OHE Lunchtime Seminar:Health Technology Assessment Scientific and Outcomes Advice on Medicinal Drug...

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

Leeza Osipenko

Email: [email protected]

www.nice.org.uk/scientificadvice

Twitter: @NICESciAdvice

NICE Scientific Advice

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 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

NIC

E S

CIE

NT

IFIC

AD

VIC

E

Since

2009SEED & 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 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


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%

Antiinfectives for systemic use


Cardiovascular system

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

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


4/10/2016 17

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

17


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


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/A1

1%

Non-clinical4

2% Phase 125

15%

Phase 210463%

Phase 332

19%

N/A

Non-clinical

Phase 1

Phase 2

Phase 3


4/10/2016 21

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


4/10/2016 22

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%


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 seminarLondon • 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 - overviewM

easu

rem

ent Collect

PRO data from

patientsA

nal

ysis Analyse

PRO data

Val

uat

ion Assign

utilities Mo

del 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.”

https://www.nice.org.uk/process/pmg9/chapter/the-reference-case

https://www.nice.org.uk/media/default/about/what-we-do/research-and-development/social-value-judgements-principles-for-the-development-of-nice-guidance.pdf


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.

https://www.nice.org.uk/process/pmg9/chapter/glossary#time-trade-off

http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-5d-5l-value-sets.html#c655


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.

https://www.ncbi.nlm.nih.gov/pubmed/22867780


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.

http://hqlo.biomedcentral.com/articles/10.1186/s12955-015-0356-8


4/10/2016 41

3L or 5L: Valuation

Panel 1: All unique “theoretical” EQ-5D-3L and EQ-5D-5L valuesPanel 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

chere.uts.edu.au

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 valuesMildest 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

chere.uts.edu.au


4/10/2016 44

0.5

11.5

2

De

nsi

ty

-.594 0 .5 1MVS-based EQ-5D-5L index values

Community Rehabilitation Patients

0.5

11.5

22.5

De

nsi

ty

-.281 0 .5 1EVS-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 (egcancers) 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!

http://www.slideshare.net/OHENews/age-utilities-and-selfreported-health-issues-for-hta


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)

http://mdm.sagepub.com/content/30/5/556

http://www.springer.com/gp/book/9781402055102


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).

http://onlinelibrary.wiley.com/doi/10.1002/hec.736/abstract

http://econpapers.repec.org/article/eeesocmed/v_3a165_3ay_3a2016_3ai_3ac_3ap_3a66-74.htm


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

http://www.ispor.org/Event/ProgramList/2016Vienna?type=IssuePane


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 [email protected], Francois Maignen [email protected], Professor Nancy Devlin at [email protected]

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OHE Lunchtime Seminar:Health Technology Assessment Scientific and Outcomes Advice on Medicinal Drug...

Presentations & Public Speaking