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Multi-Criteria Decision Analysis The Key to Successful Product Development and Market
Access
Kevin Marsh, PhD David Neasham, PhD
Disclaimers The processes and case study material described and presented
herein relate solely to the kind of methodologies and representations that can be used for MCDA.
The material neither replaces nor is intended to replace or comment on any regulatory decisions made by national regulatory agencies, nor the European Medicines Agency.
2
Objectives
Understand how MCDA can support product development and market access
Understand what MCDA is, and how to do it
Understand how to get started implementing MCDA
Overview
What is MCDA?
How Can MCDA Support Product Development and Market Access?
How is it done? A case study
Implementing MCDA: Some challenges
Three Key Tips to Help You Get Started with MCDA
What is MCDA?
broad set of approaches and methods to guide decision-
making while accounting for multiple criteria. These methods share
the fact that they allow for the explicit trade-off between multiple
criteria, establishing the relative importance of these criteria.
5
‘ ’ Ethgen & Marsh (in press)
A
Decision in Health Care Involves Trading-off Multiple Criteria
Source: Golan et al., 2010
MCDA Has Been Used to Support a Variety of Health Decisions
Source: Marsh et al., 2013
The Use of MCDA in Health Care is on the Rise
Source: Diaby et al., 2013
8
How Can MCDA Support Product Development and Market Access?
How Can MCDA Support Product Development and Market Access?
Patient application
Investigational new drug application or clinical trial
application
Time (years)
Development phases
Clinical phases
Phase 4 more patients
Post-marketing Development
Phase 1 50–100
volunteers or patients
Regulatory Review
Clinical Development Pre-clinical
Development Discovery Research
Basic Research to Understand
Disease
Synthesis Biological Testing
and Pharmacologic
al Screening
Phase 3 3,000+ patients
Phase 2 200–400 patients
0–2 5–7 3
Achieve reimbursement • IQWiG has recommended conjoint analysis and AHP techniques to
weight the multiple endpoints considered in its assessments • NICE methods for assessing orphan drugs (June 2013): MCDA-based
Marketing application
Reimbursement/formulary submissions
How Can MCDA Support Product Development and Market Access?
Patient application
Investigational new drug application or clinical trial
application
Time (years)
Development phases
Clinical phases
Phase 4 more patients
Post-marketing Development
Phase 1 50–100
volunteers or patients
Regulatory Review
Clinical Development Pre-clinical
Development Discovery Research
Basic Research to Understand
Disease
Synthesis Biological Testing
and Pharmacologic
al Screening
Phase 3 3,000+ patients
Phase 2 200–400 patients
0–2 5–7 3
MCDA can support payer value messages • If the QALY does not capture the value of a technology
• Unmet need, patient convenience, or innovation • Improved safety and tolerability
Marketing application
Reimbursement/formulary submissions
Paradigm Shift Regulation 1235/2010 and Directive 2010/84/EC on EU pharmacovigilance published on 31 December 2010
On July 2012, legislation was activated
International Conference on Harmonisation Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E2C (R2) guideline Periodic Safety Update Reports (PSURs) will become basis of periodic benefit-risk evaluation reports
Periodic Benefit-Risk Evaluation Report (PBRER) is intended to be a common standard for periodic benefit-risk evaluation reporting on marketed products
January 2013, the European Medicines Agency (EMA) will expect market authorisation holders to submit the new PSUR
Requirements: PSUR will change from being largely a document based on long line listings, narratives and simple sales-based incidence statistics, to a complex benefit-risk tool
How Can MCDA Support Product Development and Market Access?
Patient application
Investigational new drug application or clinical trial
application
Time (years)
Development phases
Clinical phases
Phase 4 more patients
Post-marketing Development
Phase 1 50–100
volunteers or patients
Regulatory Review
Clinical Development Pre-clinical
Development Discovery Research
Basic Research to Understand
Disease
Synthesis Biological Testing
and Pharmacologic
al Screening
Phase 3 3,000+ patients
Phase 2 200–400 patients
0–2 5–7 3
Achieve authorisation • EMA has recommended MCDA as a tool to support benefit risk
assessment • MCDA is valued by regulators: Anecdotal evidence from our clients
suggests that regulators value MCDA when used to supplement submissions
Marketing application
Reimbursement/formulary submissions
How Can MCDA Support Product Development and Market Access?
Patient application
Investigational new drug application or clinical trial
application
Time (years)
Development phases
Clinical phases
Phase 4 more patients
Post-marketing Development
Phase 1 50–100
volunteers or patients
Regulatory Review
Clinical Development Pre-clinical
Development Discovery Research
Basic Research to Understand
Disease
Synthesis Biological Testing
and Pharmacologic
al Screening
Phase 3 3,000+ patients
Phase 2 200–400 patients
0–2 5–7 3
MCDA can support authorisation submissions
• Where the benefit-risk (BR) balance is marginal
• To reflect the patient point of view
Marketing application
Reimbursement/formulary submissions
How Can MCDA Support Product Development and Market Access?
Patient application
Investigational new drug application or clinical trial
application
Time (years)
Development phases
Clinical phases
Phase 4 more patients
Post-marketing Development
Phase 1 50–100
volunteers or patients
Regulatory Review
Clinical Development Pre-clinical
Development Discovery Research
Basic Research to Understand
Disease
Synthesis Biological Testing
and Pharmacologic
al Screening
Phase 3 3,000+ patients
Phase 2 200–400 patients
0–2 5–7 3
Keep your product on the market New pharmacovigilance legislation: Periodic Safety Update Reports (PSURs) will become true periodic benefit-risk evaluation reports
Marketing application
Reimbursement/formulary submissions
How Can MCDA Support Product Development and Market Access?
Cascade requirements throughout the
development process
Patient application
Investigational new drug application or clinical trial
application
Time (years)
Development phases
Clinical phases
Phase 4 more patients
Post-marketing Development
Phase 1 50–100
volunteers or patients
Regulatory Review
Clinical Development Pre-clinical
Development Discovery Research
Basic Research to Understand
Disease
Synthesis Biological Testing
and Pharmacologic
al Screening
Phase 3 3,000+ patients
Phase 2 200–400 patients
0–2 5–7 3
Marketing application
Reimbursement/formulary submissions
How is it Done? Case Study: MCDA Supports the Decision to Authorise Tysabri
Source: Nixon & Oliviera, 2011 and Ashby, 2012
Context Active drug Natalizumab
Indication Relapsing-remitting multiple sclerosis
Regulatory history
• Approved 2004
• Licence withdrawn 2005
• Reintroduced due to patient demand 2006
• The Committee for Medicinal Products for Human Use (CHMP) reassesses benefit risk and continues approval in 2009
Comparators Avonex, Copaxone, Movectro
Challenge
• Treatments are effective at reducing disease progression and relapse rate
• But they also have frequent or serious adverse events
• How to judge if the benefits are worth the risks? 18
Definition of Criteria
19
Adverse events
Efficacy
Convenience
Flu-like symptoms
Injection-site reactions
Serious herpes zoster
Hepatic AE
Annual relapse rate
% not progressing after 2 years
Overall value
Benefit-risk
EDSS progression
# patients/1000 after 2 years
Oral qm, oral qd, im qwk, sc qd, iv qm
Treatment
Decision Criteria category Criteria
Populate Effect Table
20
# Patients/1000
Avonex Copaxone Tysabri Movectro
Adverse events
Flu-like symptoms 938 533 485 433
Injection-site reactions 125 980 252 0
Serious herpes zoster 0 0 0 2
Hepatic adverse events 0 0 55 7
Benefits
Relapses 270 234 104 140
EDSS progression 134 199 128 154
Convenience i.m. qw s.c. qd i.v. qm Oral qm
Generate Criteria Weights
21
Outcomes
Category Unit of Measurement Worst Best
Convenience Administration
route and frequency
Subq injection,
daily
Oral, once a month
Disability progression
Number of patients out of 1,000 whose EDSS scores increase by at least 1 point at
two years
270 100
Serious herpes zoster
Number of patients out of
1,000 with AE in two years
3 0
Rank
3
1
2
Weight
30
100
90
Results: Tysabri vs. Placebo
Results: Tysabri vs. Comparators
Implementing MCDA: Some challenges
What is MCDA?
Overall value message
Weight criteria
Measure criteria
Identify criteria
Common steps (for instance, CLG, 2009)
– Identify criteria
– Measure criteria
– Weight criteria
– Analysis, sensitivity analysis
– Dissemination
What Criteria Should be Included in MCDA?
0
2
4
6
8
10
12
14
16 N
umbe
r of s
tudi
es
Source: Marsh et al., in press. Figure 3 Criteria included in MCDAs designed to support investment decisions
MCDA is used to capture a range of
value criteria
MCDA requirements (see for instance, CLG, 2009) • Completeness • Non-redundancy • Mutual independence of preferences • Double counting
What Criteria Should be Included MCDA?
27
Source: Hughes-Wilson et al., 2012
Criteria proposed for MCDA of orphan drugs
– Rarity
– Level of research undertaken
– Level of uncertainty of effectiveness
– Manufacturing complexity
– Disease severity
– Available alternatives
– Impact on condition
– Use for unique indication
Rarity is only valuable as a proxy for unmet
need?
Should uncertainty be included as a criteria?
Some factors are proxies for cost and should be excluded?
How Should Criteria be Measured?
28
Source: Marsh et al., 2013
Clinical trials
Epidemiological studies
Patient registries data
Models
Literature review
Which Weighting Methods Should be Employed?
29
Source: Marsh et al., 2013
How should we choose the appropriate weighting method?
– Consider magnitude of criteria?
– Importance versus trade-off?
– Decision maker accessibility/acceptability?
– Research effort?
– Whose values?
Which Weighting Methods Should be Employed?
30
Sources: Garau, 2012; Sussex et al., 2013
Three Key Tips to Help You Get Started with MCDA
1. Design the MCDA Carefully
Ensure you understand the decision context
Engage with relevant stakeholders
Ensure the MCDA method is fit for purpose
Consider the synergies with existing evidence generation
33
2. Ensure You Have Access to the Necessary Skills
MCDA MCDA
Evidence review and synthesis
Pharmacoepidemiology
Modelling Stakeholder insights
Eliciting weights(surveys)
Eliciting weights (workshops)
3. Start the MCDA Early
Cascade requirements throughout the
development process
Patient application
Investigational new drug application or clinical trial
application
Time (years)
Development phases
Clinical phases
Phase 4 more patients
Post-marketing Development
Phase 1 50–100
volunteers or patients
Regulatory Review
Clinical Development Pre-clinical
Development Discovery Research
Basic Research to Understand
Disease
Synthesis Biological Testing
and Pharmacologic
al Screening
Phase 3 3,000+ patients
Phase 2 200–400 patients
0–2 5–7 3
Marketing application
Reimbursement/formulary submissions
Thank you
David E. Neasham, PhD, MSc, MFPH Senior Research Scientist United BioSource Corporation E-mail: [email protected] Phone: +44 (0) 20 8834 7052
Kevin Marsh, PhD Senior Research Scientist United BioSource Corporation E-mail: [email protected] Phone: +44 (0) 20 8834 9569