WHAT IS THE ROLE FOR PRAGMATIC TRIALS IN REGULATORY APPROVAL? Moderator: Penny Mohr MA, Vice President, Programs, Center for Medical Technology Policy, Baltimore, MD, USA Panelists: Marc L. Berger MD, Vice President, Eli Lilly, Global Health Outcomes, Indianapolis, IN, USA; Robert Temple MD, Director, Office of Drug Evaluation I, Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA ISSUE: Pragmatic clinical trials (PCTs) are prospective studies designed to assist patients, clinicians and payers in making informed choices from among available alternative interventions for a specific clinical condition. While payers are demanding real world evidence of effectiveness, regulatory agencies are often wary of the use of PCTs for regulatory approval. This issues panel presents the viewpoints of representatives from the pharmaceutical industry and the Food and Drug Administration about the potential for expanded use of PCTs for Phase III/IIIb trials. OVERVIEW: A major value of pragmatic trials is they provide evidence that is generalizable to real world conditions, but they do so at a loss of internal validity. By incorporating the heterogeneity of patients and physician practice, one compromises the scientific method of experimental design. In general, PCTs have been viewed as being complementary to more tightly controlled efficacy trials. They are most often discussed as being useful for post-marketing evaluation examining safety. However, it would be preferable to generate evidence with the smallest possible number of separate clinical trials. Panel members debate the competitive, regulatory, and methodological barriers to using PCTs for regulatory approval and innovative ways to resolve them, using specific examples.
ECONOMIC OUTCOMES RESEARCH ISSUES
IP2:
MODEL CALIBRATION: LOCUS FOCUS OR HOCUS POCUS? Moderator: David Thompson PhD, Vice President, i3 Innovus, Health Economics and Outcomes Research, Medford, MA, USA Panelists: Milton C. Weinstein PhD, Professor, Health Policy and Management, Harvard School of Public Health, Boston, MA, USA; Alistair McGuire PhD, Chair in Health Economics, LSE Health and Social Care, London, UK ISSUE: Calibration of model inputs has been recommended by the ISPOR Task Force on Good Modeling Practices as an important step in the process of model validation. In addition, calibration has evolved to become an indirect method for inferring values of model parameters from data on model endpoints. Some important caveats associated with model calibration need to be recognized. OVERVIEW: A model may require calibration when data directly informing model input parameters are lacking, or when model outputs do not accurately reflect known external benchmarks. A variety of calibration methods exist, but the general process involves running the model, comparing the outputs to the benchmarks, adjusting the inputs, re-running the model, and continuing until a predetermined stopping criterion is reached. The modeler has discretion to choose which inputs to calibrate, what benchmark data to use as calibration targets, what criteria to use to adjudicate how well the calibration has performed (goodness of fit), what methods to use to search for the optimal parameter set (manual, random, algorithmic), and when to terminate the search process. There is little guidance for making these choices, and it should be recognized that the calibration results – and the calibrated model itself – will almost certainly differ depending upon the decisions taken. This raises a variety of questions to be addressed by the panelists: How concerned should we be regarding the subjective nature of modeler input in the calibration process? When is calibration preferred over conventional parameter estimation from data? Are Bayesian methods helpful and/or necessary in inferring model parameters via calibration from data on inputs and outputs? Is a calibrated model a black box, in which only the outputs are trusted, or do the calibrated model parameters and internal structural relationships have validity? Audience members will be encouraged to provide additional questions and thoughts to spark further discussion.
PATIENT-REPORTED OUTCOMES RESEARCH ISSUES
IP3:
COMPARISONS BETWEEN THE MEDICATION POSSESSION RATIO (MPR) AND GAPS MEASURES OF MEDICATION COMPLIANCE: ARE WE SELLING OURSELVES SHORT BY RELYING ON THE MPR? Moderator: Femida Gwadry-Sridhar BScPhm, MSc, PhD, Assistant Professor, University of Western Ontario, Department of Medicine, London, ON, Canada. Panelists: Elizabeth Manias MPharm, PhD, Professor, Associate Head of Research, The University of Melbourne, School of Nursing and Social Work, Carlton, Australia; Vernon F. Schabert PhD, Senior Director, IMS Consulting, Health Economics and Outcomes Research, Santa Barbara, CA, USA; Dyfrig Hughes PhD, MRPharmS, Deputy Director, Centre for Economics and Policy in Health, IMSCaR, Bangor University, Bangor, Wales LL57 1UT.
ISSUE: What are the advantages, limitations and uses of the medication possession ratio (MPR) and gaps measures of medication compliance? The MPR and Gap measures provide a different glimpse into patient taking behaviour. The issue under consideration relates to the clinical meaningfulness of the measures for decision making. Are we selling ourselves short by relying on the MPR? OVERVIEW: The use of medication compliance in decision making has evolved over the last 20 years, with compliance being utilized more frequently. Measures commonly used include the medication possession ratio (MPR) and gaps measures. The MPR is a ratio of the total days' supply compared to the number of days of study participation. Gaps measures, such as the Continuous Measure of Medication Gaps (CMG) or the Continuous Multiple Interval Measure of Oversupply (CMOS), focus on the number of treatment days during which a patient is without medication. We will discuss the usefulness of each measure for decision making. The advantages, limitations and uses of each form of measure will be compared and contrasted, highlighting controversies associated with their application and use. More specifically, consideration will be given to how calculations of these measures are affected by the types of medications administered, the clinical environment in which medications are administered, the degree of tolerance for non-compliance or interruptions to therapy, the length of time for the follow-up period, and the potential for using a grace period. Methodological challenges relating to calculations of these measures and statistical analysis of data will also be addressed. In addition, issues related to economic evaluations and measurement choice will be discussed. Members of the Analyses Standards Working Group will present and facilitate the discussion on this issue and panel participants will be encouraged to provide feedback and examine their experiences. *Panelists represent the ISPOR Medication Compliance and Persistence Special Interest Group (MCP). A list of members is available on the ISPOR website.
IP4:
MODELS FOR COLLABORATIVE DEVELOPMENT OF PATIENT-REPORTED OUTCOME MEASURES FOR CLINICAL TRIALS - DIFFERENT PATHS, SAME DESTINATION? Moderator: Asha Hareendran PhD, Senior Research Scientist, United BioSource Corporation, London, UK Panelists: Priti Jhingran PhD, US Health Outcomes Director, GlaxoSmithKline, Research Triangle Park, NC, USA; Dennis A. Revicki PhD, Director, United BioSource Corporation, Center for Health Outcomes Research, Bethesda, MD, USA ISSUE: With the increasing importance of the need for patient-reported outcome (PRO) endpoints for measuring treatment benefit, there have been multiple efforts to develop PRO tools to measure the same concept by different groups. Recognizing the inefficiencies of these multiple approaches, there have been a few efforts for pre-competitive collaboration. The US FDA has also proposed an overarching framework for collaboration called the PRO Consortium. This panel will address issues around the process and methods of collaborative instrument development, comparing two approaches to collaboration. Dennis Revicki will present the ANMS collaboration on gastroparesis tools and the ROME collaboration on Irritable Bowel Syndrome (IBS) tools. Laurie Burke, Bob Assenzo and Asha Hareendran will lead the panel discussion. OVERVIEW: The development and validation of new PRO instruments can be expensive and time consuming. This panel will discuss issues around collaborative efforts in the development of PRO instruments comparing efforts in functional gastrointestinal (fGI) disorders. 1) The American Neurogastroenterology and Motility Society (ANMS) is leading a public-private collaboration for developing a gastroparesis symptom diary. Participants include a steering committee of ANMS members, and resources for the project are provided by the medical society and several pharmaceutical companies. The tool is undergoing psychometric evaluation. 2) Working groups within the ROME Foundation are addressing issues related to PRO endpoints for IBS trials, including a meta-analysis across trials to measure psychometric properties of PRO tools, assessment of predictors of IBS severity based on patient input, and organized meetings to discuss these issues among key stakeholders for such information, to help lay the groundwork for the development of valid PRO endpoints. The implications of the varying levels of participation by key customers of PRO information will be discussed, with an opportunity for the audience to participate in discussions about initiating and implementing such approaches.
HEALTH POLICY DEVELOPMENT USING OUTCOMES RESEARCH ISSUES
IP5:
ASSESSMENT AND APPRAISAL OF CANCER MEDICINES: DO THEY DESERVE A SPECIAL TREATMENT? Moderator: Michael F. Drummond DPhil, Professor of Health Economics, Centre for Health Economics, University of York, York, UK Panelists: Adrian Towse MPhil, Director, Office of Health Economics, London, UK; Mark Sculpher PhD, Professor of Health Economics, Centre for Health Economics, University of York, York, UK; Scott Ramsey MD, PhD, Associate Member, Fred Hutchinson Cancer Research Center, Seattle, WA, USA ISSUE: This panel seeks to consider the strengths and weaknesses of the cost-per-QALY- based approach used by HTA bodies (such as the National Institute for Health and Clinical Excellence - NICE) for valuing cancer therapies and explores how concerns can be addressed. The panel will focus on: • How well does the QALY, particularly EQ-5D, assess cancer patients' health gain from a treatment? • How should QALY values for cancer treatments be interpreted in the context of societal preferences for treating cancer patients? • How can cost-per-QALY-based decision making processes take into account factors including health gains which may not be reflected in the QALY and societal preferences? These issues will be discussed by Adrian Towse providing an academic view from a manufacturer-sponsored study; by Mark Sculpher from an academic view and from the perspective of a health economist involved in decision making; by Scott Ramsey providing a view as a cancer clinician also involved in decision making.
OVERVIEW: In recent years, decisions by NICE on the availability of cancer medicines in the UK NHS have attracted significant publicity. Media attention has been given to patients who have been denied oncology medicines due to NICE decisions. In some cases, these patients have paid for drugs and other treatment out-of-pocket, and others have been unable to afford drugs that could improve their length or quality of life. These cases can be seen as a challenge to the methods used by NICE from patients and from the broader community. Tensions between HTA bodies and other stakeholders regarding coverage decisions of cancer treatments have also been seen in other countries. The focus in this panel is on whether standard approach used by HTA bodies is appropriate for assessing and appraising oncology drugs and, if not, how possible changes could be researched and introduced.
HETEROGENEITY AMONG HOMO SAPIENS: IMPLICATIONS FOR CLINICAL DEVELOPMENT, CLINICAL PRACTICE, AND PRICING AND REIMBURSEMENT Moderator: William Crown PhD, President, i3 Innovus, Waltham, MA, USA Panelists: Marc L. Berger MD, Vice President, Eli Lilly, Global Health Outcomes, Indianapolis, IN, USA; Victor M. Montori MD, Associate Professor, Mayo Clinic, Rochester, MN, USA; Ernst Berndt PhD, Professor, Massachusetts Institute of Technology, Sloan School, Cambridge, MA, USA ISSUE: Heterogeneity analysis (HA) applies information and analytical methods to detect differential treatment response. This Issue Panel explores the benefits and challenges of incorporating HA into the clinical development, clinical practice, and pricing and reimbursement decisions associated with tailored therapeutics. OVERVIEW: Biomarkers or genetic characteristics hold great promise as a primary emphasis of HA. However, biomarkers and diagnostics are not available for many conditions. The probability of success associated with tailored therapeutics may be enhanced by using multiple sources of information (e.g., comorbidity profiles, phenotypic markers, biomarkers, and diagnostics). With regard to clinical trial design robust predictors of response and differential outcomes may enable identification of patient populations with a high degree of response to therapy. Augmentation with other tailoring/methodological approaches (e.g., adaptive designs, Bayesian methods) may further enhance the probability of success. However, several potential challenges for the design and conduct of clinical trials remain, including uncertainty regarding adequate evidence of validation to meet regulatory standards and smaller potential target markets for tailored therapeutics. Tailored therapeutics offer considerable promise in terms of improved patient outcomes and safety profiles. By reducing the variance in treatment introduced by non-responders, tailored therapeutics may both raise the average response to treatment and improve its predictability. Although for several reasons, tailored therapeutics tend to be expensive, they may help to reduce costs associated with failed treatments--particularly in situations where the costs associated with treatment failure are high. Successful adoption of tailored therapeutics in clinical practice also requires the ability to identify and restrict use by patients who would have responded to less expensive therapies. A high probability of predicted patient response is a necessary but not sufficient condition for payer reimbursement. Discussion: Approximately half of the available time for this issues panel will be devoted to audience participation.
ECONOMIC OUTCOMES RESEARCH ISSUES
IP7:
USE OF THE QALY FOR ECONOMIC EVALUATION: PRAGMATIC CHOICE OR UNJUSTIFIED EVIL? Moderator: Louis Garrison PhD, Professor and Associate Director, Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington, Seattle, WA, USA Panelists: Michael F. Drummond DPhil, Professor of Health Economics, Centre for Health Economics, University of York, York, UK; J. Jaime Caro MDCM, FRCPC, FAC, Senior Vice President, Health Economics, United BioSource Corporation, Health Care Analytics, Lexington, MA, USA ISSUE: The use of cost/QALY ratios has become commonplace in economic evaluation as exemplified by NICE in the UK. IQWiG in Germany has chosen not to use them because they are judged to be unethical. What should HT agencies do? OVERVIEW: For more than a decade, the idea has prevailed that to allocate resources efficiently in a health care system, it is necessary to have a common measure of the value of health effects. This universal measure is felt to be necessary so that the efficiency of all interventions can be assessed relative to a common standard. Given the multiple dimensions on which health care interventions can have an effect, this measure must be an aggregate and the predominant technique is to classify these into two dimensions: life expectancy or "quantity" of life on the one hand and everything else into a “quality” that is used to weight the survival. The resulting QALY is then taken as the value of the health effects and the incremental cost of obtaining any gains is referenced to threshold efficiency in order to appraise whether the intervention is worth it. Although many researchers have pointed out technical problems with the estimation of QALYs, have raised questions about how well it reflects relevant preferences, and have argued that the use of efficiency does not ensure rational resource allocation, the use of the QALY continues to be the recommended approach because “there is nothing better”. The recent methodological guidelines issued by IQWiG in Germany have rejected this approach and the justification for the QALY on fundamental rather than methodological grounds: it is felt to be unethical and unnecessary. This panel will present these two positions, aiming to engage--even stoke--the audience into a discussion of the merits of each approach.
PATIENT-REPORTED OUTCOMES RESEARCH ISSUES
IP8:
IMPLEMENTING FDA PRO GUIDELINES -- CONTENT VALIDITY AND GOOD MEASUREMENT PRACTICES: WHAT IS THE RIGHT BALANCE? Moderator: Valerie S. L. Williams PhD, Senior Director, Patient-Reported Outcomes, RTI Health Solutions,
Research Triangle Park, NC, USA Panelists: Carla DeMuro-Mercon MS, Senior Director, Patient-Reported Outcomes, RTI Health Solutions, Research Triangle Park, NC, USA; Bryce Reeve PhD, Program Director and Psychometrician, National Cancer Institute, Outcomes Research Branch, Applied Research Program, Division of Cancer Control and Population Sciences, Bethesda, MD, USA; M. Haim Erder PhD, Vice President, Forest Research Institute, Health Economics & Outcomes, Jersey City, NJ, USA ISSUE: A PRO measure used in clinical trials to support approval or label claims must be capable of demonstrating treatment-related changes while withstanding extensive review by the FDA/SEALD. In recent years, establishing the content validity of PRO measures to the agency's satisfaction has become more important and more challenging. OVERVIEW: While there are quantitative standards for many psychometric properties, evidence supporting content validity is qualitative in nature, making its evaluation inherently subjective. It is standard practice to gather qualitative evidence from patients early in the instrument development process to ensure the measure addresses the concepts important to patients. Although FDA guidelines recommend all important concepts be included, item reduction is often necessary to limit patient burden and optimize psychometric performance. Our objective is to share ideas from various perspectives and facilitate discussion with colleagues about how to ensure the content validity of PRO measures in a way that is acceptable to the FDA/SEALD but also balances these requirements with patient burden and psychometric considerations. Sheri Fehnel PhD, an instrument developer, will raise numerous practical questions. For example, where can we reasonably draw the line between measuring every possible symptom of a condition and measuring only a distinct subset of symptoms important to a significant proportion of patients? Potential definitions and metrics will be posed for audience consideration. M. Haim Erder PhD, will provide an industry perspective, describing recent experiences and competing objectives, including the need to meet FDA requirements while facing potential trade-offs in terms of data quality (e.g., respondent fatigue, missing data) and analytical complexity. Bryce Reeve PhD, representing a government sponsor perspective, will reflect on issues and concerns for assessing PRO endpoints in clinical trials and describe current work toward developing more valid and precise PROs. Discussion will focus on how to satisfy content validity while minimizing respondent burden.
HEALTH POLICY DEVELOPMENT USING OUTCOMES RESEARCH ISSUES
IP9:
DEVELOPING AND ADDRESSING PAYER EVIDENCE REQUIREMENTS FOR MOLECULAR DIAGNOSTICS AND PERSONALIZED MEDICINE: HOW CAN HEALTH OUTCOMES AND ECONOMICS APPROACHES HELP FILL THE GAP? Moderator: Eric C. Faulkner MPH, Senior Director, RTI Health Solutions, Pricing & Reimbursement, Research Triangle Park, NC, USA Panelists: Patricia Deverka MD, MS, MPE, Research Associate Professor, Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; David L. Veenstra PharmD, PhD, Associate Professor, Department of Pharmacy, University of Washington, Seattle, WA, USA; Penny Mohr MA, Vice President, Programs, Center for Medical Technology Policy, Baltimore, MD, USA ISSUE: Changing payer evidence requirements and reimbursement uncertainty in the field of molecular diagnostics and personalized medicine remain a significant limiting factor to realizing the promise of personalized medicine. How can health outcomes and economics approaches help fill the gap and improve rational integration of this new wave of health technologies into care delivery? Eric Faulkner will represent a payer perspective and open the panel with new research on current payer practices and evidence expectations for personalized medicine products from 2008 US member surveys of the National Association of Managed Care Physicians. Pat Deverka will provide a clinical and health policy researcher perspective and discuss the Smart Drug Project which mines existing evidence to identify opportunities where diagnostics could currently be developed, but system incentives or other factors may preclude translation into practice. David L. Veenstra will provide an economist perspective on how economic modeling may help address practical challenges associated with developing direct evidence to characterize the value of diagnostics and companion diagnostic scenarios. Penny Mohr will represent a non-profit research organization's perspective and discuss collaborative approaches for piloting new methodological and study approaches suitable for personalized medicine. OVERVIEW: Emerging molecular diagnostics and personalized medicine approaches promise to markedly improve health care efficiency and outcomes at a time when health systems struggle to balance quality and costs. Despite this promise, payers face technology assessment and decision challenges because conventional evidence development and evaluation approaches are insufficiently developed, variably applied or have not kept pace with rapid technology evolution in this field. Alternatively, technology manufacturers face reimbursement uncertainty and practical challenges of meeting ‘ideal' payer evidence requirements, diminishing incentives for innovation. Because of these obstacles, there is a significant need for novel outcomes and economics approaches sufficient to payer needs and sensitive of practical limitations.
IP10:
HTA IN THE AGE OF OBAMA Moderator: Peter J. Neumann ScD, Director, Tufts Medical Center, Center for the Evaluation of Value and Risk in Health, Boston, MA, USA Panelists: Peter Bach MD, MAAP, Associate Attending Physician, Memorial Sloan-Kettering Cancer Center, Former Senior Adviser to the Administrator of the Centers for Medicare and Medicaid Services, New York, NY, USA; Brian Sweet BSPharm, MBA, Chief Pharmacy Officer, WellPoint, Indianapolis, IN, USA; Jeff Thompson MD, MPH, Chief Medical Officer, Washington State Department of Social & Health Services, Health and Recovery Services Administration, Olympia, WA, USA. ISSUE: The panelists will explore how American health technology assessment (HTA) organizations differ from others around the globe, and how they are responding to the new health care and political environment. OVERVIEW: HTA has been described as a multi-disciplinary field of policy analysis, studying the medical, economic, social and ethical implications of development, diffusion and use of health technology. HTAs are being performed by a variety of public and private sector organizations in the U.S. American HTA organizations face unique challenges given the decentralized and largely privately delivered and financed health care system. The ongoing economic crisis and the push for health reform by the new Administration and Congress present unique situations for public and private organizations that conduct health technology assessment (HTA). In this issues panel we discuss the extent to which HTA organizations in the U.S. endorse and implement key principles for the conduct of HTA. For example, how transparent are their assessments? How much stakeholder involvement do they allow? Do they communicate findings appropriately? Findings from a recent analysis that compared U.S. HTA organizations with other HTA entities around the globe will be presented. Leaders from both public and private U.S. payers will present their views on these questions, and discuss how American-style HTA might change in the Obama era.
