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pCODR Reimbursement Decision




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  Afinitor
Generic Name Everolimus
Manufacturer Novartis Pharmaceuticals Canada Inc.
pCODR Indication Pancreatic Neuroendocrine Tumours
pCODR Tumour Type Gastrointestinal
Funding Request Patients with well- or moderately differentiated neuroendocrine tumours of pancreatic origin (pNETs) in patients with unresectable, locally advanced or metastatic disease.
Submission Date 2012-02-27
Submission Type New Indication
Review Status Notification to Implement Issued
Recommendation Date 2012-08-30
Notification to Implement Date 2012-09-17
RD Interpretation of pERC Recommendation Recommended - conditional on improved cost-effectiveness.
pERC Recommendation

The pCODR Expert Review Committee (pERC) recommends funding everolimus (Afinitor) conditional on the cost-effectiveness of everolimus being improved to an acceptable level. Funding should be for the treatment of patients with progressive, unresectable, well- or moderately differentiated, locally advanced or metastatic pancreatic neuroendocrine tumours, with WHO performance status ≤ 2. Treatment should be continued until disease progression. The Committee made this recommendation because it was satisfied that there is an overall clinical benefit of everolimus based on the magnitude of the observed progression-free survival difference between everolimus and placebo. However, the Committee noted that everolimus could not be considered cost-effective at the submitted price and the Economic Guidance Panel`s estimates of the range of incremental cost-effectiveness ratio.

Patient Population

Patients with progressive, unresectable, well- or moderately differentiated, locally advanced or metastatic pancreatic neuroendocrine tumours, with WHO performance status of <= 2.

RD Interpretation of Patient Population Requested vs Actual

Same, but pERC noted that because of the limited evidence base in patients with less favourable performance status 2, clinical judgement would need to be exercised when determining if these patients are appropriate candidates for therapy.

Summary of pERC Deliberations - Clinical

pERC discussed the results of the randomized controlled trialincluded in the pCODR systematic review, which compared everolimus with placebo (RADIANT-3, Yao 2010). pERC considered that RADIANT-3 was an appropriately conducted trial that followed its pre-specified analysis plan, giving pERC confidence in the trial results. The Committee considered that the hazard ratio and the magnitude of the absolute difference in progression-free survival for everolimus compared with placebo were both statistically significant and clinically meaningful. pERC also noted that a consistent benefit in progression-free survival was observed across pre-specified subgroups. There was no statistically significant difference in overall survival. However, pERC noted that results were likely confounded by the cross-over of the majority of patients from the placebo group to everolimus following disease progression, although further collection of survival data is ongoing. Upon reconsideration of the pERC Initial Recommendation and based on feedback from the manufacturer, the Committee discussed the use of everolimus in patients with WHO performance status 2. pERC noted that only a small proportion of patients included in RADIANT-3 had a WHO performance status score of 2 (approximately 3%). pERC considered that while the RADIANT-3 evidence primarily supports the use of everolimus in patients with WHO performance status scores of 0 or 1, it does not preclude the use of everolimus in patients with a performance status score of 2. pERC further noted that because of the limited evidence base in patients with the less favourable performance status 2, clinical judgment would need to be exercised when determining if these patients are appropriate candidates for everolimus therapy.

Summary of pERC Deliberations - Safety

pERC also considered the safety of everolimus based on grade three/four adverse events and the most frequently observed adverse events in RADIANT-3. pERC considered that the toxicity profile, which included fatigue, stomatitis and diarrhea, was consistent with the use of everolimus in other indications and that the majority of adverse events are manageable through dose reductions. However, pERC noted that dose reductions would not result in an accompanying decrease in drug costs because the prices of 2.5 mg, 5 mg and 10 mg tablets are the same and tablets are not scored to allow for splitting.

Summary of pERC Deliberations - Cost-effectiveness

pERC discussed the cost-effectiveness of everolimus and noted that the manufacturer's estimates were substantially lower than the pCODR Economic Guidance Panel's estimates. The Economic Guidance Panel considered the structure of the economic model to be inadequate, primarily because the manufacturer's model assumed that there was a similar risk of dying before and after disease progression. The pCODR Gastrointestinal Clinical Guidance Panel considered this assumption unrealistic from a clinical perspective and pERC agreed. Upon reconsideration of the pERC initial Recommendation, the Committee discussed feedback from the manufacturer that claimed they had assumed a different risk of dying before and after tumour progression. However the Economic Guidance Panel pointed out that in the manufacturer's submitted economic model, while the patient’s risk of dying changes over time, it did not account for the increasing proportion of patients in the post-progression state over time. Therefore, pERC agreed with the Economic Guidance Panel that the structure of the economic model was still inadequate. pERC also discussed feedback from the manufacturer on the Economic Guidance Panel’s re-analyses of the time horizon, in which the time horizon was shortened to better align with the clinical data. pERC noted that shortening the time horizon from ten years to five years was supported by the Clinical Guidance Panel, who suggested there is unlikely any survival benefit accrued beyond five years by patients receiving everolimus based on currently available data. Therefore, pERC considered the Economic Guidance Panel’s estimates based on the five-year time horizon to be more realistic than the manufacturer’s estimates of cost-effectiveness. pERC noted that the impact of the time horizon on the cost-effectiveness estimates of everolimus was greater than the impact of the model’s assumptions around the risk of dying. Overall, pERC concluded that the manufacturer’s feedback did not change pERC’s conclusions on the cost-effectiveness of everolimus. pERC accepted the Economic Guidance Panel’s conclusions and estimates of cost-effectiveness, which are likely even higher than estimated, recognizing that their estimates were limited by the structure of the economic model that was provided. Therefore, pERC concluded that everolimus is not cost-effective at the submitted price and based on the Economic Guidance Panel’s estimates.

Provincial Funding Report: pCODR Provincial Funding Summary Report  pCODR Provincial Funding Summary report
https://www.cadth.ca/sites/default/files/pcodr/pcodr-provfund_afinitor-pnet.pdf
Final Recommendation Report: pCODR-pERC Final Recommendation report  pCODR-pERC Final Recommendation report
https://www.cadth.ca/sites/default/files/pcodr/pcodr-afinitor-fn-rec.pdf
Final Clinical Guidance Report: pCODR Final Clinical Guidance Report  pCODR Final Clinical Guidance report
https://www.cadth.ca/sites/default/files/pcodr/pcodr-afinitor-pnets-fn-cgr.pdf
Final Economic Guidance Report: pCODR Final Economic Guidance report  pCODR Final Economic Guidance report
https://www.cadth.ca/sites/default/files/pcodr/pcodr-afinitor-pnets-fn-egr.pdf

†The information referenced on this page is compiled from publicly available documents published by pCODR and is available through the embedded links.


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