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Improving the evaluation of new cancer therapies to expedite patient access

Improving the evaluation of new cancer therapies to expedite patient access

Professor Jonathan Karnon

University of Adelaide

The research team have received a grant from the Australian National Health and Medical research Council (NHMRC) to support the proposed research.

Is a current member of the Economic Sub-Committee of the Pharmaceutical Benefits Advisory Committee in Australia.

20 June 2018

Lay Summary
In Australia, the Pharmaceuticals Benefits Scheme (PBS) provides affordable access to pharmaceutical therapies. New medicines are listed on the PBS on the basis of their clinical effectiveness and their value for money. In 2014-15, 33 of 42 (79%) submissions for medicines for advanced cancer were rejected or deferred. Most of these drugs are clinically effective, but they were not recommended for listing because the proposed price was too high.

When evaluating new cancer medicines, a common methodological issue is the extrapolation of costs and benefits beyond those observed in pivotal randomised controlled trials (RCTs). A review of decisions made by four reimbursement agencies identified methods for the extrapolation of survival data as the most important issue to be addressed by manufacturers in submissions to all agencies.

The listing of ipilimumab for metastatic melanoma illustrates the importance of extrapolation methods. The first submission in July 2011 was rejected, noting that the “extrapolation method was not appropriate”, the subsequent submission in March 2012 included changes to the extrapolation but was also rejected because the alternative extrapolation methods reduced the cost-effectiveness of the drug. The medicine was recommended for listing in November 2012. Accepted extrapolation guidelines would inform the earlier use of appropriate extrapolation methods and expedite patient access to effective medical therapies. Increasing public access to patient-level data from RCTs funded by the pharmaceutical industry provides a significant opportunity to compare alternative approaches to the extrapolation of survival benefits across a wide range of cancers and drug therapies.

The aims of the proposed research are to compare the validity of alternative extrapolation approaches over RCTs across different cancer types, and to work with an expert advisory panel to develop extrapolation guidelines to improve the evaluation of value for money, reduce the number of resubmissions for PBS listings and provide earlier access to new cancer medicines.

Data is sought for a range of available RCTs of therapies for alternative forms of advanced cancer and study designs. The analysis of the case study trials will reflect the issues and recommendations raised by the most recent literature on extrapolation methods, providing a comprehensive set of analyses to inform guideline development. An expert panel will then review the alternative extrapolation analyses and assumptions that are applied by the research team to each case study RCT. Working with the panel, the research team will develop guidelines for the extrapolation of survival data that reflect the varying characteristics of the observed data and the biological mechanisms of alternative new cancer medicines.

[{ "PostingID": 1309, "Title": "ROCHE-BO17708", "Description": "A randomized, double-blind study of the effect of first line treatment with Avastin (bevacizumab) in combination with docetaxel on progression-free survival and disease response in patients with HER2 negative metastatic breast cancer" },{ "PostingID": 1310, "Title": "ROCHE-AVF3694G", "Description": "A multicenter, phase III, randomized, placebo-controlled trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy regimens in subjects with previously untreated metastatic breast cancer" },{ "PostingID": 1314, "Title": "ROCHE-BO17704 (AVAIL)", "Description": "A randomized, double-blind multicenter 2-stage phase III study of bevacizumab in combination with cisplatin and gemcitabine versus placebo, cisplatin and gemcitabine in patients with advanced or recurrent non-squamous non-small cell lung cancer, who have not received prior chemotherapy" },{ "PostingID": 1316, "Title": "ROCHE-NO16966", "Description": "2 x 2 Factorial randomized phase III study of intermittent oral capecitabine in combination with intravenous oxaliplatin (q3w) (\"XELOX\") with/without intravenous bevacizumab (q3w) versus bolus and continuous infusion fluorouracil/intravenous leucovorin with intravenous oxaliplatin (q2w) (\"FOLFOX-4\") with/without intravenous bevacizumab (q2w) as first-line treatment for patients with metastatic colorectal cancer." },{ "PostingID": 1340, "Title": "ROCHE-WO20698 (CLEOPATRA)", "Description": "A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of Herceptin + docetaxel + pertuzumab versus Herceptin + docetaxel + placebo in previously untreated HER2-positive metastatic breast cancer" },{ "PostingID": 1964, "Title": "BI-1200.23", "Description": "BIBW 2992 and BSC Versus Placebo and BSC in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib (LUX-LUNG 1)" },{ "PostingID": 2549, "Title": "ROCHE-AVF3693G", "Description": "A Phase III, Multicenter, Randomized, Placebo-controlled Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy Regimens in Subjects With Previously Treated Metastatic Breast Cancer" },{ "PostingID": 2560, "Title": "ROCHE-MO22224", "Description": "AURELIA: A Multi-center, Open-label, Randomised, Two-arm Phase III Trial of the Effect on Progression Free Survival of Bevacizumab Plus Chemotherapy Versus Chemotherapy Alone in Patients With Platinum-resistant, Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer" },{ "PostingID": 2574, "Title": "ROCHE-BO21977", "Description": "A randomized, Multicenter, Phase III Open-Label study of the efficacy and safety of Trastuzumab-MCC-DM1 vs. Capecitabine + Lapatinib in patients with HER2-Positive locally advanced or metastic breast cancer who have received prior Trastuzumab-based therapy." },{ "PostingID": 3183, "Title": "LILLY-H3E-EW-S124", "Description": "A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed Plus Best Supportive Care Versus Best Supportive Care Immediately Following Induction Treatment With Pemetrexed + Cisplatin for Advanced Non-squamous Non-Small Cell Lung Cancer." },{ "PostingID": 3358, "Title": "ROCHE-BO16216", "Description": "A randomized, open-label study of the effect of Herceptin plus Arimidex compared with Arimidex alone on progression-free survival in patients with HER2-positive and hormone-receptor positive metastatic breast cancer" },{ "PostingID": 3359, "Title": "ROCHE-H0648G", "Description": "Chemotherapy and Antibody Response Evaluation (CARE): A phase III, multinational, randomized study of recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) combined with chemotherapy in patients with HER2 overexpression who have not received cytotoxic chemotherapy for metastatic breast cancer." },{ "PostingID": 3362, "Title": "ROCHE-H0659G", "Description": "An open-label extension study with recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) for patients whose metastatic breast cancer progressed during treatment on protocol H0648g." },{ "PostingID": 3636, "Title": "EISAI-E7080-G000-303", "Description": "A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Lenvatinib (E7080) in 131I-Refractory Differentiated Thyroid Cancer" },{ "PostingID": 3851, "Title": "ROCHE-AVF3671G", "Description": "A randomized, Double-BLIND, Placebo-controlled, phase IIIb trial comparing BEVACIZUMAB therapy WITH OR WITHOUT ERLotInib AFTER COMPLETION OF CHEMOTHERAPY WITH BEVACIZUMAB for the first-line treatment of Locally Advanced, Recurrent, or metastatic nON SMALL CELL LUNG CANCER" },{ "PostingID": 3852, "Title": "ROCHE-OSI3364G", "Description": "A Phase III, Multi-Center, Open Label, Randomized Clinical Trial to Evaluate The Efficacy of Avastin (BEVACIZUMAB) in Combination with Tarceva (Erlotinib Hydrochloride) Compared with Tarceva Alone for Treatment of Recurrent or Refractory Stage IIIB/IV Non Small Cell Lung Cancer" },{ "PostingID": 3961, "Title": "BI-1200.42", "Description": "LUX-Lung 5: Afatinib Plus Weekly Paclitaxel Versus Investigator's Choice of Single Agent Chemotherapy Following Afatinib Monotherapy in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib" },{ "PostingID": 4540, "Title": "LILLY-I4T-MC-JVBA", "Description": "A Randomized, Double-Blind, Phase 3 Study of Docetaxel and Ramucirumab versus Docetaxel and Placebo in the Treatment of Stage IV Non-Small Cell Lung Cancer Following Disease Progression after One Prior Platinum-Based Therapy (REVEL)" },{ "PostingID": 4542, "Title": "BI-1200.125", "Description": "LUX-Lung 8: A Phase III Trial of Afatinib (BIBW 2992) Versus Erlotinib for the Treatment of Squamous Cell Lung Cancer After at Least One Prior Platinum Based Chemotherapy" },{ "PostingID": 4551, "Title": "ROCHE-BO25734", "Description": "A Phase III Randomized, Multicenter, Two Arm, Open-label Trial to Evaluate the Efficacy of Trastuzumab Emtansine Compared With Treatment of Physician's Choice in Patients With HER2-positive Metastatic Breast Cancer Who Have Received at Least Two Prior Regimens of HER2 Directed Therapy" },{ "PostingID": 4772, "Title": "SANOFI-D4200C00032", "Description": "A Phase III, Randomized, Double-Blinded, Multi-Center, Study to Assess the Efficacy of Docetaxel (TAXOTERE™) in Combination With ZD6474 (ZACTIMA™) Versus Docetaxel (TAXOTERE™) With Placebo in Subjects With Locally Advanced or Metastatic NSCLC" }]

Statistical Analysis Plan

The publication citation will be added after the research is published.