Rare Disease Clinical Trials: Strategies Learned from Duchenne Muscular Dystrophy

Applied Clinical TrialsApplied Clinical Trials-10-01-2022
Volume 31
Issue 10

Approaches sponsors, CROs, and investigators can take from the DMD experience.

Delivering successful outcomes in rare disease clinical trials requires special attention to study planning, patient recruitment and retention, collaboration, and management. The R&D track record in one disease setting in particular, Duchenne muscular dystrophy (DMD), has shown this to be true. DMD is an x-linked genetic disorder affecting an estimated six in 100,000 individuals.1,2 It is characterized by mutations in the dystrophin gene that cause progressive weakness due to muscle cell damage as a result of routine physical activity. Over the last 10 years, drug developers have completed multiple successful clinical trials in DMD, leading to regulatory approvals of mutation-specific drugs in the US and Europe.3

With a long history of active engagement and interest in clinical trials, DMD clinical care, sites, and communities are uniquely positioned to support clinical study success. Patient groups have brought together clinicians, regulators, and nonprofit organizations to collaborate on various research, clinical, and funding initiatives. As a result, standard clinical care guidelines for DMD are being implemented around the world and have continued to evolve since initial publications on respiratory care in 2004.4-7 In 2018, FDA published industry guidelines for DMD drug development,8 and, today, the landscape is crowded with multiple sponsors conducting competing clinical trials in global multicenter networks. While each new trial has its own specific needs, past success of DMD clinical studies can offer valuable strategies sponsors, CROs, and researchers can draw upon today.

Seek supportive input, relationships

As DMD illustrates, it is important to consider all available resources when planning a rare disease clinical trial. First, consider if there is regulatory guidance specific for the disease space, as such guidance can inform key trial design decisions about the patient population and outcome measures. When planning international rare disease trials, regulatory agencies may have conflicting preferences and requirements to be addressed—and clinical care for rare diseases can be vastly different, particularly if there is no established standard of care. Even within the same country, sponsors cannot assume a patient in one location is receiving the same type of care as one in another; patient priorities and available support options can vary greatly across communities.

Sponsors and CROs should, therefore, seek to develop relationships with existing academic and medical networks as well as patient organizations during the trial-planning stages. This will allow them to connect with potential investigators and better understand patient perspectives on clinical trial participation. In addition, these relationships can be particularly valuable for understanding the variable regional landscapes. For example, in the case of DMD, the Duchenne Natural History Study9,10 was conducted by the Cooperative International Neuromuscular Research Group (CINRG), and its datasets have been a key part of the success of many DMD trials.11 Natural history data for rare diseases can be used to inform sample size estimation and outcome measure selection, and, in some cases, serve as a comparator group for investigational trials.

Nevertheless, despite these tools, sponsors of trials targeting rare diseases inherently face operational challenges—the first being practical decisions around whether even investing in clinical development is reasonable, given the landscape of known competitors with late-stage or approved products. As DMD has shown, if the development space is crowded, there is more competition for a limited participant pool. And, fundamentally, healthcare providers, patients, and families need to perceive a new investigational therapy as worthwhile relative to other experimental or approved treatments. Clinical sites can become overburdened with operating too many studies for too few patients. Sample sizes in rare disease trials are typically smaller than those for more chronic, widespread conditions; optimizing data collection and minimizing missing data are even more critical with a small study population. To that end, sites may need additional resources to adequately manage participant follow up and trial assessments. Patients, for example, may need assistance with transportation and accommodations if they live far from a site.

Sponsors should also consider engaging specialized CROs with experience in conducting rare disease trials. These organizations may have connections with sites and patient groups to potentially help bolster recruitment. And their experienced data managers can design case report forms appropriate for the patient population, particularly when standard values in healthy populations are not in alignment with those found in the patient setting. It is important as well for sponsors, when determining outcome measures for rare disease trials, to engage with subject matter experts who have experience standardizing outcome measures across the patient population. Primary outcomes in rare disease studies should be ones that are likely to change and have clinical meaningfulness tied directly to the investigational drug; rather than outcomes that represent disease progression.

Equipped to educate

Patient recruitment and retention is, of course, critical to the chances of a successful rare disease trial. Recruitment planning begins with understanding the clinical and social contexts of eligible participants. Given the inclusion and exclusion criteria of the study protocol, sponsors and CROs should define what an eligible participant’s symptoms are and how they impact daily life, where the person lives and receives care, and the knowledge level of the individual in regards to research and interventions concerning their condition. This portrait can guide site selection and recruitment strategy, and aid in the development of educational tools. At the patient level, investigators can be better prepared for participants’ expected levels of science and health literacy during recruitment and the informed consent process. In turn, at the study level, sites and CROs may be more apt to set aggressive recruitment goals, use proactive recruitment tactics, and work compassionately with participants.

Regardless of interaction point, patient advocate organizations, such as CureDuchenne in DMD, are playing ever-expanding and critical roles in helping prepare patients for clinical trial readiness through education and outreach. CureDuchenne collaborates directly with sponsors and researchers to fund, advise, and help accelerate the drug development process. Further, its centralized data hub, CureDuchenne Link, has been built to support researchers by combining clinical data, biological samples, and patient-reported data for individuals with DMD and Becker muscular dystrophy, factoring in female carriers, which are very rare in both, as well. The platform facilitates data sharing, which is important to advancing a deeper understanding of the disease and accelerating research closer to a cure.

CureDuchenne also conducts regular workshops and webinars to keep the community informed on the latest scientific developments in DMD research, including status and participation in clinical trials. The group also educates on best practices to extend ambulation, and offers guidance on disease management and care. While DMD may be better positioned for drug development than other rare diseases, there are several approaches sponsors, CROs, and investigators can take from the DMD experience and apply into any rare disease clinical trial.

First, evaluate the available resources

  • Natural history data: Select endpoints and outcome measures based on the natural history data. Leverage natural history study protocols to develop methods for outcome measure collection. If natural history data is not available, investment in this area is critical and will support multiple future clinical trials.
  • Standardization of clinical care: Clinical trials will struggle to meet endpoints if the clinical care is variable. Design protocols to align with published clinical care guidelines for consistency across sites. Development and publication of guidelines increases the chances for success.

Next, recruit collaborators

  • Site selection: Select sites with the experience and capacity to successfully conduct the trial. Choose sites to provide adequate geographic coverage with the provided travel support. Prioritize sites that can provide excellent customer service to participants throughout the study.
  • Advocacy groups: Engage with patient advocacy groups early. Once oriented to the study, they will be invaluable partners to help educate families, find eligible participants, and resolve unexpected problems.
  • Global community: Most rare disease clinical trials will need a global network to succeed. Engage with regional partners to better understand the clinical context in their geography.

Finally, build in recruitment and retention up front

  • Recruitment plan: Set aggressive recruitment goals and motivate sites to actively find participants and engage with them about the protocol. Work with advocacy groups and clinical networks to drive referrals and meet recruitment goals.
  • Build consensus: Sponsors and CROs may need to educate each other about the intricacies of conducting a smaller clinical trial in a rare disease. Stakeholders may need to reset expectations of what a “large” clinical trial might be in a given disease or therapeutic area. Building internal consensus supports setting effective strategies.

Mary P. Kotlarczyk, PhD, Project Manager in Clinical Operations, TRiNDS, Ana K. Christensen, MPH, Director of Strategic Solutions, TRiNDS, Michael G. Kelly, PhD, Chief Scientific Officer, CureDuchenne, and Lauren P. Morgenroth, MS, CGC, Chief Executive Officer, TRiNDS


  1. Crisafulli S, Sultana J, Fontana A, Salvo F, Messina S, Trifirò G. Global epidemiology of Duchenne muscular dystrophy: an updated systematic review and meta-analysis. Orphanet J Rare Dis. 2020 Jun 5;15(1):141. doi: 10.1186/s13023-020-01430-8.
  2. Mah JK, Korngut L, Dykeman J, Day L, Pringsheim T, Jette N. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscul Disord. 2014 Jun;24(6):482-91. doi: 10.1016/j.nmd.2014.03.008.
  3. Guiraud S, Davies KE. Pharmacological advances for treatment in Duchenne muscular dystrophy. Curr Opin Pharmacol. 2017 Jun;34:36-48. doi: 10.1016/j.coph.2017.04.002.
  4. Finder JD, Birnkrant D, Carl J, Farber HJ, Gozal D, Iannaccone ST, Kovesi T, Kravitz RM, Panitch H, Schramm C, Schroth M, Sharma G, Sievers L, Silvestri JM, Sterni L; American Thoracic Society. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med. 2004 Aug 15;170(4):456-65. doi: 10.1164/rccm.200307-885ST.
  5. Sejerson T, Bushby K; TREAT-NMD EU Network of Excellence. Standards of care for Duchenne muscular dystrophy: brief TREAT-NMD recommendations. Adv Exp Med Biol. 2009;652:13-21. doi: 10.1007/978-90-481-2813-6_2.
  6. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010 Jan;9(1):77-93. doi: 10.1016/S1474-4422(09)70271-6.
  7. Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Colvin MK, Cripe L, Herron AR, Kennedy A, Kinnett K, Naprawa J, Noritz G, Poysky J, Street N, Trout CJ, Weber DR, Ward LM; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Lancet Neurol. 2018 May;17(5):445-455. doi: 10.1016/S1474-4422(18)30026-7.
  8. Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment https://www.fda.gov/media/92233/download
  9. McDonald CM, Henricson EK, Abresch RT, Han JJ, Escolar DM, Florence JM, Duong T, Arrieta A, Clemens PR, Hoffman EP, Cnaan A; Cinrg Investigators. The cooperative international neuromuscular research group Duchenne natural history study--a longitudinal investigation in the era of glucocorticoid therapy: design of protocol and the methods used. Muscle Nerve. 2013 Jul;48(1):32-54. doi: 10.1002/mus.23807.
  10. Henricson EK, Abresch RT, Cnaan A, Hu F, Duong T, Arrieta A, Han J, Escolar DM, Florence JM, Clemens PR, Hoffman EP, McDonald CM; CINRG Investigators. The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve. 2013 Jul;48(1):55-67. doi: 10.1002/mus.23808.
  11. https://cinrgresearch.org/publications/
Related Content
© 2024 MJH Life Sciences

All rights reserved.