1. 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

2. 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

3. 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

4. Establishing a Clinical Trial Assume all this already done!!

5. 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

6. MRC Centre for Neuromuscular Disease Barriers to recruitment FINDING THE PATIENTS Accurately defined cohorts of patients/ genotype Demographic data Functional status data Registries Databases Effective communication pathways to patient & dr Doctor patient relationships Patient organisations-networks Professional and Patient networks Embedding a trials culture in clinical practice PROVIDING ACCURATE INFORMATION TO PATIENTS & Drs BMS BPNS TREAT-NMD MDC

7. Patient Registries UK Clinical Networks Bio-stats Trial design Outcomes research Trial strategy UK Clinical trials development/support North and South Trial Centres UK Trial centre Network CLINICAL TRIALS British Myology Society/British Peripheral Nerve society/TREAT-NMD Patient Organizations and Charities

8. Clinical Trials Centres NEWCASTLE LONDON

9. NORTH AND SOUTH ENGLAND NM CLINICAL TRIALS UNITS

11. 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

12. 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

13. Channelopathy service- trial 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

14. NCG for Rare Mitochondrial Disorders of Adults and Children Newcastle London Oxford

15. Mitochondrial NCG Centres NEWCASTLE OXFORD LONDON

16. 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

17. 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:

18. 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

19. 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

20. 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.

21. Mitochondrial Disease Website http://www.mitochondrialncg.nhs.uk

22. 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

23. 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

24. 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

25. 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

26. Adapt existing systems Entry and storage of information –Adaption of NorthStar –Collaboration with Certus –MDC supported National Neuromuscular Database

27. 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.

28. Patient Clinician Consent Curator Inclusion in IBM-net Data entry, housekeeping

29. London Oxford Newcastle Manchester IBM research MRC Centre IBM Clinic IBM Arimoclomol Study IBM Natural History Study IBM DNA Study IBM MRI Study IBM Research IBM Laboratory Work IBM Histology Study

30. PMG TREAT-NMD MDC NaNDa Project Management Group (PMJ) Clinical Networks Cong MD & myopathy IBM SMArtNet SMA North Star DMD Clinical Dev PMGClinical Dev PMGClinical Dev PMGClinical Dev BMS National nm database structure CERTUS Database dev, hosting

31. 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

32. 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)

33. INTERNATIONAL CMT REGISTRY International registry will be vehicle for: National history studies (ongoing in RDCRC registry) Eventually trial recruitment (especially rare forms of CMT)

34. 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. 35 Top 10 exon skips (published in Hum Mut 2009) RankLeiden1860 1Exon 51 620 2Exon 45 386 3Exon 53 367 4Exon 44 296 5Exon 46 6Exon 52 7Exon 50 191 8Exon 43 9Exon 6 & 7 10Exon 8 Global PR2386 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

36. Acceleron enquiry: DMD patients in Europe (June 2010) age 4-7 age 8-14 aged 15+ Steroid use age 4-7 age 8-14 aged 15+ Ambulation

37. 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

38. 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

39. 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) Potential of registries for trial recruitment

40. StudyDiseaseStatusLocation AVI-4658Antisense (DMD)openICH/Newcastle Vitamin CCMTFollow-up phaseION-QS RMCCIDPCompletedION-QS Cardio prot DMDPlanning phaseICH/Newcastle AriomoclomolIBMOPENION-QS Hyp-Hop Periodic paralysisOPENION-QS MexiletineNDMOPENION-QS TAPP-ATSAndersen-Tawil SyndromeSet upION-QS Exercise trialCMTOpenION-QS ExerciseMitoOpenNewc/ION-QS Cohort NHIBMOPENUCL Cohort NHMitoOPENNewc/ION-QS PTC124Nonsense-mutation (DMD & BMD)Open ICH/Newcastle NH NDM – ion channelsCloseION-QS NHAndersen-Tawil SyndromeOpenION-QS

41. 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

42. David Hilton-JonesMike RoseDoug TurnbullMary Reilly Matt PartonChris TurnerB MacfarlandMike Lunn Janice Holton/Caroline SewryBerch GriggsS Rahman M Sweeney Adrian MillerRichard BarohnDipa R Rayan M Davis John HardyHenry HouldenD Kullmann K Bushby Pedro MachadoEmma MatthewsZ ScottF Muntoni Liz DewarJames BurgeJ MorrowR Pitceathly Acknowledgements