Creating Criteria Using Patient Experience for High- Cost & Rare-Use Drugs With Limited Evidence Dr. James Silvius Dr. Irvin Mayers Jeremy Slobodan April 25, 2017
Disclosures James L. Silvius No industry conflicts of interest to declare Current Vice-Chair of CDEC Former Chair of Alberta Expert Committee on Drug Evaluation & Therapeutics (ECDET) Former Chair AHS Drugs & Therapeutics Committee (DTC) 2
Disclosures Irvin Mayers Consultations Boehringer Ingelheim Novartis AstraZeneca Research Grants/Contracts CIHR Multiple Clinical Trials Lectures Novartis Boehringer Ingelheim Current member of CDEC 3
Disclosures Jeremy Slobodan No industry conflicts of interest to declare Current member of Alberta Expert Committee on Drug Evaluation and Therapeutics Current member of AHS Drugs & Therapeutics Committee 4
Outline Overview of AHS/STEDT Program Case Examples Pirfenidone Eculizumab Alpha-1 Proteinase Inhibitor Summary and Discussion 5
Alberta Health Services Single operational health entity for Alberta Cross-province strategic planning Hospitals Medical Clinics Continuing Care: Home Care; Residential Care Prevention and Promotion Services Corporate Services Separate from Alberta Health Separate from Community 6
STEDT Program Short Term Exceptional Drug Therapy Principles Evidence-informed Fairness and equitability Consistency Universality 7
STEDT Program Implemented in 2012 Reviews high-cost non-formulary drug requests Built to cross community/ahs boundaries and ensure consistency of coverage Not first payor 8
STEDT Program - Key Features Has a structured review process Considers: Rare therapies with limited evidence Off-indication use Not for study use 9
STEDT Program - Process Specialist application Evidence; outcomes required Pharmacist and/or MD review Content expertise may be sought Processes: Novel Repeat High cost (>$100K) 10
Outcomes Defined a priori by: Requesting specialist Established criteria Reported at defined intervals to renew therapy Requires patient response Kept in a database for future use 11
Challenges Insufficient information Single studies Case reports Study design: Open label Surrogate outcomes Practitioner opinion/political involvement 12
Study Outcome Measurement Desired Survival Quality of Life Events Usually Provided Surrogate markers Laboratory tests Interim measures (e.g. 6 minute walk test) Patient rating scores 13
STEDT Criteria Ideal to mirror primary study: Populations Measurements Results Based on patient response, need breakpoints to: Continue Therapy Stop Therapy 14
Stopping Criteria With limited evidence: Rarely strictly objective criteria Objective criteria not always clinically meaningful Difficult to exclude subjective criteria Perception of improvement 15
Specific Drug Examples Pirfenidone (Esbriet ) Idiopathic Pulmonary Fibrosis Eculizumab (Soliris ) ahus Alpha-1 Proteinase Inhibitor (Prolastin C ) Alpha-1 antitrypsin deficiency 16
Pirfenidone (Esbriet ) Health Canada Approved indication Idiopathic Pulmonary Fibrosis Average annual cost (List price) ~$44,000 (801mg TID) 17
CDEC Recommendations The Canadian Drug Expert Committee (CDEC) recommends that pirfenidone be listed for the treatment of adults with mild to moderate idiopathic pulmonary fibrosis (IPF), if the following clinical criteria and conditions are met: Mild to moderate IPF, defined as forced vital capacity (FVC) greater than or equal to 50% of predicted Stable disease, defined as FVC not decreased by 10% during the previous 12 months Treatment discontinued if FVC declines by 10% within any 12-month period while receiving therapy 18
Outcomes Mortality Meta-analyses of three pivotal trials showed significant reduction in all-cause mortality at 52 weeks (HR 0.52; 95% CI, 0.31 to 0.87and IPFrelated mortality at 52 weeks (HR 0.42; 95% CI, 0.22 to 0.81) Exacerbations The pirfenidone group lower frequency of acute exacerbations (8.6%) than the placebo group (14.4%) (P = 0.034) 19
Outcomes Disease progression Rate of decline of FVC% improved pirfenidone compared with placebo in one trial (mean difference 4.8%; 95% CI, 2.4% to 7.2%) MCID for this outcome estimated to be between 2% and 6% Function 6MWT distance decline was lower for patients treated with pirfenidone than placebo (mean difference 26.7 m; 95% CI, 8.3 m to 44.9 m) 20
Outcomes Progression free survival Favors pirfenidone compared to placebo (HR 0.57%; 95% CI, 0.43 to 0.77). Cost Benefit CDR estimated ICUR of $137,000 per QALY for pirfenidone versus best supportive care. 21
STEDT Criteria Starting Idiopathic Pulmonary Fibrosis (IPF) confirmed by CT scan and followed by Respirologist Lung Function mild to moderate severity Forced vital capacity (FVC) between 50% and 80% predicted normal Diffusing Capacity (%DLCO) between 30% and 90% predicted normal. Stopping Rapid loss of lung function absolute decline in percent predicted FVC of > 10% from initiation of therapy until renewal at 6 months and then 12 months Confirm progression with repeat testing at 4 weeks 22
STEDT Criteria Advantages Defined patient population for use Clear objective stopping criteria Attempts to identify nonresponders Stops drug for later stages of disease Disadvantages Potential patients for benefit on either side of criteria Patients with faster disease progression may still be helped by pirfenidone Objective testing has a margin of error 23
Eculizumab (Soliris ) Health Canada Approved indication atypical Hemolytic Syndrome (ahus) Average annual cost (List price) $650,000 ( average adult) 24
CDEC Recommendations July 18, 2013 The Canadian Drug Expert Committee (CDEC) recommends that eculizumab not be listed August 2015 Participating Drug Plans submitted a request for advice Coverage through exceptional access programs Seeking advice on potential coverage criteria 25
Jurisdictional Criteria Confirmed diagnosis of ahus at initial presentation Evidence of ongoing active thrombotic microangiopathy (TMA), defined by laboratory test abnormalities despite plasmapheresis Evidence of at least one of the following documented clinical features of active organ damage or impairment: Kidney impairment, OR Onset of neurological impairment related to TMA 26
CDEC Evidence Review 15 reports & abstracts identified #1 study: 3 conference abstracts #2 study: series of case reports #3 study & #4 study: full-text articles of previously known studies from 2013 27
CDEC Evidence Review Primary Outcomes: Platelet Count increase TMA event-free status Hematologic normalization Secondary Outcomes TMA outcomes Hematologic outcomes Renal function Change in HRQoL 28
CDEC Evidence Review Pediatrics: conference abstract 68% complete TMA response at 52 weeks Platelet levels & egfr improved 82% on dialysis off & 100% not on stayed off at 1 year Pediatrics: Case reports Full recovery of parameters 29
CDEC Evidence Review Adolescents: All but 2 patients discontinued PE/PT at week 26 11.8% remained on dialysis at 2 years in 1 study; 1 of 2 remained on & 1 transplanted in 2 nd study HRQoL SS improved in both studies TMA event-free in 88% and 80% at 26 weeks Complete TMA response in 76% and 55% at 2 years Platelet count normalization 88% at 2 years (both) egfr improved by 26 weeks in both 30
STEDT Initiation Criteria 1. Confirmed diagnosis of atypical hemolytic uremic syndrome (ahus) at initial presentation: ADAMTS-13 activity 10% on blood samples taken prior to plasma exchange or infusion (PE/PI); AND Confirmed Shiga toxin-producing E.coli-negative (STEC-negative) if diarrhea has been present in the preceding 14 days; AND Absence of alternative diagnosis unlikely to respond to PE/PI or eculizumab 31
STEDT Initiation Criteria 2. Evidence of active and progressing TMA, in patients despite receiving at least four plasmapheresis or plasma exchange (PE); or fresh frozen plasma infusion (PI) treatments the week prior (i.e. plasma therapy resistant). 3. Evidence of at least ONE of the following documented clinical features of active organ damage or impairment: Renal; neurological; cardiac; GI; pulmonary due to TMA 32
STEDT 6-month Renewal Criteria Renewal at 6 months requires treatment response Hematological normalization; AND EITHER Increase in egfr of >25% from baseline; OR Stabilization defined as an egfr within ± 25% from baseline; OR Avoidance of dialysis-dependence but worsening of kidney function with a reduction in egfr 25% from baseline. 33
STEDT 6-month Renewal Criteria Discontinued coverage for Treatment failure defined as: dialysis-dependent at 6 months AND has failed to demonstrate significant resolution of extra-renal complications if originally present; OR on dialysis and has been on dialysis for 4 of the previous 6 months while receiving eculizumab AND has failed to demonstrate significant resolution of extra-renal complications if originally present. 34
STEDT 12-month Renewal Criteria 1. Ongoing treatment response ; AND 2. The patient has limited organ reserve defined as either: Severe cardiomyopathy, severe neurological impairment; severe gastrointestinal impairment, severe pulmonary impairment related to TMA; OR Grade 4 or 5 chronic kidney disease (egfr <30ml/min). 35
STEDT Criteria 1. Criteria for post-renal transplant 2. Criteria for resumption after discontinuation and recurrance 36
STEDT Criteria Advantages Defined patient population for use Objective stopping criteria Identifies responders & non-responders Issues Low quality data Costly Drug Limited therapeutic options must be tried first Has generated criticism Pressure for populations with less evidence 37
Health Canada Approved indication Congenital deficiency of alpha1-pi (alpha1- antitrypsin deficiency) with clinically demonstrable panacinar emphysema Average annual cost (List price) ~$110,000 ( average adult) 38
Alpha-1 Proteinase Inhibitor (Prolastin C ) Definition Augmentation therapy is infusion of pooled α1- proteinase inhibitor product into α1- proteinase inhibitor deficient patients with COPD Problem Literature is limited primarily by the small sample sizes of the studies. The larger studies cohort studies are generally nonrandomized longitudinal studies. The Alpha-1-Antitrypsin Deficiency Registry Study Group. Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. Am J Respir Crit Care Med 1998;158:49-59. 39
Alpha-1 Proteinase Inhibitor (Prolastin C ) Biological Rationale for Treatment Untreated patients with α1- proteinase inhibitor deficiency have a more rapid decline in lung function as assessed by FEV 1 when compared to normal. Average decline in FEV 1 of 49.9 ml/year The subset of patients with moderate severity group (FEV 1 50% to 80% predicted normal) showed the largest loss of FEV 1 at 90.1 ml/yr. Normal loss of FEV 1 in nonsmokers would be near 20 ml/yr. Dawkins et al., Rate of progression of lung function impairment in a1-antitrypsin deficiency. Eur Respir J 2009; 33:1338-1344 40
Alpha-1 Proteinase Inhibitor (Prolastin C ) Decrease rate of loss of lung density at Total Lung Capacity Active drug (n=93) or matched placebo (n=87) Surrogate marker for rate of emphysema progression No other clinical outcomes improved Chapman et al., Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 386: 360 68 41
Alpha-1 Proteinase Inhibitor (Prolastin C ) CADTH Review in 2006 Evidence showing health improvement is inconclusive. Controlled trials Lung function impairment no different compared with normal care. Observational studies Outcomes suggestive of therapeutic benefit in patients with severe AAT deficiency and moderate airflow obstruction. Chen et al., Human α1-proteinase inhibitor for patients with α1-antitrypsin deficiency [Technology report no 74]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007. 42
Alpha-1 Proteinase Inhibitor (Prolastin C ) Cost-utility analysis Lifetime costs could average almost US$1 million Gain 2.57 QALYs $333,349 (US) per QALY gained Anticipated that Canadian costs would be similar. Chen et al., Human α1-proteinase inhibitor for patients with α1-antitrypsin deficiency [Technology report no 74]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007. 43
Canadian Thoracic Society Guidelines Recommendation Non-smoking or ex-smoking COPD FEV 1 25% to 80% predicted normal Receiving optimal pharmacological and non- pharmacological treatment A1AT level <11 mmol/l Grade of evidence 2B for CT scan dentistry improvement and 2C for reduced mortality Weak recommendation with RCT major methodological weakness (B) and observational studies (C) Marciniuk et al, Can Respir J 2012; 19:109-16 44
Clinical Outcomes Mortality Registry supportive Lung function decline One meta-analysis Would need 500 subjects in RCT to be properly powered CT scan densitometry Surrogate marker RAPID study 2015 Problems Low prevalence High disease burden No proven therapies Poorly validated surrogate markers Expensive treatment 45
Goldilocks problem Too sick to see survival benefit Too well to need therapy Just sick enough Puhan, et al., Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: The updated BODE index and the ADO index. Lancet 2009; 374: 704 11 Markers of Disease Severity FEV 1 Weak correlation with survival in COPD 6 Minute Walk Test Under 100 m has 70% mortality at 4 years 200-300 m has 30% mortality at 4 years ADO (Age, Dyspnea, Airflow) or BODE (BMI, Obstruction, Dyspnea, Exercise) Better prognostic ability 46
What about normal lung function (FEV 1 )? Some patients with mild COPD have exercise limitation No data of any benefit for people with normal CT and normal lung function Starting Rules Current non-smoker Proven COPD/emphysema Spirometry CT scan Predicted 3-5 year mortality less than 50% Uses BODE or ADO 47
Stopping Rule Intolerance Non-compliance Restarted smoking?lung transplantation Summary Low quality data Costly drug No other therapeutic options Pick those most likely to show benefit Preventative therapy so unable to generate stopping criteria 48
Starting and Stopping Medications with ICURs Outside Range for Reimbursement Problem Medications may have large benefits in selected populations e.g. Prolastin C data suggests long term mortality benefit Clinical trials weak or population tested do not represent typical patients found in Canadian Clinics e.g. Registry data for Prolastin C now old and mainly American Solutions Starting Rules Enrich population with those most likely to benefit Likely to survive long enough to receive benefit of drugs These rules may not have evidence based upon RCTs BODE Index not in RCTs Stopping Rules Very difficult in medications that slow or prevent disease progression in slowly progressive disease e.g. How rapidly would disease progress in untreated IPF or untreated alpha-1 emphysema? 49
Summary Program designed to get the results it achieves Challenges with: Evidence to support decisions Identification of outcomes a priori Data from clinicians to support ongoing/future use 50
Discussion/Questions 51