Cell Culture Drug Resistance Testing (CCDRT) Cell Death Assays:
Misconceptions Versus Objective Data
Cell culture drug resistance testing (CCDRT) refers to obtaining fresh biopsy specimens of human neoplasms, isolating tumor cells from these specimens, exposing the tumor cells to drugs during short-term (3 - 7 days) culture, and assessing drug effects by measuring either cell proliferation or cell death. The clinical application of these assays is based on the fact that drug effects in these assays correlates with and predicts for drug effects in the patient. The results of these assays are then used by clinical oncologists to select drugs to be used for the treatment of individual patients. This may be a "negative" selection (avoidance of drugs with a below-average probability of clinical benefit) and/or a "positive" selection (selection of drugs with an above-average probability of clinical benefit).
As with any medical test, CCDRT results must be interpreted and applied in the context of the clinical situation as a whole. Prior to the performance of the tests, a test panel of drugs has only an "average" probability of providing clinical benefit, where "average" is defined by pre-existing data from the medical literature and the clinical status of the patient. After performance of the tests, drugs are sorted into categories - some with above-average probabilities of benefit and others with below-average probabilities of benefit. As will be discussed below, there is every reason to infer that, all other considerations being equal, the patient is better served by receiving assay "above-average" drugs and not receiving assay "below-average" drugs.
The application of CCDRT in clinical oncology has been controversial in the past. The clinical application of CCDRT was formerly opposed by the Northern California Medical Oncology Association (a policy recently changed to allow for the selective, non-investigational use of CCDRT in a case-by-case basis), while it has been officially endorsed by the Southern California Medical Oncology Association. It has been opposed in two recent editorials by Dr. Maurie Markman (one written in conjunction with a physician employed by the Aetna Insurance Company (1,2)). It has been supported by other reviewers (e.g. (3) and DeVita, pp. 344-347, in the most recent edition of Cancer: The Principles and Practice of Oncology, Fifth Edition (ed. DeVita, Hellman, and Rosenberg; Philadelphia, Lippincott-Raven Publishers, 1997).
The issue is very complex. We are dealing here not with a single operation, or single diagnostic device, or a single drug regimen, or a single disease. We are dealing with hundreds of diseases (individual forms of cancer) and hundreds of potential drug regimens and a dozen individual assay technolologies. I have been a full-time worker in this field dating to 1979. I am familiar with the fact that many medical school professors and the physicians trained by these professors oppose this testing. When pressed for objective reasons for this opposition, all reveal ignorance and misconceptions.
On October 15, 1997, the issue was considered for a second time by the nationally-respected California Blue Shield Medical Policy and Technology Assessment Committee. This issue has previously been considered in March of 1994, where the reimbursement for CCDRT as a non-investigational procedure had been unanimously approved.
In the period between 1994 and 1997, additional questions had been raised. These included negative reviews by the National Blue Shield Association, the American Medical Association, and two negative editorials authored by Dr. Maurie Markman of the Cleveland Clinic, in conjunction with a physician employee of the Aetna Insurance Company. Thus, the entire issue was re-opened for scrutiny and re-consideration.
An outside consultant from the University of California San Francisco did an ostensibly thorough examination of the issue. He prepared a detailed report, recommending against considering CCDRT a reimbursable, non-investigational service.
What is different about the California Blue Shield review, compared to the other reviews, is that California Blue Shield invites input from all affected parties, publishes preliminary conclusions and recommendations, and then holds an open hearing, where all points of view can be considered. It is a fact that, prior to obtaining input from proponents of CCDRT and carefully hearing both sides of the issue in a back and forth presentation of points of view and open debate, the Medical Directors of California Blue Shield were pre-disposed to change their policy. However, upon consideration of all points of view and due consideration of all arguments and counter-arguments, the expert technology assessment panel, including the Blue Shield Medical Directors, unanimously voted against their UCSF consultant, against the findings of the National Blue Shield technology assessment, in favor of continuing the policy of considering CCDRT to be a fully-reimbursable, non-investigational service.
This was a very significant event. There is no question that the California Blue Shield committee did the only thing that it could do, when faced with all points of view and when forced to examine all evidence in an objective and impartial manner. There is also no question that this outcome will be repeated in future cases that go to arbitration or other legal procedures.
More recently, it was determined in a Medicare Hearing (Social Security Administration Docket Number 96-1936, Decision rendered April 24, 1998, Appellant Larry Weisenthal, MD) that "By June 30, 1996, Cell Culture Drug Resistance Testing was sufficiently proven and accepted by the general medical community to be part of the generally accepted medical practice. From that time forward it is no longer experimental."
Most recently (on November 15-16, 1999), there was a national Medicare meeting held in Baltimore of the Medicare Coverage Advisory Committee for Laboratory and Diagnostic Services. At this meeting, the various proponents made presentations supporting a decision for Medicare to provide coverage for Cell Culture Drug Resistance Testing (CCDRT), which Medicare refers to as Human Tumor Assay Systems (HTASs). Making presentations in favor of coverage were me, Andrew Bosanquet (Bath, England, Cancer Research Unit), John Fruehauf (Oncotech), Robert Nagourney (Rational Therapeutics), Robert Hoffman (Anticancer, Inc.), and David Kern (Impath). Also making supporting presentations were clinical oncologists (Richard Nalick, Los Angeles; William Grace, New York City; and James Orr, Orlando), as well as a pancreatic cancer survivor, Randy Stein, Laguna Niquel, CA). A Medicare-selected consultant, Harry Handelsman, representing the Center for Practice & Technology Assessment, AHCPR, gave a generally supportive technology evaluation. Making presentations generally opposed to coverage were Edward Sausville, representing the National Cancer Institute; Harry Burke, New York Medical College; and Mitchell Burken, representing Medicare. A representative from the American Society for Clinical Oncology (ASCO) made a brief statement expressing the view that ASCO was essentially neutral on the issue. The independent committee of 11 voting members and 2 non-voting members listened to all of the testimony, pro and con. They were not allowed to vote on the central issue of coverage, but rather they were to express their opinions concerning the value of the technology in clinical oncology, after hearing both pro and con arguments. Despite the fact that Medicare staff misled and confused the committee by presenting the results of studies with discredited and abandoned technologies which have never been used by any of the laboratories petitioning for coverage, the committee members strongly endorsed the promise and clinical utility of these technologies, as is documented in the verbatim transcripts and videotapes of the meeting. It is obvious that a vote for coverage, had it been allowed by Medicare, would have been a strong endorsement for coverage. I fully expect Medicare to revise it national coverage guidelines to include CCDRT as a Medicare covered service sometime before Spring, 2000.
I will now briefly review some of the information most relevant to this issue.