Medicare Coverage for Cell Culture Assay Test

[gdpawel]

Medicare Contractor Establishes Reimbursement Coverage Policy for Cell Culture Assay Tests

National Heritage Insurance Company (NHIC), the contractor that administers Medicare programs in California, has established a positive coverage policy for Cell Culture Assay Tests known as Chemosensitivity (Resistance) Testing or Oncologic In Vitro Chemoresponse Assays 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 Southern California. Medicare bills for this testing are billed through NHIC because the test is conducted by the approved laboratories in California.

This pre-test can help see what treatments have the best opportunity of being successful for "high" risk cancer patients. The test measures the response of "live" tumor cells to drug exposure. Following this exposure, the assays measure both cell metabolism and cell morphology (Functional 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. Assays based on "cell-death" occur in the entire population of tumor cells.

This 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.

Following the collection of "fresh" tumor cells obtained from surgery or tru-cut needle biopsies, a cell culture assay is performed on the tumor sample to measure drug activity (sensitivity and resistance). This will pinpoint which drug(s) are most effective. Tissue, blood, bone marrow, and ascites and pleural effusions are possibilities, providing tumor cells are present. At least one gram of fresh tissue is needed to perform the tests, and a special kit is obtained in advance from the lab. The treatment program developed through this approach is known as assay-directed therapy.

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.

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 abandoned the artificial distinction between "resistance" testing and "sensitivity" testing and are providing coverage for the whole FDA-approved kit. Drug "sensitivity" testing is merely a point a little farther along on the very same continuum which "resistance" testing resides.

Cell cuture assay tests based on "cell-death" have proven very effective in identifying novel treatment combinations for a variety of cancers. The value of cell-death assays is that they can and do accurately predict clinical outcomes and define novel chemotherapeutic synergies. It can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).

The current clinical applications of in vitro chemosensitivity testing is ever more important with the influx of new "targeted" therapies. Given the technical and conceptual advantages of "functional profiling" of cell culture assays together with their performance and the modest efficacy for therapy prediction on analysis of genome expression, there is reason for renewed interest in these assays for optimized use of medical treatment of malignant disease.

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.

The coverage became effective for claims for services performed on or after February 19, 2007. The decision is posted at:

http://www.medicarenhic.com/cal_prov/articles/chemoassaytest_0107.htm

http://weisenthalcancer.com/Patient%...QuickFacts.htm

NHIC Medicare Services reimburses qualified laboratories in Southern California for cell culture assay tests on a Medicare patient anywhere in the United States.

Likewise, Highmark Medicare Services reimburses a qualified laboratory in Pennsylvania for cell culture assay tests on a Medicare patient anywhere in the United States.

NHIC has jurisdiction over Southern California, so that is who gets billed when the laboratory is located in California.

Highmark has jurisdiction over laboratories in Pennsylvania, so that is who gets billed when the laboratory is located in Pennsylvania.

The coverage decision is posted at:

http://www.highmarkmedicareservices.com/bulletins/partb/news06132007.html

[Lani]

tumor tissue is required. Therefore if you know of someone newly diagnosed, it will be necessary for them to ask their surgeon that a portion of their biopsy specimen not be placed in paraffin if they want to consider this test (should it be available to them)

[gdpawel]

Thanks Lani. Very important point. 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.

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.

National Heritage Insurance Company found that even back in 1999, the Medicare Advisory Panel concluded that cell culture assay tests offered "clinical utility." After listening to detailed clinical evidence, the Medicare Coverage Advisory Committee (MCAC) found that these assay systems can aid physicians in deciding which chemotherapies work best in battling an individual patient's form of cancer.

MCAC's laboratory and diagnostic services panel heard presentations from experts regarding the clinical data associated with the assay systems. The panel questioned presenters carefully on clinical performance, study findings, literature analyses, and patient impact of the tests. After considering the evidence, the panel conclued that the tests demonstrated clinical utility for directing therapy.

Although Medicare had been reimbursing for cell culture drug "resistance" tests since 2000, it wasn't until the beginning of this year they abandon the artificial distinction between "resistance" testing and "sensitivity" testing and are providing coverage for the whole FDA-approved kit.

[Hopeful]

gdpawel,

Can you help me understand something I have been struggling with? In your post above, you stated:

>>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. <<

Can you help me understand what the statistics from empiric therapy represent? I am no math whiz, but can grasp concepts. When a certain treatment is said to reduce the risk of recurrence by a relative 20%, what I am reading this to say is that out of 5 people who have the treatment, 1 person responds completely and the rest not at all, i.e., it is 100% for one person and 0% for the other 4. To say the treatment offers a 20% relative risk reduction is then to take the one person who did respond and attribute a percentage of their sucessful treatment to all patients who have the treatment, regardless of the sucessfulness of it. In this way, all 5 people are said to have their risk reduced from 100% to 80%. Am I getting this?

Hopeful

[gdpawel]

LOL. I am no math whiz either. But again, that doesn't stop people like us grasping concepts. At least for me, it just takes a little longer than others. But in the end, I get the job done. Your graps seems to be pretty good.

Evidence-based medicine is a "trial and error" process of a clinical trial to see what might "appear" to be improving cancer survival. While new regimens "appear" to be improving survival, when these same regimens are tested on a wider range of cancer patients, the results have been very disappointing. In other words, oncologists at a single institution may obtain a 40% to 50% response rate (not cure) in a tightly controlled study, when these same regimens are tested in a real-world setting, the response rates may be 17% to 27%.

There appears to be a number of patients who have had long-term survival after high dose therapy, but there are a number of patients whose tumors are responsive to chemotherapy who have had long-term remissions from standard dose chemotherapy, as well as a number who show no difference in survival when treated with standard-dose or high-dose chemotherapy.

Does chemotherapy shorten survival of some patients, while prolonging the survival of others? You do help some patients, but for every patient helped, there's another one you may hurt. Are you an "average population?" I know I'm not. I am an individual. Take notice the cancer establishment is now using the concept "personalized" cancer treatment. There must be a good reason.

You may want to reserve aggressive therapy for those patients who will derive more benefit than harm, while identifying the most promising treatment regimens for everyone. In patients with tumors very resistant to cytotoxic chemotherapy, the most promising treatments may be angiogenesis inhibitors, growth factor inhibitors, or more integrative medicine approaches.

It may be better not to give more aggressive and toxic, mutagenic and immunosuppressive combinations, but to give targeted single agents, or give least toxic, mutagenic synergistic combinations. One of the most important drug combinations introduced for the treatment of solid tumors in the last 15 years has been the gemcitabine + platinum combination. However, giving this combination to everyone would not be that helpful, because the immunosuppression and mutagenicity of the combination cancels out in many patients, the gains in a few, fortunate patients.

Although an above-average regimen, it is not a highly active regimen in everyone, and it's activity is nicely predicted by cell culture assay results. What is unique about gemcitabine + platinum combination is that, in a subset of patients, it produces responses the likes of which are seldom seen with anything else.

More emphasis should be put on matching treatment to the patient, through the use of individualized genetic and cellular pre-testing, having more respect for minimal partial response or stable disease, when it can be achieved through use of the least toxic and mutagenic drug regimens, and reserve the use of higher dose therapy or aggressive combination chemotherapy to those patients with tumor biologies most amenable to attack and destroy by these aggressive treatments. Sounds good to me.

[Hopeful]

gdpawel,

Thanks, as always, for your thoughtful and reasoned response. I appreciate all of the thought provoking insights and information you share on this Board. I always come away from reading your posts feeling I have learned something new.

Hopeful

[gdpawel]

Medicare's National Coverage Decision specifically notes noncoverage on two distinct types of assays: a. human tumor stem cell assay, and b. clonogenic assay. These are what most academic oncologists still mistakenly refer to as chemosensitivity testing.

In October 2003, CMS notified all contractors that the NCD was very specific to those tests and does not include tumor cell sensitivity or resistance testing on any other class of cells other than tumor stem cells. In 2006, Medicare officially recognized cancer chemosensitivity tests as a special test category in Federal Regulations (42 CFR 414.510(b)(3), 71 FR 69705, 12/01/2006).

Two Medicare contractors (NHIC Medicare Services and Highmark Medicare Services) established reimbursement coverage policies for cell culture assay tests, the same way that the Oncotype DX assay is being covered. Medicare bills for Chemosensitivity (Resistance) Testing, from any Medicare patients, anywhere in the United States, are billed through NHIC and Highmark Medicare Services because the test is conducted by approved laboratories in Southern California and one in Pennsylvania. As far as payments for this test, it is just as good as having a NCD. Numerous private payors pay for the tests also.

As with any other laboratory tests in cancer medicine, the determination of the efficacy of cell culture assays is based on clinical correlations (comparisions of laboratory results with patient response). The "standard" of retrospective correlations between treatment outcomes and laboratory results is sufficient in the case of ALL laboratory tests. It is what established FDA-approval for the test kit.

[gdpawel]

It amazes me not only that some private insurance carriers don't like to pay for cell culture assay tests but that they don't emphatically mandate it as a requirement for obtaining chemotherapy reimbursement against ill-directed treatments.

The validation standard that private insurance companies is accepting from "molecular" profiling tests is "accuracy" and not "efficacy." The "bar" has been instantly lowered. No longer will it be essential to prove that the use of a diagnostic test improves clinical outcomes, all they have to do for these "molecular" profiling tests is prove that the test has a useful degree of "accuracy." However, at the same time, the validation standard they want for "cell-based" profiling tests is "efficacy."

The "cell-based" profiling tests have the same entitlement to be judged by the same validation standard as "molecular" profiling tests. The combination of measuring morphologic (structural) effects and metabolic (cell metabolism) effects constitutes measuring the "profile" at the whole cell level. It must be noted that both types of dignostic tests are just that, "tests" and not treatment.

Profit, as we have seen, is a powerful motivating force. Among the private payors, at least, the profit motive is entirely consistent with the goal of the test, which is to identify efficacious therapies irrespective of drug mark-up rates.

The evidence in support of these assays is more than sufficient to justify the funding of validation trials, if any more truly are needed, as claimed - speciously and self-servingly - by the medical establishment.

Everyone is scared to death - and rightly so - at what is going to happen to the healthcare economic system with the introduction of increasingly expensive new drugs that benefit only a small percentage of patients who receive them, hence the headlong rush to develop tests to identify molecular predisposing mechanisms whose presence still does not guarantee that a drug will be effective for an individual patient.

Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class, such as Sutent, Tarceva, Iressa, and Nexavar.

The FDA could benefit too, as they find themselves under increasing pressure to allow new drugs into marketplace while at the same time protecting the safety of potential recipients of those drugs as well as the financial interests of those who will have to pay for them.

It explains the new paradigm of requiring a companion diagnostic as a condition for approval of new targeted therapies. The pressure, in fact, is so great that the companion diagnostics they've approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.

I think that in both of these areas - private insurance carriers and the FDA - there is a very real opportunity to make a substantial impact and contribution, an interest in saving the healthcare system perhaps billions of dollars a year (and thereby the healthcare system itself) by ensuring that expensive treatments are used appropriately.

Committee chairpersons, committee members and persons in congress who may have personal interests not only in discovering new cancer treatments - everybody wants that - but also, in the "here and now," using currently-available cell culture assay technologies to improve the effectiveness of existing drugs and save lives today by administering the right drug to the right patient at the right time.