February 2012 Archives

The most recent lots of counterfeit Avastin (Roche), which found their way to various oncology clinics in the United States (most of which are in California), originated in Egypt and were essentially a slurry of inactive ingredients, reports Fox News. The fake vials of the purported anticancer drug contained a hodgepodge of salt, starch, citrate, isopropyl alcohol, "propandiol" (probably propylene glycol), t-butanol, benzoic acid, difluroinated benzene, acetone, and phthalate—but no bevacizumab, the monoclonal antibody and active ingredient in Avastin that is intended to suppress angiogenesis and tumor growth.

The counterfeit vials were reportedly processed through legitimate distributors in Switzerland, Denmark, and Britain before entering the United States, where the fake drug was sold to 19 oncology clinics or physicians by Quality Specialty Products (aka Montana Health Care Solutions). A company with the terribly generic name of Volunteer Distribution,* located in Gainesboro, Tennessee distributed QSP's products, according to the FDA.

A web search reveals an address for Volunteer Distribution in Gainesboro: 101 W. Gore Ave. Google Maps provides this lovely screenshot for the Tennessee address, although the location is identified on the annotated street view as "Anderson & Haile Drug Co Phrm." A web search also reveals the listed phone number for Volunteer Distribution as 931-268-4506; that for Anderson & Haile is 931-268-0233.** Important update: Further searching of Google Maps and its street-view feature shows that Anderson & Haile is actually located in a commercial property at the corner of W. Gore Ave. and S. Union St. in Gainesboro, Tennessee.

Fake Avastin (or Lucentis) on the market is evidently an ongoing problem for Roche (and susceptible patients). Shanghai was the source for a bogus version in 2010, and Syria in 2009, says Fierce Pharma.

What vials of Avastin should contain are bevacizumab (the active ingredient), along with trehalose dihydrate, sodium phosphate (both monobasic monohydrate and dibasic), polysorbate 20, and water.

* I suppose that "Volunteer" must refer to Tennessee.

** And another web search provides these listed contacts for Anderson & Haile at 101 W. Gore Ave: Teneal Jenkins and Christie Banker. Yet another web search shows that Teneal Jenkins is "doing business as" Anderson and Haile Drug Company, a pharmacy and supplier of medical equipment and supplies. And yet another web search shows that Teneal Jenkins has a PharmD. A license lookup at the Tennessee Department of Health shows that Teneal Chaffin Jenkins of 101 W. Gore Ave in Gainesboro, Tennessee (Anderson and Haile Drug Co.) graduated with a PharmD in 2004 from the University of Tennessee (Memphis) and has sustained no disciplinary or significant liability claims.

And a clarification: I have no idea if Anderson & Haile Drug Company, located at 101 W. Gore Ave., in Gainesboro, TN, or pharmacist Teneal Jenkins and Volunteer Distribution, located at the same commercial building, have (or had) any connection whatsoever. Although it would be an unfortunate coincidence for Anderson & Haile and pharmacist Jenkins if they did not. FWIW, street images of the area, courtesy of Google Maps, show unreadable hanging shingles and ascending stairs to an entrance at the back of the building.

Pushover (1954): Back to noir. As a cop after a bank robber, Fred MacMurray romances the criminal's girlfriend (Kim Novak) to get a lead on the stolen money; but then he falls hard for real. Essential elements of Pushover, specifically the police surveillance of Novak, echo the entire setup of Hitchcock's Rear Window (1954)—which was released almost simultaneously. And of course, Novak's turn as a potentially duplicitous girlfriend anticipates her troubling role in Vertigo (1958). With E. G. Marshall, Philip Carey, and Dorothy Malone.

Murder! (1930): Despite its year of production, this very early effort from Hitchcock (his third talkie!) displays the important signature elements of the director's enduring stories of suspense and murder, including deliberate camera placement, liberal scenes of comedic relief, and an exploration of abnormal psychology. Particularly notable here is the blurred distinction between events on and off the theatrical stage.

While serving on a jury, a famous English thespian, "Sir John," reluctantly votes to convict a pretty young actress of murder. But nagging doubts about the actress's guilt prompt a reexamination of the crime, and Sir John uses his dramatic knowledge in an attempt to catch the real killer.

Poster for Murder! from Wikipedia and reproduced under fair use law.

Both MedPage Today and Medscape report that some kind of legislative "deal" is near completion for an intermediate-term fix of the pesky sustainable growth rate (SGR) formula—the done-broke formula used to determine physician reimbursement for Medicare-funded services.

Medscape, really by way of Reuters, reports that the deal will be a 10- or 24-month fix, depending on whether Congressional Democrats or Republicans, respectively, prevail in the ongoing negotiations. Senator Jon Kyl (R-AZ) is quoted by the wire service, saying that remaining disagreements could be resolved within the next 2 or 3 days.

Kyl also says that Congress "is unlikely to repeal the contentious reimbursement mechanism because a long-term solution would cost more than $300 billion." The current temporary fix is due to expire at the end of February, at which time a 27.4% cut in physician reimbursement for Medicare-funded services would kick in.

It has been proposed that compensation for the latest, anticipated SGR fix could be found (at least partially) in savings from ending the wars in Iraq and Afghanistan.

02/17/12 update: Congress opts for a 10-month delay.

And reasonably, I might add. Here's the video link. Notably the piece was done with the cooperation from higher-ups at Duke Med (ie, Robert Califf).

Potti is now an oncologist at South Carolina's The Coastal Cancer Center, the website for which advertises Potti's time at Duke University and (not surprisingly) makes no mention his colossal scientific fraud while there.

Forbes's Matthew Herper recalculates the cost of drug development and comes up with an average of $4 billion per approved drug—which is $3 billion more than the oft-cited number of $1 billion (from the oft-cited DiMasi study). Moreover, some companies (Amgen, Novartis) have been a whole lot better—or a whole lot luckier—at parlaying their R&D investment into marketable products. AstraZeneca, with a nearly $12-billion-per-approved-pill cost: Eh, not so much.

Toss one or two more potential biomarkers for dementia into the CSF soup.

European investigators found that the activity of the enzyme chitinase, a marker of telomere dysfunction and DNA damage, was significantly increased in the spinal fluid of patients with AD or non-AD dementia (when compared with similarly aged, nondemented controls).

The results of the study, published in the latest online issue of Neurology, indicate that elevated chitinase activity in the CSF has a nearly 86% accuracy for distinguishing between patients with dementia and those without. When combined with the more traditional CSF markers of AD—namely, decreased beta amyloid levels and increased tau—the accuracy of elevated chitinase activity for identifying dementia rose to 91%. Levels of a secondary biomarker, stathmin (also an indicator of telomere dysfunction and DNA damage), were likewise elevated in individuals with AD or non-AD dementia; but the distinction between nondemented controls was not as robust as that with chitinase activity.

Biomarker	AD Dementia (n = 94)	Non-AD Dementia (n = 30)	No Dementia (n = 40)	P Value
Tau, pg/mL	604 (399.75-1045.5)	309 (229-494)	327 (231.5-410.025)	6.462 x 10-11
Aβ42, pg/mL	494.5 (381.25-578.75)	734 (617-1001)	843 (588.7-1062.25)	1.020 x 10-8
Stathmin, ng/μL	0.76 (0.67-0.8975)	1.00 (0.94-1.14)	0.655 (0.56-0.7375)	1.590 x 10-13
Chitinase activity, ng/μL	0.665 (0.5525-1.09)	0.76 (0.61-0.94)	0.32 (0.19-0.5325)	8.442 x 10-8

Important caveats to the study are 1) there is a substantial overlap of these biomarker levels between demented and nondemented subjects (see Figure 1 in the article); and 2) chitinase activity in the CSF does not appear to aid a distinction between AD and non-AD dementia.

CSF = cerebrospinal fluid.

At least one physician thinks so and that we should label the condition accordingly.

A reassessment of patients classified with early Alzheimer disease indicates that almost all of them have mild cognitive impairment (MCI) instead—that is, if the reassessment is based on the newly revised diagnostic criteria for AD and MCI, which were released last April by the National Institute on Aging and the Alzheimer's Association. The results of the reclassification study are published in the latest online version of the Archives of Neurology and raise questions about the changing and admittedly arbitrary distinction between the two conditions.

John C. Morris, MD, a neurologist at Wash U (St. Louis), reassessed the functional scores of more than 17,000 individuals enrolled at federally funded Alzheimer's Disease Centers, including nearly 5000 people with MCI and about 6200 with probable AD. When the new diagnostic criteria, which now allow for some degree of functional impairment (eg, mild impairment of daily activities, like paying bills, shopping, etc) in MCI, were applied, more than 90% of patients originally classified with mild AD could be reclassified as having MCI. Morris concluded that the "categorical distinction between MCI and milder stages of AD dementia has been compromised by the revised criteria." But rather than advocate a renewed distinction between MCI and AD on the basis of functional impairment, he proposed, perhaps controversially, that MCI should really be called what it is, early AD, or at the very least, MCI due to AD.

However, physicians may be reluctant to label MCI as AD in clinical practice, possibly because of the distressing and stigmatizing effect of the latter condition, Morris conceded. Nevertheless, he argued, "many individuals with MCI are treated with pharmacological agents approved for symptomatic AD, indicating that clinicians often do not distinguish the 2 conditions when faced with issues of medical management." Moreover, the renaming will allow patients with milder dementia to be enrolled in bona fide AD studies of investigational agents (eg, anti-amyloid agents) that may show benefit in earlier stages of illness.

Morris's renaming argument has some merit and support, specifically in the form of a longitudinal study published in 2010 by the Alzheimer's Disease Neuroimaging Initiative. In a follow-up of 800 elderly subjects, including nearly 400 with MCI, the estimated annual rate of conversion from MCI to AD was 16.5%. However, a few individuals with MCI (8/398) also reverted to normal cognition—suggesting that the diagnosis of early cognitive impairment remains somewhat fluid and/or is misapplied in a small minority of cases.

Some may attempt to apply the same kind of spectrum-of-disease argument to the accumulation of beta amyloid in the brain (as observed on PET images with radioactive amyloid tracers): meaning that the age-related accumulation of beta amyloid is a harbinger of clinical AD (provided that the patient lives sufficiently long). However, I would counter that these potential biomarkers of age-related disease become increasingly imperfect indicators of anything meaningful during advancing life and more and more irrelevant without clinical manifestations of age-related disease. A correlate of similar imperfection would be something like the PSA test for prostate cancer in elderly men.

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

Pimpernel Smith (1941) is Leslie Howard's updated riff on his previous leading role in The Scarlet Pimpernel (1934), the classic espionage adventure of rescue set during the French Revolution. In the former movie, released just 2 years before Howard's shocking and untimely death at the hands of the Luftwaffe, Howard is Horatio Smith, an absent-minded archeology professor at Cambridge who recruits his students for a summer trip to Socialist Germany. From the very beginning of the film, it is utterly transparent that the professor leads a double life as a smuggler of human cargo out of the terrorist state, but Howard consistently sustains the film with his nonpareil blitheness and comical faux obliviousness in the company of Nazi officers. In the end, the film is nothing but shameless Allied propaganda,* complete with a heavy-handed, proselytizing monologue; but by God, Howard's unapologetic delivery at this point is truly energizing.

* Which is possibly why the Luftwaffe targeted Howard for death in 1943.

Poster for Pimpernel Smith, released as Mister V in the United States, from Wikipedia and reproduced under fair use law.

Two articles in this week's Neurology consider the significance of biomarkers for Alzheimer disease in the cognitively normal elderly.

Essentially confirming a recently published Mayo Clinic study, investigators from Texas reported the high prevalence of beta amyloid deposits (detected with Avid Pharmaceutical's PET tracer florbetapir) in the brains of a substantial portion (~20%) of healthy elderly subjects (aged 60 years or older). A high burden* of beta amyloid was associated with 1) the presence of the e4 allele of APOE, a genetic risk factor for AD and 2) poorer cognitive performance on more sophisticated** cognitive tests. The authors, two of whom receive financial support or have a financial interest in Avid Pharmaceuticals, suggest that "subtle cognitive changes accrue as amyloid progresses." The implication being that brain amyloid in the so-called healthy elderly may be more predictive than not about the risk of AD (an essential point or spin, if you will, which argues for the clinical utility of Avid's amyloid tracer). However, the authors also concede that "the relative contribution of amyloid vs other well-demonstrated predictors of cognitive aging (eg, regional atrophy, leukoaraiosis) is unclear." Among recommended follow-up studies is the assessment of the long-term consequences of amyloid deposition—ie, Are cognitively normal elderly with high amyloid burdens more like to development AD...that is, if they live long enough?. The question can only be answered with longitudinal follow-up study, which is planned.

Another multi-multi-authored international study assessed the effect of aging on the diagnostic value of CSF biomarkers for AD—specifically the triad of decreased amyloid and increased total and phosphorylated tau—in cognitively normal elderly. This study was distinctive in that, in addition to assessing individuals with AD and healthy elderly controls, a short (2-year) longitudinal assessment was made of subjects with mild cognitive impairment (MCI). The related conclusions (if I'm reading this article correctly and can recall anything useful about specificity, sensitivity, and positive and negative predictive values***) are 1) that there is substantial overlap in the biomarker distributions among these subgroups with advancing age and 2) that (therefore) the specificity of the biomarkers for ruling out AD decreases with age. Nevertheless, the sensitivity (85% cutoff) for the triad in MCI and AD, perhaps not too surprisingly, remained stable. In other words, the biomarker triad lost its strength to identify people with truly negative results as they aged (a decreased negative predictive value), but its ability to recognize truly AD-consistent findings (positive predictive value) remained stable—at least according to the authors and/or how I'm reading the study.

The overall conclusion, therefore, is that positive biomarkers for AD become less and less meaningful (as an indicator of AD) in the general elderly population—which is, ironically, the group in which these tests are most likely to be needed and used.

Addendum: Some would view these study results to mean that amyloid deposits and the triad of CSF changes are suggestive (or even indicative) of age-dependent cognitive dysfunction, albeit very subtle cognitive dysfunction. But the capacity of these tests to support or even confirm a diagnosis of clinical AD—depending on how we're defining the condition (there's the rub, isn't it?)—appears to be eroded in the older, general population (because they're more likely to demonstrate these findings, regardless of whether they demonstrate clinical meaningful cognitive dysfunction).

APOE = apolipoprotein E; SUVR = standardized uptake value ratio.

* At a mean SUVR cutoff of 1.22 or greater.
** Meaning more sophisticated than the Mini-Mental State Examination (MMSE).
*** Damn you, rudimentary biostatistics, when will you leave me alone!

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