Filling the gaps for rare and orphan diseases

In the European Union, a rare disease is defined as one that affects no more than one person in 2000.¹ With such a small number of patients, often heterogeneous and geographically scattered, it can be difficult to develop drugs to treat rare diseases. Orphan diseases, the subset of rare diseases without any current approved treatments, pose an even greater challenge, as there often is incomplete information regarding the disease pathology, and identifying patients can be difficult.

Because of this, the best path toward approval for a rare or orphan disease treatment is to gather as much data as possible, while involving as few participants as possible in clinical trials. A natural history study, which collects information on the course of a disease without intervention, is an advantageous approach. It provides insights that can shorten a development timeline and improve success in research.

 

Study designs

Natural history studies often begin early in the development timeline, and can extend for years to capture data over time. Each clinical trial comes with its own unique needs and timelines, which can be used to guide how best to approach the use of a natural history study. For sponsors planning to implement such a study, there are a number of designs that can be used, each with distinct advantages and disadvantages.

• Retrospective cohort studies collect data from past records, such as healthcare databases or medical charts. While these can be completed quickly, they typically lack patient-reported outcomes.
• Cross-sectional studies gather information, such as biomarker distribution or patient reported burden, from the study population at one specific point in time. As with retrospective cohort studies, this has the benefit of being completed quickly. But, since it only represents one moment in time, it does not provide information related to disease progression.
• Registry studies are observational studies that gather information on the patient population over a period of time. This allows for the observation of disease progression, as well as more comprehensive insights on biomarkers, clinical outcomes and patient reported burden. However, these take significantly longer.

Data from a natural history study are often used in an external control arm, to be compared with data gathered from the treatment arm of a clinical study. This is beneficial because the patient population with a given rare disease tends to be small, and most participants wish to receive active treatment. Additionally, this can increase the operational efficiency of trials, lowering trial costs and getting life-saving therapies to market faster.

 

Hurdles to overcome

Because of their unique nature, natural history studies of rare and orphan diseases face a variety of challenges that typical studies do not. For example, with many rare and orphan diseases, there is little existing clinical research to build upon. As a result, studies of these conditions often break new ground by collecting patient data.

A particularly significant challenge for such studies is finding patients to participate. By definition, patients with rare diseases are small in number, and they may be spread across a wide geographical range. Further complicating the issue is the fact that physicians may have difficulty identifying a rare disease in their patients, particularly when diagnosis requires specific equipment or facilities to which some physicians may not have access. This means that sponsors might have trouble finding patients via electronic health records, and may wish to explore other resources, such as registries or rare patient organisations.

Each country involved in a natural history study will present its own specific challenges as well. If sponsors wish to conduct a global or multi-national study, as may be necessary due to the geographical dispersal of patients with rare diseases, they will need to conduct a comprehensive feasibility assessment. Such an assessment will help answer questions that will guide strategies to overcome regional challenges, including:

• The availability and willingness of sites to participate
• The likelihood of disease recognition
• Ways to motivate patient participation over a long period of time, and more

It will also help determine the timing and cost of various study scenarios based upon the answers to such questions.

 

The Value of Natural History Studies

Natural history studies are important to rare and orphan diseases, as they provide a wealth of information necessary to bringing much-needed treatments through clinical trials and to patients. While they require the investment of time and resources, with proper planning and strategy, they can prove invaluable to sponsors and improve the success of research programs.

References:

1. Rare diseases. EU research on rare diseases.