NICE scientific advice between 2009 and 2015

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).


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


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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.


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


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.


4/10/2016 7

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completed / withdrawn have been excluded)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 8

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 9

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


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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


4/10/2016 11

Type of project per year


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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


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


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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


Cardiovascular system

Diabetes

Immunological disorders

Mental health

Nervous system

7000 products currently under development (source: EFPIA Annual Review 2016)


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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


CARDIOVASCULAR SYSTEM

DERMATOLOGICALS

GENITO URINARY SYSTEM AND SEX HORMONES

MUSCULO-SKELETAL SYSTEM

NERVOUS SYSTEM

RESPIRATORY SYSTEM

SENSORY ORGANS


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Therapeutic class of the products appraised by NICE between 2011 and 2015

15


116%

ANTIINFECTIVES FOR SYSTEMIC USE20

10%


11560%


179%

CARDIOVASCULAR SYSTEM3

2%

NERVOUS SYSTEM6

3%

RESPIRATORY SYSTEM6

3%


ANTIINFECTIVES FOR SYSTEMIC USE



CARDIOVASCULAR SYSTEM

GENITO URINARY SYSTEM AND SEX HORMONES

MUSCULO-SKELETAL SYSTEM

NERVOUS SYSTEM

RESPIRATORY SYSTEM

SENSORY ORGANS


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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 (?)


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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%?)


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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


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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


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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%


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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%)


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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]


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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]


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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.


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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%.


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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.


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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.

Health & Medicine

NICE scientific advice between 2009 and 2015