- The NHS reforms have established new structures including NHS England which commissions clinical services and is accountable for improving outcomes as outlined in the NHS Outcomes Framework. - The framework includes overarching indicators related to preventing premature death, enhancing quality of life for people with long-term conditions, helping people recover from episodes of ill health or injury, and ensuring that people have a positive experience of care. - The new system aims to improve quality, outcomes and experience of care but also faces challenges in coordinating services across new organizational boundaries and ensuring the needs of patients with long-term conditions like MS remain a priority.

2. Trials in Secondary progressive
multiple sclerosis
design & efficiency
Jeremy Chataway
Queen Square MS Centre
National Hospital for Neurology and
Neurosurgery, UCLH, London

3. The talk
1. What is Progression?
2. How would an anti-progressive drug be
found?
3. What outcome would be measured?
4. What trial design could/would be used?
5. Where are we now?

4. Symptoms
• Eye problems
Double vision
Balance
Bladder
Fatigue
•Weakness

5. What’s going on?

6. Cum. Probability of Relapse
RR stage almost containable?
0.6
Hazard ratio = 0.50
P<0.0001
0.5
Avonex +
Placebo
0.4
Avonex +
Natalizumab
0.3
0.2
0.1
0.0
Alemtuzumab
0
12
24
36
Weeks
48
60
Number of Patients at Risk
582
589
474
528
401
483
339
437
235
307
118
170

7. Many new drugs here/coming very
soon
•
•
•
•
•
Prevention of T cell circulation and transmigration
– Natalizumab
– Fingolimod
Anti-metabolities
– Teriflunomide
– Cladibrine [Phase III completed]
Leukocyte depletion
– Alemtuzumab
– Daclizumab [Phase III]
B-cell directed therapies
– Ocreluzimab [Phase III]
Oral drugs with ambiguous mechanism
– Laquinomod
– Fumarate

8. Playing the long game
>60%
MS Onset
30ys
SPMS onset
45-50yrs

9. The progression

10. In MS? - Say walking
Primary/Secondary

11. ECTRIMS 2013-can we define SPMS
early: MSBase n~3550/21000; median
8-9yrs follow-up
•
•
•
D1) Physician designation
D2) first EDSS of 4 or more
D3) first EDSS of 3 or more associated with at least one 1-point
EDSS progression event within the 2 years prior to this onset date
• Identification of SPMS phase by physicians
occurs 4 to7 years later when compared with
pure EDSS based definitions
• Physician designation of SPMS is more specific
than EDSS-based definitions, but occurs later

12. Predictors of progression
Up to EDSS 4.0
–
–
–
–
–
Older age of onset
Cord onset>brainstem>visual/sensory
Incomplete recovery from initial index event
?early second event
?frequency of attacks first 2-5 yrs
• From EDSS 4.0
– Unclear
• Not as clear as you might think!

13. SPMS pathology
Demyelination
Neuronal/
Axonal loss
Gliosis
Trapp Lancet Neurology 2009

14. Mechanisms
• Oligodendrocyte loss/demyelination
• Energy failure
• Reactive oxygen/nitric oxide species
• Excitotoxicity

15. Trials
a rough guide

17. Words
•
•
•
•
What’s a trial
Placebo
Phase
Randomisation

18. Doing a trial (running a race)
• Runners & riders [drugs]
• Course [eg 2-3 years]
• Measure [eg MRI/disability]

20. Two horse race

21. What’s a placebo?

22. Early stage: beta-interferon

23. What’s a phase?

24. Randomisation

25. Doing a trial in SPMS
1. Runners & riders [drugs]
2. Measure [outcome]
3. Course type [length/time]

26. 1.Find a drug

27. Find a drug-animal data

28. Find a drug?

29. Find a drug - human

30. Ibudilast

31. Riluzole
• Phase IIa: 16 patients with Progressive MS were studied
1 year before treatment, followed by riluzole 50mg bd for
1 year.
• Primary outcome was change in cervical spinal cord
cross-sectional area that showed a reduction from -2%
(yr 1) to -0.2% (yr 2).
• In addition the increase in T1 hypointense lesion load
was reduced from 15% in year 1 to 6% in year 2
• and reduction in whole brain parenchymal/intracranial
volume went from -1.0% (yr 1) to -0.7% (yr2).
Killestein J, Kaljers NF, Polman CH, et al. Glutamate inhibition in MS: the neuroprotective properties of riluzole.J Neurol Sci 2005;233:113–115

32. Amiloride

33. 2.Measuring what you’ve done
• Clinical
– EDSS
– MSFC
– MSIS29
– MSWS
• Surrogate

34. EDSS – problem child

35. MRI in Progressive Disease
Whole brain segmentation
in Native Space
3D rendered image
Whole brain
volumes generated
•
Then repeat and screening scans are registered using a 12dof affine registration.
– Linear transformation (rotation, translation, scaling and shear) to spatially align repeat
scan to the baseline scan.
•
This registration step allows for the automatic quantification of longitudinal changes with
the BSI (Boundary Shift Integral).

36. Baseline

37. Registered Year 2

38. Screening showing
BBSI colour overlay

39. Novel MRI methods

40. 3.Course design

41. Repeatedly negative (n~5000)

42. Big money!: Dirucotide (MBP)
• ‘BioMS Medical terminates exclusive
licensing agreement with Eli Lilly for
dirucotide’

43. Lessons learnt

44. Lamotrigine-pseudoatrophy
CCV linear over time with modelled pivot at 6months
Monthly mean EDSS
by tablet compliant comparison
260000
by ITT comparison
6.4
255000
EDSS (score)
CCV
6.2
250000
245000
6
5.8
-6
0
6
e6_months
12
Active
18
5.6
24
Placebo
57
61
56
56
57
54
56
49
57
52
0
240000
6
12
month
18
24
Active
Placebo
Bars show standard error around mean
Numbers of valid monthly observations shown
Monthly mean TWT
by ITT comparison
.1
TWT (1/sec)
.09
.08
A.
.07
61
57
56
56
54
56
49
55
52
56
0
.06
6
12
month
18
24
Active
Bars show standard error around mean
Numbers of valid monthly observations shown
Kapoor
Placebo
B.
C.

45. CUPID
12 month follow-up (80%)
To finish….
And can turn out negative (phase III): 2013

46. We need this in SP/PPMS

47. Multi-arm Multi-stage (MAMS)

49. Multi-arm (Multi-stage)
STAMPEDE

50. Dropping and adding

51. Adaptive trial designs
•
•
•
•
•
•
•
•
•
•
Adaptive randomization design
Group sequential design
Flexible sample size re-estimation design
Drop-the-losers (play-the-winner) design
Adaptive dose finding design
Biomarker-adaptive design
Adaptive treatment-switching design
Adaptive-hypotheses design
Seamless adaptive trial design
Multiple adaptive design

52. MS Trial Design
e.g. Design for 4 test treatments and 1 control (placebo)
1
4 Phase 2
2
Trials
3
2 Phase 3
Trials
Stage 1 cohort
Chataway J et al: A novel adaptive design strategy increases the efficiency of clinical trials
in secondary progressive multiple sclerosis. Multiple Sclerosis 2011; 17: 81-8
52

53. Linkage
F
I
MRI
0
EDSS
0
6
12
Δ MRI
18
24
30
Crucial data
Interim
36

54. Embracing Repurposing

55. Advantages
• Drug known in detail eg AE
• Better phase II [25% vs 10%] and phase
III success [65% vs 50%] than new
molecular entities
• Cost

56. Examples

57. Trial Design
Our Work for 2014!
Stage 2 cohort
e.g. Design for 4 test treatments and 1 control (placebo)
1
3 Phase 2
2
Trials
3
2 Phase 3
Trials
Stage 1 cohort
57

58. Primary Objective
 Volumetric MRI (Siena)
Secondary Objectives
 Disability (EDSS/MSIS29v2/MSFC/MSWSv2/SDMT/SLCVA)
 EQ5D
 New/enlarging lesions T2 MRI
 Pseudoatrophy
 Relapses
 Neuropathic pain
 Safety

59. Patient Flow
0
6m
2yr
1yr
-30d
EDSS
EDSS
MSIS29v2
MSIS29v2
MSIS29v2
MSFC
MSFC
MSFC
MSWSv2
Safety
EDSS
MSWSv2
MSWSv2
1 2
3
6
9
1yr
1.5yr
2yr

60. 440 people
SPMS
UK

61. Inclusion Criteria







Confirmed diagnosis of SPMS at randomisation
Steady progression rather than relapse major cause of increasing disability
in the preceding 2 years (Progression evident from either an increase of at
least one point in EDSS or clinical documentation of increasing disability)
Expanded Disability Status Scale (EDSS) 4.0-6.5
Aged 25 to 65
Men or Women of childbearing age must be using an appropriate method of
contraception from time of consent, to 6 weeks after treatment
Females - negative pregnancy test (as applicable)
Willing and able to give full written informed consent
Able to undertake MRI

62. Exclusion Criteria
•
•
•
•
•
•
•
•
•
•
Significant organ co-morbidity (e.g. malignancy/ renal or hepatic failure)
Routine screening blood values
Relapse within 3 months of baseline visit
Patients who have been treated with iv or oral steroids within 3 months of
baseline visit
commencement of Fampridine within 6 months of baseline visit
Use of immunosuppressants, disease modifying treatments within 6 months
of baseline visit
Use of fingolimod/fumarate/teriflunomide/laquinomod/or other experimental
disease modifying treatment (including research of an investigational
medicinal product) within 12 months of baseline
Use of mitoxantrone/ natalizumab/ alemtuzumab/ daclizumab if treated
within 12 months of baseline visit
Use of: lithium, chlorpropamide, triamterene, spironolactone
Use of potassium supplements

63. Exploratory Outcomes





Advanced MRI
T1hypointensity
GM
MTR
MRS
Cervical cord
 OCT
 CSF Neurofilament levels

64. Centres
Glasgow
Edinburgh
Newcastle
Sheffield
Liverpool
Nottingham
North
Staffordshire
Oxford
London – 3 sites
TTT
UCLH, Barts & the
London, Imperial
T
Truro
T
T
Plymouth
Brighton/Haywards H

65. Meanwhile
MS-STAT trial
High dose oral Simvastatin
in Secondary Progressive Multiple Sclerosis
Jeremy Chataway
for the MS-STAT Collaborators
CTN:NCT00647348
EUDRACT NUMBER 2006-006347-31

66. Institutions
•
Clinical Assessments: Imperial College Healthcare NHS Trust,
UCLH NHS Foundation Trust, Brighton and Sussex University
Hospitals NHS Trust
•
•
MRI analysis: Institute of Neurology, University College London;
London School of Hygiene and Tropical Medicine,London
•
Queen Square MS Centre, University College London
•
Immunology: Institute of Ophthalmology, University College London
•
Proteomics: Imperial College,London
•
Neuropsychology: Brighton and Sussex University

67. People
Clinical Fellows: Ali Alsanousi, Imran Saddiqi, Rosella Padama, Paulo Giannetti,
Miriam Mattoscio
Trial Managers: David Wilkie, Bella Polito, Jennifer Siegel
Trial Pharmacists: Lucy O’Driscoll, Stephanie Steadman
MRI: Philippa Bartlett, David MacManus, Kelvin Hunter, Val Anderson, Jo Foster
Shona Clegg, Casper Nielsen, Ged Ridgway, Mark Whalley, Nick Fox
Statistics: Constantinos Kallis, Chris Frost, Jennifer Nicholas
Proteomics: Charles Bangham, Aviva Witkover, Alexandra Lewin
Immunology: John Greenwood, Virginia Calder, Nadine Schuerer
Psychology: Dennis Chan, Rebecca Cooper, Malaka Awad, Katherine
Meadmore, Kirsty Chandler, Kim Marrick
RICHARD NICHOLAS

68. Why Simvastatin and MS?

69. Inflammation in SPMS

70. Mechanism

71. Baseline

72. Registered Year 2

73. Screening showing
BBSI colour overlay

74. Worked example in MS (phase II)
MS-STAT trial
High dose (80mg) simvastatin
Mean (SD)
placebo
Mean (SD)
simvastatin
Difference in means
(95% CI)*
p-value
Change WBV (%/year)
0.589
(0.528)
0.298
(0.562)
-0.254
(-0.423 to -0.085)
0.003
Number patients evaluated
64
66
*Adjusting for minimisation variables and MRI site
Chataway et al ECTRIMS 2012; AAN 2013

75. Change whole brain volume (%/yr)

76. Change in EDSS 0 to 24 months
Change in EDSS from Baseline to 24 months

77. Conclusions
• MS is very hard
• But the RR phase maybe almost dealt with
• Drug choice will become
broader/combinatorial
• However whether we can decouple
progression is unknown
• Progression is very hard to treat
• Multiplex-trial [multi-arm/multi-stage]
design is needed to quicken drug testing

78. Thank you

80. NHS reforms –
opportunities and
challenges for MS Care
Karen Middleton CBE
Chief Allied Health
Professions Officer

81. Summary
• Context - the narrative for the reforms
• The key structures that clinicians need to be
aware of
• Key messages
• Challenges
• Opportunities
81

82. Some NHS facts and figures
•
•
•
•
•
•
82
1.3 million staff
£109 billion annual budget
Over 1 million patients treated every 36 hours
15 million hospital admissions per year
88 million outpatient attendances
C.12 billion spent on medicines

83. Context
83

84. Context – Quality (safe, effective, good experience)
‘In the next room you could hear the buzzers sounding. After
about 20 minutes you could hear the men shouting for the
nurse, ‘nurse, nurse’ and it just went on and on. And then very
often you would hear them crying, like shouting ‘nurse’ louder,
and then you would hear them crying, just sobbing, they would
just sob and you presumed that they had had to wet the bed.
And then after they would sob, they seemed to then shout
again for the nurse, and then it would go quiet…’
84

85. 85

86. Commissioning of services
86

87. First Mandate for NHS England
•First Mandate published on 13th November
2012
•Sets out what the Government expects in
return for handing over £95bn of tax payers
money to NHS England
•The NHS Outcomes Framework sits at the
heart of this Mandate and the Board is
expected to demonstrate progress across the
entire framework
87
•In turn, the NHS Outcomes Framework sits
at
the heart of NHS England’s planning
guidance ‘Everyone Counts’, published in
December 2012

88. NHS Mandate
88
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/127193/mandate.pdf.pdf

89. Tools and levers of the Quality Framework
89

90. NHS ENGLAND
Our focus – delivering improved outcomes
The NHS
Outcomes
Framework
90

91. How we align these tools and levers will be key to
success
91

92. NHS Outcomes Framework ‘At a Glance’
1
Preventing people from dying prematurely
Overarching indicators
1a Potential Years of Life Lost (PYLL) from causes considered amenable to
healthcare
i Adults ii Children and young people
1b Life expectancy at 75
i Males ii Females
Improvement areas
Reducing premature mortality from the major causes of death
1.1 Under 75 mortality rate from cardiovascular disease* (PHOF 4.4)
1.2 Under 75 mortality rate from respiratory disease* (PHOF 4.7)
1.3 Under 75 mortality rate from liver disease* (PHOF 4.6)
1.4 Under 75 mortality rate from cancer* (PHOF 4.5)
i One- and ii Five-year survival from all cancers
iii One- and iv Five-year survival from breast, lung and colorectal cancer
Reducing premature death in people with serious mental illness
1.5 Excess under 75 mortality rate in adults with serious mental illness* (PHOF 4.9)
Reducing deaths in babies and young children
1.6 i Infant mortality* (PHOF 4.1)
ii Neonatal mortality and stillbirths
iii Five year survival from all cancers in children
Reducing premature death in people with a learning disability
1.7 Excess under 60 mortality rate in adults with a learning disability
2
Enhancing quality of life for people with long-term
conditions
3
Helping people to recover from episodes of ill health or
following injury
Overarching indicators
4
Ensuring that people have a positive experience of care
Overarching indicators
3a Emergency admissions for acute conditions that should not usually require
hospital admission
3b Emergency readmissions within 30 days of discharge from hospital* (PHOF 4.11)
Improvement areas
Improving outcomes from planned treatments
3.1 Total health gain as assessed by patients for elective procedures
i Hip replacement ii Knee replacement iii Groin hernia iv Varicose veins
v Psychological therapies
Preventing lower respiratory tract infections (LRTI) in children from becoming
serious
3.2 Emergency admissions for children with LRTI
4a Patient experience of primary care
i GP services
ii GP Out of Hours services
iii NHS Dental Services
4b Patient experience of hospital care
4c Friends and family test
Improvement areas
Improving people’s experience of outpatient care
4.1 Patient experience of outpatient services
Improving hospitals’ responsiveness to personal needs
4.2 Responsiveness to in-patients’ personal needs
Improving people’s experience of accident and emergency services
4.3 Patient experience of A&E services
Improving recovery from injuries and trauma
3.3 Proportion of people who recover from major trauma
Improving recovery from stroke
3.4 Proportion of stroke patients reporting an improvement in activity/lifestyle on the
Modified Rankin Scale at 6 months
Improving recovery from fragility fractures
3.5 Proportion of patients recovering to their previous levels of mobility/walking ability
at i 30 and ii 120 days
Helping older people to recover their independence after illness or injury
3.6 i Proportion of older people (65 and over) who were still at home 91 days
after discharge from hospital into reablement/ rehabilitation service***
(ASCOF 2B)
ii Proportion offered rehabilitation following discharge from acute or
community hospital
Improving access to primary care services
4.4 Access to i GP services and ii NHS dental services
Improving women and their families’ experience of maternity services
4.5 Women’s experience of maternity services
Improving the experience of care for people at the end of their lives
4.6 Bereaved carers’ views on the quality of care in the last 3 months of life
Improving experience of healthcare for people with mental illness
4.7 Patient experience of community mental health services
Improving children and young people’s experience of healthcare
4.8 An indicator is under development
Improving people’s experience of integrated care
4.9 An indicator is under development *** (ASCOF 3E)
Overarching indicator
2 Health-related quality of life for people with long-term conditions** (ASCOF 1A)
NHS Outcomes
Framework 2013/14
Improvement areas
Ensuring people feel supported to manage their condition
2.1 Proportion of people feeling supported to manage their condition**
Improving functional ability in people with long-term conditions
2.2 Employment of people with long-term conditions** * (ASCOF 1E PHOF 1.8)
Reducing time spent in hospital by people with long-term conditions
2.3 i Unplanned hospitalisation for chronic ambulatory care sensitive
conditions (adults)
ii Unplanned hospitalisation for asthma, diabetes and epilepsy in under
19s
Enhancing quality of life for carers
2.4 Health-related quality of life for carers** (ASCOF 1D)
Enhancing quality of life for people with mental illness
2.5 Employment of people with mental illness **** (ASCOF 1F & PHOF 1.8)
Enhancing quality of life for
92i Estimated diagnosis rate people with dementia (PHOF 4.16)
2.6
for people with dementia*
ii A measure of the effectiveness of post-diagnosis care in sustaining
independence and improving quality of life*** (ASCOF 2F)
at a glance
5
Treating and caring for people in a safe environment and
protect them from avoidable harm
Overarching indicators
5a Patient safety incidents reported
5b Safety incidents involving severe harm or death
5c Hospital deaths attributable to problems in care
Improvement areas
Alignment across the Health and Social Care System
*
**
Indicator shared with Public Health Outcomes Framework (PHOF)
Indicator complementary with Adult Social Care Outcomes
Framework (ASCOF)
*** Indicator shared with Adult Social Care Outcomes Framework
**** Indicator complementary with Adult Social Care Outcomes
Framework and Public Health Outcomes Framework
Indicators in italics are placeholders, pending development or identification
Reducing the incidence of avoidable harm
5.1 Incidence of hospital-related venous thromboembolism (VTE)
5.2 Incidence of healthcare associated infection (HCAI)
i MRSA
ii C. difficile
5.3 Incidence of newly-acquired category 2, 3 and 4 pressure ulcers
5.4 Incidence of medication errors causing serious harm
Improving the safety of maternity services
5.5 Admission of full-term babies to neonatal care
Delivering safe care to children in acute settings
5.6 Incidence of harm to children due to ‘failure to monitor’

93. Key work programmes
1.Prevention, early diagnosis and intelligence
2.Community services
3.Acute services
4.Integrated care and support
5.Patients in control
6.Parity of esteem
93

94. Clinical Senates
94

95. 12 Clinical Senates
North East, north Cumbria,
and the Hambleton &
Richmondshire districts of
North Yorks
Yorkshire &
The Humber
Greater
Manchester,
Lancashire and
south Cumbria
East Midlands
Cheshire &
Mersey
East of
England
West
Midlands
Thames
Valley
London
South West
South East
Coast
95
Wessex

96. Strategic Clinical Networks (SCNs)
96

97. Innovation
‘An idea, service or product,
new to the NHS
or applied in a way
that is new to the NHS,
which significantly improves
the quality of
health and care
wherever it is applied.’
97
http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_131299

98. Academic Health Science Networks
• 15 – designated and licensed
• 5 year contracts
• Systematic delivery mechanism for diffusion of innovation
and best practice and collaboration between partners
including industry
• Align education, clinical research, informatics, training and
healthcare delivery
• Improving patient and population health by translating
research into practice and developing and implementing
integrated health care systems
98

99. AHSNs
Academia
99
Industry
Oxford
Eastern
Wessex
UCL Partners
South London
East Midlands
West Midlands
West of England
North West Coast
Greater Manchester
Yorkshire and Humber
South West Peninsula
Kent, Surrey and Sussex
North East and North Cumbria
Imperial College Health Partners
NHS

100. Health Education England
• National
• Local – 13 Local Education training Boards (LETBs or
HEELs)
Purpose:
To support the delivery of excellent healthcare and health
improvement by ensuring that our workforce has the right
numbers, skills ,values and behaviours, at the right time in
the right place.
100

101. HEE advisory arrangement
PAF
PAF
Exec
101
Primary Decision Making Body/ Overarching Governance
HEE Advisory & Decision Making Support Bodies
Sub Groups, Special Projects & National Advisory Groups
Board Recommendations & decision under scheme of
delegation
* SLT = HEE Exec & LETB MD’s

102. Key messages
• Stop looking up for direction and guidance
• It really is a commissioning-led system
• Understand patient power
• You have to be bi-lingual
• Clinical care has to be paramount
• Clinical LEADERSHIP is critical
102

103. Challenges
• Doing more for less – or doing different for less
• Transformational rather than transactional change
• Generalists versus specialists
• Education and training numbers
• Reactive versus proactive
103
• Exerting influence – more later!

104. Opportunities
• The focus on outcomes
• Rehab, rehab, rehab!
• Multi-disciplinary approach
• Patient voice
104

105. Exerting influence
•
•
•
•
•
•
•
•
•
105
Put yourself in the shoes of the other person
Avoid perception of self-interest
Respect
Prepare
Build alliances
Tell a story
Private persuasion over public passion
Resilience
Wild Cards - Evidence; humour: sprinkling stardust

106. A final great thought from a great inspiration…
”When you are done
changing, you are done”
Benjamin Franklin
4

107. Thank you
Karen.middleton1@nhs.net
karen@chpo
107