Cadth 2015 e4 fields slides for adaptive panel final
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This document discusses pCODR's experience with adaptive clinical trial designs and how they impact drug funding assessments. It provides examples of two clinical trials for chronic lymphocytic leukemia (CLL) and non-small cell lung cancer (NSCLC) that used adaptive designs. The CLL trial had early stopping rules and treatment switching based on interim analyses. The NSCLC trial allowed patients who progressed on chemotherapy to switch to the experimental drug crizotinib, introducing uncertainty into estimating the treatment's effectiveness and cost-effectiveness. pCODR will likely see more complex adaptive designs as cancer treatments increasingly target biomarker-defined subgroups and employ personalized medicine approaches, requiring continuous evolution of its assessment expertise.
Cadth 2015 e4 fields slides for adaptive panel final
- 1. pCODR Experience with Adaptive Clinical Trial Designs Tony Fields Chair pCODR Expert Review Committee CADTH
- 2. 2 • No significant conflicts of interest • Opinions expressed are not necessarily those of pCODR or CADTH Disclosures
- 3. 3 • Most common experiences: – Early stopping rules – Treatment switching • Emerging and anticipated: – More complex adaptive designs pCODR and Adaptive Clinical Trial Designs
- 4. 4 • The disease: chronic lymphocytic leukaemia • The patient population: patients with a significant burden of coexisting problems • The standard treatment: – Chlorambucil (an alkylating agent) in most of Canada – Chlorambucil plus rituximab (a type 1 anti-CD20 monoclonal antibody) (actually not robustly evidence- based for this population, therefore not available in most provinces) • The experimental treatment: – Chlorambucil plus obinutuzumab (GA101, a type 2 anti- CD20 monoclonal antibody) Obinutuzumab plus chlorambucil for CLL
- 5. 5 Study CLL11: Design GA101 = obinutuzumab Supplement to: Goede et al. N Engl J Med 2014; 370:1101.
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- 7. 7 Stage 1a Ob-Ch vs. Ch N=238 n=118 Stage 1b R-Ch vs. Ch N=233 n=118 Median PFS (mos) 23.0 10.9 15.7 10.8 HR 0.14 (0.09, 0.21) p<0.0001 HR 0.32 (0.24, 0.44) p<0.0001 Median OS (mos) Not reached HR 0.68 (0.29, 1.60) p= 0.3820 Not reached HR 0.70 (0.34, 1.45) p= 0.3374 Stage 1a and Stage 1b planned analyses Supplement to: Goede et al. N Engl J Med 2014; 370:1101.
- 8. 8 Stage 1a Ob-Ch vs. Ch N=238 n=118 Stage 1b R-Ch vs. Ch N=233 n=118 Stage 2 Ob-Ch vs. R-Ch N=333 n=330 Med PFS (mos) 26.7 11.1 16.3 11.1 26.7 15.2 HR 0.18 (0.13, 0.24) p<0.001 HR 0.44 (0.34, 0.57) p<0.001 HR 0.39 (0.31, 0.49) p<0.001 OS (Death rate%) HR 9% 20% HR 0.41 (0.23, 0.74) p=0.002 15% 20% HR 0.66 (0.39, 1.11) p=0.11 8% 12% HR 0.66 (0.41, 1.06) p=0.08 Stage 1a, 1b updated analyses, Stage 2 interim analysis
- 9. 9 • Recommended for funding for defined patient population based on net clinical benefit and cost-effectiveness compared to Canadian standard of chlorambucil monotherapy pCODR recommendation: OB-Ch
- 10. Crizotinib for ALK+ NSCLC Funding Request • For treatment of patients with advanced ALK+ NSCLC. Evidence • One open-label RCT (Profile 1007); crizotinib (n=173) vs. pemetrexed or docetaxel (n=174) in 2nd line treatment after platinum doublet • Two single-arm studies (Profile 1001, 1005) 10
- 11. Treatment Switching and Uncertainty Profile 1007, crizotinib vs. chemo: PFS: 7.7 vs. 3.0 mos (HR 0.49, CI 0.37 – 0.64) OS: 20.3 vs. 22.8 mos (HR 1.02, CI 0.68 – 1.54) (112 of174 pts switched from chemo to crizotinib upon progression) 11
- 12. 12 • Magnitude of clinical benefit • Estimation of ICER • Can it be corrected for? Uncertainty due to treatment switching
- 13. 13 Mean PFS (mos) Mean PD (mos) PFS:PD ratio Mean Δ OS crizotinib Crizotinib 9.6 23.4 1:2.4 N/A Chemotherapy RPSFT 3.9 23.3 1:6.0 5.8 IPCTW 5 3.9 16.8 1:4.3 12.3 Adjusting for treatment switching: data presented to NICE Adapted from: http://www.nice.org.uk/guidance/ta296/documents/lung-cancer-nonsmallcell-anaplastic-lymphoma-kinase- fusion-gene-previously-treated-crizotinib-evidence-review-group-report3 Accessed 2015/04/09 HR for death Crizotinib vs. chemo ITT 1.02 RPSTF 0.83 (0.36, 1.35) IPCTW 5 Not disclosed
- 14. 14 • Expect increase in proportion of submissions involving adaptive clinical trial designs – Biomarker defined subpopulations of cancers – Personalized treatments • Need for continuous evolutionary adjustment of expertise and capacity for effective HTA assessment Message for Cancer Drug HTA