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Clinical Trials Recruitment UK and European Perspective Beaver Hollow 21.9.10 Michael G Hanna

Overcoming barriers in clinical trial recruitment for neuromuscular diseases with improved communications, patient support, and research networks. UK and European experiences shared.

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Clinical Trials Recruitment UK and European Perspective Beaver Hollow 21.9.10 Michael G Hanna

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  1. 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

  2. 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

  3. 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

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

  5. 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

  6. Barriers to recruitment FINDING THE PATIENTS Accurately defined cohorts of patients/ genotype Demographic data Functional status data Registries Databases 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 BMS BPNS TREAT-NMD MDC MRC Centre for Neuromuscular Disease

  7. 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

  8. Clinical Trials Centres NEWCASTLE LONDON

  9. NORTH AND SOUTH ENGLAND NM CLINICAL TRIALS UNITS

  10. 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

  11. 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

  12. 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

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

  14. Mitochondrial NCG Centres NEWCASTLE OXFORD LONDON

  15. 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

  16. 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:

  17. 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

  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

  19. 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.

  20. Mitochondrial Disease Websitehttp://www.mitochondrialncg.nhs.uk

  21. £ £ 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

  22. 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

  23. 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

  24. 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

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

  26. 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.

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

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

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

  30. 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

  31. 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)

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

  33. 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)

  34. Rank Global PR Leiden 2386 1860 1 Exon 51 620 Exon 51 712 Exon 53 555 2 Exon 45 386 Exon 45 485 3 Exon 53 367 Top 10 exon skips (published in Hum Mut 2009) 4 Exon 44 296 Exon 44 399 5 Exon 46 Exon 50 235 6 Exon 52 7 Exon 50 191 8 Exon 43 9 Exon 6 & 7 10 Exon 8 AVI enquiry: DMD patients worldwide (February 2009) DMD patient registry

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

  36. Potential of registries for trial recruitment Yellow pins: German and Austrian trial sites in CTSR (16) Blue pins: DMD & BMD patients in German/Austrianpatient registry (693) May 2010

  37. Potential of registries for trial recruitment Yellow pins: German and Austrian trial sites in CTSR Green pins: Exon 51 skippable DMD patients inGer/Aus registry (67) May 2010

  38. Potential of registries for trial recruitment Yellow pins: German and Austrian trial sites in CTSR Green pins: Exon 51 skippable DMD 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)

  39. Study Disease Status Location AVI-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

  40. 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

  41. Acknowledgements David Hilton-Jones Mike Rose Doug Turnbull Mary Reilly Matt Parton Chris Turner B Macfarland Mike Lunn Janice Holton/Caroline Sewry Berch Griggs S Rahman M Sweeney Adrian Miller Richard Barohn Dipa R Rayan M Davis John Hardy Henry Houlden D Kullmann K Bushby Pedro Machado Emma Matthews Z Scott F Muntoni Liz Dewar James Burge J Morrow R Pitceathly

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