Appendix
Developing Biomarker-Based Tools for Cancer Screening, Diagnosis,and Treatment: The State of the Science, Evaluation, Implementation, and Economics, Workshop Summary

Margie Patlak and Sharyl Nass, Rapporteurs



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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Appendix Developing Biomarker-Based Tools for Cancer Screening, Diagnosis,and Treatment: The State of the Science, Evaluation, Implementation, and Economics, Workshop Summary Margie Patlak and Sharyl Nass, Rapporteurs

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract Nos. HHSH25056133, HHSN261200611002C, 200-2005-13434, HHSM-500-2005-00179P, HHSP23320042509XI, and 223-01-2460 between the National Academy of Sciences and the Department of Health and Human Services. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-10 0-309-10134-4 International Standard Book Number-13 978-0-309-10134-9 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2006 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment INTRODUCTION Research has long sought to identify biomarkers that could detect cancer at an early stage, or predict the optimal cancer therapy for specific patients. Fueling interest in this research are recent technological advances in genomics, proteomics, and metabolomics that can enable researchers to capture the molecular fingerprints of specific cancers and fine-tune their classification according to the molecular defects they harbor. The discovery and development of new markers of cancer could potentially improve cancer screening, diagnosis, and treatment. Given the potential impact cancer biomarkers could have on the cost effectiveness of cancer detection and treatment, they could profoundly alter the economic burden of cancer as well. Despite the promise of cancer biomarkers, few biomarker-based cancer tests have entered the market, and the translation of research findings on cancer biomarkers into clinically useful tests seems to be lagging. This is perhaps not surprising given the technical, financial, regulatory, and social challenges linked to the discovery, development, validation, and incorporation of biomarker tests into clinical practice. To explore those challenges and ways to overcome them, the National Cancer Policy Forum held the conference “Developing Biomarker-Based Tools for Cancer Screening, Diagnosis and Treatment: The State of the Science, Evaluation, Implementation, and Economics” in Washington, D.C., from March 20 to 22, 2006.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment At this conference, experts gave presentations in one of six sessions: Brief overview of technologies, including genomics, proteomics, metabolomics, and functional imaging Overcoming the technical obstacles, with presentations on informatics and data standards, and biomarker validation and qualification Coordinating the development of biomarkers and targeted therapies, with a clinical investigator and representatives from industry and the National Cancer Institute offering their perspectives Biomarker development and regulatory oversight, including current regulations governing biomarker tests as well as new clinical trial designs needed to incorporate biomarker tests that predict patient responders Adoption of biomarker-based technologies, with discussion on what motivates private insurers and Medicare to cover biomarker-based tests and what various organizations consider when recommending such tests be adopted into clinical practice Economic impact of biomarker technologies, with an exploration of cost-effectiveness analyses of biomarker tests and a payor perspective on the evaluation of such tests In addition, seven small group discussions explored the policy implications surrounding biomarker development and adoption into clinical practice: Clinical development strategies for biomarker utilization Strategies for implementing standardized biorepositories Strategies for determining analytic validity and clinical utility of biomarkers Strategies to develop biomarkers for early detection Mechanisms for developing an evidence base Evaluation of evidence in decision making Incorporating biomarker evidence into clinical practice This document is a summary of the conference proceedings, which will be used by an Institute of Medicine (IOM) committee to develop consensus-based recommendations for moving the field of cancer biomarkers forward. The views expressed in this summary are those of the speakers and discussants, as attributed to them, and are not the consensus

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment views of the participants of the workshop or of the members of National Cancer Policy Forum. OVERVIEW OF TECHNOLOGIES USED TO DISCOVER CANCER BIOMARKERS Technology is constantly evolving and recent technological advances have made it easier to discover many potential cancer biomarkers through high-throughput screens. Advances in imaging technology also are furthering the discovery and use of biomarkers. The goal of the first session of the conference was to provide a brief overview of the technologies currently being used to identify and develop cancer biomarkers (Figure 1). Genomics, Proteomics, and Metabolomics Todd Golub, MD, of the Dana-Farber Cancer Institute, began by discussing several of the genomics-based techniques commonly used to discover biomarkers for cancer detection or for patient stratification for therapy. Some of these techniques detect changes at the DNA level (are DNA-based), whereas others detect changes at the RNA level and are considered RNA-based. Dr. Golub explored which type of genomics test—DNA based or RNA based—would be likely to serve as a better biomarker if cost were not an issue. DNA-based tests are advantageous because DNA is more stable than RNA, and because most changes related to cancer occur at the DNA level, he said. But he noted that perhaps one could make a stronger argument for RNA-based tests because not only can they detect oncogenic RNA missteps, but molecular signatures at the RNA level also help reveal upstream DNA-level abnormalities that could contribute to a cancer. These abnormalities include base substitutions, and amplifications or deletions that alter the copy number or heterozygosity of specific genetic sequences. Dr. Golub noted that studying epigenetic changes in DNA, such as methylation, and genome rearrangements, such as chromosome translocations, can also lead to discovery of important cancer biomarkers, although he did not have time to address these topics in his presentation. Although early genetic analyses of cancers focused on detecting changes in the copy number of genes, Dr. Golub stressed that it is also important to screen for loss of heterozygosity (LOH). LOH can occur without a change

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment FIGURE 1 The spectrum of potential biomarkers suggests that no single technology can cover the entire biomarker space. TG = triglycerides; Aβ = β-amyloid; HbA1c = hemoglobin A1c; PSA = prostate-specific antigen; CRP = C-reactive protein; CGH = comparative genomichybridization; SNP = single nucleotide polymorphism; eCRF = electronic case report form; eMR = electronic medical record. SOURCE: Adapted from Schulman presentation (March 20, 2006).

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment in gene copy number, he noted, if both alleles for a specific gene have been mutated or epigenetically altered. This copy-neutral LOH may account for as much as half of all LOH in the genome. Two main types of arrays are used to detect changes in copy number or LOH linked to cancer. Single nucleotide polymorphism (SNP) arrays have between 50k and 500k SNPs across the genome and can detect both copy number changes and other forms of LOH. Comparative genomic hybridization arrays can detect changes in copy number of DNA content, but are unable to detect LOH in which the copy number remains the same. For this reason, Dr. Golub prefers SNP arrays for detecting cancer biomarkers. Higher density SNP arrays can give sharper resolution by reducing the signal-to-noise ratio than lower density SNP arrays, he pointed out. But the optimal amount of density that is the most cost-efficient means for detecting cancer biomarkers remains to be determined. Standard DNA sequence analysis of tumor samples as a means of detecting cancer biomarkers has numerous drawbacks, which Dr. Golub pointed out. Not only is it difficult and costly to do, but it is frequently inaccurate, causing false negatives because of normal tissue contamination of the tumor samples used. Most tumor samples contain a mixture of normal cells, such as inflammatory cells, as well as tumor cells. Because the Sanger sequencing results are an average of both the normal and tumor cells in a sample, normal genome contamination can obscure mutations in tumor cells that might serve as cancer biomarkers. However, newer techniques, such as single-molecule sequencing, may substantially lower the cost of sequencing, and should avoid the problems of normal cell contamination that plague standard sequencing efforts. “I think this is exactly the type of technology, even if cost neutral, that would dramatically accelerate our ability to detect important mutations in cancer,” Dr. Golub said. To exemplify this, Dr. Golub reported on results from his colleagues at Dana-Farber who used single-molecule sequencing to detect a mutation that was linked to resistance of the drug Iressa in a lung cancer patient. The lung fluid sample the researchers analyzed only had 3 percent tumor cells, and a standard Sanger sequencing analysis missed the mutation. Once a genetic signature with likely clinical relevance has been discovered, custom-made arrays that only have the gene sequences of interest need to be made for preclinical or clinical testing. Dr. Golub described a few genetic signature amplification and detection platforms useful for such testing, including a Luminex bead-based method. For this method, the genetic

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment material is amplified using polymerase chain reaction. The genetic signature is then read not on microarrays, but on miniscule color-coded beads that are detected by lasers in a flow cytometer. This is an inexpensive way to detect genetic signatures, costing about 50 cents for every 100 transcript signatures. One can also use the standard mRNA expression profiling platforms that are commercially available. These are all sufficiently accurate and precise to be used in a clinical setting to detect genetic signatures, according to Dr. Golub. Cost and throughput will be significant drivers of this technology, he added. The next presentation was on proteomics and metabolomics technologies, given by Howard Schulman, PhD, of PPD Biomarker Discovery Sciences. One of those techniques, which Dr. Schulman described as the traditional proteomic workhorse, uses two-dimensional polyacrylamide gels for the separation stage. This is a slow process that is less amenable to high-throughput. Surface-enhanced laser desorption/ionization is a high-throughput technology that can more quickly separate the proteins in a sample, but identifying the protein peaks is a challenge. That identification process can be bypassed by using software to differentially identify patterns of protein peaks to find a molecular fingerprint that can distinguish cancerous from noncancerous tissue. This fingerprint is based on the amounts of all the various proteins detected, without knowledge of what those individual proteins are, Dr. Schulman noted. However, it can be problematic to translate mass spectroscopy fingerprints into a clinical diagnostic test without identifying or further characterizing those proteins. One- and multidimensional liquid chromatography are also used to separate peptides in a sample (after protein digestion) that a mass spectrometer can differentially quantify and then identify (Figure 2). But the amplitude for each of the peptides can vary depending on the composition of the mixture, which makes it hard to compare one person’s sample with another’s, and one batch run versus another. This has proven problematic for researchers trying to develop cancer biomarkers based on differential quantification, otherwise known as molecular fingerprinting. To improve such differential accuracy, researchers developed a method called isotope-coded affinity tags several years ago. This technique labels a portion of a sample with a mass tag and runs both labeled and unlabeled samples through the mass spectrometer at the same time. The labeled sample serves as a sort of baseline control for the unlabeled sample. This helps normalize or eliminate a lot of the peak amplitude variability due to differences in mixture composition. But this is a more costly method because

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment FIGURE 2 One-dimensional and multidimensional liquid chromatography LC-LC/MS. LC = liquid chromatography; MS = mass spectroscopy; MW = molecular weight; HPLC = high-performance liquid chromatography; ESI = electrospray ionization. SOURCE: Schulman presentation (March 20, 2006). of the need for the reagents, and it has some bias introduced by the type of tag used, according to Dr. Schulman. The field is rapidly adopting a label-free approach in which chromatographic separation techniques and mass spectrometry are coupled with software-based solutions for normalizing the variation in amplitude signal due to differences in mixture composition to yield accurate differential expression data. Dr. Schulman concluded his talk by noting that the current state of proteomics is comparable to the early days of microarrays, which could detect about one-sixth the number of genetic sequences that can now be detected. But proteomics is still highly effective even without the ability to profile every protein, he said. He noted that one can profile more than a thousand proteins by using multidimensional chromatography. But the tradeoffs with more fractionation are lower throughput (due to slower processing) and higher costs. The advantage of proteomic and metabolomic profiling is that you can sample readily accessible tissues, such as plasma and urine, that are ideal for monitoring biomarkers in clinical trials and testing diagnostics.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment He also noted that the lowest abundance proteins, such as cytokines or other signaling molecules, will likely require antibody-based protein chips to complement liquid chromatography separation techniques. Sensitivity to such proteins could also be increased by using samples likely to have higher concentrations of biomarkers of interest. For example, cerebral spinal fluid could be tapped to find biomarkers for lymphoma metastases in the central nervous system, or prostatic fluid could be used to detect biomarkers for prostate cancer. Affinity capture of protein subcategories, such as phosphorylated proteins, could also selectively profile lower abundance proteins of interest. Drs. Schulman and Golub stressed the need to experimentally validate the biological basis and importance of detected genetic or proteomic differences in a disease process. For example, researchers in Dr. Golub’s laboratory used high-density expression arrays to detect an RNA signature in bone marrow samples that correlated with response to a drug for myelodysplastic syndrome. They found a group of genes that were only highly expressed in patients who responded to the drug. Many of these genes previously had been identified as markers for late red blood cell differentiation, leading to the hypothesis that such differentiation may be predictive of drug response. To test this idea, they induced normal immature blood cells to differentiate into red blood cells. They found that all of the genes, whose boosted expression was linked to drug response in their biomarker discovery study, also had heightened expression during the red blood cell differentiation that occurred in their experiments. This validated their hypothesis and put the concept of genetic signature for drug response on firmer footing. “The most valuable and robust biomarkers will be those that have some component of experimental validation accompanying them,” Dr. Golub said. He added that “the challenge looking forward is going to be to move from simply cataloging mutations or genome abnormalities to coalescing those abnormalities into more of a molecular taxonomy that brings biological understanding to this catalog. The more we can integrate these anonymous molecular signatures with biological knowledge, the more they’re likely to stick.” Dr. Golub also pointed out the need to develop biomarker diagnostics that can easily be used on the paraffin-embedded or formalin-fixed tissues that are routinely collected in the clinic. “We need to make the technology work for those routinely collected samples rather than retrain the medical community to collect samples in a different way,” Dr. Golub said.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Drs. Golub and Schulman noted that a lack of good-quality samples can be a stumbling block for biomarker discovery. Rarely are enough samples collected in a clinical trial, and those samples that are collected are usually fixed in formalin, which can affect their ability to be analyzed in a mass spectrometer. Dr. Schulman suggested that pharmaceutical and biotechnology companies have experimental medicine groups that are best positioned to collect the samples required to discover biomarkers. But the biggest impediment for biomarker development, which Drs. Golub and Schulman both cited, was a lack of a critical mass of research in the discovery phase. “The bottleneck is not so much on the regulatory side or the validation side, but that not enough of the discovery effort has been made,” said Dr. Schulman. As to whether such efforts at biomarker discovery should take a hypothesis-driven or open-ended approach, Drs. Golub and Schulman agreed that both approaches were necessary. Open-ended discovery aims at uncovering a molecular understanding of a particular type of cancer that may eventually lead to useful biomarkers. A hypothesis-driven approach, in contrast, is more streamlined at finding molecular changes likely to predict a response to therapy or some other useful clinical endpoint. There is a role for both these approaches, Dr. Schulman said. But he added that pharmaceutical companies are unfortunantely more likely to conduct a hypothesis-driven search for biomarkers that predict drug response than to support a more open-ended search. Dr. Golub noted that the danger of conducting only hypothesis-driven research on biomarkers is that it does not address the challenge of “how do we get beyond discovering what we already know, in terms of biological knowledge?” Molecular Imaging Next, Michael Phelps, PhD, of the University of California, Los Angeles, discussed molecular imaging biomarkers for drug discovery, development, and patient care. He described how positron emission tomography (PET) can be used as a molecular camera to image in vivo processes at the molecular level. But PET is more than an imaging device, as it also can be used analytically to perform a variety of quantitative biochemical and biological assays. There are currently about 600 PET probes for metabolism, receptors, enzymes, DNA replication, gene expression, antibodies, hormones, drugs, and other compounds in nanomole amounts. Typical antibody probes get

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment smears, volume requirements akin to what is required for radiologists who read mammograms, and requirements for collecting, analyzing, and reporting data on test performance. There was no consensus on which measures, if any, should be pursued to improve the quality of biomarker testing. INCORPORATING BIOMARKER EVIDENCE INTO CLINICAL PRACTICE DISCUSSION Moderator Robert McDonough, MD, of Aetna U.S. Healthcare summarized his group’s discussion on incorporating biomarker evidence into clinical practice. He noted that there are many sources of information on biomarkers that reach clinicians, including journals, colleagues, product vendors, patients, popular media, practice guidelines, clinical trials abstracts, meetings, and continuing medical education. But when the group evaluated what prompts clinicians to adopt biomarker tests into their clinical practices, evidence-based information was not high on the list. “If you are looking at the screening for cancers, there is no correlation between the strength of the evidence and adoption,” said discussant Mark Fendrick, MD, of the University of Michigan. For example, an impressive 75 percent of the target population undergoes regular screening for prostate cancer, despite the fact the USPSTF gave it an unimpressive I rating. This is in contrast to the 50 percent of the target population who undergo regular colon cancer screening, which the USPSTF gave its highest rating because of its proven effectiveness. Academic practitioners appear to be more influenced by evidence, however, and may delay adopting a new test until there is evidence showing its effectiveness, several discussants agreed. This is in contrast to community practitioners, who may more readily adopt a new test or drug, even when there is little to no evidence of its clinical value. As a consequence, once a product enters the market, it may be impossible to gather the evidence on a test’s clinical value because of difficulties accruing patients to serve as controls for the trials needed to gather that evidence. Other factors beyond evidence appeared to be more important in influencing the incorporation of biomarker tests into clinical practice, the group noted. The most influential factor they identified was reimbursement for a test at a sufficient level. “If you look at the adoption of CT scans, PSA testing, or even COX-2 inhibitors, until they were paid for, they were not used,” said Dr. Fendrick. Because most diagnostics are relatively inexpensive, insurers are more likely to reimburse their costs without scrutinizing

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment the evidence base for the test, the group also noted. “If they didn’t pay for even low-cost biomarkers unless they were validated in a proper way, that would be an incentive to do those [validation] studies,” said discussant Dr. Carbone. The promotion that health insurers and employers do for various tests also influences their use, some discussants pointed out. For example, insurers often promote preventive health tests, such as those used to screen for various cancers, via informational mailings and their websites. “Some employers give discounts on health insurance to employees who undergo a self-assessment that indicates what types of screening and other health maintenance measures they should undertake,” Dr. Carbone said. “I think it is widely adopted when you give people a buck to do it.” Another highly influential factor was whether the test was adopted by what the group called “thought leaders.” A thought leader is someone who other members of a group look to as an authority. A thought leader may be misinformed, but he or she is still influential. In academic settings, thought leaders tend to be the lead investigators of clinical studies or the chairs of departments. In clinical practices the thought leader “is the clinician down the hall who seems to be knowledgeable about what is new in medical technology,” Dr. McDonough said. He said one discussant noted that physicians who practice in groups seem to adopt technology more rapidly than solo practitioners, possibly because of the presence of thought leaders in group practices. Another potential driver for the uptake of new biomarker tests is patient requests for the tests, the group noted. Studies reveal that if a patient asks for a drug by name, there is an 80 percent chance that a physician will prescribe it, Dr. Fendrick observed. Presumably patients have the same influence over the tests they request, he suggested. Through promotional efforts, product manufacturers also influence doctors and patients to use their biomarker tests, Dr. McDonough noted. “What I always thought was an important factor was the guy who knocks on your door—the vendor of the new device or new drug or new test,” he said during his group’s discussion. Dr. Waring also noted that for a test such as the FISH test for HER2, used to determine patient responsiveness to a specific treatment, the pharmaceutical company that provides that treatment may pay the costs of the test if it is not covered by an insurance provider. This is especially the case in Europe where national health plans may not offer the test as part of their services. “Roche until recently was paying for those tests to be performed in their own central laboratories,” he

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment said. “So these tests were becoming available not because of reimbursement issues—they were being made available by the pharmaceutical company for business reasons.” Other influences on the clinical adoption of a biomarker test hinge on features of the test itself, the discussion group said. Ease of interpretation is one such feature. If the test is easy to interpret and has a simple positive versus negative result, it will be adopted more readily than a test whose results require “some kind of complex algorithm to understand,” said Dr. McDonough. Clinicians are also more inclined to adopt tests that are reliably accurate and have timely results. “If you need to make a decision today, and the test is going to take 2 weeks, regardless of how easy or reliable that test is, it may not be very clinically useful,” said Dr. McDonough. Clinicians are also more likely to adopt tests if there is little to no risk in using them, and there are no alternative tests or test-linked treatments. Insurers are also more likely to reimburse for both the test and treatment, for those that are linked, if there are no treatment alternatives and the disease the drug targets is life threatening, the group noted. Inconvenience to the patient is another important test feature that influences its adoption in the clinic. Physicians are more likely to prescribe a simple blood test than an endoscopic procedure or a test that requires a stool sample, Dr. McDonough pointed out. Practitioners are also more likely to use a test that will influence their clinical decision making. “Is it a test that might give you some idea of the prognosis of lung cancer, but will not actually influence the type of therapy you might actually give to the patient? If the test does not seem to have any influence on the clinical management we would hope that would make it less likely that a clinician would use it,” Dr. McDonough said. Like other discussion groups, Dr. McDonough’s group recognized that low profit margins on diagnostic tests act as a disincentive to the development of biomarker tests and their evaluation in clinical trials. This led to the suggestion by Dr. McGivney that payors help subsidize some of this clinical research. “A payor who is asking for evidence should actually support, in part, the development of some of that evidence,” he said. Dr. McDonough said that some insurers, such as Aetna, do pay for routine costs of their patients in clinical trials. But Dr. McGivney countered that there is an increasing trend for payors not to cover such costs. Given that reimbursement levels highly influence the adoption of clinical tests, other discussants suggested that payors tailor their copay amounts for biomarker tests based on a test’s value or degree of evidence to support

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment any positive impact on patient outcomes. Zero copayment amounts could be allotted for those biomarker tests that are highly cost effective and likely to affect clinical management. High copayments could be required for tests whose cost effectiveness is questionable due to a lack of evidence on their benefits. But the group recognized that “it would not be easy to structure a benefit program to that fine a degree of assigning copays based on someone’s assessment of cost effectiveness,” Dr. McDonough said. There would be legal issues that might be difficult to overcome, such as varying state regulations that affect copayment levels. In addition, both legislators and the insurance clientele might look askance at plans that specify high copayments for treatment-linked tests for life-threatening illnesses. For payors to more adequately influence the adoption of biomarker tests, those tests need to have their own Current Procedural Terminology (CPT) codes, group members noted. These identifying codes are established by the American Medical Association and are used to report medical procedures and services to health insurers. Health insurers then specify reimbursement rates for each code. CPT codes are also used for developing guidelines for medical care review. “Many of these biomarkers do not have specific CPT codes,” said Dr. McDonough. “They are defined by process steps so that the insurer, even if they were willing to scrutinize biomarkers, often find it difficult to know what type of biomarkers are being used. What this means is that many of these biomarkers are being incorporated into clinical practice without much scrutiny.” This is especially true for home-brew tests, which are always defined by process steps. These tests, therefore, bypass scrutiny by both regulators and reimbursers, the group noted. Even when a test has been approved by the FDA, some discussants said, there is no guarantee that laboratories will use that test. Instead, they may offer their own home-brew version of the test, which may not be as acurate. Home-brew versions of the HercepTest, Dr. Waring said, help explain the variability in accuracy among laboratories. In a discussion following Dr. McDonough’s summary, Dr. Ramsey gave an overseas perspective of health care payors playing a role in gathering clinical data to evaluate new products. For example, the United Kingdom’s National Health Service pays for a new drug at an agreed upon price, with the requirement that data on the drug’s effectiveness be collected in a patient registry. If the drug does not show effectiveness at the expected level, the drug’s price is reduced so that the total reimbursement over time

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment reflects the actual quality of life gain observed. He thought such risk sharing in drug development was valuable, and noted that the group’s suggestion that payors cover the costs of clinical trials on biomarker tests would put all the burden of risk on insurance companies. He suspected they would balk at such a suggestion and reiterated that risk sharing has some value. REFERENCES Check E. 2004. Proteomics and cancer: Running before we can walk? Nature (429), 6991: 496-497. Ellis IO, et al. 2004. Best Practice No 176: Updated recommendations for HER2 testing in the UK. Journal of Clinical Pathology 57:233-237. FDA (Food and Drug Administration), Center for Devices and Radiological Health, OVID (Office of In-Vitro Devices), Analyte Specific Reagents; Small Entity Compliance Guidance; Guidance for Industry. Letter from OIVD to Roche Molecular Diagnostics Re: AmpliChip, http://www.fda.gov/cdrh/oivd/amplichip.html. Medical Devices; Classification/Reclassification; Restricted Devices; Analyte Specific Reagents, 61 Fed. Reg. at 10,484. March 14, 1996. Michiels S, et al. 2005. Prediction of cancer outcome with microarrays: a multiple random validation strategy. Lancet 365(9458):488-492. Paik S, et al. 2002. Real-world performance of HER2 testing—National Surgical Adjuvant Breast and Bowel Project experience. Journal of the National Cancer Instititute 94(11):852-854. Perez EA, et al. 2006. HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. Journal of Clinical Oncology 24(19):3032-3038. Petricoin EF, et al. 2002. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 359(9306):572-577. Pharmaceutical Research and Manufacturers of America Biomarker Working Group presentation (2004). FDA Advisory Committee Meeting. Reddy JC, et al. 2006. Concordance between central and local laboratory HER2 testing from a community-based clinical study. Clinical Breast Cancer 7(2):153-157. Rhodes A, et al. 2004. The use of cell line standards to reduce HER-2/neu assay variation in multiple European cancer centers. American Journal of Clinical Pathology 122:51-60. Simon R, et al. 2003. Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification. Journal of the National Cancer Institute 95(1):14-18. Van de Vijver MJ, et al. 2002. A gene-expression signature as a predictor of survival in breastA gene-expression signature as a predictor of survival in breast cancer. New England Journal of Medicine 347(25):1999-2009. Wagner JA. 2002. Overview of biomarkers and surrogate endpoints in drug development. Disease Markers 18(2):41-46.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment WORKSHOP AGENDA National Cancer Policy Forum Workshop on Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment: The State of the Science, Evaluation, Implementation, and Economics National Academy of Sciences Building Auditorium 2101 Constitution Avenue, N.W. Washington, DC Agenda 2.5 days, March 20-22, 2006 Day 1—March 20, 2006 8:30 am Welcome and introductory remarks Hal Moses, MD (Vanderbilt University, Chair, National Cancer Policy Forum) 8:45-10:15 am Session 1 Brief overview of technologies Moderator: Howard Schulman Presentations: Genomics-based technologies (including DNA microarrays, CGH, and sequencing technologies) Todd Golub, MD (The Broad Institute of Harvard and MIT) Proteomics and metabolomics technologies Howard Schulman, PhD (PPD Biomarker Discovery Sciences) Technologies for physiological characterization (including functional imaging) Michael Phelps, PhD (University of California, Los Angeles)

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment 10:30 am-12:00 noon Session II Overcoming the technical obstacles Moderator: Charles Sawyers Presentations: Informatics and data standards John Quackenbush, PhD (Harvard) Biomarker validation David Ransohof, MD (University of North Carolina) Biomarker qualification: Fitness for use John Wagner, MD, PhD (Merck and Co., Inc.) 12:00 noon-1:00 pm Lunch break 1:00-3:00 pm Session III Coordinating the development of biomarkers and targeted therapies Moderator: David Parkinson Presentations: Therapeutics industry perspective/realities (examples of successes and difficulties/failures of targeted therapy) Paul Waring, PhD (Genentech) Diagnostics industry perspective (industry mission/business models/marketing strategies, & IP) Robert Lipshutz, PhD (Affymetrix) NCI/NIH perspective (goals and funding initiatives) James Doroshow, MD (National Cancer Institute) Clinical investigator perspective Charles Sawyers, MD (University of California, Los Angeles)

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment 3:15-5:45 pm Small Group Discussions Policy implications surrounding biomarker development—prioritizing problems and solutions 1) Strategies for implementing standardized biorepositories Moderators—Carolyn Compton, Brent Zanke, Hal Moses Invited Discussants—Edith Perez, Margaret Spitz, B. Melina Cimler, Indra Poola, Ann Zauber 2) Strategies for determining analytic validity and clinical utility of biomarkers Moderators—Janet Woodcock, Howard Schulman, John Wagner Invited Discussants—Walter Koch, Zoltan Szallasi, Scott Patterson, Ronald Hendrickson, David Carbone, Laura Reid 3) Clinical development strategies for biomarker utilization Moderators—Charles Sawyers, Stephen Friend, David Parkinson, Richard Simon Invited Discussants—Richard Schilsky, David Agus, Barbara Weber, Richard Frank, Robert Gillies 4) Strategies to develop biomarkers for early detection Moderators—Scott Ramsey, David Ransohof Invited Discussants—Jean-Pierre Wery, Kathryn Phillips, Larry Norton, Hongyue Dai, David Muddiman 5:45 pm Adjourn Day 1

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Day 2—March 21, 2006 8:30 am Welcome—Opening remarks Hal Moses 8:45-10:15 am Session IV Biomarker development and regulatory oversight Moderator: Janet Woodcock Presentations: FDA Critical Path Initiative Janet Woodcock, MD (Food and Drug Administration) Clinical laboratory diagnostic tests: Oversight for analytical and clinical validation Mark Heller, JD (Wilmer Cutler Pickering Hale and Dorr) Clinical trial design and biomarker-based tumor classification systems Richard Simon, DSc (National Cancer Institute) 10:30 am-12:00 noon Session V Adoption of biomarker-based technologies Moderator: Alfred Berg Presentations: CMS strategies for biomarker coverage Jim Rollins, MD, PhD (Centers for Medicare & Medicaid Services) Insurance coverage and practice guidelines William McGivney, PhD (National Comprehensive Cancer Network) Technolgy assessment and clinical decision making Alfred Berg, MD, MPH (University of Washington) 12:00 noon-1:00 pm Lunch Break

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment 1:00-2:30 pm Session VI Economic impact of biomarker technologies Moderator: Scott Ramsey Presentations: Cost-effectiveness analysis and technology adoption in the UK Andrew Stevens, MD (UK National Institute for Health and Clinical Excellence) Cost-effectiveness analysis and the value of research David Meltzer, MD, PhD (University of Chicago) The payer perspective Naomi Aronson, PhD (BlueCross BlueShield Technology Evaluation Center) 2:45-5:15 pm Small Group Discussions Policy implications surrounding biomarker adoption—prioritizing problems and solutions 1) Mechanisms for developing an evidence base Moderators—Janet Woodcock, David Parkinson, Charles Sawyers Invited Discussants—Walter Koch, Indra Poola, Laura Reid, Richard Frank 2) Evaluation of evidence in decision making Moderators—Naomi Aronson, Scott Ramsey Invited Discussants—Ronald Hendrickson, Ann Zauber, Kathryn Phillips, Barbara Weber, Robert Gillies 3) Incorporating biomarker evidence into clinical practice Moderators—Robert McDonough, William McGivney Invited Discussants—David Carbone, David Agus, Hongyue Dai, Mark Fendrick, Judith Hellerstein, Judith Wagner 5:15 pm Adjourn Day 2

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Day 3—March 22, 2006 Reports from small group discussions 8:30-10:00 am Reports from day 1 group leaders 10:15 am-12:15 pm Reports from day 2 group leaders 12:15 pm Wrap up/summary Hal Moses 12:30 pm Lunch—Adjourn