Assessing innovation of end-of-life treatments appraised by NICE

Presenting Author: Adam Hutchings1

Co-Authors: Michael Harris2, Louisa Pericleous2, Anthony Batty3, Andrew Briggs4, Anne Prenzler5, Michael Lees2, Max Lebmeier2

1. GMAS, London, UK 2. Bristol-Myers Squibb, Uxbridge, UK 3. Bresmed, Sheffield, UK 4. University of Glasgow, UK 5. University of Hannover, Germany

Background (1)

• European governments have created sophisticated rules, assessment mechanisms and negotiation processes to determine the selling terms of new medicines.

• These systems constitute a ‘reward framework’ to incentivise manufactures to research drugs of value to society

• Innovation is frequently considered to be a key attribute to be encouraged

• In the UK, encouraging innovation is part of the remit of NICE1

• NICE has stipulated that higher ICER thresholds are acceptable for ‘step-change’ innovations2:

1. NHS. Directions and Consolidating Directions to the National Institute for Health and Clinical Excellence. 2005 http://www.nice.org.uk/niceMedia/pdf/DirectionFromSecretaryOfState2005.pdf2. National Institute for Health and Clinical Excellence. Guide to the methods of technology appraisal. June 2008.

‘The innovative nature of the technology, specifically if the innovation adds

demonstrable and distinctive benefits of a substantial nature which may

not have been adequately captured in the QALY measure.’ (NICE

Methods Guide)

Background (2)

• This is evident in NICE’s ‘End of Life’ guidance issued in 20091

• In situations where all of the criteria described below are met, Appraisal Committees can chose to recommend the use of treatments outside the Institute’s normal ICER threshold

1. National Institute for Health and Clinical Excellence. Appraising life-extending, end of life treatments. January 2009.

End of Life Criteria Definition

RarityThe treatment is licensed or otherwise indicated, for small patient populations

Alternative treatment

No alternative treatment with comparable benefits is available through the NHS

Life expectancyThe treatment is indicated for patients with a short life expectancy, normally less than 24 months

Survival benefitThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared to current NHS treatment

Study Objectives

1. To explore how in practice NICE has recognised innovation within the End of Life guidance

2. To identify which aspects of innovation NICE is rewarding within the End of Life guidance

3. To examine the nature of the relationship between the appraisal decision and the degree to which products are deemed to meet the End of Life criteria

Study Methods

• Review of all End of Life drugs appraised by NICE between January 2009 until April 2012

• Data for each criteria collected for each drug from NICE Guidance documents

Metric

Rarity • Number of eligible patients in England and Wales

Alternative treatment

• The availability of alternative treatments for the disease in question as considered by Appraisal Committee

Life expectancy

• Survival time in months seen in the control arm of the pivotal study

• Appraisal committee estimate of survival time based upon expert advice

Survival benefit• Median survival benefit from pivotal clinical trial

• Mean survival benefit estimated from Kaplan-Meier curves

Other variables

• Ratio of survival benefit to control arm survival

• Most plausible ICER

• Duration of study data

Drug Indication Base Case ICER ICER Range‡ NICE Decision

Sunitinib First line advanced/metastatic renal cell carcinoma (RCC) £49,300 £49,300 - £105,000 Positive

Lenalidomide Relapsed/refractory multiple myeloma (MM) £43,800 £ 22,589 - £69,000 Positive

SorafenibSecond line advanced/metastatic renal cell carcinoma

(RCC)£65,929 £65,929 -£368,830 Negative

Temsirolimus First line advanced/metastatic renal cell carcinoma (RCC) £102,000 £49,690- £253,443 Negative

Sunitinib Gastrointestinal stromal tumours (GIST) £31,800 £27,365 - £90,500 Positive

Topotecan (oral) Second line relapsed small cell lung cancer (SCLC) £33,851 £26,833 - £33,900 Positive

Trabectedin Second line advanced soft tissue sarcoma (STS) £34,500 £28,712 – £80,000 Positive

Sorafenib First line advanced hepatocellular carcinoma (HCC) £52,600 £28,105 - £76,592 Negative

PemetrexedMaintenance for advanced/metastatic non-small cell lung

cancer (NSCLC) £47,000 £33,732 - £105,826 Positive

Ofatumumab* Relapsed/refractory Chronic lymphocytic leukaemia (CLL) £60,500 £24,635 - £81,500 Negative

Trastuzumab First line IHC3+ metastatic gastric cancer (GC)† £45,000 £37,180 to £99,797 Positive

Pazopanib Advanced renal cell carcinoma (RCC) £38,900 £21,625 to £72,274 Positive

AzacitidineIntermediate/high-risk myelodysplastic syndromes (MDS); chronic myelomonocytic leukaemia (CML); acute myeloid

leukaemia (AML)£47,200 £32,823 - £71,522 Positive

Everolimus Second line renal cell carcinoma (RCC) £51,700 £33,749- £253,051 Negative

Trabectedin* Relapsed, platinum-sensitive ovarian cancer (OC) £94,800 £24,869 - £113,432 Negative

Ipilimumab Malignant melanoma (MMel) £59,456 - TBC

Results: End of Life treatments

†IHC3 positive patients only; *Trabectedin in OC and Ofatumumab in CLL were – considered ‘marginal’ for fulfilling End of Life criteria when interpreted strictly; ‡ Range of plausible ICERs under different scenarios quoted by NICE in guidance

Results: Rarity

Negative decision

Positive decision

Estimated size of eligible patient population in UK1

1. All data obtained from NICE Guidance documents for respective appraisal

Results: Life Expectancy

Negative decision

Positive decision

Pivotal Study Control Arm Survival1NICE estimate of patient prognosis based upon expert advice1

1. All data obtained from NICE Guidance documents for respective appraisal

Results: Survival Benefit

• Median and mean survival benefit was higher for those End of Life treatments recommended by NICE compared with those that were not recommended.

• Survival benefit relative to control survival appeared to show a relationship with NICE decision

• Adjusting for patient crossover created greater uncertainty around survival benefit

*In trials where patients didn’t cross between treatment arms

Survival gain months

Recommended*Not

Recommended*

Median 4.7 (7.35) 2.4 (3.5)

Mean 4.3 1.7

*Numbers in brackets account for adjustment for crossover

Ratio of survival benefit / control arm life survival1

Results: Other Variables

• Availability of alternative treatments: all End of Life treatments met criteria, even when existing treatments available (e.g pazopanib and sunitinib)

• Duration of survival data available at the time of the NICE appraisal varied from 10 months (everolimus) to 56 months (ipilimumab).

• Duration of data at the time of NICE appraisal appears potentially relevant to the decision, with those recommended by NICE having an average of 43 months of data at the time of the appraisal vs 22 months for those rejected.

• Trial design and comparator choice were not obviously associated with NICE appraisal decision: of the two treatments with only uncontrolled data, one had been accepted (trabectedin in STS) and one rejected (ofatumumab).

• A strong association was seen between the ICER level and the NICE decision, with products with ICER > £50,000 per QALY more likely to be rejected than those with ICERs <£50,000.

Conclusions and Discussion

• End of Life guidance recognises innovation and informs on the elements that constitute innovation

• NICE currently taking dichotomous approach to End of Life criteria, with no evident relationship between the extent to which drugs meet the criteria and the ICER threshold

• Rarity and availability of alternative treatments appear less important in determining decision

• Criteria that appear most important in determining decision are:

– Base case ICER

– Life expectancy in patient population

– Additional survival benefit

• Relative survival benefit – additional survival over control arm survival – also appeared to show a trend between those products that were accepted versus rejected