Appraisal Frameworksuitable for Rare Disease Treatments

8 June 2021 – IMPACT HTA Conference

IMPACT HTA is a European Commission (EC) funded Horizon 2020 project.

The results presented here reflect the authors’ views and not the views of the EC.

The EC is not liable for any use of the information communicated.

This work is licenced under a Creative Commons Attribution 4.0 International Licence

Team

Karen Facey PhD CStatHonMFPH (co-lead)

Senior Research Fellow

Trenholme Junghans PhDConsultant Anthropologist

Visiting Research Fellow

Mike Drummond PhD Professor of Health

Economics University of York

SDA Bocconi Visiting Professor

Elena Nicod PhD (co-lead)Research Fellow

Michela Meragaglia PhDResearch Fellow

Amanda Whittal PhDResearch Fellow

Sheela UpadhyayaConsultant to NICE Methods Review and Accelerated Access Programme

Entela Xoxi PharmD, PhDResearch Consultant

Collaborators

Work Package 10 team and collaborators

The difficulties to develop medicines for rare diseases lead to HTA challenges

Source: Nicod E, Annemans L, Bucsics A, Lee A, Upadhyaya S, Facey K. HTA programme response to the challenges of dealing with orphan medicinal products: Process evaluation in selected European Countries. Health Policy, 2019

CHALLENGES AT HTA-LEVEL

High Cost/QALY

CLINICAL CHALLENGES ECONOMIC CHALLENGESREGULATORY CHALLENGES

Lack of knowledge and expertise

Ability to run confirmatory

trials

High cost medicines

Financial burden on patients, family, carers

and society

Incentives from regulators to overcome

clinical challenges

Nature of rare diseases

Small patient

populations

Heterogeneous conditions

Many genetically acquired,

early onset

Negative impact on patients,

families and carers

Severe, disabling, life-threatening

Post-marketing surveillancePhase IV trials

Pricing and reimbursementNational-level

Marketing authorisation

Clinical researchPhase I, II, III trials

Drug discoveryPreclinical research

Misaligned with regulatoryprocesses

Small samples, lack statistical

power

Uncertain clinical

pathways

Limited clinical

and QoL evidence

Limited trial

duration

Issues in dealing with subgroups

Uncertainties in cost

effective modelling

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01 02 03 04

COUNTRY APPRAISAL PROCESSES

COMMITTEE OBSERVATIONS

PATIENT REPORTED OUTCOMES

MANAGED ENTRY AGREEMENTS

Do country appraisal processes for RDTs

differ, and how?

How can appraisal processes for medicines forrare diseases be

improved?

How to better use patient reported outcome

measures and utilitiesin the appraisal

process?

When and how to implement outcome-based managed entry agreements?

IMPACT-HTA WP 10: Appraisal of Rare Disease Treatments (RDTs)

APPRAISAL FRAMEWORK

*More information can be found at: https://www.impact-hta.eu/work-package-10

1 Overview of appraisal processes for RDTs

IMPACT-HTA WP10 country vignettes of appraisal processes for RDTs (n=36)

Available at: impact-hta.eu/work-package-10

Overview of countries with supplemental process for RDTs and process characteristics

Nicod et al. 2020. Are supplemental/appraisal reimbursement processes suitable for rare disease treatments? An international comparison of country approaches. OrphanetJournal of Rare Diseases

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SMC (Scotland)

NICE (England)

CADTH (Canada)

• New Drugs Committee (NDC)

• Patient & Clinician Engagement (PACE)

• SMC Appraisal Committee (orphan, ultra-orphan

framework/pathway)

• HST and TA Appraisal Committee

• Canadian Drug Expert Committee (CDEC)

TisagenlecleucelB-cell acute lymphocytic

leukaemia

Patisiran Amyloidosis

Lumacaftor/Ivacaftor &

Tezacaftor/Ivacaftor Cystic Fibrosis

Voretigene

Neparvovec Inherited Retinal Disorder

Onasemnogene

Abeparvovec Spinal Muscular Atrophy

Volanesorsen Familial chylomicronaemia

EmapalumabPrimary paediatric haemophagocytic

lymphohistiocytosis

2 Ethnographic observation and interviews of Appraisal Committees

30 interviews of individuals involved throughout the Appraisal process of those observed

OBSERVATIONS

INTERVIEWS

TREATMENTS OBSERVED

3 Better use of PRO data and HSUVs in HTA of rare diseases

What is known in the literature on use of PROs/utilities in rare diseases and implications for

HTA

Consideration of PROs/utilities for RDTs in practice across 4 countries

PROM/HSUV techniques• Interpretation• Influence on decision• Other evidence to

support assessment, interpretation of QoL

Recommendations for improving use of PRO data and utilities in HTA of RDTs

4 Implementation of outcome-based managed entry agreements

Tools to support use and implementation of OBMEAs with a rare disease treatment

Other major activities

• Analysis of 283 MEAs initiated in Italy over a 15-year period (Xoxi E, Facey K. 2021 – under review)

• Documentation of the purpose, form, construct and analysis of OBMEA in countries in EU, Australia and Canada for two case studies (nusinersen in spinal muscular atrophy and tisagenlecleucel in refractory haematological cancers) (Facey F et al. 2021 – under review)

Facey et al. 2020 – available at: impact-hta.eu/work-package-10

Checklist to determine feasibility of an OBMEA

Template for an OBMEAToR for an OBMEA monitoring

committee

Patient Group submission form for re-appraisal after an

OBMEA

Process adaptations

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Different process adaptationshelp deal with high uncertainty/price

Value frameworkbeyond clinical/cost-effectiveness

Decision modifiers acceptance of greater

uncertainty/price

How can we adapt the appraisal process to better deal with the unique circumstances of RDTs?

…. Is this sufficient?

➢ Detailed consideration of each aspect of value

➢ Addresses all dimensions of value➢ Identifies uncertainties

What is needed to ensure that committees can make the best decision possible, • given the unique circumstances of each rare disease,

• limitations in evidence and uncertainties that are bound to arise, and

• considering fairness across the overarching health system and those living with rare conditions?

Appraisal Deliberation

Critical Assessment

Evidence Submission

➢ Explains context of condition, care pathway

➢ Helps resolve uncertainties

Iterative clinical and patient involvement

Consistent flexibility

IMPACT-HTA WP10 - Appraisal Framework suitable for Rare Disease Treatments

Process adaptations

Source: Facey K, Whittal A, Drummond M, Upadhyaya S, Junghans T, Nicod E. IMPACT HTA WP10 HTA Appraisal Framework Suitable for Rare Disease Treatments. 12 May 2021. [Online]. Available from: Impact HTA | Health Technology Assessment | Work Package 10 (impact-hta.eu)

Structured Appraisal DeliberationExpanded Evidence Submissions and Critical

Assessment

Recommendations for an appraisal framework that enables consistent flexibility to ensure fairness for RDTs – Not an RDT appraisal framework!

The entire HTA process is shaped around clearly

defined decision-making domains and modifiers

All relevant evidence is obtained for each domain of

decision-making and all modifiers

Critical assessment of clinical evidence explicitly

considers what evidence could have been

generated in the rare condition

Critical assessment of economic models takes

account of paucity of knowledge in RDs and judges

whether the model is sufficient for decision-making

Appraisal committees are bespoke for RDTs, or

general appraisal committees include several RD

specialists

The deliberative appraisal discussion is driven by

the domains of decision-making and use of

modifiers is clearly understood

Uncertainties are characterized in terms of form,

extent and implications for decision-making

Outcomes-Based Managed Entry Agreements may

be used to resolve decision-relevant uncertainties, if

collection of sufficient data is feasible

Clinical and patient experts are involved throughout appraisal process to explain context of condition, existing care pathway and help resolve uncertainties related to determination of treatment value

Iterative

Clinical and

Patient Input

Source: Facey K, Whittal A, Drummond M, Upadhyaya S, Junghans T, Nicod E. IMPACT HTA WP10 HTA Appraisal Framework Suitable for Rare Disease Treatments. 12 May 2021. [Online]. Available from: Impact HTA | Health Technology Assessment | Work Package 10 (impact-hta.eu)

Any questions or comments, please contact:Karen Facey: karen.facey@ed.ac.ukElena Nicod: elena.nicod@dolon.com

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• Facey K, Whittal A, Drummond M, Upadhyaya S, Junghans T, Nicod E. IMPACT HTA WP10 HTA Appraisal Framework Suitable for Rare Disease Treatments. 12 May 2021. [Online]. Available from: impact-hta.eu/work-package-10

• Nicod E, Whittal A, Drummond M, Facey K. Are supplemental appraisal/reimbursement processes needed for rare disease treatments? An international comparison of country approaches. Orphanet Journal of Rare Diseases. 2020 (in press)

• Whittal A, Nicod E, Drummond M, Facey K. Examining the impact of different country processes for appraising rare disease treatments: a case study analysis. International Journal of Technology Assessment in Healthcare. 2021 (in press)

• Facey K, Rannanheimo P, Batchelor L, Borchardt M, de Cock J. Real-world evidence to support Payer/HTA decisions about highly innovative technologies in the EU –actions for stakeholders. International Journal of Technology Assessment in Healthcare. 2020 (in press)

• Facey K. OBMEA tools to support use and implementation with a rare disease treatment. Available from: impact-hta.eu/work-package-10

• Meregaglia M, Whittal A, Nicod E, Drummond M. 'Mapping' Health State Utility Values from Non-preference-Based Measures: A Systematic Literature Review in Rare Diseases. Pharmacoeconomics. 2020 Jun;38(6):557-574.

• Meregaglia M, Nicod E, Drummond M. The estimation of health state utility values in rare diseases: overview of existing techniques. Int J Technol Assess Health Care. 2020 Oct;36(5):469-473

• Whittal A, Meregaglia M, Nicod E. The Use of patient-reported outcome measures in rare diseases and implications for health technology assessment. The Patient. 2021 Jan (open access, in press)

• Facey K, Espin J, Kent E, Link A, Nicod E, O'Leary A, Xoxi E, can de Vijver I, Zaremba A, Benisheva T, Vagoras A, Upadhyaya S. Implementing Outcomes-Based Managed Entry Agreements for Rare Disease Treatments: Nusinersen and Tisagenlecleucel. PharmacoEconomics 2021

• Nicod E, Meregaglia M, Whittal A, Upadhyaya S, Facey K, Drummond M. Consideration of quality of life in the health technology assessments of rare disease treatments. Under review

• Xoxi E, Facey K, Cicchetti A. The evolution of AIFA registries to support Managed Entry Agreements for orphan medicinal products in Italy. Under review

• Nicod E, Lloyd A, Morel T, Meregaglia M, Upadhyaya S, Whittal A, Facey K, Drummond M. Improving use of patient quality of life measures in health technology assessment of rare disease treatments - a European perspective. Under development

• Facey K, Xoxi E, Kent E, Upadhyaya S, Nicod E. Outcomes-Based Managed Entry Agreements for Rare Disease Treatments. Under development