This presentation details the role of European HTA bodies in the value of new cancer therapies in Europe. The presentation also describes the NICE scientific advice activities and the activities of the HTA / regulatory parallel advice.

1. © NICE 2019. All rights reserved. Subject to notice of rights.
NCCN Global Corporate Council
Determining Cancer Care Value in the
European Market: The Role of NICE and
Health Technology Assessment (HTA)
Agencies
Francois MAIGNEN, Principal Scientific Adviser,
NICE
September 26, 2019 – Barcelona

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The NICE portfolio in 2019

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Anticancer medicinal products
• Rising price of anticancer medicines observed in early 2000’s
• In the European Union, anticancer products fall under the
mandatory scope of the centralised procedure (Regulation EC No
726/2004)
• Orphan drugs regulation in the EU (Regulation EC No 141/2000)
Source: WHO Pricing of cancer medicines and its impacts. 2018 https://apps.who.int/iris/handle/10665/277190

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In 2017, the HAS issued the foll. ASMR …
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Therapeutic added value of new technologies
Source: HAS 2017 annual report.
https://www.has-sante.fr/portail/upload/docs/application/pdf/2018-07/has_rapport_activite_2017.pdf

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Do new anticancer medicines improve survival?
In their study of cancer drugs approved by
the European Medicines Agency between
2009 and 2013, 57% (39/68) had no
supporting evidence of better survival or
quality of life when they entered the
market. After a median of 5.9 years on the
market, just six of these 39 (15%) agents
had been shown to improve survival or
quality of life.
Surviva
l
Source: Prasad. BMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j4528 (Published 04 October 2017)
https://www.bmj.com/content/359/bmj.j4528

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Do new medicines improve quality of life?
In 2017, of the 45 new substances
authorised via the centralised procedure
40% of the products had evidence
on improved quality of life
Statement included in the SPC for
24% of the products
No statements included in the
patients leaflets

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Price regulation seem to lead to lower
prices
Source: Goldstein DA, Clark J, Tu Y, Zhang J, Fang F, Goldstein RM, et al. Global differences in cancer drug prices: a comparative analysis.
J Clin Oncol. 2016;34(18_suppl):LBA6500–LBA6500 in WHO Pricing of cancer medicines and its impacts. 2018 https://apps.who.int/iris/handle/10665/277190

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Anticancer medicines @ NICE
Source: Zamora et al. Routine Funding in the NHS in the UK of Medicines Authorised Between 2011 and 2016
via the European Centralised Procedure. November 2017.
https://www.ohe.org/publications/routine-funding-nhs-uk-medicines-authorised-between-2011-and-2016-european-centralised

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Anticancer medicines @ NICE
0
5
10
15
20
25
30
35
40
45
50
Published NICE technology appraisals in cancer
Updated: January 2019
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Key questions for NICE
How well does the technology work compared with established
practice in the health service?
How much does this course of action cost compared with
established practice in the health service?
Benefit
Cost
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Certainty of the ICER
HRQL inadequately captured
Innovative nature of technology
Non-health objectives of the NHS
Life extending treatment at the end of
life
£20,000
per QALY
£30,000
per QALY
£50,000
per QALY
Flexible decision making

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Challenges in evidence generation for NICE
• Adaptive designs (platform trials, group sequential
designs, seamless phase 2/3, etc.)
• Other master protocols (basket and umbrella trials)
• Not designed to inform clinical practice (based on
surrogate endpoints).
Novel trial designs
• Increasing number of single arm trials
• Biased historical comparisons (matched case-
control methods)
• Observational / real-world evidence
• Cross-over between arms
Fewer comparative
randomised clinical
trials
• Lack of long term phase 3 or phase 4 studies
conducted on clinical outcomes (survival)
• Increased uncertainty
Conditional approval
/ exceptional
circumstances
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Exciting and challenging times for HTA
Challenges
High costs
Uncertain long-term
benefits and adverse
effects
Timely patient access
while the evidence is still
emerging
Pipelines of novel (bio)pharmaceuticals and advanced therapy
medicinal products (ATMPs) with potential for major benefits – cures?
Immunotherapies /
Chimeric antigen
receptor T-cell
Gene therapies
Therapies
targeting
biomarkers
Combination
therapies
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Direct consequence
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UNCERTAINTY
PRICING
Patients Access Schemes (discounts) or
Conditional reimbursement decisions

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Cancer Drugs Fund (CDF)
The CDF launched in 2010 under the department of health as an
additional funding source for cancer drugs
 A way for patients to access anticancer medicines that would
not otherwise have been routinely available from the NHS.
However the fund was criticised....
 No patient outcome data was collected
 Multiple budget overspends
– Was this a good use of tax payer’s money?
– Were patient outcomes improved?

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Shortcomings of the first CDF
Outcomes
• No data collected
• Were patient
outcomes
improved?
• Was this good use
of taxpayers’
money?
0
50
100
150
200
250
300
350
400
450
500
2010-11 2011-12 2012-13 2013-14 2014-15 2015-16
Budget Cost
Affordability
£ millions
Total lifetime budget of £1.27 billionSource: House of Commons Committee of Public Accounts. Cancer Drugs Fund.
Twentieth Report of Session 2015–16. https://publications.parliament.uk/pa/cm201516/cmselect/cmpubacc/583/583.pdf

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• To provide faster access to new cancer
treatments
• Drive stronger value for money for taxpayers
• Address uncertainty about the effects of new
cancer treatments through data collection
• Offer a new fast-track route to the most
promising drugs when companies price
responsibly.
On 29 July 2016, a new approach to the appraisal and funding of
cancer drugs in England began operating in a partnership between
NICE and NHS England.
The objectives of the reformed CDF are:
Reformed CDF …future……
Source: NHS England. Cancer Drugs Fund. https://www.england.nhs.uk/cancer/cdf/

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NICE-approved drugs are funded sooner
Committee
meeting
Final
appraisal
determinati
on
published
Write FAD Appeal
period
Final
guidance
90
days
Old
system
New
CDF
*When any eligible cancer treatment is recommended (either routine commissioning
or via Cancer Drugs Fund [CDF]). The funding mandate applies sooner if
consultation is not required, and for EAMS drugs (30 days after publication)
No funding
Interim CDF funding for all positive guidance*
Funding
mandate
applies
Funding
available
Funding
available
Access is up to 8 months quicker

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Technology appraisals of oncology products
• Between March 2000 and Jan
2019, NICE published 240
technology appraisals on cancer
drugs.
• Since 2016, all new cancer drugs
and significant new licensed
indications for cancer drugs are
referred automatically to NICE for
appraisal.
151
31
19
69
9
0
20
40
60
80
100
120
140
160
NICE recommendations
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 72% of recommendations
for oncology products have
been positive

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Breakdown of decisions in published technology
appraisals for anti-cancer agents
Non-submissions and withdrawn recommendations have been excluded from
both analyses
12
4518
24
1
August 2016 to November 2018
No Yes CDF Optimised Only in research
59
107
12
8
March 2000 to July 2016

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PAS – Simple & Complex
• Discount on original
invoice
• All supplies
• Can be confidential
Simple
Discount
• Everything else
• Can be indication specific
• Cannot be confidential
Complex
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Cancer Drugs Fund recommendation criteria
2. Does drug have plausible potential to be
cost-effective at the current price, taking
into account end of life criteria?
1. Why is drug not recommended? Is it due
to clinical uncertainty?
3. Could data collection reduce uncertainty
4. Will ongoing
studies provide
useful data?
5. Is CDF data
collection
feasible?
Recommend enter CDF
and
Starting point: drug not recommended
for routine use
Indicate research question, required analyses and
number of patients in NHS in England needed to collect
data
 Not recommended
 Yes
 Yes
 Yes
 Yes
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What is a CDF recommendation
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NICE works with the Company, NHS England and Public
Health England to agree a time-limited Managed Access
Agreement comprised of 2 key components:
Managed access agreement
Commercial agreement
(CAA)
Data Collection Agreement
(DCA)

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The CAA and DCA: an overview
• Defines eligible population and the data that
must be collected to resolve committee
uncertainty
Data collection
agreement
(DCA)
• NICE CDF team produce a briefing note for
negotiation between NHSE and company
• Negotiation to bring range of plausible ICERs
to below the relevant cost effectiveness
threshold
• Agree to the CDF budgetary cap. £340 million
per year
• Overspend subject to proportional rebate
from companies
Commercial
agreement
(CAA)
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What outcome data is collected whilst a drug
is available on the CDF?
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Health
technology
appraisal
RCTs (phase
IIb/III)
Review of
health
technology
appraisal
Phase II single
arm
Observational
data
Observational
data
Ongoing trial
Managed access period

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How can industry help
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• Be transparent about clinical uncertainty, and its
impact on the ICER
• Identify potential data sources. Justify to
committee that this will resolve uncertainty
• Be prepared for further commercial negotiation
Identification of
CDF potential
of submissions
• Not engaging until after committee make a CDF
recommendation will lead to delays in FAD
publication
• Opportunities to engage with NHS England and
NICE CDF team
• No engagement is too early
Early
engagement

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NICE Scientific Advice can advise on:
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NS
A
Study
population
&
subgroups
Relevance
of
comparators
Acceptability
of endpoints
Relevant
patient
reported
outcomes
Resource
use and
cost data
Economic
modelling
approach
Other
sources of
data:
registries
etc.
Clinician
HTA expert
Health economist
Patient
Expert input:

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NICE Scientific Advice core services
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Standard or express
advice
NICE-EUnetHTA NICE-MHRA or
NICE-CADTH
Company submission Draft and Final Briefing
package
Draft and Final Briefing
package
Draft and Final Briefing
package
Clarification stage
(NICE)
Written Teleconference /
email/written
Written
Meeting Face-to-face
(3 hours)
Face-to-face (4 hours) Face-to-face
(3 hours)
Advice Full report Joint report or individual
parallel reports
Full report
(joint)
Optional clarification
stage (company)
Written - Written
Process length 18 weeks (standard)
12 weeks (express)
15 – 19 weeks 18 weeks

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Scientific Advice procedures
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Pre-clinical
• MHRA
• EMA
Phase I
• NICE
• EMA-
HTA
• MHRA-
NICE
Phase II
• NICE
• EMA-HTA
• MHRA
• EUNetHTA
• CADTH
Phase III
• Advice on
economics
/additional
data
generation
plans
• PRIMA
(NICE)
Phase IV
• PRIMA
(NICE)
• Advice on
economic
questions
When to seek scientific advice?
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It is important that advice is sought prior to plans being finalised

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NICE Scientific Advice so far …
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Planning regulatory and HTA pathway together
Stopping a
clinical trial for
futility is
scientifically
and ethically
justified
Stopping a
study for early
efficacy based
on an interim
analysis will
induce a bias in
the estimate of
the relative
efficacy
This will
increase the
uncertainty
(limiting the
available data
on OS)
Extrapolation
associated
with high
degree of
uncertainty
Uncertain
cost-
effectiveness
estimates
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33. © NICE 2019. All rights reserved. Subject to notice of rights.
Is It Useful? HTAB and Regulator Agreement
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Tafuri G et al. Br J Clin Pharmacol. 2016;82(4):965-73
77%
44%
59% 60% 59%
14%
25%
29%
19% 18%
9%
30%
12%
21% 23%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Population (n=112) Comparator (n=63) Endpoints (n=222) Other study design
characteristics (n=48)
Overall efficacy and
safety data package
(n=73)
Level of agreement for each domain: HTABs vs regulators (based on
31 procedures
n represents the total number of HTABs expressing an opinion for each domain
Full agreement Partial agreement Disagreement

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Issues to consider
Investigate management
of the condition and
variations between
countries
Review evidence
available on management
of the condition,
treatments and data on
efficacy, safety and use
of resources
If not available, try to
collect these data in
existing registries or
prospective observational
studies
Validate any outcomes
relevant for measuring
changes in the condition
and estimate their
relationship with health-
related quality of
life/survival
Characterise your
population and the most
appropriate place of
treatment within the
clinical pathway
Consider the data
needed to be collected to
support your value
proposition
Seek advice from
regulators and HTA
bodies on these plans!
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Conclusions
• Changing landscape in the development of new anticancer medicinal
products.
• Evidence gap and increased uncertainty on major endpoints used by
HTA to assess the relative effectiveness of new anticancer products:
survival and quality of life.
• High prices of new products.
• Increased use of conditional reimbursement decisions.
• Additional implementation and cost-effectiveness issues: genetic
profiling, tests (performance, reproducibility, centralisation, etc.).
• Importance of early engagement.
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36. © NICE 2019. All rights reserved. Subject to notice of rights.
Or contact us directly:
Francois MAIGNEN
Principal Scientific Adviser
Francois.Maignen@nice.org.uk
www.nice.org.uk/scientificadvice
Follow us on Twitter
@NICESciAdvice
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37. © NICE 2019. All rights reserved. Subject to notice of rights.
Links
Technology Appraisals Programme
https://www.nice.org.uk/about/what-we-do/our-programmes/nice-
guidance/nice-technology-appraisal-guidance
Office for Market Access
www.nice.org.uk/OMA
Cancer Drugs Fund
www.nice.org.uk/about/what-we-do/our-programmes/nice-
guidance/nice-technology-appraisal-guidance/cancer-drugs-fund
Scientific Advice
www.nice.org.uk/scientificadvice
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