Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment The State of the Science, Evaluation, Implementation, and Economics: Workshop Summary (2006) / Chapter Skim
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Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment
Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment
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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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DEVELOPINGCANCERBIOMARKERS 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.
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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)
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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.
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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.
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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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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.
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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.
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A probe for an estrogen receptor may be used to determine if breast cancer metastases are likely to respond to hormonal therapy. PET is especially useful for revealing whether a tumor is responding to therapy.
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meetIng the technIcal challenges of BIomarker valIdatIon and QualIfIcatIon Appropriate analysis and interpretation of biomarker data presents enormous challenges, especially with the advent of genomic and proteomic technologies that can generate a tremendous amount of data on individual samples. Three speakers at the conference addressed the technical challenges involved with validating the accuracy and clinical relevance of cancer biomarkers.
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Drs. Quackenbush and Ransohoff stressed that the same issues that apply to standard hypothesis-driven clinical studies are also applicable to studies in genomics, proteomics, and metabolomics, which they collectively called "omics." "This is an exciting era because we have very powerful tools to measure the biology [of cancer]
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Ransohoff. Instead, results from a new group of subjects are often combined with those from the original group to further assess the accuracy of a predictive genetic signature or proteomic pattern.
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2002. A gene-expression signature as a predictor of survival in breast cancer.
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Because of mass spectrometer drift over time, this created a bias because a "signal," from the machine, was introduced into one group but not the other, making the proteomics test result invalid.5 In clinical research, the bias of baseline inequality is usually avoided easily and effectively by using randomization, but researchers still go to great lengths simply to report that there are no statistical differences in the baseline conditions of the study populations they are comparing. In contrast, the features needed to assess "baseline inequality" are seldom reported in the same detail in much "omics" research.
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Most researchers are not keen on creating an omics database, because such work is considered "blue-collar science," he said. "It's not very sexy -- nobody is going to win a Nobel Prize for creating a database, yet bringing such data together and integrating it is absolutely essential if we want to look beyond these demonstration studies that have been done and really do the largescale clinical studies we'd like to be able to do." There also is a need to develop tools that can visualize and interpret omics data in a way that is easy for clinicians to access and understand.
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Dr. Wagner explored a new angle of biomarker validity in his talk by showing how pharmaceutical companies classify biomarkers and tailor their degree of validity assessments according to the type of biomarker and how it will be used.
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Demonstration biomarkers are considered one step up from that and termed probable or emerging biomarkers, according to FDA parlance. BOX 1 Biomarker Types Characterization -- known or established biomarker that often aids drug development decision making.
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clinical trials. Improvement of a partial surrogate endpoint is necessary for, but not sufficient to, ensure improvement of the primary clinical endpoint of interest.
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. Characterization biomarkers are known or established biomarkers that often aid drug development decision making, and surrogacy biomarkers can substitute for clinical endpoints in drug efficacy studies.
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Due to the diagnostic test's ability to enrich the study population with drug responders, a clinical trial was able to show that Herceptin lengthened the survival time of about 25 percent of women with metastatic breast cancer who overexpress the HER2 gene. If the study population had not been enriched with responders, a mathematical model revealed the clinical efficacy of the drug would have been difficult, if not impossible, to demonstrate with the number of patients typically recruited for a clinical trial.
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Colorectal cancer patients were not entered into the clinical trials of cetuximab unless they had a positive result in the EGFR test (had 1 percent or greater tumor cells showing positivity)
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. taBle 3 False-Negative HER2 Test Results Local Local Local vs.
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He also noted the importance of making distinctions between clinical assays used to enroll patients in clinical trials of unproven therapies versus those used to test patients in clinical practice prior to making therapeutic decisions. diagnostics Industry Perspective The next talk was given by Robert Lipshutz, PhD, of Affymetrix.
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A number of costs and risks are linked to every step of developing a biomarker-based test, he pointed out. If the diagnostic is only going to be useful if the targeted therapy gains FDA approval, the risk of the new drug failing clinical trials must be added to the risk of developing a new diagnostic.
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One of these is a $100 million investment in a program to develop and test new animal models molecularly engineered to mimic human cancers. These animal models can be used to predict the pharmacodynamics for new cancer drugs, and can ease the development of assays that can predict effectiveness or safety of new drugs in clinical trials.
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He also noted that the predictive power of preclinical models could be transformed by parallel experiments in genetically engineered mice. The NCI also increased its support of efforts to develop and validate pharmacodynamic invitro assays well in advance of early phase clinical trials.
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An important deterrent to academic researchers discovering and developing cancer biomarkers is the high cost associated with such efforts, he pointed out. Genomic tests can add more than $1 million to the cost of running a clinical trial, he estimated.
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Lipshutz discussed how intellectual property uncertainties can act as a disincentive for diagnostic companies to develop tests that may require the licensing of multiple sources of genetic information. For example, one company that uses Affymetrix's microarray platform plans to use a few hundred genes for their diagnostic tests, but they estimate they would have to examine 20,000 pieces of intellectual property patents before pursuing such tests.
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As sophisticated biomarker tests that take advantage of the latest developments in molecular biology begin to enter the market, questions have been raised regarding the level of oversight that is warranted for them. The fourth session of the conference explored recent FDA initiatives regarding biomarkers, ways to design new drug clinical trials that use biomarkers, and how biomarkers should be regulated.
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"The clinical trial process has been highly observational in its conduct, primarily because we don't have the tools to look at the basis for individual response so we look at population responses. But these trials are extremely expensive and it really is important that we get maximum information when we subject human subjects to experiments." The FDA white paper also called for more development of bioinformatics, which would encourage the sharing of data and databases so that "we can learn generalizable knowledge about biomarkers, rather than knowledge that simply stays in a particular trial or drug development program," Dr.
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The FDA, through an exercise of its enforcement discretion, 8A PMA application usually requires manufacturers to submit clinical data showing that their devices are safe and effective for their intended uses. PMA requirements for diagnostic tests include clinical data demonstrating sensitivity, specificity, and predictive value.
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Home-brew tests are subject to the regulations of the Clinical Laboratory Improvement Amendments (CLIA) , which mandate that each lab create its own performance specification and provide evidence of accuracy, reproducibility, and analytic specificity for the target patient population of a home-brew test.
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Specifically, Roche Molecular Diagnostics planned to introduce a microarray genetic test for drug metabolism (AmpliChip CYP 450) into marketplace in 2003.
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Mr. Heller described a meeting and letters in 2004 between the FDA and the developer of a new serum protein test that used mass spectrometry for ovarian cancer screening (OvaCheck)
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This results in the effectiveness of many drugs being missed in traditional clinical trials because the proportion of patients who would benefit from the drug was too small to make its presence felt among the majority. "I think it is almost the rule, rather than the exception in cancer therapy,
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Instead, he noted that enriching trial populations with likely responders not only will reduce the cost of a clinical trial, but will make it more likely that participants will benefit from the drug being tested. "Cancer clinical trials of molecularly targeted agents may benefit a relatively small proportion of patients, but the benefit for the sensitive subset can be very substantial," he pointed out.
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DEVELOPINGCANCERBIOMARKERS Develop Predictor of Response to New Drug Patient Predicted Responsive Patient Predicted Non-Responsive New Drug Control Off Study fIgure 6 Trial strategy I: Utilization of a classifier in developmental strategy for novel drugs. SOURCE: Simon presentation (March 21, 2006)
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clinical trials. "If we have developed a classifier in Phase I and Phase II studies, we need to know that we can reproducibly measure that with some assay, and then we need to know something about treatment effect on the subset determined by that classifier.
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A member of the current USPSTF, Dr. Berg explained that it is a rotating, interdisciplinary panel, which regularly publishes its guidelines and recommendations on the web.15 Its mission is to produce scientific evidence-based reviews of preventive interventions given to asymptomatic patients in primary-care clinical settings.
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Although it found good evidence that screening can detect early stage prostate cancer, there was mixed and inconclusive evidence that such early detection improves health outcomes. In addition, it found very strong evidence that screening and subsequent treatment are both linked to important harms, and concluded that the benefits of treating early prostate cancer are unknown.
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. "This is a classic dilemma for the patient and the clinician trying to decide whether prostate cancer screening is a good idea for one personally; trying to balance the potential for an enormous benefit against a somewhat more likely potential for harm," Dr.
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.There are also few clinical trials that compare a genomic intervention with no intervention, and many studies do not assess all the relevant outcomes, he said. Often little attention is paid to documenting the harms of a genomic test, or to its cost and feasibility.
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McGivney said. Cost effectiveness is not used as a criterion for coverage determinations, he said.
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Some cancer biomarker tests, such as those for HER2 or the estrogen receptor, play important roles in NCCN guidelines for the treatment of breast cancer (Figure 9)
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He explained that CMS bases its coverage of a new diagnostic test on its accuracy and whether the test will lead to a better health outcome. To assess the accuracy, sensitivity and specificity measures may not be adequate, he added, and instead the agency may focus on the test's analytic validity, clinical validity, and clinical utility.
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Cancer biomarkers used to monitor or manage the care of patients with cancer, including those that predict recurrence, are usually covered by Medicare. For example, the agency on a national level covers the use of CA-125 for peritoneal and ovarian cancer patients.
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Similarly, if biomarker-based screening tests could be developed to detect cancer at an earlier, more easily treated stage, these new biomarker technologies could have a substantial impact on the economic burden of cancer by reducing the cost of treatment, as well as the overall burden and consequence of disease. The goal of the last session of the conference was to examine how the cost effectiveness of biomarker tests and the value of the information they provide affects their acceptance by health care payors, such as insurance companies and CMS.
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Dr. Stevens spent much of his discussion elaborating on the experience NICE has had in evaluating or employing various biomarker diagnostics in their assessments of medical interventions.
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PSA is a useful biomarker for prostate cancer recurrence or prognosis, but NICE called for more clinical trial evidence when evaluating PSA as a screening test for prostate cancer. In addition to the standard measures of a screening test, such as false-positive and false-negative rates, NICE wanted measures of how the test affected patient health outcomes.
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As cost effectiveness increases, high cost is less of a deterrent to providing the treatment. SOURCE: Stevens presentation (March 21, 2006)
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Dr. Meltzer also pointed out how the value of a diagnostic test, including a biomarker test, depends on how it is used.
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But he pointed out that the real value of research can be far less than expected, in part because it does not always generate the complete information needed to improve a health outcome. For example, he estimated that the expected value of perfect information about prostate cancer generated from research would be $21 billion, but the expected value of more limited information about certain aspects of the disease would be only $1 billion.
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Aronson, these challenges include inadequate quality of studies done on a topic, selective reporting and publication bias, and incomplete data from studies that are published; an example is that they do not consider important variables needed to determine medical policy decisions. Often there is a lack of prospective, randomized, double-blinded, and placebo-controlled clinical studies, Dr.
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We think something like this is so complicated that it needs to be tested, and I expect many biomarkers for prediction of response may fall into that category," she said. A final challenge to making assessments of medical interventions or tests that Dr.
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She criticized the design of many studies to formally assess tumor markers as being inconsistent and inadequate, and questioned the frequent use of biomarkers as surrogates for outcomes in clinical trials. "A correlate does not a surrogate make," she said, because the biomarker may not be in the causal pathway of the disease, there may be multiple causal pathways, or there may be unintended adverse effects of an intervention.
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These challenges were: · Gaining more access to patient materials and data; · Coordinating the development of diagnostics and treatments; · Providing incentives for diagnostic companies; · Developing "smarter" clinical trial designs; and · Better integrating basic science and clinical research efforts. Patient biopsy tissue and other patient materials collected during clinical trials are invaluable for researchers trying to discover or develop biomarkers.
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But a diagnostic company might be more willing to pursue a biomarker test if it could be coupled with a therapeutic that a drug company is developing such that the risks, revenues, and products are shared between the two companies. Another way to make diagnostic biomarker development more appealing is to give efforts in this regard "type two patents." Australian political philosopherThomas Pogge coined this term for patents that reward research and development work that results in useful drugs or diagnostics that normally would have a low margin of return.
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He noted that there needs to be a certain level of rigor to a responsepredicting diagnostic used in a clinical trial. But the development of such a rigorous biomarker diagnostic often lags behind that of a related drug, so the diagnostic is not ready to enter Phase III testing at the same time as the drug.
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One person in the group noted that the bulk of a company's drug development costs are for developing unsuccessful drugs -- those that do not "pass" clinical trials and enter the market. The use of biomarkers to enrich the number of responders in a clinical trial population should therefore lower development costs overall, he noted, if it makes it more likely that drugs would fare well in clinical trials.
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This effort led to the development of NCI Guidelines for Biorepositories,18 the second generation of which is currently being developed in collaboration with the College of American Pathologists and other relevant extramural groups. The first-generation guidelines include recommendations for the following: · Common best practices for research biorepositories · Quality assurance and quality control programs · Informatics systems · Ways to address ethical, legal, and policy issues (e.g., informed consent, privacy, data security protections, Institutional Review Board oversight, ownership of and access to biospecimens and data)
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The Ontario Tumour Bank offers the following products: · Fresh frozen tumor · Frozen plasma · Frozen buffy coat · Paraffin-embedded tumor · Normal tissue adjacent to tumor samples Future plans are to offer paraffin sections, stained sections, and tissue microarrays. Researchers can retrieve extensive data, including specimen 19http://www.ontariotumourbank.ca.
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"The reason the Ontario Tumour Bank can do it for $10 million is that their surgeons, pathologists, etc., are on government salary." These presentations led to a general discussion on how to fund biorepositories in the United States. Group participants noted that NCI alone cannot bear the costs of supporting national biorepositories, and suggested public-private consortia as a means for supporting biorepositories.
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For example, certain government agencies require informed consent before using tissues from patients who have died, while others do not have such a requirement. The privacy provisions of the Health Insurance Portability and Accountability Act (HIPAA)
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One case is testing whether the investigator or hospital owns patient samples. Some research consortia have clearly specified, in advance, issues related to access and ownership of samples.
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. Similarly, distinctions should be made for biomarkers used only by pharmaceutical companies during the initial stages of drug development versus those used in clinical trials that affect clinical decisions.
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Schulman noted that a consortium for biomarker validation that includes the FDA, CMS, and various pharmaceutical companies is already under way. He added that "there is a general feeling that there is an opportunity to do something right on a bigger scale where oftentimes the intellectual property issues are not problematic." Group participants noted that investigators who discover biomarkers often do not understand what is required for analytical or clinical validation.
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"This is one of the reasons for sharing both samples and information because the more people work on the same set of biomarkers, the more we learn about their flaws and good points and come up with a better test." To further that communal process, the group suggested that investigators publish all raw data from their biomarker studies. Group participants also noted that better access to clinical specimens would be a boost to diagnostic development, but a number of obstacles must be overcome.
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Biomarker tests that detect whether people are at higher risk of developing a specific cancer, such as those for breast cancer-related mutations in the BRCA genes, are problematic in that regard. As there are no known measures to substantially reduce the risk of breast cancer in women who test positive for these mutations short of prophylactic mastectomies, the clinical usefulness of the test is questionable, some group members asserted.
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Tests used for early detection of cancer should be assessed for that purpose, the group stated, with some measure of benefit and risk. In addition to the FDA's regulatory role, group members noted that coverage decisions play a role in determing the use of biomarker tests in clinical settings.
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According to Dr. Ramsey, "if a biomarker diffuses into clinical use and we really do not know what it is doing to folks, the cost of that could be enormous and exceed the cost of doing a clinical trial itself." Members of the discussion group stressed that clinical trials of biomarker tests should be designed so that the diagnostic test is tied to a therapeutic intervention.
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Discussant Walter Koch, PhD, of Roche Molecular Systems suggested that such trials be reserved for screening biomarker tests for which there is a diagnostic test that can help determine whether the cancer it detects would need to be treated; for example it may be indolent. He also suggested additional criteria for selecting the most promising candidate tests on which to conduct clinical trials; criteria would include a clinical need for the tests and the availability of effective treatments for the cancers they detect.
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For example, surrogate endpoint markers are beneficial to all parties conducting clinical trials for the purpose of achieving FDA approval for a drug to enter the market. An example of such a consortium was one created to develop CD4 count and HIV viral load as surrogate endpoints for clinical trials used to gain FDA approval of various antiretroviral drugs for HIV infection.
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Start-up diagnostic companies also are not likely to develop biomarker assays because of the low profit margins of diagnostic tests, which make them unattractive to investors. "There was some discussion that if we wait and hope that this happens through free enterprise, we could be waiting awhile," Dr.
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"If it were, then reimbursement paradigms could be built in that would incentivize companies to make them sooner." Group discussants also suggested working with payors to establish alternatives to basing reimbursement decisions on evidence generated from large, long-term clinical trials. CMS and other insurers often require more evidence than does the FDA for a biomarker's effectiveness prior to reimbursing its clinical use, Dr.
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Several discussants thought some "success stories" via such a demonstration project would overcome the inertia that is preventing extensive biomarker development. The science needed to do such work is already in place, they noted, and what is lacking is leadership and funding.
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There is also such a wide range of uses for biomarkers in the cancer arena that standards for one use, such as a surrogate endpoint in clinical trials, may not be applicable to another use, such as a predictor of patient responsiveness. In addition, the standards for a biomarker that predicts responsiveness to a drug may vary depending on the type of cancer on which it is tested, such as lung or breast.
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Even for CLIA-governed or CAP-governed labs, there is no specific cookbook or guidance you can go to." Industry representatives in the discussion group pointed out that companies often evaluate their biomarker diagnostics in phases, with a more complete evaluation of their broader applications not occurring until after the tests enter the market. For example, a cancer detection test may at first only be evaluated for its accuracy and predictive value in high-risk populations because this evaluation can be done relatively quickly compared to one done in the general public.
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Waring stressed the need to engage the pathology community when setting standards for biomarker tests. "When we are talking about predictive tests that determine treatment decisions for patients with serious life-threatening diseases, I think that the pathologists and the pathology community are often the afterthought in this process.
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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.
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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.
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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.
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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.
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DEVELOPINGCANCERBIOMARKERS 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.
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