December 2010 Archives

Where the Sidewalk Ends*

(1950) is another grossly underappreciated noir film from Fox Studios, which reunites several individuals from the iconic Laura (1944), including director Otto Preminger and lead actors Dana Andrews and Gene Tierney.

A hot-headed New York detective, Mark Dixon (Andrews), attempts to cover up his unintentional killing of a gambling thug and then tries to pin the murder on his longtime nemesis, asthmatic crime boss Nicky Scalise (Gary Merrill of All About Eve). But the police, namely Dixon's boss (Karl Malden), believe that the thug's father-in-law is the perp. Dixon is ultimately torn between his hatred for Scalise and his growing admiration for the thug's lovely, saintly wife (Tierney).

Once again, entertaining and informative commentary is given by noir export Eddie Muller, who provides little-known background on several character actors and highlights Preminger's understated camera work and spare editing style.

* Not to be confused with the Shel Silverstein work.

No. 1: Judicial and Other Threats to PPACA's Insurance Mandate

Even before the Patient Protection and Affordable Care Act (PPACA) was signed into law, on March 23rd, objections were raised to its Constitutionality. The overriding issue: Whether Congress has the authority to mandate the purchase of health insurance (starting in 2014) and to impose a financial penalty for not doing so. For its part (and before the passage of the bill), the Obama administration flatly rejected the notion that the legislated penalty for not buying insurance could be construed as a tax—largely because of the political poison of the T word.

But in January, Yale law professor Jack Balkin, writing in the NEJM, explained that the Constitutionality of PPACA rests squarely on the notion that the penalty is a tax on those persons* who fail to buy health policies and that, by extension, Congress has the authority to impose taxes that serve the general welfare. End of story. Balkin further predicted that the Supreme Court wouldn't even touch the insurance mandate/tax issue, unless a federal court of appeals knocked it down. And in that case, the high court would uphold it.

In one of many pending state-based cases that have now been brought against PPACA (including a suit in Florida), Balkin and others filed an amicus brief arguing the "tax point," reported the NYT in July. Balkin also criticized President Obama for not being "honest with the American people about the nature of [PPACA]." The criticism has some merit, given the fact that the Justice Department is now rebutting PPACA detractors with the same the-penalty-is-a-tax argument.

Also challenging PPACA's insurance mandate is the argument that Congress (under the Commerce Clause) doesn't have the power to regulate "inactivity." It was the rationale used by Federal Judge Henry Hudson, who ruled on December 13 that Congress lacks the authority to require the purchase of individual health insurance (and, by extension, to levy taxes [or penalties?] on citizens for not buying insurance). 

With Hudson's ruling, legal scholar Mark Hall, also writing in the NEJM, expressed relative dismay at the mandate's future (as the issue inexorably wends its way through the federal court system). Nevertheless Hall noted that there is a long judicial precedent for giving serious leeway to Congress when it comes to interstate commerce—like the commerce of health insurance. And negating PPACA's insurance mandate can't necessarily be done in isolation. Hall wrote,

[T]he Court must also decide whether to strike the accompanying insurance regulations and subsidies, which are much more popular and clearly within congressional power. Judge Hudson struck only the individual mandate, “severing” it from the rest of the [PP]ACA. But because the [PP]ACA’s ban on medical underwriting would wreak havoc on the marketplace without the mandate, other judges might feel torn between striking both and letting both stand.

Outside the court system, there are otherwise toothless threats to PPACA in the form of newly proposed state laws. The propositions—like those considered in the Red States of Missouri, Arizona, and Oklahoma—seek to nullify the federal mandate; however, they are largely symbolic, given the fact that federal law routinely trumps state law and that the Constitutionality of PPACA will have been decided by the time its insurance mandate goes into effect (in 2014). 

* Meaning individuals who don't already have employer-provided health insurance. The "mandate" also does not apply to dependents, Medicare or Medicaid recipients, military families, overseas ex-pats, or religious objectors.

No. 2: Congress Repeatedly Delays Cuts in Medicare Reimbursements to Physicians

This year, Congress repeatedly passed "kick-the-can" measures to delay legislated cuts in Medicare reimbursements to physicians. The latest bill, passed earlier this month by the Senate, is distinct from previous bandaid measures, because it will stave off the SGR-defined cut in Medicare payments by 1 whole year, as opposed to 1 or a few months.

The Medicare-reimbursement cut, now calculated at a painful 25%, would have otherwise kicked in on January 1st. According to Medscape's Robert Lowes, who is a recommended go-to source on the subject, Congress has now acted 5 times this year to delay the SGR-defined cut, which was legislated way back in 1998.* Congressional measures to delay the cuts began in 2003 (at least by my notes) and have become more pressured as the SGR formula dictates ever-increasing slashes in Medicare reimbursements.

It is hoped (by the AMA, for instance) that the latest bill's 12-month reprieve will give Congress time to repeal the SGR formula altogether. The big trick is to find palatable ways to make up the huge cost of killing the formula entirely. The price tag of the latest 12-month bill, estimated at more than $19 billion, will be answered by a proposed amendment to the Patient Protection and Affordable Care Act (PPACA), say the bill's sponsors. The amendment would address thresholds for tax credits to Americans who will be legally mandated to buy health insurance in 2014.

But the Brookings Institute's Henry Aaron, writing in a July issue of the NEJM, says that Congress won't repeal the formula because the Congressional Budget Office will view the act as an increase in spending. So Congress has repeatedly suspended the formula, while keeping the law "on the books" to avoid a monstrous increase in the already monstrous deficit.

Nevertheless Aaron offers hope—albeit faint hope. Several provisions in PPACA allow for the study of pilot programs (eg, accountable-care organizations) that may (may) 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 an even deeper SGR-defined gash in Medicare reimbursement. In a not particularly happy scenario, Aaron evokes the near-future image of Congress as Vito Corleone ("...make physicians offers they can't refuse).

SGR = sustainable growth rate.

* The SGR formula was designed to reduce Medicare growth, but physicians' costs have grown at a rate beyond that of the economy.

Photo of weathered can from magannie at Flickr.

No. 3: The Judicial Threat to hESC Research

It was a blindsiding judgment for many scientific investigators. On August 23rd, federal judge Royce C. Lamberth ruled that President Obama's 2009 executive order to expand government funding for work on human embryonic stem cells (hESCs) conflicts with a legislated ban on using federal money to destroy embryos (first contained in the Dickey-Wicker Amendment to the Balanced Budget Downpayment Act of 1996). The immediate effect was the halting of more than 160 scientific grants from the National Institutes of Health, representing nearly $150 million.

Lamberth's decision was the culmination of a year's worth of court proceedings in the case of Sherley et al v Sebelius et al, in which James L. Sherley, MD, PhD, and Theresa Deisher, PhD filed suit (along with an original, motley group of right-to-life organizations) against the Health and Human Services Secretary and others in the US District Court for the District of Columbia. The plaintiffs sought declaratory and injunctive relief to prevent the NIH's recently issued Guidelines for Human Stem Cell Research, which were produced in response to Obama's executive order, from taking effect. The plaintiffs argued that the NIH guidelines violated the Dickey-Wicker Amendment and created unfair competition for those researchers (like Sherley and Deisher) who choose to work with non-embryonic stem cells.

Two months after the plaintiffs filed their suit, Judge Lamberth dismissed it in October of 2009, on the basis of a lack of standing. But in June of this year, the Court of Appeals reversed Lamberth's dismissal, concluding that Drs. Sherley and Deisher had standing under the competitor-standing doctrine.* The Court of Appeals remanded the matter back to Lamberth—who made his stunning pro-plaintiff decision in August.

One month later, Lamberth denied the Justice Department's emergency motion for a stay of his preliminary order, citing the language of the Dickey-Wicker amendment.** However, the Court of Appeals again reversed Lamberth's decision and granted the DOJ's motion to stay the injunction. Fast forward (sort of) to this month, when appellate arguments from both sides were made before a 3-judge panel, which focused on legislative precedent (argued by the DoJ); the "plain" language of the Dickey-Wicker amendment (argued by the original plaintiffs); and the harm factor (to both the plaintiffs and the NIH).

The panel's decision, which is still pending, will determine whether Lamberth's preliminary injunction against the federal funding of hESC research is upheld or overturned. Notably Lamberth could also decide, either before or after the latest appellate decision, to permanently block federal funding for hESC work—which would, no doubt, be appealed by the losing party.

A most comprehensive and recommended source for this ongoing story is and has been Nature's The Great Beyond blog.

In the meantime, research with hESCs gingerly steps into the clinical-trial arena, after the FDA gave its nod in July and November to 2 trials, respectively, of hESCs in humans: one in subacute spinal-cord injury and the other in an inherited macular degeneration.  

* Because the other plaintiffs did not contest the Court’s prior finding, the Court of Appeals treated "their lack of standing as conceded."

** Which has been serially ratified as an amendment to each yearly budget act.

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

No. 4: Pradaxa

—Drum Major for the Coming Anticoagulant Parade

In October, the FDA approved dabigatran (trade name, Pradaxa), the first drug to seriously challenge and potentially replace warfarin in the anticoagulant market. The direct thrombin inhibitor—developed by the private, German company Boehringer Ingelheim—is a potential uber-blockbuster, because it is a potential godsend for those patients with atrial fibrillation who would otherwise require warfarin to reduce the risk of stroke. Pradaxa's main advantage over the traditional anticoagulant: It does not necessitate laboratory monitoring (ie, protime measurements) and the consequent (and constant) adjustments of dosage.

On the basis of the huge RE-LY trial, the FDA approved Pradaxa at a dosage of 150 mg BID, which (when compared with warfarin) provided superior efficacy and comparable safety. An alternate dosage in the trial, 110 mg BID, was—curiously enough—not approved by the FDA, despite the fact that it showed comparable benefits to warfarin. Instead the agency gave a nod to a 75-mg alternative for renally compromised patients, on the basis of pharmacokinetic studies.

It's a regulatory decision that leaves many clinicians, save for cardiologist Sanjay Kaul, scratching their heads. In October, Kaul told told heartwire, "The 110-mg dose, while associated with reduced bleeding, had a 12% higher incidence of ischemic stroke. In my opinion, it would not offer much of an advantage over warfarin and would likely be an ineffective alternative."

But not allowing the 110-mg pill on the US market leaves Americans who don't respond reliably to warfarin and who can't tolerate the 150-mg BID dosage of Pradaxa with no reasonable options. In an effort to cater to these patients, some US physicians have been attempting to approximate the 110-mg BID dosage of Pradaxa by prescribing 75 mg TID; however, finding adequate pharmacy stocks of the 75-mg pill has been difficult, according to anecdotal reports. For some patients, this means returning to warfarin therapy and all its attendant frustrations—for the time being.

Pradaxa's FDA approval was followed, 1 month later, by the publication of a favorable, independent cost-effectiveness study—which showed that BI could justify asking up to $13.70 per day for its 150-mg BID regimen. But the company, in a show of fiscal responsibility, set a wholesale acquisition price at $6.75 per day, or $202.50 per month. The website destinationrx.com offers 60, 150-mg pills for $218.70.

The advent of Pradaxa may signify something more than just 1 option for warfarin-requiring patients. It may herald a Pharma resurgence, according to Forbes's Matthew Herper (The Medicine Show). Herper predicts that several emerging anticoagulants, along with Pradaxa, will likely replace warfarin altogether. Among these is Bayer Healthcare's Xaralto (rivaroxaban), a direct factor Xa inhibitor, which may be as good as or better than warfarin for preventing stroke in a-fib patients, according to clinical data presented in November at the American Heart Association meeting. Other promising, warfarin-shunning candidates in development include edoxaban (Daiichi Sankyo) and betrixiban (Merck).

However, one potential competitor, BMS/Pfizer's apixaban, recently hit a development brick wall. Excess bleeding in the APPRAISE-2 trial, a large phase 3 study of the factor Xa inhibitor (like Xarelto), led to a screeching halt of the trial. According to a joint company press release, "There was clear evidence of a clinically important increase in bleeding among patients randomized to apixaban. This increase in bleeding was not offset by clinically meaningful reductions in ischemic events."

But the APPRAISE-2 trial was just 1 of 9 trials assessing the potential benefits of apixaban in patients at risk of ischemic events. Other conditions in which apixaban continues to be investigated are a-fib and venous thromboembolism.

APPRAISE-2 = Apixaban for Prevention of Acute Ischemic Events-2; RE-LY = Randomized Evaluation of Long-term Anticoagulant Therapy.

* And despite the fact that it is approved in Europe and Canada.

No. 5: Another Salmonella Outbreak Prompts Overhaul of Food Regulation

It wasn't biggest food-borne outbreak of infection. Nor was it even deadly. But this year's epidemic of salmonellosis, due to contaminated shell eggs, prompted—perhaps by cumulative effect—the Congressional passage of the FDA Food-Safety Modernization Act.

As of November 30th, the CDC estimated that nearly 2000 Americans were sickened by eating contaminated shell eggs, many of which came from Wright County Egg in Galt, Iowa, and its close business affiliate, Hillendale Farms. The outbreak led to the recall of more than 500 million eggs, beginning in August. An FDA inspection at the time revealed horrifying conditions at Wright County's massive hen-house facility—including mountains of chicken excrement, rodent infestations, and maggots and flies "too numerous to count."

Owner and career mass-farmer Austin "Jack" DeCoster, dubbed a "habitual violator" of environmental regulations by Iowa's Attorney General,* received a merciless, public grilling from a Congressional panel in September. A follow-up letter from the FDA to DeCoster in October suggested that he might be the subject of criminal proceedings; however, the agency allowed Wright County Egg to resume "limited sales" on November 30th, after the company had taken "necessary corrective measures."

The Food-Safety Act, expected to be signed imminently by President Obama, is the first major overhaul of food regulation since the historic Food, Drug, and Cosmetic Law of 1938. The crux of the act: It allows the FDA to demand recalls of tainted food, instead of relying on the voluntary cooperation of offending suppliers.

For the record, the suspected worst outbreak due to Salmonella-tainted food was perpetrated by the Peanut Corporation of America in Blakely, Georgia. The outbreak, which occurred during 2008 and 2009, was believed to have sickened 22,500 and caused 9 deaths, according to NYT coverage.

* In 2000.

No. 6: The First, Oral Disease-Modifying Drug for Multiple Sclerosis Is Approved

In September, the FDA approved fingolimod, trade name Gilenya, the first orally administered disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. The pill, at a dosage of 0.5 mg once daily, was approved approximately 9 months after drugmaker Novartis quietly submitted its NDA to the agency and nearly a year after Merck Serono trumpeted its first application for an oral competitor, cladribine.

Gilenya's approval came with a number of safety caveats—including the institution of an FDA-mandated REMS (Risk Evaluation and Mitigation Strategy) program and a pregnancy registry. Uptake of the drug is also potentially hampered by its staggering cost—about $4000 per month, wholesale.* A company-sponsored program has been instituted to (slightly) ease the financial burden for patients. Despite these potential barriers to prescriptions, Novartis expects worldwide sales of Gilenya to reach $1.5 billion by 2017.

The final stretch of the approval horse race for the first, disease-modifying pill for MS was significant for a bad stumble taken by Merck Serono, after the FDA refused to file its application in December of last year. Speculation: the submission was incomplete. Merck Serono filed a new application last June, and the company received a priority review.

FDA approval for cladribine was anticipated at the end of this year; however, in November, the company announced that the agency was extending its original 6-month priority review by another 3 months. Why the FDA requested the extra review time is unclear, but a company spokesperson told Bloomberg in November that the FDA was not requesting additional clinical trials.

The prospect for cladribine's US approval remains murky, given a thumbs-down opinion from the European Medicines Agency in September. However, the pill is currently available for the treatment of MS in Russia and Australia.

NDA = new drug application.

* The web site destinationrx.com offers 30, 0.5-mg capsules for $4268.16.

No. 7: Continued Big, Colossal, Troubling Disappointment in the AD Pipeline

For 3 years running now, there's been "Colossal Disappointment" or otherwise "Big Trouble" in the drug pipeline for Alzheimer disease. A major reason appears to be that companies are far too invested in the idea that amyloid is a major cause of AD, rather than a mere byproduct of the dementing illness.* Consequently firms like Pfizer and JNJ—codevelopers of bapineuzimab—and Eli Lilly—developer of semagacestat and solanezumab—have been loathe to concede defeat in their investigation of anti-amyloid products; although Lilly did announce the termination of its clinical program for semagascestat in August, after unfavorable results from 2 large, ongoing, multinational phase 3 trials were reported.

Nevertheless, phase 3 study of Lilly's anti-amyloid mAb solanezumab continues, and the company announced in November that it is buying Avid Pharmaceuticals, for access to the amyloid tracer florbetapir. Pfizer and JNJ soldier on with bapineuzumab, another anti-amyloid mAb, which has performed marginally in late-stage trials and is associated with major safety issues—namely, vasogenic brain edema. To generate continued interest (and investment) in the compound, the pharma giants are emphasizing a new molecular angle. In July, pooled data from bapineuzumab's phase 2 trials suggested that the drug lowers P-tau in CSF, another (and perhaps more important) marker of established AD.

A new assay, which was heavily publicized in August and measures P-tau, total tau, and beta amyloid (1-42), indicates a distinctive CSF pattern change as dementia progresses for mild cognitive impairment (MCI) to early AD and then onto advanced disease: beta amyloid levels fall while tau levels rise. If anti-amyloid therapies have their place at all in the treatment of AD, it may be in early disease; established AD may respond in a more meaningful fashion to anti-tau therapies.

AD = Alzheimer disease; CSF = cerebrospinal fluid; mAb = monoclonal antibody; P-tau = phosphorylated tau.

* Some investigators have argued that amyloid-laden plaques in brains of AD patients might actually be neuroprotective.

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

No. 8: Transparency in the Age of Transparency Gets Even More Transparent

Santa's not the only one checking a list. ProPublica, a self-appointed vigilante-ish investigative-journalistic-type group based out of Manhattan, compiled publicly available physician-payment information from 7 drug companies* and made it all searchable in a free, online database. The intent—other than to potentially embarrass 384 top-earning physicians—was to facilitate access to information that was otherwise difficult to mine in a comprehensive fashion. ProPublica's one-stop, nonprofit shop now represents (according to ProPublica) a total of nearly $282 million to more than 17,700 providers (including non-physicians).

In addition, ProPublica cross-checked their compiled data with regulatory information and found that more than 250 speakers (including the best compensated doctors) had been charged with professional misconduct. Some physicians had even lost their licenses to practice. Government actions (eg, state citations, FDA warnings) had been dispensed in 292 cases. In response, 5 of the 7 drug companies acknowledged that "they don't routinely check state board websites for discipline against doctors."

The most recent charge from ProPublica is that medical schools—including those with policies that prohibit participation on speakers' bureaus—are flunking in their oversight. Stanford University, in particular, was called out, when ProPublica revealed that more than a dozen of the school's physicians received payments for their participation on speakers' bureaus, in direct violation of the school's policy.

But the overriding caveat when using ProPublica's database: The information relates to physicians' relationships with drug, not medical device, companies. Professional compensation becomes even more dumbfounding in the case of orthopedic surgeons, some of whom earn in excess of $1 million from industry and some of whom aren't particularly forthcoming about their financial ties to industry. In September, Chimonas et al showed that the disclosure rate among ridiculously compensated orthopod authors was only 46%. Like other investigators, Chimonas et al used the OIG-mandated disclosure of physician payments from 5 orthopedic-device companies** in 2007 to assess whether the highest-paid docs were fessing up when disclosure was requested—like when journal editors asked for it. 

OIG = Office of the Inspector General.

* Eli Lilly, GSK, AstraZeneca, Pfizer, Merck, JNJ, and Cephalon.

** Biomet, DePuy, Smith & Nephew, Stryker, and Zimmer.

No. 9: Sports-Related Concussions—No More Walking It Off

Despite the fact that neurologist Ira Casson, former co-chairman of the NFL's panel on brain injury, essentially denied a relationship between repeated head injury and lasting brain damage in January,* the prevailing zeitgeist 11 months later is this: That sports-related concussions should be taken very seriously, and that safeguards should be in place to allow for recovery—at all levels of play.

Casson's functional denial was based on the fact that scientific data are limited on the subject, but that deficiency is being answered by clinical and pathologic studies from, among others, investigators at the Center for the Study of Chronic Traumatic Encephalopathy (CTE)—the raison d'etre of which is to examine the very issue of CTE in sports and, by extension, to be an advocate for athletes who put themselves at risk of acute or chronic brain injury.

The Center's latest, and perhaps most controversial, proposal is that the CTE associated with collision sports increases the risk of motor neuron disease (aka ALS, aka Lou Gehrig's disease). Ongoing data from others, which were highlighted in a recent, dedicated issue of Sports Illustrated, suggest that the risk of lasting brain injury is not confined to concussed players, but that functional damage can be demonstrated in completely asymptomatic jocks who've sustained nonconcussive head blows.

Of course, the study of sports-related head injury is nothing new—despite the rising sensitivity to its potentially lasting consequences among NFL officials specifically and the general public, well, generally. A PubMed search with the terms "concussion" and "football" produces 273 English-language articles, dating back to 1970 (when Brett Favre was just a wee babe!). About three quarters of these articles were published within the last 10 years.

A historic gem from 1983 ("Concussion incidences and severity in secondary school varsity football players") provides the results of a survey of more than 3000 high school football players in Minnesota, circa 1977. In the age of overtly endorsed disco and surreptitiously endorsed butt-blocking and face-tackling, the concussion rate was 19%, and nearly 70% of affected athletes returned to play the same day. A prior history of concussion was found to increase the risk of subsequent concussion 4-fold. As a result of head trauma, 6 high schoolers sustained permanent disability, ranging from "extensive" brain dysfunction to quadriplegia to death.

* In front of a House Judiciary Committee, no less.

They seemed like good, though not particularly original, ideas at the time: Initiate a med-pharma blog and inaugurate the coming new year with the top 10 stories from the waning year.

Seemingly good ideas can become millstones with time; nevertheless, these 2 particular self-inflicted burdens have been carried for at least another 365 days—to make a grand total of 3 years. Happy freekin' birthday, Pathophilia. Here's what really plagued, worried, or otherwise elevated our royal-we blog spirits in 2010.

No. 10: A Record-Busting Pertussis Outbreak in California.

Way to go, California parents who eschew routine childhood vaccinations.* Nice erosion of herd immunity. You've contributed to the worst statewide outbreak of pertussis (aka whooping cough) in the last 63 years. The last 63 years. Meaning since Truman was President. Meaning since Jackie Robinson broke the MLB color line.

Here's the latest from the California Department of Public Health while I/we simply stew in my/our juices of frustration: 

• There have been 7824 confirmed, probable, or suspect cases of pertussis reported between January 1st and December 15th. (There were 9394 reported cases in 1947.)
• This year's pertussis incidence rate in California is 20.0 per 100,000, which is the highest rate in 52 years. (The rate was 26.0 cases per 100,000 in 1958.)
• There have been 10 deaths, 9 of which were Hispanic infants (who were too young to be immunized)
• Children younger than 6 months of age have been particularly vulnerable to disease.
• The California outbreak peaked in late July-early August, but "relatively high numbers of cases continue to be reported each week."
• Because a high level of herd (aka community) immunity is needed to reduce the incidence and spread of pertussis and the fact that vaccine-induced immunity wanes with time, a campaign to urge booster shots among adolescents and adults is ongoing. 
• According to the CDPH, mothers or other close contacts are the most likely sources of pertussis for at-risk infants. The agency advises,

Thus vaccinating household contacts, health care personnel, and child care workers against pertussis is recommended at least 2 weeks before their contact with young infants. Increasing community immunity through widespread immunization will also decrease the chances that vulnerable infants will be exposed to pertussis. Immunization will also prevent debilitating cases of pertussis in older children, adolescents, and adults.

Unlike the historic California outbreak, which appears to be subsiding, a pertussis epidemic in upstate New York is gaining steam. It's now at the point at which the Public Health Agency of Canada is advising its citizens "to be on guard against" the disease in the United States. Yes, Canadian officials are now warning about infectious travel risks...south of the 49th parallel.

* Because of, largely, the disproven fears of vaccine-related autism.

Photo of symptomatic child with pertussis from pertussis.com.

Doing what it does best, the New York Times provides an elegantly written (albeit relatively brief) obituary, this time for Eugene Goldwasser—the U of C biochemist who discovered erythropoietin (aka Epo) and famously shared his then-unpatented discovery with a biotech startup, Amgen.* The fledgling company became the big house that Epo built, and the compound provided substantial revenue, as well, for Big Pharma's JNJ and Roche.

After about 2 decades of failed animal work, from 1955 to 1975, the NYT recounts, Goldwasser was able to isolate a tiny amount of Epo from a dried, concentrated slab of urine that had been collected from Japanese patients with aplastic anemia. The paper describes a mind-blowing exchange between Goldwasser and the Japanese courier of the urine, Dr. Takaji Mayake, in the lobby of Chicago's stodgily refined Palmer House hotel.

The isolation process took about 2 years, and Goldwasser (as anchor author) published his landmark paper, "Purification of human erythropoietin," in 1977. (Mayake was first author.) The rest, per the tired cliche, is history, thanks to the work of Amgen scientist Fu-Kuen Lin. Lin cloned Epo's human gene, which enabled mass production of the protein. Results of the first human trial of Epo (a combined phase 1/2 affair) were published in the NEJM in 1987 (25 anemic patients with end-stage renal disease on hemodialysis). According to a Google Scholar search, that article has been cited by more than 1400 others.

Goldwasser recounted his experience with Epo in a 1996 essay, "Erythropoietin: a somewhat personal history," for the medical-history journal Perspectives in Biology and Medicine. Online access to the article remains elusive, but the story is also relayed in Merrill Goozner's The $800-Million Pill (2005),** which draws on Goldwasser's essay, in addition to interviews with the scientist.

* Known at the time as Applied Molecular Genetics, Inc.

** Parts of which are available through Google Books.

A schematic blob of molecular Epo, according an anonymous Wikipedia donor.

Daisy Kenyon

(1947): Joan Crawford and her mannered theatrics are such potential distractions in this noir story of a love triangle that the movie's a qualified recommendation. But director Otto Preminger was apparently able to temper (or tamp down) Crawford's old-school mugging to the point, at least in some scenes, of producing nearly admirable acting. The fact that Dana Andrews and Henry Fonda (who received third billing) gave naturalistic and relatively understated performances also probably checked Crawford's hammy tendencies on set—providing that the woman had a modicum of self-awareness.

In the DVD commentary, Preminger biographer and fan Foster Hirsch provides thoughtful insight on the director's stylistic choices, praises the underappreciated Andrews, and describes production dynamics with "Mommie Dearest." Notable behind-the-scenes skinny from Hirsch are, in part, courtesy of his prior interview with supporting actress Ruth Warrick.

Blogs and traditional sources are abuzz with the news that the FDA is considering the withdrawal of Avastin's indication for breast cancer. The agency, in what may be a harsh, but necessary decision, concluded that Roche's monoclonal antibody—which is otherwise approved for the treatment of colon cancer, non-small cell lung cancer, glioblastoma, and metastatic kidney cancer—"has not been shown to be safe and effective for [breast cancer]."

The FDA based its looming rescission on the postmarketing results of 4 clinical studies, which showed that Avastin does not prolong overall survival or slow disease progression to an extent that outweighs drug-related risks (like hemorrhage, organ perforation, and MI). The agency evidently reached its conclusion after agreeing with input from an oncology advisory committee (which voted, 12-1, in July of this year to pull the breast-cancer indication).*

For now, Genentech (Roche's subsidiary) has not agreed to voluntarily pull the drug. Confusing the US regulatory decision is the fact that the European Medicines Agency affirmed the utility of Avastin in metastatic breast cancer (with paclitaxel). Genentech will evidently accept the FDA's invitation for a Notice of Opportunity for a [Public] Hearing, according to a company press release. In the meantime, the drug will retain its breast-cancer indication in the United States.

There are others who also oppose the FDA's decision on Avastin, including patient advocates, US breast-cancer experts (who observe that subgroups of patients clearly respond remarkably to the drug), and House Republicans. The political charge is that the FDA is considering cost—not merely efficacy and safety—in its decision to withdraw Avastin for breast cancer. Two statements jump out in a joint press release.

Reps. Gingrey, Myrick, Pitts and Upton are gravely concerned that the FDA is putting economics ahead of proper courses of treatment and that today's announcement is the first step towards government rationing of health care.

And

Allowing the FDA to factor in the cost of a drug when determining whether that drug should be approved is the first big step towards government rationing.

If this is true (that the FDA considered the cost of Avastin in its approval process),** the government would be overstepping its legislated bounds. It's not the FDA's legal job or purview to consider what the free market can or should bear (despite the rising costs of health care). That issue should be left up to the free market. Perhaps House Republicans are creating a diverting issue by raising drug cost in the case of Avastin withdrawal, but it is an issue worth exploring (by further probing the FDA's review process of Avastin).

According to the AP and other sources, Avastin costs about $8000 a month, but Roche caps the annual price at $57,000. The drug brings in about $1 billion from use in breast-cancer patients (which is a fraction of overall Avastin revenue). According to the NY Post (I know), agency officials deny that their decision is based on cost. 

Of course, individuals with breast cancer could still receive Avastin off-label, if the FDA's withdrawal sticks; however, insurance coverage for the indication may be jeopardized as a consequence. That's the point and fear of Avastin advocates and patients.  

* In a July analyst call, Avastin director Stefan Frings reportedly complained openly about the biased makeup of the advisory panel and the FDA's statistical methods.

** Although I've found no evidence that the FDA considered the cost of Avastin in the process of making its latest decision.

In a late-breaking NEJM editorial, legal scholar Mark Hall responds to the recent decision by Federal Judge Henry Hudson on PPACA's insurance mandate. On December 13, Hudson notably concluded that Congress lacks the authority to require the purchase of individual health insurance, because Congress (under the Commerce Clause) doesn't have the power to regulate "inactivity." 

This route to knocking down PPACA (or at least the individual insurance mandate on which PPACA rests) complements a closely related argument: That Congress doesn't have the authority to levy a penalty for not buying insurance. But PPACA supporters counter that the associated penalty is really a tax—which Congress clearly has the authority to impose. For spectators (namely, the vast majority of Americans like me), it appears that much of the judicial wrangling around the insurance mandate will rest on this semantic point*: Whether the fine imposed by the government for not purchasing health insurance is a penalty or a tax.

In a previous NEJM piece, Yale law professor Jack Balkin implied a Constitutional slam dunk for PPACA and the tax argument. But with Hudson's ruling, Mark Hall isn't so sanguine about the mandate's future (as the issue will inexorably wend its way through the federal court system). Nevertheless, Hall notes that there is a long judicial precedent for giving serious leeway to Congress when it comes to interstate commerce—like the commerce of health insurance. And negating PPACA's insurance mandate can't necessarily be done in isolation. Hall writes,

[T]he Court must also decide whether to strike the accompanying insurance regulations and subsidies, which are much more popular and clearly within congressional power. Judge Hudson struck only the individual mandate, “severing” it from the rest of the [PP]ACA. But because the [PP]ACA’s ban on medical underwriting would wreak havoc on the marketplace without the mandate, other judges might feel torn between striking both and letting both stand.

PPACA = Patient Protection and Affordable Care Act.

* In addition to Hudson's "inactivity" argument.

Unbeknownst to many Duke alumni, more controversy rocks the university's medical center as some kind of "resolution" was reached in the 2-year investigation of a biochemistry professor, Homme Hellinga. Just last month, Duke physician and scientist Anil Potti resigned after a protracted investigation of serious resume padding and, more important, allegations of scientific fraud. The latest news on Hellinga, who (as far as I know) had no relationship to Potti, comes by way of the school's newspaper, the Duke Chronicle, which also reported yesterday that the university has not disclosed the actual outcome of its investigation.

In a pass-the-buck response for comment, Duke's vice president for public affairs and government relations wrote in an e-mail to the paper that the investigation's outcome was confidential. If the World Wide Web is any indication, Dr. Hellinga's faculty web page is still up and running—giving the impression that the biochemist, a computational designer of synthetic proteins, is still on staff. Hellinga also declined to respond in detail to the school paper, saying, "[I]t is my duty to abide by University policies and procedures and federal law. The results of the investigation are only made public in the event of a federal finding of research misconduct." Hellinga's statement, of course, suggests that no there was no finding of research misconduct.

The background on Hellinga is that, in 2008, he retracted papers in Science and the Journal of Molecular Biology  on the basis of their irreproducible results. As a consequence, Hellinga accused his former graduate student Mary Dwyer, who had performed most of the published work, of scientific misconduct. However, an internal investigation of Dwyer by Duke led to a clearing of the charges against her. (According to a 2008 Nature news report, the misleading findings of Hellinga et al were due to their erroneous reliance on a certain protein purification method. In other words, the results were not deliberately falsified but were, instead, the result of "innocent" error. Dwyer, understandably traumatized, is now evidently a postdoc in a pharmacology lab at Duke.)

Then, several months after Dwyer was cleared, the university began an investigation of Hellinga. Last year, data in 2 other papers that were coauthored by Hellinga, 1 in Nature and another in PNAS, were called into question. (Dwyer was also coauthor on the Nature article.) The concern: That Hellinga's results in these papers could not be reproduced or were very difficult to replicate—by Hellinga's former postdocs no less. (A PubMed search reveals that the articles have not been retracted.)

The subtextual upshot of the entire affair: That Hellinga's questionable protein-design work is not the result of outright fraud but, rather, a consequence of either human error or nuances in his scientific methods. In contradistinction to the case of Anil Potti, Hellinga's work may be (may be) bogus, but not—importantly—on the basis of deception. There is a big difference between charlatanism and simply being wrong.

Photo of Homme Hellinga, who is a man and not, despite appearances, my former PE teacher.

As someone who's recently cut the landline cord, I wondered how many other Americans are tossing the same—like a vintage Broderick Crawford rotary phone. The answer: a lot. And who's keeping tabs on this information? The CDC.

According to the Centers' most recent information, published last spring, the percentage of American households relying solely on wireless coverage has increased from about 10% in the first half of 2006 to about 24% in the last half of 2009 (see the CDC's impressive growth table below). Yes, about 1 in 4 homes (as of 1 year ago) use cell phones exclusively.

An expected outcome of the CDC's ongoing survey: sole reliance on cell phone use is age dependent, with only about 15% of cell-phone users aged 45-64 years without a landline. Among individuals aged 65 years or older, that percentage drops to about 5%.

Other factors that increased the likelihood of going completely wireless (which, in some cases, are probably age dependent):

• living with unrelated adult roommates
• renting (vs owning)
• being male
• living in or near poverty
• not living in the Northeast
• being Hispanic

Why does the CDC care about the wireless trend? Because the CDC, like many other organizations, collects much of its health survey data by phone. The Centers' admonition:

The potential for bias due to undercoverage is not the only threat to surveys conducted on landline telephones. Researchers are also concerned that some people living in households with landlines cannot be reached on those landlines because they rely on wireless telephones for all or almost all of their calls.  

The Street With No Name

(1948): When making The Departed (2006), Martin Scorsese appears to have gotten more inspiration from this docudrama-noir hybrid than the acknowledged template of Infernal Affairs (2002) (to which Scorsese's film really has little resemblance).

In today's recommendation, an FBI agent (Mark Stevens) infiltrates a murderous inner-city racket, headed up by Alec Stiles (the deliciously snarly Richard Widmark). But Stiles has his own cop-friendly mole, who can possibly finger the undercover agent. A mid-film sequence of hushed pursuit, between Stevens and Widmark, has all the tension of a similar (but much noisier) scene in The Departed, in which Leonardo Dicaprio famously trailed his doppelganger, Matt Damon, through Boston's nighttime alleys.

It should be noted that The Street With No Name was remade, also in very loose fashion, as House of Bamboo (1955), with Robert Stack and perennial noir thug Robert Ryan.

Over at The Medicine Show (nice blog name, BTW), Forbes's Matthew Herper showcases Roche's antipsychotic in development, known currently by the catchy name RG1678 (or the even catchier RO4917838). The drug profile is prompted by Roche's recent press release of phase 2 data and enthusiasm from psychiatrist Jeffrey Lieberman of Columbia University, lead author of the NIMH's landmark CATIE project from several years ago.*

Lieberman's evidently pumped because RG1678 has an MOA that is entirely different from that of existing antipsychotics—which generally block dopamine receptors.* The drug inhibits glycine reuptake, which may translate into better management of the so-called negative symptoms of schizophrenia, like apathy and withdrawal. Currently existing antipsychotics, of both the first- and second-generation varieties, are typically excellent at addressing the positive symptoms of schizophrenia, like hallucinations or paranoia; however, their historical downfall has been a lack of effect on negative symptoms. (The general, natural history of schizophrenia, a life-long disease, is an early burden of positive symptoms followed by a predominance of negative symptoms as the disease progresses.)

Data from Roche's 8-week, placebo-controlled, phase 2 study (N = 323), which were presented at the very recent annual meeting of the ACNP in Miami (Umbricht et al), showed a "clinically meaningful" reduction of negative symptoms in patients who received RG1678 (10 or 30 mg) in combination with second-generation antipsychotics. Withdrawal of treatment for any reason (the most common of which historically, like in CATIE, is a lack of drug efficacy) was observed in 13%-20% of patients. Withdrawal rates did not appear to differ appreciably among treatment groups, according to the PR.

Roche's Chief Medical Officer says a phase 3 program for the compound is underway. A search of the NIH's clinical trials database for "RO4917838" reveals 3, longer (eg, 24-week), phase 3 trials that are recruiting. The studies will pit the investigational drug against placebo, without the use of concomitant antipsychotic therapy, and are expected to be completed in 2015.

MOA = mechanism of action; NIMH = National Institute of Mental Health.

* CATIE showed a relatively high rate of discontinuation (~70%) of antipsychotics in people with schizophrenia.

** Along with other pharmacodynamic properties, like effects on serotonin receptors. In the case of Roche's compound, inhibition of glycine reuptake by neurons is intended to normalize glutamate transmission, the abnormality of which has been implicated in schizophrenia (along with a variety of other neurotransmission defects).

Yesterday the Senate passed a bill that would delay the perpetually looming cut in Medicare reimbursement to physicians by 1 whole year. This proposed delay is distinct from Congress's previous bandaid measures to stave off the SGR-defined drop in Medicare reimbursement, which have lasted anywhere from 1 to 6 months, iirc. (The most recent bill to postpone the cut was passed earlier this month. If Congress hadn't acted, Medicare reimbursement to physicians would have dropped by 25% on January 1st of 2011.)

According to the intrepid Robert Lowes, writing for Medscape, the House is now expected to pass the Senate's new legislation, which had bipartisan support. The total cost of the bill, which addresses a few other Medicare and government-insurance issues, exceeds $19 billion. But the lion's share of that, nearly $15 billion, represents the so-called Medicare "doc fix."

Sponsors of the bill say that its cost will be taken care of by an amendment to PPACA, or the part of PPACA that concerns thresholds for tax credits to those who would be legally mandated to buy health insurance (in 2014).

SGR = sustainable growth rate.

Photo of weathered can from magannie at Flickr.

In the contest for "Most Boneheaded Business E-mail," Dr. Martin Freed,* former Vice President of Clinical Development of GSK, has competition. In its investigation of interventional cardiologist Mark Midei and his relationship with Abbott Vascular, the staff of the Senate Committee on Finance turned up 2 whoppers.

After Midei lost his privileges at St. Joseph's Medical Center in Towson, Maryland, owing to the performance of unnecessary stent procedures, Charles Simonton, Abbott Vascular's Chief Medical Officer, wrote in February,

I would continue to work with him, behind the scenes, at this point. We've just decided not to have him doing any public type work in the U.S. right now.

Note to Simonton: If you have to write something like "behind the scenes" in a company e-mail, don't write the e-mail. (And we're not even addressing whether Simonton should have worked with Midei at all.)

But the possible leader in this curious competition of comminiques is David Pacitti, Abbott Vascular's Vice President of Global Marketing, who commented in January on this Baltimore Sun piece. The Sun writer, Jay Hancock, had written an article that criticized the overuse of cardiac stents and called out Midei specifically. With his beefy mitts, David Pacitti pounded out the following to Sam Conaway, Division Vice President of Sales of Abbott Vascular, who had transmitted the article,

Don't you have connections in Baltimore???? Someone needs to take this writer outside and kick his ass! Do I need to send the Philly mob?

That's funny.

On Monday, the Sun's Hancock wrote that an Abbott spokesman (but not Pacitti) apologized "if this [e-mail] caused you any concern or distress" and that the comment "wasn't meant to be taken seriously." This was the response after Hancock called Pacitti to ask why the Abbott employee wanted his knees caps broken.

BTW, Abbott Vascular makes and promotes drug-eluting cardiac stents, which Midei apparently used with impunity. That is, until he was investigated.

* In July, the NYT's Gardiner Harris revealed that Freed had written a company e-mail, which stated that the results of a 1999 GSK-sponsored trial of Avandia, Actos, and glyburide "should not see the light of day."

In yesterday's appellate arguments for the federal funding of research on human embryonic stem cells (hESCs), the 3-judge panel* focused on several issues, according to transcript excerpts provided at The Great Beyond blog.

In one exchange, Judge Thomas Griffith shot down the government's (ie, Beth Brinkmann's) argument of precedent (on the basis of repeated Congressional ratification).

In an exchange with Thomas Hungar (who represents the original plaintiffs, Sherley et al), Judge Douglas Ginsberg emphasized the exact wording of the Dickey-Wicker amendment that relates to whether research on existing hESC cell lines necessarily means the continued destruction of hESCs.

The harm factor (to the plaintiffs and defendants) was also discussed by the panel. According to The Great Beyond blog, spectating proponents of hESC research were pumped about the government's performance during the appellate hearing.

The panel's decision, whenever that happens, will determine whether a preliminary injunction against the federal funding of hESC research, issued on August 23rd by US District Court judge Royce Lamberth, is upheld or overturned. On September 9th, the appeals court stayed Lamberth's preliminary injunction, while preparations were being made for yesterday's hearing. But Lamberth could also decide, either before or after the latest appellate decision, to permanently block federal funding for hESC work—which would, no doubt, be appealed by the losing party.

* A previous post here indicated that the 3-judge panel consisted of Brett Kavanaugh and Janice Rogers Brown, in addition to Griffith (and this was the panel that temporarily lifted Judge Lamberth's preliminary injunction against hESC research). It's not entirely clear why the judge panel is different, but maybe the judges of the US Court of Appeals for the DC Circuit perform a kind of round-robin in their judicial duties.

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

Today's big wake-up news: The abrupt resignation of Pfizer's CEO, Jeff Kindler, over the weekend. In a press release, Kindler explained that the job had been "extremely demanding" "personally," and he indicated that he wanted to "spend some rare time" with his family—which means to anyone older than the age of 10 years, "I'm resigning unwillingly."

Today's bigger wake-up news: That somebody older than 10 years actually believes Kindler's explanation.

Others cite too much company growth or too little company growth as the reason for the ouster.

Image of macho Kindler, who now admits he has to "recharge his batteries."

12/07/10 update: Bloomberg reports that there was considerable internal disgruntlement at Pfizer with Kindler's management style and that the former CEO refused to name a head of operations as part of an agree-upon plan with senior managers. Kindler reportedly quit "hours before a special board meeting" on Sunday, December 5th, "to discuss his future." Then Kindler climbed on top of a local water tower (in Manhattan!), screamed something about, "Top o' the world, Ma!" and blew up real good.

Nightmare Alley

(1947): Tyrone Power, as an apprentice carny and then headlining mentalist, can't escape his destiny in this dark tale of ambition and sociopathy. In the ever-winding story (so typical of noir), Power's con is only seriously challenged by a woman psychologist (Helen Walker), who appears to be—consciously or unconsciously—the inspiration for David Mamet's Dr. Margaret Ford of his most excellent House of Games (1987).

Disregard the slapped-on sappy ending of Nightmare. The movie, based on the dystopian novel by William Lindsey Gresham, should have ended with the line, "Mister, I was born for it."

The DVD features reasonably informative commentary from noir experts Alain Silver and James Ursini.

FDA Commissioner Margaret Hamburg's editorial in this week's NEJM is read with interest here, but not so much for Hamburg's recounting of the FDA's history and the historic legislation that enables the agency's activities. Rather, what's really interesting is that Hamburg, in an effort to sustain and justify the FDA's purview, cites 2 recent lawsuits that "have challenged the FDA's authority to review the safety and effectiveness of products before they are marketed."

Curiously enough, one of lawsuits that Hamburg cites is the much-blogged-about Allergan v. United States, in which the drug company (maker of Botox) contested, back in October of 2009, the FDA's prohibition of off-label speech. Hamburg argued that if Allergan's (now-dropped) lawsuit had been successful, it "could [have undermined] the premarket review system that has been in place for drugs since 1962 and for devices since 1976. Indeed, [lawsuits like Allergan's] place at risk efforts that are currently under way at the agency to ground FDA practices more solidly in public health practice." She continued,

Without question, such legal challenges, if successful, would turn back the proactive role of the FDA in American medicine, threaten current efforts to ground FDA practices in public health science, and jeopardize the safety of patients, as well as the future of innovation and medical progress. Quite simply, they would ignore the lessons of history.

For all her reproach, what Hamburg fails to acknowledge in her editorial is the confounding position that the FDA created for Allergan, when the agency demanded in April of 2009 that the drug company warn, in relatively comprehensive fashion, of the risks of Botox when used for the unapproved condition of limb spasticity. It was the FDA's demand that prompted Allergan's lawsuit. The company rightly and logically countered that the agency had placed the company in a double-bind—by simultaneously asking for and prohibiting Allergan's public dissemination of information about the off-label use of Botox.

Who can forget the government's ambiguous and ambivalent response to Allergan's free-speech complaint, when it failed to clearly distinguish promotional speech from nonpromotional speech and an unapproved use from an intended use? With waffling language (ie, "usually"), the government attempted (and failed, in my mind) to reassure the court and Allergan that it would not overstep its regulatory bounds: 

In practice, FDA usually does not treat an unapproved use as an intended use solely because the manufacturer knows that the unapproved use is taking place [emphasis added].

It's also not lost on anyone (who's interested) that the FDA squirmed out of its illogical stance (at least partially) by approving Botox for the treatment of limb spasticity in March of this year—thereby making the condition an approved, on-label condition.

I'd stay tuned for the response letters.  

Not to anyone's surprise (because it's happened multiple times since 2003), Congress approved on Monday yet-another measure to postpone a big cut (this time, 23%) in Medicare reimbursement that would have gone into effect today. The bandaid bill extends the repeatedly delayed SGR-defined cut in Medicare reimbursement until January 1—which means that Congress will have to convene during the holidays to draft and pass yet-another bill that postpones the cut that is scheduled to begin on New Year's Day, now calculated at 25%.* (The current bill awaits the President's sig—which is a given.)

According to Robert Lowes at Medscape, longer-term fixes are in the works, which would extend the "Medicare guillotine," as he calls it, about 12 months. The big trick is finding palatable ways to make up the huge cost of repeatedly (or indefinitely) extending the SGR-defined cuts or of repealing the formula entirely.

SGR = sustainable growth rate.

* Or Medicare will probably delay the processing of physicians' submissions for reimbursement in January until Congress acts.

Photo of weathered can from magannie at Flickr.