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Advancing Health Economics, Services, Policy and Ethics
Collecting Real World Evidence: HTA’s perspective
Dr. Kelvin Chan, MD FRCPC MSc MScClinical Lead, Provincial Drug Reimbursement Programs, CCO
Co-Director, Canadian Centre for Applied Research in Cancer Control Medical Oncologist, Sunnybrook Odette Cancer Centre
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• What types of uncertainty do HTA committees encounter in their deliberations?
• How often does pCODR request collecting evidence to reduce uncertainty?
• What types of deliverables can be considered by collecting RWE?
Contents
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Ontario Cancer Plan IV (2015-2019)
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Health Technology Assessment (HTA) Committee’s Recommendations
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Recent Example
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In general, HTA committees (pCODR, CED, OSCCD) consider the following inputs:•Clinical benefit (from clinical trial data)
– Efficacy (survival) data – Safety data– Quality of Life (QOL) data
•Patient values•Cost-effectiveness and budget impact•Adoption feasibility
Things that we consider before making a recommendation to fund (or not to fund)
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• Uncertainty in clinical data– Survival data
• Missing or limited (e.g. Busutinib in CML)• Non-comparative (e.g. Romidepsin in PTCL)• Surrogate of overall survival (e.g. progression-free survival)• Short term data (numerous examples)
– Safety data• Missing data (e.g. Rituximab in HIV and lymphoma)
– Quality of life data• Missing data (numerous examples)
Uncertainty in clinical data
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Missing or Limited DataBosutinib in CML
“pERC noted the absence of a direct comparison to other TKI’s to be a limitation in the presented evidence for bosutinib”
- pCODR Expert Review Committee Final Recommendation
• No median OS data available
• Major Cytogenic Response was used in exchange for OS data
• pERC noted that there are no current or upcoming trials that can serve as comparators
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Non-Comparative DataRomidepsin in PTCL
“It was noted that due to the limitations of relying on non-comparative, non-randomized evidence and the heavy reliance on extrapolation of overall survival data, there was substantial uncertainty in the
magnitude of the net clinical benefit associated with romidepsin.”
- pCODR Expert Review Committee Final Recommendation
Adapted from Piekarz et al. BLOOD 2011 Adapted from Coiffier et al. JCO 2012
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Missing Relevant Comparative Efficacy/Safety DataOpdivo for Metastatic Melanoma
“pERC also noted the absence of evidence on the comparative efficacy and safety of nivolumab and pembrolizumab.”
- pCODR Expert Review Committee Final Recommendation
• The Submitter assumed that because nivolumab and pembrolizumab function using similar mechanisms, there will be a similar clinical or survival benefit
• Standard Treatment for Metastatic Melanoma• Ipilimumab• Vemurafenib• Dabrafenib• Trametinib• Dacarbazine• Best Supportive Care
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Short Term Survival DataPembrolizumab in Unresectable Metastatic Melanoma
“In the absence of longer term data, pERC was unable to accept this assumption of prolonged benefit and agreed with the EGP’s use of alternative data sources to extrapolate survival in both settings.”
- pCODR Expert Review Committee Final Recommendation
Adapted from Robert et al. NEJM 2015
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Missing Quality of Life Data Vismodegib in Basal Cell Carcinoma
“… quality of life and functional outcomes are very important in this population. Patients with BCC who are inappropriate for surgery may experience severe disfigurement, leading to extreme social
isolation and decreased quality of life.”
- pCODR Expert Review Committee Final Recommendation
• Survival is main a concern for patients with locally advanced or metastatic disease
• Disease progression may lead to facial disfigurement, and thus a decreased QoL
• This study presents no QoL data, however researchers connected a response and decreased tumour size to an improvement in overall QoL
Adapted from Sekulic et al. NEJM 2012
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• Cost-effectiveness analysis and budget impact analysis– Conducted by manufacturer
• Model structure and methods• Uncertainty in the inputs of the model
– Number of patients– Duration of drug treatments– Resource utilization
• Underestimation of ICER (sometimes 1-2 fold difference)• Underestimation of BIA
Economic evidence:Estimation or “guess-timation”
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• Trial patients are different from real world patients – e.g. age, co-morbidities, performance status, diffusion – Intensive monitoring on trial
• Different practice patterns in the real world– Duration of treatment (treatment until progression vs. discontinuation before
progression)– Dose intensity of treatment in the trials vs. in the real world– Management of side-effects (e.g. febrile neutropenia are managed mostly as
in-patient in Ontario)• Sequencing of subsequent lines of available therapy
– Different from what was available on the trial• Changes in drug price over time (e.g. generics)
– Drop in price in the older drugs will make the new drug less cost-effective
Loss in “Translation”: Uncertainty about Translating clinical trial evidence to the
real world
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EXPERIENCE OF pCODR EXPERT REVIEW COMMITTEE (pERC)
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Requesting Real World Evidence
• pCODR searched 60 reviews• 13 pCODR reviews explicitly requested Real World
Evidence • 10 pCODR reviews potentially requested Real World
Evidence
Potential RWE Request:The literature is unclear if pERC requested RWE, but it
could be beneficial
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Breakdown of pCODR Reviews60 Final Recommendations
(4 requested RWE)
(17 requested RWE)
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Temporal Trends in RWE Requests60 pERC Final Recommendations
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Breakdown by Tumour Site60 pERC Final Recommendations
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Breakdown by Drug Type: 21 Studies
Other: •Vismodegib (Erivedge) a Hedgehog pathway inhibitor
•Lenalidomide (Revlimid) a immunomodulatory agent and antiangiogenic agent
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Breakdown by Study Characteristics: 21 Studies
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Breakdown by Study Characteristics: 21 Studies
When co-primary endpoints were indicated, both were included
DSV (Decrease in Spleen Volume), M/CCyR (Major or Complete Cytogenetic Response), MaHR (Major Haematological Response)
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Next Steps for Real World Evidence Collection
23 requests for RWE for 21 studies
(including 2 potential)
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WHAT REAL WORLD EVIDENCE CAN WE COLLECT?
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Potential Deliverables (Budget)
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Potential Deliverables (effectiveness, safety, quality of life, cost-effectiveness)
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Discussions• HTA committees commonly make best possible recommendations
based on substantial uncertainties• pCODR commonly request for the collection for further evidence to
reduce uncertainties– How can further evidence be collected?
• Routinely collected data (population-based admin data)• Evidence building program (prospective collection of data)• Registry study (prospective collection of data)• Real world experiments (real world pragmatic randomized trials)
– Who will use this evidence once collected?• Practitioners – influence practice patterns• Decision-makers and payers