Advancing Rare Disease Clinical Trials: A High-Touch, Patient-Centered Approach for Biotechs

Understanding Rare Disease Challenges

Clinical trials for rare diseases present unique challenges as compared to common diseases. Patient numbers are low, with fewer than 200,000 patients in the U.S. suffering from rare diseases. Because of these low patient numbers, rare diseases aren’t as well characterized, heterogeneity within an individual rare disease can have an outstanding effect in terms of how and when they present, and there are recruitment challenges related to a lack of concentration of patients in any one geographic locality. Addressing these challenges requires developing relationships with key medical and scientific opinion leaders and patient advocacy groups to understand the patient and healthcare provider (HCP) experience.

Rare diseases are frequently chronic, progressive, and, often, life threatening. Many rare diseases present in pediatric populations, and the families of these patients face a challenging journey as they navigate obtaining an accurate diagnosis and subsequently accessing medical treatment. For companies to design clinical trials to eventually provide vital therapies to rare disease patients, a focus on ensuring accessibility along the way is critical to include from the earliest stages of trial design. Mapping out the patient journey to diagnosis can be a critical tool to finding rare disease patients.

Optimizing Trial Design Through Innovative Approaches

For rare diseases that do not already have a well described disease progression, natural history trials can be very important in determining the most clinically meaningful endpoints throughout clinical development programs and for which patients — and when in the disease progression — drug interventions have the best chance of providing clinical benefit.

Rare Disease trials may require distinct trial designs. Increasingly, advanced statistical approaches are recognized as powerful tools in facilitating rare disease clinical trials with limited subjects. Bayesian statistical approaches allow researchers to integrate existing knowledge, such as natural history data and previous studies, which are crucial in rare disease trials when robust data collection is difficult. The ability to leverage prior knowledge can be pivotal for rare disease research when working with smaller sample sizes.

Modeling and simulation approaches are being developed and used for several different purposes in rare disease trials. These approaches have been used to help sponsors simulate the effects of their therapies for dose selection, to better estimate minimal cohort sizes, and to enhance or even replace placebo groups. The Model-Informed Drug Development (MIDD) Paired Meeting Program at the FDA is a resource that can be accessed by sponsors who wish to apply quantitative models based on pharmacokinetics, pharmacodynamics, disease progression, and clinical trial simulations to guide drug development decisions and increase the probability of regulatory success.

Some rare diseases require novel endpoints not captured in already validated clinical instruments. Working with key opinion leaders (KOLs) in the field as well as patients and regulators is often part of the solution to this problem. Some rare diseases are amenable to proximal biomarker approaches, which can be used to speed trials. It is important to work with local regulators to secure agreement on the approvability of biomarkers early in the clinical trial process. For example, proteinuria has been used to gain approval for certain rare renal diseases.

Patient Recruitment: Overcoming Barriers

Conducting Rare Disease clinical trials comes with a variety of obstacles for sponsors and sites to navigate. First and foremost, because of the relatively small number of patients in the world, it is difficult to recruit enough patients to get statistically significant results for trials. Rare disease trials place several burdens on patients and their caregivers, including extended travel times to sites, increased financial burden due to travel and lost time from work, logistical challenges associated with traveling with a rare disease, and disruptions of work and/or school routines.

To address the logistical challenges of rare disease trials, sponsors can consider using either coordinated travel or concierge services to help patients and families get to the investigator sites. This provides a dedicated resource to support not only the patient and their family, but also site staff, who would otherwise have to take on this task. Because rare disease trials often involve several different countries, international travel may be required. Having a qualified vendor offering travel services can be important to the success of these trials. Another potential solution is the use of a decentralized trial (DCT) approach.

Sending healthcare professionals to patient homes is another means of accommodation. Working with nurses and other professionals to do home visits to assess subjects and collect samples will help support subjects that live far away from sites and/or subjects whose indications make it challenging to leave the house. There are also travel assistance programs to help patients and families cover the cost of travel.

Understanding the patient’s treatment journey is critical to determining when interventions have the best chance of providing clinical benefit; it can also help sponsors accelerate patient identification and recruitment. Rare disease patients often have an extended period before they are accurately diagnosed. En route to diagnosis, they may visit different HCPs who are unfamiliar with their condition. As a result, the patient is passed along until they finally find someone that can help them. Establishing relationships with rare disease patient advocacy groups is another key to success. Patient advocacy groups are constituted by patients and their care givers, who are experts on how they got diagnosed, which physicians they see, when their disease became symptomatic, and what would be the most impactful changes on their health. By collaborating with patient advocacy groups, sponsors gain greater insight into their diagnostic journey, current standard of care, and the trial endpoints that would mean the most to them. Patient advocacy groups can often provide detailed support with patient recruitment approaches (what is meaningful for the patient), direct support in identifying patients (links on website, advertising, and PI endorsements), and established intelligence in retention focal points (protocol feedback, patient/family burden, and competition). With this information, a sponsor can adapt their trial to effectively produce patient-centric protocols and ensure accessibility and retention.

Navigating the FDA Regulatory Landscape

The FDA recognized many years ago that rare diseases were underserved and in response, created several incentives to spur drug development for rare diseases. They also created regulatory pathways to help sponsors mediate the challenges of Rare Disease drug development. Some of the incentives that are offered include up to seven years of market exclusivity, tax credits for clinical trial expenses, and the waiving of certain application fees, including the prescription drug user fee. Along the way, the FDA’s Office of Orphan Products Development (OOPD) provides support and guidance to companies developing orphan drugs, including frequent access to advice and assistance with clinical trial design, regulatory strategy, and other development issues. Many rare disease programs will be eligible for the accelerated approval pathways because they tend to treat life=threatening diseases with unmet medical need.

Rare disease drug sponsors also have access to FDA-funded grant programs that provide monetary aid for research on rare diseases, including funding for clinical trials. The OOPD administers several programs to provide incentives for the development of drugs, biologics, or medical devices for rare diseases. These programs include Orphan Drug Designation, Rare Pediatric Disease Designation (administered in conjunction with the Office of Pediatric Therapeutics), Humanitarian Use Device Designation, Orphan Products Clinical Trials Grants, Orphan Products Natural History Grants, and Pediatric Device Consortia Grants.

The table below presents a non-exhaustive list of FDA initiatives or designation pathways that benefit rare disease drug development campaigns.

Rare disease drugs may also qualify for expedited programs such as:

• Fast Track Designation: Facilitates the development and expedites the review of drugs for serious conditions.
• Breakthrough Therapy Designation: For drugs showing substantial improvement over existing therapies.
• Accelerated Approval: Allows approval based on surrogate endpoints.
• Priority Review: Shortens the review time for marketing applications; 6 months compared with the 10-month standard review.

To determine how and where your team can take advantage of these regulatory incentives, start by accounting for the hurdles of rare disease trials.