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Dr. James Silvius Dr. Irvin Mayers Jeremy Slobodan April 25, 2017 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
Creating Criteria Using Patient Experience for High-Cost & Rare-Use Drugs With Limited Evidence
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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)
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Disclosures
• Irvin Mayers
• Consultations – Boehringer Ingelheim – Novartis – AstraZeneca
• Research Grants/Contracts – CIHR – Multiple Clinical Trials
• Lectures – Novartis – Boehringer Ingelheim
• Current member of CDEC
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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
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Outline
• Overview of AHS/STEDT Program
• Case Examples – Pirfenidone – Eculizumab – Alpha-1 Proteinase Inhibitor
• Summary and Discussion
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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
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STEDT Program • Short Term Exceptional Drug Therapy • Principles
– Evidence-informed – Fairness and equitability – Consistency – Universality
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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
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STEDT Program - Key Features • Has a structured review process • Considers:
– Rare therapies with limited evidence – Off-indication use
• Not for study use
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STEDT Program - Process • Specialist application
– Evidence; outcomes required • Pharmacist and/or MD review
– Content expertise may be sought • Processes:
– Novel – Repeat – High cost (>$100K)
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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
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Challenges
• Insufficient information – Single studies – Case reports
• Study design: – Open label – Surrogate outcomes
• Practitioner opinion/Political involvement
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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
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STEDT Criteria • Ideal to mirror primary study:
– Populations – Measurements – Results
• Based on patient response, need breakpoints to: – Continue Therapy – Stop Therapy
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Stopping Criteria
• With limited evidence: – Rarely strictly objective criteria
• Objective criteria not always clinically meaningful
• Difficult to exclude subjective criteria
• Perception of improvement
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Specific Drug Examples
• Pirfenidone (Esbriet®) – Idiopathic Pulmonary Fibrosis
• Eculizumab (Soliris®) – aHUS
• Alpha-1 Proteinase Inhibitor (Prolastin C®) – Alpha-1 antitrypsin deficiency
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Pirfenidone (Esbriet®)
• Health Canada Approved indication – Idiopathic Pulmonary Fibrosis
• Average annual cost (List price)
– ~$44,000 (801mg TID)
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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
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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 IPF-related 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)
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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)
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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.
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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
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STEDT Criteria
Advantages • Defined patient
population for use • Clear objective stopping
criteria – Attempts to identify non-
responders – 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
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Eculizumab (Soliris ®)
• Health Canada Approved indication – atypical Hemolytic Syndrome (aHUS)
• Average annual cost (List price)
– $650,000 (“average” adult)
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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
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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
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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
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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
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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
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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 2nd 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
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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
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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
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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.
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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.
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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).
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STEDT Criteria
1. Criteria for post-renal transplant
2. Criteria for resumption after discontinuation and recurrance
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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
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• 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)
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• 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 non-randomized 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.
Alpha-1 Proteinase Inhibitor (Prolastin C®)
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• Biological Rationale for Treatment – Untreated patients
with α1- proteinase inhibitor deficiency have a more rapid decline in lung function as assessed by FEV1 when compared to normal.
• Average decline in FEV1 of 49.9 ml/year
• The subset of patients with moderate severity group (FEV1 50% to 80% predicted normal) showed the largest loss of FEV1 at 90.1 ml/yr.
• Normal loss of FEV1 in non-smokers 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
Alpha-1 Proteinase Inhibitor (Prolastin C®)
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• 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
Alpha-1 Proteinase Inhibitor (Prolastin C®)
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• 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.
Alpha-1 Proteinase Inhibitor (Prolastin C®)
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• 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.
Alpha-1 Proteinase Inhibitor (Prolastin C®)
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• Canadian Thoracic Society Guidelines Recommendation – Non-smoking or ex-smoking – COPD
• FEV1 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
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• 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
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• Goldilocks problem – Too sick to see
survival benefit – Too well to need
therapy – Just sick enough
• Markers of Disease Severity – FEV1
• 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 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
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• What about normal lung function (FEV1)? – 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
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• 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
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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?
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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
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Discussion/Questions
