1. The document summarizes a study that explored how NICE recognizes innovation in end-of-life treatments through its guidance. 2. The results showed that treatments recommended by NICE had higher median and mean survival benefits compared to those not recommended, as well as longer patient life expectancies and durations of survival data available. 3. Key factors in NICE's decisions appeared to be the base case ICER, additional patient life expectancy provided by the treatment, and additional survival benefit relative to existing treatments.

1. 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

2. 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:
‘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)
1. NHS. Directions and Consolidating Directions to the National Institute for Health and Clinical Excellence. 2005 http://www.nice.org.uk/niceMedia/pdf/DirectionFromSecretaryOfState2005.pdf
2. National Institute for Health and Clinical Excellence. Guide to the methods of technology appraisal. June 2008.

3. 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
End of Life Criteria Definition
The treatment is licensed or otherwise indicated, for small patient
Rarity
populations
Alternative No alternative treatment with comparable benefits is available
treatment through the NHS
The treatment is indicated for patients with a short life expectancy,
Life expectancy
normally less than 24 months
There is sufficient evidence to indicate that the treatment offers an
Survival benefit extension to life, normally of at least an additional 3 months,
compared to current NHS treatment
1. National Institute for Health and Clinical Excellence. Appraising life-extending, end of life treatments. January 2009.

4. 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

5. 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
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6. Results: End of Life treatments
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
Second line advanced/metastatic renal cell carcinoma
Sorafenib £65,929 £65,929 -£368,830 Negative
(RCC)
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
Maintenance for advanced/metastatic non-small cell lung
Pemetrexed £47,000 £33,732 - £105,826 Positive
cancer (NSCLC)
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
Intermediate/high-risk myelodysplastic syndromes (MDS);
Azacitidine chronic myelomonocytic leukaemia (CML); acute myeloid £47,200 £32,823 - £71,522 Positive
leukaemia (AML)
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
†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

7. Results: Rarity
Estimated size of eligible patient population in UK 1
Positive decision
Negative decision
1. All data obtained from NICE Guidance documents for respective appraisal

8. Results: Life Expectancy
NICE estimate of patient prognosis
Pivotal Study Control Arm Survival 1
based upon expert advice1
Positive decision
1. All data obtained from NICE Guidance documents for respective appraisal Negative decision

9. Results: Survival Benefit
• Median and mean survival benefit was Ratio of survival benefit / control arm life survival 1
higher for those End of Life treatments
recommended by NICE compared with those
that were not recommended.
Survival gain Not
Recommended*
months Recommended*
Median 4.7 (7.35) 2.4 (3.5)
Mean 4.3 1.7
*Numbers in brackets account for adjustment for crossover
• 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

10. 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.

11. 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