Advanced Neuromuscular Registries

Transcription

1 1 Advanced Neuromuscular Registries Dr Karen Rafferty Institute of Genetic Medicine Newcastle University, UK

2 2 What is TREAT-NMD? A network of excellence initially funded by the EC (but with global collaborations) 2007 to 2011 Aims to help promising new treatments for neuromuscular diseases make the transition from the lab to the patient Not a research project but an infrastructure project Creating the tools for trial-readiness in the neuromuscular field Helping researchers and expert centres collaborate better Improving patient care worldwide Sustained beyond 2011 as TREAT-NMD Alliance - funded through multiple funding streams and with global partners Led by an Executive Committee

3 3 TREAT-NMD Alliance Executive Committee 13 members, global representation (Europe, USA, Australia, Japan) Clinicians, researchers and patient representatives Chair: Hanns Lochmüller, UK; vice-chair: Annemieke Aartsma-Rus, NL

4 4 TREAT-NMD Alliance Charter Ratified August 2012 Registries represented within the Alliance Charter

5 Standard Operating Procedures make it easier to compare the results of preclinical animal studies, which are used to test the effects of potential new therapies. Forty regularly updated standard operating Procedures are available on the TREAT-NMD website for use by researchers around the world. The TREAT-NMD Alliance has hosted exon skipping workshops to consolidate efforts and jointly tackle common problems in DMD research. Standard Operating Procedures Joint Research for DMD Outcome Measures are standardized tests (e.g. six minute walk test) to decide whether a potential therapy being tested in a clinical trial is effective. TREAT-NMD collates and hosts an extensive list in their Registry of Outcome Measures. Outcome Measures Patient Registries TREAT-NMD patient registries contain genetic and clinical information, and were set up with future trials and therapies in mind. Global registries for DMD and SMA are regularly used by pharmaceutical companies as a resource for trial planning and recruitment. Care & Trial Site Registry The TREAT-NMD Care and Trial Site Registry (CTSR) is a database of clinical sites around the world. It unites specialist centres caring for neuromuscular patients, and assists researchers and pharmaceutical companies to select the sites for clinical trials. TREAT-NMD Alliance has developed a proven communications platform. This includes an extensive website seen by more than 70,000 visitors every year, and a monthly newsletter sent to over 3,500 recipients. Website and Communications TACT Standards of Diagnosis & Care BioBanking EuroBioBank, currently financially supported by Telethon (Italy), is a network which stores and distributes DNA, cell and tissue samples as a service to the scientific community researching rare diseases. Approximately 440,000 samples are available to researchers worldwide. The TREAT-NMD Advisory Committee for Therapeutics (TACT) provides expert guidance and advice on the trial-readiness of potential new therapies. Investigators with promising preclinical results can receive an unbiased assessment of their plans, and advice on the steps needed to undertake clinical trials. Variations in care received by patients affect the quality of life and make it difficult to compare trial results between different centres. International work has led to the publication of consensus care guidelines for DMD, SMA and CMD. TREAT-NMD has worked with patient groups to create family guides in many different languages.

6 6 Care and Trial Site Registry (CTSR) Recently expanded to include neurodegenerative diseases in collaboration with Neuromics Neuromics aims to revolutionize diagnostics and develop new treatments for ten major neuromuscular and neurodegenerative diseases.

7 7 CTSR Poster presented by Kirsten König

8 8 Collaborative NMD and RD research projects facilitated by TREAT-NMD ( ) TREAT-NMD CARE-NMD Neuromics RD-Connect 10M EUR network of excellence for rare inherited neuromuscular diseases Implementing care standards for DMD across Europe, in particular Eastern Europe 12M EUR research project on nextgen omics approaches to neuromuscular and neurodegenerative disease 12M EUR RD infrastructure: central global hub connecting registries, biobanks and clinical bioinformatics NMD-Chip High throughput sequencing (gene chips) for NMD diagnostics OPERATING GRANT Supporting the core activities of TREAT-NMD on an annual basis RARE Bestpractices Infrastructure for best practice sharing across rare diseases EUCERD Joint Action for Rare Disease Implementing RD policy and national plans across Europe BIO-NMD SKIP-NMD OPTIMISTIC SCOPE-DMD Identifying and validating preclinical biomarkers for diagnostics and therapeutics Clinical trial for morpholino antisense oligonucleotide exon skipping (53) in DMD Natural history and exercise therapy clinical study in myotonic dystrophy Clinical trial for 2O-ME antisense oligonucleotide exon skipping (45) in DMD 3Gb TEST Introducing diagnostic applications of 3Gb Testing in human genetics BIOIMAGE-NMD Development of imaging technologies for therapeutic interventions in rare diseases COST Action Applications of MR imaging and spectroscopy techniques in neuromuscular disease SMART-RD New methodologies for clinical trials for small population groups

9 9 Patient Registries Disease Name Congenital muscular dystrophies (CMD) Congenital myasthenic syndromes (CMS) Charcot Marie Tooth disease (CMT) Duchenne/Becker muscular dystrophy (DMD/BMD) Facioscapulohumeral muscular dystrophy (FSHD) Hereditary inclusion body myopathy (HIBM/GNE myopathy) Limb girdle muscular dystrophies (LGMD) Myotonic dystrophy (DM) Myotubular and centronuclear myopathy (MTM and CNM) Spinal muscular atrophy (SMA) Type of Registry International International (under construction) International National National International International (several) National International National

10 10 Examples of online national disease specific patient registries FSHD DMD DM SMA

11 11 Examples of online national patient registries covering more than one condition

12 12 Examples of National Neuromuscular Registries Australia Canada Czech Republic

13 13 Global Registries linking up the national registries Clinical trials for rare diseases generally have to take place across many centres in many different countries There is a need to link up all of the disease specific national registries TREAT-NMD has created a Global Registry for DMD and SMA All national DMD and SMA registries feed into the respective global registry which combines the information and ensures that patients who register in their national registry can be contacted if their profile fits the criteria for a clinical trial

14 14 Global Registries linking up the national registries National DMD registries pre 2007: United Dystrophinopathy Project (UDP) Action Duchenne (PPUK) registry UK and Ireland French patient database Czech Parent project registry All independent and with different datasets TREAT-NMD approach Define a mandatory dataset and means to share core data Allow interface with patients to be variable from country to country Focus on the information that will be needed for clinical trials Make sure that the data is updated and correct (curation) Apply best practice (charter, oversight)

15 15 Global Registries: legal/ethical best practice Feedback to patients Possibility of data withdrawal Informed consent form Pseudonymised (encrypted) data Frequent updates of data The TREAT-NMD registries adhere to these principles via the TREAT-NMD Registry Charter -revised and approved 2012

16 TREAT-NMD Global 16 EPIRARE Rare Disease and Orphan Drug Registries Database Oversight Committee (TGDOC) Jan Verschuuren Hugh Dawkins Anna Ambrosini Svetlana Artemieva Alexander Baranov Farhad Bayad Peter Van den Bergh Christophe Béroud Filippo Buccella Ria Broekgaarden Craig Campbell Rasha El Sharif Monica Ensini Kevin Flanigan Pat Furlong Ole Gredal Lauren Hache Serap İnal Jacqueline Jackson Pierre-Yves Jeannet Anna Kaminska A. Ayşe Karaduman Veronika Karcagi En Kimura Janbernd Kirschner Jaana Lähdetie Hanns Lochmüller Vitaliy Matyushenko Violeta Mihaylova Vedrana Milic Rasic Ian Murphy Marie-Christine Ouillade Ludo van der Pol Carmen Paradas M. Rosário dos Santos Pascale Saugier-Veber Inge Schwersenz Thomas Sejersen Eduardo Tizzano Isabela Tudorache Sylvie Tuffery- Giraud Miriam Rodrigues Petr Vondráček Jen Wang Simon Woods

17 17 Global Patient Registries Publications Global DMD Registry > 13,000 patients Bladen CL. et al. The TREAT-NMD Duchenne Muscular Dystrophy Registries: Conception, Design and Utilization by Industry and Academia. Human Mutation Aug; 34(11): Global SMA Registry > 5,000 patients Bladen CL. et al. Mapping the difference in care for 5000 Spinal Muscular Atrophy patients, a survey of 24 national registries in North America, Australasia and Europe. J. Neurol. In press.

18 18 Global Registries - Use by Industry Year Feasibility Enquiry Recruitment Enquiry Other (including trial site enquiry

19 19 International Patient Registries International Dysferlinopathy Registry Congenital Muscle Disease International Registry Global FKRP Registry MTM and CNM Patient Registry LGMD2A Patient Registry

20 20 Example of an International Patient Registry Global FKRP Registry Collects clinical and genetic data on persons affected by conditions caused by mutations in the FKRP gene Limb girdle muscular dystrophy type 2i (LGMD2I) Congenital muscular dystrophy type 1C (MDC1C) Muscle eye brain disease (MEB) Walker-Warburg syndrome (WWS) Combination of patient selfreport and professional reporting Online consent

21 21 Data Collected Patient reported data: Contact details (name, address, address, telephone number) DOB Diagnosis Motor function (best achieved and current) Wheelchair use Myalgia Ventilation Other family members affected Professional reported data: Presenting symptoms (incl. date) Pulmonary function (FVC results) Cardiac function (echo results, medication) MRI (brain, muscle) Contractures 6 Minute Walk Distance MRC scores Genetics Optional questionnaires for patients to complete: Quality of Life (SF36) Pain (McGill)

22 22 Registry Steering Committee Prof. Volker Straub, MD, PhD, Newcastle University, UK Dr. Katherine Mathews, MD, University of Iowa, USA Dr. Claudia Mitchell, MBA, PhD, Director LGMD2I Fund, USA Dr. Anne Rutkowski, MD, Cure CMD Chairman, USA Prof. John Vissing, MD, PhD, University of Copenhagen, Denmark Prof. Maggie Walter, MD, Ludwig- Maximilians-University, Germany Lacey Woods, patient representative, USA

23 23 Leaflets and Newsletters

24 International GNE registry a part of the GNE 24 EPIRARE Rare Disease and Orphan Drug Registries Myopathy Disease Monitoring Program (GNE-DMP)

25 25 GNE Registry Overview Patient self reported database International coverage Data integration with the GCP compliant data from Natural history study Advanced reporting features Longitudinal data collection Mandatory data set: 1. Name 2. Contact details 3. Date of birth 4. Geographic origin 5. Height and weight 6. Data of diagnosis 7. FH of GNE-M 8. Biopsy report 9. Genetic report/ mutation 10. GNE-M symptoms 11. Activity level 12. Lung and heart problems 13. Use of assistive devices Inclusion criteria 18 years old Genetically confirmed or clinically suspected GNE myopathy Willing to participate in the project Data collection form Demographic Biopsy and Genetic test Medical history Activity level and use of assistive devices Care and support Validated questionnaires o o Functional activity scale SF-12Quality of life

26 26 Natural History Study Overview Study sites with on going recruitment: UK- Newcastle upon Tyne USA- Irvine (CA) Canada-Hamilton (Ontario) Study procedures: Validated and non-validated questionnaires Physiotherapy assessment Serum biomarkers (SA and CK) Outcome measures: o Muscle strength o Jebsen-Taylor Hand Function Test o 6MWT o Sit-to-stand test o Stair climb test Patient reported outcome o HIBM Functional Activities Scale o Perceived Change in Function Questionnaire o Heath Survey Biomarkers Study visits: 1. Baseline 2. 6 months months 4-6 Once a year

27 27 Product specific postmarketing surveillance registries Postmarketing surveillance strategies are becoming a necessary part of an orphan drug manufacturer s responsibilities Biopharmaceutical companies spend many millions of dollars per year implementing and maintaining surveillance registries for their own products Major problems arise when there is more than one registry for the same disease, e.g. Lysosomal Storage Disorders (LSDs) Lots of fragmentation without any data being shared Data is frequently incomplete Lack of transparency

28 28 Disease specific postmarketing surveillance registries Disease specific registries will allow a centralised platform to be utilised secure portals for each product Independent governing board Economy of scale, better reporting to regulators and the wider NMD field, better buy-in from clinicians, reliable longer-term effectiveness data Linking a postmarketing surveillance registry with the Global DMD Registry drug related adverse events reported with more confidence (background events in the absence of treatment will be known)

29 RD-Connect

30 RD-Connect: main objectives 30 An integrated platform connecting databases, registries, biobanks and clinical bioinformatics for rare disease research Overarching objectives: Contribution to the IRDiRC objectives of delivering 200 new therapies for rare diseases and means to diagnose most rare diseases by the year 2020 Development of an integrated, quality-assured and comprehensive platform in which complete clinical profiles are combined with -omics data and sample availability for rare disease research, in particular IRDiRC-funded research

31 Linked with omics research projects 31 HEALTH B: Clinical utility of -omics for better diagnosis of rare diseases TWO projects, EU contribution EUR 12 million per project Duration: 5 years European Consortium for High-Throughput Research in Rare Kidney Diseases (Franz Schaefer, Universitätsklinikum Heidelberg, Germany) Integrated European Project on Omics Research of Rare Neuromuscular and Neurodegenerative Diseases (Olaf Riess, Institute of Human Genetics, University of Tübingen)

32 Workpackage overview 32 WP1: Coordination WP2: Patient registries WP3: Biobanks WP4: Bioinformatics Hanns Lochmüller Newcastle and TREAT-NMD Domenica Taruscio ISS and EPIRARE Lucia Monaco Fondaz. Telethon & EuroBioBank Christophe Béroud INSERM Marseille WP5: Unified platform WP6 Ethical/legal/social WP7: Impact and innovation For more information contact the Project Coordinator Hanns Lochmüller on Ivo Gut CNAG Barcelona Mats Hansson Uppsala Kate Bushby Newcastle and EUCERD/ EJARD

33 33 Key interactions: platform and data exchange

34 RD-Connect additional objectives: Patient Registries 34 Patient registries: developing best practice for registries used for research establishing interoperability standards, common data elements => feeding into central platform Map existing registry infrastructure Establish Registries Core Implementation Group (CIG) Bring together leaders of flagship registries from Neuromics, EURenOmics plus other advanced registries e.g. CF, Huntington's Evaluate best practice, define registry common data elements, implement standardised coding systems and ontologies and establish SOPs for consent, oversight, collection, storage and retrieval of data to improve the suitability of databases/registries for research use Implement agreed best practice and global unique identifier (GUID)

35 35 Thank you for your attention!