The main challenges encountered during clinical trials include patient recruitment and retention, but also regulatory hurdles and methodological complexities need to be overcome. Drug repurposing is one of the possibilities used by Orfenix that aims to ease the regulatory hurdles and thereby reduce timelines and costs for clinical development.
Patient Recruitment
The limited number of patients with a specific rare disease is an obvious, yet very significant challenge in conducting clinical trials for orphan drugs. The small patient population often leads to difficulties in recruiting enough participants to meet the necessary sample size for statistical significance. Many rare diseases have prevalence rates so low that it may take years to enroll an adequate number of participants.
About 70% of rare diseases have a genetic origin. In some cases, for those diseases or group of diseases active patient organisations exist. Patients and caregivers interact with each other on a national level and often there is a good collaboration between caregivers in different countries. Nowadays, drug developers engage both patients and dedicated caregivers through these organisations in the early phases of designing a clinical trial. This is not only valuable for protocol design, but also helps to create awareness amongst the patients and the participating investigators about the upcoming clinical trials, which may speed up recruitment.
Patient Retention
Unlike more common conditions, where patients are more readily available in a concentrated area, rare disease patients may be spread across various regions or even countries. This dispersion necessitates extensive logistical planning and can lead to increased costs and extended timelines for trial completion. It can also lead to patients’ withdrawal from the study due to the overwhelming effects on their daily lives or the lives of patient’s parents. Therefore you often see that trial sponsors and site personnel do their utmost to reduce the burden for patients, especially those travelling from long distance. To promote patient retention, there are several possibilities varying from home nursing, home medication delivery and interpreter services to the use of a patient-specific credit card for trial related expenses. Although these services will improve patient retention, they can cause a huge increase in trial costs per patient.
Regulatory Hurdles
While agencies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) provide incentives for orphan drug development, the approval processes can still be lengthy and require extensive documentation. Regulatory guidelines for orphan drugs can vary significantly between regions. Differences in requirements for clinical trial design, endpoints, and data analysis can complicate multinational studies.
Orphan drugs often need to demonstrate full safety and efficacy through rigorous clinical trials, which can be challenging given the limited patient populations.
In order to reduce unexpected delays in obtaining trial approval, Orfenix is in favor of requesting protocol assistance from EMA, FDA or any national agency.
Methodological Complexities
Designing clinical trials for orphan drugs often involves unique methodological challenges. Due to the small number of available participants, traditional randomized placebo-controlled trials may not be feasible. Alternative study designs, such as adaptive trials or use of historical controls, can be employed, but these approaches may introduce difficulties in regulatory acceptance.
Choosing appropriate endpoints in clinical trials for orphan drugs is critical yet challenging. Researchers must balance the need for meaningful clinical outcomes with the limitations posed by small sample sizes. Also a good balance should be found in chosing the patient population. While in common disease trials, the list of exclusion criteria will cause a homogenous population in the trial, for orphan diseases the trial population will be more diverse, and will for example include both adults and children and patients in different stages of the disease. In a diverse patient population it is more difficult to show findings with statistical difference.
Ethical Considerations
Informed consent processes can be particularly challenging in the context of orphan drugs. Given the limited treatment options available for many rare diseases, patients may be willing to accept higher risks. Patients with rare diseases may feel desperate for treatment options or may feel obligated to participate because of the longstanding relationship they usually have with their caregiver. Therefore sponsors must carefully evaluate whether the potential benefits of the drug outweigh the risks associated with its use, when designing (placebo-controlled) clinical trials.
Conclusion
While the development of orphan drugs is a crucial area of pharmaceutical innovation, the clinical trial process is full of challenges that can hinder progress. Each step in the trial process requires careful planning and execution. Collaborative efforts among regulatory agencies, researchers, and patient advocacy groups can help to streamline the process, making it easier to bring innovative therapies to those who need them most. As we continue to advance our understanding of rare diseases, overcoming these hurdles will be vital in improving the lives of many patients affected by these conditions.
