Recently in Oncology Category

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:

1. Swiss drug wholesaler Hadicon AG ordered Avastin from an Egyptian company, Sawa—the legitimacy of which is questionable.
2. 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.
3. Hadicon then shipped the drug to a Danish wholesaler, CareMed Aps in Copenhagen, which passed it onto River East Supplies in Nottingham, England.
4. 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.

* AKA Richards Pharma, Richards Services, Warwick Healthcare Solutions, or Ban Dune Marketing, Inc, according to the FDA.

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.

The WSJ provides essential background on the story, including recent federal convictions of a former owner and an employee of Ban Dune Marketing for selling adulterated anti-cancer drugs (eg, Herceptin, Rituxan). These dubious drugs also reportedly bore tell-tale Turkish labeling. At least one Missouri oncologist who bought the fake drugs administered them to patients. Like the Ban Dune associates, the doctor pleaded guilty in February (specifically to ordering a drug that isn't FDA approved).

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.

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.

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.

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.

This time from the NEJM.

Multiple authors, lead by disgraced, former Duke geneticist Anil Potti, retracted their 2006 article, "A Genomic Strategy to Refine Prognosis in Early-Stage Non–Small-Cell Lung Cancer." (For background, start here.) The authors (all of them) wrote in a nearly inconspicuous letter to the editor that they had "tried and failed to reproduce results supporting the validation of the lung metagene model described in the article." Deep regret was expressed for "the effect of this action on the work of other investigators," but regret for any patients who enrolled in clinical trials on the basis of the unreproducible work was not mentioned.

This is now the fourth Potti-authored article to be retracted since the veracity of Potti's work was called into serious question last year in The Cancer Letter.

1. A 2007 article in the Journal of Oncology was retracted in December of last year.
2. A 2006 Nature Medicine article was pulled in January.
3. And, on the basis of this action, a 2007 article in the Lancet Oncology was retracted, also in January.

The Duke Chronicle reports that the NEJM retraction is "somewhat unexpected," because a journal spokesperson told the web site Retraction Watch in January that there were no plans to pull the article.

Today's PubMed search reveals that "A Potti" is coauthor on 128 returned articles, beginning in 2000, and first author on 33 articles—including 2 of the 4 retracted articles. The Potti-authored articles include a self-promoting piece in an April 2010 issue of Science Translational Medicine, in which Potti (along with Richard Schilsky of the University of Chicago and Joseph Nevins, Potti's Duke mentor) wrote "that it is now imperative that future clinical trials be designed with a plan to incorporate biomarker development."

Photo of Anil Potti, formerly from Duke's ISGP web site.

Today's Duke Chronicle reports the retraction of yet another article by geneticist Anil Potti. (For important story background, go here, here, and here.) On Friday, editors of The Lancet Oncology and the article's European coauthors justified their retraction of "Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy," expressing "concern over the validity of the results."

They continued: 

The chemotherapy sensitivity predictions reported in the Article were based on an approach described by Anil Potti and colleagues in Nature Medicine. Re-examination of the validation datasets used for the Nature Medicine study has uncovered errors in the labeling of the clinical response in some of the datasets. Reanalysis of the predictive accuracy with correctly labeled data has shown that in two instances the reported signatures do not predict the response of the validation samples to chemotherapy.

In other words, the article was retracted because the results were founded on the flawed (ie, mislabeled) data from another retracted article by Potti et al (in Nature Medicine). An investigation into the validity of the Lancet Oncology article was begun last October, when editor David Collingridge relayed an "expression of concern" from 15 European investigators who were coauthors with Potti and 3 other Duke researchers. After a damning report in July from biostatisticians at M. D. Anderson about data-labeling errors in another article by Potti et al, the Lancet Oncology coauthors repeatedly attempted to contact their Duke colleagues, but they were ignored, wrote Collingridge.

This is the third article by Potti to be retracted since his work was called into serious question last year. A 2007 article in the Journal of Oncology was retracted in December, and the Nature Medicine article was pulled this month. In October, Collingridge also revealed that "a large group of scientists" wrote to NCI director Harold Varmus on July 19th, expressing their concerns about the validity of a) Potti's cancer-treatment prediction models and b) 3 clinical trials that were based on these prediction models.

On a related note, Friday's The Cancer Letter (subscription required), by way of The Great Beyond Blog, reveals that FDA auditors have visited Duke to determine if the university obtained proper approval for 3 cancer trials, which were based on the demonstrably flawed work of geneticist Anil Potti.  At issue, from the agency's standpoint, is whether Duke obtained an Investigational Device Exemption (IDE), which was necessary because genomic chips were used to identify genetic biomarkers on which treatments was based.* There was evidently some confusion at Duke about whether an IDE was needed.

* The trials used Potti's (mislabeled) data to determine what anticancer drugs or combination of drugs cancer patients would receive on the basis of genetic biomarkers.

Responding to a charge by some House Republicans that the FDA considered cost in its decision to pull Avastin's indication for breast cancer, the agency's oncology director says that drug price was not considered. Dr. Richard Pazdur responded, according to today's WSJ, 

We made the decision because the drug has a marginal effect on tumor growth in breast cancer and in light of Avastin's severe side effects, the risks outweigh the limited benefit.

Pazdur cited "issues" and "problems" with a pivotal study, E2100, which showed that Avastin (with paclitaxel) delays the growth of advanced breast cancer for 5 months. Not surprisingly, drugmaker Genentech, a subsidiary of Roche, rejects the FDA's view of the controversial study and its results. But follow-up studies failed to confirm the favorable results of E2100, reports the WSJ. Some insurance companies, acting independently of the FDA, have already denied coverage for the use of Avastin in metastatic breast cancer.

For the full story go here. For background, go here.

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

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

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

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

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

And

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

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

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

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

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

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