Rare disease is getting more attention as the potential of cell and gene therapy (CGT) continues to grow and attract funding. Yet the challenges that beset clinical trials – too slow, expensive, and unpredictable – are amplified for the development of orphan drugs. Joan Busner, PhD, clinical vice president at Signant Health, explains that the nature of these studies means there are also additional considerations, which must be well understood to achieve the necessary data quality and desired clinical efficiency.

Here, Busner lays out five ways to improve the chances of trial success.   

1. Be aware of the evolving requirements of your trial demographic

As rare diseases targeted for orphan drug development often begin in childhood, integrating protocols with this age group in mind are essential. For example, long visits may need to be split, while arrangements, like accommodation, may be needed for accompanying family members. For children able to complete self-report assessments, child-friendly digital platforms with the ability to accommodate “smiley face” visual analogue scales may be required. eCOA that tracks age and automatically re-provisions required age-specific scales or automatically tracks and applies age-dependent scoring algorithms should be arranged prior to initiating the trial. In addition, as proxy or parent/caregiver reports are typically central data elements, a standardised means of ensuring caregiver comprehension of scale instructions, and, for eCOA, the ability to track the consistent input of a single designated caregiver is critical for generating high quality, credible data.

2. Provide translation and localisation services

 To be considered a rare disease, a condition must affect fewer than 200,000 people in the US at any given time, or in Europe, fewer than five people for every 10,000. Given the scarcity of patients, rare disease studies typically recruit from sites around the globe to achieve recruitment targets. Without ensuring that scales are accurately translated, scale administration consistency and data quality are at risk. An experienced scale management team can help your study get started faster by taking care of the more time-consuming processes, such as identifying copyright owners, locating commercially available translations, and negotiating costs or licensing for your study-specific needs. We recommend that sponsors obtain scale management services that follow an ISPOR compliant process, including linguistic validation. At times regulators may ask for cognitive debriefing and you will need a scale management team able to accommodate this request.

3. Invest in rater training and remediation

One common challenge of rare disease studies is the limited pool of experienced investigators due to the rarity of the condition. There may be only one or two centres per country that diagnose or treat the disorder and the teams there may not routinely conduct research. In addition, each clinician may have their own way of interacting with, assessing, and evaluating patients and these differences, while acceptable for clinical practice, may affect ratings and reduce a trial’s ability to successfully detect a drug effect. Designing a training programme that acknowledges and respects clinician differences but brings cohesion for the common good of the study requires thought, experience, and expertise. It can also help prevent rater drift. An eCOA solution with built-in pointers and guidance to guide raters as scales are administered is one way of managing this. Many of today’s eCOA solutions contain reminders and automated scoring to improve data quality. Some are also able to video record assessments for subsequent independent review, scoring and rater remediation by experts.

4. Prevent excessive placebo response and expectation bias

Excessive placebo response is a major concern in rare disease studies. The level of hope among patients and families is understandably high, and this is further heightened when the patient is a child. If not managed well, such expectations can lead to placebo response rates that prevent the study from demonstrating the effects of the investigative treatment. It is critical to teach investigative sites effective strategies that allow them to work with patients and their families in a compassionate manner while preventing placebo response. In addition to investigative site training, you might consider a placebo response mitigation training programme that can help patients and caregivers understand their role in the study and the value of objective reporting.

5. Take advantage of remote technologies  

There are various reasons for conducting remote rare disease trials. Patients may be too ill to travel, or widespread sites may require long and burdensome travel. The pandemic-associated lockdowns made travel impossible or ill advised. As the technology exists to conduct remote assessments and connect patients with experts more easily, then doing so is only of benefit to all involved.  

When functional unblinding (tell-tale side effects) threatens the integrity of a trial, a remote group of experts (“central raters”) can be used rather than site raters to conduct key assessments. Today’s remote technologies allow for remote assessments, video capture, and central ratings through a variety of secure digital platforms. Telemedicine increases diversity in studies and access to research, both especially critical features for rare disease studies.   

Read how Signant Health can help you prepare for your next rare disease study in the free guide below.