1st WP2 F-t-F training Course for all EUnetHTA stakeholders - EUnetHTA Tools and Methodology. Brussels, 16 Jan. 2014

1. Choice of Endpoints for
Reimbursement
Purposes in Europe
Mira Pavlovic, MD
HAS
EUnetHTA JA2 WP7 Lead Partner
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu

2. Europa
• Subsidiarity principle:
• a central authority should have
a subsidiary function,
performing only those tasks
which cannot be performed
effectively at a more immediate
or local level
• Healthcare systems are financed
and organized at national level
• Healthcare interventions are
evaluated by national HTA
bodies
• Criteria, procedures, rules are
defined at national level
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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3. Mandate for EU co-operation
• Reduce duplication of assessments (*)
• Consider:
• early dialogue during product development to improve initial evidence
generation (**)
EMA – HTA cooperation:
• Member States, with the involvement of the EMA, should continue their
efforts to consider how EPARs can further contribute to relative
effectiveness assessments. (**)
• Decision to set up a permanent network
• Each Member State determines:
• Criteria for admission to reimbursement
• Choice of HTA bodies and decision bodies
• Price: no EU-HTA decision or EU appraisal of added benefit
(*) Article 15 DIRECTIVE on the application of patients’ rights in cross-border healthcare
(**) Pharma Forum Recommandations
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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4. The timeline of reaching a sustainable
and permanent HTA network in Europe
Health
Programme
2014-2020
2005
2011
Call for joint
action
Call for
joint
action
2006-2008
2009
2010-2012
2012-2015
2016-2020
EUnetHTA
Project
Legislation
2009
Call for
project
proposals
EUnetHTA
Collaboration
EUnetHTA
JA
EUnetHTA
JA2
EUnetHTA
Scientific and
technical cooperation
Financial support
HTA
2008-2011
2011-12
2013
2013+
Draft Cross Border
Healthcare Directive.
Article 15 on HTA network
CBHC Directive
now decided
EU
Cooperation
on HTA
Implementing
Decision
HTA Network
DG R&I
2011 FP7-Health
Horizon 2020
2012-Innovation-1
Calls
New methodologies for HTA
Health Care
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu

5. Collaborative EUnetHTA actions
• Reduce duplication of work
• HTA core model for REA of pharmaceuticals
• Reduce heterogeneities in methodology of
assessment
• EUnetHTA methodology guidelines
• Improve the quality and appropriateness of the data
produced
• Initial evidence generation
• Additional evidence generation
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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6. Reduce heterogeneities in methodology of
assessment
EUnetHTA Methodology guidelines
• Already produced 9 guidelines for the REA of pharmaceuticals
1. Choice of comparator
2. Clinical endpoints
3. Composite endpoints
4. Surrogate endpoints
5. HRQoL
6. Safety
7. Direct and indirect comparisons
8. Internal validity
9. Applicability
 Ongoing: Guidelines for methodology assessment of medical devices
and procedures and disease-specific guidelines
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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7. Endpoints for relative effectiveness
assessment for reimbursement
purposes
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8. Endpoints A terminology adopted by EUnetHTA
• Endpoint instead of outcome
• Clinical endpoint = patient relevant endpoint
•
a valid measure of clinical benefit due to treatment;
•
the impact of treatment on how a patient feels, functions and survives.
• Patient relevant endpoint may or may not be assessed by patient (PRO,
ClinRO, ObsRO)
• Patient-reported outcome (PRO): an umbrella term used to describe
any outcome evaluated directly by the patient himself/herself, without
interpretation by clinicians or others, and based on patients’
perception of a disease and its treatment(s).
• HRQoL represents a specific type/subset of PROs, distinguished by its
multi-dimensionality.
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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9. Endpoints for REA Framework
Clinical endpoints = Clinical endpoints relevant to patients: death, pain
(symptoms), disability, effects of the disease or its treatments on activities of
daily living and quality of life
Clinical endpoints
(How a patient feels,
functions or survives)
Mortality
Morbidity
(e.g. symptoms, clinical
events, function, activities of
daily living, adverse events)
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
Health-related
Quality of Life
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10. Endpoints in clinical trials
Primary, secondary, others
Primary endpoint:
•
Main symptom/sign of a disease
•
Valid measure of clinical benefit
˗Hard endpoint (mortality, MI, stroke) or symptoms
˗Surrogate (HbA1c, BP, HIV viral load)
˗Single or composite
•
Relevant
•
Responsive to change
Depends on:
•
Target population
•
Characteristics of disease
•
Core symptom/sign
•
Intended claim
•
Valid measure of clinical benefit
•
Hierarchy of endpoints in a trial (primary, co-primary, secondary, exploratory)
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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11. Endpoints for REA
Trial still to power on primary endpoint
Simultaneous assessment of all endpoints (e.g. clinical events relevant
for the disease and its treatment, symptoms, HRQoL) considered relevant
for patients in parallel to the primary endpoint
HRQoL, symptoms:
• One of REA endpoints (mortality, morbidity, HRQoL)
• Systematically assessed (if data available)
• Assessed “at the same level” as other endpoints
• Its improvement (for equivalent effectiveness and/or harms) may be the
basis for “added benefit” of a new drug compared to an adequate
comparator
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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12. Endpoints for REA and added clinical benefit
• Added clinical benefit:
˗HT does more good than harm (has an added benefit) in a target
population compared to one or more intervention alternatives (standard
of care) for achieving the desired results when provided under the usual
circumstances of health care practice
• Added clinical benefit of a new drug is assessed:
˗In head to head trials and from indirect comparisons
˗In adequate patient population
˗In comparison to an adequate comparator(s)
˗On relevant clinical endpoints:
 Appropriately measured primary endpoint (final patient-relevant
endpoint or acceptable surrogate)
 Other endpoints considered relevant for the disease and aim of
treatment
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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13. Clinical endpoints
EUnetHTA guideline
Clinical endpoint: a valid measure of clinical benefit due to treatment; the impact of
treatment on how a patient feels, functions and survives.
The relevance and hierarchy of the different endpoints will depend on:
the research question,
the disease/condition and
the aim of treatment investigated (preventive, curative, symptomatic, palliative)
REA: preference for
˗ objectively measured clinical EP
˗ long-term or final EP whenever possible (OS, all-cause mortality);
Short-term endpoints acceptable for acute conditions with no long-term
consequences
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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14. Surrogate Endpoints
• In the absence of evidence on final patient-relevant clinical endpoint
that directly measures clinical benefit, both biomarkers and
intermediate endpoints are considered as surrogate endpoints in
REA if they
˗reliably substitute for a clinical endpoint and
˗predict the effect of therapy (clinical benefit and/or harm).
• The acceptability of an endpoint as a surrogate for a specific clinical
endpoint is based on its biological plausibility and empirical evidence
(validation)
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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15. Surrogate Endpoints (2)
• The HTA should be based whenever possible on final patientrelevant clinical endpoints (e.g. morbidity, overall mortality). However,
˗for the initial (first) assessment, surrogate endpoints accepted if the
validity of the surrogate/final clinical endpoint relationship has been
previously clearly established. Sufficient safety database important.
˗For the re-assessment, effectiveness should be demonstrated
whenever possible on final clinical morbidity and mortality endpoints
(e.g. stroke, myocardial infarction, fracture).
• The absence of data on clinical endpoints relevant for REA might be
acceptable when a clinical endpoint is difficult or impossible to study
(very rare or delayed) or target population is too small to obtain
meaningful results on relevant clinical endpoints even after very long
follow-up (very slowly progressive and/or rare diseases).
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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16. Composite Endpoints
– To avoid if suitable single primary EP available
– Number of components to be limited to 3 or 4 of similar clinical
importance
– Prior empirical evidence of the value of each components to be
defined
– Each component of a composite EP should be reported in the way it
contributed to the result within the composite EP. All components
should also be reported separately as secondary EP according to
hierarchical levels
– Effect of the intervention on all components
– If a significant difference is obtained on the composite EP, but the
effect is not homogeneous, it cannot be concluded that the treatment
has an effect on the composite EP as a whole.
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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17. HRQoL
HRQoL:
• One of REA endpoints (mortality, morbidity, HRQoL)
• Systematically assessed (if data is available)
• Assessed “at the same level” as other endpoints
• Relevance and hierarchy of the different endpoints will depend on the
research question, on the disease and the aim of treatment
investigated.
The improvement in HRQoL alone (for equivalent
effectiveness and/or harms) may be the basis for
“added benefit” of a new drug compared to an
adequate comparator
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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18. HRQoL (2)
• The appropriateness of the HRQoL measure used depends on
the purpose of the relative effectiveness assessment (REA):
• to inform patients and health care professionals about the
HRQoL benefit of an intervention as compared to its comparator
• to inform health care policy makers about the relative value of a
product
• In the latter case, the decision-making context plays a crucial
role:
• is cost-effectiveness taken into account in drug reimbursement
decisions and
• are decisions taken within indications only or also comparing
relative values across indications?
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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19. HRQoL (3)
Across indications:
˗Generic HRQoL measures preferred, disease-specific measures may be
added in necessary
˗Utility measures for cost-effectiveness
Within indications to inform clinical decision making:
˗Disease-specific HRQoL sufficient
˗Generic measures may be added
˗Utility measures for cost-effectiveness
Methodological considerations
˗cf EMA, FDA
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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20. Adequate comparator
• A health care intervention or a HT with which a new pharmaceutical is
compared in order to establish if this new pharmaceutical has an added
therapeutic benefit.
• Can be another pharmaceutical, medical device, procedure, radiotherapy,
physiotherapy, surgery, providing advice, a combination of health care
interventions carried out simultaneously or in sequence, watchful waiting
• If drug, of a similar pharmaceutical class or not
• Ideally:
˗the reference treatment in EU with good quality evidence on effect size and
adverse effects
˗an EU marketing authorisation in the indication and line of treatment, optimally
dosed or scheduled
˗Allows for a randomised controlled comparison.
˗Additional comparators if different severity/stages of disease (subpopulations) are
considered.
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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21. What if
Comparator: “standard of care”
˗
What to do when SC is an off-label drug?
“Investigator’s best choice” (BSC? Routine practice?)
˗
Can it include an active treatment or only
supportive care?
˗
Can it be both?
What if a “traditional” primary endpoint is considered not (directly)
relevant for patients? (e.g. BP, HbA1c)
EUnetHTA multi-HTA early dialogue recommended
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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22. Endpoints for HTA and added
clinical benefit
Added clinical benefit of a new drug is assessed:
˗in adequate patient population
˗in comparison to an adequate comparator
˗Direct and indirect comparisons
˗on relevant clinical endpoints:
˗Primary endpoint (final patient-relevant endpoint or acceptable surrogate)
˗Other endpoints considered relevant for the disease or its treatment
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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23. Relative effectiveness assessment
USA - FDA road map
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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24. Understanding the Disease or Condition
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25. Conceptualizing Treatment Benefit
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26. Selecting/Developing the Measure
• Measure:
˗
exists,
˗
does not exist,
˗
exists but needs to be modified
• The selection criteria for adequate
measures/endpoints are very similar to
those described by EUnetHTA
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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27. Global development for global registration?
DIFFERENT
• Regions: EU, USA, Japan, other regions
• Regulatory requirements
• Pricing and reimbursement criteria
• Medical practices: patient management, hospital care, concomitant
treatments, invasive procedures
• Lifestyle: diet, tobacco, alcohol, sun exposure, compliance…
Differences in intrinsic and extrinsic factors (ICH-E5)
I: genetic polymorphism, age, weight
E: environmental and cultural factors
Differences in outcomes observed regionally WHATEVER THE TYPE OF
OUTCOME (mortality, symptom scales)
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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28. Divergent regulatory outcomes
in EU and USA
Period: January 1995 to March 2009
• 31 products approved in the US but had negative outcome in
Europe
• 24 products approved in Europe but had negative outcome in the
US
Reasons for negative outcome:
Clinical efficacy:
EU neg: 19,
Clinical safety:
EU neg 14,
Study design:
EU neg 7,
Comparators:
EU neg 4,
Further data needed: EU neg 12,
US neg: 9
US neg 11
US neg 1
US neg 0
US neg 15
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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29. Endpoints to show treatment benefit
Links to make
• With national assessments/requirements for pricing
and reimbursement
• With all stakeholders
˗With regulators
• EMA: ongoing
• FDA: road map to patient-focused outcome
measurement in clinical trials
˗With developers
˗With payers
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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30. EUnetHTA early dialogue
• Early Dialogue/scientific advice between HTA bodies and companies
˗Multi HTA Early dialogue
˗Supported by EC, Part of EUnetHTA JA2 (2012 – 2015)
• Experience to get on
˗Consolidated/transparent/harmonised(?) views on the initial and
additional evidence requirements
˗Assessment methodology requirements tested on real examples of
product development
˗Help develop disease-specific guidelines
• Develop sustainable collaboration
˗Among HTA bodies
˗With regulators
˗With national payers/other parties
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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31. Multi-HTA Early dialogue
JA2 WP7 ED pilots
• 10 in total, all on drugs
• 2 pre-pilots (2012) and 8 pilots (2013)
• Coordinated and hosted by HAS, France
• HTA participants: AIFA, ASSR, IQWIG, GBA, NICE, HVB, CVZ, KCE/INAMI,
GYEMSZI, TLV and HAS
• EMA invited as observer
• All documents remain confidential (unless explicit company’s request)
• Various therapeutic fields
• Small and big companies
• One or 2-day FTF meeting (one product/day)
• Successful experience: improvement of collaboration between partners and
process efficiency
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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32. Additional ED (2014) EC Call for tender
In addition to EUnetHTA ED
• At least 10 EDs - 7 drugs and 3 MD/diagnostics/procedures
• At least 10 HTA organisations.
• Consortium HAS (lead) + 13 partners, selected by EC
• SEED: Shaping European Early Dialogues
• Regulators, payers, patient representatives as observers.
• Sustainable process to put in place, including collaboration with EMA
• Kick off meeting (D1): October 21, 2013
• Preliminary work :
˗procedures
˗Templates for BB (medicines, MD)
• All ED in 2014, interim report after 5 ED
• Model for permanent network at the end
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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33. Disease-specific guidelines for technology
developers
˗CER on the Treatment of Chronic Wounds (CMTP)
˗Green Park Collaborative (CMTP):
˗Alzheimer’s disease
˗PRO in oncology
˗Diagnostics
˗EUnetHTA Disease specific guidelines: initial and additional evidence
requirements to support effectiveness and cost-effectiveness
1st guideline: Osteoarthritis
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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34. ED and DSG integrate EUnetHTA reasoning
on endpoints and methodology of assessment
•
ED example FOR DISCUSSION: ALL
• Indication: locally advanced unresectable or metastatic pancreatic
adenoK 1st line
• XX+gemcitabine vs gemcitabine alone
• Superiority trial
• PE: OS
European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
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35. Acknowledgements
EUnetHTA partners (guidelines), Eric Abadie (regulatiry input),
Laurie Burke (FDA road map)
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