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Ultra-Rare Disease and Clinical Research– Different Approaches for Unique Studies

Cassidi Williams

In a previous blog, we discussed ultra-rare diseases and the unique research challenges they pose to the development of new therapies. The nature of rare and ultra-rare disease means that drug development pathways and the types of studies commonly conducted can differ from the pathways and approaches used for more common diseases.

In this piece, we will discuss some of the approaches commonly taken to bring new ultra-rare disease therapies to market, and how decentralized clinical trial (DCT) elements help.

Natural History Studies

Due to their inherent rarity, ultra-rare diseases are often not well understood or characterized. ICD-10 codes may not exist and physicians may only be able to describe the disease symptomatically. The genetic nature of many of these diseases means there can be considerable heterogenicity in the patient population due to the involvement of different genes or alleles. Furthermore, little may be known about disease progression, clinical endpoints may not be established, and standards of care across different geographies may not be known.

Natural History studies can support gathering this information to allow sponsors to design clinical studies that are both patient-centric and able to gather data that is both meaningful and acceptable to regulators and payers.

A Natural History Study in an ultra-rare disease not only helps to support the understanding of the disease but can, if well-designed, serve as a control arm in subsequent clinical studies, helping to overcome the ethical issues regarding use of placebo in a patient group who do not have other treatment options. Natural History studies lend themselves well to decentralized approaches, as participants can provide information via surveys, eDiaries and ePROs, disease progression can be followed over time, and geographical differences can be mapped. While most rare disease clinical studies are likely to be conducted hybrid decentralized approach, given that Natural History studies are non-interventional, there is the potential to conduct these studies fully remotely.

Open Label Extension Studies (OLEs)

For most participants involved in ultra-rare disease clinical studies, unfortunately, there are unlikely to be other treatment options available and the disease is likely to be debilitating and/or life-threatening. It follows that once a participant has enrolled it may be unethical to cease treatment at the end of the trial treatment period. Thus, it’s very common for ultra-rare disease clinical studies to be followed by an open label extension (OLE) phase or a separate OLE study. This allows both participants who have received the investigational product and those in the placebo control arm to continue or begin receiving the investigational product, often up until market authorization. This is valued by participants and indeed can be an incentive to enroll in the first place. The OLE is an ideal stage to introduce or increase the number of remote procedures; because the data collection requirements are likely to be reduced, participants and sites are likely to feel more secure about the clinical outcomes and it makes participation easier for patients and families to work in to their day to day lives.

Long Term Follow-Up Studies

Since the majority of ultra-rare diseases have a genetic component, it’s not surprising that many of the treatments being developed are gene and cell therapies. DCT approaches are ideal for these therapies as studies typically consist of a single infusion event followed by short-term follow-up within the same protocol and then a separate long-term follow up which, depending on the vector and safety profile, may extend up to 15 years. Remote technologies utilized in DCTs help to collect follow-up data and keep participants engaged without requiring frequent in-person visits and reduce the likelihood of lost to follow-up over these extended periods.

Despite the many challenges to developing new therapies for ultra-rare diseases, it is important to consider all possible routes to success. By utilizing DCT elements, we can better understand these diseases and provide less intrusive ways for patients to submit valuable data. By making research participation as easy and accessible as possible, we can increase the number of possible ultra-rare disease studies and enable sponsors to conduct these studies more efficiently and with less burden to participants and their families.

For more information on how to employ decentralized approaches in your rare disease drug development program, visit THREADresearch.com