Clinical Trials Recruitment
UK and European Perspective
Beaver Hollow 21.9.10
Michael G Hanna
MRC Centre for Neuromuscular Diseases
UCL Institute of Neurology, Queen Square, London
MRC Centre for Neuromuscular
Disease
Barriers to recruitment
MAKING CLINICAL TRIALS HAPPEN IS NOT EASY.....
EMBEDDING A TRIALS CLUTURE IN CLINICAL NEUROMUSCULAR
PRACTICE IS KEY
ALL PATIENTS WITH NM DISEASE FOR WHICH THERE IS NO
STANDARD TREATMENT SHOULD HAVE THE OPTION TO ENTER A
TRIAL
MRC Centre for Neuromuscular
Disease
Barriers to recruitment
UK experience-adults
Muscle channelopathies
Inclusion Body Myositis
Mitochondrial Disease
Inherited neuropathies-CMT
UK-European experience-paediatrics
DMD/ SMA
MRC Centre for Neuromuscular
Disease
Establishing a Clinical
Trial
Assume
all this already
done!!
Barriers to recruitment
•FINDING THE RIGHT PATIENTS FOR THE TRIAL
•EFFECTIVE COMMUNICATIONS SYSTEMS TO PT & DR
•EMBEDDED IN CLINCAL CARE OR NOT
•TRIAL DESIGN AND ENTRY CRITERIA
•IMPACT OF TRIAL ON PATIENTS LIFE-FAMILY
•PROXIMITY TO TRIAL CENTRE
•GEOGRAPHICAL SPREAD OF PATIENT POPULATION
•COUNTRY SPECIFIC REFERRAL PATTERNS-REF CENTRES
MRC Centre for Neuromuscular
Disease
Barriers to recruitment
FINDING THE PATIENTS
Accurately defined cohorts of patients/ genotype
Demographic data
Registries
Databases
Functional status data
PROVIDING ACCURATE INFORMATION TO PATIENTS & Drs
Effective communication pathways to patient & dr
Doctor patient relationships
Patient organisations-networks
Professional and Patient networks
Embedding a trials culture in clinical practice
MRC Centre for Neuromuscular
Disease
BMS
BPNS
TREAT-NMD
MDC
CLINICAL TRIALS
UK Clinical trials development/support
North and South Trial Centres
UK Trial centre Network
Patient
Registries
UK Clinical
Networks
Bio-stats
Trial design
Outcomes
research
Trial
strategy
British Myology Society/British Peripheral Nerve society/TREAT-NMD
Patient Organizations and Charities
Clinical Trials Centres
NEWCASTLE
LONDON
NORTH AND SOUTH ENGLAND NM CLINICAL TRIALS UNITS
BRITISH PERIPHERAL NERVE
SOCIETY (BPNS) 2003
President Mary Reilly- meets twice yearly
Adult neuropathy specialists
Forum nationally to discuss, plan and recruit
for trials
Forum for collaboration in international trials
Channelopathy service
Service for the whole England (Wales
Scotland)
Funded centrally by DoH, not by local
PCT
Clinical assessment
Diagnostics-one stop clinic
Clinical neurophysiology
Genetics
Functional Expression
Treatment
Clinical trials-natural history studies
Channelopathy servicetrial recruitment benefits
Clinical trials embedded in
the clinical service
NIH-CINCH collaborative studies
NMD nat history
EA2 nat history
ATS nat history
FDA Mexiletine trial
NIH HypHop trial
NCG for Rare Mitochondrial
Disorders of Adults and
Children
Newcastle London Oxford
Mitochondrial NCG Centres
NEWCASTLE
OXFORD
LONDON
Combined Clinical & Diagnostic
Service
• Clinical Service
–
–
–
–
–
–
–
Outpatient
Inpatient
Daycase [muscle biopsy / investigations]
Physiotherapy
Speech and Language Therapy
Genetic Counselling
Nurse Specialists
• Diagnostic Service
– Muscle Histochemistry & Biochemistry
– Biochemical (COX) analysis of fibroblasts
– Genetics
•
•
•
•
Specific nuclear gene sequencing
Specific mtDNA mutation analysis
Whole genome sequencing
Prenatal testing
Collaborative Working
Internal collaboration
– Quality assurance programme – genetic &
biochemical
– The MRC Centre for Translational Research in
Neuromuscular Disease - Mitochondrial Disease
Patient Cohort (UK)
– Audit of prenatal testing for Mitochondrial Disease
– ‘Twinkle’ cohort:
MRC Centre Mitochondrial Cohort
London Newcastle
MRC funded Protocol based collection 09
1500 mito pts over 3 years- 650 to date
Doug Turnbull
Mike Hanna
Robert McFarland
Shamima Rahman
Jo Poulton
18
MRC Mitochondrial Cohort
Study
CONTACTS:
NEWCASTLE
Dr Robert McFarland / Prof Doug Turnbull
MRC Centre for Neuromuscular Diseases Ncl
LONDON
Prof Mike Hanna / Dr Shamima Rahman /
Dr Robert Pitceathly
MRC Centre for Neuromuscular Diseases UCL
OXFORD
Prof Joanna Poulton
Public Engagement
• Patient Information Events biannual
– Short talks on aspects of mitochondrial disease
– Demonstrations of clinical aids and laboratory
equipment
– Recorded and uploaded to website & DVD
– CLINICAL TRIALS INFORMATION
•
• National Specialised Commissioning Team
baseline audit of Patient and Public
Engagement throughout specialised services.
Mitochondrial Disease Website
http://www.mitochondrialncg.nhs.uk
Value of Nationally Commissioned
Service for Rare Diseases?
• How do we demonstrate our real value?
– Benchmarking
• (Inter-) National management guidelines
• Clinical and laboratory ‘best practice’ protocols
– Patient Satisfaction, outcomes
• Meeting patient needs and expectations?
– Satisfaction surveys
• Raising public profile and awareness
– Recruitment into clinical trials
Queen Square Great Ormond
Street UK McCardle NCG Service
Commissioned Nov 2010
Dr Ros Quinlivan
National reference centre
Clinical assessment
Genetic and biochemical
Registry
Clinical Trials
IBM-net:
UK registry and clinical
database for inclusion body
myositis
Matt Parton, Adrian Miller,
Mike Rose, Stefan Brady
Janice Holton James Miller
David Hilton-Jones, Mike Hanna
Aims IBM-net
•Prospective natural history data
•IBM-DNA bank genome-wide screen
•Cohort of IBM patients for clinical trial
• Patient organization
•Myositis Support Group
•Muscular Dystrophy Campaign
25
Adapt existing systems
• Entry and storage of information
– Adaption of NorthStar
– Collaboration with Certus
– MDC supported National Neuromuscular
Database
IBM-net
• Patient data supplied by clinician with
expertise/experience in IBM
– Quality of data essential
– Diagnostic difficulty
• Initial demographics
– DOB, sex, ethnicity, onset of illness, etc.
• Biopsy report
• Detailed clinical assessment
– Strength testing, IBM-FRS, use of medication, etc.
Patient
Clinician
Consent
Curator
Data entry, housekeeping
Inclusion in IBM-net
London Oxford Newcastle Manchester
IBM research
IBM Natural
History Study
MRC
Centre
IBM Clinic
IBM
Research
IBM MRI Study
IBM DNA Study
IBM Arimoclomol
Study
IBM Laboratory
Work
IBM Histology
Study
National nm database structure
NaNDa
TREAT-NMD
MDC
Project
Management
Group
(PMJ)
BMS
CERTUS
Database dev, hosting
North Star
SMArtNet
Cong MD &
myopathy
IBM
DMD
Clinical
Dev
SMA
PMG
Clinical
Dev
PMG
Clinical
Dev
Clinical Networks
PMG
Clinical
Dev
PMG
INTERNATIONAL CMT REGISTRY
NIH RDCRC (Shy, Reilly and Pareyson)
Minimal dataset for CMT for natural history studies
Online registry housed and managed by DMCC
in Florida
INTERNATIONAL CMT REGISTRY
2009 / 2010 plan to extend the registry internationally
Partnered with TREAT-NMD
National curator for each national registry
(e.g. UK Mary Reilly running national database in MRC
Queen Square)
INTERNATIONAL CMT REGISTRY
International registry will be vehicle for:
National history studies
(ongoing in RDCRC registry)
Eventually trial recruitment
(especially rare forms of CMT)
Registries used by industry – feasibility studies
• 7 feasibility enquiries from February 2009 to June 2010 (6
on DMD, 1 on SMA; 6 from industry, 1 academic)
• All enquiries approved by TGDOC in less than 14 days
(>90% participation, all votes positive)
• All enquiry reports completed in time according to
agreements (<3 weeks to 8 weeks)
• Total revenue from feasibility enquiries: ca. 50,000.- €
• Revenue ear-marked for further education and training
(registry curator and OC meeting)
AVI enquiry: DMD patients worldwide
(February 2009)
Top 10 exon skips (published in Hum Mut 2009) DMD patient registry
Rank
Leiden
1860
Global PR
2386
1
Exon 51
620
Exon 51
712
2
Exon 45
386
Exon 53
555
3
Exon 53
367
Exon 45
485
4
Exon 44
296
Exon 44
399
5
Exon 46
Exon 50
235
6
Exon 52
7
Exon 50
8
Exon 43
9
Exon 6 & 7
10
Exon 8
191
35
Acceleron enquiry: DMD patients in Europe
(June 2010)
Ambulation
Steroid use
1600
1200
1400
1000
1200
800
1000
on steroids
ambulant
800
non-ambulant
600
not
on steroids
600
400
400
200
200
0
0
1
age 4-7
2
3
age 8-14 aged 15+
1
age 4-7
2
3
age 8-14 aged 15+
Potential of registries for trial recruitment
Yellow pins:
German and Austrian
trial sites in CTSR
(16)
Blue pins:
DMD & BMD patients
in German/Austrian
patient registry
(693)
May 2010
Potential of registries for trial recruitment
Yellow pins:
German and Austrian
trial sites in CTSR
Green pins:
Exon 51 skippable
DMD patients in
Ger/Aus registry (67)
May 2010
Potential of registries for trial recruitment
Yellow pins:
German and Austrian
trial sites in CTSR
Green pins:
Exon 51 skippable
DMD patients in
Ger/Aus registry (67)
Red circle:
Under the care of
Freiburg (4) and
Essen (9)
Blue circle:
Recruitment potential
(within 2 hours reach)
Freiburg (15) and
Essen (15)
Study
AVI-4658
Disease
Antisense (DMD)
Status
open
Location
ICH/Newcastle
Vitamin C
CMT
Follow-up phase
ION-QS
RMC
CIDP
Completed
ION-QS
Cardio prot
DMD
Planning phase
ICH/Newcastle
Ariomoclomol
IBM
OPEN
ION-QS
Hyp-Hop
Periodic paralysis
OPEN
ION-QS
Mexiletine
NDM
OPEN
ION-QS
TAPP-ATS
Andersen-Tawil Syndrome
Set up
ION-QS
Exercise trial
CMT
Open
ION-QS
Exercise
Mito
Open
Newc/ION-QS
Cohort NH
IBM
OPEN
UCL
Cohort NH
Mito
OPEN
Newc/ION-QS
PTC124
Nonsense-mutation (DMD & BMD)
Open
ICH/Newcastle
NH
NDM – ion channels
Close
ION-QS
NH
Andersen-Tawil Syndrome
Open
ION-QS
Barriers to recruitment
•FINDING THE RIGHT PATIENTS FOR THE TRIAL
•EFFECTIVE COMMUNICATIONS SYSTEMS TO PT & DR
•TRIAL DESIGN AND ENTRY CRITERIA
•IMPACT OF TRIAL ON PATIENTS LIFE-FAMILY
•PROXIMITY TO TRIAL CENTRE
•EMBEDDED IN CLINCAL CARE OR NOT
•GEOGRAPHICAL SPREAD OF PATIENT POPULATION
•COUNTRY SPECIFIC REFERRAL PATTERNS-REF CENTRES
MRC Centre for Neuromuscular
Disease
Acknowledgements
David Hilton-Jones
Matt Parton
Janice Holton/Caroline Sewry
Adrian Miller
John Hardy
Pedro Machado
Liz Dewar
Mike Rose
Chris Turner
Berch Griggs
Richard Barohn
Henry Houlden
Emma Matthews
James Burge
Doug Turnbull
B Macfarland
S Rahman
Dipa R Rayan
D Kullmann
Z Scott
J Morrow
Mary Reilly
Mike Lunn
M Sweeney
M Davis
K Bushby
F Muntoni
R Pitceathly
