Scott Ramsey, MD, PhD Definition Trials for which the hypothesis and study design are formulated based on information needed to make a decision Synonyms Pragmatic clinical trials Practical clinical trials Naturalistic clinical trials 1
Decision Makers need high quality evidence about: 1. Effectiveness What are the outcomes for the product when it is used in the real world? 2. Incremental clinical impact How does the product compare to the treatment(s) that patients usually receive? 3. Cost and Value How much will it cost to adopt the new product? How much benefit for added cost? Or are there savings? Medicare Spending Per Capita, United States 2006 Dartmouth Atlas Days in the Hospital, Last 6 Months of Life (77 major U.S. teaching hospitals) Days in hospital, last 6 months of life Source: Dartmouth Atlas 2
Rationale for Real World Outcomes Studies The IOM estimates that less than 50% of treatments delivered today are supported by evidence. Reviews of practice guidelines developed by prominent expert groups found few recommendations were based on high quality evidence American College of Cardiology American Heart Association National Comprehensive Cancer Network Of the nation s $2 trillion annual health expenditure, currently less than 0.1 percent is invested in assessing the comparative effectiveness of available interventions Goal Understand how or why a particular intervention works Address practical questions about the risks, benefits, and costs of competing interventions Design Maximize the chance that a biological effect of a new treatment is revealed Treatment vs. placebo Randomization necessary Blinding compulsory Treatment assignment Evaluator Identify differences between competing treatments New therapy vs. established therapy Established therapy vs. established therapy Randomization necessary, but may need to account for patient preferences Blinding to treatment assignment may not be possible 3
Setting Carefully controlled environment Expert clinician/researchers Real world Variety of settings private practice/academic, i rural/urban HMO/FFS Practicing clinicians Patient Population Strict entry criteria Minimize extraneous patient factors (comorbidities) that could influence outcome E.g., heart disease in a study of COPD therapy Clinical trial friendly individuals Define patient groups by presentation vs. diagnosis Minimize exclusion criteria Comorbid conditions acceptable Real world patients desirable Whole US Population People who live in the areas in which the study was conducted People with headaches People with migraine Excluded bed rest vomit 20% of the time Included IHS criteria /2mo<X<6/mo Actual >18yr. old Study good health Subjects 4
Structure Complexity if necessary Multiple subaims, subpopulations acceptable Within established research infrastructure Time horizon dictated by the duration needed to measure an effect Simplicity Low cost Feasibility Must be acceptable to practitioners Timeliness The clinical question is waiting! Outcomes Intermediate Reflecting disease processes that support biological plausibility Mortality Morbidity What do researchers and clinicians care about? Broad range of functional outcomes, e.g., Quality of life Symptom severity Satisfaction Costs Mortality Morbidity What do patients care about? What should we pay for? Example: Antidepressant Treatment: 1990 Major depressive disorder is one of the top ten diseases in primary care Tricyclic antidepressants are most frequently used depression medication therapy Clinical trial evidence supports safety and efficacy Many generic products, relatively low cost Fluoxetine introduced in 1988 Clinical trial evidence shows comparable clinical efficacy Lower rates of adverse events and treatment discontinuation Relatively high cost (compared with TCAs) 5
SSRI Use Early 90 s Enthusiastic acceptance of SSRIs by clinicians and patients Little research evidence that advantages of SSRIs result in improved effectiveness Uncertainty about impact of SSRI use on total medical costs Existing economic studies based on retrospective claims data or modeling studies Managed Care Pharmacy Reaction Concern that first line SSRI treatment would prove costly to pharmacy budgets Limit use of SSRIs to second line treatment In 1994, US expenditures for SSRIs were $1.27 billion, equivalent to amount spent on psychotherapy visits Group Health s Perspective Large staff model HMO serving about 400,000 members in Seattle area Pharmacy estimates indicate that switching all current TCA prescriptions to SSRIs would exceed GHC mental health budget Guidance recommending SSRI second line treatment 6
Lilly Perspective Increase in MCO or MCO like health insurance coverage (restricted formularies) Formulary restrictions limit patient access and sales Interest in providing convincing pharmacoeconomic evidence Anti Depressant Phase 4 Lilly Grp Hlth Coop (Puget Sound) Partnership Naturalistic clinical trial design Randomization to imipramine, desipramine or fluoxetine Physician control over dosage and duration of antidepressant therapy 536 patients followed for 6 months (91% complete) and 2 years (72% complete) Measures of depression severity, HRQL and medical costs Research Question Does initial selection of fluoxetine result in better clinical, quality of life, and economic outcomes compared with initial selection of less expensive TCAs? 7
Design and Management Issues: Solutions Research grant and publication rights Investigator independence and authority Study advisory committee including GHC investigators MEDTAP investigators External clinical and economic experts Industry representative Antidepressant Treatment Persistence: TCAs vs. SSRIs 1 Month 3 Months 6 Months TCAs 60 70% 45 50% 30 35% Fluoxetine 85% 70% 60% Source: Simon et al (1996) Main Study Findings* Fluoxetine lower discontinuation rates Fluoxetine lower reported side effects No differences in depression or HRQL outcomes *Initial antidepressant choice in primary care: effectiveness and cost of fluoxetine versus tricyclic antidepressants. Simon, G.E., Revicki, D.A., et al JAMA 275:1897 1902, 1996. 8
Direct Medical Costs: Six Month Results Desipramine Fluoxetine Imipramine Total outpatient costs $1702 $1654 $1604 Total inpatient costs $ 659 $ 313 $ 501 Total costs $2361 $1967* $2105 *not statistically significant Group Health Actions Based on Study Findings Removed guidance restricting SSRIs to second line therapy Patient and physician preferences appropriate basis for treatment selection Focused efforts on improving Detection of depression by primary care physicians Treatment of depression by primary care physicians Adherence to antidepressant therapy Practical Matters Make sure all stakeholders are involved in the design of the trial at the outset. Balance the need for additional data collection with participant ii burden. Use validated d data collection tools. Undertake sample size determination for the hypotheses even if it is academic. Write an analysis plan before the trial is finished. Do not deviate from the analysis plan 9
Key Questions Is the treatment likely to substantially affect endpoints that are meaningful to patients? Are these meaningful differences likely to be detectable between treatment groups within the time constraints of the trial? Is it financial feasible to collect the outcomes needed to influence practice? Is the control arm a treatment that is commonly used in clinical practice? Funding Even with increased government funding, pragmatic trials are difficult to fund Entrenched stakeholder interests Inertia of current practice Lack of clear responsibility for funding Infrastructure issues Multi partner collaborative funding is likely the future model (e.g., gov t + industry + health plan) Final Thoughts and Practical Issues Pragmatic trials are valuable and relevant for clinical practice The current health care climate is right but not ripe for pragmatic trials When considering PCTs, consider Clinical equipoise Burden of disease Practice political considerations Availability of partnerships and funding Feasibility 10