Value in Medicine. Why should we are about value? Conceptual Value Framework. Overview

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1 Why should we are about value? Value in Medicine Jeffrey A. Tice, MD Professor of Medicine Division of General Internal Medicine Value based payments by insurers Health care cost increases are unsustainable Health care costs directly impact the health of our patients Adherence Out of pocket costs #1 reason for bankruptcy in our country Overview A Framework for Value Real world cases: break out sessions New drugs for Hepatitis C (Harvoni) PCSK9 inhibitors for high cholesterol Anabolic drugs for osteoporosis Wrap up: your thoughts on how to assess value Conceptual Value Framework Comparative Clinical Effectiveness Long-Term Value for Money Incremental Costeffectiveness Goal: Sustainable Access to High-Value Care for All Patients Short-Term Affordability Potential Budget Impact Other Benefits or Disadvantages Contextual Considerations

2 Comparative Clinical Effectiveness Evidence Rating Matrix Evidence Rating Matrix Magnitude of the comparative net health benefit Level of certainty in the evidence on net health benefit Incremental Cost-effectiveness The quality-adjusted life-year (QALY) is the primary measure of clinical benefit for comparisons across different conditions and treatments A range of thresholds between $50,000 and $150,000 per QALY are generally considered to be cost-effective. Societal willingness to pay (~1-3x per capita GDP) Individual WTP (~2x annual salary) Empiric studies (~1x per capita GDP) Other Benefits or Disadvantages Benefits of treatment that extend beyond patient-specific health improvement? Reducing complexity of the treatment regimens will significantly improve patient outcomes Reducing important health disparities: racial, ethnic, gender, socio-economic, or regional Impact on caregiver or broader family burden New mechanism of action that is likely to help patients who have not responded to other treatments Impact on productivity and ability of the patient to contribute to personal and national economic activity Other Institute for Clinical and Economic Review, 2017

3 Contextual Considerations Intervention intended for patients with a high lifetime severity of illness (i.e., impact on length/quality of life) Childhood leukemia First intervention for patients with the condition Emflaza for Duchenne muscular dystrophy Significant uncertainty about the incidence magnitude, or durability of the long-term risk of benefit or harms of the treatment New drug with 1 year RCT data only: less willingness to pay Potential Budget Impact Estimate of potential budget impact of a new drug, minus cost offsets, over a five-year time horizon Affordability and access alert Issued if discussion w/ stakeholders indicates clinically-necessary utilization at net price would exceed threshold (without active intervention by insurers, others to limit access) Signals that additional costs would be difficult to absorb without displacing other services, contributing to rapid growth in healthcare spending, threatening sustainable access to high-value care for all patients Institute for Clinical and Economic Review, 2017 Conceptual Value Framework Long-Term Value for Money Goal: Sustainable Access to High-Value Care for All Patients Short-Term Affordability Hepatitis C Treatment Comparative Clinical Effectiveness Incremental Costeffectiveness Potential Budget Impact Other Benefits or Disadvantages Contextual Considerations

4 Six HCV genotypes Natural history of HCV infection GT 2 15% HCV in the US GT 3 10% GT 1 74% GT 4-6 1% Condition Number of individuals Infection with hepatitis C 100 Remain asymptomatic Develop chronic infection Develop chronic liver disease Develop cirrhosis over years 5 20 Die from cirrhosis or liver cancer 1 5 This CTAF assessment will focus on genotypes 1, 2 and Treatment of Chronic HCV Infection Rapid evolution of treatment for genotype 1 Pegylated interferon + ribavirin (PR) 2001 Boceprevir or telaprevir + PR 2011 Simeprevir or sofosbuvir + PR 2013 Interferon-free DAA combinations 2014 Intermediate outcome Sustained virologic response (SVR) Key patient oriented outcomes Cirrhosis, hepatocellular carcinoma (HCC), liver transplantation, death Current treatment for GT 1: B&T 2011: the first DAAs approved for GT 1 PR + boceprevir or telaprevir Benefits Improved SVR24: 70 to 75% in treatment naïve Shorter duration in some patients: 24 to 48 weeks Burdens More pills: 6-12 a day on a q 8 hour schedule Increase in anemia from 30% to 50% Dysguesia, rash, drug interactions 16

5 New Drugs Reviewed Simeprevir/Sofosbuvir (SMV + SOF Olysio + Sovaldi) weeks: cost of ~$150, ,000 Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni) 8-24 weeks: cost of ~$63, ,000 3D ± R (Viekira Pak) weeks: cost of ~$84, ,000 Questions for discussion Does ledipasvir/sofosbuvir (Harvoni) for the treatment of chronic hepatitis C infection represent: A. Low Value B. Reasonable Value C. High Value How much does 1 pill of Harvoni cost? Four Subgroups within GT1 Clinical Effectiveness Treatment-naïve / non-cirrhotic 69% Treatment-experienced / non-cirrhotic 19% Treatment-naïve / cirrhotic 9% Treatment-experienced / cirrhotic 3%

6 21 Treatment-experienced, Cirrhotic: SVR SVR (%) GENOTYPE 1 SVR IN EACH SUBGROUP SMV + PR SOF + PR SOF + R SMV + SOF LDV/SOF DCV + SOF 3D + R Adverse Events (AEs) SMV12 PR24 SOF12 PR12 SOF24 R24 SMV12 SOF12 LDV12 SOF12 DCV12 SOF 12 3D12 R12 N Flu 26% 16% 3% NR <5% 0% NR Anemia 12% 23% 9% 0% 0% 0% 3% Rash 28% 18% 8% 11% 4% 5% 11% Flu-like symptoms with P Anemia with PR or 24 weeks R therapy Photosensitivity rashes with simeprevir Limitations No direct comparisons between therapies, randomized or observational Possible selection bias Intermediate outcome: SVR12 Imperfect measure of cure Residual risk for HCC Small numbers studied Great uncertainty around the estimates of SVR and harms Real world results likely not as impressive

7 Summary Multiple DAA therapy better than single DAA therapy Moderate certainty Greater SVR12 (>90%) with fewer side effects Fewer pills, no injections No direct comparisons Small sample sizes in many subgroups Cost Methods Inputs Population: US, 60 years old, prevalent mix of fibrosis stages Lifetime time horizon HCV natural course Without treatment or treatment failure After successful treatment Costs: Drugs, ongoing HCV care, HCV complications Quality of life: Utilities (measures quality of life) Results: Treatment-naïve Tx naïve, treat all New treatments vs. PR Net cost Effect (QALYs) ICER LDV/SOF(8/12 weeks) $ 28, $ 20,132 SOF + PR (12 weeks) $ 45, $ 38,386 LDV/SOF (12 weeks) $ 46, $ 31,234 SMV + SOF (12 weeks) $ 116, $ 79,341 SOF + R (24 weeks) $ 123, $ 189,160 Tx Naive, treat F3/F4 Net cost Effect (QALYs) ICER LDV/SOF (8/12 weeks) $ 16, $ 15,940 SOF + PR (12 weeks) $ 22, $ 25,134 LDV/SOF (12 weeks) $ 32, $ 29,257 SMV + SOF (12 weeks) $ 66, $ 62,261 SOF + R (24 weeks) $ 66, $ 146,472

8 Probabilistic Sensitivity Analysis: LDV/SOF vs. PR, Treatment-naïve, Treat all $50,000 QALY threshold $150,000 QALY threshold Key Findings: Incremental cost-effectiveness Under a wide range of values for price and effectiveness, LDV/SOF and SMV + SOF show cost-effectiveness ratios (ICERs) below commonly accepted thresholds Model shows that treating everyone rather than waiting until fibrosis levels F3/F4 meets commonly accepted costeffectiveness thresholds of $50,000 to $150,000 per quality-adjusted life year (QALY) gained Key Findings: Budget Impact Budget impact of treating all patients never offset fully After 20 years, about 25% of the additional costs of treatment with LDV/SOF (vs. PR) would be offset by savings from reduced liver-related complications and fewer deaths Cost of new therapy that would allow treatment of all patients at a cost threshold that payers describe as manageable: $34,000 $42,000 In other words: it breaks the bank at the current cost Summary LDV/SOF and other potential interferon-free regimens provide substantial clinical benefits over historical treatment The new drug combinations are cost effective at current prices (cost/qaly < $50,000) Short-term budgetary impact would be high at current prices Price of new drugs for HCV that would allow treatment of all infected individuals with known infection without exceeding 0.5%-1.0% PMPM increase: $34,000 $42,000

9 Questions for discussion Does ledipasvir/sofosbuvir (Harvoni) for the treatment of chronic hepatitis C infection represent: A. Low Value B. Reasonable Value C. High Value PCSK9 Inhibitors for Treatment of High Cholesterol How much does 1 pill of Harvoni cost? Topic in Context PCSK9 Cardiovascular disease is the most common cause of death in the U.S. LDL hypothesis: Lower is better True for statins and ezetimibe Not true for estrogen, niacin, fibrates, others Example: RCT torcetrapib x 5 years, n > 15,000 LDL decreased by 25%, HDL increased CVD events increased 25%; total mortality increased 58% Proprotein convertase subtilisin/kexin type 9 Binds to LDL receptors and prevents recycling Fewer LDL receptors More LDL in blood Genetic mutations studies Gain of function: high LDL, early strokes and MIs Loss of function: low LDL, less CVD

10 PCSK9 inhibitors Alirocumab (Praluent, Sanofi and Regeneron) 75 mg SC every 2 weeks 150 mg SC every 2 weeks Evolocumab (Repatha, Amgen) 140 mg SC every 2 weeks 420 mg SC every 4 weeks Clinical Effectiveness Results Study Description Results: LDL reduction 25 randomized trials: low risk of bias Alirocumab 13 RCTs, n = 5,137 Evolocumab 11 RCTs, n = 5,022 Control: placebo in 14 trials, ezetimibe in 7, both in 3 Comparator Placebo Ezetimibe 58.8% 36.2% Similar for alirocumab and evolocumab Similar for background statin intensity

11 Outcomes: CVD Other adverse events No trials designed to evaluate CVD outcomes CVD outcomes were adverse events in trials designed to evaluate LDL lowering 2 large CVOTs to report in OR (95% CI) Mortality 0.45 ( ) CVD mortality 0.50 ( ) MI 0.49 ( ) Stroke 1.97 ( ) Unstable angina 0.61 ( ) OR (95% CI) Serious AE 1.01 ( ) AE discontinuation 1.03 ( ) Myalgias 1.16 ( ) Neurocognitive AE 1.08 ( ) ALT elevation 0.82 ( ) CK elevation 0.72 ( ) Injection site AE 1.30 ( ) Hypersensitivity AE 0.69 ( ) Summary of the Evidence: Promising, but inconclusive High certainty of LDL lowering with the PCSK9 inhibitors (59% versus placebo; 36% versus ezetimibe) Low to moderate certainty of improvements in CVD outcomes Outcomes studies in progress (n > 40,000; 5 year FU) Borderline significant benefits when all trials combined Clear evidence of injection site reactions; no other AEs clearly associated with PCSK9 inhibitors, but the person-years of experience is modest The magnitude of the net benefit is either incremental or substantial Cost

12 Costs Results: CVD on statins, not at goal Annual drug costs = average wholesale acquisition costs: Statin: $812 PCSK9 inhibitor: $14,350 (average of two agents) 7,271,000 patients in 2015 Statin Statin + PCSK9 inhibitor Total MACE averted NNT 5 QALYs gained Incremental Drug Costs (million $) comparator Incremental Costs, Other CV Care (million $) ICER ($/QALY) 5,621, ,573,800 $3,406,692 $210,702 $302,000 Threshold Analyses: Annual cost Conclusion Patient Subpopulation ASCVD - Statin intolerant LDL-C 70 mg/dl ASCVD on statins LDL-C 70 mg/dl Willingness-to-pay threshold $50,000/QALY $100,000/QALY $150,000/QALY $3,400 $5,800 $8,300 $3,100 $5,300 $7,600 Assuming that LDL-C lowering observed with PCSK9 inhibitors translates into clinical benefit consistent with that observed with statins, PCSK9 inhibitors are likely to yield considerable reductions in CV morbidity and mortality NNT 5 for FH = 28 NNT 5 for ASCVD = 21 Incremental cost-effectiveness ratios at list price Range from $274,000-$302,000 per QALY for all three subpopulations Even hypothetical use in population immediately following MI produces cost/qaly > $150,000

13 49 Budget Impact: Methods POTENTIAL BUDGETARY IMPACT Size of key subpopulations from CVD Policy Model: CVD: 1.5 million & 7.3 million for statin-intolerant and not at LDL-C goal Assumed 5-year uptake: 75% for FH, 25% for CVD subpopulations Year 5 treated estimates: FH: 453,000 CVD statin-intolerant: 365,000 CVD not at goal: 1,818,000 TOTAL 2,636,000 Budget Impact: Results at 5 Years Questions for discussion Population Number Treated (thousands) Annualized Budget Impact (billions) Discount to Match Annual Budget Impact Threshold TOTAL 2,636 $ % Do the PCSK9 inhibitors to prevent cardiovascular events represent: A. Low Value B. Reasonable Value C. High Value Why?

14 Anabolic Therapies Anabolic Therapies for Osteoporosis in Postmenopausal Women Teriparatide 20 mcg: FDA approval 11/26/2002 PTH analog Given once daily via subcutaneous (SC) injection (pen) Abaloparatide 80 mcg: FDA approval 4/28/2017 PTHrP analog Given once daily via SC injection (pen) Fracture Outcomes Clinical Effectiveness Fragility: low impact fractures Morphometric Vertebral fractures Compare lateral spine x-rays before and during therapy Clinical vertebral fracture ~35% of morphometric fractures Non-vertebral fragility fractures Hip, forearm, humerus, pelvis Exclude: skull, face, fingers, toes, pathologic fractures

15 Insights from Discussions with Patients NOF Survey Top Two Patient Concerns Loss of independence Loss of mobility Top caregiver concern No longer being able to care for loved-one Why not taking prescribed medication Concern about side effects Use of needles, need for refrigeration matter Insurance barriers are confusing Clinical trials don t measure outcomes that matter to patients Key Clinical Trials Reference Study Group N Neer 2001 Prevrhal 2009 Fracture Teriparatide Prevention Placebo Trial Miller 2016 ACTIVE Abaloparatide Teriparatide* Placebo Black 2007 HORIZON Zoledronic acid Placebo F/U, months Age, years BMI, kg/m Non-V: non-vertebral fracture, V: vertebral fracture *Teriparatide was open label; fracture adjudication was done by central committee blinded to allocation status Prior Fracture 100% V 24% V 63% any 63% V Major difference between trials is prevalence of vertebral fractures at baseline Relative Risk for Vertebral fractures Non-Vertebral Fractures: NMA Abaloparatide (80 mcg) Abaloparatide (80 mcg) 0.76 ( ) Teriparatide (20 mcg) 0.83 ( ) Teriparatide (20 mcg) 0.44 ( ) 0.57 ( ) Zoledronic Acid (5 mg) 0.69 ( ) 0.82 ( ) Zoledronic Acid (5 mg) 0.13 ( ) 0.17 ( ) 0.30 ( ) Placebo 0.51 ( ) 0.61 ( ) 0.75 ( ) Placebo

16 Hip Fractures Patient-Reported Outcomes Zoledronic acid: relative risk (RR) 0.59 ( ) Insufficient data for teriparatide and abaloparatide Observational data for teriparatide comparing patients adherent for 2 years to those adherent less than 3 months RR 0.55 ( ) No trial reports on loss of independence, activities of daily living (ADLs), instrumental ADLs, mobility, caregiver burden, or quality of life Harms Summary No differences from placebo in serious adverse events No differences from placebo in discontinuation due to adverse events except for abaloparatide more than teriparatide and placebo in ACTIVE trial (10% vs. 7% vs. 6%) More injection site reactions with abaloparatide NMA: abaloparatide and teriparatide reduce vertebral and non-vertebral fractures compared to placebo No significant differences from each other or zoledronic acid Minimal harms: more injection site reactions and hypercalcemia with abaloparatide Extensive real-world experience with teriparatide that supports RCT findings Both require daily SC injection

17 Other Benefits or Disadvantages and Contextual Considerations Both abaloparatide and teriparatide require daily SC injections vs. annual 15-minute infusion for zoledronic acid Burden for caregiver if they need to give daily injections Teriparatide requires refrigeration, abaloparatide does not require refrigeration after first dose per pen No other factors that differ between drugs Cost Economic Inputs Drug Costs Zoledronic acid: average generic wholesale acquisition cost (WAC) of $306 (Redbook Online, 2017) Teriparatide: Net price of $1, per pen (38% discount from WAC): ~$24,200 per year Abaloparatide: WAC price of $1,625 per pen: 27% discount Net price of $1, or ~$14,200 per year 30 doses per pen; approximately 12 pens / year Primary Results Regimen ICER vs. Zoledronic Acid Teriparatide $941,537 Abaloparatide $333,892 ICER: incremental cost effectiveness ratio

18 Probabilistic Sensitivity Analysis Summary The cost per additional QALY was estimated to be above $150,000 per QALY for each anabolic agent. This finding remained over a wide range of sensitivity and scenario analyses, including patients at even higher risk for fracture. Results were most sensitive to uncertainty in relative risk estimates for hip fracture, long-term fracture utility multipliers, and drug costs. When anabolic agents are compared to no treatment, results suggest that anabolic treatments would not produce incr. cost-effectiveness ratios <$150,000 /QALY. Questions for discussion Do the anabolic drugs for osteoporosis represent: A. Low Value B. Reasonable Value C. High Value Why? Wrap up What are your thoughts on the elements that should be considered when assessing the longterm value of new therapies and diagnostic tests in medicine? 1. Magnitude of clinical benefit 2. Impact of disease that is treated 3. Following well defined guideline for treatment