E VIDENTIARY S TANDARDS FOR D ETERMINING THE C LINICAL U TILITY OF G ENOMICS -B ASED D IAGNOSTIC T ESTS G ENOMICS -B ASED D IAGNOSTIC T ESTS Sean Tunis MD, MSc May 23, 2012
High Hopes for CER “Better information about the costs and benefits of different treatment options, combined with new incentive structures reflecting the information….is essential to putting the country on a sounder long- essential to putting the country on a sounder long- term fiscal path.” term fiscal path.” Peter Orszag, CBO (later OMB) Congressional Testimony, June 2007 2
CER Defining Characteristics (IOM) Objective of directly informing clinical or health policy decision Study in “real world” patients and settings Compares at least 2 alternative, each with Compares at least 2 alternative, each with potential to be best practice Measures outcomes important to patients Results at population and subgroup level Methods and data sources appropriate for the decision of interest 3
SACGHS Recommendation “Information on clinical utility is critical for managing patients, developing professional guidelines, and making coverage decisions.” “HHS should create a public private entity of “HHS should create a public private entity of stakeholders to….establish evidentiary standards and levels of certainty required for different situations” 4
The Fundamental Trade-off There is an inherent tension between level of certainty about risk-benefit and early access to new technologies (innovation, ROI) Not easily determined what is the optimal Not easily determined what is the optimal balance to maximize long-term public health Varies by stakeholder interest and perspectives Clarity, consistency and predictability of evidence expectations are essential 5
Effectiveness Guidance Documents Specific recommendations for study design reflecting information needs of patients, clinicians, payers Targeted to public/private sector clinical researchers researchers Describe study designs that provide “reasonable confidence of improved health outcomes” Balance internal validity with generalizability, feasibility, timeliness and cost 6
Contact Info sean.tunis@cmtpnet.org www.cmtpnet.org 410 547 2687 x120 (W) 410 547 2687 x120 (W) 410 963 8876 (M) 7
Example: PROs in off-label studies of oncology drugs Include the following 14 patient-reported symptoms (“core symptom set”) in all research designs for post-market cancer clinical trials: anorexia, anxiety, constipation, depression, diarrhea, dyspnea, fatigue, insomnia, mucositis- diarrhea, dyspnea, fatigue, insomnia, mucositis- oral, nausea, pain, sensory neuropathy, rash, and vomiting. 8
PCORI Methods Committee View JAMA. 2012;307(15):1636-1640 “Engagement of patients at every step of the research process is viewed as essential, including in the selection of research questions, study design, conduct, analysis, and implementation of findings.” findings.” “As such, the Methodology Committee is engaged in developing standards to support the validity and generalizability of research, as well as patient-centeredness.” 9
Methodological Guidance for Molecular Diagnostics Research in Oncology Diagnostics Research in Oncology May 23, 2012 Washington, DC
Project Goals Use a stakeholder-driven process to develop specific methodological recommendations to address the evidence gaps regarding the clinical validity and clinical utility of actionable MDx tests in oncology (solid tumors). in oncology (solid tumors). Improve the relevance, timeliness and quality of the evidence available to patients, clinicians and payers for clinical and policy decision-making. 11
Meeting Overview Welcome & Introductions Sean Tunis 4:00 PM – 4:15 PM Molecular Diagnostics EGD Pat Deverka 4:15 PM – 4:45 PM Initiative Methods Panel: Establishing Pat Deverka, Donna Messner 4:45 PM – 6:00 PM Clinical Utility of Molecular (Moderators), Gary Lyman, Diagnostics Robert McCormack, David Nelson, Margaret Piper, Richard Simon, Mary Lou Smith Break for Dinner 6:00 PM – 6:30 PM Dinner Panel: Payer Perspectives Sean Tunis (Moderator), 6:30 PM – 7:30 PM on Clinical Utility Michael Doherty, Elaine Jeter, Lee Newcomer, Ed Pezella , Jeff Roche, Alan Rosenberg Progressive Validation of Sean Tunis & Steve Phurrough 7:30 PM – 8:15 PM Molecular Diagnostics to establish Clinical Utility Wrap up and Next Steps Sean Tunis & Pat Deverka 8:15 PM – 8:30 PM
Meeting Objectives Discuss key issues and methodological recommendations Make recommendations more specific & actionable Evaluate feasibility of implementation Discuss study design features relevant to establishing clinical Discuss study design features relevant to establishing clinical utility Obtain payer perspectives on establishing clinical utility of MDx* Discuss the existing policy framework & alternative mechanisms to establish Clinical Utility of MDx* Progressive validation of MDx* to establish clinical utility Evaluate potential study designs Assess the feasibility of implementation 13
Effectiveness Guidance Document (EGD) Aims Provide specific recommendations on the design of prospective studies intended to inform decisions by patients, clinicians and payers Balance between internal validity, relevance and feasibility to provide decision-makers with and feasibility to provide decision-makers with a reasonable level of confidence that the intervention improves net health outcomes Target audience: clinical researchers working in industry or academic settings Analogous and complementary to FDA guidance, focused on design elements particularly relevant to clinical and health policy decision-making 14
Spectrum of Molecular Diagnostic Tests Predisposition/ Staging Prognosis Predictive Monitoring Risk • Various •PSA • Oncotype • EGFR Assessment IHC/FISH •BCR-ABL Dx • K-RAS •BRCA1/2 • BRAF •Lynch Syndrome testing testing • HER-2 • HER-2 15
MDx EGD Process Overview Project Initiation: July 2010 Conduct Literature Protocol Development for Institutional Review Board 1 Review Qualitative Interviews (IRB) Review Identify additional experts **Define Project Scope *Conduct Key Informant (Snowball Sampling) 2 Interviews Identify Key Methodological Issues Review interviews to identify key Related to Clinical Validity & issues and themes 3 Clinical Utility Draft major issues and Develop Delphi survey for recommendations TWG members 4 TWG meetings to develop consensus on issues and draft 5 recommendations MDAG & IOM workshops to obtain stakeholder input & refine 6 recommendations Final Effectiveness Guidance Document (EGD) on Molecular 7 Diagnostics for Solid Tumors Target Completion : December 2012
Project Scope POSSIBLE BIOMARKERS BIOMARKER EVALUATION TYPES OF CANCER Analytic Clinical Prognosti c Predictive Validity Validity Solid Hematologic Tumors Tumors Early Clinical Predisposition ELSI Detection Utility Focus on Clinical Validity & Clinical Prognostic & Predictive Focus on Solid Tumors Utility Actionable Tests 17
Scope of MDX EGD IN OUT Type of Test Actionable (Companion Diagnostics) High risk Low/Moderate risk New test/existing drug Stand-alone test Stand-alone test Single gene “omics” Target Condition Solid Tumors Hematologic Malignancies Circulating Tumor Cells Recommendations Clinical Validity Analytic Validity Clinical Utility Economic considerations (e.g. cost- effectiveness) Methodological 18 Implementation barriers
Rules of Engagement for Discussions Participant’s Role CMTP’s Role Ensure recommendations Listen carefully are actionable and specific Elicit viewpoints Ensure recommendations Ensure recommendations Ensure all viewpoints are Ensure all viewpoints are are comprehensive articulated and encouraged Ensure recommendations are grounded in reality Please speak up- the meeting is being recorded 19
General Questions for Discussions Discussion Focus: Is the recommendation actionable? Is the language specific enough? Is the recommendation Is the recommendation designed to reflect the designed to reflect the information needs of patients, clinicians and payers? Can the recommendation be implemented in a study that is likely to be timely and feasible? What are the barriers/enablers? Also, are there additional recommendations you would make? 20
Recommendation #2 Rationale By itself, associational evidence is not sufficient to establish the clinical validity of an MDx test. Odds ratios, hazard ratios, regression coefficients, and area under the ROC curve are inadequate as and area under the ROC curve are inadequate as standalone tools for demonstration of clinical validity. Developers need to ensure that the target goal is clinically relevant (e.g., enrich for a particular level of response, and discriminate for avoidance of particular level of adverse events) 21
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