Summary of the United Kingdom National Workshop on Duchenne Muscular Dystrophy Clinical Trial Capacity

Transcription

1 Summary of the United Kingdom National Workshop on Duchenne Muscular Dystrophy Clinical Trial Capacity

2 Organised on behalf of TREAT-NMD by Dr Annemieke Aartsma-Rus, Chair of the TREAT-NMD Alliance Executive Committee Professor Kate Bushby, Professor of Neuromuscular Genetics at the John Walton Muscular Dystrophy Research Centre, Newcastle University Dr Stephen Lynn, TREAT-NMD Network Project Manager, the John Walton Muscular Dystrophy Research Centre, Newcastle University Gillian Kenyon, Clinical trials Co-ordinator, the John Walton Muscular Dystrophy Research Centre, Newcastle University Kim Down, Duchenne Muscular Dystrophy Co-ordinator, the John Walton Muscular Dystrophy Research Centre, Newcastle United Kingdom & Ireland Patient Organisation Participants: Action Duchenne Alex s Wish DMD Pathfinders Duchenne Ireland Duchenne Now Harrison s Fund Joining Jack Join our Boys Trust Muscular Dystrophy UK The Duchenne Children s Trust The Duchenne Family Support Group The Duchenne Research Fund 2

3 Table of Contents Introduction 4 Workshop Rationale 4 Clinical trial readiness for Duchenne Muscular Dystrophy 4 Current Support Received from Patient Organisations 6 What Does it Take to Run a Trial for DMD? 6 Clinical Trial Site Perspective 6 Industry Perspective 8 Session One Discussion 8 Service Delivery for DMD: Standards of Care and North Star Network 9 UK North Star Clinical Network for DMD 9 Physiotherapy Perspective 10 How Does the National Institute for Health Research Support TrialS? 11 Parent Project Muscular Dystrophy: A US Model for Capacity Building and Supporting Care 12 Session Two Discussion 13 The Newcastle Plan 13 Action Timeline 14 In Conclusion 15 Appendix A Ongoing DMD Studies in the UK with Sites and Numbers of Participants 17 Appendix B Action Plan Template 19 Appendix C Working Goup Discussion 20 Appendix D Workshop Summary Feedback 23 Appendix E List of Workshop Attendees 26 Tables: Table 1 Sites and Numbers of Participants for Ongoing DMD Studies in the UK Images: Image 1 Clinical Trial Timeline 3

4 INTRODUCTION WORKSHOP RATIONALE Patient organisations representing Duchenne muscular dystrophy (DMD) are concerned about the apparent lack of capacity for trials in DMD in the UK. DMD is the most common fatal genetic disorder diagnosed in childhood, affecting approximately 1 in every 3,500 live male births (around 2500 people have DMD in the UK). Because the DMD gene is found on the X-chromosome, it primarily affects boys with less than 1% of those with Duchenne being female. However, it occurs across all races and cultures. Duchenne results in progressive loss of strength and function and is caused by a mutation in the gene that encodes dystrophin. Because dystrophin is absent, the muscle cells are easily damaged. The progressive muscle weakness leads to serious medical problems, particularly issues relating to the heart and lungs. 1 Clinicians in larger centres are involved in multiple DMD studies and are reaching capacity, while smaller centres need support to develop their clinical trial capacity. The workshop brought together a group of 75 people representing patient organisations, clinical staff from different centres as well as representatives from the National Institute for Health Research (NIHR) and industry both to assess the current situation and to develop a strategy to improve capacity and better utilise resources. These representatives met in Newcastle on the 10 th of July, 2015 under the chairmanship of Annemieke Aartsma-Rus, the current chair of the TREAT-NMD Alliance. CLINICAL TRIAL READINESS FOR DUCHENNE MUSCULAR DYSTROPHY Emily Crossley, from Duchenne Children s Trust eloquently described the rationale for the meeting from the patient perspective. DMD is fatal and currently there is only one approved treatment helping a small sub-group of boys with the disease. The relentless progression of the disease makes the urgent need for drug development and the capacity to undertake all upcoming trials abundantly clear. Far from turning away trials the aim of the entire community is that all boys and 1 Action Duchenne. What is Duchenne Muscular Dystrophy? Available at < viewed 13 July

5 men with DMD are part of a trial, be it therapeutic or part of a natural history study. Turning away clinical trials is not acceptable. DMD research is at an unprecedented stage in terms of numbers of possible therapies coming to trials. Supported by extensive patient registries, work on outcome measures and regulatory interactions led by TREAT-NMD and other groups, multinational studies in DMD are clearly feasible. National efforts have been supported for many years by a patient registry funded by Action Duchenne and the North Star network supported by Muscular Dystrophy UK. However, to date involvement of trial sites in the UK outside the main centres at Newcastle and London has been limited, especially in industry funded studies. See Appendix A for a list of ongoing DMD studies in the UK and table 1 with totals below. Site Studies Participants Birmingham* 2 8 Cambridge 1 0 Glasgow 1 8 Leeds 1 8 Liverpool* 3 20 London* Manchester* 2 4 Newcastle* 8 75 Oxford* 1 3 Table 1 Sites and Numbers of Participants for Ongoing DMD Studies in the UK 2 2 *Indicates Industry studies are taking place at this site. 5

6 CURRENT SUPPORT RECEIVED FROM PATIENT ORGANISATIONS Patient organisations have been major supporters of the clinical trial infrastructure in DMD for many years. Patient organisations provide a great deal of support for infrastructure to support clinical trials and communication. The following are examples of the support patient organisations in the United Kingdom currently provide: Muscular Dystrophy-UK funds a Clinical Trials Coordinator in Newcastle and London (longstanding). Joining Jack, Action Duchenne, Duchenne Now, Duchenne Children s Trust, Duchenne Research Fund, Harrison s Fund and Alex s Wish fund a Clinical Trial Principal Investigator with co-funding from Newcastle University (from July 1st 2015). Action Duchenne: DMD patient registry, International Duchenne Conference, Tripartite funding with the Chief Scientific Office (Scotland) and MD-UK for 3-year Clinical Research Fellowship (Dr Shuko Joseph this yet to be formally announced by the CSO). Joining Jack, Duchenne Children s Trust and Duchenne Research Fund: fund the TREAT-NMD DMD Programme coordinator (from June 1st 2015). Action Duchenne fund the DMD patient registry (longstanding). Muscular Dystrophy-UK supports the North Star clinical network data collection, data management and network meetings (longstanding). The support of Patient Organisation s has allowed the development of trial capacity in the centres at Newcastle and London in particular. Both centres have significant research income which also underpins their trial capacity. WHAT DOES IT TAKE TO RUN A TRIAL FOR DMD? CLINICAL TRIAL SITE PERSPECTIVE Gillian Kenyon, Trial Co-ordinator, The John Walton Muscular Dystrophy Research Centre (JWC), described the process of trial set up, using a recent example from a Pfizer funded study. The JWC centre currently has 8 DMD trials open (along with a number of non-dmd related trials) supported by two full time trial coordinators and one part time, eight doctors who contribute to clinical trials, four physiotherapists and they work closely with the Clinical Research Facility (the team 6

7 includes nurses, trial coordinators and data managers) where the trials are conducted. The study team at Newcastle is supported predominantly via University and grant funding streams. Gillian demonstrated the timelines for the trial, discussed the regulatory hurdles, and clarified the process of setting up a clinical trial. Image 1 Clinical Trial Timeline Once the study is up and running there are additional requirements which take time and resources such as: scheduling of appointments within study window and liaison with patients to arrange; availability of nurses, doctors, physios; increase in trials needs more admin time; completion of ecrfs and data entry; query resolution; monitoring visits; study specific amendments. 7

8 INDUSTRY PERSPECTIVE Christine Medhurst from Pfizer provided an overview of the perspective of an industry sponsor in site selection and feasibility. She discussed the drug development process and product development timeline. The key factors that industry take account of when choosing a site for a clinical trial is the selection of an appropriate investigator and the resources that a site offers (e.g. study required equipment, product storage, room availability, access to subjects etc.). Of nine sites which were identified in the UK for feasibility for a DMD study only two were selected. The others were not selected for the following reasons: 2 Sites did not meet the requirements for MRI. 1 Site had a competing study. 1 Site declined because of insufficient resources. 1 Site could not commit to recruit 3 patients. 1 Investigator was on long term sick leave. 1 Investigator was not interested to participate. The current DMD study status for this study is that globally 11 patients have been recruited and if the proof of concept study is positive there may be a request for early registration of the drug. Within the UK the NIHR is providing excellent support and the UK sites are open to recruitment, with Newcastle recently recruiting the first European patient. Pfizer will fund a nursery for siblings to attend during study visits and a website for the study will be launched to keep people up to date on study outcomes. SESSION ONE DISCUSSION The discussion following these presentations centred on elements of support which might be able to deliver increased trial capacity and increase the attractiveness of UK sites to industry. In essence, the steady state is already complicated and the UK does not have the capacity for currently offered studies in DMD. We are also facing an exponential increase in trials coming online for which we are manifestly not prepared. Some principal investigators and other site staff are working in their own time at evenings and weekends to be able to deliver studies. Research and Development approvals also remain a bottleneck in the UK: in the Pfizer study presented, there was a time lag of 4 months between US sites being ready to recruit and the UK due to R&D delays. Global trials are set up on a competitive basis. If there are no UK sites which have capacity and can respond in a timely manner other countries will 8

9 step in. If companies see gaps in the infrastructure they will move their studies to other countries. A major issue for UK sites is the way that studies are funded. There is little flexibility for upfront funding from industry or other sources. Here funding follows recruitment, leaving no possibility to put staff in place to support a study before it is actually up and running. Centres need a credit line that they can draw upon which would also ensure continuity (due to patchy funding experienced staff cannot be maintained). Site set up is costly and this cost is the same for highly complex, low recruiting studies in rare diseases such as DMD as for large scale studies where the financial benefits on successful recruitment of large patient numbers are greater. From the point of starting trial set up there is a cost which is typically not funded via the study allocation. These elements of trial set up have been greatly facilitated at the London and Newcastle sites with Muscular Dystrophy UK (MDUK) funded Trial Coordinators and support from the Medical Research Council Neuromuscular Centre. At the end of trials, patients are typically offered the opportunity to participate in extension studies. This adds to patient numbers at the sites involved as essentially patients never come to the end of studies, this in turn however, adds to the burden for those site teams. Additional data on long term effectiveness of drugs will require a systematic investment in post marketing surveillance efforts. TREAT-NMD and the MDUK funded North Star network are hoping that a Duchenne specific registry will be able to fulfill these obligations, in line with recent European Medicines Agency (EMA) advice on the use of disease registries rather than registries set up specifically for individual drugs. SERVICE DELIVERY FOR DMD: STANDARDS OF CARE AND NORTH STAR NETWORK UK NORTH STAR CLINICAL NETWORK FOR DMD Professor Francesco Muntoni, Director of the Dubowitz Neuromuscular Centre, University College London illustrated the effect of networking via the UK North Star Clinical Network for DMD. The objectives of the North Star network are: To develop a nationally agreed and standardised clinical and physiotherapy assessment protocol to monitor change in DMD. 9

10 The initial focus was to optimise and standardise steroid therapy in ambulant boys with DMD. To develop a national clinical database for a large cohort of patients with DMD to facilitate clinical audit and review. The network consists of lead consultants and senior physiotherapists from 17 paediatric neuromuscular centres across the UK, who have formally signed up to the project and 3 or 4 others who continue to be involved through meetings and distribution lists. Groups of staff meet on a regular basis to discuss best management and to formulate guidelines for professionals and information for families. Site participation is voluntary and there is no reimbursement for participation. The North Star network developed a functional assessment scale for ambulatory boys with DMD and maintains a database of patients. The North Star network has 20 UK neuromuscular centres within its network. However, it faces the following challenges: funding insecurity (year on year) for coordinator and Certus (IT provider); limited supporting infrastructure in NHS clinics; discussion with NHS England to consider this a fundable network (like renal and Cystic Fibrosis) not productive to date; no funding to individual centres for facilitating compliance (medical; physio; coordination); lack of resources to collect missing data, perform accuracy checks; the above is an obstacle for post-marketing surveillance; links with NHS databases for forward planning and alerting; non-ambulant DMD individuals adoption. PHYSIOTHERAPY PERSPECTIVE Anna Mayhew, Consultant Physiotherapist, The John Walton Muscular Dystrophy Research Centre, summarised the physiotherapy training efforts which have underpinned the network. The North Star network offers many clinical benefits for physiotherapists ensuring that: they are all trained in standardised clinical assessments; linked to standards of care; there are audits able to be carried out 10

11 e.g. range of movement and NSAA. The network also brings benefits to trial readiness including: outcomes assess eligibility for clinical trials (FVC, NSAA score, ankle ROM); giving confidence to physiotherapists taking part in trials; linearization of the NSAA score for better measurement for trials (Mayhew 2013). Again, the challenges for the future include the funding required to introduce a new physiotherapy trainer in order to ensure that assessments, standards of care and management (orthotics, respiratory) are standardised across sites and are of a high standard. National meetings, online training and a training hub with at site access to patients are all areas which the network should look to expand within if funding is made available. Anna also discussed the current research focusing on the development of validated outcome measures for the non-ambulant DMD population and adults with DMD. Non-ambulant groups Performance of Upper Limb Myometry Patient reported outcome measures (PROMs) Adults Arm and trunk function FVC PCF Contractures Quality of Life These lists came with an acknowledgement that there is more work to be done on standards of care for adults in order to facilitate future trial readiness in this population group as well. HOW DOES THE NATIONAL INSTITUTE FOR HEALTH RESEARCH SUPPORT TRIALS? Matt Cooper, Business Development and Marketing Director from the National Institute for Health Research (NIHR) Clinical Research Network (CRN) summarised the success of the NIHR infrastructures and local network support in improving trial capacity and efficiency in England. The NIHR CRN has research active clinicians across 30 Specialties, with 15 Local Clinical Research Networks (LCRNs) allowing for flexible deployment of resources. 11

12 The Clinical Research Network s activities centre on the NIHR Clinical Research Network (NIHR CRN) Portfolio. The portfolio consists of clinical research studies that are eligible for consideration for support from the Clinical Research Network in England. The Portfolio database captures research activity data and provides analysis tools to facilitate active management of current studies, and the feasibility of future studies run within the Clinical Research Network. All of the DMD studies currently ongoing in the UK are on the NIHR CRN portfolio. The recent re-structuring of the Clinical Research Network has resulted in the creation of The Children Specialty through the alignment of the Medicines for Children Research Network (MCRN) and the Paediatric (non-medicines) Specialty Group into one specialty covering children s research. The specialty is made up of research-interested clinicians and practitioners at both national and local levels. The NIHR CRN s job is to ensure that studies related to children included in their national portfolio of research receive the support necessary to ensure they are delivered successfully in the NHS. PARENT PROJECT MUSCULAR DYSTROPHY: A US MODEL FOR CAPACITY BUILDING AND SUPPORTING CARE Parallel efforts in the US led by Parent Project Muscular Dystrophy, presented by Kathi Kinnet, Vice President, Clinical Care, have established accredited care centres and standards for clinical trials. The Certified Duchenne Care CETMER Program was set up in order to ensure that sites were providing care in agreement with the DMD Care Considerations; to improve patient access to optimal comprehensive care and with the goal of reducing variation in clinical trial outcomes. The accreditation is given through gathering application surveys, performing site visits, chart reviews, and the decision of the certification committee. Reports by patients and parents as well as annual center metrics are taken into account. Following on from the program PPMD are assessing the feasibility of building a clinical trials network and deciding the criteria for certification as a DMD clinical trial site. There is a clear imperative for sharing of good practice across international settings, and efforts such as the MDUK centre of excellence audit and the PPMD initiative have many similarities. In addition, there is a strong emphasis on collection of specific NMD related trial capacity information via the TREAT-NMD Care Trial Site Registry. 3 3 Rodger, S., et al. (2013) The TREAT-NMD care and trial site registry: an online registry to facilitate clinical research for neuromuscular diseases. Orphanet Journal of Rare Diseases. 8, pp

13 SESSION TWO DISCUSSION In the discussion following session one, the lack of data on adult patients was highlighted as well as the lack of adult trials. There are developments within the North Star and other registries in this area and new outcome measures are in development. Given this increase in knowledge, the next step should be engagement of industry in the initiation of trials in older patients, once regulators are in agreement that these outcome measures are reliable and clinically meaningful. The North Star network has generated a wealth of data but has struggled with funding. MDUK remains committed to its support and development. Needs for equipment for the roll out of non-ambulant measures might be met by requests to industry for small grants. NIHR support for trials has concentrated to date inevitably on common diseases. There are specific elements of need for rare disease populations, including the high upfront costs for small patient numbers and lack of capacity of specialised doctors and physiotherapists. One model to explore could be a partnership between patient organizations and NIHR so that contracting could be agreed whereby upfront investment from Patient Organisations could be repaid on the receipt of funding for patient visits. A very positive opportunity would include the NIHR brokering this model as well as possible partnerships with industry. Dr Oliver Rausch, Programme Director of the NIHR Translational Research Partnerships made the point that the Translational Research Collaboration (TRC) in rare diseases could have an impact in organisation of Rare Disease networks engaged in clinical research. Initial funding has concentrated on deep phenotyping but ways to move forward with these initiatives to concentrate also on capacity issues could also be explored. THE NEWCASTLE PLAN Three breakout groups (discussion from the working groups is outlined in Appendix C) discussed a series of questions relating to the presentations during the day and an action plan was generated. The following outlines the ideas from the groups in the form of a one, two and five year plan. Overall, the meeting concluded that the UK must continue to be one of the key go to countries for clinical trials in DMD, and a huge willingness was clearly demonstrated from all parties to increase capacity and maintain and improve quality. 13

14 Three phases of development were discussed, to be taken forward by a working group derived from the meeting participants. The five year objective should be to ensure that all patients with DMD, children and adults, have access to clinical research opportunities. An action plan template is available in Appendix B. A one year plan would aim to immediately boost capacity at existing UK centres of excellence, so that no more trials are turned away. The aim is for posts to be filled within the next 6-9 months. A two year, or medium term plan would aim to build excellence and capacity at existing sites that have trial experience but need resource. The aim of a five year plan is to ensure that all patients with DMD, including children and adults, have access to clinical research opportunities. ACTION TIMELINE Year One (2015/16) Years 2 3 (2017/2019) Year Five (2020) 1. Convene steering group & patient organisation group. 2. Map current staffing, training and equipment requirements. 3. Explore current models such as the Trial Acceleration Programme, epilepsy surgery model, and boost support for current networks etc. 4. Increase knowledge sharing through developing mechanisms for mentoring and sharing. 5. Explore co-funding models in collaboration with NIHR, industry and patient organisations (review current international models, proposals and other initiatives). 6. Focus on trials and outcome measures for adults. 7. Explore closer working with the NIHR. 1. Pilot co-funding models. 2. Build capacity outside the main sites of Newcastle and London. 3. Development of a monitoring and feedback mechanism for care standards in sites. 4. Development of models where trial activities could be shared between sites and where extension studies could be performed in centres near patients homes (adult developments would be in years 2-5). 1. Consolidation of a DMD Clinical Research Consortium underpinning a clinical trial and care delivery network wherein all patients with DMD are offered the option to participate in clinical research. 2. Enroll every patient enrolled on the register and in a trial, be it therapeutic or as part of a natural history 14

15 study. IN CONCLUSION Overall, the meeting concluded that the UK must continue to be one of the key go to countries for clinical trials in DMD, and a huge willingness was clearly demonstrated from all parties to increase capacity and maintain and improve quality. Three phases of development were discussed, to be taken forward by a working group derived from the meeting participants. The five year objective should be to ensure that all patients with DMD, children and adults, have access to clinical research opportunities. A smaller group will form who will oversee how the plan takes shape over its lifetime. This group will look at a summary of the current situation, will consider a map of resources and look to produce a publication which will carry more weight in the long term. The patient organisations will meet to ensure that the funding which is available to move the process forward can be identified and efforts coordinated. The ongoing MDUK audit will also be extended to ensure that detailed information about requirements for capacity building is systematically collected. Additional capacity at other sites will need to be addressed for both children and adults. Key to this will be discussion with the NIHR to maximize the mechanisms for DMD research as a paradigm for the growing field of rare diseases. This will require a way to match the existing infrastructure of the field (including the North Star network and TREAT-NMD) with the resources of the NIHR and the ways that NHS services for DMD are provided. One outcome of this kind of collaboration could be the development of a DMD clinical research consortium in the UK. Collaborative funding models including pharma and patient organizations need to be systematically explored: preferably NIHR brokered with the possibility for reimbursement to patient organisations on the basis of income generated from trials. Moving to a position where the UK position in trials is assured would add extra possibilities including the ability to attract and retain more physios, research fellows, nurses and trial co-ordinators. The development of models where trial activities could be shared between sites and where extension studies could be 15

16 performed in centres closer to patients homes could begin to inform protocol development once there was confidence in the overall UK approach. History is made in small moments of time opportunities grasped that can change the landscape of DMD for this and future generations of children diagnosed with DMD for the better. Let s make this one of those moments. Emily Crossley, Founder and Director of Duchenne Children s Trust and mother of Eli, who has DMD. 16

17 APPENDIX A ONGOING DMD STUDIES IN THE UK WITH SITES AND NUMBERS OF PARTICIPANTS Title Sponsor Sites # Recruited A study of corticosteroids in Duchenne muscular dystrophy (FOR-DMD) National Institutes of Health Birmingham Cambridge Glasgow Leeds Liverpool London Manchester Newcastle A double-blind randomised multi-centre, placebocontrolled trial of combined ACE-inhibitor and betablocker therapy in preventing the development of cardiomyopathy in genetically characterised males with DMD without echo-detectable left ventricular dysfunction (DMD Heart Protection Study) Newcastle upon Tyne Hospitals NHS Foundation Trust Liverpool London Newcastle Outcome measures in Duchenne Muscular Dystrophy: a Natural History Study French Muscular Dystrophy Association (AFM) London Newcastle An Open-Label study for previously treated Ataluren (PTC 124 ) Patients with Nonsense mutations Dystrophinopathy (PTC019) PTC Therapeutics London Newcastle 8 11 Prosensa 045: A phase I/IIb, open-label, escalating dose study to assess the safety and tolerability, pharmacokinetics, Prosensa London Newcastle

18 pharmacodynamics and clinical effects of multiple subcutaneous doses of PRO045 in subjects with Duchenne muscular dystrophy (Pro045) A phase 3 efficacy and safety study of Ataluren (PTC124) in patients with nonsense mutation dystrophinopathy (PTC020 & extension study) PTC Therapeutics London Newcastle 7 4 A Phase I/II, open-label, dose escalating with 48- week treatment study to assess the safety and tolerability, pharmacokinetics, pharmacodynamics and efficacy of PRO053 in subjects with Duchenne muscular dystrophy (Pro053) Prosensa London Newcastle 1 1 A 2-Part, Randomized, Double-Blind, Placebo- Controlled, Dose-Titration, Safety, Tolerability, and Pharmacokinetics Study (Part 1) Followed by an Open-Label Efficacy and Safety Evaluation (Part 2) of SRP-4053 in Patients with Duchenne Muscular Dystrophy (DMD) Amenable to Exon 53 Skipping. (SKIP) Sarepta London Newcastle 3 2 Phase 1b/2, double-blind, placebo-controlled, withinsubject, dose escalation study to evaluate the safety, efficacy, pharmacokinetics and pharmcodymamics of PF administered to ambulatory boys with Pfizer Newcastle 1 18

19 Duchenne Muscular Dystrophy. A Phase 1b Placebocontrolled, Multi-centre, Randomized, Double-blind Dose Escalation Study to Evaluate the Pharmacokinetics (PK) and Safety of SMT C1100 in Patients With Duchenne Muscular Dystrophy (DMD) Who Follow a Balanced Diet SUMMIT Birmingham Liverpool London Manchester A Randomized, Double- Blind, Placebo-Controlled, Phase 3 Trial of Tadalafil for Duchenne Muscular Dystrophy Eli Lilly Oxford 3 APPENDIX B ACTION PLAN TEMPLATE Goal: Form a Smaller Group to oversee how the plan takes shape over its lifetime Action Step What needs to be done? Responsible Person Who should take action to complete this step? Deadline When should this step be completed? Necessary Resources What is needed in order to complete this step? Potential Challenges What might impede completion of this goal and how will it be overcome? Result Was this step successfully completed? Were any new steps generated? Find interested parties Convene Group 19

20 Goal: Patient organisations meeting to ensure funding needed for short term can be aggregated Action Step What needs to be done? Responsible Person Who should take action to complete this step? Deadline When should this step be completed? Necessary Resources What is needed in order to complete this step? Potential Challenges What might impede completion of this goal and how will it be overcome? Result Was this step successfully completed? Were any new steps generated? Find date for meeting in September. Kim Down 17 July Administration Time N/A Sort meeting arrangements. Kim Down 28 August Administration Time Venue and cost of meeting. Conduct meeting. Kim Down TBC Administration Time N/A APPENDIX C WORKING GOUP DISCUSSION WORKING GROUP ONE Suggestions from working group one included: Putting in resource to prevent trials being turned away due to lack of capacity. In practice this will most likely involve investment at the London and Newcastle sites and the other sites with current industry studies but limited additional capacity. Training and capacity must be enhanced and those trained in Newcastle and London should in turn be facilitated able to train people in other centres and share experiences. A clinical trial capacity road show should be held so that other sites can learn from Newcastle and London s experience. 20

21 Develop a mechanism for mentoring and sharing of experience from the teams at Newcastle and London: for example from the trial co-ordinators, physio teams and mentorship of young doctors. Provide the equipment and support required to allow all sites to develop full capacity for upper limb and other assessments so that the strengths of the North Star network can be fully realized. To move from these immediate priorities to the ultimate aim of access to clinical trials for all patients will require a series of targeted interventions and collaborations to be established and deliver over the intervening 4 years. Additional capacity at other sites will need to be addressed for both children and adults. Key to this will be discussion with the NIHR to maximize the mechanisms for DMD research as a paradigm for the growing field of rare diseases. This will require a way to match the existing infrastructure of the field (including the North Star network and TREAT-NMD) with the resources of the NIHR and the ways that NHS services for DMD are provided. One outcome of this kind of collaboration could be the development of a DMD clinical research consortium in the UK. Collaborative funding models including industry and patient organizations need to be systematically explored: preferably NIHR brokered with the possibility for reimbursement to patient organisations on the basis of income generated from trials. Moving to a position where the UK position in trials is assured would add extra possibilities including the ability to attract and retain more physios, research fellows, nurses and trial co-ordinators. The development of models where trial activities could be shared between sites and where extension studies could be performed in centres closer to patients homes could begin to inform protocol development once there was confidence in the overall UK approach. WORKING GROUP TWO Lack of staff remains the major barrier in implementing trial capacity across sites. This includes clinical fellows, paediatric research nurses, physiotherapists and administrative personnel. Different sites require varied support (generally NHS sites are more in need of clinical fellows, while academic sites might require physiotherapists, nurses and administrators). Funding for staff conducting clinical trials is an issue. Initiating a discussion with the NIHR on this is essential with the plan to have matching funding between NHS, NIHR, Charities and pharmaceutical companies, to allow payment upfront and long 21

22 term (short term, trial specific posts are not attractive to applicants especially where contracts are continually under review). There could be de-centralisation of some study procedures (e.g. drug administration and safety monitoring) and performing efficacy assessments and highly specialised procedures centrally would enhance trial capacity. This has been done for one study (Prosensa/GlaxoSmithKline with home dosing, but the approval system required more than 12 months to be in place so such arrangements are best set up prospectively). It was highlighted that research should be part of the training requirements for doctors so we can prepare the next generation of trial doctors and other specialists. Good research requires maintaining high standards of care and outcome measures (e.g. physiotherapist training and the North Star Ambulatory Assessment database). It may be useful to discuss merging the North Star and UK DMD registries if funding is secured from the NHS. There is also urgent need of clinical trials in non-ambulatory patients. Suggestions for working group two included: Start interaction with the commissioning to ensure that research is a service specification for all neuroscience centres. This will allow us to monitor them against this target. Research should be therefore added in the document currently under review regarding service specification for neuromuscular centres and should be added in NICE guidelines. Produce a map with specific staff requirements for each UK site. A questionnaire to be produced and circulate asking which staff is required at each site to increase trial capacity. Initiate a discussion with NIHR regarding funding and the possibility of a system of matching funding within R&D, NIHR, charities and pharmaceutical companies, to allow payment upfront and long term. Start discussion with NIHR how to facilitate collaborations with different R&D departments to speed regulatory approvals for satellite sites. Discuss with Helen Roper how to ensure that research can be added in the training program for specialists through the BPNA. Consider the possibility of a core team from the specialised centres (Newcastle and London) to provide training to other sites (physiotherapy, trial coordinators, nurses, clinicians). Charities (MDUK) to implement/improve funding for the NSAA as discussed during the workshop. 22

23 Encourage pharmaceutical companies to design studies for nonambulant population using the scales currently available (respiratory and cardiac function, PUL, PROMM). WORKING GROUP THREE There was agreement within the groups that the UK can provide plenty of experience for research studies, that there is expertise, numbers for trials and willingness to participate. Although there was also recognition that trial capacity was limited. It was suggested that a large number of research centres would not work in the UK but that they should potentially increase to 5 centres of excellence. Funding for these centres could benefit from a combined approach between charity, industry and the NIHR, brokered by the NIHR. Some doubts regarding this approach were expressed by industry who felt that there may be an issue with regards to funding sites which may be used for rival company s studies; however, there may be solutions to this issue. There was also the idea expressed that costs could also be saved through sites having a more group approach (for example between CRF s) where staff or facilities could be shared. The need to ensure that care standards in sites are monitored through some mechanism was also raised. APPENDIX D WORKSHOP SUMMARY FEEDBACK Comments from Matt Cooper, National Institute for Health Research (NIHR): The NIRH portfolio supports both rare disease and common disease studies but as there are more common disease studies so the proportion of funding given over to support those common diseases is larger. Regarding Action Timeline: Year One Action Two Produce a 'site CV' documenting the capacity and capability to conduct DMD research and act as a promotional tool to engage life sciences companies to place studies. How does this link to areas of excellent service provision? 23

24 Make service provision and research opportunity seamless - link to ongoing audit. Use patient organisations to lobby for better service provision with the research part of the patient journey. Year One Action Five Map out all of the global life sciences companies engaged in product development in DMD. Year One Action Seven Develop the patient organisation s understanding of the NIHR infrastructure and funding routes. Comments from Action Duchenne: First of all Action Duchenne would like to thank you for the comprehensive nature of this report and the detailed summation of discussions from the meeting in Newcastle on July 10th We are furthermore broadly supportive of the conclusions drawn, and the directional strategy posited within the Newcastle Plan. We welcome the opportunity however; to push for further specificity within the Action Timeline designed to underpin the achievement of clinical research opportunities for all DMD patients within five years. It will be important to tie the emergency funding measures, taken within the initial year, to an overarching and sustainable model centred upon the needs of industry and the research pipeline for DMD. There should be no disconnection. This will necessitate a holistic appraisal of existing Phase 1, 2 & 3 studies along with the broader research pipeline and direction of travel. If our initial and primary short-term concern should be that the UK is open for business and doesn t turn down clinical trials, this has to be our starting point, and will in turn, determine what posts/infrastructure/equipment needs to be funded, at what centres, by the patient organisations in the first year. Secondly, whilst we acknowledge and support the short-term commitment to Explore closer work with the NIHR, this strategy needs to be fleshed out more sufficiently to explore how to bring in the necessary additional stakeholders (NHS England, APBI etc.) who will be integral to ensuring continuity of funding in the longer term. This will, to some extent, be dependent on our success in formulating a persuasive narrative around NHS England and NIHR responsibility for rarer conditions and the importance of Life Sciences to the UK economy etc. 24

25 Thirdly, while we support the intention to proliferate capacity development beyond the main sites of Newcastle and London within the 2-3 year strategy, this should in no way preclude the possibility for this to begin within the opening year, if indeed such developments are congruent with the research pipeline and needs of industry within the immediate short term. On the question of building capacity outside the main existing sites, there needs to be a recognition and understanding of why this is crucial to the Newcastle Plan s ultimate aim. Indeed, whilst such developments should be made if they are consistent with the needs of industry and the ability of the UK to host all prospective clinical trials possible, we need also to consider the question of patient accessibility to trials from a geographical perspective. As a long term objective it should not be unachievable for the majority of Duchenne patients to have access to clinical research opportunities within approximately two hours travelling distance of their home. Whilst we welcome the commitment to boost clinical trial opportunities and accessibility for the adult population living with Duchenne, we need to tackle an overreliance upon Queens Square and formulate a coherent and measurable long term plan that begins in the first year. Mapping the Duchenne pipeline to its current and future needs is integral to the high level plan; in doing so this may mean that the satellite centres can develop and support the current centres of excellence, in the shortterm. Young men and adults living with Duchenne and their clinical needs are also integral in the emergency plan and beyond. Comments from Kerry Rosenfeld Co-founder of the Duchenne Research Fund: It would be helpful to explore the possibility of collaboration with other neuromuscular charities/organisations, to see how we could jointly fund machinery/technicians that would benefit many trials across different muscular issues. That way more machinery and staff would be in use constantly, and the expense is more justifiable. I realise these sorts of machines cost a fortune to buy and maintain. MRI machines, a big issue in past trials, would need to be in use every day to be cost effective so the expense could be potentially be shared with departments with people with general muscle problems not just rare diseases. 25

26 APPENDIX E LIST OF WORKSHOP ATTENDEES Name Annemieke Aartsma-Rus Gautam Ambegaonkar Julie Anderson Jayne Banks Peter Baxter Marta Bertoli Michael Binks Louise Bishop Nic Bungay Kate Bushby Jordan Butler Jonathan Calthrop Saleel Chandratre Mark Chapman Charlotte Chapman Lawrence Charnas Michelle Cioffi Janis Clayton Matt Cooper Emily Crossley Damian Culhane Becky Davis Marina Di Marco Celeste Di Johnson Kim Down Jennifer Dunne Paul Fitzpatrick Aidan Gill Vasantha Gowda Katie Groves Michael Hanna Imelda Hughes Paul Humphrey Meredith James Anne Jeffers Alexandra Johnson Kathi Kinnett Organisation Leiden University Medical Center Addenbrookes Hospital, Cambridge Great North Children's Hospital Newcastle NHS Trust Sheffield Children s Hospital John Walton Medical Research Centre, Newcastle University Pfizer Duchenne Children s Trust Muscular Dystrophy United Kingdom John Walton Medical Research Centre, Newcastle University University College London PA for Mark Chapman Oxford University Hospitals NHS Trust DMD Pathfinders Bristol-Myers Squibb Parent Project Muscular Dystrophy Summit Therapeutics PTC Therapeutics NIHR CRN Coordinating Centre Duchenne Children's Trust Parent John Walton Medical Research Centre, Newcastle University National Health Service, Scotland Sarepta Therapeutics John Walton Medical Research Centre, Newcastle University Neuromuscular Clinical Nurse Specialist, Scotland Duchenne Now PTC Therapeutics Evelina London Children's Hospital Great Ormond Street Hospital Institute of Neurology, University College London Royal Manchester Children's Hospital Biomarin John Walton Medical Research Centre, Newcastle University Join Our Boys Trust Joining Jack Parent Project Muscular Dystrophy 26

27 Gillian Kenyon Paula Naughton Stephen Lynn Anirban Majumdar Anna Mayhew Janet McCay Heather McMurchie Robert Meadowcroft Christine Medhurst Sharon Moran Francesco Muntoni Hattie Murdock Marita Pohlschmidt Richard Pye Oliver Rausch Aaron Revel Dionne Reynolds Diana Ribiero Valeria Ricotti Vici Richardson Alasdair Robertson Eric Romero Kerry Rosenfeld Joel Schneider Alex Smith Stefan Spinty Katherine Tanney Cathy Turner Edith van Dijkman Olav Veldhuizen Thomas Voit Katherine Wedell Fiona Yelnoorkar John Walton Medical Research Centre, Newcastle University Join Our Boys Trust John Walton Medical Research Centre, Newcastle University University Hospital Bristol John Walton Medical Research Centre, Newcastle University South West Neuromuscular ODN Heart of England, National Health Service Trust Muscular Dystrophy United Kingdom Pfizer Tallaght Hospital, Dublin Ireland Institute of Child Health, University College London Newcastle University Muscular Dystrophy United Kingdom Summit Therapeutics National Institute for Health Research Office for Clinical Research Infrastructure, National Institute for Health Research Action Duchenne Clinical Research Facility Royal Victoria Infirmary, Newcastle Action Duchenne Institute of Child Health, University College London Duchenne Now Duchenne Children s Trust PA to Mark Chapman Duchenne Research Fund SOLID Biosciences Harrison's Fund Alder Hey Children's Hospital, Liverpool Newcastle upon Tyne Hospitals NHS Foundation Trust John Walton Medical Research Centre, Newcastle University Biomarin John Walton Medical Research Centre, Newcastle University Institute of Myology Action Duchenne National Institute for Health Research 27