Recently in FDA Category
There's tremendous speculation on the pending outcome of phase 3 results with bapineuzumab, 1 of 2 anti-amyloid compounds in late-stage development for Alzheimer disease. The general buzz is that the monoclonal antibody won't perform tremendously well, given phase 2 results—specifically those indicating tepid efficacy and limited safety (particularly regarding vasogenic brain edema). But Elan chief executive Kelly Martin, whose company has a 25% stake in the drug (along with Pfizer and Janssen [ie, JNJ]), is doing what drug execs do: talking up the company's prospects vis-a-vis its pipeline. In this case, the prospects hinge mightily on bapineuzumab, the phase 3 results for which won't be publicly available until the "middle of the year," Martin confirms.
But there is other telegraphed information in Elan's latest public cheerleading for bapineuzumab. That is: the phase 3 results for the MAb won't be a clear home run, but that the compound may show some clinical benefit, however marginal. Elan's chairman, Robert Ingram, appears to predict FDA approval for bapineuzumab on the basis of 2 complementary forces: 1) increasing pressure on the agency to approve something for AD; and 2) the probability that company statisticians will be able to demonstrate some clinical benefit of the drug at least in some subset of AD patients (like those who aren't APOE e4 carriers).
The telling quote from the Elan chairman: "The FDA won't approve the drug if it doesn't have a single benefit but they are signalling that they will be very reasonable about getting something to patients that has a modicum of benefit [emphasis added]"
And this statement predicts a really unsatisfactory outcome for bapineuzumab's clinical development and, more importantly, the therapeutic prospects for patients with AD and their caregivers. That is: there won't be a clear-cut thumbs up or thumbs down for the MAb, because the efficacy and safety data won't allow a clear-cut thumbs up, and the backing companies and prevailing zeitgeist won't allow a clear-cut thumbs down. In other words, the drug, at best, may provide some benefit (however minimal or marginal) in AD (or more likely, a subset of AD patients) that may or may not outweigh safety concerns. And Elan, more or less, predicts that the FDA will be pressured to approved the iffy* drug, because there's no other disease-modifying** option on the market.
That's a disappointment all-around.
* And likely, very expensive.
** That is, putative disease-modifying option.
But there is other telegraphed information in Elan's latest public cheerleading for bapineuzumab. That is: the phase 3 results for the MAb won't be a clear home run, but that the compound may show some clinical benefit, however marginal. Elan's chairman, Robert Ingram, appears to predict FDA approval for bapineuzumab on the basis of 2 complementary forces: 1) increasing pressure on the agency to approve something for AD; and 2) the probability that company statisticians will be able to demonstrate some clinical benefit of the drug at least in some subset of AD patients (like those who aren't APOE e4 carriers).
The telling quote from the Elan chairman: "The FDA won't approve the drug if it doesn't have a single benefit but they are signalling that they will be very reasonable about getting something to patients that has a modicum of benefit [emphasis added]"
And this statement predicts a really unsatisfactory outcome for bapineuzumab's clinical development and, more importantly, the therapeutic prospects for patients with AD and their caregivers. That is: there won't be a clear-cut thumbs up or thumbs down for the MAb, because the efficacy and safety data won't allow a clear-cut thumbs up, and the backing companies and prevailing zeitgeist won't allow a clear-cut thumbs down. In other words, the drug, at best, may provide some benefit (however minimal or marginal) in AD (or more likely, a subset of AD patients) that may or may not outweigh safety concerns. And Elan, more or less, predicts that the FDA will be pressured to approved the iffy* drug, because there's no other disease-modifying** option on the market.
That's a disappointment all-around.
* And likely, very expensive.
** That is, putative disease-modifying option.
The FDA has revised its recommendations for cardiovascular monitoring after the initiation of Gilenya (fingolimod), Novartis's oral drug for relapsing-remitting MS. The new recommendations, which extend the post-dosage monitoring for bradycardia from 6 to 24 hours, are based on the report of a woman who died within a day after starting the drug. Although the cause of the woman's death was not determined, the agency reported that she was taking two antihypertensive medications, including the beta-blocker metoprolol. In addition, she had "extensive" MS lesions in her brainstem, which have been associated with sudden death.
On the basis of a post-hoc analysis of clinical-trial data, the FDA also concluded that the possible depressant effect of Gilenya on the heart rate is biphasic: There is an initial risk during the first 6 hours after the first dose and a second risk during hours 12-20. Therefore the agency believes that cardiac monitoring beyond 6 hours is warranted in patients whose heart rate falls below 45 bpm during the first 6 hours after the first dose.
Other reports of cardiovascular death in Gilenya-treated patients are being examined. However, the FDA cautions, "For each of these deaths, Gilenya’s contribution to the death was unclear. The number of deaths of apparent cardiovascular origin or of unknown origin does not appear to be higher than in MS patients not treated with Gilenya."
Regardless it seems prudent to consider the drug very carefully in MS patients with concomitant cardiovascular disease (especially arrhythmia) and particularly those patients taking beta-blockers or antiarrhythmics.
This morning, the FDA has finally stepped in and is warning healthcare professionals and MS patients alike about death and other injuries associated with the so-called "liberation procedure" (ugh), which amounts to either angioplasty or stenting of (typically) jugular veins. The procedure, which is ostensibly designed to promote the egress of blood flow from the brain, has no basis for use, because there is no confirmed link between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis. For background on this ever-vexing issue, start here.The FDA has received reports of associated adverse events, which include "death, stroke, detachment and migration of the stents, damage to the treated vein, blood clots, cranial nerve damage and abdominal bleeding." In February, the agency sent a letter to a NY vascular surgeon, warning of "objectionable conditions" and the lack of regulatory protocol and oversight for what amounts to an investigational (ie, non-FDA-approved) procedure.
Much to my disquiet, the FDA approved Amyvid (florbetapir), an amyloid imaging agent, late last Friday. The radiolabeled tag for amyloid-beta, which is intended to be used with PET scanning, latches onto the stuff of neuritic plaques in the brains of people with Alzheimer disease (AD) and shows up as bright red on color-coded images. Amyvid is the product of a Lilly subsidiary, Avid Radiopharmaceuticals. (In November 2010, Lilly bought Avid for $300 million, and will now
fork over another $500 million to Avid with approval of the amyloid tracer.)
Last March (meaning 13 months ago), the agency all but rejected Amyvid, after an advisory panel gave its unanimous recommendation for conditional approval in January of 2011. The FDA said that it wanted Avid/Lilly to establish a reader training program, because of potential problems with inconsistent interpretations among readers of Amyvid-enhanced PET images. The lack of inter-reader reliability with the tracer-enhanced PET images has been a major concern of the pharma watchdog group Public Citizen. Presumably the FDA was satisfied with Avid/Lilly's response to this issue.
Amyvid's package insert (found here) stipulates that use of the amyloid-imaging agent is intended to...
According to the WSJ, Amyvid will cost $1600 per dose, and various online sources indicate that the price of brain PET imaging ranges from $3000 to $6000. Moreover, there's no indication that Medicare will pay for or supplement the cost of new imaging agents for PET; although Lilly is reportedly hoping to change the relevant Medicare policy.
PET = positron emission tomography.
* Although more sophisticated neuropsychiatric tests may indicate small, but distinct, cognitive impairments in these people, according to a recent study.
** PIB has a substantially shorter half-life than Amyvid, and its use therefore requires an on-site PET-imaging facility. Amyvid, on the other hand, has a substantially longer half-life (~110 minutes), and can be administered at a site fairly remote from a PET scanner (to which the Amyvid-injected patient must be transported).
N.B.--Two other amyloid tracers are in late-phase clinical development: GE's flutemetamol and Bayer's florbetaben.
Last March (meaning 13 months ago), the agency all but rejected Amyvid, after an advisory panel gave its unanimous recommendation for conditional approval in January of 2011. The FDA said that it wanted Avid/Lilly to establish a reader training program, because of potential problems with inconsistent interpretations among readers of Amyvid-enhanced PET images. The lack of inter-reader reliability with the tracer-enhanced PET images has been a major concern of the pharma watchdog group Public Citizen. Presumably the FDA was satisfied with Avid/Lilly's response to this issue.
Amyvid's package insert (found here) stipulates that use of the amyloid-imaging agent is intended to...
...estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s Disease (AD) and other causes of cognitive decline. A negative Amyvid scan indicates sparse to no neuritic plaques, and is inconsistent with a neuropathological diagnosis of AD at the time of image acquisition; a negative scan result reduces the likelihood that a patient’s cognitive impairment is due to AD. A positive Amyvid scan indicates moderate to frequent amyloid neuritic plaques; neuropathological examination has shown this amount of amyloid neuritic plaque is present in patients with AD, but may also be present in patients with other types of neurologic conditions as well as older people with normal cognition. Amyvid is an adjunct to other diagnostic evaluations.In other words, clinical context is mandatory when using Amyvid-enhanced PET, particularly because of the high rate of brain amyloid in cognitively normal elderly (~30%). In some cases, the PET scans of elderly individuals with ostensibly normal cognition* are indistinguishable from those of patients with clinical AD. This fact and the associated caveat are stressed in a 2009 article by Rabinovici et al in the context of using a different, purely investigative amyloid tracer, 11C-Pittsburgh compound B (PIB).**
The high rate of PIB-positivity in normal controls underscores that a positive PIB scan cannot be interpreted without a careful clinical evaluation, and emphasizes that amyloid imaging alone must not serve as a surrogate for a clinical diagnosis of AD or dementia.Clinical utility aside, physicians and their patients will have to decide if the staggering cost of PET imaging is worth the marginally useful information that may be provided. The possible clinical scenarios—dementia with brain amyloid, dementia without brain amyloid—may help establish the presumptive clinical diagnosis: Alzheimer dementia or some other dementia type (eg, Pick's disease), respectively. But if treatment is not substantively altered, what's the point of 1) exposing a patient to a radiolabeled tracer, 2) requiring that a cognitively impaired patient be transported to the nearest PET imaging center, and 3) leaving a patient to deal with the enormous cost of the study?
According to the WSJ, Amyvid will cost $1600 per dose, and various online sources indicate that the price of brain PET imaging ranges from $3000 to $6000. Moreover, there's no indication that Medicare will pay for or supplement the cost of new imaging agents for PET; although Lilly is reportedly hoping to change the relevant Medicare policy.
PET = positron emission tomography.
* Although more sophisticated neuropsychiatric tests may indicate small, but distinct, cognitive impairments in these people, according to a recent study.
** PIB has a substantially shorter half-life than Amyvid, and its use therefore requires an on-site PET-imaging facility. Amyvid, on the other hand, has a substantially longer half-life (~110 minutes), and can be administered at a site fairly remote from a PET scanner (to which the Amyvid-injected patient must be transported).
N.B.--Two other amyloid tracers are in late-phase clinical development: GE's flutemetamol and Bayer's florbetaben.
And at least one questionable wholesaler, Thomas Houghton through his UK-based River East Supplies, appears to be involved in both the February and most recent transactions.
The WSJ traces the route of fake Avastin that cropped up in the United States in February:
The WSJ traces the route of fake Avastin that cropped up in the United States in February:
- Swiss drug wholesaler Hadicon AG ordered Avastin from an Egyptian company, Sawa—the legitimacy of which is questionable.
- An intermediary working for Sawa contacted a Syrian businessman, who located (the fake) Avastin in Istanbul, Turkey, from which the drug was shipped (through yet-another murky intermediary) to Hadicon.
- Hadicon then shipped the drug to a Danish wholesaler, CareMed Aps in Copenhagen, which passed it onto River East Supplies in Nottingham, England.
- River East Supplies then exported the drug to the United States through Montana Healthcare Solutions in Belgrade, Montana (which Houghton may have also owned). The fake Avastin was distributed to several oncologic practices (most of which are located in California or Texas) through Volunteer Distribution in Gainesboro, Tennessee.
In the latest case of fake Avastin (or really fake Altuzan) in the United States, the drug was imported again from Turkey (but this time from an unnamed or unknown source) to UK-based Richard's Pharma,* a licensed wholesaler. Richard's Pharma bought 120 packs of the counterfeit drug and exported 28 of these directly into America. The remaining 82 packs were sold to River East Supplies, which also exported the fake drug into the United States.
Not surprisingly wholesalers involved in both cases claim that they didn't know the peddled Avastin/Altuzan was fake. No matter: The FDA says that the importation of non-approved drugs into the United States is illegal.
From the FDA. The facts (ma'am):
- A counterfeit version of bevacizumab, disguised as Roche's Altuzan—a brand that is approved in Turkey but not the United States—was recently discovered.
- The product "contained no active ingredient," although the agency didn't reveal what it did contain.
- The product (along with "other unapproved products") was obtained from Richards Pharma, aka Richards Services, aka Warwick Healthcare Solutions, aka Ban Dune Marketing, Inc.
- The FDA implies that Richards Pharma is generally a bad actor and that none of its products should be trusted.
Image of packaging of fake Altuzan from FDA web site.
There may be no good guys in the questionable chain of international drug wholesalers that recently peddled fake Avastin. Yesterday the WSJ reported that the 2 managing directors of the Danish wholesaler ran afoul of local law in 2007 by illegally importing medicines into Denmark. Although the paper, citing the Danish National Board of Health, was not able to convey the particulars—eg, what medicine from what country.
Previous news reports imply that it was either the Danish wholesaler or the Swedish outfit that notified US authorities of the counterfeit Avastin, which then passed through a British wholesaler, River East Supplies, Ltd., before reaching the United States. Canadian Thomas Haughton reportedly manages a network of drug distributors, including River East Supplies, Ltd, as well as the US supplier of the fake drug, Montana Healthcare Solutions, which Haughton acquired in 2010 through a Barbados holding company. The Avastin-that-was-not-Avastin was then distributed by a Tennessee-based distributor to 19 medical practices, most of which are in California or Texas. It is unclear whether any cancer patient actually received the fake IV drug, which contained salt and starch (among other inactive ingredients).
The origin of the fake Avastin is also unclear. Named suspects include China, Egypt, and Turkey.
Previous news reports imply that it was either the Danish wholesaler or the Swedish outfit that notified US authorities of the counterfeit Avastin, which then passed through a British wholesaler, River East Supplies, Ltd., before reaching the United States. Canadian Thomas Haughton reportedly manages a network of drug distributors, including River East Supplies, Ltd, as well as the US supplier of the fake drug, Montana Healthcare Solutions, which Haughton acquired in 2010 through a Barbados holding company. The Avastin-that-was-not-Avastin was then distributed by a Tennessee-based distributor to 19 medical practices, most of which are in California or Texas. It is unclear whether any cancer patient actually received the fake IV drug, which contained salt and starch (among other inactive ingredients).
The origin of the fake Avastin is also unclear. Named suspects include China, Egypt, and Turkey.
The path of the fake Avastin that recently entered the United States is painfully complex and possibly a template for the terribly circuitous travel of questionable drugs throughout the globalized marketplace.
According to the latest coverage by the WSJ, the ersatz cancer drug—which possibly originated in China (where else, folks, where else?)—traveled through Turkey and Egypt before being sold by Swiss and/or Danish wholesalers to a UK-based wholesaler. From the UK, the phony vials were sold and imported into the US by a Canadian, Thomas Haughton, who lives in Barbados and manages a "network of drug distributors," including the UK wholesaler, River East Supplies, Ltd.
As well, Haughton owns or manages a Barbados-based holding company that acquired Montana Healthcare Solutions in 2010. Montana Healthcare Solutions, the reported contact for which is (or was) one Paul Bottomley in tiny Belgrade, sold the fake Avastin to 19 medical practices, most of which are in California. The drug was then shipped or distributed by the Tennessee-based Volunteer Distribution, the management of which is pretty damn sketchy.
The FDA is leading the necessarily complex federal investigation, but the US Attorney in Los Angeles is also issuing subpoenas to the California practices, writes the WSJ. The paper adds that Haughton had no idea that the Avastin was fake (despite the product's rock-bottom price). Furthermore Haughton "no longer does business with" the Tennessee distributor (although this end-of-the-line company, whatever it is, may be a mere scapegoat for the much-more globally connected Haughton).
Here's hoping that news sources like the WSJ stay on top of this developing story.
According to the latest coverage by the WSJ, the ersatz cancer drug—which possibly originated in China (where else, folks, where else?)—traveled through Turkey and Egypt before being sold by Swiss and/or Danish wholesalers to a UK-based wholesaler. From the UK, the phony vials were sold and imported into the US by a Canadian, Thomas Haughton, who lives in Barbados and manages a "network of drug distributors," including the UK wholesaler, River East Supplies, Ltd.
As well, Haughton owns or manages a Barbados-based holding company that acquired Montana Healthcare Solutions in 2010. Montana Healthcare Solutions, the reported contact for which is (or was) one Paul Bottomley in tiny Belgrade, sold the fake Avastin to 19 medical practices, most of which are in California. The drug was then shipped or distributed by the Tennessee-based Volunteer Distribution, the management of which is pretty damn sketchy.
The FDA is leading the necessarily complex federal investigation, but the US Attorney in Los Angeles is also issuing subpoenas to the California practices, writes the WSJ. The paper adds that Haughton had no idea that the Avastin was fake (despite the product's rock-bottom price). Furthermore Haughton "no longer does business with" the Tennessee distributor (although this end-of-the-line company, whatever it is, may be a mere scapegoat for the much-more globally connected Haughton).
Here's hoping that news sources like the WSJ stay on top of this developing story.
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.
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.
First Jeffrey Kindler, then Lipitor, and now this: Pfizer announced today that * Bloody hell.
