Biomarker Tests for Molecularly Targeted Therapies Key to Unlocking Precision Medicine (2016) / Chapter Skim
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3 Supportive Policy Environment for Biomarker Tests for Molecularly Targeted Therapies
3 Supportive Policy Environment for Biomarker Tests for Molecularly Targeted Therapies
Pages 69-142
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. Coding related to biomarker tests for molecularly targeted therapies is discussed further in Appendix B of this report.
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health care reimbursement system, which while still predominantly feefor-service, is in flux as alternative payment models are introduced that shift risk to health care providers and are aligned more closely with health care value (Anderson et al., 2015; Bipartisan Policy Center, 2015; Burwell, 2015) .2 Developing appropriate and effective regulatory and reimbursement frameworks responsive to rapidly evolving technologies is critical to ensuring that health care providers and their patients have access to -- and the ability to benefit from -- the potential of biomarker tests for molecularly targeted therapies to optimize care.
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The first part explores the issue of evidentiary standards for clinical utility, which is a cross-cutting issue that influences regulatory, reimbursement, and clinical practice areas. The discussion then shifts to an overview of the current regulatory structure for biomarker tests for molecularly targeted therapies and discusses communication and information related to test performance and intended use.
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developed a useful framework known as the ACCE Model,4 which presents a process for evaluating scientific data on emerging genetic tests. ACCE refers to four main evaluation criteria: analytic validity, clinical validity, clinical utility, and ethical/legal/social implications (see Figure 3-2)
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The lack of such common standards of evidence of clinical utility represents a significant challenge in the implementation of effective biomarker tests for molecularly targeted therapies into routine clinical practice, with significant consequences for patient access to tests, as well as potential for patient harm if 5 See list of questions at http://www.cdc.gov/genomics/gtesting/ACCE/acce_proj.htm (accessed June 4, 2015)
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Clinical validity encompasses clinical sensitivity and specificity (integrating analytic valid ity) , and predictive values of positive and negative tests that take into account the disorder prevalence (the proportion of individuals in the selected setting who tests with limited evidence of clinical utility are used to direct treatment, or if effective tests are not being used clinically due to lack of reimbursement.
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A clinically valid biomarker test for a molecularly targeted therapy is able to define a patient population for which a specific therapy or class of therapies would or would not be beneficial. Clinical Utility EGAPP defines the clinical utility of a genetic test as "the evidence of improved measurable clinical outcomes, and its usefulness and added value to patient management decisionmaking compared with current management without genetic testing.
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Enrichment The test is applied to Advantages: studies all patients, but only Useful when clinical utility of some test-positive patients of the test-designated categories are randomized and/or is already established or assumed treated. and need not be re-evaluated, while other categories require prospective Test-negative patients evaluation in a clinical trial.
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. Study design can be used if prospective trial is not feasible for ethical or other reasons.
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78 BIOMARKER TESTS FOR MOLECULARLY TARGETED THERAPIES TABLE 3-1 Continued Type of Trial Design Description Advantages and Limitations Longitudinal A variety of possible Advantages: observational designs, which do not Can help generate hypotheses studies include any study-directed related to large hypothesized effect testing or intervention sizes, evolving treatment strategies, and instead prospectively real-world clinical use of tests and collect clinical and multiple corresponding therapies, outcomes data, including patient/provider preferences related "Quasi-experimental": to test use, long-term outcomes, and collection of clinical very large required sample sizes. outcomes data pretest and posttest for at Limitations: least two groups under Careful consideration of the rationale investigation.
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Such models would include all relevant risks Limitations: and benefits related to Tests to be assessed need to meet an remaining survival and established threshold for plausible quality of life. evidence of clinical utility.
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. As discussed further in the next section, the current regulatory oversight structure for biomarker tests for molecularly targeted therapies does not include assessment of clinical utility.
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CDC also manages the Clinical Laboratory Improvement Advisory Committee, a body that offers guidance to the federal government on clinical laboratory quality improvement and revising CLIA standards (CDC, 2014)
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The regulatory pathways for clinical laboratory tests differ from that for drugs. Clinical laboratory tests such as biomarker tests for molecularly targeted therapies are introduced into standard clinical practice through several pathways.
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of the Act requires device manufacturers who must register to notify FDA of their intent to market a medical device at least 90 days in advance. This is known as Premarket Notification or 510(k)
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Biomarker tests that are co-developed with a drug and co-approved by FDA are known as companion in vitro diag 6 The alternative LDT pathway is not possible for drug development; premarket approval by FDA is required for all drugs. 7 The majority of biomarker tests for molecularly targeted therapies currently in clinical use are LDTs.
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. As Parkinson points out, "The approval in recent years of companion diagnostics developed with targeted therapies serve as the best available examples of successful clinical utility efforts" (Parkinson et al., 2014, p.
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. Laboratories performing medium- and high-complexity tests, including those for biomarker tests for molecularly targeted therapies, are subject to additional quality control and proficiency testing (PT)
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. Given CLIA regulations only explicitly require demonstration of analytic validity, concerns have been raised that a CLIA-certified laboratory potentially could develop an analytically valid test for clinical use without demonstrating the clinical validity or clinical utility of the test to positively impact patient care.
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FDA has stated that LDTs should be subject to further risk-based regulation requiring sufficient evidence to deem them safe and effective. The initial focus after the LDT guidance is finalized will be on premarket review of LDTs that have the same intended use as existing FDA-cleared or -approved companion diagnostics or high-risk medical devices (laboratories providing these LDTs will have a 12-month grace period to file for premarket approval [PMA]
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Further more, AMP asserts that for a certain class of high-risk LDPs (e.g., those predicting risk of disease or response to targeted therapy, AND used in diseases associated with significant morbidity/mortality, AND providing results through hidden or "black box" algorithms or otherwise not transparent to other laboratory professionals) , third-party oversight through FDA or other entities may be required to assess analytic and clinical validity.
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. DTWG asserts that an IVCT differs from a traditional medical device in that analytic and clinical validity are the central regulatory attributes, rather than safety and effectiveness.
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. REIMBURSEMENT CHALLENGES As noted at the beginning of this chapter, the policy challenges to biomarker tests for molecularly targeted therapies must be viewed within the context of the broader U.S.
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Consequently there are significant state-by-state differences in Medicaid coverage for genetic tests and services (SACGHS, 2006) , which can serve as a source of disparity in access to biomarker tests for molecularly targeted therapies, discussed further in Chapter 5 of this report.
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. The lack of evidentiary standards for clinical utility influences payers' willingness to cover and reimburse the cost of biomarker tests for molecularly targeted therapies (Cohen and Felix, 2014; Hresko and Haga, 2012)
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. It remains to be seen if the proposed market-based pricing approach for advanced laboratory tests, such as biomarker tests for molecularly targeted therapies, represents progress toward the goal of value-based reimbursement (Carey, 2014)
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. As discussed earlier in this chapter, the lack of common evidentiary standards for biomarker tests for molecularly targeted therapies may limit health care providers' and patients' access to such tests.
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.17 Randomized controlled trials are widely considered the gold standard for generating evidence, as noted earlier in this chapter, but they are costly and require tracking large numbers of patients over time; as a result they are not typically conducted to evaluate biomarker tests for molecularly targeted therapies. This is due in part to the thinner profit margins of IVD test developers relative to pharmaceutical companies, which makes it less likely they would be able to support clinical trials on the scale of those funded by pharmaceutical companies (Faulkner, 2009)
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. Further discussion of the development of CPGs, as well as the committee's recommended approach to CPGs related to biomarker tests for molecularly targeted therapies, is presented in Chapter 5 of this report.
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Medicare's coverage with evidence development (CED) program is a policy tool through which CMS agrees conditionally to cover new medical technologies provided that sponsors/manufacturers collect additional data to support more informed coverage decisions (CMTP, 2010, 2013)
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CED provides temporary reimbursement as the evidence is further developed by requiring patients to participate in a registry or clinical trial20 to qualify for coverage of the technology. This is particularly important for biomarker tests for molecularly targeted therapies, given the time and financial resources required to collect data on the impact of testing on patient management and clinical outcomes.
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. CED holds the promise of an effective approach to providing coverage while simultaneously strengthening the evidence base for emerging technologies such as biomarker tests for molecularly targeted therapies.
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Data obtained are more broadly representative of patient populations compared to clinical trials, though the observational nature of CED studies may serve as a potential limit to the generalizability of study conclusions. Challenges Related to Next-Generation Sequencing Though single-analyte tests currently are the most commonly used biomarker tests for molecularly targeted therapies, test technology is rapidly advancing with the introduction of next-generation sequencing.
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The guidelines represent a framework for coverage of targeted NGS gene panels that recognizes the unique evidentiary challenges of demonstrating clinical utility for a panel of tests rather than evaluating a specific diagnostic test for a welldefined clinical use. The initial draft coverage guidelines include two specific recommendations for payers: the first is that payers cover NGS panels with 5 to 50 genes when those panels include a subset of genes considered to be medically necessary,23 and the second recommendation is for payers to rely on the College of American Pathologists' accreditation program and proficiency testing to assure the analytic validity of NGS tests (CMTP, 2015)
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. Lack of Alignment of Regulatory and Reimbursement Decision Processes In addition to multiple regulatory pathways, the policy environment for biomarker tests for molecularly targeted therapies is further complicated by the existence of separate processes for regulatory and reimbursement decisions.
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. The increasing number of complex biomarker tests for molecularly targeted therapies being implemented in clinical practice has raised concerns about insufficient access to information about test performance and intended use.
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The committee subsequently developed a recommended set of associated policy measures. These recommendations represent important steps in the development of a supportive policy environment as one component of a rapid learning system for biomarker tests for molecularly targeted therapies.
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. Thus, the committee recommends that the Secretary of HHS should facilitate the development of common clinical utility evidentiary standards that are applied for initial and ongoing coordinated regulatory, coverage, and reimbursement decisions for biomarker tests for molecularly targeted therapies.
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. The committee acknowledges the considerable challenges involved in bringing together diverse perspectives to establish common standards of clinical utility across all stakeholders, but believes it is imperative that this initiative be undertaken to enable biomarker tests for molecularly targeted therapies to achieve the promise of precision medicine.
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Therefore, HHS could determine that more than one advisory body may be necessary to develop disease-specific evidentiary standards of clinical utility for biomarker tests for molecularly targeted therapies. The evidentiary standards for clinical utility developed in collaboration with multiple stakeholders will be used to guide the creation of new labels for biomarker tests and corresponding therapies (see Recommendation 3)
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Other examples of independent, multistakeholder collaborations exist, such as the partnership that was formed between Friends of Cancer Research and the Engelberg Center for Health Care Reform at the Brookings Institution. These two organizations joined forces to convene an annual conference on clinical cancer research, which brought "together a diverse group of experts in cancer drug development from academic and clinical research centers, federal health and regulatory agencies, patient advocacy organizations, and the private sector to develop practi 24 See http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders (ac cessed July 22, 2015)
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These and other working partnerships may serve as a guide for HHS as it addresses the long-standing and increasingly urgent need for a common evidentiary framework for current and emerging biomarker tests for molecularly targeted therapies -- to facilitate patient access to appropriate tests, and to protect them from potential harm as well. 25 See http://www.focr.org/conference-clinical-cancer-research (accessed October 11, 2015)
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. Thus, the committee recommends that the Secretary of HHS should facilitate the development of a new integrated federal review process involving FDA and CMS, as a pathway for coordinated regulatory, coverage, and reimbursement decisions for IVD and LDT biomarker tests for molecularly targeted therapies, including multianalyte tests performed using current or new technologies, and any corresponding molecularly targeted therapies27 (Recommendation 2)
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Evidence could include:* • Enrichment studies • Prospective-Retrospective studies • Randomized controlled trials • Single-arm studies ü Regulatory decision and national uniform coverage decision for biomarker test and molecularly targeted therapy for specific clinical uses Results ü Incentives for data submission to national repository ü Patient- and provider-friendly labels ü Coordinated updates of test and drug labels ü Public sharing of summary data upon which test-drug combination approval was based FIGURE 3-3 FDA–CMS Integrated Review Process.
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For this to occur, it will be important for private payers to have confidence in the rigor of the integrated review process, including the standards of evidence that are being applied when making such decisions. The process for developing evidentiary standards described in Recommendation 1 above will determine a minimum level of evidence of clinical utility to enable a biomarker test for molecularly targeted therapy to enter into clinical use, with the understanding that stronger evidence may be generated through the monitoring of the test's clinical use and patient outcomes, including potential changes to patient management, over time.
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Finally, as an important initial step in the committee's vision of a rapid learning system for biomarker tests for molecularly targeted therapies, the integrated review process will include financial incentives designed to encourage health care providers and health systems to submit test data on patient use and outcomes to a national data repository, as discussed further below. Thus, in summary, this coordinated pathway should accomplish all of the following through application of common evidentiary standards (as described in Recommendation 1)
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The committee's call for FDA and CMS to work closely together in an effort to streamline the decision-making process for biomarker tests for molecularly targeted therapies builds upon existing precedent. Indeed, FDA and CMS are well positioned to work together to support timely review, coverage, and reimbursement of new advanced tests; a key example of interagency collaboration is the FDA–CMS parallel review pilot program.29 Historically, FDA and CMS have worked independently, with separate staff focused on different points of a product's development lifecycle, and with different evidentiary expectations from FDA's focus on safe and effective, to CMS's focus on reasonable and necessary.
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The development of a pathway for coordinated regulatory and reimbursement decisions has the potential to create a more harmonized process for market entry for biomarker tests for molecularly targeted therapies. Such FDA–CMS integrated review with simultaneous regulatory and reimbursement decisions will serve to reduce delays inevitable with dual decision-making processes, and by clarifying requirements for coverage and reimbursement will enable test and drug manufacturers to plan accordingly, which in turn will help to increase the rate at which new 31 See http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409021.
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The committee recognizes that its recommended approach may entail implementation challenges, but the current lack of coordination between the two agencies is detrimental to patients and test and drug manufacturers. The coordinated review process would provide benefits to both patients and manufacturers: test and drug manufacturers could receive FDA approval and meet evidentiary standards for payment in parallel, providing patients with faster access to appropriate biomarker tests for molecularly targeted therapies.
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This standardized labeling system will apply to all biomarker tests for molecularly targeted therapies -- regardless of whether the tests undergo the integrated review process described above. The committee recommends that labels should prominently feature an easily understood ranking system (e.g., 4-star scales)
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The structure of such a label should be uniform for all biomarker tests for molecularly targeted therapies used in clinical practice, regardless of their status (i.e., whether evaluated and labeled by FDA or not)
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The committee proposes that the test labeling process be initiated as a pilot program for biomarker tests for molecularly targeted therapies, given that such tests are the focus of the committee's statement of task. The impact of the pilot labeling program would be monitored and tracked in a formal evaluation process designed to determine the program's effectiveness and whether it has the potential to improve transparency of test information and could be expanded beyond biomarker tests for molecularly targeted therapies and implemented on a broader scale to apply to all biomarker tests.
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d Clinical Utility, or evidence of improved measurable clinical outcomes, useful ness, or added value. tests for molecularly targeted therapies.
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* d FIGURE 3-4b Mock label for a biomarker test directing molecularly targeted therapy for cystic fibrosis.
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, for example, operates a state certification program that currently has been deemed by CMS to meet or exceed CLIA standards, rendering laboratories under its jurisdiction exempt from specific CLIA oversight.36 NYSDOH's Clinical Laboratory Evaluation Program (CLEP) entails regular inspection and PT, and additionally reviews all non-FDA-cleared or -approved tests for evidence of analytic and clinical validity (SACGHS, 2008)
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, where Reimbursement Policy Mechanism to Support Ongoing Assessment of Biomarker Tests for Molecularly Targeted Therapies Ongoing data collection Continued Adequate coverage Investigational evidence for initial Experimental clinical utility No longer covered Analytic Clinical Validity Validity Assessing Clinical Utility Strength of Evidence High Low FIGURE 3-5 Evidence continuum.
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In most cases, however, additional evidence will be needed to confirm the impact of the test based on longer-term clinical outcomes, to define the patient subgroups for whom testing is most useful, and to compare the outcomes achieved with use of the test to alternative approaches to patient management. Thus, it will be extremely valuable for payers to apply policy mechanisms designed to promote the ongoing assessment of evidence of the clinical utility of biomarker tests for molecularly targeted therapies.
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Also consistent with the committee's proposed rapid learning system, the committee further recommends that payers consider innovative incentives to promote the submission of data to a national repository for biomarker tests and molecularly targeted therapies that have initial evidence of clinical utility (discussed further in Chapter 4)
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. Under the latter of the two arrangements, known alternately as managed entry or coverage with evidence development, the payer provides coverage and reimbursement of a biomarker test for molecularly targeted therapies if the patients receiving the test agree to enroll in a clinical study to generate the additional evidence required for ongoing assessment of clinical utility.
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. The committee recommends that CMS should seek to clarify and expand appropriate implementation of CED, which has potential to be an effective policy lever to generate evidence to support reimbursement decisions for promising technologies, such as biomarker tests for molecularly targeted therapies.
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. The Consortium may therefore serve as an ideal organization to assist with research into clinical utility for biomarker tests for molecularly targeted therapies.
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should facilitate the development of com mon clinical utility evidentiary standards that are applied for initial and ongoing coordinated regulatory, coverage, and reimbursement decisions for biomarker tests for molecularly targeted therapies. One mechanism for the development of these evidentiary standards could be convening one or more independent, public–private, mul tistakeholder bodies.
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• HHS should continue to support ongoing refinement of common evidentiary standards as they evolve. Goal 2: Establish a more coordinated and transparent federal pro cess for regulatory and reimbursement decisions for biomarker tests for molecularly targeted therapies.
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• Public sharing of the summary data upon which the review pro cess based the approval and coverage decisions for a biomarker test and drug combination. Goal 3: Enhance communication to patients and providers about the performance characteristics and evidence for use of specific biomarker tests for molecularly targeted therapies.
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. Goal 5: Ensure ongoing assessment of the clinical utility of bio marker tests for molecularly targeted therapies.
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• Consider innovative incentives to promote the submission of data to the national repository for biomarker tests and molec ularly targeted therapies that have initial evidence of clinical utility. • CMS should seek to clarify and expand appropriate implementa tion of CED, which has potential to be an effective policy lever to generate evidence to support reimbursement decisions for promising technologies, such as biomarker tests for molecularly targeted therapies.
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New York: American Clinical Laboratory Association. CMS (Centers for Medicare & Medicaid Services)
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2013. Evaluation of clinical validity and clinical utility of actionable molecular diagnostic tests in adult oncology.
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2014. Molecular diagnostics clinical utility strategy: A six-part framework.
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2013d. Genome-based diagnostics: Demonstrating clinical utility in oncology: Workshop sum mary.
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Presentation to the Committee on Policy Issues in the Clinical Development and Use of Biomarkers for Molecularly Targeted Therapies, May 4, 2015, Washington, DC. McShane, L
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Presentation to the Committee on Policy Issues in the Clinical Development and Use of Biomarkers for Molecularly Targeted Therapies, April 1, 2015, Washington, DC. NIH (National Institutes of Health)
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Presentation to the Committee on Policy Issues in the Clinical Development and Use of Biomarkers for Molecularly Targeted Therapies, May 4, 2015, Washington, DC. Ramsey, S
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2010. Assessing the clinical utility of diagnostics used in drug therapy.
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