QUALITY/POLICY/PHARMA: More on the costs of chemo

So the fight over cancer drug reimbursement is getting quite nasty. The doctors, who as we’ve explained in TCHB many times, have done very well over the last decade or so by dispensing drugs and charging Medicare and private payers a whopping margin, are crying foul as the details of the current price cutting by CMS emerge. Apparently they believe that the overall cut will be 15% as opposed to CMS’s stated 8%. There’s much more in this AP Article.

There’s actually some real money at stake here. About $600m is being cut from the chemo drug budget. ASCO claims 20,000 members but my mole in the business tells me that there are somewhere around 10,000 oncologists (or docs dispensing enough chemo to be counted as oncologists) in the US with an average income in the high-$300,000s of which roughly half comes from the drug mark-up. So you could argue that actually 30% of the doctors’ drug income (i.e. their margins rather than total drug spending) or around $60,000 per physician, is on the table. So expect the fight to continue, and of course have ramifications downstream on the pharma companies, and upstream on the patients.

Meanwhile, back on the subject of chemo, Harvey Fry writes concerning the post last week by Greg Pawelski on chemosensitivity testing.

I fought for chemo-sensitivity testing of cancers over 20 years ago, and finally lost because of the problems with the tests. First, it’s often hard to get a representative sample of tumor cells by biopsy. Then it’s hard to get them to grow. Then you’re not sure whether the cells that grew out are the tumor cells, or normal matrix, like fibroblasts. Then there’s the delay in starting treatment while waiting for the cells to grow out. Then there’s the question of whether cells in metastases have the same response as those in the primary. But the killer was that the clinical response was not that well predicted by the cell survival tests in the lab. And of course, there was the expense.

Unless there has been some major advance in the intervening years, I can understand the reluctance of some oncologists to go back to it. Alternatives to growing the cells and seeing what kills them may now exist, but they are only surrogates for the real end-point of interest.

Sidebar: I was struck by an amusing wrinkle in the end of the chemo article which showed how close the two sides are politically, even if they are fighting over money:

Ketchum Communications, the public relations company working with the cancer doctors to call for a change in the Medicare law, also is the principal contractor employed by the administration to promote that same law. The administration has spent $87 million on television ads, mailings and other means to promote the new law, most of it to tout prescription drug coverage that will be available through Medicare in 2006, the Health and Human Services Department said.

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  1. Medicare Coverage for Cell Culture Assay Test
    A genomic test can help to find out if a cancer patient will benefit from chemotherapy or not, and if they do (high risk patients), further pre-tests like cell culture assays can help see what treatments have the best opportunity of being successful. A cell culture assay measures the response of the tumor cells to drug exposure. Following this exposure, one of these assays measures both cell metabolism and cell morphology (Whole Cell Profiling). The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome.
    Cell culture assay technology has been clinically validated for the selection of optimal chemotherapy regimens for individual patients. It is a laboratory analysis based on tumor tissue profiling that uses fresh human tumor biopsy or surgical specimen to determine which drugs or combinations of chemotherapeutic agents have the highest likelihood of response for individual cancer patients.
    Individualized assay-directed therapy is based on the premise that each patient’s cancer cells are unique and therefore will respond differently to a given treatment. This is in stark contrast to standard or empiric therapy, which chemotherapy for a specific patient is based on average population studies from prior clinical trials.
    ASCO’s 2004 position paper focused on an older cell-growth assay method and not on a newer cell-death method, which is the most relevant biological measure. Their panel made no attempt to distinguish cell-death from cell-growth techniques. Their conclusions simply did not apply to cell-death assays. In fact, cell-death assay results have consistently correlated with response, time to progression, and overall survival.
    The ASCO paper focused solely on a lack of prospective, randomized clinical trials proving superior outcomes with assay-directed therapy, a standard not met by ER/PR testing, HER2 protein or gene analysis, or any other clinical test in cancer medicine, and has seldom been met by even the eimpiric chemotherapy treatments supported by ASCO. Were they to apply the standard measure of predictive test accuracy, the results of their analysis would have been much different and in favor of the use of cell-death assays in clinical practice.
    This omission was so significant that Medicare contractor, National Heritage Insurance Company (NHIC) which spent six months reviewing everything about the cell culture assay, including all of the ASCO arguments, and upon reviewing all available information, approved Medicare coverage for the tests as Oncologic in Vitro Chemoresponse Assays. They made the courageous decision to reverse trend and noted that the ASCO paper had failed the consider any of the many studies which support the predictive accuracy of cell death-based in vitro chemosensitivity testing.
    As part of this favorable coverage decision, NHIC carefully documented the historical progression of Medicare policy dating from the “colony assays” of the 1970’s to the noncoverage-National Coverage Decision regarding “stem cell” assays (1980), to the 1999 National Medicare Coverage Advisory Committee review, to the initial coverage by NHIC in the late 2000, to the present comprehensive review, culminating in this favorable Local Coverage Decision.
    The decision had been made that the assay is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. What is of particular significance is that they are finally abandoning the artificial distinction between “resistance” testing and “sensitivity” testing and are providing coverage for the whole FDA-approved kit.
    Cell cuture assay tests based on cell-death have proven very effective in identifying novel treatment combinations for a variety of cancers. It is unfortunate that ASCO had not carried out studies to assess the value of cell-death assays, because they can and do accurately predict clinical outcomes and define novel chemotherapeutic synergies. In many cases, these same tests have induced highly durable remissions in patients whom current medical literature have deemed otherwise hopeless.
    (Note) Medicare coverage is available for Chemosensitivity (Resistance) Testing for a tumor specimen from a Medicare patient obtained anywhere within the United States, but submitted for testing by one of the approved laboratories located within California.
    The payment provided will be sufficiently realistic that all Medicare patients for whom this testing is indicated will be able to get it with only the routine 20% co-payment, as Medi-gap insurance secondaries are mandated to provide payment for co-pays for Medicare-approved services.
    Fresh Tumor Cells
    These cellular-based pre-tests can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient by testing that patient’s “live” cancer cells. One gets more accurate information when using intact RNA isolated from “fresh” tissue than from using degraded RNA, which is present in paraffin-fixed tissue.
    A “fresh” sample tumor can be obtain from surgery or biopsy (Tru-cut needle biopsies). For newly diagnosed patients, the test is most reliable before a tumor has been exposed to chemotherapy. However, patients that have failed previous chemotherapy treatment, the test still can be done once a patient waits at least four weeks. A FDA-approved kit is obtained from the lab for the surgeon or pathologist.
    Reference: Various Bio-Assay Laboratories

  2. NCI’s Failure at assay-directed therapy
    NCI studies never determine if “fresh” tumor assays worked. All of the considerable literature which supports the use of these assays in patient management has been based on true “fresh” tumor (non-passaged) cell assays.
    Some years ago, NCI made an attempt to study “assay-directed” therapy of lung cancer. The study was a failure because it was done with established permanent cell lines (instead of fresh cells), which have been conclusively proven to have no predictive value at all with respect to the clinical activity spectrum. The result was a dismal 11% response.
    The NCI used “cell lines” because the major expertise of the investigators who carried out any study was in the creation of cancer cell lines, and they wanted to see if they could perform assays on these cell lines to use in patient therapy. The results showed they were able to test successfully only 22% of specimens received, including only 7% of primary lesions.
    This contrasts with a 75% overall success rate reported by earlier investigators who used the same assay system in “fresh” tumor and a routinely obtained >95% success rate using improved (cell death) methods available today.
    The NCI spent $15 million on a single-cell suspension “fresh” tumor assay with cell proliferation (cell growth) rather than cell death as an endpoint. When that didn’t work, they folded their hand and specifically discouraged future applications of cell culture testing in their grant and contract guidelines, dating from the late 1980’s. They never supported any drug development work based on primary cultures of three dimensional cell clusters with cell death endpoints, which very nicely recapitulate known disease specific activity endpoints.
    Then later, there were sophisticated programs to discover gene expression microarrays which predict for responsiveness to drug therapy. The NCI has a huge lab working on microarrays to look for patterns of mRNA and protein expression which are predictive of chemotherapy response. They spent 2 years trying to find patterns which correlated using the NCI’s various established ovarian “cell lines.”
    They thought they had something, but when they started to apply them to “fresh” tumor specimens, none of the results in the “cell lines” was applicable to the “fresh” tumors. Everything they worked out in the “cell lines” was not worth anything and they had to start over from square one.
    However, the limitations and non-applicability of the NCI efforts, failed to realize that the way to identify informative gene expression patterns is to have a “gold standard” and the (cell-death) cell culture assays are by far the most powerful, efficient, useful “gold standard” to have, adding the potential value of the assays to individualize cancer therapy.
    It was routine for the NCI to append statements to grant and contract initiative announcements that applications relating to cell culture assays were strongly discouraged. Dan Von Hoff published a paper around 1990 in which he stated that clinical trials of cell culture assays would never be supported. And the cooperative groups have utterly refused to do the studies. Why should they? Five times as much work for much less (financial) reward.
    There was an enormous amount of published, peer-reviewed research documenting the “accuracy” of cell culture assays. Scores of studies in thousands of patients. Based on both response and survival, but all of it excluded from the ASCO and insurance industry reviews. And it’s the only evidence existing to validate any other medical test used as an aid in drug selection.
    Disallow the introduction of published, peer-reviewed evidence documenting accuracy. While allowing the introduction of hearsay, unstated, undocumented, undescribed, unpublished, unpeer-reviewed non-evidence.
    And the fact that “proving” efficacy in one situation would do nothing to prove efficacy in any other situation. This is why the FDA demands clinical trials data showing efficacy for each and every indication relating to drugs.
    Let’s say a plan assay-directed clinical trial in relapsed NSCLC proves efficacy. All we prove is that it improves things for one small indication. Relapsed NSCLC, not ovarian cancer. And it gets worse. The year after the close of the study, two new drugs become available and the assay-directed clinical study only proves efficacy with the old drugs. It doesn’t prove efficacy involving the new and improved drugs. A constantly moving target. So then you say, just go out and get a grant to do another one.
    Sounds like the Twilight Zone!

  3. Public Interest Watch had called for a government investigation into ASCO, for the manipulative ways in which it had attempted to scuttle badly-needed reforms in this inherently corrupt system. An Associated Press account of maneuverings by ASCO in its attempts to preserve its lucrative chemotherapy concession, stated that Public Interest Watch called on the U.S. Department of Health and Human Services have a formal investigation of its contract with Ketchum Communications to promote reforms to Medicare.
    According to Associated Press, Ketchum was Health and Human Services principal contractor in its $87 million public campaign to gain acceptance of changes to Medicare. In its report, it also noted that Ketchum simultaneously was under contract with ASCO to scuttle some of the very changes Health and Human Services was paying it to promote.
    A Pulbic Interest Watch executive Lewis Fein stated, “Ketchum’s conduct in this matter appears to be so blatantly unethical that it defies explanation. It is literally working both sides of the same issue and millions of taxpayer dollars are being wasted.” Fein also noted, “We believe the American Society of Clinical Onoclogists is just as at fault as Ketchum. ASCO’s decision to retain Ketchum appears to be nothing more than a premeditated attempt to corrupt to legislative process and to waste millions in public funds in the process.”
    ASCO has run into trouble before in the course of its campaign against Medicare reform. In March 2004, the editorial board of the New York Times criticized “angry doctors” for terrorizing their patients” into believing that a reformed Medicare drug reimbursement plan would force them to turn cancer patients out to less convenient and less comfortable hospitals for chemotherapy treatment.
    A 2006 update report showed instilling that fear was unfounded:

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