Guest Column | September 22, 2022

Overcoming 4 Challenges In Orphan Disease Clinical Trials

By Richard Straube, MD, MSc, chief medical officer, Soligenix, Inc.


The impact of rare diseases goes beyond medical symptoms; they negatively affect quality of life and mental health, causing stress and often financial strain for patients, families, and caregivers. Although each rare disease affects a very limited number of patients, the cumulative number of patients with rare diseases is substantial. Today, rare diseases affect approximately 300 million1 people worldwide, and while the diseases are uncommon, challenges associated with clinical trials are not. Tailored strategies, communications, and collaboration can all make a notable difference in addressing and overcoming these challenges.

Development of innovative treatments for patients with orphan and rare diseases offers substantial challenges. The potential income from such treatments, even at high per patient costs, is limited, while the clinical trials to prove efficacy and safety are often more expensive and longer. Nonetheless, in these diseases with limited treatment options, healthcare teams and patients are often highly motivated to participate in assessing new therapies.

Interestingly, there is nothing unique about clinical trials in rare and orphan disease indications. Challenges that exist in all trials — patient recruitment, communication, and costs, to name a few — are simply magnified in rare disease trials, making it critical to ensure every detail of the trial design is meticulously planned.

Regardless of the study, drug development companies must make several critical decisions before entering the clinic: how to facilitate patient recruitment; how to best collaborate with the FDA; choosing to work with a CRO or manage a trial in-house; and determining the best patient-centric approach.

1. Recruiting From Small Patient Populations

One of the major hurdles for successfully completing these clinical trials is recruiting a sufficient number of patients to participate in a reasonable period of time. To achieve the minimum number of patients for statistical proof of efficacy in a clinical trial targeting a very small patient population, a larger percentage of potential participants must be recruited than in a more common disease. One approach is to design the trial to be appealing to the patient; however, this often comes at a resource cost.

Soligenix’s most recent trial, which evaluated a novel combination therapy for cutaneous T-cell lymphoma (CTCL), a rare skin cancer, evaluated patients across 36 clinical sites, with recruitment taking more than three years. Our trial was designed to make participating as attractive as possible for patients without compromising the generation of robust results.

Rather than a typical 1:1 randomization of patients into treatment and placebo groups, we chose to offer patients two out of three chances of getting the active drug, which in turn required that we recruit more patients to achieve the same statistical power for the study. All patients who participated in the initial portion of the trial were offered the opportunity to continue to receive the drug for several additional treatment cycles. While these incentives were critical in helping with recruitment, they extended both the cost and duration of the study.

Patient advocacy groups were a tremendous support in sharing information about the study nationwide. We were able to forge a strong connection with the Cutaneous Lymphoma Foundation (CLF), which acted as a conduit to get objective information to patients in a manner they could understand and that would allow them to be both aware of the research trial opportunity and provide a context for assessing the risks and benefits of participating.

Design the trial to be as appealing as possible to potential participants (both researchers and patients) and inform as many patients as possible about the trial. Designing reliable and objective information to educate the patient also is critically important.

2. Partnering With The FDA

The FDA has publicly stated a desire to be an active collaborator in all clinical trials, especially in rare and orphan drug development. It offers programs to teams managing trials in rare and orphan indications that permit closer interactions with the agency than available for more common diseases. The process and requirements are as rigorous, but, depending on the specific FDA division reviewing the development, FDA reviewers are often more willing to consider practical limitations on designing a development plan in these orphan or rare indications.

Drug development companies can establish a constructive working relationship with the FDA by preparing early and managing internal expectations around timelines and requirements, including understanding the drivers for the specific division that will be assessing the data. In our recent Phase 3 trial, Soligenix worked with two FDA divisions: dermatology and oncology. Knowing who we were presenting to was critical in how we framed information.

A lengthy trial duration can mean that reviewers who were involved with early negotiations and agreements on trial design may have moved on by the time trial results become available, which has the potential to affect program continuity. This can happen in any trial, but it serves as a reminder that in managing a trial investigating rare and orphan diseases, it is essential to maintain ongoing communication with the FDA.

3. Is A CRO Right For Me?

Choosing whether to engage a CRO is another central consideration for small biotechs. Plugging into a larger organization that will offer comprehensive support can be hugely beneficial, although it may come at a cost too steep for some companies. I would always advise any company considering working with a CRO to find a provider that has done research in your field and to talk to physicians who have dealt with that specific CRO to get an idea of how they operate.

In our CTCL trial, Soligenix chose to manage the trial internally from beginning to end. There are advantages to working with a CRO, but from my perspective, these are outweighed by the benefits of being involved with every detail of a trial. Every clinical trial design includes a number of compromises, and it is important to be able to defend every step in the strategy and understand why certain choices were made.

We focused on gathering considerable input from, and building relationships with, our customers – physicians, nurse practitioners, the CLF, and patients – which will continue to be an asset as we work toward commercialization of our drug, HyBryte. The day-to-day nuances can be lost when trial physicians and support staff are speaking to your representative, the CRO, versus providing feedback directly to you. In our case, it has been feasible to manage our Phase 3 trial in-house. There is certainly some heavy lifting, but we have been fortunate in developing strong working collaborations with highly reliable vendors for practical applications of the trial execution, such as database management, statistical analyses, and study drug packaging and labeling. Additional vendors exist for other needs, such as electronic Case Report Form creation and use, auditing, randomization, etc.

4. Determining A Patient-Centered Approach

The FDA is becoming increasingly interested in patient feedback and satisfaction. Patients living with chronic rare or orphan diseases are often very knowledgeable about their condition, having had to advocate for themselves through obtaining their diagnosis and managing symptoms, usually over a period of years. Every patient wants to be heard, and we involve them as often as possible, from designing a trial with their convenience in mind through dosing and beyond. We believe patient satisfaction is imperative and that opportunities for patient feedback should be worked into trial design, in moderation.

Patient convenience is important in any trial, but it is critical when working with rare or orphan diseases. Nobody likes going to the doctor’s office and, depending on the distance, it can be a huge commitment. In designing a trial where patient retention is essential, investigators should ask questions such as: Does the treatment have to be administered by a physician? Can a clinic visit be done while patients are at home? Can a satellite clinic be established closer to patients’ homes when the primary clinical site is located in a large city? How do patients want to take their treatment? What would be most convenient to most lifestyles?

Communication Is Key

Communication can be a key challenge in small trials. Early in the trial design process, we ensured the buy-in of our PI physicians and the CLF, which provided information to patients on our behalf.  Soligenix placed an emphasis on personal contact with our CRAs, nurse practitioners, and PI physicians to ensure they had the information they needed and that we were learning about any concerns or issues as soon as they were identified. Strong communication is standard with any trial but becomes a much bigger determinant of success in a smaller trial.

The CLF was a critical participant in our study, and its deep investment in advocacy for and support of its extensive membership was essential in allowing us to successfully complete the largest double-blind, placebo-controlled study ever undertaken in CTCL. We are now preparing to submit a New Drug Application to the FDA to commercialize our product.



About The Author:

Richard Straube, MD, MSc, is chief medical officer at Soligenix, Inc. He has over 35 years of experience in academia and industry as a board-certified pediatrician with clinical research experience in host-response modulation. Straube was responsible for the clinical trials and subsequent approval of inhaled nitric oxide for the treatment of persistent pulmonary hypertension in the newborn. He received his medical degree at the University of Chicago, completed an infectious diseases fellowship at the University of California, San Diego (UCSD), and completed training in clinical trial design as a Milbank Scholar at the London School of Hygiene and Tropical Medicine.