Exploring the assessment and appraisal of regenerative medicines and cell therapy products

296 Pages·2016·3.54 MB·English

by  Nerys Woolacott

CRD/CHE University of York
Exploring the assessment and appraisal of regenerative medicines and cell therapy products

Exploring the assessment and appraisal of regenerative
medicines and cell therapy products

Produced by CRD and CHE Technology Assessment Group, University of York,
Heslington, York YO10 5DD
Authors Robert Hettle, Honorary Research Fellow, CHE
Mark Corbett, Research Fellow, CRD
Sebastian Hinde, Research Fellow, CHE
Robert Hodgson, Research Fellow, CRD
Julie Jones-Diette, Research Fellow, CRD
Nerys Woolacott, Senior Research Fellow, CRD
Stephen Palmer, Professor of Health Economics, CHE
Correspondence to Stephen Palmer, CHE, University of York, York YO10 5DD
Email: [email protected]
Date completed 21/12/2015
Source of funding
This report was commissioned by the NIHR HTA Programme as project number 14/151/06.
Declared competing interests of the authors
All authors have no personal or pecuniary conflict of interests.
Acknowledgements
We acknowledge and thank Professor Robert Hawkins (Cancer Research UK Professor of Medical
Oncology, University of Manchester and Christie Hospital) and Dr Beki James (Consultant Paediatric
Haematologist, Leeds Teaching Hospitals NHS Trust) for their advice on clinical issues; Natalie
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Mount and Panos Kefalas from Cell Therapy Catapult for their advice and their comments on the
report; and Kath Wright for her help in searching for studies and managing references.
Rider on responsibility for report
The views expressed in this report are those of the authors and not necessarily those of the NIHR
HTA Programme. Any errors are the responsibility of the authors.
Contributions of authors
Robert Hettle contributed to the project protocol and conducted the analysis and modelling for the
exemplar and wrote sections of the report.
Mark Corbett contributed to the project protocol and was lead reviewer for the clinical issues sections
and the clinical review of the exemplar and wrote sections of the report.
Sebastian Hinde contributed to the protocol, conducted the review of issues for cost-effectiveness,
contributed to the analysis and modelling for the exemplar, and wrote sections of the report.
Robert Hodgson contributed to the protocol and prepared the clinical issues section on study biases.
Julie Jones-Diette prepared the clinical issues section on surrogate outcomes.
Nerys Woolacott had overall responsibility for the clinical sections of the report. She contributed to
the protocol, the preparation of all clinical sections, and the writing of the report.
Stephen Palmer had overall responsibility for the cost-effectiveness sections. He contributed to the
protocol and to all aspects of the cost-effectiveness work including the writing of the report.
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Abstract
In response to the House of Lords’ inquiry into regenerative medicines, an expert group (RMEG) was
convened to develop an action plan for the NHS. RMEG proposed that the National Institute for
Health and Care Excellence (NICE) commission a “mock technology appraisal” to assess whether
changes to its methods and processes are needed. This report presents the findings of independent
research commissioned to inform this appraisal and the deliberations of a panel convened by NICE to
evaluate the mock appraisal.
The specific objective of our research was to investigate the application of existing NICE appraisal
methodology to regenerative medicines, identifying challenges and areas where adaptation may be
appropriate. Our research included reviews to identify conceptual differences and the relevance of
alternative decision frameworks, alongside the development of an exemplar case study of CAR T-cell
therapy for treating acute lymphoblastic leukaemia.
An assessment of previous evaluations of regenerative medicines by NICE and other bodies found
that while previous assessments were associated with a number of evidential challenges, none were
unique to regenerative medicines or beyond existing methods used to conceptualise uncertainty of a
decision.
Regarding the clinical evidence for regenerative medicines, it is not universally the case that they are
trialled using non-randomised study designs. However, there may be high variation in response across
both individuals and centres. Also regenerative medicines may be subject to continuing development,
posing problems when evaluating long-term efficacy and safety. Where single-arm trials are used to
assess efficacy the relative treatment effect generated is likely to be optimistic, unless the historical
control data are very certain. Pivotal trials may use surrogate endpoints, which, on average,
overestimate treatment effects. Also, surrogate primary outcomes are likely to be associated with
immature overall survival data. To reduce overall uncertainty, multivariate meta-analysis methods to
analyse all available data should be considered. Incorporating indirectly relevant but more reliable
(more mature) data into the analysis can also be considered.
For the exemplar case of CAR T-cell therapy, Target Product Profiles (TPPs) were developed which
considered the ‘curative’ and ‘bridging to stem-cell transplantation’ treatment approaches separately.
Within each TPP, three ‘hypothetical’ evidence sets (minimum, intermediate and mature) were
generated to simulate the impact of alternative levels of precision and maturity in the clinical
evidence. Subsequent assessments of cost-effectiveness were undertaken, employing the existing
NICE reference case alongside additional analyses suggested within alternative frameworks. The
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additional exploratory analyses were undertaken to demonstrate how assessments of cost-
effectiveness and uncertainty could be impacted by alternative Managed Entry Agreements (MEAs),
including price discounts, performance related schemes and technology leasing.
The Panel deliberated on the range of TPPs, evidence sets and MEAs presented, commenting on the
recommendations they would be likely to make for each scenario. The Panel discussed a wide range
of challenges associated with the exemplar and regenerative medicines more broadly, focussing on the
need for a robust quantification of the level of uncertainty in the cost-effective estimates and the
potential value of MEAs in limiting the exposure of the NHS to high upfront costs and loss associated
with a wrong decision.

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Table of Contents
List of abbreviations 13
Glossary 17
Plain English Summary 23
1 Scientific Summary 24
1.1 Background 24
1.2 Objectives 24
1.3 Potential issues for the evaluation of clinical effectiveness 25
1.4 Potential issues for the evaluation of cost-effectiveness 26
1.5 Exemplar NICE appraisal of CAR T-cells for relapsed/refractory B-ALL 28
1.5.1 Clinical evidence for the efficacy and safety of CAR T-cells for relapsed/refractory B-
ALL 28
1.5.2 Development of exemplar cost-effectiveness model – summary of approach and key
findings 29
1.5.3 Assessment of cost-effectiveness, uncertainty and the value of alternative policy options –
summary of approach and key findings 33
1.6 Issues arising from the NICE panel meeting 35
1.7 Summary conclusions 37
2 Introduction and aims 38
3 Background 41
3.1 Issues identified by the EMA as being specific to advanced therapy medicinal products
(ATMPs) 41
3.2 Overview of wider regulatory evidence requirement issues and the evolving pathways for
approval 42
4 Technology appraisal methodology issues which may be particularly relevant to regenerative
medicines 49
4.1 Clinical efficacy and safety issues arising from EMA, NICE and FDA assessments of
licensed regenerative medicines 49
4.1.1 Methods 49
4.1.2 Results 49
4.1.3 Summary 54
4.2 Study biases: an overview of their importance and methods to quantify and adjust for their
impact 54
4.2.1 Methods 55
4.2.2 Results 56
4.2.2.1 Quantification of bias in observational studies 56
4.2.2.2 Adjustment for bias in NRS 57
4.2.2.3 Challenges of using single-arm trials to estimate effectiveness 58
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4.2.2.4 Effect estimates from single- versus multi-centre trials 62
4.2.3 Relevance to future regenerative medicine submissions 63
4.3 Review of the use of surrogate endpoints as primary outcome measures in definitive
effectiveness trials of new therapeutic agents 64
4.3.1 Introduction 64
4.3.2 Methods 64
4.3.3 Definition and examples of surrogate outcomes 64
4.3.4 Validation 66
4.3.4.1 General principles of validation 66
4.3.4.2 Validation of specific surrogate outcomes 67
4.3.5 Current issues for HTA and cost effectiveness models 69
4.3.6 Summary 71
4.4 Scoping exercise of potential cost-effectiveness issues 72
4.4.1 Previous regenerative medicine evaluations evaluated within the NICE TA process 72
4.4.2 Broader consideration of potential conceptual differences and possible methodological
challenges for cost-effectiveness analyses 79
4.4.2.1 Potential approaches to addressing HTA challenges 83
5 Exemplar technology appraisal of a regenerative medicine 92
5.1 Selection of exemplar 92
5.1.1 About CAR T-cell therapies 92
5.1.2 Overview of disease 93
5.1.3 Overview of current practice 95
5.1.4 Decision problem 98
5.2 Review of evidence of clinical effectiveness: CAR T-cell therapies 99
5.2.1 Methods 99
5.2.2 Overview of studies 99
5.2.3 Efficacy Results 99
5.2.4 Adverse effects 100
5.2.5 Summary issues for the target product profile and hypothetical data sets 106
5.3 Review of licensed treatments for relapsed/refractory B-ALL 106
5.3.1 Single arm B-ALL trials: identifying appropriate control data 107
5.3.2 Summary 108
6 The target product profile and hypothetical data sets 109
6.1 Summary of issues to consider to inform creation of the Target Product Profiles (TPPs) and
hypothetical data sets 109
6.2 Background to developing the TPPs and evidence sets 111
6.3 Defining a historical control 113
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6.4 Developing the evidence sets and target product profiles 115
6.5 Defining the sample size and maturity of evidence in the evidence sets studies 115
6.6 Estimating the efficacy of CAR T-cell and comparator treatments in the evidence sets 116
6.7 Finalised TPPs 118
6.7.1 Bridge to HSCT TPPs 118
6.7.2 Curative intent TPPs 119
7 Review of cost-effectiveness evidence for CAR T-cell therapy and other interventions for ALL
130
7.1.1 Methods 130
7.1.2 Results 130
7.1.2.1 Implications for model conceptualisation 132
8 The exemplar economic model 134
8.1 Overview 134
8.1.1 Patient population 134
8.1.2 Comparator 135
8.2 Model development 135
8.2.1 Bridge to HSCT scenario 136
8.2.1.1 Key structural assumptions 136
8.2.1.2 Efficacy parameter estimates 144
8.2.2 Curative intent model 151
8.2.2.1 Structural assumptions 151
8.2.2.2 Efficacy parameter estimates - Partitioned survival model (“curative intent”) 154
8.3 Resource use and costs – Bridging and curative models 162
8.3.1 Acquisition costs 163
8.3.1.1 CAR T-cell therapy 163
8.3.1.2 Administration and monitoring costs 164
8.3.1.3 Adverse events 165
8.3.1.4 HSCT 165
8.3.2 Model inputs – utilities 168
8.3.2.1 Literature Review 168
8.3.2.2 Informing the model states 170
8.3.2.3 Treatment disutilities 170
8.3.2.4 Adverse events 171
8.3.2.5 Short-term health-related quality of life 171
8.3.2.6 Long-term health-related quality of life 171
8.4 Conclusions 171
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9 Assessment of cost-effectiveness, uncertainty and the value of alternative policy options 177
9.1 Overview 177
9.2 Acquisition costs of CAR T-cell therapies 177
9.3 Bridge to HSCT TPP 179
9.3.1 Per-patient analyses – minimum evidence set 179
9.3.2 Population-level analyses – minimum evidence set 180
9.4 Curative intent TPP 196
9.4.1 Per-patient analyses – minimum evidence set 196
9.5 Conclusions 211
10 Issues arising from the NICE panel meeting 214
11 Discussion 225
11.1 Implications for NICE technology appraisal processes 225
12 References 229
13 Appendices 241
13.1 Appendix 1: Regenerative medicines licensed by the EMA 241
13.2 Appendix 2: Adjustment for bias in non-randomised studies 261
13.3 Appendix 3: Studies comparing bias adjustment methods 273
13.4 Appendix 4: Studies on surrogate endpoints 275
13.5 Appendix 5: Licensed treatments for relapsed/refractory B-ALL 285
13.6 Appendix 6: Review of previous economic evaluations in ALL 292
13.7 Appendix 7: Summary of patient characteristics in previously published multivariate
prognostic models of ALL 293
13.8 Appendix 8: Incidence of relevant population estimate 294
13.9 Appendix 9: Full list of Advisory Group and NICE Panel members 295

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Table of Tables
Table 1 EMA regulatory access pathways which allow accelerated access to treatments .................... 45
Table 2 Regenerative medicines granted EU marketing authorisation: summary data from EMA,
FDA, and NICE reports ......................................................................................................... 51
Table 3 The evolution of autologous chondrocyte implantation (ACI) therapies ................................. 54
Table 4 Summary of challenges to interpretation of single group study designs ................................. 58
Table 5 Summary of results from systematic review of trial-level meta-analyses of randomised trials
quantifying the association between surrogate and final outcomes in cancer ....................... 67
Table 6 Data available for the three published CAR T-cell trials in patients with B-ALL................. 101
Table 7 Ongoing commercial CAR T-cell trials registered on clinicaltrials.gov ................................ 104
Table 8: Summary of the sample size and maturity of trial evidence assumed in the 3 evidence sets 116
Table 9: Overall survival endpoint for bridge to HSCT datasets ........................................................ 121
Table 10: Other efficacy and safety endpoints for bridge to HSCT datasets ...................................... 123
Table 11: Overall survival endpoint for curative intent data sets ....................................................... 125
Table 12: Other efficacy and safety endpoints for curative intent datasets ........................................ 126
Table 13: Summary of key attributes of the six evidence sets ............................................................ 128
Table 14: Baseline characteristics of patients ..................................................................................... 134
Table 15: Key common features of de novo economic models .......................................................... 136
Table 16: Summary of key modelling assumptions for Bridge to HSCT responder model ............... 141
Table 17: Parameter estimates for bridge to HSCT scenario .............................................................. 145
Table 18: Survival rates in patients who receive HSCT based on MRD and remission status ........... 148
Table 19: Summary of key modelling assumptions ............................................................................ 154
Table 20: Summary of goodness of fit statistics and weights for survival distributions (minimum set)
............................................................................................................................................. 156
Table 21: Summary of goodness of fit statistics and AIC-based weights for survival distributions
(intermediate set) ................................................................................................................. 159
Table 22: Summary of goodness of fit statistics and AIC-based weights for survival distributions
(mature set) .......................................................................................................................... 159
Table 23: Model inputs - costs ............................................................................................................ 166
Table 24: Model inputs - utilities ........................................................................................................ 170
Table 25: Estimated acquisition costs for CAR T-cell therapies (excluding costs for conditioning
therapy and leukapheresis) .................................................................................................. 178
Table 26: Summary of costs and outcomes ........................................................................................ 179
Table 27: Expected cost-effectiveness of CAR T therapy per patient treated (lifetime horizon) ....... 180
Table 28: Expected cost-effectiveness of CAR T therapy at population level (including incident
patients) ............................................................................................................................... 181
Table 29: Results of one-way sensitivity analysis (population level) – Bridge to HSCT TPP ........... 182
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Table 30: Results of base case probabilistic analysis, presented at population-level (Bridge to HSCT)
............................................................................................................................................. 183
Table 31: Consequences of decision uncertainty across different thresholds - Bridge to HSCT TPP
(minimum evidence set) ...................................................................................................... 186
Table 32: Impact of different pricing schemes on the cost-effectiveness of CAR T therapy, and the
associated consequences of decision uncertainty: Bridge to HSCT TPP (minimum evidence
set) ....................................................................................................................................... 188
Table 33: Probabilistic results comparing across evidence sets: Bridge to HSCT TPP ..................... 193
Table 34: Summary of costs and outcomes in the Curative intent TPP (minimum evidence set) ...... 197
Table 35: Per patient expected cost-effectiveness: Curative intent TPP (minimum evidence set) ..... 197
Table 36: Expected cost-effectiveness of CAR T therapy (population level): Curative intent TPP
(minimum evidence set) ...................................................................................................... 199
Table 37: Results of one-way sensitivity analysis at population level: Curative intent TPP (minimum
evidence set) ........................................................................................................................ 200
Table 38: Base case probabilistic analysis results: Curative intent TPP (minimum evidence set) ..... 201
Table 39: Consequences of decision uncertainty across different thresholds - Curative TPP (minimum
evidence set) ........................................................................................................................ 203
Table 40: Impact of different pricing schemes on the cost-effectiveness of CAR T therapy, and the
associated consequences of decision uncertainty: Curative intent TPP (minimum evidence
set) ....................................................................................................................................... 205
Table 41: Probabilistic results comparing across evidence sets: Curative intent TPP ........................ 209
Table 42: Additional exploratory analyses: Curative intent TPP (minimum evidence set) ................ 224
Table 43 Regenerative medicines which are (or have been) licensed by the EMA ............................ 241
Table 44 Methods and results from studies comparing RCTs with NRSs .......................................... 268
Table 45 Studies comparing bias adjustment methods ....................................................................... 273
Table 46 Review and data extraction of the literature on the use of surrogate measures as clinical
endpoints in therapeutic trials .............................................................................................. 275
Table 47 Licensed treatments for relapsed/refractory B-ALL ............................................................ 285
Table 48 Systematic review of previous economic evaluations in ALL............................................. 292
Table 49: Incidence of new ALL diagnosis in 2013195 ....................................................................... 294
Table 50: Members of the Advisory Group for the project ................................................................ 295
Table 51: NICE Panel meeting participants ........................................................................................ 296

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