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.

1. pCODR Experience with Adaptive
Clinical Trial Designs
Tony Fields
Chair
pCODR Expert Review Committee
CADTH

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• No significant conflicts of interest
• Opinions expressed are not necessarily
those of pCODR or CADTH
Disclosures

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• Most common experiences:
– Early stopping rules
– Treatment switching
• Emerging and anticipated:
– More complex adaptive designs
pCODR and Adaptive Clinical Trial Designs

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• 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

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Study CLL11: Design
GA101 = obinutuzumab
Supplement to: Goede et al. N Engl J Med 2014; 370:1101.

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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.

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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

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• 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)
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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)
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• Magnitude of clinical benefit
• Estimation of ICER
• Can it be corrected for?
Uncertainty due to treatment switching

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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

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• 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