Document
Reference number
Publication date
Concept paper on the need for a guideline on the treatment of Duchenne and Becker muscular dystrophy
EMA/CHMP/CNSWP/236981/2011
– Adoption by CHMP for release for consultation June 23, 2011
– End of consultation (deadline for comments) September 30, 2011
(Draft) guideline on the clinical investigation of medicinal products for the treatment of Duchenne and Becker muscular dystrophy
EMA/CHMP/236981/2011
– Adoption by CHMP for release for consultation February 21, 2013
– End of consultation (deadline for comments) August 31, 2013
The draft version of the guideline was intended to provide guidance for the evaluation of medicinal products in the treatment of these diseases, including study design, choice of appropriate efficacy endpoints, and definition of reliable surrogate outcome measures.
The scope of the guideline is limited to DMD, the most severe form of MD, and the milder version, BMD. Other neuromuscular diseases, such as FSHD, are currently outside the scope of this guideline.
Highlights of the document are described below. These include factors related to study design:
1.
Outcomes that reflect improvement in symptoms and in disability in affected patients (maintenance of muscle strength and function, prevention of damage to non-muscular target organs [such as the lung, heart, and eyes], orthopedic corrections, and physiotherapeutic interventions).
2.
In confirmatory trials, the efficacy and safety of the product should be studied in the full range of patients that the investigational product is intended to treat.
3.
Confirmatory trials to show symptom or disability improvement should be randomized, double-blind, parallel group, and possibly placebo-controlled.
4.
Trials investigating symptomatic treatment should last at least three months; trials to show an improvement in disability, at least six months.
The document also examines the choice of appropriate efficacy endpoints:
1.
For patients without a confirmed genetic diagnosis, a combination of clinical symptoms, family history, elevated creatine kinase (CK) concentration, magnetic resonance imaging (MRI), and muscle biopsy is considered sufficient for a diagnosis, but it is not sufficient for inclusion in clinical trials in which potential medicinal products targeting certain type of genetic defects are investigated.
2.
Efficacy: the objectives of the study should be well-defined according to the expected stage- and age-related improvement in certain types of symptom domains (e.g., walking, daily functioning, maintaining ambulant state, use of upper limb in non-ambulant subjects, and overall survival).
3.
Muscle strength should be evaluated by clinical assessment using a validated tool.
The document also provides a definition of reliable surrogate outcome measures:
1.
Modifications of the natural course of the disease (which causes continued muscular weakness) or increasing survival (clinically, a sustained effect on disability progression has to be shown).
2.
Improvement in motor function could be achieved by correcting or counter-acting the underlying genetic defect, by increasing muscle growth and regeneration, or by modulating inflammatory responses.
U.S. Regulatory Guidance
Although no formal guidance related to treatments for MD has been issued in the U.S. (at the time this chapter was written), several notable milestones have been reached, edging the U.S. closer to releasing formal regulatory guidance. Consider the following:
Six FDA officers published an article addressing issues associated with DMD drug development. See the paper by McNeil and colleagues for additional details [7].
FDA’s Office of Orphan Products Development (OOPD) has provided grant funding to support two studies of products to treat DMD and has granted orphan designation to 15 products for the treatment of DMD [8].
A webinar aimed at increasing dialogue between patient advocacy groups and FDA and entitled, “Accelerated Approval–Duchenne Disease,” was presented by Robert Temple, MD, deputy center director for Clinical Science, Center for Drug Evaluation and Research, on February 20, 2013 [9]. Temple cited 21 CFR 312.80 (Subpart E) of 1988 Investigational New Drug (IND) registration for “serious and life-threatening diseases” and then discussed four pathways that could be leveraged for the study of treatments for MD: (1) Fast Track Designation, (2) Breakthrough Therapy Designation, (3) Accelerated Approval, and (4) Priority Review. These four pathways, it should be noted, are not specific for MD.
Examples of FDA’s use of existing pathways over the last three years include granting orphan drug status to Acceleron Pharma’s ACE-031 (August 2010) [10] and Breakthrough Therapy Designation to Prosensa for drisapersen (June 2013) [11]. Prosensa regained the rights to drisapersen from GSK in January 2014 [12].
However, even though the FDA has not yet issued specific guidance for MD treatments, the agency appears to be willing to accept assistance from others—especially given the rarity of the disease and paucity of clinical trial data collected to date. In a letter dated June 25, 2014, from Pat Long, President of PPMD, to FDA’s Dr. Janet Woodcock, the group announced that it had met as a forum with the FDA on December 12, 2013 and concluded with an agreement that the Duchenne community, led by the PPMD, would develop the first draft guidance on Duchenne for industry.
The draft guidance, titled, Guidance for Industry: Duchenne Muscular Dystrophy, Developing Drugs for Treatment over the Spectrum of Disease, is unprecedented since, to the author’s knowledge, the FDA has not, to date, accepted input from advocacy groups with the goal of issuing guidance to industry. Indeed, in a PR Newswire news release titled, “First-Ever Patient Initiated ‘Guidance for Industry’ for Duchenne Muscular Dystrophy,” the PPMD President is quoted as saying: “This landmark guidance represents a major milestone for the Duchenne community and may open the way for other rare disease groups to incorporate the patient perspective in a well-documented and quantifiable way.” In the panel on Page 1 of the guidance, the first line states, “This draft guidance represents the first FDA guidance initially composed by a disease community, with input from industry, sponsors, academia and the DMD patient community.”
Written in a form similar to historical draft FDA guidances, the DMD document was written to help accelerate the development and review of potential therapies for Duchenne MD.
As acknowledged by the members and subcommittees who wrote the Guidance for Industry, it is possible that the Agency may choose not to formally adopt all or part of the proposed guidance in the future. However, since there is no other official guidance in the U.S. and some of the DMD-specific material is already covered in the EU draft guidance, a summary of the PPMD document is highlighted below, noting the sections that may have significance and relevance for the other types of MD.
PPMD/U.S. Issued Guidance for Industry
Caregiver tolerance to risk “does not mean flexibility with regard to whether a trial’s findings are statistically significant,” PPMD said in its cover letter to the guidance [13].
Rather, the flexibility we are seeking may concern where the line is drawn as to whether an intermediate clinical endpoint is clinically meaningful, whether post-hoc analyses can support an NDA [New Drug Application] or whether a less-than-precise biomarker is reasonably likely to produce clinical benefit.
“Families affected by Duchenne often feel as if the FDA is an untouchable and unreachable group of professionals tasked with making critical decisions on potential drugs,” the letter states. “Consequently, the community has been advocating that the FDA be more flexible in its review of rare and progressive diseases like Duchenne and to decrease the time and cost of conducting those trials for companies engaged in or considering trials for potential therapies for Duchenne… given some of the recent delays.”
It will be interesting to see the potential effect of the PPMD guidance should an NDA for Sarepta’s eteplirsen for Duchenne MD be submitted to FDA, a step planned for mid 2015 [14].
The proposed guidance is divided into the following areas aimed at overcoming challenges in trial design and implementation:
Benefit–Risk Assessment: This section takes the position that clinical trial sponsors should engage with the patient advocacy community from the start of drug development to understand “that meaningful benefit risk tolerance and acceptable trade-offs may vary across clinical subtypes, across disease progression status, or as a consequence of preference heterogeneity across patients, parents and caregivers.” A recent survey published in Clinical Therapeutics [15] provides new insights into caregiver perspectives on benefits and risks of emerging therapies for DMD, the most common form of the disease. The survey, carried out by researchers from the PPMD and Johns Hopkins Bloomberg School of Public Health, found that “caregivers were willing to accept a serious risk when balanced with a noncurative treatment, even absent improvement in life span.” A total of 119 DMD caregivers completed the online survey, which used best–worst scaling. Six relevant and understandable attributes describing potential benefits and risks of emerging DMD therapies were identified through engagement with advocates, clinicians, pharmaceutical companies, academic centers, and other stakeholders. The attributes were: muscle function, life span, knowledge about the drug, nausea, risk of bleeds, and risk of arrhythmia. Treatment effect on muscle function was rated as the most important experimental attribute (28.7%), followed by risk of heart arrhythmia (22.4%) and risk of bleeding (21.2%). Having additional post-approval data was relatively the least important attribute (2.3%). The authors emphasized that “these preferences should inform the FDA’s benefit–risk assessment of emerging DMD therapies.”Related posts:
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