OHE Lunchtime Seminar:Health Technology Assessment Scientific and Outcomes Advice on Medicinal Drug Development: Current and Future Perspectives and Challenges

OHE Lunchtime Seminar:
Health Technology Assessment
Scientific and Outcomes Advice
on Medicinal Drug
Development:
Current and Future
Perspectives and Challenges

Leeza Osipenko
Email: Leeza.osipenko@nice.org.uk
 www.nice.org.uk/scientificadvice
Twitter: @NICESciAdvice
NICE Scientific Advice

Study of the NICE scientific
advice between 2009 and 2015
Francois MAIGNEN
Head of operational research and data
analytics
OHE
London • 5 October 2016

Analysis of NICE scientific advice between 2009 and 2015
4/10/2016 4
Medicinal product development and
scientific advice
• It becomes more and more difficult for
companies not to engage in early dialogue with
payers
• Some HTA bodies (e.g. NICE) offer a fee for
service scientific advice to companies:
• Exclusively on the issues which are under the
responsibilities of the HTA (i.e. quality, safety
are not addressed)
• Some HTA bodies also provide an advice on
the cost-effectiveness evaluations (NICE).

4/10/2016 5
Educational seminars for
Pharma, Medtech and
Cell Therapies
National Advice -
Standard Process
NICE - MHRA
EMA - HTA
European
Joint HTA
National Advice -
SMEs
NICESCIENTIFICADVICE
Since
2009
SEED & EUNetHTA

4/10/2016 6
NICE scientific advice process
• Companies submit a briefing book with their clinical
development plans
• Set out their proposal and ask a set of questions
(typically approx. 5-15)
• NICE supported by experts (clinicians from the NHS,
health economists, former committee members)
answer the questions (NICE does not address issues
which are not raised in the questions)
• Advice report including summary points (key
recommendations)
• Reference: NICE methods guide to technology
appraisals 2013.

4/10/2016 7
The idea behind the study …
New technology
Evidence of
effectiveness
Evidence on
costs & resources
Uncertainty
Appropriateness
(absence of biases,
generalisability)
Scientific
advice
C/E Model

4/10/2016 8
Primary objective
• Perform a descriptive overview of the
scientific advice given by NICE between
2009 and 2015 on medicinal products
under clinical development to understand
• The mechanisms by which companies seek scientific
advice and
• How HTA advice integrates and influences medicinal
product development.
• Two articles have been submitted to peer-reviewed
scientific journals.

4/10/2016 9
Materials and methods (1)
• Scientific advice relational database developed in ACCESS
• All the completed and ongoing advice given by NICE on medicinal
products development since 2009 until now (advice which were not
completed / withdrawn have been excluded)
• Status of the clinical development and phases of development for
which the advice was sought taken from the briefing books
submitted by Companies
• International non-proprietary name & current clinical development
taken from validated sources of information (regulatory clinical trials
databases e.g. ClinicalTrials.Gov), peer-reviewed and grey
literature and pipelines or statements published by Companies

4/10/2016 10
Materials and methods (2)
• Marketing authorisation status obtained from relevant
authorities (EC Community register, European
Medicines Agency EMA) or UK product information
(SPC). Orphan designation or Marketing Authorisation
in the EU
• Mapping of the therapeutic indication with ICD10 and
WHO ATC classification (1st level)
• Mapping of the questions and summary points with the
NICE methods guide
• Analysis performed until end 2015.

4/10/2016 11
Results
• A total of 166 scientific advice projects involved
medicinal products
• At least 122 products (73%) fall under the mandatory
scope of the centralised procedure (authorisation by the
European Commission following an opinion given by the
European Medicines Agency - Regulation No 726/2004)
because of:
• Chemical nature
• Indication
• Orphan designation

4/10/2016 12
Type of project
0
20
40
60
80
100
120
EMA-HTA EUNetHTA MHRA-HTA NICE Project NICE Project - Light SEED

4/10/2016 13
Type of project per year

4/10/2016 14
Therapeutic areas (scientific advice)
Alimentary tract and metabolism
14
8%
Antiinfectives for systemic use
7
4%
Antineoplastic and
immunomodulating agents
44
27%
Cardiovascular system
20
12%
Musculo-skeletal system
25
15%
Nervous system
30
18%
Respiratory system
10
6%
Sensory organs
3
2% Alimentary tract and metabolism
Antineoplastic and immunomodulating agents
Blood and blood forming organs
Dermatologicals
Genito-urinary system and sex hormones
Musculo-skeletal system
Nervous system
Respiratory system
Sensory organs
Systemic hormonal preparations, excluding sex
hormones and insulins

4/10/2016 15
Medicinal products under development
Antiinfectives for systemic use,
1415, 20%
Antineoplastic and
immunomodulating agents, 1813,
25%
Cardiovascular system, 599, 8%
Diabetes, 475, 7%
Immunological disorders, 1120,
15%
Mental health, 511, 7%
Nervous system, 1329, 18%
Antineoplastic and immunomodulating agents
Diabetes
Immunological disorders
Mental health
Nervous system
7000 products currently
under development
(source: EFPIA Annual
Review 2016)

4/10/2016 16
Therapeutic class of the products authorised
centrally between 2009 and 2015
ALIMENTARY TRACT AND
METABOLISM
61
12%
ANTIINFECTIVES FOR SYSTEMIC
USE
63
13%
ANTINEOPLASTIC AND
IMMUNOMODULATING AGENTS
118
23%
BLOOD AND BLOOD FORMING
ORGANS
39
8%
CARDIOVASCULAR SYSTEM
35
7%
MUSCULO-SKELETAL SYSTEM
19
4%
NERVOUS SYSTEM
77
15%
RESPIRATORY SYSTEM
35
7% ALIMENTARY TRACT AND METABOLISM
ANTIINFECTIVES FOR SYSTEMIC USE
ANTINEOPLASTIC AND IMMUNOMODULATING
AGENTS
ANTIPARASITIC PRODUCTS, INSECTICIDES AND
REPELLENTS
BLOOD AND BLOOD FORMING ORGANS
DERMATOLOGICALS
GENITO URINARY SYSTEM AND SEX HORMONES
NERVOUS SYSTEM
RESPIRATORY SYSTEM
SENSORY ORGANS

4/10/2016 17
Therapeutic class of the products appraised
by NICE between 2011 and 2015
17
ALIMENTARY TRACT
AND METABOLISM
11
6%
ANTIINFECTIVES FOR SYSTEMIC
USE
20
10%
ANTINEOPLASTIC AND
IMMUNOMODULATING AGENTS
115
60%
BLOOD AND BLOOD FORMING
ORGANS
17
9%
3
2%
NERVOUS SYSTEM
6
3%
RESPIRATORY SYSTEM
6
3%
ALIMENTARY TRACT AND METABOLISM
ANTIINFECTIVES FOR SYSTEMIC USE
ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
BLOOD AND BLOOD FORMING ORGANS
GENITO URINARY SYSTEM AND SEX HORMONES
NERVOUS SYSTEM
RESPIRATORY SYSTEM
SENSORY ORGANS

4/10/2016 18
Therapeutic areas: summary
- Most of the SA projects involve oncology products
- NICE projects mostly in neurological disorders (nearly half in
Alzheimer’s disease with products acting on the beta-amyloid
pathway)
- EMA-HTA dominated by oncology (mandatory scope of the
centralised procedure)
- Important differences between the proportion of the
therapeutic areas of the newly centrally authorised
products (CAPs), products appraised by NICE and the
therapeutic classes of the products for which an advice
was given by NICE
- Difficult to explain the pattern of therapeutic areas of
the products for which an advice is sought: reflects the
current pipeline (?)

4/10/2016 19
Orphan medicines
- 28 projects (17%) involved
products which had received an EU
orphan designation
- Anticancer agents represent 60% (17) of
these products
- Difficult to estimate the proportion
of orphan drugs among the
number of products under clinical
development (6%?)

4/10/2016 20
Phase of development of the products when
advice was sought
N/A
1
1%
Non-clinical
4
2% Phase 1
25
15%
Phase 2
104
63%
Phase 3
32
19%
N/A
Non-clinical
Phase 1
Phase 2
Phase 3

4/10/2016 21
Phase of development for which the advice
was sought
CE analysis
18
11%
Clinical development
programme
6
4%
Phase 2
2
1%
Phase 2b
1
0%
Phase 3
115
69%
Phase 3b
3
2%
Phases 1b & 3
2
1%
Phases 2/3
18
11%
Phases 2b/3
1
1%
CE analysis
Clinical development programme
Phase 2
Phase 2b
Phase 3
Phase 3b
Phases 1b & 3
Phases 2/3
Phases 2b/3

4/10/2016 22
Status of development of the products
reached at the end of 2015
Phase 1
16
10%
Phase 2
56
34%
Phase 3
48
29%
Marketing authorisation
application submitted
3
2%
CHMP Positive Opinion
1
1%
Authorised
8
5%
Authorisation refused
3
2%
Failure
22
13%
NICE Appraisal
6
4%

4/10/2016 23
Current development status
- SA: 1/3 of the products under clinical development
have progressed in their development
- Clinical development failed in 25 cases
- Clinical development stopped for 22 products
- Marketing authorisation refused in 3 cases
- Review of MA for 4 products
- 15 products (9%) have been authorised
- Phase 1: 13%, Phase 2: 47% and phase 3: 40%
(Short median follow-up: 3 years)
- ClinicalTrials.gov phase 1: 35%, phase 2: 35%,
phase 3: 30% (development 82%, authorised 18%)

4/10/2016 24
Odds of success (marketing
authorisation)
- The highest crude odds ratios of
success (defined as the granting of
a marketing authorisation)
compared with the other products
of our study:
- Dermatology OR 5.82 95CI [0.5; 68.26]
- Cardiovascular OR 3.32 95CI [0.94; 11.64]

4/10/2016 25
Odds of failure
- The highest crude odds ratios of failure
compared with the other products of our
study:
- Cardiovascular OR 3.29 95CI [1.13; 9.59]
- Neurological OR 1.79 95CI [0.65; 4.94]
- Musculo-skeletal OR 1.76 95CI [0.59, 5.22]
- Pulmonary OR 1.69 95CI [0.34; 8.48]

4/10/2016 26
Development status of the products
- Number of products which received a marketing
authorisation is increasing. Quite substantial despite short
follow-up time.
- Mostly via the centralised procedure (95%)
- 80% of the products which are authorised undergo a
NICE appraisal
- Attrition rate fairly high (15%)
- Not necessarily depends on when the advice was given
- Two products for which no appraisal is scheduled are me-
toos or copies of existing products (insulins and beta
agonist for asthma)
- Products for which the appraisal is scheduled are
potentially products of major interest.

4/10/2016 27
Areas of convergence and advice
The crude ORs for the issues addressed in the advice provided by NICE compared with issues raised by the companies in their
briefing books. The areas of likely agreement (ORs below 1) are highlighted in red. The areas likely disagreement (ORs above
1) are highlighted in green. ORs are presented with 95% CIs (the upper bounds are truncated to 10) (‘tt’ denotes ‘treatment’).

4/10/2016 28
Discussion
• This study provides some insight on the
issues that companies face when they
undertake the clinical development of
their products:
• How to integrate the HTA requirements into
their clinical development plans
• How HTA requirements can be integrated in
the regulatory process and requirement
• Gap between the regulatory and HTA
requirements is narrowing.

4/10/2016 29
Discussion
• The study also highlights the new approaches to the clinical
development of medicines aimed at generating evidence with
external validity (which can be generalisable to different types
of populations of patients e.g. NHS but not only)
• More atypical designs (single arm trials, observational
evidence addressed in 24% of the questions).
• Clinical trials.gov (Oct 2016): 182,000 interventional studies
incl. single arm trials 31% (55,000), non-randomised
studies: 16% (23,000), open-label 57% (100,000)
• Difficult to perform and interpret extrapolations between the
clinical trials endpoints and the endpoints relevant to NICE
(HRQL and survival)
• clinical trials.gov survival measured in 17% of trials and
HRQL in 10%.

4/10/2016 30
Discussion
• More and more innovative and
personalised medicines or medicines
developed in orphan indications.
• Products developed in orphan indications
represent now 50% of the products
newly authorised.

4/10/2016 31
Conclusions
• First evaluation on HTA scientific advice
and how companies try to accommodate
HTA requirements
• Provides a new insight on the clinical
development of medicines with efforts
made to improve the generalisability of
evidence
• Future issues: new designs, atypical
developments.

Issues in measuring and valuing
HRQoL in HTA
Professor Nancy Devlin
OHE lunchtime seminar
London • October 5th 2016

4/10/2016 33
Disclaimer
Views expressed in this presentation are my own,
and do not necessarily represent the views of
NICE, the EuroQol Group or the Office of Health
Economics.

4/10/2016 34
Contents
• HRQoL in HTA: an overview
• The NICE reference case
• Selected issues:
• 3L or 5L?
• The problem of healthy patients
• Including utilities in sensitivity analysis
• Is there a role for patients’ utilities?
• Health and social care outcomes
• Is HRQoL data strictly comparable?
• HRQoL in children
• Concluding remarks

4/10/2016 35
HRQoL in HTA - overviewMeasurement
Collect
PRO data
from
patients Analysis
Analyse
PRO data
Valuation
Assign
utilities
Model
Populate
cost-
effectiveness
model
What instruments to
select?
Patients or proxies?
How frequently to
seek measurements?
How to analyse and
report patients’ data?
Which utilities to
use?
Whose
preferences?
What utilities to use
beyond the clinical
trial?
How to reflect
uncertainty?

4/10/2016 36
The NICE reference case
NICE approach to HTA described in two key documents:
• Methods guide (2013 – updated approx. every 5 years)
• Social value judgements (2008)
Key issue:
• “For the cost-effectiveness analyses health effects should
be expressed in QALYs. For the reference case, the
measurement of changes in health-related quality of life
should be reported directly from patients…The EQ-5D is
the preferred measure of health-related quality of
life in adults.”

4/10/2016 37
The role of the EQ-5D
• The EQ-5D an important ‘common denominator’ for cost
effectiveness studies
• if the goal is allocative efficiency across the health care
budget, important that ‘benefit’ be measured in a consistent
way across repeated decisions (and that benefit foregone is
considered in those same terms).
• Condition specific measures provide detailed information on
specific health problems that effect QoL.
• Can help identify whether the EQ-5D may be failing to
capture any important health effects.
• Good practice: collect both a generic PRO (such as EQ-5D)
and a condition specific PRO. Provide complementary
evidence.

4/10/2016 38
Source of utilities for estimating
QALYs
“A set of preference values elicited from a large UK population
study using a choice-based method of valuation (the time
trade-off method) is available for the EQ-5D health state
descriptions.” (NICE 2013)
• Sources of utilities:
(a) value sets
(b) where EQ-5D data are not available, ‘mapping’ from
another instrument to the EQ-5D, and using EQ-5D value
sets
• The MVH (Dolan 1997) value set for EQ-5D has been very
widely used in the UK and internationally, despite known
problems.

4/10/2016 39
EQ-5D-5L and utilities in HTA
“The EQ-5D-5L may be used for reference-case
analyses… but no valuation set to derive utilities currently
exists…the validated mapping function to derive utility
values for the EQ-5D-5L from the existing EQ-5D (-3L)
may be used” (NICE 2013)
• Crosswalk value set for the 5L (van Hout et al 2013).
• Shares many of the characteristics of the MVH value set
(because it uses that value set)
• The new 5L value set for England (Feng et al 2016; Devlin
et al 2016) has quite different characteristics. Implications
for HTA?
• The status of the EQ-5D-5L and value set will (presumably)
be considered in NICE’s next methods review.

4/10/2016 40
3L or 5L? Measurement
• The 5L version of EQ-5D led to a considerably reduced
ceiling effect and a larger proportion of respondents
reporting severe health problems compared to the 3L.
• The 5L version yields a wider spread of health states; just 3
health states on the 3L account for 75% of the sample,
compared to 12 states on the 5L.
Feng Y, Devlin N, Herdman M.
(2015) Assessing the health of
the general population in
England – how to the 3L and 5L
compare? Health and Quality of
Life Outcomes.

4/10/2016 41
3L or 5L: Valuation
Panel 1: All unique “theoretical” EQ-5D-3L and EQ-5D-5L values
Panel 2: All unique “theoretical” Crosswalk and EQ-5D-5L values
Coming soon: Mulhern B, Feng Y, Shah K, van Hout B, Janssen B,
Herdman M, Devlin N. Comparing 3L and 5L value sets: implications for
HTA in England and UK. OHE Research Paper (forthcoming).
All unique theoretical
values

4/10/2016 42
EQ-5D-3L value set
(MVH)
EQ-5D-5L crosswalk EQ-5D-5L value set for
England
Value range 1 to -0.594 1 to -0.594 1 to -0.281
Health states valued as
worse than dead
34.6%
(84 out of 243)
26.7%
(833 out of 3,125)
4.9%
(154 out of 3,125)
Dimension importance 1. Pain/discomfort
2. Mobility
3. Anxiety/depression
4. Self-care
5. Usual Activities
1. Pain/discomfort
2. Mobility
4. Self-care
5. Usual Activities
1. Pain/discomfort
3. Mobility
4. Self-care
5. Usual Activities
Selected values
Mildest state
11211*
Intermediate state
22222 (3L) / 33333 (5L)
Worst state
33333 (3L) / 55555 (5L)
0.883
0.516
-0.594
0.906
0.516
-0.594
0.951
0.627
-0.281

4/10/2016 43
Comparing change in adjacent states
• EQ-5D-5L:
• Largest change from severe to moderate problems,
and slight to no problems.
• Crosswalk:
• Largest change from extreme/unable to severe (linked
to N3 term)
• Change from slight to no problems is larger than EQ-
5D-5L value set.
• EQ-5D-3L:
• Change in adjacent states across all five dimensions is
substantially larger

4/10/2016 44
0
.5
1
1.5
2
Density
-.594 0 .5 1
MVS-based EQ-5D-5L index values
Community Rehabilitation Patients
0
.5
1
1.5
2
2.5
Density
-.281 0 .5 1
EVS-based EQ-5D-5L index values
Community Rehabilitation Patients
• The value sets effects the distribution of the EQ-Index in
patient data
Coming soon: Feng Y, Devlin N, Bateman A, Zamora B, Parkin D. (2016) The
distribution of the EQ-5D-5L Index in patient data. OHE Research Paper
(forthcoming).

4/10/2016 45
Measurement + valuation?
• Although there are important differences
between the value sets, the impact on quality-
adjusted life years (QALYs) gained is unclear as
they will apply to both control and intervention
groups.
• The increased sensitivity of the EQ-5D-5L may
favour QALY gains even if the changes in utility
are smaller.

4/10/2016 46
The problem of ‘healthy patients’
• Instances where patients with severe conditions (eg
cancers) report average QoL at baseline higher than that
of the relevant UK age/sex population norms.
• NICE committees have occasionally questioned the
credibility utilities/trial data; leading to ‘adjustment’
of utilities in models.
Example:
• NICE TA343: “The Committee agreed that it was not
plausible that the utility value for progression free
survival off treatment was higher than the utility
value for members of the general public without
the disease”

4/10/2016 47
How might this arise?
• ‘Population norms’ (especially for older age groups where
cancer prevalent) aren’t ‘healthy’ comparators: they
contain people with illnesses and co-morbidities.
• Heteroskedasticity: the variance in health increases with
age; outliers (very poor health) drag the population norm
mean down.
• Cancer patients may be very well managed?
• Adaptation?
• EQ-5D insensitive…?
• Further research on these issues is required.
• New population norms required for both 5L and 3L –
current ones two decades old!

4/10/2016 48
Including utilities in sensitivity
analysis
• Each value set has its own properties (the weight attached to
dimensions and levels and interactions)
• Use of a value set introduces exogenous source of variance
(variance that does not come from the data patients have provided)
– Parkin, Rice, Devlin (2010)
• In future – may be more than one value set available eg. England
and UK 5L value set
• For any given value set, the utilities are a product
of researcher judgements about (a) what methods
were used to elicit preferences, and (b) how to
model them.
• Important to check sensitivity of QALYs gained to
(a) confidence intervals/standard errors around
point estimates (b) choice of value set (Devlin and
Parkin 2007)

4/10/2016 49
Is there a role for patients’ utilities?
• This is a normative question ie. involves a value judgement.
• NICE requires use of general public values
• Reasoning: the general public are taxpayers; it is both patients
and potential patients whose values should be considered.
• Alternative views:
• Sub-population values may differ and should be taken into
account eg. the elderly may have different view about the
importance of the 5 dimensions than the general public
(Sculpher and Gafni 2001)
• Patients: some HTA organisations prefer use of experience-
based values of patients (eg Sweden’s TVLA). Growing
support for at least considering these alongside general
population values (e.g. Versteegh and Brouwer 2016).

4/10/2016 50
Health and social care outcomes
• Integration between health and social care a key
consideration for the NHS, and therefore for NICE.
• EQ-5D a measure of ‘health status’ or ‘health-
related QoL’.
• Can it also capture the problems experienced by
those with social care needs – and the benefits of
social care?
• Alternative outcomes tools exist specifically for use
in social care eg. ASCOT and ICECAP.
• An ‘exchange rate’ required between the two? A
composite measure?

4/10/2016 51
Is HRQoL data strictly comparable?
• PRO data often collected in global trials
• Data pooled – assumes strict comparability
• Issues with conceptual and semantic differences –
may not always be overcome in translation
• Cultural differences in self-completion
• Heterogeneity and sub-group differences
• For more on this, come to Issues panel no. 17,
ISPOR European Congress, Vienna.
IP17: CAN WE REALLY COMPARE AND AGGREGATE PATIENT REPORTED OUTCOME DATA
BETWEEN PEOPLE AND SETTINGS? IMPLICATIONS FOR CLINICAL TRIALS AND HEALTH
TECHNOLOGY ASSESSMENT

4/10/2016 52
HRQoL in children
NICE: “consideration should be given to alternative standardised
and validated preference-based measures of health-related
quality of life that have been designed specifically for use in
children. The standard version of the EQ-5D has not been
designed for use in children. An alternative version for children
aged 7–12 years is available, but a validated UK valuation set is
not yet available” (NICE 2013).
• Challenges in obtaining PRO data - proxy completion.
• Challenges in valuation:
• Whose values? Adult general public? Valuing states from
what perspective (their own? A child’s?)
• What methods: EuroQol pilot study suggests TTO
problematic: people reluctant to trade off length of life for
children = high values.

4/10/2016 53
Concluding remarks
• >30 years of research on measuring and
valuing HRQoL for HTA
• Yet fundamental questions remain, both
normative and empirical.
• Considerable scope remains for improving the
way HRQoL data are collected, analysed and
used in HTA.

4/10/2016 54
For enquiries relating to this presentation, please contact Dr Leeza
Osipenko Leeza.Osipenko@nice.org.uk, Francois Maignen
fmaignen@ohe.org, Professor Nancy Devlin at ndevlin@ohe.org
To keep up with the latest news and research, subscribe to our blog, OHE News
Follow us on Twitter @OHENews, LinkedIn and SlideShare
Office of Health Economics (OHE)
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OHE Lunchtime Seminar:Health Technology Assessment Scientific and Outcomes Advice on Medicinal Drug Development: Current and Future Perspectives and Challenges

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