The market opportunity of rare diseases is tremendous. Experts predict global sales of drugs with orphan designations will reach $176 billion by 2020. Biopharma as an industry is collectively investigating some 450 different orphan drugs, demonstrating the strategic value inherent in the category. But with over 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. Established pharma companies are increasingly exploring models that rely 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: shifting the cost of early stage research to places that have external investment funding, and 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 are often greater. Rare disease patient populations have unique characteristics, in terms of co-morbid conditions, ethical concerns and logistical considerations. Protocols must account for the inherent vulnerability of the patient populations.

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 and minimization of distress and discomfort.

Testing in adult populations prior to investigating drugs in children is recognized as ethically appropriate in general clinical research, but many rare diseases affect the very young, and often clinical research in these disease rely 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 add another layer of intricacy. For example, assessing renal function in young children using creatinine clearance, the standard for adults, may not be sensitive enough. Additional evaluation of measures such as the ratio of urine protein to creatinine may be necessary.

Fundamentally, the real challenge in orphan-drug trials is a problem of numbers. Regulatory bodies around the world have codified an approach to clinical trials based on diseases that affect large numbers of the population. That approach mandates the use of randomized trials using thousands of patients. In rare diseases, it’s doubtful that a trials can enroll more than a few hundred.

According to Yaffa Rubinstein, director of Patient Resources for Clinical and Translational Research at the National Institute of Health, “The fact that there are a small number of patients for each disease, scattered over large geographical area and around the globe, requires developing new models for conducting clinical, and other studies, with small patient population.”

Traditional methods of sourcing patients from existing healthcare system databases may come up short because there often 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, and cultural differences among patient populations and investigators.

A number of industry experts have published best practices for success, consolidated into the following key requirements:

• Coordination between trial sites that will be working under different regulations, with varying technical environments, and multi-cultural conditions.
• Consensus among investigators and regulatory bodies about definition of terms, such as diagnosis.
• 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 for both medical and technical staff 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 executive vice president, Strategy & Growth for PALIO, an inVentiv Health company. A leader in digital strategy, he has provided the fuel for digital businesses visited by more than 100 million people every month. Email matthew.howes@inventivhealth.com.

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