MRC Centre for Neuromuscular Disease

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

Establishing a Clinical TrialAssume all this alreadydone!!

MRC Centre for Neuromuscular Disease

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 recruitmentFINDING THE PATIENTS

Accurately defined cohorts of patients/ genotype

Demographic data

Functional status data

RegistriesDatabases

Effective communication pathways to patient & dr Doctor patient relationshipsPatient organisations-networksProfessional and Patient networksEmbedding a trials culture in clinical practice

PROVIDING ACCURATE INFORMATION TO PATIENTS & Drs

BMS BPNS TREAT-NMD MDC

Patient Registries

UK ClinicalNetworks

Bio-statsTrial design

Outcomes research

Trial strategy

UK Clinical trials development/supportNorth and South Trial Centres

UK Trial centre Network

CLINICAL TRIALS

British Myology Society/British Peripheral Nerve society/TREAT-NMDPatient 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 recruitfor 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 assessmentDiagnostics-one stop clinic

Clinical neurophysiologyGeneticsFunctional Expression

TreatmentClinical trials-natural history studies

Channelopathy service-trial recruitment benefits

Clinical trials embedded in the clinical service

NIH-CINCH collaborative studiesNMD nat historyEA2 nat historyATS 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 CohortLondon NewcastleMRC funded Protocol based collection 091500 mito pts over 3 years- 650 to date

Doug TurnbullMike Hanna Robert McFarland Shamima RahmanJo Poulton 18

MRC Mitochondrial Cohort Study

CONTACTS:NEWCASTLEDr Robert McFarland / Prof Doug TurnbullMRC Centre for Neuromuscular Diseases Ncl

LONDONProf Mike Hanna / Dr Shamima Rahman / Dr Robert PitceathlyMRC Centre for Neuromuscular Diseases UCL

OXFORDProf 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 Websitehttp://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 QuinlivanNational reference centreClinical assessmentGenetic and biochemicalRegistryClinical Trials

IBM-net:

UK registry and clinical database for inclusion body

myositisMatt 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

Inclusion in IBM-net

Data entry, housekeeping

London Oxford Newcastle ManchesterIBM research

MRC Centre

IBM Clinic

IBM Arimoclomol Study

IBM Natural History Study

IBM DNA Study

IBM MRI Study

IBM Research IBM Laboratory

WorkIBM Histology

Study

PMG

TREAT-NMD  MDC

NaNDa

Project Management

Group(PMJ)

Clinical Networks

Cong MD &myopathy

 IBM

 SMArtNet

SMA

North Star

DMD

ClinicalDev

 

PMGClinicalDev

 

PMGClinicalDev

PMGClinicalDev

BMS

National nm database structure

CERTUS

Database dev, hosting

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 centre,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)

35

Top 10 exon skips (published in Hum Mut 2009)

Rank Leiden 1860

1 Exon 51 620

2 Exon 45 386

3 Exon 53 367

4 Exon 44 296

5 Exon 46

6 Exon 52

7 Exon 50 191

8 Exon 43

9 Exon 6 & 7

10 Exon 8

Global PR 2386

Exon 51 712

Exon 53 555

Exon 45 485

Exon 44 399

Exon 50 235

AVI enquiry: DMD patients worldwide(February 2009)

DMD patient registry

Acceleron enquiry: DMD patients in Europe (June 2010)

0

200

400

600

800

1000

1200

1 2 3

on steroids

not on steroids

age 4-7 age 8-14 aged 15+

Steroid use

0

200

400

600

800

1000

1200

1400

1600

1 2 3

ambulant

non-ambulant

age 4-7 age 8-14 aged 15+

Ambulation

Yellow pins:German and Austriantrial sites in CTSR(16)

Blue pins:DMD & BMD patientsin German/Austrianpatient registry(693)

May 2010

Potential of registries for trial recruitment

Yellow pins:German and Austriantrial sites in CTSR

Green pins:Exon 51 skippableDMD patients inGer/Aus registry (67)

May 2010

Potential of registries for trial recruitment

Yellow pins:German and Austriantrial sites in CTSR

Green pins:Exon 51 skippableDMD patients inGer/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)

Potential of registries for trial recruitment

Study Disease Status LocationAVI-4658 Antisense (DMD) open 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

MRC Centre for Neuromuscular Disease

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

David Hilton-Jones Mike Rose Doug Turnbull Mary Reilly Matt Parton Chris Turner B Macfarland Mike LunnJanice Holton/Caroline Sewry Berch Griggs S Rahman M SweeneyAdrian Miller Richard Barohn Dipa R Rayan M Davis John Hardy Henry Houlden D Kullmann K BushbyPedro Machado Emma Matthews Z Scott F MuntoniLiz Dewar James Burge J Morrow R Pitceathly

Acknowledgements