Pharma: 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.

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.

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.