The future of clinical research is being redefined by a growing emphasis among biopharmaceutical companies on rare diseases.

Shire’s recent attempt to become the leader in rare disease therapies through the acquisition of Baxalta for $30 billion, and Baxalta’s rebuke—claiming the offer undervalued the company—shows it is a competitive space that is becoming increasingly intense.

The market opportunity of rare diseases is tremendous. Biopharma as an industry is collectively investigating some 450 different orphan drugs, demonstrating the strategic value inherent in the category. But with more than 6,000 rare diseases affecting an estimated 350 million people around the world, they have only just begun to tap the full market potential.

The shift from mass-market, blockbuster drugs to individualized medicines and smaller patient populations has been driven by government incentives and scientific advances that have enabled pharmaceutical companies to invest in targeted therapies for many rare diseases.

What does this mean for R&D sponsors and the clinical investigators conducting research?

Rare diseases clearly offer the opportunity to make a meaningful contribution to the field of medicine, and work on the forefront of clinical innovation. More than that, though, they introduce new ways of organizing and working in the clinical research setting.

For example, Baxalta’s model relies on relationships with university and small biotech companies to perform heavy lab work—discovery and preclinical research—while they focus on later-stage clinical development. This model leverages cost efficiencies in two ways: first, by shifting the cost of early-stage research to places that have external investment funding; and second, by taking advantage of lower-cost orphan drug trials.

While the cost of conducting phase III trials in rare diseases may be lower than in non-orphan drugs, the challenges often are greater. Rare disease patient populations have unique characteristics in terms of co-morbid conditions, ethical concerns and logistical considerations.

Patients and caregivers often travel long distances to participate in trials, and may require assistance with travel and lodging. What may seem like routine procedures—such as imaging, taking height and weight measures, and drawing blood—often require modification to ensure accuracy.

Many rare diseases affect the very young, and often clinical research in these diseases relies on the participation of a much younger population. Explaining procedures to younger children may require the use of video, illustrations and child-friendly live demonstrations.

Understanding the physiological differences between pediatric and adult volunteers adds another layer of intricacy. 

Fundamentally, the real challenge in orphan drug trials is numbers. Regulatory bodies globally have codified an approach to clinical trials based on diseases that affect large numbers of the population. In rare diseases, it’s doubtful that a trial can enroll more than a few hundred.

Traditional methods of sourcing patients from existing healthcare system databases may come up short because often there is no ICD-10 classification code for rare diseases. Investigators will have to work with advocacy groups and NGOs to identify which countries patients can be recruited from to achieve necessary enrollment numbers.

International multicenter trials may increase the pace of recruitment, but they also introduce complexities related to lack of alignment among regulatory requirements, as well as cultural differences among patient populations and investigators.

A number of industry experts have published best practices for success, with key requirements including:

• Coordination between sites that will be working under different regulations;
• Consensus among investigators and regulatory bodies about definition of terms such as “diagnosis”; and
• Measurement that relies on objective efficacy endpoints rather than subjective, patient-reported measures, monitored by a third party who assesses a treatment’s risk-benefit ratio.

Following these guidelines may require training at each study site, but the promise is that conclusions will be consistent from country to country, which in turn will accelerate approval times in foreign markets. 

Matthew Howes is senior vice president, marketing innovation for PALIO, an inVentiv Health company. Email matthew.howes@inventivhealth.com.

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