Guest Column | November 4, 2021

Rare Disease Clinical Trials: 3 Areas We Could Improve On

By Matthew B. Klein, PTC Therapeutics

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More than 7,000 rare diseases have been identified, but only 5% of those diseases have an approved treatment.1 While significant strides in conducting rare disease clinical studies have been made over the past few years, there are still opportunities for improvement that can help address persistent unmet medical needs.

Rare disease clinical trials pose unique and complex challenges. Small and geographically dispersed locations of treatment centers, disease heterogeneity, and incomplete disease natural history (the course a disease takes in the absence of treatment) can complicate the process. However, there are actionable and tangible steps we can take to improve the process and enable development of innovative and meaningful therapies. Below are the challenges we’ve encountered and insights I’ve gained to overcome them over the course of my career.

Expand Knowledge And Geographic Reach To Improve Clinical Trials

The natural history of a disease captures disease progression and informs endpoint selection and clinical trial inclusion criteria. With this critical piece of information often missing for rare diseases, combined with a lack of data from previous clinical trials available, developing and executing accurate and impactful clinical studies that can meet regulatory standards for approval is challenging. Further, small and heterogeneous patient populations make the absence of comprehensive natural history even more impactful. It is critically important to appreciate that rare does not mean homogeneous; in fact, many rare genetic diseases are heterogeneous and patients with the same genetic mutation may have very different disease courses in terms of symptomology, rate of progression, and disease severity. Therefore, a comprehensive natural history that can provide an understanding of this diversity is essential to inform clinical trial inclusion criteria, endpoints, and duration.

In addition, drug developers must become experts in the diseases for which they are developing therapies. It is critical to immerse oneself in learning about the given disease – through textbooks, the internet, physicians, and, most importantly, patients and families. Hearing directly from patients and families about the impact the disease has on their life provides valuable insight into their individual experience, the unique history of their disease progression, and their treatment goals.

It’s also incredibly important to consider the global disease community. Rare diseases affect 30 million people in the United States and 400 million worldwide.1 Expanding the geographic reach of a trial not only alleviates size limitations typically associated with rare disease clinical trials but offers hope and potential treatment options to more patients living with rare diseases. However, it is important to be aware that standards of care and approaches to disease management may differ around the world.

Bring Clinical Trials To Patients

In addition to these typical rare disease clinical trial limitations, the COVID-19 pandemic highlighted additional shortcomings associated with the clinical trial patient experience and process. While the pandemic has caused a lot of uncertainty and has been devastating on a global scale, I believe we were able to make changes to the conduct of clinical trials that may ultimately improve the inclusiveness of clinical trials and ultimately, better serve the patient community. For example, clinical trials typically require frequent visits to study sites for interim evaluations. These visits are often incredibly burdensome to patients with rare diseases, who may not be able to easily travel long distances. Some patients are wheelchair and ventilator-dependent, and travel requires the assistance of one or more caregivers or family members. In addition, during the COVID-19 pandemic, travel was even more challenging and risky, particularly for patients with compromised immune systems.   

To address this at PTC Therapeutics, we’ve made an effort to minimize the number of visits patients are required to make to study sites and, when possible, make visits remote through video technology and visiting nurses.  Decentralized clinical trials that leverage advancements in technology have long been seen as a way to improve trial participation and inclusiveness; however, it took the global pandemic to really catalyze this evolution. I encourage all companies and organizations working in rare disease to attempt to incorporate virtual visits into clinical trials, reserving in-person appointments for critical visits only. Of course, this too will require collaboration and acceptance from regulatory authorities, who have already voiced their support of exploring this decentralized approach.

Partner Closely With Those You Aim To Serve

Rare disease drug development is a team effort. Close collaboration between patients, families, foundations, physicians, and industry organizations is essential. Many crucial aspects of conducting clinical trials – including study design, endpoint selection, natural history work, trial recruitment, and retention – require input from those most familiar with a particular disease. Working with patients, families, and advocacy organizations is crucial to understand the patient experience. While truly understanding the patient experience is impossible unless experiencing it firsthand, listening and hearing about what treatment success looks like from their perspective can, and should, influence thinking around endpoints and clinical efficacy.

Overall, our goal is to improve the quality of life for those affected by rare diseases. While the patient population for a given rare disease may be small, the total population of all rare disease patients is significant. We strive to give patients hope, and they give us purpose, and it’s important that we continue to put building blocks in place to develop transformative treatments for the rare disease patient communities globally.  

About the Author:

Matthew B. Klein, MD, MS, FACS is chief development officer at PTC Therapeutics, Inc. Prior to joining PTC, Klein was CEO of BioElectron Technology Corporation, a biotechnology company focused on development of redox active small molecules for mitochondrial disease and related disorders of oxidative stress. Prior to joining BioElectron, he was the Auth-Washington Research Foundation Chair of Restorative Burn Surgery at the University of Washington. Klein completed his undergraduate degree at the University of Pennsylvania, where he graduated summa cum laude and Phi Beta Kappa, and he received his MD degree with honors from Yale University.

  1. Global Genes. “Rare Disease: Facts and Statistics.”