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Study of the NICE scientific advice between 2009 and 2015
Francois MAIGNENHead of operational research and data analyticsOHELondon • 5 October 2016
Analysis of NICE scientific advice between 2009 and 2015
4/10/2016 2
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).
Analysis of NICE scientific advice between 2009 and 2015
4/10/2016 3
Educational seminars for
Pharma, Medtech and
Cell Therapies
National Advice -Standard Process
NICE - MHRA
EMA - HTA
European
Joint HTA
National Advice -SMEs
NIC
E S
CIE
NT
IFIC
AD
VIC
E
Since
2009SEED & EUNetHTA
Analysis of NICE scientific advice between 2009 and 2015
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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.
Analysis of NICE scientific advice between 2009 and 2015
4/10/2016 5
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
Analysis of NICE scientific advice between 2009 and 2015
4/10/2016 6
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.
Analysis of NICE scientific advice between 2009 and 2015
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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
Analysis of NICE scientific advice between 2009 and 2015
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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.
Analysis of NICE scientific advice between 2009 and 2015
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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
Analysis of NICE scientific advice between 2009 and 2015
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Type of project
0
20
40
60
80
100
120
EMA-HTA EUNetHTA MHRA-HTA NICE Project NICE Project - Light SEED
Analysis of NICE scientific advice between 2009 and 2015
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Type of project per year
Analysis of NICE scientific advice between 2009 and 2015
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Therapeutic areas (scientific advice)
Alimentary tract and metabolism148%
Antiinfectives for systemic use7
4%
Antineoplastic and immunomodulating agents
4427%
Cardiovascular system20
12%
Musculo-skeletal system25
15%
Nervous system30
18%
Respiratory system106%
Sensory organs3
2% Alimentary tract and metabolism
Antiinfectives for systemic use
Antineoplastic and immunomodulating agents
Blood and blood forming organs
Cardiovascular system
Dermatologicals
Genito-urinary system and sex hormones
Musculo-skeletal system
Nervous system
Respiratory system
Sensory organs
Systemic hormonal preparations, excluding sexhormones and insulins
Analysis of NICE scientific advice between 2009 and 2015
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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%
Antiinfectives for systemic use
Antineoplastic and immunomodulating agents
Cardiovascular system
Diabetes
Immunological disorders
Mental health
Nervous system
7000 products currently under development (source: EFPIA Annual Review 2016)
Analysis of NICE scientific advice between 2009 and 2015
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Therapeutic class of the products authorised centrally between 2009 and 2015
ALIMENTARY TRACT AND METABOLISM
6112%
ANTIINFECTIVES FOR SYSTEMIC USE63
13%
ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
11823%
BLOOD AND BLOOD FORMING ORGANS
398%
CARDIOVASCULAR SYSTEM357%
MUSCULO-SKELETAL SYSTEM194%
NERVOUS SYSTEM77
15%
RESPIRATORY SYSTEM357% ALIMENTARY TRACT AND METABOLISM
ANTIINFECTIVES FOR SYSTEMIC USE
ANTINEOPLASTIC AND IMMUNOMODULATINGAGENTS
ANTIPARASITIC PRODUCTS, INSECTICIDES ANDREPELLENTS
BLOOD AND BLOOD FORMING ORGANS
CARDIOVASCULAR SYSTEM
DERMATOLOGICALS
GENITO URINARY SYSTEM AND SEX HORMONES
MUSCULO-SKELETAL SYSTEM
NERVOUS SYSTEM
RESPIRATORY SYSTEM
SENSORY ORGANS
Analysis of NICE scientific advice between 2009 and 2015
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Therapeutic class of the products appraised by NICE between 2011 and 2015
15
ALIMENTARY TRACT AND METABOLISM
116%
ANTIINFECTIVES FOR SYSTEMIC USE20
10%
ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
11560%
BLOOD AND BLOOD FORMING ORGANS
179%
CARDIOVASCULAR SYSTEM3
2%
NERVOUS SYSTEM6
3%
RESPIRATORY SYSTEM6
3%
ALIMENTARY TRACT AND METABOLISM
ANTIINFECTIVES FOR SYSTEMIC USE
ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
BLOOD AND BLOOD FORMING ORGANS
CARDIOVASCULAR SYSTEM
GENITO URINARY SYSTEM AND SEX HORMONES
MUSCULO-SKELETAL SYSTEM
NERVOUS SYSTEM
RESPIRATORY SYSTEM
SENSORY ORGANS
Analysis of NICE scientific advice between 2009 and 2015
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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 (?)
Analysis of NICE scientific advice between 2009 and 2015
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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%?)
Analysis of NICE scientific advice between 2009 and 2015
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Phase of development of the products when
advice was sought
N/A1
1%
Non-clinical4
2% Phase 125
15%
Phase 210463%
Phase 332
19%
N/A
Non-clinical
Phase 1
Phase 2
Phase 3
Analysis of NICE scientific advice between 2009 and 2015
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Phase of development for which the advice
was soughtCE analysis
1811%
Clinical development programme
64%
Phase 22
1%
Phase 2b1
0%
Phase 311569%
Phase 3b3
2%
Phases 1b & 32
1%
Phases 2/318
11%
Phases 2b/31
1%
CE analysis
Clinical development programme
Phase 2
Phase 2b
Phase 3
Phase 3b
Phases 1b & 3
Phases 2/3
Phases 2b/3
Analysis of NICE scientific advice between 2009 and 2015
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Status of development of the products
reached at the end of 2015
Phase 116
10%
Phase 256
34%
Phase 348
29%
Marketing authorisation application submitted
32%
CHMP Positive Opinion1
1%
Authorised8
5%
Authorisation refused3
2%
Failure22
13%
NICE Appraisal6
4%
Analysis of NICE scientific advice between 2009 and 2015
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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%)
Analysis of NICE scientific advice between 2009 and 2015
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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]
Analysis of NICE scientific advice between 2009 and 2015
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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]
Analysis of NICE scientific advice between 2009 and 2015
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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.
Analysis of NICE scientific advice between 2009 and 2015
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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’).
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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.
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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%.
Analysis of NICE scientific advice between 2009 and 2015
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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.
Analysis of NICE scientific advice between 2009 and 2015
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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.