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QUALITY/PHARMA: Chemosensitivity Testing and its relation to the Chemotherapy Drug Concession, by Greg Pawelski

Contributor Gregory Pawelski is back with another look at the chemotherapy market. He’s writing about a wrinkle in the use of chemo drugs that has some big implications. The Sept 1 Press release at this site has the science behind the issue. I’m in no position to judge any of the science being disputed, but the implications for pharma, Medicare, insurers, the taxpayer and oncologists are obvious.

Without information provided by Chemosensitivity Testing (assay-testing), oncologists have the freedom to choose between a multiple of different drug regimens, all of which have approximately the same probability of working. Some of these regimens are highly profitable to oncologists. Other regimens are much less profitable. Assay-testing takes away a lot of this freedom to choose and narrows the selection to those drugs that have the highest probability to be successful but may have lower profitability for the oncologist. This cuts into the oncologist’s bottom line, though it benefits the patient.

Many of these less profitable regimens are oral-dose. As I reiterated in my previous article in office-based oncology practices the core activity in medical oncology is the provision of infusional chemotherapy. The entire structure of the practice revolves around this activity and is what distinguishes medical oncology from most other specialties.

The new Medicare bill offered patients benefits they did not have before. There is now “some” coverage for oral-chemotherapy drugs, which were not available before. Since April of this year, $200 million was available so that some Medicare cancer patients would have transitional coverage for these drugs, until the bill goes into full effect in 2006. Providing some compensation for oral-chemotherapy drugs was a major emphasis for a number of cancer support groups. Although some benefit was realized, more might have been achieved if ASCO (American Society of Clincial Oncology) and other groups had lobbied as much for the oral-chemotherapy drug issue as they did for office-practice expense reimbursement.

ASCO fought long and hard to retain the Chemotherapy Drug Concession and never once suggested the need for a clinical trial to show when drugs were selected with and without the presence of profit differential (which included oral-dose drugs), clinical outcomes would be the same. It is a real credit to oncologists who utilize assay-testing in their management of their cancer patients, despite the fact that their use constrained their freedom to choose and doubtlessly reduced their incomes.

Take an example of ovarian cancer. After 25 years of prospective, randomized clinical trials to identify the best treatments to give to the average patient, there has been absolutely no progress. A meta-analysis of all trials showed that there was no difference. During those 25 years, Taxol came along. Two large clinical trials showed that Taxol/Platinum combinations were better than single platinum regimen. And Taxol became one of the most remunerative cancer drugs of all time. So Taxol/Platinum became “standard” therapy.

But then two more very large trials were done, showing that there was no advantage to giving Taxol/Platinum over single agent platinum (like Carboplatin). And Taxol/Platinum also wasn’t any better than another non-Taxol combination (not previously tested against Taxol/Platinum). But Taxol/Platinum remained “standard” therapy. Now that Taxol is going off patent, some academic oncology groups have (as their major ovarian cancer project) clinical trials to show that Platinum/Taxotere (a drug like Taxol, but still on patent) can now be the new “standard” therapy.

All the while doing this, ASCO is refusing to suggest clinical trials of “cell death endpoint” chemosensitivity testing, because, lacking something patentable or proprietary, all assay-testing laboratories can offer is free assays and not the millions of dollars that someone like Bristol-Myers-Squibb can offer to push its Taxotere trials.

The present system exists to serve the clinical investigators and the clinical oncologists, but not to serve the best interests of the cancer patients. I think it is time to set aside empiric one-size-fits-all treatment in favor of recognizing that breast, lung, ovarian and other forms of cancer represent heterogenous diseases, where the tumors of different patients have different responses to chemotherapy. It requires individualized treatment based on testing the individual properties of each patient’s cancer.

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  1. The best work in Cell Culture Assays with “cell death” endpoints for the last 24 years has been in the area of what is referred to as Cell Culture Drug Resistance Testing (CCDRT), Chemosensitivity Testing, or Chemotherapy Sensitivity and Resistance Assays (CSRAs).
    The concept is to obtain a biopsy of a patient’s solid cancer (or leukemia, etc.) and isolate the cancer cells from the biopsy, culture these cells in the laboratory, and test them to determine if they are likely to be “sensitive” or “resistant” to different forms of chemotherapy.
    There are two main endpoints for these tests. The first endpoint is whether the drugs prevent the cells from reproducing themselves. These are called “cell proliferation assays.” The second enpoint is whether the drugs kill the cells. These are called “cell death assays.”
    The history of this field is that there was tremendous interest in the cell proliferation assays between 1979 (when an influential study was published in the New England Journal of Medicine) and 1983 (when a critical editorial was published in the New England Journal of Medicine, exposing serious artifacts with cell proliferation assays). Between 1979 and 1983, some scientists had already been working on the alternative endpoint of cell death, but had the misfortune of working on it at the time when the whole field was imploding, as a result of the critical NEJM editorial exposing the problems with the cell proliferation endpoints.
    From the mid-80s onward, there was absolutely no support for research in this field, as grant reviewers felt that cell proliferation was the best endpoint and cell proliferation had failed and that it was a waste of time studying cell death as an endpoint, as the importance of APOPTOSIS (programmed cell death as an important mechanism of action of anticancer drugs) was, at that time still 5 years into the future.
    Owing to the lack of support within the academic oncology community, research into the field was largely driven into the venture-capital-backed private sector. Ultimately, a very large and compelling body of evidence emerged to document the predictive accuracy of these assays (drugs ‘active’ in the assays being, on average 6 times – or more – likely to work in the patient than drugs ‘inactive’ in the assays, and patients treated with drugs ‘active’ in the assays enjoying a significant survival advantage over patients treated with drugs ‘inactive’ in the assays).
    Workers in the field made heroic efforts to convince the Cooperative Oncology Groups to do studies of these cell death assays (which are public domain, and which would never find a private sector sponsor willing to invest millions of dollars on such clinical trials). Efforts to get clinical trials done were and continue to be unsuccessful. In the meantime, several private laboratories like have been offering these assays as a non-investigational, paid service to cancer patients (the average cost of the tests being about $2,000, in a situation where they test 20 different drugs and combinations at two drug concentrations in three different assay systems).
    Some individual oncologists across the United States have made extensive use of the assays in their practices, and are convinced of their clinical utility. The “official” oncology lead organizations (e.g. ASCO and the NCI) have consistently not supported the use of these outside the setting of clinical trials which neither organization has been willing to support.
    In the September 1, 2004 issue of the Journal of Clinical Oncology, there were two separate articles which again condemn the use of these assays in oncology practice. In their press, both the reviews and conclusions were outrageously misleading, and the bias and ineptitude shown by the authors of each article (and in the official position taken by ASCO) was breathteaking.
    The way that this relates to the Chemotherapy Concession” is this:
    Absent the information provided by cell culture assay testing, oncologists have the “freedom to choose” between multiple different drug regimens, all of which would have approximately the same probability of working, when given in an empiric fashion, to unselected patients. Some of these regimens are highly profitable to the oncologists. Other regimens are much less profitable.
    There is also the issue of what is called “chair time.” This is similar to the way that a restaurant owner doesn’t want customers to linger for a long time over a meal, but instead wants them to eat, drink, pay their bill and free up the table for the next customer. Some chemotherapy treatments (e.g. cisplatin, an off-patent, relatively inexpensive drug) require the patient to remain in the oncologist’s chemotherapy chair for many hours. Other treatments are in and out in a matter of minutes.
    Reimbursement for costs associated with treatment are the same in either case. The cell culture assay, however, take away a lot of this “freedom to choose.” This cuts into the oncologist’s bottom line, though it benefits the patient. The American Society of Clinical Oncology fought long and hard to retain the Chemotherapy Concession, and never once suggested the need for a clinical trial to show that when drugs were selected with and without the presence of profit differential, clinical outcomes would be the same.
    It is a real credit to those oncologists that utilized cell culture assay tests in their management of their cancer patients, despite the fact that their use constrained their “freedom to choose,” and therefore doubtless reduced their incomes.
    The situation in ovarian cancer is a perfect microcosm which explains just how intellectually and morally corrupt the entire field of clinical oncology is, from the academic institutions to the individual practioners.
    After 25 years of prospective, randomized clinical trials to identify the best treatments to give to the average patient, there has been absolutely no progress. In 1970, the standard therapy was what is called “single agent alkylator” therapy.
    Then cisplatin and carboplatin came along, and dozens of prospective, randomized trials were done to prove that platinum combinations were better than single agent alkylators. A meta-analysis of all trials showed that there was no difference. But platinum combinations became standard therapy, anyway (the platinums were on-patent; single agent alkylators were not on patent).
    Then Taxol came along. Two large clinical trials showed that Taxol + platinum combinations were better than a single or other platinum combinations. And Taxol was one of the most remunerative cancer drugs of all time. So platinum + Taxol became standard therapy.
    But then two more very large trials were done, showing that there was no advantage to giving platinum + Taxol over single agent platinum. And platinum + Taxol also wasn’t any better than another non-Taxol combination (not previously tested against platinum + Taxol). But platinum + Taxol remained “standard” therapy, for reasons which are not defensible.
    When Taxol went off patent, all the academic oncology groups had (as their major ovarian cancer project) clinical trials to show that platinum + Taxotere (a drug like Taxol, but on patent) might not work 1% better in at least one clinical trial, so that platinum + Taxotere can be the new ‘standard’ therapy.
    All the while refusing to perform clinical trials of cell death endpoint assays, because, lacking something patentable or proprietary, all that these labs can offer is free assays and not the millions of dollars from a Big Pharmaceutical company can offer to push its Taxotere trials.
    The whole system exists to serve the clinical investigators and the clinical oncologists, but not to serve the best interests of the cancer patients.
    TransAmerica eventually lost their contract and was replaced by National Heritage Insurance Company (NHIC). NHIC initially maintained TransAmerica’s policies until 2006, Medicare asked NHIC to reevaluate their position. They held two “public” meetings in April, 2006.
    Because there was a “paper trail” between the “colony assays” of the 70’s, and the noncoverage National Coverage Decision of stem cell assays, and the 1999 MCAC meeting, and the current coverage at NHIC since 2000, and it was also noted that the MCAC meeting had specifically voted that “clinical response,” not just survival, was an appropriate parameter, they specifically followed Medicare’s guidance on this point.
    After NHIC Medicare held those two “public meetings” in April and had a 45 day period of public commentary, they then spent 6 months reviewing everything for the last 20 years. They read all of ASCO arguments. But they did something which national BC/BS and ASCO didn’t do. They invited commentary. They were willing to review data and arguments provided by all sides of the case. Upon reviewing all available information, they made the courageous decision to reverse themselves and go on record as formally approving the service and providing what will be “complete” coverage.
    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 is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. It’s 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.
    The abandonment of support for cell culture testing research and application (along with the hidden support for the Chemotherapy Concession) 20 years ago, has been one of the greatest lost opportunities in all of cancer medicine. They’ve been keeping cell culture assay testing under a breadbox for all that time.
    What is particularly sweet is that they are finally abandoning the artificial distinction between “resistance” testing and “sensitivity” testing and they are providing coverage for the whole kit and kaboodle, and 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 (covered by Medi-gap insurance), as Medi-gap insurance secondaries are mandated to provide payment for co-pays for Medicare-approved services.
    Why wasn’t there support for these assays over the last 20 years? NCI’s Failure at assay-directed therapy. Good review papers exist on cell culture assays and are increasingly appreciated, understood and applied by the private sector and European clinicans and scientists. The literature on these assays have not been understood by many NCI investigators and by NCI-funded university investigators, because their knowledge was almost always geared towards an assay technique (cell-growth) that hasnt’ been used in private labs for over fifteen years now.
    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. Dr. Dan Von Hoff (after his failed attempt at the old technology cell-proliferation assays) published a paper in 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! If NCI can’t do it, nobody can. Thank goodness for private researchers.
    The controversy is over what is the appropriate standard to judge medical tests.
    1. Efficacy (use of tests improves clinical outcomes)?
    2. Accuracy (the tests accurately measure what they are purported to measure)?
    In the ASCO and insurance industry reviews, all papers dealing with point number 2 were specifically EXCLUDED from review. Only papers relating to point number 1 were included.
    If the same criteria were applied to evaluate every single other test used as an aid in selecting treatments, exactly ZERO tests would be available. Criterion number 1 is not being applied to a single test currently under development for use as an aid in selecting treatment. This criterion isn’t being applied by the FDA, which regulates test kits. The FDA applies the same criterion it applies to every single other of the hundreds of test kits that they do approve. ACCURACY.
    Without information provided by Cell Culture Assay Testing, oncologists have the freedom to choose between a multiple of different drug regimens, all of which have approximately the same probability of working. Some of these regimens are highly profitable to oncologists. Other regimens are much less profitable. Assay-testing takes away a lot of this freedom to choose and narrows the selection to those drugs that have the highest probability to be successful but may have lower profitability for the oncologist. This cuts into the oncologist’s bottom line, though it benefits the patient.
    ASCO and others fought long and hard to retain the Chemotherapy Concession and never once suggested the need for a clinical trial to show when drugs were selected with and without the presence of profit differential (which included oral-dose drugs), clinical outcomes would be the same. It is a real credit to oncologists who utilize assay-testing in their management of their cancer patients, despite the fact that their use constrained their freedom to choose and doubtlessly reduced their incomes.
    References:
    http://www.healthyskepticism.org/news/2007/Jun.php

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