or quality issues.

Merck/ MSD is taking action to manage available product supply of SINEMET and SINEMET CR through a process that primarily takes into account patient needs, as well as the availability of alternative treatments and contractual obligations. In most markets, alternative products are available to treat Parkinson's disease.

Merck/ MSD currently expects to be able to supply full global needs of these products sometime in 2011; but some countries are expected to return to regular supply earlier than this date.

Merck/ MSD will notify customers and others as appropriate about the supply shortage and allocation plan.

I found no official comment at the Parkinson's Disease Foundation website regarding the current shortage of Sinemet tablets, but supplies of the pills were evidently limited in 2003, because of "manufacturing issues."

Important addendum #2: And here's today's e-mail from BMS, which indicates that US patients who want branded Sinemet have little to worry about.

Bristol-Myers Squibb distributes Sinemet and Sinemet CR in the US only. At this time, Bristol-Myers Squibb had has sufficient inventory of Sinemet and Sinemet CR to meet US market demand. Questions about other geogrphic regions should be directed to Merck & Co.

On the heels of the absolutely wonderful I Know Where I'm Going (1945), another film from The Archers.

Britain's second most-beloved movie of all time (if one film poll is to be believed), A Matter of Life and Death (1946) was finally (finally) pounded out on DVD last year. David Niven is a WW2 pilot who attempts to avert a certain, imminent death while falling in love with an American radio dispatcher (Kim Hunter). Like Heaven Can Wait (both versions) and The Devil and Daniel Webster (1941), A Matter of Life and Death concerns the fanciful struggle between the desire to continue an earthly existence, with all its ephemeral virtues, and the demands of mortality, the gods, or whatever you want to call it.

The distinctiveness of this movie lies in its juxtaposition of a black-and-white afterlife against a very technicolor existence on Earth (in a wry homage to The Wizard of Oz); the adherence to intricacies of British jurisprudence (even in the afterlife); and the attempt to weave in a neurologic disorder* (somewhat dubiously, I might add) to explain Niven's visions of his afterlife courier, an executed French aristocrat. The courier, or Conductor, as he is called, has got to be one of the most bizarre filmic oddities around, both visually and in personality—even by the very liberal standards of eighteenth-century French nobility.

* Chronic, adhesive arachnoiditis due to a previous head injury.

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.