Rare disease clinical trials call for intelligent design: ICON

Designing a clinical trial is a challenging prospect, but when the condition at the center of a study is a rare disease, sites and sponsors must consider an additional level of complexity. Patients living with rare and orphan diseases frequently deal with unique symptoms and limitations that must be taken into consideration at the design stage.

Outsourcing-Pharma checked in with two leaders from clinical research organization ICON about what it takes to succeed in designing an effective rare-disease trial:

• Will Maier (vice president of rare disease and drug development sciences)
• Scott Schliebner (clinical executive, strategic advisor, and patient advocate)

OSP: Could you please share an overview of trends in the rare disease clinical research arena? Are we seeing an increasing number of such studies, and in what ways do the recent changes in the field (including those created or accelerated by COVID) compare to more traditional therapeutic areas?​

ICON: Drug developers in the rare disease sector often encounter flexible regulatory pathways, as many rare diseases are fatal and have a high degree of unmet medical need and no alternative treatments available to patients. This has created a favorable drug development landscape whereby clinical development may require fewer patients; smaller overall clinical trials; lower overall clinical development costs; and higher chances of ultimately receiving marketing authorization compared to other more common indications.

Additionally, patient groups and patient advocacy efforts have created a grassroots infrastructure for many rare diseases by establishing patient registries and natural history studies, by developing integrated patient communities, and by raising funds to support research themselves. This has helped to reduce or eliminate some of the more common hurdles to developing a drug for a rare disease, and I believe we are seeing an increase in rare disease clinical research as a result of these various factors.

OSP: Please offer some of your thoughts on why incorporating patient voices in study and protocol design helps patient participants, and how the practice benefits the trial teams.​

ICON: Incorporating patients into clinical trial design is critical to developing realistic, feasible studies. Including the patient voice and perspective in the early study design phase provides drug developers with important input and feedback from a clinical trial’s ultimate stakeholders – the patients themselves.

Incorporating this important “end-user” or “consumer” input results in studies that enroll more rapidly; it creates studies with fewer screen fails; it ensures more patients actually complete the study and do not drop out mid-study due to overly burdensome study requirements. Ultimately, this accelerates clinical development, reduces the cost of developing new treatments, and brings medicines to patients faster.

We have developed a tool to facilitate sponsor/patient interactions, and to help sponsors assess the burden of a prospective clinical trial prior to finalizing and opening the study to enrollment. This stakeholder feedback tool is designed to help reduce the burden of clinical trials and thereby facilitate greater access for all patients, regardless of their geography and SES factors.

OSP: Soliciting and incorporating patient perspective and voice in trial/protocol design is challenging—could you please share some of the ways in which this process is even more challenging when rare/orphan diseases are the condition at the center of a trial?​

ICON: Clinical development is a difficult and highly regulated process. Conducting clinical trials in common, less complex disease states has its own challenges, but when clinical development moves to rare diseases, the hurdles become exponential. For many rare diseases, there is great variability in the natural course of disease; variability in the standard of care for patients, or perhaps no standard of care at all.

Pressure testing a new clinical trial design with rare disease patients is critical. Many rare diseases are genetic in nature or occur in children, thereby requiring the involvement of parents, caregivers, and often the entire family in a clinical trial. With very few, geographically dispersed patients, we often don’t fully understand the natural course of a rare disease, making it challenging to establish baselines to measure the effectiveness of new therapies. Further, many rare diseases are multi-disciplinary in nature, requiring a diverse group of medical experts to help diagnose and manage the particular condition.

OSP: What are some ways study teams might fall short in their efforts to include input and perspective from rare disease patients, and what might be some of the negative impacts on a trial if they do so?​

ICON: A lack of understanding as to how, and when, to engage patients in the clinical design process. Often a lack of time to do so or a fear that including patient input will slow down the protocol development phase or result in feedback from patients that is not actionable. Difficulty gaining consensus on a protocol, and difficulty including layperson/patient perspective within an otherwise medical and scientific collaboration.

Impacts include:

• less appealing study
• lower enrollment rates
• higher drop-out rates and lower participant retention
• higher screen-fail rates
• lengthened overall clinical development timelines
• higher overall development costs
• decreased buy-in from the ultimate stakeholders: the patients themselves.

OSP: How might a study team utilize data sources and informatics to bring about better design?​

ICON: Leverage diagnostic claims data; pharmacy claims data from both specialty and hospital pharmacy systems; procedural claims data – all can be used to illustrate what a patient journey looks like and what baseline health care utilization looks like for a given rare disease.

Understand the patient population better via demographics, healthcare utilization levels, SES factors. Leverage natural history data to select endpoints, eligibility criteria, and expected levels of efficacy. Historical enrollment rate data and site performance data can help support projections around trial parameters such as number of countries to be selected; which countries to be selected; number of sites to participate; expected enrollment rate per month; and overall enrollment duration

OSP: Decentralizing a trial is more than just sending patients home. Could you please share some of the technology tools trials can use to help bring DCTs to rare disease patients?​

ICON: Decentralizing a trial involves using some of the technology and tools available to us to create a clinical trial that is less site-based and is more focused on bringing a study directly to patients. These include:

• home health care nursing
• telehealth direct-to-patient drug shipment
• mobile health platforms to administer ePROs
• eSource direct EHM/EMH data collection
• Bluetooth-enabled devices for remote data capture.

OSP: What are some things trial teams should keep in mind when weighing disease burden and treatment impact?​

ICON: Consider the selection of endpoints – are they satisfactory to regulators and patients? Consideration of unmet medical needs and patient motivation to participate in a clinical trial. Ensure that disease variability amongst patients doesn’t result in selection bias.

OSP: How can ICON’s Rare Diseases Advisory Committee (RDAC) help rare disease studies?​

ICON: Our external RDAC is comprised of a group of rare disease patients, advocates, parents, and caregivers, assembled to provide a diverse yet holistic view of rare disease communities. The RDAC actively partners, and guides, ICON’s Center for Rare Diseases as we strive to create innovative patient tools, as we seek to understand the patient perspective, and as we ensure we design and conduct clinical trials that are realistic for families.

The RDAC was critical in the development of our recently released Patient-Centric Trial Development Toolkit, a first-of-its-kind open-access tool for sponsors and patients to be able to assess the level of study burden prior to a clinical trial being opened.