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Antisense oligonucleotide (ASO) mediated exon skipping aims to reframe dystrophin transcripts for patients with Duchenne muscular dystrophy (DMD). Currently 4 ASOs have been approved by the Food and Drug Administration targeting exon 45, 51 and 53 based on low level dystrophin restoration. Additional studies to confirm functional effects are ongoing. Furthermore, efforts are ongoing to increase muscle specific delivery of ASOs. Consequently, there are 5 clinical trials ongoing or planned for exon 51 skipping ASOs in Europe. While exon 51 skipping applies to the largest group of patients, DMD expert centers do not have sufficient numbers of patients or capacity to run all these trials in parallel. Even at a national level numbers may be too scarce. At the same time, some families now face the choice between participation in different clinical trials of exon 51 skipping, sometimes in addition to the choice of participating in a micro-dystrophin gene therapy trial. In this opinion paper, we outline the challenges, compare the different exon 51 skipping trials, and outline how different European centers and countries try to cope with running multiple trials in parallel for a small group of eligible patients.

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Caregivers routinely inform medical and regulatory decision making in rare pediatric diseases. While differences in treatment preferences across caregivers and patients have been observed for Duchenne muscular dystrophy, this evidence was limited by small samples of patients and results were confounded by patient age and disease progression. We tested caregiver and patient preference concordance for treating Duchenne.Preferences and demographic/clinical information from 115 caregivers and 107 patients were collected in an international study (response = 80%) using a previously developed discrete-choice experiment consisting of 12 experimentally controlled choice tasks. Each task presented two profiles that varied across four attributes: disease progression, drug failure probability, kidney damage risk, and fracture risk. Caregivers and patients were matched 1:1 based on patient age. We tested for concordance across each task and by comparing caregivers' and patients' maximum acceptable risk of drug failure, kidney damage, and fracture for a slowing of disease progression.The final analysis included 77 caregivers and 77 patients. No differences were observed in nationality (p = 0.969), disease stage (p = 0.180), or demographic/clinical factors (p = 0.093-0.857); however, patients were more optimistic (p = 0.030). Caregivers and patients chose similarly across tasks (p = 0.101-0.993). To slow disease progression by 1 year, caregivers and patients would tolerate a 9% and 11% increase in drug failure probability, respectively (p = 0.267). Alternatively, they would accept a 3% and 4% increase in the risk of kidney damage (p = 0.719) or a 15% and 20% increase in the risk of fracture (p = 0.534).Caregivers and patients had concordant preferences for treating Duchenne. Providers and regulators can trust both caregiver and patient report of preferences to inform medical decision making.

The drug development process is a long and arduous one, especially for rare diseases. Patient and patient representatives can and should be involved in this process from an early stage, since they have the perspective of living with a disease on a daily basis and can best identify which symptoms are the largest burden and which benefits would be more important to them. In this perspective, we outline how patients can be involved optimally in drug development. We outline success factors such as finding the right partners, bilateral education, having realistic expectations, and an open and honest dialog with all stakeholders.

Background: For patients with rare diseases such as Duchenne and Becker muscular dystrophy (DMD/BMD), access to their health data is key to being able to advocate for themselves and be in control of their care. Since 2018, the DMD/BMD patient community has been committed to making DMD/BMD-related data FAIR, i.e., Findable, Accessible, Interoperable, and Reusable. On March 3, 2021, the second international meeting on FAIR data sharing for DMD/BMD was held virtually. Objective: The aim of this meeting report is to summarize the presentations and discussions of the meeting. Methods: During this meeting, the progress of FAIRification efforts since the first international meeting in 2019, new developments, stakeholder perspectives, and experiences from implementing FAIR data principles in practice were presented and discussed. Results: Over 120 attendees representing various stakeholder groups (ie, patient organizations, clinicians, clinical and academic researchers, pharmaceutical companies, regulators, and EU organizations) from 22 countries participated in the meeting. This meeting report summarizes the presentations and discussions from the meeting, provides an overview of the key lessons learned since the first meeting, and outlines the next steps. Conclusions: Patient organizations are key drivers of the FAIRification process in practice and dialogue with stakeholders is critical to success.

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Introduction: There is a groundswell of interest from patient, industry, and regulatory groups to rigorously and transparently integrate patient-voice into regulatory decision-making. Patient-focused drug development (PFDD) is an approach established by the US Food and Drug Administration to systematically incorporate patient experiences into drug development and evaluation. It has created a demand for scientific advancement to measure and integrate patient-voice into decision-making.Areas covered: This narrative review describes the evolving nature of advocacy-regulatory relations preceding PFDD, characterizes current PFDD and other patient-engagement activities, and explores future opportunities for patient participation along the drug development pipeline. We present Duchenne muscular dystrophy as a case study to illustrate how PFDD is being operationalized by patient groups and regulators using both verbal and written data sources.Expert opinion: PFDD represents the most widespread approach yet to integrate the patient voice as a source of evidence to inform regulatory decision-making. Regulatory approvals are just one frontier in drug development. On the horizon remain uncertainties in how patient experience can inform post-marketing surveillance, pricing, reimbursement, and health technology assessment. Patient-input may be particularly crucial to demonstrate the value of expensive first-generation rare disease treatments that confer meaningful benefits but do not meet traditional thresholds for cost-effectiveness.

The number of clinical trials for Duchenne muscular dystrophy is increasing. Many trials require muscle biopsies, which involve an invasive surgical procedure. Little is known about short- and long-term impacts of muscle biopsies as perceived by patients and caregivers. Therefore a survey was held among patients and their caregivers who participated in trials involving muscle biopsies, in seven countries. Seventy-eight responses were received. Analysis revealed that many patients and parents had significant anxiety before the biopsy. The main concern of caregivers was the required general anaesthesia. In most cases biopsies caused pain and temporarily hampered daily activities. The main long-term impact was scarring, although large variation in size was reported. Seventy-nine percent of caregivers were little bothered and 21% were moderately or severely bothered by the scar. Willingness to consider another biopsy in future protocols was higher for open-label studies than for placebo-controlled trials. Caregivers stressed the importance of knowing the results of biopsy analyses; only a minority actually received this information. Recommendations are made on the informed consent procedure regarding risks and consequences of muscle biopsies, and communication of results. Furthermore, efforts should be made to minimise the impact of biopsies through pain management and by considering plastic surgery.

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Graphical abstract, At the moment, little treatment options are available for Duchenne muscular dystrophy (DMD). The absence of the dystrophin protein leads to a complex cascade of pathogenic events in myofibres, including chronic inflammation and oxidative stress as well as altered metabolism. The attention towards dietary supplements in DMD is rapidly increasing, with the aim to counteract pathology-related alteration in nutrient intake, the consequences of catabolic distress or to enhance the immunological response of patients as nowadays for the COVID-19 pandemic emergency. By definition, supplements do not exert therapeutic actions, although a great confusion may arise in daily life by the improper distinction between supplements and therapeutic compounds. For most supplements, little research has been done and little evidence is available concerning their effects in DMD as well as their preventing actions against infections. Often these are not prescribed by clinicians and patients/caregivers do not discuss the use with their clinical team. Then, little is known about the real extent of supplement use in DMD patients. It is mistakenly assumed that, since compounds are of natural origin, if a supplement is not effective, it will also do no harm. However, supplements can have serious side effects and also have harmful interactions, in terms of reducing efficacy or leading to toxicity, with other therapies. It is therefore pivotal to shed light on this unclear scenario for the sake of patients. This review discusses the supplements mostly used by DMD patients, focusing on their potential toxicity, due to a variety of mechanisms including pharmacodynamic or pharmacokinetic interactions and contaminations, as well as on reports of adverse events. This overview underlines the need for caution in uncontrolled use of dietary supplements in fragile populations such as DMD patients. A culture of appropriate use has to be implemented between clinicians and patients’ groups.

The care of individuals with Duchenne muscular dystrophy (DMD) now extends into adulthood. Childhood to adulthood transition planning is an important aspect of care, affecting health outcomes as well as other important aspects of adult life. In this article, we address transition planning as it relates to DMD health care, education, steps toward vocations, personal care, accessing the home and community, and the importance of relationships with others. Because of the complex, disabling, and progressive nature of DMD, coordinated, well-timed planning is critical to ensure that all components of transition are accomplished. In this article, we introduce the DMD Transition Toolkit. The toolkit is designed to help assess readiness for transition, track progress toward transition goals, and provide a template for documenting key elements of medical care, medical equipment, and services. The transition readiness assessment for young adults with DMD is used to gauge readiness for adult health care and living practices. Consistent with the 2018 DMD Care Considerations, the transition checklist for young adults with DMD is a comprehensive list to be considered, discussed, and planned for during transition. The medical summary for young adults with DMD can be used by a provider or individuals with DMD to communicate details of their health plan, provider contacts, and medical equipment needs. It can be used in transition handoffs, when adding new providers, or when informing new nursing agencies or personal care attendants. It could also be useful in urgent care settings by providing baseline information about the individual with DMD.

Twenty-three participants from 6 countries (England; Germany; Italy; Sweden, The Netherlands; USA) attended the 226th ENMC workshop on Duchenne biomarkers “Towards validated and qualified biomarkers for therapy development for Duchenne Muscular Dystrophy.” The meeting was a follow-up of the 204th ENMC workshop on Duchenne muscular dystrophy biomarkers. The workshop was organized with the support of Parent Project Muscular Dystrophy (PPMD) and Marathon Pharmaceuticals, which provided travel support for participants from the US via an unrestricted grant to PPMD in addition to ENMC support. It was attended by representatives of academic institutions, industry working in the Duchenne muscular dystrophy field and patient representatives. 1.1. Background to the workshop 1.1.1. Biomarkers Biomarkers are defined as biological, measurable and quantifiable indicators of underlying biological processes. Different types of biomarkers can be distinguished: diagnostic biomarkers indicate the presence of disease, prognostic biomarkers correlate with predicted disease course, and therapeutic biomarkers are designed to predict or measure response to treatment [1]. Therapeutic biomarkers can indicate whether a therapy is having an effect. This type of biomarker is called a pharmacodynamics biomarker and can be used to e.g. show that a missing protein is restored after a therapy. Safety biomarkers assess likelihood, presence, or extent of toxicity as an adverse effect, e.g. through monitoring blood markers indicative of liver or kidney damage. Sometimes biomarkers can also be used as primary endpoints in clinical trials instead of functional outcome measures, and these are termed “surrogate endpoints”. In Europe [2,3] biomarkers can only be used as surrogate endpoints after going through a rigorous regulatory process to officially qualify them for this purpose. Similar pathways exist in the US, where the Food and Drug Administration (FDA) also supplies a process for qualification of biomarkers for other contexts of use.

Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD. A unique aspect of the exon-skipping approach for DMD is that, depending on the size and location of the mutation, different exons need to be skipped. This challenge raises a number of questions regarding the development and regulatory approval of those individual compounds. In this study, we present a perspective on those questions, following a European stakeholder meeting involving academics, regulators, and representatives from industry and patient organizations, and in the light of the most recent scientific and regulatory experience.

Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and interpretation of appropriate clinical outcome measures. Others are inherent to the antisense oligonucleotide (AON)-mediated exon skipping approach, which employs small modified DNA or RNA molecules to manipulate the splicing process. This is a new approach and only limited information is available on long-term safety and toxicity for most AON chemistries. Furthermore, AONs often act in a mutation-specific manner, in which case multiple AONs have to be developed for a single disease. A workshop focusing on preclinical development, trial design, outcome measures, and different forms of marketing authorization was organized by the regulatory models and biochemical outcome measures working groups of Cooperation of Science and Technology Action: "Networking towards clinical application of antisense-mediated exon skipping for rare diseases." The workshop included participants from patient organizations, academia, and members of staff from the European Medicine Agency and Medicine Evaluation Board (the Netherlands). This statement article contains the key outcomes of this meeting.

Background: Duchenne muscular dystrophy (DMD) is a progressive muscle disease. No curative therapy is currently available, but in recent decades standards of care have improved. These improvements include the use of corticosteroids and mechanical ventilation. Objective: To present a detailed population based report of the DMD disease course in The Netherlands (1980–2006) and evaluate the effect of changes in care by comparing it with an historical Dutch DMD cohort (1961–1974). Methods: Information about DMD patients was gathered through the Dutch Dystrophinopathy Database using a standardized questionnaire and information from treating physicians. Results: The study population involved 336DMDpatients (70% of the estimated prevalence), of whom 285 were still alive. Mean age at disease milestones was: diagnosis 4.3 years, wheelchair dependence 9.7 years, scoliosis surgery 14 years, cardiomyopathy (fractional shortening

Rare kidney diseases encompass at least 150 different conditions, most of which are inherited. Although individual rare kidney diseases raise specific issues, as a group these rare diseases can have overlapping challenges in diagnosis and treatment. These challenges include small numbers of affected patients, unidentified causes of disease, lack of biomarkers for monitoring disease progression, and need for complex care. To address common clinical and patient issues among rare kidney diseases, the KDIGO Controversies Conference entitled, Common Elements in Rare Kidney Diseases, brought together a panel of multidisciplinary clinical providers and patient advocates to address five central issues for rare kidney diseases. These issues encompassed diagnostic challenges, management of kidney functional decline and progression of chronic kidney disease, challenges in clinical study design, translation of advances in research to clinical care, and provision of practical and integrated patient support. Thus, by a process of consensus, guidance for addressing these challenges was developed and is presented here.

Summary Duchenne muscular dystrophy is a rare, progressive, muscle-wasting disease leading to severe disability and premature death. Treatment is currently symptomatic, but several experimental therapies are in development. Implemented care standards, validated outcome measures correlating with clinical benefit, and comprehensive information about the natural history of the disease are essential for regulatory approval of any treatment. However, for Duchenne muscular dystrophy and other rare diseases, these requirements are not always in place when potential therapies enter the clinical trial phase. A cooperative effort of stakeholders in Duchenne muscular dystrophy—including representatives from patients' groups, academia, industry, and regulatory agencies—is aimed at addressing this shortfall by identifying strategies to overcome challenges, developing the tools needed, and collecting relevant data. An open and constructive dialogue among European stakeholders has positively affected development of treatments for Duchenne muscular dystrophy; this approach could serve as a paradigm for development of treatments for rare diseases in general.

How do healthcare consumers perceive the use of medical data for scientific research, within the framework of protection of their personal data?Survey among 731 members of the Healthcare Consumer Panel of the Netherlands Institute for Health Services Research (NIVEL).A written and online questionnaire was used, consisting of general questions and 4 cases per respondent. The questions concerned the degree of trust respondents have in the use of previously registered data for different kinds of healthcare research, and their willingness to make data available under various conditions without being asked for explicit consent.Respondents showed a high degree of trust in scientific researchers and physicians concerning the re-use of medical data for research. A majority agreed that it is not necessary to be explicitly asked for consent for this kind of research, providing they are informed: one-third found their autonomy in being able to decide to be more important than scientific progress; three-quarters found explicit permission unnecessary as long as the data is well-protected and only used for scientific research.Data protection in research should be proportional to the risks of misuse and the benefits of the use of the data for research. A large majority of healthcare users trust the researchers, and the existing codes of conduct protect data sufficiently. Therefore, we see no need for stricter requirements for the use of health data, which would unnecessarily limit healthcare research. We do consider greater transparency about the research process to be necessary, in order to maintain a proper balance between personal-data protection and the need to emphasise the necessity for learning in the healthcare system.

Twenty clinicians, physiotherapists and representatives from advocacy groups and industries from six countries convened for a Parent Project sponsored workshop on ‘Assessment of Upper Limb Function in Duchenne Muscular Dystrophy (DMD)’. Following previous meetings [1,2] highlighting the lack of outcome measures in non ambulant patients, a number of exploratory studies have been planned to investigate the suitability of the available measures. The focus of this workshop reflects the need to harmonize the efforts from different groups in order to identify suitable tools and plan appropriate validation, activities and natural history studies. The aims of the workshop were to: • bring ‘experts’ together to assess the suitability of the existing measures, • ascertain that these tools cover the whole spectrum of abilities in DMD, • identify possible gaps in the existing measures, • find a consensus on the tools to be adopted and evaluator training, • have common datasets to allow data sharing. Eugenio Mercuri (Italy) gave a brief review on the existing measures used for assessing upper limb function in DMD [3]. Some of these measures are observer-rated, performance-based scales exploring the effect of progressive weakness on upper limbs including manual abilities and dexterity. The other tools are patient reported scales investigating different aspects of activities of daily living, such as transferring, feeding, or washing therefore providing a measure of the patients’ level of independence and ability to interact with the environment. Craig Mc Donald (USA) reported a summary of recent meetings held in Washington and Baltimore in June 2010 and July 2011 [1]. These meetings allowed to map outcome measures in DMD and compare recent natural history data from 1900 patients from eight networks. The data showed a consistent improvement in natural history with a clear shift in age of decline, age of loss of ambulation, need for ventilation and survival. These shifts are thought to reflect improved standards of care and use of steroids. A spectrum of functional milestones with meaningful relevance to patient and families was generated from previous meeting. In the present workshop these milestones were further discussed with the family representatives and modified to include actions such as sitting independently (Table 1). Table 1 Loss of Clinically Meaningful Milestones. Julaine Florence (USA) reported preliminary data from an on-going collaborative study in non-ambulatory DMD boys using the Brooke scale, the Jebsen and the 9 hole peg tests. Preliminary data at baseline showed that the measures could be completed in the majority of the boys assessed and had good test–retest and inter-observer reliability. The preliminary data also provided useful information on starting positions and procedures to be used in DMD. Flaviana Bianco and Elena Mazzone (Italy) presented an exploratory study on upper limb function in 61 DMD patients. This study, rather than being a formal suitability study, explored whether the existing scales [4–7] were appropriate for DMD patients at different ages and spectrum of abilities ranging from ambulant boys with antigravity shoulder movements to older non ambulant boys with only limited finger movements. The study highlighted pros and cons of each measure, and possible shortcomings related to posture, pattern of weakness, contractures requiring compensatory strategies, also providing some suggestions on how to overcome some of these difficulties (Table 2). Table 2 Details of the existing measures for assessment of upper limbs. Craig McDonald (USA) reported previous experience of the CNRG network on previous tools assessing upper limb function, including: Brooke scale, manual and quantitative muscle testing, hand grip and newly developed tools such as the kinematic assessment of Volume of Reachable workspace or a quality of life questionnaire (NeuroQol) [8,9]. The challenge of the NeuroQol is to determine changes over a short period of time, to be sensitive to treatment effect, and to bridge the gap between paediatric and adult age groups. Laurent Servais and Valerie Decostre (France) reported the application of new devices, developed to assess different aspects of function and activity. The Actimyo is a light-weight, wireless device for home monitoring of upper limb movements. The device can be used across spectrum of abilities including very weak non ambulant patients. An update of a suitability study using other tools in non ambulant DMD showed that MyoPinch, MyoGrip and MOVIPLATE were the most sensitive and suitable tools that could be reliably used with no floor/ceiling effect [10]. Anna Mayhew (UK) reported a summary of a physiotherapist meeting recently held in Newcastle which helped to: • redefine a list of activities proposed in previous TREAT NMD meetings, • create a graded hierarchical system from strongest to weakest and from proximal to distal, following the gradient of weakness observed in DMD, • associate each activity with the items already available from different assessments and identifying possible gaps, • relate activities and items to clinically meaningful activities of daily living and life events. The meeting also provided useful suggestions on how to modify the existing items in order to make them suitable for stronger younger boys and overcome ceiling effect. The suitability of the available measures was discussed in a round table, taking advantage of the presence of family representatives and industries who provided their view on clinical meaningfulness and relevance of the measures for possible clinical trials. • The round table confirmed the need to identify measures covering upper limbs activities from antigravity shoulder movements to limited finger movements in order to have reliable measures also for non ambulant patients who are likely to be considered for clinical trials. • At the other end of the spectrum, such measures would also allow to follow stronger ambulant patients once they have lost ambulation. • Observer-rated measures are preferred because they are more easily standardizable but patient-reported measures can complement information on activities of daily living which cannot otherwise be observed in a clinical/research setting. • Further work is needed to modify the existing patient-reported measures in order to include the meaningful activities that cannot be assessed using observer rated measures. • Moviplate, pinch and hand-grip can be reliably used in both ambulant and non ambulant patients providing information on specific aspects of functional domains but functional scales should also be used to allow assessment of a wider spectrum of activities. • None of the functional scales previously used in DMD covers the whole spectrum of abilities found in ambulant and non ambulant DMD boys. • Not all the items in the available scales are suitable for DMD patients. In the Jebsen for example, writing a sentence is inappropriate because of frequent cognitive difficulties in DMD patients. • Other items may be suitable because easily and reliably performed but do not reflect clinical meaningful activities for DMD patients, the last two points probably reflecting that none of the available scales was specifically devised for DMD. A general discussion on individual items brought to a further selection of those thought to be appropriate for assessing clinically meaningful activities in both ambulant and non ambulant patients (Table 3). Table 3 Upper limb motor performance module for DMD (PUL for DMD)a. The selected items will be used by all the participants in order to identify possible shortcomings in patients at different ages. A physical therapist working group will take into account the proposed amendments providing manuals and instructions for the selected items. The data collected by all centers will also be used for a preliminary Rasch analysis which will allow to identify redundancies/gaps, and more generally, to improve the statistical robustness of the new scale.

Duchenne muscular dystrophy (DMD) is a progressive, life-limiting muscle-wasting disease. Although no curative treatment is yet available, comprehensive multidisciplinary care has increased life expectancy significantly in recent decades. An international consensus care publication in 2010 outlined best-practice care, which includes corticosteroid treatment, respiratory, cardiac, orthopedic and rehabilitative interventions to address disease manifestations. While disease specialists are largely aware of these care standards, local physicians responsible for the day-to-day care of patients and families may be less familiar. To facilitate optimal care, a one-page document has been generated from published care recommendations, summarizing the key elements of comprehensive care for people living with DMD (“Imperatives for Duchenne muscular dystrophy). This document was developed through an international collaboration between Parent Project Muscular Dystrophy (PPMD), United Parent Projects Muscular Dystrophy (UPPMD) and TREAT-NMD.

• The manuscript elaborates on what is clinically meaningful and how to measure this in DMD.

The 195th ENMC International Workshop on newborn screening for Duchenne muscular dystrophy (DMD) was held in Naarden, The Netherlands, on 14–16th December 2012. Twenty-one participants from seven countries (UK, The Netherlands, Germany, Italy, Canada, USA, and Australia), with expertise in neuropediatrics, neurology, genetics, biochemistry, pathology, psychology, ethics, sociology and parent representatives were present. DMD NBS was last discussed at an ENMC workshop in 1992 [1], where it was concluded that the justification to screen for DMD ‘is to provide optimal and specific information to the parents in time, so they can make the decisions which are the most appropriate for their family’. This point was reviewed in the current workshop. DMD is a progressive muscle wasting disorder, leading to wheelchair confinement in the mid-teens, and development of an associated cardiomyopathy. Death is mainly from respiratory failure [2] although with the implementation of optimal respiratory care, mean age at survival is now well into the late 20s [3–7]. A milder form of the condition, Becker uscular dystrophy (BMD) is also recognised. DMD is an X-linked condition, arising from out-of-frame or frame shift mutations in the DMD gene, encoding for the cytoskeletal protein dystrophin. Two unusual features of this disease are: (i) the large size of the DMD gene and thus susceptibility to de novo mutations; (ii) the absence of specific clinical symptoms sufficient to alert medical professionals to the presence of the disease in neonates. The most commonly recognised

Drug trials in children engage with many ethical issues, from drug-related safety concerns to communication with patients and parents, and recruitment and informed consent procedures. This paper addresses the field of neuromuscular disorders where the possibility of genetic, mutation-specific treatments, has added new complexity. Not only must trial design address issues of equity of access, but researchers must also think through the implications of adopting a personalised medicine approach, which requires a precise molecular diagnosis, in addition to other implications of developing orphan drugs. It is against this background of change and complexity that the Project Ethics Council (PEC) was established within the TREAT-NMD EU Network of Excellence. The PEC is a high level advisory group that draws upon the expertise of its interdisciplinary membership which includes clinicians, lawyers, scientists, parents, representatives of patient organisations, social scientists and ethicists. In this paper we describe the establishment and terms of reference of the PEC, give an indication of the range and depth of its work and provide some analysis of the kinds of complex questions encountered. The paper describes how the PEC has responded to substantive ethical issues raised within the TREAT-NMD consortium and how it has provided a Abstract Drug trials in children engage with many ethical issues, from drug-related safety concerns to communication with patients and parents, and recruitment and informed consent procedures. This paper addresses the field of neuromuscular disorders where the possibility of genetic, mutation-specific treatments, has added new complexity. Not only must trial design address issues of equity of access, but researchers must also think through the implications of adopting a personalised medicine approach, which requires a precise molecular diagnosis, in addition to other implications of developing orphan drugs. It is against this background of change and complexity that the Project Ethics Council (PEC) was established within the TREAT-NMD EU Network of Excellence. The PEC is a high level advisory group that draws upon the expertise of its interdisciplinary membership which includes clinicians, lawyers, scientists, parents, representatives of patient organisations, social scientists and ethicists. In this paper we describe the establishment and terms of reference of the PEC, give an indication of the range and depth of its work and provide some analysis of the kinds of complex questions encountered. The paper describes how the PEC has responded to substantive ethical issues raised within the TREAT-NMD consortium and how it has provided a Abstract Drug trials in children engage with many ethical issues, from drug-related safety concerns to communication with patients and parents, and recruitment and informed consent procedures. This paper addresses the field of neuromuscular disorders where the possibility of genetic, mutation-specific treatments, has added new complexity. Not only must trial design address issues of equity of access, but researchers must also think through the implications of adopting a personalised medicine approach, which requires a precise molecular diagnosis, in addition to other implications of developing orphan drugs. It is against this background of change and complexity that the Project Ethics Council (PEC) was established within the TREAT-NMD EU Network of Excellence. The PEC is a high level advisory group that draws upon the expertise of its interdisciplinary membership which includes clinicians, lawyers, scientists, parents, representatives of patient organisations, social scientists and ethicists. In this paper we describe the establishment and terms of reference of the PEC, give an indication of the range and depth of its work and provide some analysis of the kinds of complex questions encountered. The paper describes how the PEC has responded to substantive ethical issues raised within the TREAT-NMD consortium and how it has provided a wider resource for any concerned parent, patient, or clinician to ask a question of ethical concern. Issues raised range from science related ethical issues, issues related to hereditary neuromuscular diseases and the new therapeutic approaches and questions concerning patients rights in the context of patient registries and bio

Aim: An international Clinical Outcomes Group consisting of clinicians, scientists, patient advocacy groups, and industries identified a need for a scale to measure motor performance of the upper limb. We report the steps leading to the development of the Performance of the Upper Limb (PUL), a tool specifically designed for assessing upper limb function in ambulant and non-ambulant patients with Duchenne muscular dystrophy (DMD). Method: The development of the PUL followed a number of steps, from the systematic review and a preliminary study exploring the suitability of the existing measures, to the application of a pilot version in a multicentric setting, with Rasch analysis of the preliminary results, leading to a revised pro forma. Results: The PUL was specifically designed for DMD, with a conceptual framework reflecting the progression of weakness and natural history of functional decline in DMD. Modern psychometric methods were used to create a scale with robust internal reliability, validity, and hierarchical scalability; males with DMD and their families were involved iteratively throughout the process of the clinician-reported outcome assessment tool development to establish clinical meaningfulness and relevance of individual PUL items to activities of daily living. Interpretation: The module was developed using innovative approaches and will be useful for designing clinical trials. © 2013 Mac Keith Press.

Traditional Chinese medicine has been advocated to alleviate symptoms in Duchenne muscular dystrophy. To investigate this hypothesis, a pilot study was carried out in Beijing on 10 DMD boys treated with various regimens, including pills, decoctions, massages and acupuncture at various stages of their disease course. Despite the limited scientific impact of such a study, it seems as if the benefit, if any, is minimal. Moreover, some indirect clinical clues such as the cushingoid appearance found in a few patients suggest these drugs may also contain corticosteroids to some extent.

There is currently no cure for Duchenne muscular dystrophy, but there are some promising treatments in development, of which antisense-mediated exon skipping is close to clinical application. The results of the first trials have resulted in significant enthusiasm among clinicians, patients, and their parents and attracted widespread attention in both the scientific and lay press. As in many other rare diseases with significant morbidity this fuels the hope that at last an effective therapy might be within our reach. Parents, but also some clinicians, are now seriously considering treating individual patients with antisense oligonucleotides without waiting for proof from well-designed clinical trials that the new therapies are indeed effective and safe. We understand the sense of urgency that is experienced by patients, parents and their clinicians, but we hope to explain that the preliminary introduction of incompletely tested drugs might lead to dangerous and harmful situations for the patients, endanger the continuation of the development of possible effective therapeutic strategies, or even lead to a complete stop in the further development of promising drugs.

Dystrophinopathy patient registries are very useful for improvement of standard care and planning of clinical trials. The Dutch Dystrophinopathy Database contains information of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients in the Netherlands. The historical incidence of DMD is estimated at 20 boys per year and unknown for BMD. DMD and BMD patients received information through patient organisations, treating physicians, the genetic test centre or a website ( www.lumc.nl/duchenne ). Included patients gave consent for registration in the national patient registry and the international TREAT-NMD database, permission to contact their physician and filled out a questionnaire about their disease course. On January 2013 the database contained disease milestones of 420 DMD and 140 BMD patients, including data from 78 deceased DMD and 16 deceased BMD males. 324 DMD and 104 BMD patients have a DNA confirmed diagnosis. The mean yearly incidence for DMD was 18 between 1980 and 2000. Given a mean life expectancy of 27 years this would suggest a prevalence of 486 DMD patients, and thus an inclusion rate in the database of 70%. The mean yearly incidence for BMD was 4 between 1960 and 2000. The mean life expectancy was 55 years suggesting a prevalence of 220 BMD patients, and thus an inclusion rate in the database of 56%. In the DNA confirmed DMD cohort mean age at diagnosis decreased from 5.6 years before 1970 to 4.0 years more recently. The mean age at loss of ambulation increased to 9.8 years and for scoliosis surgery to 14 years. Age at start of mechanical ventilation ranged from 14 to 28 years. Close collaboration during five years between patient organisations, physicians and researchers resulted in a patient registry covering three quarters of all Dutch DMD patients. The yearly update is a constant challenge, but the advantage is one national registry representative for the whole population, limiting selection bias to a minimum.

Exon skipping, a promising new approach for the treatment for Duchenne muscular dystrophy (DMD), relies on the systemic administration of exon-specific antisense oligonucleotides (AONs) to reframe genetic mutations. As the targeted exon is relevant to specific subpopulations of patients with DMD, a number of AONs targeting increasingly smaller patient populations are required. Orphan drug designation and development is ongoing for six compounds, and a comprehensive development program is underway for the most prevalent subpopulation, representing approximately 13% of patients with DMD. Such a program is not feasible for less prevalent groups. Discussions with regulators, clinicians, and scientists are underway to find appropriate ways to develop these compounds, building on information gained from the lead molecule. Concepts such as abrogated preclinical development packages, manufacturing design space, and seamless trial designs may facilitate this process. Central to this theme is the patient’s perception of risk, which is being pursued independently by patient advocacy groups. Here we will discuss the seamless design accepted by the EMA and FDA for two exon skipping programs targeting sub-populations too limited to carry out fully powered, placebo-controlled pivotal Phase III studies and how future programs may be further accelerated in the ‘ultra-orphan’ DMD space.

Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy, affecting around 1 in 3,600 boys, which results in muscle degeneration and eventual death. Long before any promising drug was at the horizon Duchenne parents came forward to organise research meetings where they made it clear they were willing to shoulder responsibility and contribute towards advancing treatments and a cure. They became funders of peer reviewed research and advocated for government support. Some organisations started their own research institutes others invested in extramural research, clinical centers and industry to develop viable treatments for DMD and BMD. Currently several potential drugs are in phase 3 trials. Through this experience Duchenne parents have learned including Patient Organisations in trial design and selection of endpoints can make drug development more efficient. Patients participate in clinical trials and will ultimately be the ones to decide whether the tested drugs are beneficial to them to an extent that EMA and FDA allow these drugs. Hence patient input and advice is essential to develop a clinically meaningful endpoint. A clinical meaningful endpoint is an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. Therefore, a primary endpoint should be a direct measure of one of these. A primary endpoint should generally not be a measure of something that is not important to the patient [1]. Who knows better than the patients what is important to them? It is remarkable that clinicians and industry often don’t discuss the choice of primary outcome measures with patient organisations in an early phase, but only after they have already collected the data and are at the point to discuss outcomes with regulators. Regarding trial design, ethic committees mostly decide about the burden and risk of participation in relation to a certain trial design without asking the patients or patients’ organisations for their opinion. That is remarkable because they are the ones who have to deal with the burden and take the risk. Often researchers and regulators only look at the burden of the medical intervention, where for many patients other factors add much more to the total burden of participation in a trial. Care revolves around the people with a disease. Without them there would be no need for research and drug development. It is important that the needs of these groups are the starting point for initiatives concerning them. Patients know what it means to have this condition. It means they will bring in a different perspective. Their questions and needs are based on their own experiences, interests and vision. There is a lot to gain from well utilised experience and expertise.

A white paper addressing the ethical and technical challenges of returning meaningful individual clinical trial results to trial participants