Innovative designs for clinical trials on rare and very rare diseases

Innovative clinical trial designs for rare and extremely rare disease

By Mariia Salova, Avalere

Companies face greater challenges in designing clinical trials for rare and ultra-rare diseases than for chronic disease trials. Populations are smaller, awareness of the disease is low or nonexistent, and primary care physicians are unaware of how the disease develops and manifests. Geographical barriers make patient recruitment and retention difficult, and there is little information to guide endpoint selection and clinical trial duration. Randomizing patients to placebo groups also presents ethical challenges.

This article describes the challenges life sciences and medical device companies face when planning and conducting clinical trials and highlights a company that is using innovative approaches to its trials and considering the perspective of a rare disease patient.

How COVID and current guidelines are revolutionizing clinical trials

In some ways, COVID-19 spurred the evolution of clinical trials. During the pandemic, the research community rapidly adopted a new way of disseminating research findings that allows clinical investigators to accelerate the pace of trials, recruit underrepresented patient populations, and expand the geographic coverage of trials. Decentralized clinical trials (DCTs), or the ability to expand trial activities beyond brick-and-mortar sites, revolutionized the research community and led to more innovation in new therapies and medical devices.

The Inflation Reduction Act (IRA), which took effect on August 16, 2022, exempts orphan drugs from the requirement to negotiate drug prices and encourages manufacturers to focus their resources on rare indications. Another important development in the pharmaceutical industry that impacts clinical trial innovation in rare and ultra-rare diseases is the creation of the Center for Clinical Trial Innovation (C3TI) within the Center for Drug Evaluation and Research. C3TI is the central point of contact that supports clinical trial innovation activities through collaboration and communication. C3TI can accelerate the development process by providing guidance on how to optimally design clinical trials that meet regulatory approval.

How a biotech company created innovations

Beacon Therapeutics, a clinical-stage ophthalmic gene therapy company, takes an innovative approach to developing clinical trials to support the unmet needs of patients. Founded in 2023, Beacon Therapeutics is on a mission to save and restore sight to patients with a range of rare and common retinal diseases that lead to blindness. Amy House, head of portfolio strategy, notes that their approach is based on their successes in developing clinical trials for patients with rare eye diseases.

“We are aware of the complexity of our studies,” she explained.

To participate in Beacon's trials, patients must undergo a variety of vision tests, comprehensive medical histories and genetic testing. The target populations are much smaller, making patient recruitment and retention difficult. In addition, House emphasized that providers, optometrists, ophthalmologists and patients are often unfamiliar with rare diseases such as X-linked retinitis pigmentosa, which causes vision loss and blindness in approximately 17,000 patients in the US and EU5 countries (France, Germany, Italy, Spain and the UK) – especially young men.

An example of out-of-the-box thinking? Beacon partnered with a mobile eye clinic and offered free vision screenings. The mobile eye clinic visited many advocacy events and medical centers and reached patients who were previously unreachable.

“We have also built an extensive global referral network to reach patients outside the United States,” noted House. “Patients are transferred to the operating rooms for the procedures, while they can have their screenings and follow-up visits at locations closer to their homes.”

The company offered patients a “white glove” treatment to reduce their participation burden as much as possible. The clinical trial team also worked with key opinion leaders and physicians to educate primary care physicians about the disease and generate excitement about the trials. This unique approach helps Beacon Therapeutics expand patient identification beyond its clinical trial sites.

What patients think about DCTs

Mike Stodhill, patient advocate

Mike Stodghill is a rare disease patient and speaker for Mackenzie's Mission Amyloidosis Speakers Bureau. Amyloidosis is a rare bone marrow disease that occurs when misfolded amyloid proteins are not broken down and accumulate in vital organs and tissues such as the heart, brain, kidneys, spleen, liver, nerves or digestive system. Ten to 15 percent of patients with multiple myeloma, a rare blood cancer, are also diagnosed with light chain amyloidosis; Mike is part of this patient group. The Amyloidosis Speakers Bureau was created to educate the medical community – and the general public – about this often misdiagnosed and overlooked disease through the patient's voice.

Discussions with other patients and providers indicate that decentralized clinical trials can improve participation rates.

“Some patients in underserved communities do not have the necessary education, access to support groups or access to technology such as the Internet to participate in clinical trials,” he said. “Patients may also be limited in their ability to travel and require the assistance of caregivers. Decentralized clinical trials could extend this reach to these communities and increase the number of patients participating in trials.”

He pointed out that patients participate in clinical trials for a variety of reasons, such as to gain access to new treatments, to help find a cure, or to receive free medical care. DCTs reduce the burden of participation.

Stodghill also suggests that companies need to work closely with advocacy groups and minority groups to find new participants. Some groups meet at local health centers where patients are treated. Companies can work with social workers, discharge planners and nurses to inform and educate patients about new trials.

“Most rare disease patients learn about clinical trials from their doctors, at medical centers, at live seminars and webinars,” Stodghill emphasizes.

The future of DHTs, AI and ML in clinical trials

Digital health technologies (DHTs) bring significant improvements to clinical trials and enable the collection of real-world data. DHTs, such as electronic sensors in wearable devices, enable continuous remote monitoring of health data directly from patients. These novel measurements can provide insights into physiology and outcomes.

House says the technology is not yet fully developed, but has the potential to reduce the time and cost of trials. Incorporating DHTs into rare disease trials could also benefit those who want to participate but have difficulty getting there.

“There are new technologies that apply AI and machine learning (ML) to ophthalmic images to quickly identify potential patients,” House added. “This technology could also be useful in natural history studies.”

Although it is possible to reduce the time and cost of trials and improve access to trials, the use of AI and ML in clinical trials is still in its infancy. The industry must also address challenges related to data privacy and access to electronic health records.

To facilitate the use of DHTs in validation of studies, adapted regulatory guidelines are needed. The guidelines issued by the FDA to support decentralized clinical trials and digital health technologies (DHTs) for remote data collection are significant advances and demonstrate that the industry is ready to adopt DHTs, or a variant thereof, on a larger scale.

Mariia Salova is a Principal Scientist at Avalere, part of Avalere Health. Salova advises companies on market access, product commercialization, launch and reimbursement strategies for pharmaceutical and biotechnology companies, including rare and ultra-rare disease manufacturers.