April 25, 2002
Superior Court of California, County of San Diego
Dept. 19; Judge Yuri Hofmann
325 S. Melrose Vista, CA 92083

ref: Case # 325; Doe vs. WellPoint Blue Cross of California

Dear Judge Hofmann:

I have been given the opportunity to prepare a written response to the document shown to me for the first time just 5 minutes prior to the beginning of the trial on April 12. This is a BlueCross/BlueShield Association document, entitled: "Technology Evaluation Center: Chemotherapy Sensitivity and Resistance Assays."

The BlueCross/BlueShield Association http://www.bcbs.com/ is an umbrella trade organization, representing the interests and providing services on behalf of its membership of different medical insurance companies, each of which operates independently. For example, in the State of California, Blue Cross (a wholly-owned, for-profit subsidiary of Wellpoint, Inc.) operates entirely separate from (and, as will be discussed, has different reimbursement policies than) Blue Shield of California, a non-profit company.

Up until the time that this document was given to me, it had never previously been cited or referenced by WellPoint Blue Cross of California, who had previously referred only to their internal policies and their own, in most cases anonymous, reviewers and consultants (please see the many letters from WellPoint Blue Cross to Ms. Doe included in the materials which she provided to the court). I came prepared to address the specific points of contention previously raised, but I was forced at the last minute to try and address this latter, long and complex, document as well. Therefore, I am grateful for the opportunity to address this in detail at this time.

Before I begin, I want to apologize for any breaches in legal protocol or imprecise use of legal terminology which may follow.

I believe that this seemingly small and isolated small claims case will have a major effect on the future course of cancer medicine in the USA, whichever way the decision goes. After previously losing more than 10 cases of a similar nature, this is the first time that WellPoint Blue Cross has appealed and argued its case at the level of a formal Superior Court proceeding. Although I understand that this will not establish a legal precedent, this case will have great bearing on the outcome of future cases, as it will surely be cited in these future proceedings, and the decision is likely to be widely publicized. If WellPoint Blue Cross is held to be legally in the wrong, as I believe them to be, then the outcome of this case will also get the attention of the opinion leaders in cancer medicine and force a more serious consideration of the role of these assay technologies in the care of cancer patients.

The first opinion leaders to be so influenced will be the 18 prestigious signers (not authors, see below) of the ill-conceived and poorly-wrought BlueCross/Blue Shield Association document which I shall review below.

Firstly, I tried to get details of the BlueCross/BlueShield Association technology review. Despite the statement at the trial by Mr. Loftin that this document was published on the BlueCross/BlueShield Association Website, I was unable to find it there or at any other place on the World Wide Web.

On Friday, April 19, 2002, I spoke by phone with Naomi Aronsen, Ph.D., supervisor of the Technology Evaluation Center for the BlueCross/BlueShield Association (headquartered at 225 N. Michigan Ave., Chicago, IL 60601-7680).

What I wanted to learn were the details of the review process. Who actually performed the review? What was the level of transparency during the review process? Were outside comments solicited? Did the document receive peer review? Was input invited from the laboratories, physicians, and published medical scientists, with established expertise relating to the technologies actually provided as a non-investigational service to cancer patients today? Did they make any attempt to contact any of the hundreds of expert oncologists who are using the technology in their everyday patient management? Did they solicit input from these physicians expert in the management of patients with reference to the information provided by the assays? What was the role of the panel of 18 physicians who approved the document? Did these physicians actually research and write the document, or did they merely discuss, make isolated suggestions, and then vote to approve the document prepared by a full-time BlueCross/Blue Shield Association technical staff?

Dr. Aronsen pointedly refused to answer any questions at all, stating that I could submit "information" to her in writing, but that she would, under no circumstances, answer questions about the review process.

Finally, out of exasperation, I just asked her if she would listen to a single question, and that she could feel free to hang up without answering it if this was necessary. The question I asked her was whether the technology assessment was prepared by a BlueCross/BlueShield-employed staff and then discussed and voted on by the outside panel of 18 physicians, or whether the 18 physicians themselves actually did the research and prepared the report. I was told only that "the panel had a lot of active input" into the report, and given no other details. From my knowledge of such "expert review boards," I believe that the most likely scenario was that the report was, indeed, researched and prepared by a BlueCross/BlueShield Association full time staff, and then discussed and voted on at a meeting of the "expert review board." This is of importance, as not a single member of the review board has any expertise whatsoever in the technologies being considered. Not a single member of this panel has ever had a patient whose tumor was sent to our laboratory for testing and not a single member of the panel has published even a single paper in the peer-reviewed medical literature on anything having to do with this testing.

As the actual members of the internal BlueCross/BlueShield staff who prepared the technology assessment are anonymous and as the process remains totally opaque, we still do not know the level of expertise of the people who prepared this report. However, as will be discussed below, one can easily infer that the preparers of the report (as well as the panel of 18 physicians who voted on the report) had no standing whatsoever as experts qualified to evaluate the technologies applied in the care of Jane Doe.

As just noted, it is my belief that the 18 member Medical Advisory Panel who voted to approve the document did not actually draft the document themselves, but rather just voted to approve a document largely prepared on their behalf by the BlueCross/BlueShield Association-employed technical staff. It is of importance that the panel of physicians were not afforded the opportunity to consider commentary concerning the merits and deficiencies of the staff-prepared document from parties with expertise in this field. As will be shown below, the document is erroneous in important respects, on its face inconsistent with established member Blue Cross/Blue Shield reimbursement policies, and grossly misleading in all other respects.

The BlueCross/BlueShield Association technology review procedures contrast unfavorably with the procedures used by other technology assessment committees. For example, on October 15, 1997, the issue of reimbursing for chemotherapy sensitivity and resistance assays 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 this testing 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 BlueCross/BlueShield Association review, 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 chemotherapy sensitivity and resistance testing and prior to hearing both sides of the issue in a back and forth presentation of data and open debate, the Medical Directors of California Blue Shield were pre-disposed to change their policy that this testing was a Blue Shield-covered service. 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.

More recently, it was determined in a Medicare hearing, with an extensive and detailed opinion authored by the Administrative Law Judge (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." Subsequent to this, Medicare paid for all back claims covered by the Administrative Law Judge proceeding and formally approved coverage for chemotherapy resistance testing, effective September 1, 2000.

As a separate issue, I would also like to report an extraordinary encounter which occurred in the hallway outside the courtroom on April 12, just as the participants in the oral presentations were leaving the courtroom. The WellPoint Blue Cross representative, Mr. Loftin, approached Dr. Dwight McKee (who had just finished testifying on Ms. Doe's behalf).

Mr. Loftin told Dr. McKee that WellPoint Blue Cross would be contacting him (Dr. McKee) in the near future. Mr. Loftin went on to explain that it is written in the WellPoint Blue Cross participating provider contracts that participating physicians are not permitted, while under contract, to testify in court proceedings on behalf of their patients who are contesting WellPoint Blue Cross coverage decisions.

Dr. McKee quickly informed Mr. Loftin that Dr. McKee (at the time of his initial involvement in the care of Ms. Doe a WellPoint Blue Cross participating provider, as are the great majority of the board certified oncologists practicing in California) was no longer a participating provider, and thus free to provide sworn testimony to support his patient. Dr. McKee noted that the Ms. Doe's current oncologist, Dr. Vicario, did not have this legal freedom to testify against WellPoint Blue Cross, although Dr. Vicario did provide a letter to WellPoint Blue Cross supporting the patient's appeal for coverage. This encounter was witnessed by me, by Jane Doe, and by a personal friend of Ms. Doe who accompanied her to the trial.

Before I begin a point by point evaluation of the BlueCross/BlueShield Association document (and therefore get lost in the "trees"), I want to outline my point of view about the "forest" of the case, with the benefit of hindsight considering the sworn testimony offered by both sides on April 12.

Ms. Doe's position is that she paid her insurance premiums and is entitled to coverage for medical expenses required for the management of her breast cancer. She was faced with the daunting challenge of a disease with a known 5 year survival rate of only 10%. There were a variety of chemotherapy choices and she wanted to receive the treatment most likely to work. Two different board certified medical oncologists experienced in managing cancer patients on the basis of information provided by our assays determined that the information provided by our testing would be of help in selecting the treatment most likely to work. This testing was, therefore, ordered and performed on two separate occasions (February 24, 1998 and June 16, 2000).

On each occasion, there is both sworn testimony and written documentation that the results of the testing did, indeed, influence directly the choice of treatment to be used. WellPoint Blue Cross did, indeed, pay for the cost of the treatments (one of which, at the time, would have been considered to be somewhat unconventional if by no means unreasonable, but which would not have been given absent performance of our testing services). However, WellPoint Blue Cross did not pay for the laboratory testing, itself, on the basis of the fact that the tests did not meet the internal coverage guidelines of WellPoint Blue Cross. Ms. Doe (who has continued to do quite well on assay-directed treatment 5 years following her diagnosis, thus doing much better than the average patient faced with this most aggressive and feared form of breast cancer) has been forced to pay for the tests herself and believes that WellPoint Blue Cross was wrong to deny coverage. WellPoint Blue Cross's position was clearly spelled out by Mr. Loftin, if very ambiguously defended in the pre-trial letters to Ms. Doe authored by various WellPoint Blue Cross-employed physicians.

Mr. Loftin stated that WellPoint Blue Cross determines its own coverage policies, despite whatever opinions I or others may have. The patient agreed to those coverage policies in accepting the contract provisions of her policy and, thus, is not entitled to payment for what WellPoint Blue Cross has determined is a non-covered service. Furthermore, WellPoint Blue Cross maintains that, in the event a judgement for Ms. Doe is rendered, the total amount of the award should only be for $550, which WellPoint Blue Cross says is all that would be paid for this type of service provided by a non-participating ("out of network") provider, such as myself.

The specific reasons that WellPoint Blue Cross maintains my services were not covered by Ms. Doe's policy are the following :

A. (e.g. as explained in the letter from WellPoint Blue Cross Medical Director Richard Lehrfield to Ms. Doe, dated April 2, 1001):

The service provided did not meet WellPoint Blue Cross's specific technology criteria, including:

(1). appropriate for the symptoms, diagnosis or treatment of the patient's medical condition.

(2). provided for the diagnosis or direct treatment of the patient's medical condition.

(3). within the standards of good medical practice.

(4). not be primarily for the convenience of the patient's physician or another provider

(5). the most appropriate procedure which safely be provided

(6). there must be valid scientific evidence to demonstrate that the expected health benefits from the procedure are clinically significant and likely to produce a greater benefit for the patient than other possible alternatives.

Comment: See below.

B. (e.g. as referenced in Dr. Lehrfeld's letter to Ms. Doe of July 5, 2001):

The service is specifically excluded by existing WellPoint Medical policy (# 2.11.04).

Document 2.11.04 states the following:

Section: Medicine Subsection: Hematology/Oncology
Subject: Human tumor cell in vitro chemotherapy assay
Initial review: 3/17/83
Latest review: 10/08/98
Latest revision: [blank]

Human Tumor Cell In Vitro Chemotherapy Assay

Description:

Human tumor cell assay, also known as clonogenic assay, human cell assay and human tumor cell assay, involves exposure of human tumor stem cell colonies (grown in tissue culture) to anticancer drugs and observing for cytotoxic drug effects. Their purpose is to screen potential anticancer drugs and predict for the effect of these drugs on the tumors of individual patients, to allow the selection or deselection of the most effective drug or drugs for that patient.

Policy: Human tumor cell assay is considered NOT MEDICALLY NECESSARY.

Comment: It is VERY important to note that the above coverage policy, written in 1983, refers SPECIFICALLY to an old technology, not used by me in my 15 years of providing these services on a non-investigational basis to cancer patients and to a technology which was never used in any form in the testing of Ms. Doe's biopsy specimens. Thus, this old WellPoint medical policy has no relevance whatsoever to the services provided on behalf of Ms. Doe.

C. (e.g., as stated in Dr. Lehrfield's letter of July 5, 2001, but also previously stated several times in earlier letters to Ms. Doe from WellPoint Blue Cross):

"A board certified oncology advisor [n.b. anonymous, as in the case of all such experts cited by California WellPoint Blue Cross in defense of its position] noted that the required testing would not affect the chemotherapy treatments that were administered to you [Ms. Doe]"

Comment:

Note that Dr. McKee provided direct testimony to the fact that, in the case of both the 1998 and 2000 testing services, the testing definitely and directly influenced the choice of chemotherapy treatments given to Ms. Doe. This is also confirmed in a letter written by the patient's other oncologist, Dr. Daniel Vicario, who was prohibited from offering testimony in court in support of his patient by the terms of his "preferred provider" contract with WellPoint Blue Cross.

D. As stated in a September 26, 2000 letter to Ms. Doe from Lester Garfinkel, MD, Medical Director-Medical Review for WellPoint Blue Cross):

"Assay guided chemotherapy has not been proven to be any more efficacious than empiric based chemotherapy."

Comment:

Prior to being handed the complex BlueCross/BlueShield Association document for a brief perusal just prior to the trial proceedings of April 12, 2002, the above (A, B, C, and D) constituted the only specific reasons ever provided to Ms. Doe (or to us, in our own supporting appeals of Ms. Doe's case) for denying payment for our testing services.

I responded to Points B and C, above.

These points are obviously not applicable to Ms. Doe's case, as explained.

My response to A is as follows:

Points (1) - (5) are clearly met by our services, particularly as applied in the context of the management of Ms. Doe's illness.

Dr. McKee testified effectively to support these points, and WellPoint Blue Cross did not provide rebuttal, nor has it ever stated any specific reasons why our services in the view of WellPoint Blue Cross failed to meet these criteria.

With regard to the service being "within the standards of good medical practice," it should be noted that, over the last 9 years, we have tested the breast cancers of more than 975 patients, and that only 39 of these were referred to us by either Dr. McKee or Dr. Vicario, the two oncologists involved in the care of Ms. Doe. These breast cancer biopsy specimens were submitted to us from more than 50 major medical centers, including some of the most respected and prestigious inside and outside of the state of California, and the patients were referred by oncologists who are likewise widely-respected, superbly-trained, and well-experienced.

With regard to point A. 6, I testified (and provided documentation to WellPoint Blue Cross) of the proven (and unchallenged) ability of these assays to identify drugs which are significantly more likely than average and less likely than average to be provide clinical benefit to the patient, with "above-average" drugs being approximately seven-fold more likely to produce regression of cancer in the patient than "below-average" drugs. Not only were these data unchallenged, but they were endorsed in the BlueCross/BlueShield Association technology review to be discussed below, which used as one of its prime sources of cited information the very monograph I have provided in the past to WellPoint Blue Cross of California (Weisenthal, L, 1999, Cell culture drug resistance testing [CCDRT]: misconceptions versus objective data, discussed below and copy enclosed).

Now, if the clinical situation is one in which the ability to control the growth of non-surgically curable cancer with chemotherapy is crucial, then the value of identifying the treatment with the highest probability of working is self-evident. Furthermore, if the clinical situation is one in which there are a good half dozen or more forms of chemotherapy which would all be, on average, equally likely to work (i.e. all have an "average" probability of working), and where one has laboratory tests which can identify drugs which are significantly "above average," as well as identifying drugs which are significantly "below average," then the advantage to the patient of using these tests, as opposed to empiric selection of drug regimens is also self-evident.

Now, WellPoint Blue Cross argues under point D that "Assay guided chemotherapy has not been proven to be any more efficacious than empiric based chemotherapy." In point of fact, this statement is not correct.

In spite of my bringing the following studies to their attention, they have chosen to ignore the existence of the study in their considerations of the appropriateness of using assay-directed chemotherapy in the care of Ms. Doe.

In the case of breast cancer, there are a total of 179 published correlations between assay results and patient treatment (See attached review papers for complete breakdown of results by study and complete literature references). Patients treated with assay-"sensitive" drugs had an 82% response rate. Patients treated with assay "resistant" drugs had a 7.7% response rate. The advantage associated with treatment with "above average" drugs compared to "below average" drugs in breast cancer has thus been identified as being 10:1. The overall response rate for the patients in the studies was 66%. Thus patients treated with "above-average" drugs enjoyed a significantly higher response rate than for the patient population as a whole on the studies, while patients treated with "below average" drugs had a significantly lower response rate than the patient population as a whole.

In a peer-reviewed study published in the prestigious oncology journal Breast Cancer Research and Treatment, Xu and colleagues treated 73 breast cancer patients on the basis of MTT-assay directed chemotherapy (one of the technologies applied in the assays on Ms. Doe's tumor specimens), and compared outcomes with a control group of 73 patients treated with "physician's choice" chemotherapy. (Xu J-M, et al. . Predictive chemotherapy of advanced breast cancer directed by MTT assay in vitro. Breast Cancer Res Treat 1999; 53: 77-85).

This was a contemporaneously controlled, while non-randomized study, and the patients receiving assay-directed therapy actually had less favorable prognostic factors, such as having significantly more sites of disease, as published in the paper (in addition, the author informed me in a personal communication that the patients at her medical center with unfavorable disease were more often referred for biopsy and assay-directed therapy, while patients with more favorable disease were more likely to receive standard empiric chemotherapy).

The response rate (i.e. 50% or greater shrinkage of measurable cancerous tumors in response to chemotherapy) of the assay-directed group was 77%, while the response rate for the empiric therapy group was 44%. The advantage enjoyed by the assay-directed group was highly significant upon statistical comparison (P<0.01). In a small group of 10 patients who received assays but in which no active drugs were identified, empiric therapy was given with no responses (0% response rate). One year survivorship for the two groups was 74% for assay-directed therapy and 67% for empiric therapy. Three year survivorships were 25% and 19%, respectively. Five year survivorships were 20.5% and 12.3%, respectively.

The above study showed a clear response advantage to assay-directed therapy and a trend for a survival advantage, despite less favorable prognostic factors for the group receiving assay-directed therapy. The lack of statistical significance for survival is no doubt owing to the small numbers of patients enrolled in the study. Putting things into perspective, the adjuvant Cancer and Acute Leukemia Group B (CALGB) study comparing doxorubicin/cyclophosphamide with and without Taxol required 2,000 patients followed for many years to show an absolute 2% difference in survival. And yet this triple drug therapy has now become the standard of care in this setting. It also required a meta-analysis of studies totalling close to 50,000 patients followed for 10 to 15 years to establish a minuscule survival advantage for adjuvant chemotherapy of post-menopausal patients. And yet WellPoint Blue Cross was paying for adjuvant therapy of post-menopausal patients 15 years before this meta-analysis was available.

What is most important to Ms. Doe's case is the following:

"Despite almost 30 years of clinical cancer research, the true impact of second and subsequent lines of chemotherapy on the outcome of metastatic breast cancer patients, especially on the duration of survival, is still unknown. In the virtually incurable metastatic setting, issues like quality of life and patients' preferences gain particular relevance. At the turn of the century, in-depth rethinking of the design of clinical trials run in this challenging disease setting appears to be warranted." (Cardoso, F., et al. Second and subsequent lines of chemotherapy for metastatic breast cancer: what did we learn in the last two decades? Annals of Oncology, 13:197-207, 2002).

The importance of the above paper to Ms. Doe's case is the following:

There is the strong implication by WellPoint Blue Cross that all treatments paid for by their plan have passed the same high bar, rigorous standards of "proof of efficacy" which they are demanding of the tests we provide. But this is a false implication. In many if not most situations in which chemotherapy is used in the present era, and certainly in the situation faced `by Ms. Doe (contralateral breast and axillary disease following two different forms of chemotherapy), the value of the chemotherapy itself has yet to be clearly established in an objective fashion.

But our service is one step removed from treatment, itself. Our service is laboratory testing. And WellPoint Blue Cross is demanding proof that the use of our laboratory testing improves patient outcomes when it hasn't even been clearly established that chemotherapy itself improves treatment outcomes, much less that certain forms of empiric treatment are better than other forms of empiric treatment.

The implication that existing treatment methods have been proven at the level of the high bar standards demanded of our laboratory testing is simply incorrect. Furthermore, as will be discussed below, the service we provided was laboratory testing, and not treatment, and there are NO laboratory tests (or radiographic tests, as well) which have EVER been shown to improve the results of treatment. This is true of many precisely analogous tests for which WellPoint Blue Cross routinely provides coverage and payment (discussed below).

Thus, denial of coverage for the testing services provided to Ms. Doe constitutes a clear breach of contract, as WellPoint Blue Cross does not apply its coverage standards in an objectively consistent manner, but rather selectively applies these standards in a manner which is advantageous to WellPoint Blue Cross and disadvantageous to its subscribers, who paid their premiums with the expectation of consistently applied standards of reimbursement for health care expenses.

Analysis of BlueCross/BlueShield Association document, entitled "Chemotherapy Sensitivity and Resistance Assays."

The first thing that should be said is that the US Supreme Court has determined that objective, scientific facts are more important in these matters than are the existing opinions in the medical community (Daubert v Merrel Dow Pharmaceuticals, Inc; 113 S Ct 2786, 1993). So I would like to focus attention on the facts, themselves, and not merely on the conclusions of a panel which was clearly lacking in competence.

This 37 page document is deceptively complex, but close analysis reveals it to be superficial, incomplete, erroneous, and largely irrelevant and misleading.

The document can be divided into 4 main parts.

Part one is a general background description of the rationale for the assays (tests) and a brief description of some of the assay technologies.

There are no major problems with this section, although the authors fail to recognize the distinction between the two main categories of assays: (1) assays based on inhibition of cell proliferation as an endpoint (e.g. the long abandoned colony-forming assay which was the subject of WellPoint's non-coverage policy dating to 1983, see above) and (2) assays based on cell death as an endpoint (e.g. the DISC, MTT, ATP, and fluorescein diacetate assays). These later assays, upon direct comparison with each other, provide largely similar results, but results which are dissimilar to those provided by the cell proliferation assays. This is important, because virtually all of the clinical trials of assay-directed therapy discussed in the last (4th) part of the BlueCross/BlueShield association document utilize the cell proliferation endpoint and are, thus, irrelevant to the assays (based on cell death) which were applied as a service to Ms. Doe. A more detailed (and well-referenced) discussion of the different assay endpoints may be found in the enclosed review papers authored by me (one of which is extensively quoted in the BlueCross/BlueShield Association document).

Part two is a review of the published literature pertaining to the ability of the assays to accurately distinguish between "good drugs" (drugs which help the patient) versus "bad drugs" (drugs which don't help the patient).

The only source for these data cited in the BC/BS Association document is, in fact, a review paper authored by me, and quoted in the BC/BS Association document bibliography (Weisenthal, LM: "Cell culture drug resistance testing (CCDRT) cell death assays: misconceptions versus objective data." nb: this review paper is enclosed with this response and is available on the Web: http://weisenthal.org The paper reviewed 35 published studies testing the ability of cell death assays (the assays applied to the tumor specimens from Ms. Doe) to distinguish between "good drugs" (defined above) and "bad drugs." This included 1,603 published correlations between assay results ("sensitive" versus "resistant") and patient response to chemotherapy (50% or greater reduction in the size of cancerous tumors caused by the chemotherapy) or non-response to chemotherapy.

It is important, first of all, to note that the BC/BS Association document did not find fault with any aspect of my review and this may be taken as an endorsement of the accuracy of the scholarship which went into my review.

Quoting from page 12 of the BC/BS Association document: "patients receiving a drug that tested sensitive were 1.44 times [i.e. 44%] more likely to respond compared to all patients treated in these studies [while] patients testing resistant were approximately one quarter [nb: actually 0.23] as likely to respond as all patients." Now, it is critically important to understand the implications of the above, unchallenged data: Patients receiving treatment with drugs testing "sensitive" enjoyed a 6-fold advantage (1.44/0.23 = 6.23) over patients treated with drugs testing "resistant." These data included both patients with solid tumors (e.g breast cancer, lung cancer, etc.) and hematological (blood system) tumors (e.g. leukemia, lymphoma). In the case of solid tumors only, the advantage to receiving sensitive versus resistant drugs was 9.3 fold. In the case of breast cancer, it was more than 10-fold. Furthermore, patients receiving "sensitive" drugs were shown, in many studies (referenced in both of the enclosed review papers authored by me), to enjoy significantly longer durations of survival than patients treated with "resistant" drugs. The above data are extensive, consistent, unrefuted in either the scientific literature or the BC/BS Association document, and of greatest relevance to the clinical use of these assays in cancer medicine today.

Note that the unknown authors of the BC/BS Association document raise a very misleading concern on page 11 of their document: "The PPV [positive predictive value] of 79.1% indicates that a positive test result would be false in 20.9% of cases; a rate that may concern practitioners and patients. The NPV [negative predictive value] of 87.4% shows that a negative test result would be false 22.6% of the time." Firstly, their math is wrong. An NPV of 87.4% actually shows that a negative test result (in the theoretical population of patients under consideration) would be false only 12.6% of the time, and not 22.6% of the time. Of much greater importance, however, what this means is that patients treated with a "positive" ("sensitive") drug would respond 79.1% of the time, while patients treated with a "negative" ("resistant") drug would respond only 12.6% of the time. Once again, there would be a huge advantage to the patient to receive a "positive/sensitive" drug, compared to a "negative/resistant" drug.

In summary, the published literature, without any controversy whatsoever, documents the accuracy of these assays to distinguish between "good" treatments and "bad" treatments. This has always been the only factor required to document the clinical utility of any test used in cancer medicine; namely the demonstration that test has a degree of accuracy that reasonable people would accept as being clinically useful in the management of patients. As will be discussed below, there are a number of precisely analogous tests widely used (and universally reimbursed) in the treatment of cancer patients (including breast cancer patients) which have been documented only to be acceptably accurate, while not a single test of any kind used in the management of cancer patients has been documented to actually improve the results of cancer treatment. Recall, in this regard, the study of Xu, et al, published in Breast Cancer Treatment and Research, documenting the ability of the assays to improve treatment results, compared to a control group of patients in whom testing was not performed. Thus, the documentation of the utility of cell death assays in cancer treatment goes beyond that of any other tests currently used in cancer treatment. Specific examples will be given at the end of this critique.

The third part of the BlueCross/BlueShield Association paper is an obtusely complex and ultimately worthless and irrelevant attempt to determine if the technique of "decision analysis" may be used to compare the value of decision options.

Without going into a critique of the sometimes irrelevant considerations of this part of the BC/BS Association paper (e.g. the unavailability of tumor to sample, failure of the tumor cells to survive in culture, etc. are considerations obviously irrelevant to patients such as Ms. Doe, in which tumor was available and in which the cells did survive, etc.), let me just state that I concur entirely with their overall conclusion involving their tool of decision analysis:

"Given the uncertainties noted, decision analysis would not be a useful tool for assessing the relative effectiveness of assay-guided single agent treatment and empiric treatment...[additionally]...performing a decision analysis comparing assay-guided combination therapy and empiric therapy may be even more problematic...Thus, conducting a decision analysis would not be feasible."

The fourth part of the BlueCross/BlueShield Association paper is an "Assessment based on direct evidence," which, in this case, refers specifically to evidence that the performance of cell culture drug sensitivity/resistance testing actually improves clinical outcomes.

Briefly stated, the authors stated that they found 7 papers relating to this issue. In point of fact, 6 of the 7 papers they discuss are utterly irrelevant to the cell death assays applied in the case of Ms. Doe's breast cancer, and the authors failed to identify, consider, and discuss the two most important and relevant papers which directly relate to the ability of cell death assays to improve cancer treatment outcomes. 6 of the seven papers deal either with variations of the old clonogenic, colony-formation, cell proliferation assays or else deal with assays performed on sub-cultured, short-term cell lines and not fresh tumors.

These are very important distinctions, as discussed on pages 27 - 34 of my review paper which was quoted in the BC/BS Association paper ("Cell culture drug resistance testing cell death assays: misconceptions versus objective data"). The authors of the BC/BS Association paper, not having any expertise in this field, fail to understand that comparing cell proliferation assays (including assays performed on sub-cultured cells and especially monolayer assays on subcultured cells) with cell death assays performed on fresh tumors in three dimensional clusters is like comparing cats to dogs or apples to oranges. Such comparisons are odious and irrelevant; the only studies relevant to fresh tumor, cell death assays are studies performed using fresh tumor, cell death assays.

As just noted, the authors completely ignored the two most important studies of clinical outcomes with fresh tumor, cell death assay-directed chemotherapy. The first of these was the breast cancer study by Xu and colleagues, discussed above, showing a 77% response rate with assay-directed therapy, compared with a 44% response rate with empiric therapy (P<0.01).

The second study was by Kurbacher and colleagues in previously-treated ovarian cancer (Anticancer Drugs, 9:51-57, 1998). 25 ovarian cancer patients received assay directed therapy and were compared with a control group of 30 non-randomized but well-matched patients. The assay-directed group had a response rate of 64%, while the control group had a response rate of 37% (P=0.04). Two patients in the control group enjoyed complete remissions (complete disappearance of all known areas of cancer), compared with 8 patients in the assay-directed group. The median time before the tumor was documented to grow again in the control group was 20 weeks, compared with 50 weeks in the assay-directed group (P=0.003). The median overall survival in the control group was 69 weeks, while the median overall survival in the assay-directed group was 97 weeks (P2=0.145).

The one relevant study which was included in the BC/BS Association paper was the older pilot study by Wilbur, et al (Brit J Cancer, 1992). Twenty-five patients received assay directed therapy (this was during the mid-1980s), with a 36% response rate, which was relatively good for chemotherapy studies published in that era, while 4 patients received empiric therapy, with no responses. This early study was obviously too preliminary to allow for any conclusions.

Now, I stipulated in my testimony that controlled clinical trials to prove that assay-directed therapy was superior to empiric therapy were not conclusive beyond the shadow of a doubt, although, as noted above, the published data which currently does exist (the most important of which were entirely ignored in the BC/BS Association review) is entirely consistent with assay-directed chemotherapy being superior to empiric (trial and error) chemotherapy. These data from controlled clinical trials are entirely consistent with the extensive clinical correlation data (conclusively documenting the ability of the assays to sort drugs into clinically-meaningful good drug versus bad drug categories). Furthermore, these controlled clinical trials provide direct evidence to support the expectation (from the much more extensive clinical correlation studies) that using assay results to select from among "good/positive/sensitive" drugs and to avoid "bad/negative/resistant" drugs is generally advantageous to the cancer patient.

Lastly, I would like to emphasize (with specific examples) the centrally important point relating to WellPoint Blue Cross's denial of benefits to Ms. Doe in denying reimbursement for out testing.

WellPoint Blue Cross (as well as the BlueCross/Blue Shield Association) is being arbitrary and capricious in its patently inconsistent application of review standards in coverage decisions. The contorted (and incompetent) attempts to document that cell death assays have not been proven to improve treatment results are relevant only if other medical tests (and treatments) are held to the same high bar standards.

I charge that not only has it not been shown that WellPoint Blue Cross reimbursed medical tests have not consistently met this standard but that they have NEVER met this standard. Thus, WellPoint Blue Cross is applying an entirely unprecedented standard of coverage, in clear violation of its contractual obligations to its subscribers, including Ms. Doe.

The following are examples of medical tests (laboratory tests and radiographic tests) which are routinely used by oncologists in making treatment decisions involving the choice of anticancer drugs and routinely paid for by WellPoint Blue Cross which have NEVER been documented to improve the results of cancer treatment.

1. Estrogen Receptor (ER) testing to select or deselect drugs such as tamoxifen versus cytotoxic chemotherapy.

2. Her2/Neu testing to select or deselect the drug Herceptin versus cytotoxic chemotherapy.

3. Serial radiographic imaging studies (CT scans, MRI scans, PET scans, ultrasound scans, etc.) to monitor the growth or shrinkage of a known tumor to determine whether a given form of chemotherapy should be continued or whether a different form of chemotherapy should be given, instead.

All of the above tests have only been shown to have a degree of accuracy which is considered to be clinically useful. Never has it been shown that the use of any of the above tests actually improves clinical outcomes (response rates, quality of life, progression-free survival, or overall survival) compared to managing patients without the use of these tests.

And there are additional considerations relating to the above tests which raise the obvious issue of applying standards arbitrarily and capriciously in the selective denial of benefits under terms of insurance contracts.

For example, ER testing (universally reimbursed by WellPoint Blue Cross) has been documented to have a "true positive" rate averaging about 60%, with a "false negative" rate of about 10%. Thus, ER testing shows an approximate 6-fold differential in probability of clinical benefit for tamoxifen treatment in patients testing "positive" versus patients testing negative. This is, of course, by no means superior to the documented accuracy of cell death assays for drug resistance, as documented in the enclosed review papers authored by me and in the BlueCross/BlueShield Association review. However, the above data concerning the accuracy of ER assays come from studies in which expert laboratories performed the ER testing.

Recently, there has been alarming criticism that most of the ER testing performed (and reimbursed) in the USA is being performed in general hospital laboratories using methods which have not even been documented to correlate with clinical response, much less documented to improve treatment outcomes. The lack of data correlating ER testing as performed (and reimbursed by WellPoint) today with clinical response was extensively discussed in the trade news journal ONCOLOGY TIMES (Volume 23, No. 10, October, 2001). As stated in this article: "About five years ago, however, labs around the world stopped using ligand-binding assays [i.e. the previous method, which had been shown to correlate with response, though not shown to improve treatment results] and started doing IHC [a new and different method]...'These labs adopted this test and assumed it was as good as the ligand binding assays, but there was absolutely no proof of equivalence,' Dr. Allred [a Baylor University pathologist] noted. 'we are now where we were 20 years ago...we are in the first few years of using IHC, and nobody is doing this test the same way."

As another example, the Hercep-Test, the most commonly used method for Her2/neu testing (used to select or deselect chemotherapy with the very expensive new agent Herceptin versus other forms of chemotherapy) was not even documented to correlate with clinical response to Herceptin, and has certainly never been documented to improve treatment outcome (D. Craig Allred, MD, Baylor University pathologist, quoted in the above-referenced ONCOLOGY TIMES article). Yet WellPoint Blue Cross routinely reimburses for Her2/neu testing (most commonly performed with the Hercep-Test).

The example of serial radiographic imaging tests (which I also cited during my oral testimony) is particularly relevant.

These are very expensive tests (CT scans, MRI scans, PET scans, ultrasound tests). The idea is to "follow" the size of the patient's tumor while the patient is receiving repeated courses of chemotherapy to determine whether or not the treatment is working and whether or not different drugs should be given, instead. This is intuitively logical, but is of entirely unproven benefit, and I strongly doubt that, were the appropriate studies ever to be performed, there would be any measurable benefit at all, in terms of improving patient response to chemotherapy or patient survival with chemotherapy.

The alternative to performing thousands of dollars' worth of serial imaging studies (often at great inconvenience to the patients and sometimes at the cost of considerable physical discomfort to the patients) is to base clinical decisions concerning the efficacy of chemotherapy on simpler, much cheaper criteria readily available to all oncologists. Take a good medical history; ask the patient how he/she is feeling and how this has changed since chemotherapy was begun. Do a good physical examination (including simply weighing the patient and compare with previous weights before and during treatment). Is there evidence on physical exam that the patient is improving or worsening? Supplement the above with some relatively simple and inexpensive blood tests and plain, ordinary x-rays, when indicated. Now, if one were to perform randomized trials to "prove" response or survival benefit associated with the use of serial radiographic imaging tests, how many patients and how many years would this take? And does anyone seriously believe that an advantage would be shown? I, for one, as a board certified oncologist, seriously doubt it. Just as I, as a board certified oncologist, strongly believe that there is a clear benefit in the management of patients such as Ms. Doe, in performing drug resistance/sensitivity tests.

The purpose of these tests is to categorize the many drugs which might otherwise reasonably be chosen with respect to the relative likelihood of each drug providing clinical benefit. The oncologist thus has direct information about the relative activity of each of the tested drugs to add to all the other available information in making the best possible decision to help patients who are in truly difficult circumstances.

The medical literature conclusively documents that the tests we used on behalf of Ms. Doe are capable of providing this information. And Ms. Doe's testing was performed by a laboratory with established extensive experience and expertise.

Based on common sense inferences based on a solid medical literature; based on the sound judgement of Ms. Doe's expert oncologists; and based on WellPoint Blue Cross's own established reimbursement precedents, there is simply no reason to deny Ms. Doe the reimbursement to which she is contractually entitled.

Lastly, I would like to address the contention that, should this case be found in favor of Ms. Doe, the amount of payment to which she would be entitled under the terms of her WellPoint Blue Cross contract would be only $550. WellPoint Blue Cross apparently arrived at this figure by unilaterally determining what it deemed to be the appropriate cost of our services and then reducing this amount by some percentage on the basis of the fact that I am a non-participating provider.

Firstly, it is utterly outrageous that WellPoint would attempt to price our services without having made any attempt whatsoever to research what actually goes into providing these services, what are the costs associated with providing these services, and what is the usual and customary payments actually received by us for providing these services on behalf of our patients.

Attached is a description of our usual and customary charges, the vast majority of which are actually paid at this amount, as well as a brief description of what goes into the services provided. It should be noted that our charges are actually lower than those of the handful of other laboratories providing cell culture drug resistance/sensitivity testing, despite the fact that our procedures are much more extensive than those of all other laboratories. The attempt by WellPoint to price our services in a vacuum, without any attempt to research costs of providing the specific services in question, and without researching usual and customary charges and payments is consistent with their arbitrary and capricious policies with regard to general coverage for medical testing, as discussed above.

Secondly, the attempt to reduce benefits on the grounds that I am a non-participating provider is a blatantly malicious attempt to punish Ms. Doe for taking them to court over their breach of contract. It is also an attempt to discourage future WellPoint subscribers from utilizing our testing services as a component of their overall medical care in their battle with cancer.

It must surely be realized that the whole purpose behind reimbursing participating providers at a higher rate is to direct patients to physicians who have negotiated with WellPoint to accept lower fees in return for a higher percentage reimbursement level and to be listed on WellPoint literature and therefore to be preferentially chosen by patients seeking medical care. This is a good and efficient method of holding down overall costs of healthcare. But this method cannot be applied in cases where there are NO participating providers of a given service. In such cases, the patient has no option to receive care from a participating provider, as there are no participating providers. Although I have never personally seen Ms. Doe's insurance contract, I would be astonished to learn that the policy does not provide for coverage of life and death medical procedures in situations where there are no "participating providers" of the needed procedure.

When I raised the above point during the trial, Mr. Loftin objected that there is another provider of our services (namely Oncotech, a company I founded in 1985, but with which I have not been associated since January, 1992). But this is grossly misleading for the following reasons:

1. Oncotech, besides offering a specific type of cell culture drug resistance test, see below, is a general pathology laboratory. As a general pathology laboratory, Oncotech provides an array of laboratory testing services for which WellPoint does routinely provide reimbursement. Thus, Oncotech is a "participating provider" of general pathology services. In my own case, I do not provide general pathology services, but only provide cell culture drug resistance/sensitivity testing, and, thus, am not in a position to be a participating provider, because I do not provide any services for which WellPoint willingly provides reimbursement. It should be noted that WellPoint does NOT provide reimbursement to Oncotech for its cell culture drug resistance tests, but only for Oncotech's other, general pathology tests.

2. The patient did not have the option of receiving the tests we performed from Oncotech or from any other WellPoint participating provider. Recall the clear distinction between assays based on cell proliferation and cell death, discussed earlier. Recall that all the data cited in my reviews (and in the BlueCross/BlueShield Association review) pertained ONLY to studies using the cell death endpoint and not the cell proliferation endpoint, which provides different information. As clearly explained on Oncotech's own reports and in its promotional literature, that Oncotech performs a cell proliferation assay (not a panel of cell death assays, as in the case of my laboratory), which should only be used to identify drugs which are unlikely to be active (i.e. for negative selection of drugs) and should not be used to identify drugs with above-average probabilities of providing clinical benefit (i.e. for positive selection of drugs).

In the case of Ms. Doe, a patient with persistent/recurrent disease following chemotherapy with multiple drugs, her oncologists were specifically interested in identifying active drugs, which should be used, as well as avoiding inactive drugs, which should not be used. Therefore, they referred Ms. Doe's tumor biopsies to our laboratory to obtain this information, and there are no laboratories which are WellPoint participating providers which were available to perform the testing services which we provided on her behalf.

For the above reasons, Ms. Doe should be reimbursed by WellPoint for the full cost of our services, and not at the punitively low level sought by WellPoint. Whether Ms. Doe is entitled to additional compensation for the unnecessary ordeal through which she has been forced to undergo and whether we physicians (Dr. McKee and me) are entitled to any compensation for our expenses in supporting Ms. Doe's actions against WellPoint, are matters beyond my expertise, but, if appropriate, I hope that consideration may be given to these latter issues, as well.

Sincerely yours,

Larry M. Weisenthal
4-25-2002