Clinical trials for rare diseases: What can we expect?

Written by Marco Sancandi, PhD, Analyst. Email: [email protected]

Rare diseases, individually infrequent but collectively prevalent, are in the spotlight as scientists strive to develop safer and more effective treatments. By reimagining the traditional clinical trial framework and embracing innovative tools like wearable devices, there is potential to enhance research outcomes. A recent publication in Nature journal sheds light on the numerous innovations that have already made a substantial impact and hold promise for further advancements in drug development for rare diseases.

N-OF-1” Trials

The concept of “N-of-1” trials raises possibilities in the space of personalized medicine. These trials focus on antisense oligonucleotides (ASOs), which can modulate messenger RNA, enabling gene expression regulation without altering DNA. This approach avoids permanent hereditary changes and the associated bioethical concerns. A prominent example of ASOs is nusinersen, an approved drug for spinal muscular atrophy (SMA). In recent years, ASOs have garnered attention as a potential therapeutic option for addressing severe diseases with ultra-rare or even unique genetic mutations. In certain instances, such as Batten disease or telangiectasia ataxia, these drugs have been tested on individual patients through “N-of-1” clinical trials, where “N” signifies the involvement of just one patient. The efficacy of this type of experimentation remains an open question, as there is no definitive answer yet. Currently, there is no established method for managing such clinical trials, where the assessment of therapy effectiveness and safety relies solely on a single patient. This presents a significant challenge when compared to traditional studies, which aim to include a larger patient pool to comprehensively evaluate the validity of a drug.

The use of biomarkers

Clinical trials for rare diseases necessitate a more personalized approach, ideally with shorter durations. These trials often involve a small number of participants, primarily due to stringent enrolment criteria and the limited number of affected individuals, with the pace of disease progression greatly influencing the timeline for assessing treatment effectiveness. To address this challenge, it becomes crucial to identify and measure specific parameters tailored to the unique characteristics of each disease, offering a comprehensive perspective. A promising strategy involves the use of specialized biomarkers. For instance, when testing a genome editing technique in a particular genetic disease, researchers can aim to restore deficient protein levels in patients. These protein levels serve as measurable biological parameters, essentially functioning as biomarkers. This approach establishes a tangible link between biomarker changes and potential clinical benefits of the therapy.

Placebo, real-world data, and adaptive studies

Considering the limited number of patients affected by rare diseases, there’s an ongoing debate about the inclusion of control groups, or the use of placebos, in clinical trials. Some experts argue that patient awareness of the possibility of receiving a placebo may lead to refusals to participate, potentially undermining the study’s integrity and reducing the participant pool. Similarly, in trials involving various drug doses, some specialists propose excluding very low doses, asserting that the safety concerns can be alleviated through detailed preclinical data on the therapy.

Another important consideration is the use of real-world data, which includes parameters like blood pressure, sleep patterns, and physical activity levels, along with electronic health records, outside the confines of a controlled trial. As reported in the paper, real-world data is assuming an increasingly vital role in drug testing and has the potential to transform the design and outcomes of clinical research. For example, gene therapies for conditions like SMA and metachromatic leukodystrophy, approved for use in some countries, were evaluated not only in children with advanced disease but also in those with minimal or no symptoms. This approach may appear unconventional, but it proved essential in demonstrating the therapies’ true effectiveness when administered before the disease advanced irreversibly. Wearable devices also have the potential to play a critical role in gathering real-world clinical data, offering insights into how treatments perform in everyday life, beyond the controlled environment of clinical centres.

In many cases, traditional clinical trial models may not be suitable for rare diseases. Consequently, some researchers are exploring adaptive trials. “Adaptive” refers to a study design that evolves as the research progresses. This may involve changes in randomization methods, the addition of more patients, or adjustments to the drug dosage. While adaptive trials require more extensive statistical analysis for validation, they represent a potential future practice for evaluating new therapies for rare diseases.

Equitable access

Lastly, the pressing issue addressed in the article is the imperative need for equitable access to clinical trials. Paradoxically, certain rare diseases are more prevalent in different regions than where clinical trials are conducted. This discrepancy is both puzzling and unjust because it is crucial that populations with a higher prevalence of these diseases have opportunities to access potentially life-saving interventions. For example, clinical trials exploring cutting-edge therapies for Sickle cell anaemia, such as the first drug based on CRISPR technology, often exclude regions with a high disease burden (e.g., Africa). Economic factors are among the primary barriers to access. The development of new drugs, especially advanced therapies, demands specialized skills, clinical centres, and technologies that are not uniformly available across the globe. As advanced therapies become more common, it’s clear that global initiatives are vital to ensure access to clinical trials and approved treatments for rare disease patients. This is an urgent ethical imperative for global healthcare improvement.

P4A has been and will continue to stay updated on trends in clinical trials for rare disease, to best advise our clients on how to react, plan, and adapt to the evolving environment. Contact us to learn more about our services to support with determining ideal access pathways, and to remain up-to-date in an ever-changing space.  


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