By Han Phan, M.D., assistant professor of neurology, department of pediatrics, rare disease research, Emory University School of Medicine
There are 7,000 known rare diseases and disorders, and collectively they affect nearly 30 million people in the U.S.1 The vast majority of rare diseases currently have no approved treatments available for patients, despite the fact that research related to rare diseases has expanded significantly in the past 20 years. A key reason may be the many unique challenges researchers may face when developing drugs to treat rare diseases, including difficulties designing and executing effective and appropriate clinical trials.
One key factor in research related to rare diseases is the limited number of patients available to participate in clinical trials. Researchers must work aggressively to identify eligible patients. Once identified, patients may have to travel to only a limited number of trial sites to participate. This can be especially problematic for patients with mobility problems or for trials involving children.
In many cases, trials must be designed for diseases for which very limited prior data is available. There is often little or no information about disease mechanism of action, progression, and symptoms, as well as patient burden and impact on quality of life. Often researchers are designing one of the first clinical trials ever conducted in a patient population. In these cases, research teams must often identify new pathways to measure efficacy based on endpoints or biomarkers that have never been used or have not been fully validated. While supportive research and careful analysis may indicate these markers can provide an appropriate assessment of efficacy, there is a risk they might not. Also, with smaller pools of patients, results are often not statistically significant.
There are many examples of research programs in rare diseases that present significant challenges to both researchers and regulators. Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease caused by a lack of functional dystrophin protein that results in progressive muscle weakness. The disease almost always affects boys, and symptoms usually begin early in life. Patients eventually lose the ability to walk in their early teens and typical life expectancy is mid-20s, frequently due to life-threatening lung and heart complications. As symptoms and severity of disease can vary, it is difficult for researchers to establish appropriate criteria to demonstrate clinical benefit in studies. And in the few examples to date of clinical research in DMD, it is clear that planning and executing an appropriate clinical research program requires entirely new levels of innovation and flexibility from both clinical researchers and regulators. These efforts have consistently highlighted the essential need to review totality of data from clinical research, including efficacy and safety measures in subsets of patients. It also demonstrates the essential need to include real-world perspectives on the benefits of treatment from patients and caregivers, who are often positioned to offer insights and validations that pure assessments of trial results might miss.
The example of DMD offers us an important road map indicating how clinical research and regulatory review in rare diseases can be improved in the years ahead. In recognition of the challenges in developing therapies for rare diseases, the FDA introduced the Safety and Innovation Act (FDASIA) of 2012 and the 21st Century Cures Act of 2016, both of which include provisions that recognize the need for new levels of flexibility in the regulatory review process for many of these diseases. These acts also highlight the importance of hearing from patients and caregivers about their experiences and using those insights to assess treatment benefits.
Insights from patients — often referred to as the “patient voice” — can play a vital role in helping researchers and regulators better understand the relationship between assessment of clinical trial results based on data and the impact of treatment of a broader range of factors in patient health and quality of life. This is especially important given that the use of innovative and often first-time endpoints in clinical research may not always correlate with benefits that are meaningful to clinicians and patients. For example, a patient with DMD may consider the ability to use a restroom or eat a meal without assistance to be a major benefit. By reviewing the totality of clinical data and patient insights related to therapies for rare diseases, even in cases where a trial misses a primary endpoint, it may be possible to confirm substantial positive efficacy benefit that can support approval.
Recent DMD clinical trials included use of a six-minute walk test (6MWT) as a primary endpoint. 6MWT is considered the gold standard to guide clinical research related to many diseases that affect mobility, and the European Medicines Agency (EMA) and U.S. FDA have recommended this test to measure gross motor function in ambulatory DMD patients in clinical trials. But, the test provides a single assessment of patient response at a specific time during treatment. Insights related to shorter or longer-term benefit of treatment can be limited. As a result, with therapies where the benefit of treatment may be cumulative and progress at different rates in different patients, data related to 6MWT may not offer a precise assessment of overall efficacy. In addition, it only measures lower limb strength. Benefits in upper limb strength, lung function, and cardiac integrity, which can help patients maintain quality of life and improve morbidity and mortality, would not be considered in the endpoint assessment.
DMD is just one example. Efforts to develop therapies for many other rare and orphan diseases consistently reinforce the need for innovative approaches in clinical research, especially where a disease is progressive and life-threatening and patients have no approved therapies available. Without new levels of innovation and flexibility, it is possible that many promising therapies might be delayed for years or might not be approved at all, leaving patients without treatment options that could deliver significant clinical benefits.
About The Author:
Han Phan, M.D., is a pediatric neurologist and assistant professor of neurology in the department of pediatrics at the Emory University School of Medicine. Her research primarily focuses is on neuromuscular disorders, particularly Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). She also studies sleep related neurological conditions.