Fair, just and compassionate: A pilot for making allocation decisions for patients requesting experimental drugs outside of clinical trials.

Patients have received experimental pharmaceuticals outside of clinical trials for decades. There are no industry-wide best practices, and many companies that have granted compassionate use, or 'preapproval', access to their investigational products have done so without fanfare and without divulging the process or grounds on which decisions were made. The number of compassionate use requests has increased over time. Driving the demand are new treatments for serious unmet medical needs; patient advocacy groups pressing for access to emerging treatments; internet platforms enabling broad awareness of compelling cases or novel drugs and a lack of trust among some that the pharmaceutical industry and/or the FDA have patients' best interests in mind. High-profile cases in the media have highlighted the gap between patient expectations for compassionate use and company utilisation of fair processes to adjudicate requests. With many pharmaceutical manufacturers, patient groups, healthcare providers and policy analysts unhappy with the inequities of the status quo, fairer and more ethical management of compassionate use requests was needed. This paper reports on a novel collaboration between a pharmaceutical company and an academic medical ethics department that led to the formation of the Compassionate Use Advisory Committee (CompAC). Comprising medical experts, bioethicists and patient representatives, CompAC established an ethical framework for the allocation of a scarce investigational oncology agent to single patients requesting non-trial access. This is the first account of how the committee was formed and how it built an ethical framework and put it into practice.

Efficacy and safety of deflazacort vs prednisone and placebo for Duchenne muscular dystrophy.

OBJECTIVE: To assess safety and efficacy of deflazacort (DFZ) and prednisone (PRED) vs placebo in Duchenne muscular dystrophy (DMD). METHODS: This phase III, double-blind, randomized, placebo-controlled, multicenter study evaluated muscle strength among 196 boys aged 5-15 years with DMD during a 52-week period. In phase 1, participants were randomly assigned to receive treatment with DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, PRED 0.75 mg/kg/d, or placebo for 12 weeks. In phase 2, placebo participants were randomly assigned to 1 of the 3 active treatment groups. Participants originally assigned to an active treatment continued that treatment for an additional 40 weeks. The primary efficacy endpoint was average change in muscle strength from baseline to week 12 compared with placebo. The study was completed in 1995. RESULTS: All treatment groups (DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, and PRED 0.75 mg/kg/d) demonstrated significant improvement in muscle strength compared with placebo at 12 weeks. Participants taking PRED had significantly more weight gain than placebo or both doses of DFZ at 12 weeks; at 52 weeks, participants taking PRED had significantly more weight gain than both DFZ doses. The most frequent adverse events in all 3 active treatment arms were Cushingoid appearance, erythema, hirsutism, increased weight, headache, and nasopharyngitis. CONCLUSIONS: After 12 weeks of treatment, PRED and both doses of DFZ improved muscle strength compared with placebo. Deflazacort was associated with less weight gain than PRED. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, daily use of either DFZ and PRED is effective in preserving muscle strength over a 12-week period.

Clinical Follow-Up for Duchenne Muscular Dystrophy Newborn Screening: A Proposal.

New developments in the rapid diagnosis and treatment of boys with Duchenne muscular dystrophy (DMD) have led to growing enthusiasm for instituting DMD newborn screening (NBS) in the United States. Our group has been interested in developing clinical guidance to be implemented consistently in specialty care clinics charged with the care of presymptomatically identified newborns referred after DMD-NBS. We reviewed the existing literature covering patient-centered clinical follow-up after NBS, educational material from public health and advocacy sites, and federal recommendations on effective NBS follow-up. We discussed the review as a group and added our own experience to develop materials suitable for initial parent and primary care provider education. These materials and a series of templates for subspecialist encounters could be used to provide consistent care across centers and serve as the basis for ongoing quality improvement. Muscle Nerve 54: 186-191, 2016.

Perspectives on best practices for gene therapy programs.

With recent successes in gene therapy trials for hemophilia and retinal diseases, the promise and prospects for gene therapy are once again garnering significant attention. To build on this momentum, the National Institute of Neurological Disorders and Stroke and the Muscular Dystrophy Association jointly hosted a workshop in April 2014 on "Best Practices for Gene Therapy Programs," with a focus on neuromuscular disorders. Workshop participants included researchers from academia and industry as well as representatives from the regulatory, legal, and patient advocacy sectors to cover the gamut from preclinical optimization to intellectual property concerns and regulatory approval. The workshop focused on three key issues in the field: (1) establishing adequate scientific premise for clinical trials in gene therapy, (2) addressing regulatory process issues, and (3) intellectual property and commercialization issues as they relate to gene therapy. The outcomes from the discussions at this workshop are intended to provide guidance for researchers and funders in the gene therapy field.

Cost of illness for neuromuscular diseases in the United States.

INTRODUCTION: We conducted a comprehensive study of the costs associated with amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD). and myotonic dystrophy (DM) in the U.S. METHODS: We determined the total impact on the U.S. economy, including direct medical costs, nonmedical costs, and loss of income. Medical costs were calculated using a commercial insurance database and Medicare claims data. Nonmedical and indirect costs were determined through a survey of families registered with the Muscular Dystrophy Association. RESULTS: Medical costs were driven by outpatient care. Nonmedical costs were driven by the necessity to move or adapt housing for the patient and paid caregiving. Loss of income correlated significantly with the amount of care needed by the patient. CONCLUSIONS: We calculated the annual per-patient costs to be $63,693 for ALS, $50,952 for DMD, and $32,236 for DM. Population-wide national costs were $1,023 million (ALS), $787 million (DMD), and $448 million (DM).

Corticosteroids in Duchenne muscular dystrophy: major variations in practice.

INTRODUCTION: In 2004, a Cochrane Review and AAN practice parameter concluded that prednisone 0.75 mg/kg/day is of short-term efficacy in Duchenne muscular dystrophy (DMD). Subsequent efforts to standardize care for DMD indicated wide variation in corticosteroid use. METHODS: We surveyed physicians who follow patients with DMD, including: (1) clinics in the TREAT-NMD (Translational Research in Europe-Assessment and Treatment of Neuromuscular Diseases) network (predominantly Europe) and (2) U.S. MDA clinic directors. We also documented the co-administered corticosteroids in a trial of a putative treatment (ataluren) for DMD. RESULTS: Of 105 Treat-NMD clinicians, corticosteroids were not used in 10 clinics, and 29 different regimens were used--the most frequent 0.75 mg/kg/day prednisone (61 centers); 10 days on/10 days off (36 centers); 0.9 mg/kg/day deflazacort (32 centers); and 5 mg/kg/day on weekends (10 centers). Similar diversity was identified in MDA clinics and in the ataluren trial. CONCLUSIONS: Variability in corticosteroid use suggests uncertainty about risks/benefits of corticosteroid regimens for DMD.

Can outcomes in Duchenne muscular dystrophy be improved by public reporting of data?

OBJECTIVE: To review current approaches for obtaining patient data in Duchenne muscular dystrophy (DMD) and consider how monitoring and comparing outcome measures across DMD clinics could facilitate standardized and improved patient care. METHODS: We reviewed annual standardized data from cystic fibrosis (CF) clinics and DMD care guidelines and consensus statements; compared current approaches to obtain DMD patient data and outcome measures; and considered the best method for implementing public reporting of outcomes, to drive improvements in health care delivery. RESULTS: Current methods to monitor DMD patient information (MD STARnet, DuchenneConnect, and TREAT-NMD) do not yet provide patients with comparative outcome data. The CF patient registry allows for reporting of standard outcomes across clinics and is associated with improved CF outcomes. A similar patient registry is under development for the Muscular Dystrophy Association (MDA) clinic network. Suggested metrics for quality care include molecular diagnosis, ambulatory status and age at loss of ambulation, age requiring ventilator support, and survival. CONCLUSIONS: CF longevity has increased by almost 33% from 1986 to 2010, in part due to a CF patient registry that has been stratified by individual care centers since 1999, and publically available since 2006. Implementation of outcome reporting for MDA clinics might promote a similar benefit to patients with DMD.

Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet): case definition in surveillance for childhood-onset Duchenne/Becker muscular dystrophy.

The Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) is a multisite collaboration to determine the prevalence of childhood-onset Duchenne/Becker muscular dystrophy and to characterize health care and health outcomes in this population. MD STARnet uses medical record abstraction to identify patients with Duchenne/Becker muscular dystrophy born January 1, 1982 or later who resided in 1 of the participating sites. Critical diagnostic elements of each abstracted record are reviewed independently by >4 clinicians and assigned to 1 of 6 case definition categories (definite, probable, possible, asymptomatic, female, not Duchenne/Becker muscular dystrophy) by consensus. As of November 2009, 815 potential cases were reviewed. Of the cases included in analysis, 674 (82%) were either ''definite'' or ''probable'' Duchenne/Becker muscular dystrophy. These data reflect a change in diagnostic testing, as case assignment based on genetic testing increased from 67% in the oldest cohort (born 1982-1987) to 94% in the cohort born 2004 to 2009.

Carrier testing for spinal muscular atrophy.

Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general.

Toward more efficient clinical trials for amyotrophic lateral sclerosis.

More than 30 phase II or III clinical trials have been carried out in amyotrophic lateral sclerosis (ALS). Only riluzole, however, has been shown to extend survival and/or time to tracheostomy. Many early ALS trials lacked solid pharmacodynamic and pharmacokinetic data for the treatment being tested, challenging the interpretation of the efficacy and pathway relevance. Understanding of the genetics and pathophysiology of ALS has improved considerably in the past decade, but biomarkers of disease activity remain lacking. A more efficient approach to early phase clinical trials is needed to accelerate the identification of useful agents for ALS. Here we summarize our current thinking about phase II design options and the potential benefits of a clinical trial network for phase II trials in ALS.

American College of Chest Physicians consensus statement on the respiratory and related management of patients with Duchenne muscular dystrophy undergoing anesthesia or sedation.

This statement on the management of patients with Duchenne muscular dystrophy (DMD) undergoing procedural sedation or general anesthesia represents the consensus opinion of a multidisciplinary panel convened under the auspices of the American College of Chest Physicians. Expert recommendations on this subject are needed for several reasons. First, patients with DMD have an increased risk of complications when they undergo sedation or general anesthesia. In addition, due to improved cardiopulmonary therapies, patients with DMD are experiencing an unprecedented duration of survival. As a result, it is more common for them to require procedures involving sedation or general anesthesia. The risks related to anesthesia and sedation for DMD patients include potentially fatal reactions to inhaled anesthetics and certain muscle relaxants, upper airway obstruction, hypoventilation, atelectasis, congestive heart failure, cardiac dysrhythmias, respiratory failure, and difficulty weaning from mechanical ventilation. This statement includes advice regarding the highly interrelated areas of respiratory, cardiac, GI, and anesthetic management of patients with DMD undergoing general anesthesia or procedural sedation. The statement is intended to aid clinicians involved in the care of patients with DMD and to be a resource for other stakeholders in this field, including patients and their families. It is an up-to-date summary of medical literature regarding this topic and identifies areas in need of future research.

Amyotrophic lateral sclerosis: an emerging era of collaborative gene discovery.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.

Reduction in metabolite transverse relaxation times in amyotrophic lateral sclerosis.

BACKGROUND: Proton magnetic resonance spectroscopy (1H MRS) is used frequently to evaluate normal and pathological states in brain. MRS results are often reported as ratios of peak areas from spectra acquired at a single echo time, primarily for the peaks arising from N-acetyl groups (NA), creatine/phosphocreatine (t-Cr), and choline (Cho). Peak areas, however, are affected not only by metabolite concentration, but also by transverse relaxation times (T(2)). While the ratio approach appears to be valid in normal brain, pathology may affect T(2), thereby leading to misinterpretation of the apparent changes in metabolite ratios. The objective of the present study was to determine if any T(2) changes might affect the apparent metabolite ratio measures, which we have previously reported as being abnormal in amyotrophic lateral sclerosis (ALS). METHODS: 1H MRS data were acquired from the brainstems of ALS and control subjects, for a range of TE times, to calculate T(2) times for each of NA, t-Cr, and Cho. Metabolite ratios were measured experimentally at TE=120 ms and calculated for TE=0 ms, based on measured T(2) values. RESULTS: The T(2)'s for the ALS vs. control group were NA=272+/-10 ms vs. 351+/-58 ms (p<0.01), t-Cr=132+/-17 vs. 184+/-42 ms (p<0.02), and Cho=223+/-55 vs. 245+/-50 ms (p>0.05). The effect of these T(2) changes on metabolite ratios showed both the NA/t-Cr (ALS=0.98+/-0.13, Control=1.44+/-0.10, p<0001) and Cho/t-Cr (ALS=1.01+/-0.12, Control=1.34+/-0.24, p<0.001) ratios to differ significantly between groups. CONCLUSION: This study confirms the presence of significant abnormalities in metabolite concentration in ALS brainstem and the importance of evaluating the effects of metabolite T(2) values when making ratio measurements in disease states.