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Old 07-16-2010, 09:24 PM
gdpawel gdpawel is offline
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Default Caris Target Now Molecular Profiling Prolongs PFS In Some Cancer Patients

Caris Lifesciences is a private company which does so-called “molecular” profiling, based on immunohistochemistry, FISH, RT-PCR, and molecular microarrays.

"Caris' Target Now Molecular Tumor Profiling Prolongs Progression-Free Survival In Some Cancer Patients, Study Suggests"

Presented at the American Association of Cancer Research meeting in Denver, Colorado, was an interesting study by Daniel Von Hoff and associates of the Phoenix-based Translational Genomics Research Institute.

Sixty-six patients were treated at nine different U.S. medical centers. All of the patients had previously experienced growth of their tumors while undergoing as many as two to six prior cancer treatments, including conventional chemotherapy.

However, after molecular profiling identified precise targets, new treatments were administered that resulted in patients experiencing significant periods of time when there was no progression of their cancer.

“This clinical trial was unique because patients acted as their own control,” said Dr. Von Hoff. “We compared each patient’s progression-free survival, following treatment based on molecular profiling, to how their tumors progressed under their prior treatment regimens, before molecular profiling.”

In a significant number of patients, the targeted treatments provided significantly longer periods when tumors did not progress, or even shrunk, said Dr. Von Hoff, who also is a Medical Director of US Oncology and a former Director of the Arizona Cancer Center at the University of Arizona.

He said this clinical trial demonstrated the value of personalized medicine, in which treatments are prescribed based on an individual’s specific genetic makeup. The type of drugs, dosages, their delivery and other treatment aspects – all are based on each patient’s individual medical needs.

Among the patients, 27 percent had breast cancer, 17 percent had colorectal cancer, 8 percent had ovarian cancer and 48 percent had cancers that were classified as miscellaneous.

Patients experienced varying levels of improvement. Among those with breast cancer, the period of progression-free survival increased for 44 percent of patients; for colorectal, 36 percent of patients; for ovarian, 20 percent of patients; and for miscellaneous cancers the improvement was seen in 16 percent of patients.

The molecular profiling for this research study was performed by Caris Diagnostics (Caris Dx) in Phoenix.

These results are the first in a series of studies in support of Target Now™, a commercially-available oncology testing service offered exclusively by Caris Dx. Target Now uses molecular profiling techniques, including both DNA microarray and immunohistochemical (IHC) analysis, to provide individualized information about a patient’s tumor as an aid to the treating oncologist.

Abstract Number: LB-259

Session Title: Spotlight on Breakthroughs in Cancer Research

CME Designation: CME-Designated

Presentation Title: A pilot study utilizing molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers

Presentation: Monday, Apr 20, 2009

Location: Hall A, Colorado Convention Center

Author Block: Daniel D. Von Hoff, et al

Introduction: Unfortunately, the majority of patients with metastatic cancer eventually run out of treatment options for their tumors. This prospective study was designed to determine whether molecular profiling of patients’ tumors at this stage in their disease could provide any clinical benefit.

Methods: To be eligible, patients must have metastatic cancer and at least two prior lines of systemic therapy, have measurable or evaluable disease, have clear documentation of progression on their last treatment prior to study entry, and undergo or have available a tumor biopsy for molecular profiling. Patients’ tissue samples were submitted for molecular profiling in two formats, including formalin-fixed for immunohistochemistry assays and immediately frozen tissue for oligonucleotide microarray gene expression assays. The primary objective was to compare progression free survival (PFS) using a treatment regimen selected by molecular profiling with the PFS for the most recent regimen on which the patient progressed (i.e., patients were their own controls). The molecular profiling approach was deemed of clinical benefit for the individual patient who had a PFS ratio (PFS on molecular profiling selected therapy/PFS on prior therapy) of ≥1.3.

Results: Nine sites in the U.S. submitted tumor samples. Of 86 patients, 66 received treatment based on molecular profiling. The results of patients treated with a regimen selected by molecular profiling are outlined in Table 1 below.

Conclusion: This prospective study demonstrated that: a) it is possible to measure molecular targets in patients' tumors from nine different centers; and b) this approach may provide clinical benefit for some patients (provide a longer PFS treated by molecular profiling results than the PFS they had on their prior treatment regimen).

Table 1

Breast Colorectal Ovarian Miscellaneous
n (%) 18 (27%) 11 (17%) 5 (8%) 32 (48%)

n prior lines,
median
(range) 6 (2-13) 3 (1-4) 5 (3-13) 3 (1-9)

% pts with
documented
tumor
targets 100% 100% 100% 100%

Pts with PFS
ratio ≥ 1.3 7 (39%) 4 (36%) 1 (20%) 6 (19%)

Supported by a grant from the Stardust Foundation.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated.

Employment or Leadership Position: David M. Loesch, Caris Life Sciences (C); William Sutherland, AAIPharma (C); Arlet Alarcon, Caris Life Sciences (C); David Mallery, Caris Life Sciences (C); Robert Penny, Caris Life Sciences (C)

Consultant or Advisory Role: Daniel D. Von Hoff, Caris Life Sciences (C); Joseph J. Stephenson Jr, Caris Life Sciences (C); Peter Rosen, Caris Life Sciences (C); Stephen Anthony, Caris Life Sciences (C); Nina Cantafio, Caris Life Sciences (C); Robert Penny, Caris Life Sciences (C)

Stock Ownership: Daniel D. Von Hoff, Caris Life Sciences; Arlet Alarcon, Caris Life Sciences; David Mallery, Caris Life Sciences; Robert Penny, Caris Life Sciences, Mid America Clinical Laboratories Honoraria: Stephen Anthony, Caris Life Sciences

[url]http://jco.ascopubs.org/content/28/33/4877.long

Gene Expression In Cancer Regulated By Vast Hidden Network

[url]http://www.medicalnewstoday.com/releases/236059.php
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Last edited by gdpawel : 02-16-2014 at 01:38 AM. Reason: correct url address
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Old 09-04-2010, 09:22 AM
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Default Using Molecular Profiling to Find Potential Targets and Select Treatments

Pilot Study Using Molecular Profiling of Patients’ Tumors to Find Potential Targets and Select Treatments for Their Refractory Cancers

Daniel D. Von Hoff, Joseph J. Stephenson Jr, Peter Rosen, David M. Loesch, Mitesh J. Borad, Stephen Anthony, Gayle Jameson, Susan Brown, Nina Cantafio, Donald A. Richards, Tom R. Fitch, Ernesto Wasserman, Cristian Fernandez, Sylvan Green,† William Sutherland, Michael Bittner, Arlet Alarcon, David Mallery, and Robert Penny

Purpose

To compare the progression-free survival (PFS) using a treatment regimen selected by molecular profiling (MP) of a patient’s tumor with the PFS for the most recent regimen on which the patient had experienced progression (ie, patient as his own control).

Patients and Methods

Patients with refractory metastatic cancer had tissue samples submitted for MP in two formats including formalin-fixed tissue for immunohistochemistry and fluorescent in situ hybridization assays and immediately frozen tissue for oligonucleotide microarray (MA) gene expression assays (all performed in a Clinical Laboratory Improvement Amendments CLIA –certified laboratory). The MP approach was deemed of clinical benefit for the individual patient who had a PFS ratio (PFS on MP-selected therapy/PFS on prior therapy) of 1.3.

Results

In 86 patients who had MP attempted, there was a molecular target detected in 84 (98%). Sixty-six of the 84 patients were treated according to MP results. Eighteen (27%) of 66 patients had a PFS ratio of 1.3 (95% CI, 17% to 38%; one-sided, one-sample P.007). Therefore, the null hypothesis (that 15% of this patient population would have a PFS ratio of 1.3) was rejected.

Conclusion

It is possible to identify molecular targets in patients’ tumors from nine different centers across the United States. In 27% of patients, the MP approach resulted in a longer PFS on an MP-suggested regimen than on the regimen on which the patient had just experienced progression. Issues to be considered in interpretation of this study include limited prior experience with patients as their own controls as a study end point and overall patient attrition.

Source: J Clin Oncol 28:4877-4883. 2010 by American Society of Clinical Oncology

We are witness to a revolution in cancer therapeutics. Targeted therapies, named for their capacity to target specific tumor related features, are being developed and marketed at a rapid pace. Yet with an objective response rate of 10 percent (Von Hoff et al JCO, Nov 2011) reported for a gene array/IHC platform that attempted to select drugs for individual patients we have a long way to go before these tests will have meaningful clinical applications. - Robert Nagourney, M.D., Ph.D.

[url]http://robertanagourney.wordpress.com/?s=Von+Hoff
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Old 09-04-2010, 09:22 AM
gdpawel gdpawel is offline
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Default A grand total of three actual responses?

The molecular profiling for this research study was performed by Caris Diagnostics in Phoenix behind Dr. Dan Von Hoff and associates. Caris got a grand total of three actual responses (actual, significant tumor shrinkage) out of about 66 patients treated and close to 85 assayed. If any other assay-directed clinical trial did that badly, they'd have been out of work 20 years ago. However, they were able to do and publish an actual clinical trial, courtesy of a $5 million gift. You have to give them credit for their philanthropy.

The cell-based assay utilized by the recently defunct Oncotech was the EDR (extreme drug resistance) assay, a soft agarose tritiated thymidine assay, which is a direct descendent of the old original Salmon/Von Hoff Human Tumor Stem Cell or clonogenic assay of the late '70s/early '80s (Salmon, S. E., Hamburger, A. W., Soehnlen, B. S., et al. 1978. Quantitation of differential sensitivity of human tumor stem cells to anticancer drugs. N Engl J Med 298:1321–1327). This is the assay ASCO talks about in their infamous 2004 tech assessment of CSRAs (chemo senstivity and resistance assays). Over twenty year old material that had been discredited twenty years ago.

The so-called ASCO expert panel who did this tech assessment included only three investigators who had ever worked in the field of cell culture assay technology: Dan Von Hoff, Anne Hamburger and a German named Hanauske who worked with Von Hoff in San Antonio. All three were old-line "Human Tumor Stem Cell" (clonogenic) assay workers, who (along with Salmon) convinced the oncologic community that clonogenic assays were the only valid approach to chemosensitivity testing (no one had ever heard of apoptosis back then).

The newer studies of apoptosis occurred during the heyday of the oncogene discovery period in cancer research, where oncogene products were frequently found to be associated with cell growth and where cancer was most prominently considered to be a disease of disordered cell growth. In contrast, the concept of apoptosis (programmed cell death) had yet to become widely recognized. Also unrecognized were the concepts that cancer may be a disease of disordered apoptosis/cell death and that the mechanisms of action of most if not all available anticancer drugs may be mediated through apoptosis.

When problems with proliferation-based assays emerged, there was little enthusiasm for studying cell death as an alternative endpoint. These factors explain the abandonment of research into cell culture assays by American universities and cancer centers by the mid-80s. However, clinical laboratories began to offer cell culture assay with cell-death endpoints as a service to patients in the USA by the late 1980s, and studies of cell culture assays continued in Europe and Asia.

The clonogenic assay failed and it dragged down the whole field of inquiry along with it. So basically, the panel consisted of various oncologists who knew nothing about the technology and data, along with three proponents of a long-ago discredited approach which had nothing to do with the technologies (assays with cell-death endpoints), and with no one at all who understands anything at all about the newer technologies and published data pertaining to them.

In the tech assessments, the authors invented a brand new criterion for validating a laboratory test. The existing standard had always been the "accuracy" of the test. This is true for every single test used in cancer medicine, from estrogen receptors to bacterial culture and sensitivity testing (Kirby Bauer assays) to panels of immunohistochemical stains to diagnose and classify tumor to Her2/neu and CA-125 to MRI scans, CT scans, PET scans and on and on. Yet they never even attempted to review the voluminous literature which defined the "accuracy" of cell death assays, and instead restricted their analysis to a consideration of papers which tried to address the issue of whether the use of the assays actually improved patient outcomes. They lumped together the old and long abandoned technologies (clonogenic assay, subrenal capsule assay, etc.) with the cell death assays. And yet, even in their own review, there were five studies with cell death assays and patient outcomes that were improved in four of the five studies and one negative study wasn't even relevant, because the authors did their tests on subcultured cells (as opposed to "fresh" tumor cultures) and tested the cells in monolayers (as opposed to three dimensional cell clusters). They ignored all studies having to do with "accuracy," the criteria used in tech assessments of all previous laboratory and radiographic tests, and only included studies dealing with "efficacy," a standard never met by any laboratory or radiographic test.

Were they to have reviewed studies showing that the use of estrogen receptor improved treatment outcomes, they would have found no publications at all. Were they to have reviewed papers showing that the use of panels of immunohistochemical stains to subclassify tumors improved treatment outcomes, they would have found no publications at all. Were they to have reviewed studies showing that treatment outcomes were improved through the use of MRI scans or PET scans or CT scans to monitor growth and shrinkage of tumors (for the purpose of influencing the decision to continue the same chemotherapy or to change chemotherapy), as opposed to simply following patients with history, physical, simple plain radiographs, and simple lab tests, they would have found no publications at all.

A "valid" tech review would have started with the published "accuracy" of the tests, and would have included in excess of 2,000 published correlations, in all types of neoplasms from acute leukemia to breast cancer to ovarian cancer to colon cancer and so forth, every single one of which showed that patients treated with drugs "active" in the assays had significantly higher response rates than patients treated with drugs which were "inactive" in the assays. They would have noted a half dozen papers which also showed that patients treated with drugs "active" in the assays also enjoyed significantly longer survivals. They would have made note of the preliminary studies which supported the concept that the use of the assays influenced treatment decisions which resulted in superior outcomes. A "valid" technology assessment would have concluded that the weight of the available evidence supports the decisions of individual oncologists to make at least selective use of these assays in their clinical practices.

Chemosensitivity Testing: Lessons Learned

[url]http://robertanagourney.wordpress.com/2013/02/11/chemosensitivity-testing-lessons-learned/
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Last edited by gdpawel : 03-07-2013 at 05:41 PM. Reason: corrected url address
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Old 02-22-2011, 01:38 PM
gdpawel gdpawel is offline
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Default What is it that ASCO was saying?

Cell culture assays should not be used outside the confines of a clinical trial setting. The same people who maintain that assay-directed therapy should not be used until proven in prospective randomized clinical trials, are the same people whose entire careers are utterly dependent upon mega-trials funded by pharmaceutical companies (that, plus fees from speeches they give for these companies), are the same people who control the clinical trials system, the grant review study sections, and the journal editorial boards. Why else would they want this technology tested under the clinical trial setting?

Opponents of cell culture assay testing can blow all the smoke screens they want, but the fact is that every single time advocates for cell culture assays have been given fair consideration by an impartial, non-ASCO adjudication, the decision has been made that this testing is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. It is only when ASCO or the insurance industry has been appointed itself as the judge/jury/prosecutor/defense rolled into one and not invited input from all "relevant" parties that the decisions have been unfavorable.

Opponents of cell culture assays are insesently confused with the old "clonogenic" chemosensitivity assays, the one that Dan Von Hoff had been discredited long ago. When most academic oncologists refer to "chemosensitivity testing," they are virtually always referring to and thinking about the "human tumor stem cell" assay or "clonogenic" assay. Yet this technology hasn't been used by any private sector laboratory for more than twenty years. Nor has it ever been advocated the clonogenic assay as the best cell culture assay. But Von Hoff had tried to sell it, not within the confines of a clinical trial, but as a service to patients.

Flash forward. A study of Von Hoff and associates of the Phoenix-based Translational Genomics Research Institute was presented at the American Association of Cancer Research meeting in Denver, Colorado. Sixty-six patients were treated at nine different U.S. medical centers. All of the patients had previously experienced growth of their tumors while undergoing as many as two to six prior cancer treatments, including conventional chemotherapy.

However, after molecular profiling identified precise targets, new treatments were administered that resulted in patients experiencing significant periods of time when there was no progression of their cancer. This clinical trial was unique because patients acted as their own control. They compared each patient’s progression-free survival, following treatment based on molecular profiling, to how their tumors progressed under their prior treatment regimens, before molecular profiling.

The molecular profiling for this research study was performed by Caris Diagnostics in Phoenix. Patients eligible had to have (1) clear disease progression on prior therapy and (2) received at least two prior lines of systemic chemotherapy. “Success” was defined as a time to progression (TTP) or progression-free survival (PFS) of at least 30% longer than the TTP/PFS of the most immediate prior therapy. A total of 18 patients (of 66) achieved this 30% improvement in time to progression.

An interesting question is what percentage of cancer patients in general have increased times to progression with subsequent cycles of empiric chemotherapy, compared to the prior empiric therapy. An additional issue is the precision with which time to progression (TTP/PFS) with prior therapy was measured. With prospective clinical trials, using TTP/PFS as the primary endpoint, there is generally a protocol to standardize follow-up, with physical examination, laboratory tests, and radiographic tests being performed as standardized intervals, so that comparisons of TTP/PFS are meaningful.

There would appear to be a problem with utilizing “historical” TTP/PFS on patients enrolled from the general oncology community, in which there is no standardization regarding the methodology for determining disease progression or the intervals at which these measurements are taking place. Additionally, it was not known from what was presented in the abstract, whether or not there was “blinded” assessment of TTP/PFS by outside auditors, or whether “historical” TTP/PFS was assessed and reported by the referring oncologists who enrolled the patients onto the trial.

Using the patient as his/her own control using TTP/PFS as endpoint is a useful study design that could be used to assess predictive tests for drug selection when it is not possible to do a randomized trial or to provide a basis to start one. TTP/PFS inversion, ie longer TTP/PFS on treatment selected by test than the standard empirical treatment given just before would be a justified endpoint provided that TTP/PFS is accurately measured.

There may be some labs doing drug resistance testing in vitro that have sufficiently long experience and reasonably a large number of patient cases (considerably more than Von Hoff’s 66) that has been treated with assay-based therapy after progression on empirical standard. A proposal to show the effect of test selected therapy, i.e. a prospective trial in a number of tumor types at very high costs would be the ultimate proof of efficacy but will probably never be done.

In other words, the objective response rate was 10%. Median overall survival for the 66 patients treated with assay-directed therapy was 9.7 months versus the overall survival for all 106 patients of 5 months (but this included the patients who had progressive disease and deteriorated before any treatment at all could be given). The reason patients did not proceed to therapy was disease progression in 75%. Only 62% of all the accrued patients were treated. The drop out of 40 patients may have served to cull the most vigorous from the herd, introducing a bias for survival regardless of intervention.

So, in order to establish the merit of the genetic testing, they "invented" a new endpoint (i.e. a 30% increase in TTP over the most recent prior therapy). That is, if Dr No gave a patient rice gruel therapy and it provided a 3 day response, then CARIS genetic guided therapy needed only provide a 4 day response to show statistical significance. The 106 patient accrued had a whopping response rate of 5.6% by intent to treat with an objective response rate in the group of fully tested and treated patients of 10%.

Time to progression (TTP): a measure of time after a disease is diagnosed (or treated) until the disease starts to get worse.

Progression-free survival (PFS): the length of time during and after treatment in which a patient is living with a disease that does not get worse.

In the Annals of Oncology, it states that clinical investigators seem to be frequently using PFS and TTP interchangeably in cancer. Such use of terms may lead to confusion when results of different trials are compared.

The survival gain induced by chemotherapy is considered to be the time the tumor requires to return to a size similar to what existed before chemotherapy. In calculating survival gained by tumor shrinkage, it is approximately 2 months in 50% reduction, 3 and a half months in 75% reduction and 1 year in 99% reduction. The data indicate that in cases evaluated with reduction rates more than 90%, there may be a significant correlation between response rate and survival.

Clinical trials virtually always have time to disease progression as a primary endpoint. Without imaging studies, one can't get accurate time to progression data. So tests are performed for the benefit of drug companies seeking new drug approval, for clinical investigators seeking contracts and publications, and for clinicians seeking an easy way to make clinical decisions.

Functional profiling techniques have consistently correlated with response, time to progression, and overall survival.
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Last edited by gdpawel : 04-08-2011 at 11:02 AM. Reason: consolidate
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Old 01-29-2012, 07:55 AM
gdpawel gdpawel is offline
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Default Patients May Die When Doctors Moonlight as Big Pharma's "Key Opinion Leaders"

As the crimson sun slipped into the gray Pacific Ocean, a multibillion-dollar drug deal took shape. A group of board-certified doctors greeted each other in a private room at a luxury hotel in California. The oncologists were big buyers of an anti-anemia drug called Procrit, sold by Ortho Biotech, a Johnson & Johnson (J&J) division. That Friday evening, the company toasted its top clients and their wives with bottles of Beaujolais, porterhouse steaks and free weekend accommodations.

The event could have been just another "grin and grip" affair, but there was a catch: J&J wanted to pump the sales of its biotech drug to beat its rival Amgen and its anti-anemia drugs. "The idea," as J&J drug rep Dean McClellan later explained, "was to get the docs to increase their Procrit dosage to 40,000 units."

There was just one problem. Regulators had approved a weekly drug dose of 30,000 units, and J&J was prohibited by the Food, Drug, and Cosmetic Act (FDAC) from marketing its drugs in unapproved ways. But the doctors could prescribe in any "off-label" manner they wanted. So, McClellan, a star rep and medical consigliere, led a "discussion" about high-dose experiments. Taking his cue, one physician explained how he routinely injected patients with 40,000 units of Procrit. Another oncologist pumped his people with 10,000 units for ten consecutive days - triple the approved amount. "That seems a little extreme," said McClellan, frowning.

"Oh no," the doctor said. "I haven't seen any side effects so far."

A few months later, Procrit sales hit the $1 billion mark, beating Amgen by a hair. The resort trip had certainly helped. But it was just one part of an expansive, long-running off-label marketing campaign, according to sales documents. Slowly but surely, oncologists around the country began administering so many high Procrit doses that, in time, the off-label therapy became the "community standard."

There were problems since insurers don't always reimburse doctors for off-label use. In fact, when Medicare refused to pay the Arizona Cancer Center, a huge client, for its high-dose Procrit injections, an Ortho manager ghost wrote a letter on behalf of its chief oncologist Daniel Von Hoff. After a few more company calls - ipso presto! - the center began receiving more than $1 million in Medicare payments for the illegal therapy. As McClellan claimed in a whistleblowing suit, the cancer market grew so saturated with high doses, that six years later the Food and Drug Administration finally approved them.

The decision might have been defensible had the 40,000-unit regime had been proven to be safe and effective. But independent research later revealed that cancer patients died sooner than expected, and company trials found an alarming number of dialysis patients suffered strokes and heart attacks. Meta-studies showed that 17 percent of patients died from the drug, and stories told of blood counts so high, patients actually spit up blood and choked on their own tumors. Turns out there was little scientific evidence that Procrit, and its cousins Epogen and Aranesp, actually helped people at any dosage.

Last summer, regulators announced that the drugs should be avoided entirely by most patients. "It turns out many people are better off taking placebos," said Dennis Cotter, president of Medical Technology and Practice Patterns, a nonprofit research institute.

What this illustrates is that drug companies can create entire cultures of over-prescribers for untested, even fatal indications, and that doctors can be easily corrupted. In light of a flurry of recent federal settlements for off-label marketing crimes, it also underlines how you, dear taxpayer, foot the bill for reckless marketing.

In the case of Procrit, the J&J unit formed advisory committees made up of academic physicians and clinical oncologists. These key opinion leaders (KOLs) were paid honoraria of at least $1,000 for every speech they delivered touting off-label use. McClellan selected some pliant clients to be the featured speakers. "Some guys wanted to give three or four speeches a weekend so they can get three or four thousand dollars," he said. A few actually did. Many talks were delivered at company "conferences" organized for other doctors, who earned hourly credits toward their annual continuing medical education (CME) units, required by state licensing boards. As if that wasn't enough, Ortho also paid physicians for their rooms, meals and transportation.

Ortho eventually assembled boards of KOLs who specialized in every type of cancer. According to sales documents, the goal was "to build thought leader endorsement [sic] to establish Procrit as standard of care," not just for approved indications such as AIDs and chemotherapy, but for cancer-related fatigue, depression, and other off-label indications.

These friendly prescribers were not Dr. Feelgood types working the tenderloin. They were distinguished professors from respected institutions such as John Hopkins University, Harvard Medical School, University of Chicago, Memorial Sloan-Kettering Cancer Center, Emory University Hospital, Cornell University, Long Island Jewish Medical Center, University of Texas MD Anderson Cancer Center, and others. Dr. Nicholas J. Vogelzang of the University of Chicago was a paid spokesman for the Fatigue Coalition, a group bankrolled by Ortho. Dr. John Glaspy of UCLA penned a seminal article in the Journal of Clinical Oncology that drew rosy conclusions about high-dose Ortho-sponsored studies.

Dozens of other doctors agreed to "influence their colleagues to use Procrit" for unapproved indications such as cancer-related fatigue. One was Dr. von Hoff, the director at the Arizona Cancer Center. He collected advisory fees and perks from not just Ortho, but from about 30 other pharmaceutical firms, earning directors' fees for sitting on several companies' boards. "When I saw how many shares he owned in biotech and drug firms, my jaw dropped," McClellan later said. Many others, like Dr. Jerome Groopman of Harvard Medical School, performed J&J-funded clinical trials. He was paid to sit on Procrit's "fatigue" advisory board and was quoted often in The New York Times extolling the drug, according to public records.

Groopman also penned a bestseller called "How Doctors Think." In it, he talks about the importance of talking with patients about their diagnosis and treatments. But Groopman doesn't explain what role Big Pharma checks and trips play in his own decision making. This is noteworthy since he goes on about the influence of high-pressure drug reps and the need for physicians to weigh scientific assessments against "going with your gut."

Clearly, even esteemed doctors were swayed by Procrit's marketers. In reviewing the basic science research behind these costly anti-anemia drugs, Dr. Charles Bennett of Northwestern University found that physicians and investigators who collected money from the two drug makers were "less likely to criticize the safety, effectiveness, or cost-effectiveness of drugs" and "more likely to endorse novel and less proven treatments" like off-label. No matter what prescribers say, they seem to have indeed been bought by golf trips, grants and banquets.

The overprescribing of anti-anemia drugs roared alongside an astonishing rise in American health care expenses. For several years, Procrit and the others topped Medicare's reimbursement list. By 2007, the drugs' domestic sales approached $11 billion a year. So far, US taxpayers have shelled out more than $60 billion over the past 20 years, reimbursing doctors, KOLs and hospitals for a drug that never worked as advertised.

McClellan's whistleblowing case may be in limbo. But many prestigious doctors will soon wind up in the confessional. Thanks to the Physician Payments Sunshine Act, doctors who accept speaking fees, meals, travel, stock options, or any other compensation from drug or medical device companies will soon see their names - and their gifts - revealed publicly on the web. The rule is part of the Patient Protection and Affordable Care Act, aka "Obamacare." Data collection was supposed to begin this January, but the first report won't appear until March 31, 2013. When that day dawns, patients will gain some insight into their treatments. Was that off-label prescription supported by scientific evidence; or did my doctor "go with his gut?" If so, how often was that gut filled by the maker of my medication?

From Kathleen Sharp's book, "Blood Feud: The Man Who Blew the Whistle on One of the Deadliest Prescription Drugs Ever."
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Old 02-02-2012, 07:53 AM
gdpawel gdpawel is offline
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Default Nuclear Explosion for Clinical Oncology

"Dozens of other doctors agreed to 'influence their colleagues to use Procrit' for unapproved indications such as cancer-related fatigue. One was Dr. Von Hoff, the director at the Arizona Cancer Center. He collected advisory fees and perks from not just Ortho, but from about 30 other pharmaceutical firms, earning directors' fees for sitting on several companies' boards. 'When I saw how many shares he owned in biotech and drug firms, my jaw dropped,' McClellan later said. Many others, like Dr. Jerome Groopman of Harvard Medical School, performed J&J-funded clinical trials. He was paid to sit on Procrit's 'fatigue' advisory board and was quoted often in The New York Times extolling the drug, according to public records."

In 2010, Dan Von Hoff got the Karnofsky award from the American Society of Clinical Oncology (ASCO), which is sort of a lifetime achievement award for clinical research. This is a nuclear explosion for clinical oncology. I'm wondering who was involved in the Harvard side of it? Interestingly, it is the highest levels of academia who are most tainted. One in particular, Dan Von Hoff. These ivory tower docs were the culprits. Unfortunately, this will probably play out as one more cudgel to beat the more reasonable and gentle practitioners, who either largely avoided such abuse or were led down the path by the scholars, who will themselves skip out unfazed.

As Dr. George Lundberg at MedPage Today puts it, if you would like to learn how two megapharma companies diligently and successfully strove to make megabucks by marketing a product that had the potential to kill thousands of unsuspecting people, the Blood Feud, written by Kathleen Sharp, may be the book for you. It was reissued in paperback in 2012 as Blood Medicine.

If you want to learn how individual physicians, groups of physicians, and many hospitals took large amounts of money in bribes, kickbacks, and similar financial schemes to prescribe and administer EPO for deeply questionable reasons, then Blood Feud (Blood Medicine) is the book for you.

If you want to understand how CME has been used as a pillar of pharma marketing and may well have led you, the physician, astray, then Blood Feud (Blood Medicine) is the book for you.

If you want to learn about scientifically shoddy clinical trials performed for marketing purposes and published by allegedly reputable medical journals, Blood Feud (Blood Medicine) is the book for you.

I'd you want to learn how harmful off-label prescribing based on illegal off-label marketing can be, then Blood Feud (Blood Medicine) is the book for you.

If you like riveting detail in which NONE of the names, places, or dates has been changed to protect the innocent or the guilty, then Blood Feud (Blood Medicine) is the book for you.

And if you want to boil your blood by learning of nefarious activities known, unprosecuted, and still ongoing, then Blood Feud (Blood Medicine) is the book for you.

Disclosing conflict of interest: two pieces in TheScientist.com

Off-Label Drug Disclosure Inadequate

Some 85 percent of researchers involved in promoting off-label drug use do not adequately disclose financial conflicts of interest in published articles.

[url]http://the-scientist.com/2012/08/07/off-label-drug-disclosure-inadequate/

Opinion: Bias Is Unavoidable

Simply disclosing conflicts of interest is not enough.

[url]http://the-scientist.com/2012/08/07/opinion-bias-is-unavoidable/

A Key Opinion Leader (KOL)

Jonathan Leo, Ph.D. and Jeffrey Lacasse, Ph.D.

Their articles on ghostwriting have appeared in PLoS Medicine, The Chronicle of Higher Education, Scientific American, Science, Nature, and Society

One of the hidden secrets of medical literature is that the named authors on a paper’s byline, particularly in the case of clinical trials, are not necessarily the individuals who wrote the paper. It is not uncommon for pharmaceutical companies, or medical product manufacturers, to write their own papers and then find university professors to agree to be the named authors of the paper. The company employees are then invisible to the readers. Presumably, the suggestion that a certain medication or medical product is safe and efficacious will carry more weight if it comes from an unbiased source, often called a Key Opinion Leader (KOL), rather than a company representative. With ghostwritten papers it is hard to know where to draw the line between science and marketing. Because of its secretive nature, the true extent of this practice is unknown. What will probably surprise much of the general public, and many members of the media, is that the medical community has not called for an outright ban on ghostwriting. Rather than forbid the practice outright, some in the medical community seem to be trying to develop policies that will allow papers to be published with invisible authors, but that won’t be labeled as “ghostwritten.”

When should a paper be considered ghostwritten? In any other segment of academia, or even in popular literature, this is a fairly straightforward question, answered by simply examining the byline. If the paper’s byline has an “invisible author” (a ghost), then the paper should be considered ghostwritten. However, when charges of ghostwriting appear about a medical paper there are all sorts of reasons given why the paper should not be considered ghostwritten. The defenses are endlessly creative and include such notions as: the paper was accurate, the “named” authors signed off on the paper, the paper was peer-reviewed, the person who wrote the first draft is thanked in the acknowledgement section, or… the list goes on. These defenses are not just espoused by companies but are often put forth by university administrators. It seems slightly paternalistic to tell the readers of a paper that they shouldn’t bother themselves with concerns about who actually wrote the paper, because higher powers have determined that the paper is accurate, or that the “named” authors have signed off on it, or that the “named” authors are good scientists. If the second line of a paper - the byline usually follows the title - is not accurate, why should anyone trust the rest of the paper?

In our view there are three simple steps for finding ghosts. Step one is to examine the internal company documents to see who made significant contributions to the paper. Step two is to open up the published paper and see who is on the byline. Step three is to see if the byline has omitted some of those individuals who made significant contributions. In many cases of ghostwriting there are other issues such as excessive conflicts of interests or the accuracy of the paper, but these are peripheral issues and do not play a role in determining if the paper was ghostwritten. Also immaterial to the ghostwriting charge is whether the named authors deserve to be on the byline. Granted, honorary authorship and ghostwriting often go together but they are not the same thing. The named authors might certainly deserve to be on the byline, but the question about ghostwriting concerns unnamed authors – people who should have been on the byline but are not present. Since in most cases the internal company documents about how a paper was developed are not available, the process of detecting ghosts can only be done a limited basis, and is reserved for those cases when court proceedings or Freedom of Information Act Requests have made the documents publicly available.

Ghostwriting is neither rare nor insignificant. Virtually every single blockbuster medication has been tainted by charges of ghostwriting and some of these medications have had significant negative effects on public health. Unfortunately, until medical schools and journals make it absolutely clear that the bylines on medical papers should be accurate, readers should realize that the papers they are reading might be written by company employees. There is no reason that companies and university professors shouldn’t work together. But when they collaborate on papers just call an author an “author.” It impossible to know the true prevalence of ghostwritten papers. Some have suggested that it is close to 100% for clinical trials in certain fields. If the academic community cannot agree on the simple premise that a paper with invisible authors on the byline should be labeled as ghostwritten, then efforts to curb the practice will be difficult.
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Last edited by gdpawel : 05-16-2013 at 04:52 PM. Reason: corrected url address
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Old 02-06-2012, 09:07 PM
gdpawel gdpawel is offline
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Default Caris Diagnostics Announces Name Change to Miraca Life Sciences

Tokyo, Japan & Irving, Texas, February 3, 2012 - Caris Diagnostics, specializing in anatomic pathology services, announced a company name change to Miraca Life Sciences, Inc., following its November 2011 acquisition by Tokyo-based Miraca Holdings Inc., Japan’s largest clinical diagnostics and laboratory testing service provider. The name change, which is effective February 20, 2012, follows a successful integration process and will be reflected in all marketing and communications.

“The new name is a logical step as we complete the successful ownership transition of this world-class diagnostics organization,” said Takeo Hayashi, Chairman and CEO of the newly-named Miraca Life Sciences. “While the name has changed, the fundamental value proposition has not: a unique, high quality pathology practice with an abiding commitment to diagnostic excellence and improved patient care.”

The word “Miraca” is a combination of the Japanese words “future” and “science,” so the new corporate name is a natural fit for the company’s mission and Miraca’s global network of employees, clinicians and patients.

Miraca Life Sciences specializes in the development and commercialization of anatomic pathology services, primarily in the fields of dermatopathology, hematopathology, gastrointestinal pathology and urologic pathology. The company’s core team of more than 70 specialists utilize pathology laboratories currently headquartered in Irving, TX and throughout the United States.

With group net sales of ¥165.7 billion (FYE 3/2010), Miraca Holdings, a Japan-based holding company in the healthcare sector listed on the Tokyo Stock Exchange, is engaged in the business consisting of three segments: (i) development, manufacture, and commercialization of in vitro diagnostics, (ii) clinical laboratory testing, and (iii) other healthcare related businesses, which are conducted by its subsidiaries and affiliates including Fujirebio Inc., a supplier of in vitro diagnostics in Japan, and SRL, Inc. (“SRL”), Japan’s largest commercial laboratory. SRL offers clinical laboratory testing services to medical institutes throughout the nation, ranging from general testing to esoteric testing, including gene-based tests.

Source: Perry Street Communications
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Old 01-02-2014, 02:59 PM
gdpawel gdpawel is offline
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Default United States vs Caris Life Sciences, Caris Diagnostics, Miraca Life Sciences

It is familiar and makes me somewhat feel slightly ill, but it was refreshing to see that action is being taken. Just a note, however, that the fraud was not discovered by CMS but instead the case derived its impetus from the persistence of two (justifiably) disgruntled former employees. I suspect that many companies are just one disgruntled employee away from facing a similar experience. In this case, except for the monumental stupidity that these complainants' superiors evinced in ineptly dealing with their employees, the violations likely would never have been detected by CMS.

[url]http://pathologyblawg.com/wp-content/uploads/2013/07/Caris-Amended-Complaint.pdf
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