Wile individually rare, orphan diseases are actually collectively common, with an estimated 350 million sufferers worldwide. Since the introduction of the US Orphan Drug Act more than 30 years ago, the number of orphan designations has skyrocketed and experts are predicting worldwide sales of these drugs will reach $176 billion by the end of 20201. With the cost of developing orphan drug comparatively less than non-orphan products, appreciable regulatory support for innovative program design, and with the possibility of demonstrating significant intellectual property value, interest and investment in orphan disease development programs has been explosive.
The Importance of the Patient
In an orphan drug trial, clinical management of individual patients can be difficult. Understanding the burden of disease and managing patient and family experience within a study is key. Patients with a rare disease frequently arrive at a diagnosis through a lengthy process of evaluations and may be experiencing a reduced quality of life and, in some cases, limited life expectancy. In rare disease trials, the need to recruit and retain patients while adhering to exceptional standards of care influences every decision. The protocol must account for the vulnerability of the patient population and address ethical considerations, particularly if the study design mandates discontinuation of ongoing therapy considered essential for patient support. Eligibility criteria always influence the number of available subjects, and if artificially constrained, reduce the likelihood of establishing a clinical trials database from which evidence of efficacy and safety can be extrapolated to a larger network of representative patients with the same disorder.
Unique Challenges
There are some fundamental differences between conducting trials for non-orphan drugs and those for orphan drugs, which present unique opportunities.
First, finding and activating feasible study sites and qualified investigators can be difficult. Selection involves identifying countries with a sufficient number of suitable study participants, then determining whether these patients are accessible, and finally, identifying centers of excellence with the therapeutic and operational capabilities to execute an observational or interventional trial requested. The nature of the indication emphasizes the importance of the medical, cultural and regulatory context as well as the standard of care and treatment pathways within each country of interest.
Smaller patient groups and, occasionally, a decreased likelihood of identifying and engaging patient advocacy groups, means identifying and locating participants can be extremely challenging, while retaining them for the full study duration is key particularly when modification in longer-term outcomes influence approval. If there is no patient advocacy group, general registries such as the Global Rare Disease Patient Registry and Data Repositorya, entities such as the National Organization for Rare Disorders and the European Organisation for Rare Diseases; as well as resources such as Orphanetb â are invaluable as a first step in an algorithm leading to site identification and selection.
Once sites are selected, site-by-site recruitment, retention analysis and planning and specialized outreach, must be undertaken. When studying an orphan disease, every single patient’s participation is vitally important given limitations in patient availability, and the exceptional impact the data from a limited number of patients may have on program development. Engaging sites, investigators, and patients to confirm acceptance of the study design is vital. Proactively engaging all stakeholders can foster a collaborative approach that facilitates recruitment, retention and commercial value long-term.
To ensure high levels of participant retention, sponsors must make the patient experience as smooth as possible and where practical, reduce the burden on the patient and caregiver regarding both visit frequency, and visit intensity (the number and complexity of assessments at a site). For example, in-home nurse visits cognizant of the need for GCP compliance could be offered when patient mobility is a problem, and financial and logistical assistance should be provided to aid any travel and lodging requirements.
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