October 2009 Archives

A Blueprint for Murder*

 (1953): Slumming it in a B-movie thriller, Joseph Cotton, as Whitney Cameron, suspects his nearly perfect sister-in-law (Jean Peters) of murdering his niece with strychnine (which is affectedly pronounced STRICK-nin by every cast member). Cameron then plots to save his young nephew from the same assumed fate. With Gary Merrill (All About Eve) and a plucky Catherine McLeod as the husband-and-wife team who feed Cameron's suspicions.

* At Amazon, the DVD of the movie is coupled with Man in the Attic (1954) starring Jack Palance, an uninspired remake of The Lodger (1944).

Poster image from Wikipedia reproduced under fair-use law.

HT: Once again, KTG.

From 1.8 to 5.7 million Americans experienced symptomatic swine flu (2009 H1N1 pandemic influenza) between April and July 23rd of this year. This estimate is based on a "probabilistic multiplier model" that adjusts for the underascertainment of pandemic flu cases in the United States. The results of the model, which was created and applied by investigators at the CDC and the Harvard School of Public Health, are available in an expedited article in the journal Emerging and Infectious Diseases.

The probabilistic multiplier model was used to adjust for the underascertainment of pandemic flu cases at each of the following steps (as diagrammed in the provided figures): the pursuit of medical care; the collection of specimens from persons seeking medical care; the submission of specimens for confirmatory testing (ie, RT-PCR); the laboratory detection of the 2009 H1N1 virus; and the reporting of confirmed cases. The model was adjusted separately for hospitalized patients (B)—who, by definition, had already sought medical care.

On the basis of the model, investigators conclude the following for the time period between April and July of this year:

• Every reported case of pandemic flu represents 79 total cases (90% probability range, 47-148).
• The estimated median number of symptomatic cases is 3.0 million.
• The estimated incidence of pandemic flu in persons ≥65 years of age is 107/100,000.
• The estimated incidence of pandemic flu in persons 5-24 years of age is 2196/100,000.
• Every hospitalized case of pandemic flu represents 2.7 total hospitalized cases (90% range, 1.9-4.3)
• The estimated median number of hospitalizations is 14,000 (range, 9000-21,000).
• The estimated ratio of hospitalizations to total symptomatic cases is 0.45% (90% range, 0.16%-1.2%).
• The estimated median incidence of hospitalizations in persons <5 years of age is 13.0/100,000.
• The ratio of deaths to hospitalizations was 6%.* (Note: This value was not derived from the model).
• The estimated median number of deaths is therefore 800 (90% range, 550-1300).

"Because this [death] assumption has several limitations," the authors conclude, "more sophisticated models are also being developed to better understand the severity of the US epidemic in the spring of 2009, including intensive care unit admissions and deaths."

RT-PCR = reverse transcriptase polymerase chain reaction.

* Therefore the overall estimated death rate (although this value is not provided in the article) is 0.027%—which is within the range provided by one of the authors, Harvard epidemiologist Marc Lipsitch, to Reuters in September.

Update: From the AP by way of the CDC—At least 114 American children have now died of complications due to the 2009 H1N1 virus. 

A new report may put the kibosh on Halloween face painting.

Minuscule, but measurable, amounts of lead were found in all samples of commercially available brands of face paint that were sent for testing by the nonprofit The Campaign for Safe Cosmetics (TCSC). In addition, 6 of the brands contained levels of heavy-metal allergens (nickel, cobalt, or chromium) that exceeded recommended standards for consumer products (1 ppm).

Ten face paints—many of which were marketed for children—were purchased through Amazon.com and sent for heavy-metal testing at an independent laboratory, Analytical Sciences in Petaluma, California. Four of the brands were manufactured in China. Other countries of origin were the United States (4), the United Kingdom (1), and Spain (1).

Paint Brand	Manufacturer	Location	Heavy Metal Content, ppm
			Pb	Ni		Co		Cr
Alex Face Paint Studio	Alex Toys	China	0.650	—		—		—
Don Post Grease Paint Color Wheel	Don Post Studios	China	0.630	—		—		15
Snazaroo Face Painting Kit	Snazaroo	UK	0.560	5.5		5.5		—
Rubie’s Silver Metallic Fard d‘Argent	Rubie’s Costume Co	USA	0.260	2.1		—		2.2
Ben Nye Lumiere Wheel	Ben Nye Co, Inc	USA	0.190	—		—		—
Wolfe Face Art & FX	Wolfe Face Art & FX	China	0.180	—		—		1.6
Mehron Glow in the Dark Fantasy F-X	Mehron Inc	USA	0.140	—		—		—
Crafty Dab Face Paints Push-Up Crayons	Crafty Dab	China	0.082	—		—		—
Mehron 6-Pack Greasepaint Crayons	Mehron Inc	USA	0.074	4.1		4.8		16
Jovi Make-up	Jovi	Spain	0.054	5.9		—		120
Recommended limit			0		≤1	≤1	≤1

Detectable levels of mercury or arsenic were not found.

The study was prompted by the discovery of lead in top-selling lipsticks in 2007* and reports of heavy metals in kids' face paints sold in other countries (eg, here, here, and here).

TCSC states that there is currently no way to determine if a particular brand of cosmetic contains heavy metals unless testing is conducted by the consumer herself. The organization charges that the FDA "does little to ensure that cosmetics are safe and actually lacks the power to do so...the FDA does not conduct routine testing of cosmetic products and does not have the authority to require companies to conduct pre-market safety assessments of their products or the ingredients in them. The FDA also does not require companies to list heavy metals or other harmful contaminants on product labels, even though they are commonly found in a wide array of personal care products." 

The cost of testing each brand of face paint for heavy metals was $270 per sample.

Whether small amounts of lead in the infrequently used face paint should be a concern is debated; however, there is no good reason for heavy metals to exist in cosmetics or similar products intended for children.

Last winter, contaminated face paint caused skin reactions, some photosensitive, in participants at a Girl Scout event. The paint was manufactured in China.

ppm = parts per million.

* Last month, the FDA reported lead levels in lipstick that were higher than those discovered in 2007 by The Campaign for Safe Cosmetics.

Image of Alex Face Paint Studio, which contained the highest level of lead among the paint brands sampled, from Amazon.com.

Pediatricians may not be sufficiently proactive in urging vaccination against seasonal influenza or the 2009 H1N1 virus. The conclusion is implied by results of a recent survey of US mothers, one third of whom indicated that they would not get their children vaccinated against the seasonal or 2009 H1N1 flu, despite the fact that an overwhelming majority (91%) view influenza as a family-health threat.* The survey was sponsored by the National Foundation for Infectious Diseases (NFID).

Among the reasons for not vaccinating their children against the seasonal or 2009 H1N1 flu, 52% of moms indicated that their pediatrician "left it up to them." Other reasons for not vaccinating included the misperception that 1) healthy children do not need to be vaccinated (63%) and 2) there are other similarly effective ways to avoid influenza (57%).

Carol Baker, MD, chair of NFID's Childhood Influenza Immunization Coalition and professor of pediatrics at Baylor, called this kind of thinking among parents "magical" or "wishful" and concluded, "[T]he survey reveals the need for more disease education and for health care providers to emphasize to parents that immunization is the best way to prevent flu."

Notably a minority of respondents expressed reservations about the effectiveness (11%) or safety (7%) of influenza vaccinations and their capacity to cause disease (5%).

The survey of 500 US mothers was conducted by telephone during August 19-25 of this year. Respondents were required to have children from 6 months to 18 years of age living with them. The reported margin of error for the survey is 4.4%.

A nonprofit organization, the NFID established the Childhood Influenza Immunization Coalition in 2007 to increase awareness of pediatric influenza and the benefits of immunization. The Coalition is funded by an unrestricted, educational grant from sanofi pasteur, one manufacturer of both seasonal and 2009 H1N1 vaccinations.

* 91% of mothers were concerned that their whole family would become ill if a child contracted seasonal flu.

Last Friday, the reported number of Tysabri-related PML cases jumped to 23, according to European regulators.* The news led to an abrupt drop in share prices for Tysabri drugmakers Elan and Biogen Idec.

Identifying treated patients who are at particular risk for PML, an often fatal, opportunistic infection due to JC virus, becomes increasingly urgent as the Tysabri-related risk (albeit still small) appears to climb. It is generally believed that latent infection with JC virus occurs in up to 90% of all individuals. But Matthew Herper at Forbes reports that latent infection may exist in only 50% of us, according to Tysabri's inventor, Ted Yednock.

Yednock (whose recent work has evidently not been publicly presented or peer reviewed) argues that current antibody tests for JC virus also detect antibodies to the genetically related BK virus (which is only potentially clinically important in immunocompromised renal-transplant patients). Yednock and others are working on a more specific antibody test for JC virus that may be used to anticipate the risk of PML in Tysabri recipients or to identify Tysabri candidates.

A recently published case series by Chen et al identified the subclinical reactivation of JC virus in 19 patients who received Tysabri monotherapy. The prevalence of virus** in urine increased significantly, from 19% to 63%, after 12 months of treatment. After 18 months, JC virus was found in 20% of plasma samples and in most samples (9/15) of peripheral mononuclear cells. Measures of BK virus, used as a control, remained stable in urine and were not detected in blood samples. Increased shedding of JC virus was associated with a significant drop in the virus-specific cellular response. Whether the reactivation of JC virus in Tysabri-treated patients is associated with a limited antibody response (and I don't know if it is) may have repercussions for the utility of Yednock's antibody assay during therapy.

PML = progressive multifocal leukoencephalopathy; Tysabri = natalizumab.

* From 11 in September. 

** Detected by using quantitative polymerase chain-reaction assays.

10/30/09 update: Bloomberg reports the Tysabri-related PML case load at 24, with 4 deaths, according to the European Medicines Agency. 

A precipitous death after receiving Cervarix. Two ALS-like cases after Gardasil.

It's crucial to remember that association does not mean causation. In the former case, the media jumped the gun before knowing the autopsy results. The 14-year-old English girl died of a previously undiagnosed, malignant "chest tumour." However, the nature of the link between Gardasil and the 2 ALS-like—or more accurately motor-neuron—cases remains unclear for now.

One of the motor-neuron cases, that of 15-year-old Jenny Tetlock, is commemorated at her parents' blog, Jenny's Journey. Some details of the girl's case history are also provided here.

Jenny developed leg weakness in May 2007, about 2 months after she received her third Gardasil injection. Her clinical course was, to say the least, rapid, despite "aggressive immunosuppression"—which included high-dose corticosteroids, plasmapheresis, intravenous immunoglobulin, and cyclophosphamide. A demyelinating polyneuropathy was initially suggested by nerve-conduction studies. An inflammatory component was suggested by imaging and spinal-fluid studies. Other entertained diagnoses during Jenny's unusual clinical course included spinal muscular atrophy, progressive muscular atrophy, and multifocal motor neuropathy. Suffice it to say, her clinical picture did not fit snugly into any one of these disease categories.

Jenny became quadriplegic within a year. Her clinical picture was also atypical for ALS, a purely motor disease, in that she experienced sensory symptoms. A sural nerve biopsy revealed mild axonal degeneration; demyelinating features were not prominent. Jenny died on March 15, 2009, of respiratory failure. Her autopsy revealed loss of motor neurons and marked inflammation throughout the spinal cord—an additional finding that is uncharacteristic of ALS.*

Clinical features of the other motor-neuron case, that of a 20-year-old woman, were similar. Motor symptoms began within 4 months of the first Gardasil injection; death occurred 28 months later.

A recent review of the Vaccine Adverse Event Reporting System (VAERS) revealed no similar cases linked to Gardasil, according to the reporting physician, Catherine Lomen-Hoerth, Director of the ALS Center at the University of California, San Francisco. She and her colleagues will examine the pathologic features of young adults with motor-neuron disease who did not receive Gardasil and compare these with the recently reported cases. Similar findings would argue against a causal Gardasil connection.

Juvenile ALS, which by definition begins before the age of 25 years, is generally thought to be a disease that is distinct from adult ALS. The juvenile condition is, comparatively, slowly progressive—possibly because younger patients have more neurologic reserve. Juvenile disease is almost always familial and usually autosomal recessive. Gene culprits have been identified in a minority of these rare cases, however. (Hereditary or genetic data from the 2 Gardasil-associated cases were not provided in medical news reports.) Juvenile ALS affects 1 in every 2-3 million young persons.

More than 7 million have received Gardasil, according to news reports.  

ALS = amyotrophic lateral sclerosis.

* Other atypical clinical features include 3 epileptic convulsions during illness and no upper-motor-neuron signs (eg, hyperactive reflexes). Jenny's history is notable for some developmental delay and a rare, autoimmune skin disorder. Family history does not appear to be particularly contributory.

New sources: WebMD; DocGuide.

From London to Brighton (2006): Oi, c--t! How an extremely hard-working prostitute (Lorraine Stanley) got a lance-worthy black eye is ultimately revealed in this time-jumbled portrait of England's lowest of the low. I predict big things for Johnny Harris, who plays the boss-fearing, middleman pimp.

The payoff of pseudoscience and why it's so damned attractive are explored by writer Amy Wallace for Wired in her comprehensive profile of infectious-disease specialist Paul Offit (aka Satan incarnate to anti-vaccinationists).

Some kind of solace is what the otherwise rational Bill "All-I'm-Saying-Is-That-We-Should-Have-a-Debate" Maher must be seeking in his faith-like embrace of anything that's not "Western medicine"—a term that he has used liberally, disparagingly, and without explanation on his HBO show.* On the show's season finale, Maher once again maligned vaccination to an otherwise incredulous guest panel of Chris Matthews, Alec Baldwin, and Maryland Governor Martin O'Malley. Among the many illogical, non-sequitor, and/or flat-out wrong claims made by the host is this gem.

I also would like to say that I do understand the theory of inoculation. Yes, you give someone a little bit of the disease, and it fools your body into providing antibodies, which fight it. Brilliant. Bravo. Maybe there's some occasions where an inoculation is a wise thing to do. I hope not. I hope I would never have to have one, because, you know, to present it just as this genius medical advancement—no, it's actually a risky medical procedure that begs long-term cost-benefit analysis. I mean, if you don't believe me, look on the CDC web site as to what is in the swine-flu vaccine. You know, aluminum, insect repellant, formaldehyde, mercury. You know, that's right on their web site. Don't take it from a talk-show host.

Maher's last statement is the only one worth heeding. He continues to require education about the actual process of modern vaccination, given his statement "you give someone a little bit of disease...," and wrongly implies that vaccine advocates deny any risk whatsoever from vaccination.

As Maher indicates, the CDC web site offers some answers to FAQs about the ingredients of the 2009 H1N1 vaccine. The most obvious relates to the vaccine's mercury content, which has been falsely associated with the risk of autism. The truth of the matter: Only vials of the vaccine, not the prefilled syringes, contain measurable (but very tiny) amounts of ethylmercury (25 microg/dose), which is part of the thimerosal preservative. The seasonal flu vaccine is also available in thimerosal-free versions.

Data on other purported 2009 H1N1 vaccine ingredients, or lack thereof, are more easily found from online sources other than the CDC web site, including the FDA web site. Aluminum hydroxide is evidently used as an adjuvant in the low-dose Chinese vaccine,** but the US vaccine does not contain it.

Formaldehyde is used during vaccine production—to harvest and inactivate the cultivated virus from the chicken-egg medium, specifically the allantoic fluid. The virus is then chemically split by using a noninonic surfactant, polyethylene glycol p-isooctylphenyl ether, or Triton X-100. According to the package insert for the sanofi-pasteur 2009 H1N1 vaccine, "Each 0.5 mL dose may contain residual amounts of formaldehyde (not more than 100 microg), [Triton X-100] (not more than 0.02%), and sucrose (not more than 2.0%). It's not clear to me if the "insect repellant" that Maher refers to is supposed to be Triton X-100 or some other substance.

* The alternative, logically, is Eastern medicine--which is generally understood to encompass any idea of illness or medical therapy that's unproven. Adherence to Eastern medicine therefore requires faith. It could be said that Maher, who famously eschews religion, ironically places a religious-like faith in the benefits of these non-evidence-based ideas and practices.

** Hey Bill Maher, you still like Eastern medicine?

A major rate-limiting step in the production of the 2009 H1N1 vaccine is limited chicken eggs—at least according to the AP. So far, federally contracted companies have only been able to churn out about 10% of the promised 120 million doses for US residents, mostly because of a shortage of fertilized hens' eggs, which are required for viral cultivation. As a result, the vaccine is being restricted to the highest priority candidates.

In addition, the 2009 H1N1 strain appears to be more fastidious than typical seasonal influenza viruses, requiring 2 eggs instead of the usual one to produce a single vaccine dose. Therefore 240 million eggs are needed to make 120 million vaccine doses. According to Commercial Chicken Meat and Egg Production (only $279.20 at Amazon), 1 chicken can pound out about 300 eggs annually.* If so, 800,000 chickens can produce the required number of eggs for the US supply of the 2009 H1N1 vaccine in 1 year. The AP reports that more than 30 US farms, representing 9-12 million chickens, are under long-term contract to provide eggs for vaccine production.

Alternative methods for viral cultivation, including growth in mammalian or insect cells, are evidently being explored by industry through multimillion-dollar federal contracts.

* Dunno if the rate applies equally to unfertilized and fertilized eggs.

One month ago, results of the mammoth HIV-vaccine trial in Thailand were called "promising" by more than one media outlet. But peer review of the study, published yesterday in the NEJM, shows that the outcome was largely a statistical bust. Only a modified intent-to-treat (ITT) analysis, which excluded 7 individuals who were discovered to have HIV infection at baseline, showed a statistical benefit with the vaccine (reducing the risk of HIV infection by ~31%).

Nevertheless, the general sentiment: One tweaked outcome is better than nothing—at least when it comes to HIV prevention.

Comprehensive results of the trial, including those for the primary endpoints of HIV infection and early HIV viremia, are tabulated here. The ITT analysis accounts for all subjects who underwent randomization; the per-protocol analysis includes subjects who received the vaccination series within the defined time period and who were not found to be infected with HIV at baseline.

Outcome	ITT (N = 16,402)	Per-Protocol (n = 12,452)	Modified ITT (n = 16,395)
Vaccine efficacy, %	26.4 (P = .08)	26.2 (P = .16)	31.2 (P = .04)
HIV-1 infection	132	86	125
Vaccine	56	36	51
Placebo	76	50	74
Mean viral load, log10/mL
Vaccine	4.36*	4.24	4.30
Placebo	4.21*	4.19	4.20
Mean early postinfection CD4+T cells/mL
Vaccine	541	572	555
Placebo	568	532	568

* P = .09, vaccine vs placebo. 

The trial was randomized, double-blind, and placebo controlled. Four "priming" injections of a recombinant canarypox vector vaccine (Alvac-HIV; sanofi-pasteur) were followed by 2 booster shots of a recombinant glycoprotein-120 subunit vaccine (AIDSVAX; Global Solutions for Infectious Diseases) in adults aged 18-30 years. The prime-boost vaccination series was chosen on the basis of previous trials (Belshe et al, 1994; Russell et al, 2007; and AIDS Vaccine Evaluation Group 022 Protocol Team, 2001). Subjects were primarily at risk of HIV infection through heterosexual contact. After the 6-month vaccination series, enrollees were monitored for HIV infection and viremia every 6 months for 3 years.

Data regarding the potentially protective benefit of male circumcision were evidently not collected, but expect a good number of post-hoc subgroup analyses.

HIV = human immunodeficiency virus.

It's one thing to bury your missed primary endpoint, but nobody entertains like a renegade PR writer who's sky-high on his own fumes.

Epeius Biotechnologies, a privately held, California firm, evidently employs one such maverick (yes, I wrote "maverick")—as evidenced by some seriously entertaining press releases. Props for discovering the purple prose go to Trista Morrison at bnet.

The clumsy hyperbole concerns the firm's front-runner drug, Rexin-G, an antitumor molecule in stage 1/2 development.

Amongst the high-larity*:

October 14, 2009

The outstanding results of this advanced US clinical trial...demonstrate beyond contestation that Rexin-G...exhibits profound anti-tumor activity...

The success of landmark studies is a tribute, not only to the clinical investigators who "held the course" and the "cause" of a better medicine as a high standard, but to the US FDA who, by allowing across-the-board dose escalations in ongoing trials...served to expedite the achievement of these effective doses, and thus these heartening results. [quotation marks sic]

October 12, 2009 (regarding 3 case studies)

...Rexin-G has once again accomplished what standard cancer treatment and even much-touted biologics have failed to do: that is, to bring forth the benefits of remission in otherwise intractable metastatic cancers.

Even more remarkable, perhaps, are the profiles of...two patients, which signal the advent of Rexin-G as the vanguard of a new class of exceedingly precise, selective, and effective anti-cancer agents, and which typify a newfound societal acceptance and acknowledgement of the real-world promise and potential of this uniquely-targeted genetic medicine.

Remarkably, a Catholic priest, who was previously bedridden and in withering pain, suffering from end-stage prostate cancer that had spread to his bones, received successive courses of Rexin-G, during which time the bone pain was relieved, the PSA tumor markers fell, the bone tumors stopped growing, and even the previously inoperable primary tumor disappeared on follow-up CT scans.

As the priest’s bones began to heal and strengthen, he arose from his bed and is currently saying daily Mass and delivering lectures in the seminary. What is even more remarkable is that this revered man of the cloth was over ninety years old at the time of his treatment and remission.

...the latest good news comes from the trenches of Stage IVb pancreas cancer...

Indeed, as the unprecedented single-agent efficacy of Rexin-G is incontrovertibly demonstrated...the progressive steps of these intrepid pioneers may provide a rational basis of hope and expectation...

June 22, 2009

Epeius...stuns the medical and scientific communities...

Yet the progressive development strategy has finally paid off with real dividends...The dividends for the cancer patient can now be measured in terms of overall survival...

June 17, 2009

Rexin-G is the flagship of tumor-targeted genetic medicine: "smart," "stealth," "selective" and "potent" nano-medicine...

June 9, 2009

...Rexin-G is the world’s smallest hero! Imagine if you will, a tiny particle that can travel freely within the human body seeking out cancerous tissues and metastatic tumors that have spread far and wide. Imagine an entire army of these tiny nano-particles seeking out and accumulating to high concentrations within the flagrant, otherwise intractable tumors with one goal in mind: to destroy the metastatic cancers from the inside. Guided by nature’s own disease-seeking factors (ie, pathotropic targeting), armed with a powerful tumor-killing designer gene, and trained in the art of efficient gene delivery over aeons of evolutionary engineering, these tiny therapeutic particles represent a new paradigm in drug delivery and a new class of anti-cancer agents that exhibit profound and unprecedented single-agent efficacy in many cancers.

...these tiny nano-particles are inherently "smart." In performing a vital cancer surveillance function, they are uniformly "vigilant." By taking on a broad spectrum of cancers that are determined to be refractory to standard chemotherapy (ie, ineffectual apothecary), they are exceedingly "valiant." By reducing the cancer patient’s body burden and extending overall survival, they are truly "heroic." In a manner of speaking, these tiny nano-particles may well be the smallest heroes in all the world. [boldface sic]

December 18, 2007

...such individual accomplishments are rarely heralded by the intrepid physicians and scientists at Epeius Biotechnologies whose mission runs contrary to so many blue-sky biotechnology companies that are quick to "sell (ie, promote) the story," only to disappoint the patients, who remain the most vulnerable of society.

June 4, 2007

Epeius Biotechnologies Corporation today announced the publication of a historic landmark in medical oncology and a definitive benchmark in the emerging field of cancer gene therapy...In other words, this paper documents the unprecedented efficacy of targeted gene delivery in the tragic battlefield of metastatic cancer...  

Frederick Hall, President and CEO of Epeius, is on my short list of suspect writers, given the ex-squeeze-me style of his quotes:

It is most fitting that Rexin-G receives its first product registration in the Philippines which brought forth the stellar physician-scientist whose drive and determination to engineer a better medicine made Rexin-G possible, and also it was first in the Philippines where the dedicated clinicians, oncologists, regulatory authorities, and medical institutions worked tirelessly for years to bring this targeted genetic medicine to the bedside.

In each and every cancer patient extends their very own impedimenta, which deepens and exacerbates with time and ineffectual apothecary. The scientists and physicians at Epeius Biotechnologies are proud to have participated in the historic events that brought these first targeted genetic medicines safely and conscientiously across the threshold of history, bringing hard science gently to the bedside.

* Because of the relative sobriety of the press releases during 2008 and the first part of 2009, I conclude that the writer was either on extended vacation, forcibly restrained from contributing to the PR process, or receiving effective psychiatric medication.

N.B. The puffed-up leadership of Epeius is also suggested by a literary explanation of the company name—a tribute to the little-known architect of the Trojan Horse.

Bill Maher, put this in your glass pipe and smoke it.

A total of 86 children have now died of H1N1 illness in the United States, according to the latest data from the CDC. Nearly half (47%) of the deaths were reported to the CDC after August 30th, and 11 of these deaths occurred during the last week. Among the most recent deaths (n = 43), 19 (44%) occurred in preteens or teenagers (12-17 years of age).

For all practical purposes, H1N1 activity is now widespread in the United States.

Criss Cross

(1947): More noir with Lancaster. And about as complicated as noir gets—which is pretty complicated.

The paripatetic Steve (Burt Lancaster) returns to Los Angeles, where he pursues his gorgeous ex-wife Anna (Yvonne De Carlo, aka Mrs. Munster), who's hooked up with Slim Dundee,* the local mob boss. But Anna is inconstant in love...or in deciding her best option.

P.S. Check out De Carlo's dance partner in the Round-up Bar.

* I just wanted to write out that name, 'cause it's so goofy.

Positive results from another phase 1 study* of gene therapy in Parkinson disease (PD) support continued investigation of the novel treatment method. Details of the Avigen- and Genzyme-supported trial are available in an advanced, online edition of Neurology.

Ten patients (5 men, 5 women) with intractable motor fluctuations, despite optimal medical treatment of PD, received bilateral putaminal infusions (1 of 2 doses) of the human gene for aromatic L-amino acid decarboxylase (AADC) in an adenovirus vector. (A progressive deficiency of AADC, which converts levodopa into dopamine, may cause the diminishing response to L-dopa therapy that is observed in idiopathic PD.) Both doses were associated with improved mean motor function at 6 months, objectively (~30%) and subjectively, with a reduction of troublesome dyskinesias. Clinical improvement was also associated with a nonsignificant reduction in the level of dopaminergic medications. PET images demonstrated AADC activity in the putamen, thereby mitigating a possible placebo effect; tracer uptake was higher with high-dose gene therapy.

Three patients experienced intracranial hemorrhage, 1 symptomatic and 2 asymptomatic, which appeared to be due to placement of the gene-delivering catheters.

The authors propose similar follow-up studies with the high-dose therapy and a placebo group.

PET = positron emission tomography.

* The 2 previous studies, which used different genes: Kaplitt MG et al. Lancet. 2007;369:2097-2105; Marks WJ et al. Lancet Neurol. 2008;7:400-408.

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

Like white on rice, rational bloggers have been all over Bill Maher's goofy ideas about vaccines and vaccination. It's too bad, though, that the man has a nationally televised show, HBO's "Real Time With Bill Maher," which affords Maher an opportunity to influence potentially gullible viewers in front of (like many a talk/variety/comedy show) an audibly fawning studio audience.

Nevertheless, begrudging props may be given to Maher for inviting retired Republican Senator and physician Bill Frist on Friday to discuss vaccination. In this segment, it's not entirely clear that Maher "gets schooled" by Frist about vaccines (despite the clip's title). Schooling requires that Maher's thick skull be penetrable. And schooling requires time—much more time than television typically allows.

But a blog provides an enduring, leisurely format for dissecting and refuting some of the utterly fallible anti-vaccine statements that Maher made on Friday and that Frist didn't have the chance to challenge.

Maher comment #1: Conservatives always say, about healthcare especially: You gonna let the government run healthcare? They screw everything up. So why would you let them stick a disease into your arm? I would never get a swine flu vaccine or any vaccine. I don't trust the government, especially with my health. [Applause.] And that seems to be a conservative opinion: not to trust the government.

Dissection: The usually liberal Maher tries to create a bit of oh-gosh irony here by aligning himself with traditionally government-distrusting conservatives. He then jumps to make a very broad and loose association between government incompetence and government-recommended vaccination. However, if Maher were familiar with the monumental benefits of historical vaccination programs (eg, against smallpox and polio), the association actually supports organized intervention into healthcare (whether instigated by a government or some other authoritative entity, like the World Health Organization).

At the same time, Maher indicates that vaccination is a process whereby "disease" is injected into the body. First "disease" is a clinical manifestation of bodily dysfunction; it is not something that can be confined in a syringe. But we sort of know what Maher's means here, so we'll give him a pass on this semantic point. What Maher is really implying is that disease-causing virus is injected during vaccination. But that idea is also false.

With respect to the injected 2009 H1N1 (swine flu) vaccine, the inoculant is a killed (actually chemically "split") virus—which is incapable of causing infection (but is capable of inducing protective immunity). The nasal-spray vaccine from MedImmune contains live, attenuated H1N1 virus. The attenuated virus is engineered (ie, cold adapted and temperature sensitive) so that it can replicate in the cooler confines of the nose to induce immunity, without causing influenza-like illness.

Maher indicates that he would never get the swine flu vaccine, which is fine (assuming that Maher isn't at baseline risk for influenza complications and doesn't care for an infant younger than 6 months of age*). The 53-year-old isn't a CDC-recommended candidate for the 2009 H1N1 vaccine (although he should get a seasonal flu shot).

Maher comment #2 (in response to a Frist anecdote about a patient dying of swine flu): I cannot believe that a perfectly healthy person died of swine flu. That person was not perfectly healthy. Medical—Western medicine misses a lot.

Dissection: Maher's just flat-out wrong here. Regardless of what he believes, serious H1N1-related disease preferentially affects persons younger than 65 years of age, and about 45% of Americans who have died of swine flu were healthy, according to the CDC. With his last sentence, Maher also betrays a broad, inherent distrust of Western (really, allopathic) medicine. 

Maher comment #3: Let me read you a quote from the former control officer at the US FDA. His name is Dr. J. Anthony Morris. He said, "There is no evidence that any influenza vaccine thus far developed is effective in preventing or mitigating any attack of influenza. The producers of these vaccines know they are worthless, but they go on selling them anyway."

Dissection: By quoting J. Anthony Morris, Maher reveals a lazy reliance on an ostensibly authoritative source, about which he probably knows nothing. 

Finding reliable information on Morris (at least on the web) is a challenge; at first blush, he appears to be a quotable favorite among anti-vaccinationists—probably because of the specious appeal-to-authority angle (ie, Morris reportedly has/had a PhD in bacteriology and was an FDA employee). An archived newspaper search reveals that Morris was a virologist in the Division of Biologic Standards, which was part of the NIH until 1972 when the division was transferred to the FDA.

In the fall of 1971, Morris made news by arguing to Congress that influenza vaccines were not just useless, but dangerous (see Lyons RD. Influenza shots held ineffective. NYT. October 15, 1971). He claimed that "not only has there been little or no benefit from the use of influenza vaccine in man, but harm has resulted." However, a federally appointed, 12-person scientific committee rejected Morris's claims of incompetence within his NIH division; although the committee did concede, in ho-hum fashion, that "inactivated influenza vaccines are imperfect instruments for the prevention of influenza." (The committee may have been referring to subpotent lots of influenza vaccine that were distributed in the 1960s.) The committee then proceeded to reject Morris's claims that influenza vaccines are harmful (see Lyons RD. Charges of poor vaccine regulation rejected. NYT. November 30, 1971).

A related news story in June 1972 indicates that Morris had been demoted within his division, which was now (presumably) a part of the FDA. But later news reports indicate that Morris was appointed director of the Slow and Temperate Virus Branch of the agency.

In July 1976, Morris, then 57, was finally fired from the FDA for "insubordination" and "inefficiency." Morris claimed that he was sacked from his $35,000-a-year job because he opposed President Ford's swine flu vaccination program. FDA officials acknowledged, at the time, that it was very unusual for an FDA employee to be fired, but the process that led to Morris's departure began long before anybody recognized the swine flu threat. Later Morris showed up on fear-mongering talk shows like "Phil Donahue" and provided anti-vaccine quotes to news reporters as recently as 1988. 

A phrase search of various archived newspapers fails to return a source for the exact quote cited by Maher, except in 1 instance: Donald Harte, in a November 2007 editorial for the Marin Independent Journal ("Is there a vaccine that protects against non-science?") requotes Morris from a citation in a contemporary issue of Health & Fitness magazine. The quote was described as being 30 years old, but the original source was not identified. 

Morris, if alive this year (and I haven't been able to confirm whether he's alive or dead), would be about 90. 

Maher comment #4: But a virus is always mutating. You would agree with that? [Frist: Yeah.] So, so the vaccine that they produce back in March—that's not really what's gonna prevent what's, what's going on now. Because—I know a lot of people on the conservative side don't believe in evolution—but—and you can't see evolution in advanced species, but you can see—[Frist interrupts: We know this vaccine is 98% effective...]

Dissection: Here Maher tries to discount the efficacy of the swine flu vaccine by implying that the virus has mutated so much since the creation of the vaccine (in March) that it will evade whatever immunity is produced by inoculation. However, on October 9 (the same day that Maher's show aired), the CDC reported that the 2009 H1N1 viruses "have not undergone substantial antigenic change since they were first characterized in April 2009 and should be well-matched to the monovalent vaccine strain." 

Last month, data published in the NEJM indicated that significant antibody titers were generated in 97% of adults after 1 dose of the inactivated vaccine. Rates of antibody production among children aged 6-35 months, 3-9 years, and 10-17 years were 25%, 36%, and 76%, respectively. These data are the foundation for recommending 2 vaccine doses in children younger than 10 years of age. The suboptimal immune response in younger children is probably related to their limited immune experience with influenza viruses and is clearly not the result of viral mutation.

There have been scattered reports of 2009 H1N1 virus that is resistant to oseltamivir (Tamiflu), but all of these isolates were susceptible to zanamivir (Relenza).

Maher comment #5: Dr. Jonas Salk: "Live virus vaccines against influenza and paralytic polio, for example, may in each instance cause the disease it's intended to prevent."

Dissection: Another appeal to authority by Maher. Salk, as everyone knows, was the creator of the inactivated polio vaccine. The quote cannot be confirmed and, again, appears to be a favorite among online anti-vaccinationists. An archived newspaper search fails to return relevant hits, and without context, it's useless to interpret a statement that Salk may or may not have made.

* And don't we all hope that's the case.

A brief history of the direct-to-consumer (DTC) ad biz for prescription drugs, provided today by NPR's "Morning Edition," requires the following contextual notes—largely because the piece falsely implies that DTC advertising is responsible for escalating healthcare costs.

1. While the estimated, annual spend on DTC advertising for prescription drugs is approximately $4 billion (according to most sources), the DTC spend has actually been decreasing since 2006 (from a peak of $5.4 billion). One pundit predicts that the total dollars dished out for DTC ads this year will shrink by 11%. The prevailing speculation for the trend: general economic constraints. Clearly decreases in DTC spending do not parallel steadily increasing healthcare costs, including costs for prescription drugs (see item 2).
2. While prescription drugs (along with "nondurables") are, in fact, the third most costly aspect of the US healthcare system, they account for only about 12% of the overall healthcare spend (and are arguably one of the most cost-effective aspects of healthcare). In 2006, the spend on outpatient care was $850 billion (~41% of overall costs), and that on inpatient care was $458 billion (~22%), according to the McKinsey Global Institute. From 2003 to 2006, the costs for outpatient care, inpatient care, and drugs grew annually at rates of 7.5%, 6%, and 6.9%, respectively. The rise in prescription drug costs is due "almost equally" to an increase in consumed drug volume and a rise in drug costs. These increases have been offset, however, by "a [small] trend toward a less expensive drug mix."
3. While it is generally quoted that Americans received an average of 12 prescriptions in 2008,* they use approximately 10% fewer drugs (on a per capita basis) than Europeans and Australians—again according to the McKinsey Global Institute. Prescription drug prices in the United States are about 50% higher than those for Europeans. (Notably branded drugs for Americans are about 77% more expensive, but US generic drugs are about 11% cheaper.) The higher cost of prescription drugs for Americans is due to the use of a more expensive "drug mix"** and higher drug prices. It is generally believed that higher US drug prices subsidize pharmaceutical R&D for the world; however, the R&D subsidy does not sufficiently explain the higher costs of branded drugs for Americans.

* Note that this statement does not indicate that Americans consume 12 prescription drugs simultaneously on a regular, daily basis.

** Although there is a small trend among Americans toward a less expensive drug mix (see item 2).

Image of Novartis's now-defunct Digger the Dermatophyte for Lamisil: Not just responsible for toenail fungus, according to NPR.

Brute Force (1947): A deeply moody prison noir, photographed by black-and-white master William Daniels. 

Joe Collins (Burt Lancaster*) and his cellmates are mentally and physically tormented by the sadistic chief guard, Captain Munsey (Hume Cronyn). But when Munsey assigns the prisoners to the dreaded drain-pipe detail, the group plans their dramatic escape.

* In his 2nd movie, after The Killers.

A simplified table of the FDA-approved vaccines against the 2009 H1N1 virus is provided here, with a focus on age and dose recommendations. For complete data, see this week's MMWR.

Age	Formulation(s) Available  (Manufacturer[s])	Dose, mL	No. Doses
6-23 mos	IM injection (sanofi pasteur; CSL*)	0.25	2
24-35 mos	IM injection (sanofi pasteur; CSL*)	0.25	2
	Nasal spray (MedImmune)	0.2	2
36-47 mos	IM injection (sanofi pasteur; CSL*)	0.5	2
	Nasal spray (MedImmune)	0.2	2
4-9 y	IM injection (sanofi pasteur; Novartis; CSL*)	0.5	2
	Nasal spray (MedImmune)	0.2	2
10-17 y	IM injection (sanofi pasteur; Novartis; CSL*)	0.5	1
	Nasal spray (MedImmune)	0.2	1
18-49 y	IM injection (sanofi pasteur; Novartis; CSL)	0.5	1
	Nasal spray (MedImmune)	0.2	1
>49 y	IM injection (sanofi pasteur; Novartis; CSL)	0.5	1

The IM shots contain inactivated virus, and the nasal spray (from MedImmune) contains attenuated virus. Prefilled syringes do not contain mercury (that is, 25 microg Hg per 0.5 mL of vaccine, in the form of thimerosal preservative). When 2 doses are recommended, they are administered approximately 4 weeks apart.

The nasal spray vaccine is indicated for healthy, nonpregnant persons aged 2-49 years and should not be administered to persons with asthma. The dose of the nasal spray is divided equally between each nostril.  

Note: These data are for informational purposes only and should be confirmed by referring to authoritative sources (eg, the CDC) and/or a treating healthcare professional.

* Latter approved by FDA for age group on 11/12/09.

The recent publication of commercial payments to physicians allows anyone to compare these data with information disclosed by the very same physicians. And that's just what a few orthopedic surgeons systematically did. Their analysis of their colleagues' disclosures, or lack thereof, is available in the latest issue of the NEJM.

The authors compared online reports of payments in 2007 from the 5 major prosthetic-joint companies (Biomet, DePuy, Smith and Nephew, Stryker, and Zimmer)* with payments voluntarily disclosed by physician participants at the annual meeting of the American Academy of Orthopedic Surgeons (AAOS).

Their findings:

• About one quarter of the commercial payments in 2007 (344/1347) were made to physicians who were AAOS meeting presenters, committee members, or board members in 2008.
• 146 (42%) of these payments exceeded $100,000 (each); 135 (39%) ranged from $10,000 to $100,000; and 63 (18%) were less than $10,000. (From Figure 2, it appears that close to 40 payments exceeded $1 million each.)
• In most cases, payments were made directly to physicians (78% of payments) and were directly related to the presentation topic (70% of payments).
• The overall disclosure rate was 71% (245/344 payments)—meaning that nearly 30% of payments to orthopedic surgeons were not voluntarily disclosed, despite the fact that the meeting's disclosure instructions were broad.**
• Compliance with disclosure was somewhat higher for direct payments (79%) and was substantially lower for indirect payments (50%). (An indirect payment is made through another company or organization—for instance, a medical-education communications company, or MECC.)
• The total amount of undisclosed direct payments (n = 43) exceeded $4 million; the total amount of undisclosed indirect payments (n = 16) exceeded $7 million.
• Payments were more likely to be disclosed if they exceeded $10,000, were given to an individual physician, or included in-kind support.
• Reasons for nondisclosure (from those few nondisclosing, surveyed physicians who responded) included 1) the payment was unrelated to the presentation topic; 2) the disclosure requirements were misunderstood; or 3) the disclosure was incorrectly printed.

* The companies' publication of physician payments in 2007 was required as part of a DoJ settlement.

** The meeting participant was directed to make a disclosure "if he or she has received something of value from a commercial company or institution, which relates directly or indirectly to the subject of their presentation."

In its recent "free-speech" complaint for declaratory judgment and injunctive relief against the US government, Allergan proposes its "speech" to healthcare providers about the risk of Botox spread after injections for spasticity—an off-label indication. But the company logically fears that its proposed speech, which would include only truthful, nonmisleading statements about the off-label use of Botox, puts it in criminal and civil jeopardy. (For background on this story and the FDA's safety requirements re Botox risks, go here.)

First Allergan claims that the FDA-approved boxed warning for Botox,* the mandated Dear Health Care Provider letter, and altered Medication Guide provide only general warnings about the distant spread of toxin. These communications do not provide specific guidance for physicians**—for instance, details about patient selection, toxin dose, number of injection sites, frequency of administration, and injection technique—that would tangibly reduce the risk of remote spread when using Botox for spasticity. Allergan also proposes that it would inform physicians about the expected time frame to observe a therapeutic effect with Botox, when used for spasticity.

Allergan acknowledges that its proposed speech would not alter the official labeling for Botox, but the company recognizes that much of its proposed speech would "fall within the FDA's expansive definition of 'labeling'" and could lead to federal misbranding charges. Discussions about the safety of Botox treatment for spasticity may also be interpreted as promoting Botox for spasticity, and such an interpretation could lead to federal charges of distributing an unapproved "new drug" in the eyes of the FDA (meaning, an existing drug for a new indication).

Following the logic a step further, Allergan writes: "Even by filing this complaint and thereby exercising its First Amendment right to petition the Government, Allergan fears that it will run afoul of the FDA's regulatory regime by demonstrating its knowledge that Botox is sold to physicians who use it to treat spasticity and other off-label conditions. On the Government's view, Allergan's possession of this knowledge—and its choice to defend its constitutional rights—violates 21 CFR §201.128 [which relates to the drug maker's knowledge of intended uses] on its face."

Allergan justifies its fear of prosecution for the off-label promotion of Botox by acknowledging that the company is the subject of a DoJ investigation in the Northern District of Georgia.

* Text of boxed warning advising of distant spread of toxin: "Postmarketing reports indicate that the effects of Botox and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, and in approved indications, cases of spread of effect have occurred at doses comparable to those used to treat cervical dystonia and at lower doses."

** Allergan reports that it "does not seek to engage in direct-to-consumer communications about the off-label use of Botox."

IMHO.

Pneumococcal vaccines, which can protect against influenza complications, are underused. And there is no shortage of these vaccines. These facts were relayed by Thomas Frieden in today's CDC press conference.

The CDC recommends the PCV7 vaccine (Prevnar; Wyeth) routinely for children younger than 2 years of age (1 dose each at 2, 4, 6, and 12-15 months) and older children who have not completed the 4-series vaccination.

The CDC recommends the PPSV23 vaccine (PneumoVax; Merck) for all adults aged 65 years or older and any individual 2-64 years of age with a long-term health problem (eg, diabetes) or a condition that lowers resistance to infection (including therapy). The CDC also recommends the PPSV23 vaccine for adults 19-64 years of age who smoke or have asthma.

Pneumococcal immunization protects against infection with Streptococcus pneumoniae, the most common bacterial pathogen in reported fatal cases of H1N1 infection to date.

For authoritative and comprehensive information on this subject, see the CDC web site.

PCV7 = 7-valent pneumococcal conjugate vaccine; PPSV23 = 23-valent pneumococcal polysaccharide vaccine.

Photomicrograph of S. pneumoniae grown from blood culture from the CDC/Dr. Mike Miller.

A warning to pharma execs who are inclined to bury missed primary endpoints of clinical trials in press releases: You are personally at risk of federal indictment and conviction. No more hiding behind the company shield.

Case in point: Scott Harkonen

The former CEO of InterMune, was found guilty of wire fraud last week in a San Francisco federal court, reported the DoJ in a September 29 statement.* As a result, Harkonen faces up to $250,000 in fines and 20 years in prison. The jury-trial conviction relates primarily to a press release issued by InterMune on August 28, 2002, and reportedly at Harkonen's direction. 

The InterMune press release in question (reprinted here) claimed, in blatant up-front fashion, that the company's drug Actimmune (interferon gamma-1b) improved overall survival in a phase 3 study of patients with mild-moderate idiopathic pulmonary fibrosis (IPF). However, the trial results failed to show a statistical difference in progression-free survival, the trial's primary endpoint, between Actimmune and standard corticosteroid treatment. News of the missed primary endpoint was buried in the first paragraph of InterMune's press release and overshadowed by follow-up praise for the trial results provided by Harkonen and the study's lead investigator, Ganesh Raghu.

In January 2004, Raghu and his scientific colleagues published the results of the same trial in the NEJM. There the peer-reviewed data failed to show that Actimmune significantly improved progression-free survival, pulmonary function, or quality of life. Later that year, the DoJ launched an investigation of InterMune and its promotion of Actimmune for the off-label indication of IPF. The investigation culminated in InterMune paying a $37-million settlement to the government in October of 2006 (for a detailed timeline of InterMune's troubles, go here).** Harkonen was separately indicted by the DoJ in March of last year.

Harkonen resigned from InterMune in June 2003 and is currently President and CEO of Comentis, a San Francisco-based biotech. Notably, in his legal defense, Harkonen claimed that the InterMune press release should be protected by the free-speech clause of the First Amendment. Harkonen argued that he was engaging in "scientific debate"; the judge, however, failed to buy the argument, possibly because she found the press-release statements to be misleading.

* Harkonen was simultaneously acquitted of a misbranding charge.

** In 2007, the clinical investigation of Actimmune in IPF was abandoned by InterMune after interim results of another phase 3 trial showed no survival benefit with drug. InterMune is currently investigating pirfenidone in IPF.

The latest in the conflict between Constitutionally granted free speech and the government's prohibition of off-label drug discussions by pharma.

Last week, Allergan, maker of Botox (onabotulinumtoxinA), announced a suit against the US government, seeking "declaratory relief" from such long-time federally mandated off-label speech restrictions.* The complaint, filed in US District Court for the District of Columbia, specifically applies to the sharing of information about Botox Therapeutic (not Botox Cosmetic) and recent requirements of the FDA's Risk Evaluation and Mitigation Strategies (REMS) program. In its complaint, the company is represented by Paul Clement, former Solicitor General and a current partner in the DC law firm of King & Spalding.

Allergan's suit was filed with respect to the FDA's REMS program for botulinum toxin products. The program was instituted this year because of postmarketing reports of toxin spread after injections for off-label conditions—namely, spasticity in children with cerebral palsy and arm spasticity in adults. In the program, the FDA requires manufacturers to create a "communication plan" that provides information to physicians about the risk of the distant spread of botulinum toxin after local injection.

But Allergan argues that the FDA's required communication plan puts the company in a double bind—effectively mandating proactive discussions about the safety of off-label Botox Therapeutic, while simultaneously prohibiting proactive off-label discussions. Allergan claims that it cannot reasonably abide by the FDA's REMS program for Botox Therapeutic (ie, "proactively provide comprehensive information to physicians about these off-label uses [emphasis added]") without fear of prosecution. The company writes, "Allergan seeks a judgment that would permit it to provide currently available and truthful information to doctors for common off-label uses of [Botox]."

In a conference call on Friday, Allergan's General Counsel, Douglas Ingram, provided additional information about the complaint and fielded questions. Ingram stressed that the company's suit applies to the provision of "truthful," "nonmisleading," and "comprehensive" information about the off-label uses of Botox Therapeutic. Ingram would not comment on a recent investigation of the company by the US Attorney's Office for the Northern District of Georgia, which issued a subpoena in March to the California-based firm regarding the alleged off-label promotion of Botox for headache. Both Ingram and Allergan CEO, David Pyott, stressed that the company's current complaint does not relate to alleged past activities. Ingram also declined to comment on Pfizer's recent record-breaking $2.3-billion settlement with the government concerning off-label drug promotion.

* Mandated by the Federal Food, Drug, and Cosmetic Act of 1938. The FDCA dictates that an approved drug is "misbranded," if it is marketed (in interstate commerce) for an unapproved use. The act stipulates that the product's approved label, in this case, does not provide "adequate directions for use."

Rodgers and Hammerstein's "Cinderella" (1957): A black-and-white tape of the original live-and-in-color TV performance, with a 21-year-old Julie Andrews in the title role.

Andrews didn't have the acting chops, or perhaps the inclination, to show her character's real sadness, but the musical production is remarkable for coming off live, with nary a hitch. Especially notable are Alice Ghostley and Kaye Ballard as the stepsisters (singing, "Why would a fella want a girl like her...?") and Edith (Edie) Adams as the godmother.

The DVD's 20-minute special feature, in which Andrews and other cast members remember the show, is a must.

While I was blogging about prions last week, Pfizer and Eisai semi-quietly avoided a mammoth conflict. The two companies announced a restructuring of their comarketing deal for Aricept (donepezil), the number-one prescription med for Alzheimer disease.

Back in May, the Japan-based Eisai informed Pfizer that it had a legal right to terminate their copromotion of the drug, in place since 1994, because of Pfizer's anticipated acquisition of Wyeth. But Pfizer understandably bristled at the threat, given that Aricept generated $482 million in sales for the US firm in 2008.

The new agreement, according to Eisai's press release, continues to allow the companies to comarket Aricept in the United States, Japan, and "key markets in Europe" until 2022. However, copromotion in Japan will cease by 2013, with rights there reverting back solely to Eisai (which discovered the drug).*

The new agreement also launches a long-term comarketing deal for Pfizer's blockbuster drug Lyrica (pregabalin), which is approved in the United States for the treatment of neuropathic pain, epilepsy, and the ever-controversial fibromyalgia. An NDA for the drug has reportedly been filed in Japan. According to the AP, Lyrica generated $2.6 billion in worldwide sales last year.

* Eisai says that the basic patent on Aricept expires in 2010.

Or, to put it another way: Merck Serono remains just ahead of Novartis in the race for approval of the first oral MS drug.

Yesterday the former company announced its NDA submission for the fast-track approval of oral cladribine, an anticancer drug, in the United States. Use of the agent in relapsing-remitting MS is supported by results from the publicly presented CLARITY study.

But Novartis isn't too far behind.

Also yesterday, Novartis announced that its investigational drug, fingolimod (or FTY720), significantly reduced the relapse rate and disability progression in a 2-year, double-blind, phase 3 study of patients with relapsing-remitting MS. Although the data have evidently not been presented at a public scientific forum, nor have they been peer reviewed.

In Novartis's so-called FREEDOMS study, 2 dosages of fingolimod, 0.5 and 1.25 mg po daily, were compared with placebo in more the 4000 individuals with RRMS. The primary endpoint was the annual relapse rate. The main secondary endpoint was the reduction of the progression of disability.*

Endpoint	Relative Risk Reduction, %
	Fingolimod 0.5 mg po q d	Fingolimod 1.25 mg po q d
Annual relapse rate	54	60
Disability progression	30	32

MR data complemented the observed clinical efficacy of the drug, claimed Novartis. Fingolimod was "generally well tolerated," but fewer adverse effects were noted with the lower dosage. Given the comparable efficacies of the 2 dosages, continued clinical development will concentrate on the 0.5-mg treatment, wrote the company.

Novartis also states that it will submit data for the approval of fingolimod 0.5 mg in the United States and Europe at the end of this calendar year. The FREEDOMS data will be supported by results from another phase 3 study, TRANSFORMS, in which fingolimod outperformed IM interferon beta-1a (Avonex; Biogen Idec). Novartis is also conducting the follow-up FREEDOMS II study.

Fingolimod is a sphingosine-1-phospate receptor modulator, which is believed to reduce circulating lymphocyte counts by trapping them within lymph nodes. The agent may also have direct deactivating effects on CNS cells. Cladribine, a purine analog, has an extensive history as an anticancer agent—particularly in the treatment of certain leukemias and lymphomas. 

* Defined by the Expanded Disability Status Scale (EDSS).

CLARITY = Cladribine Tablets Treatment MS Orally; FREEDOMS = FTY740 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; NDA = new drug application; TRANSFORMS = Trial Assessing Injectable Interferon vs FTY720 Oral in RRMS.

According to today's MMWR.

Among the 77 fatal cases of 2009 H1N1 influenza that were reported in the United States from May 1 to August 20, bacterial pathogens were identified in 22 cases (29%). Streptococcus pneumoniae was detected in 10 (45%).

The breakdown: