Expert Insights

Expert Insights

7 Key Challenges of Drug Development for Rare & Orphan Diseases

7 Key Challenges of Drug Development for Rare & Orphan Diseases
12 April 2019

Drug development for rare diseases is gaining traction, as patients fight to elevate the standard of care for themselves, their loved ones, and the rare disease community as a whole, through the promise of clinical trials. Research has also been aided by government incentives and funding opportunities that are making research into therapies for rare diseases more financially viable.

A disease or disorder is considered rare when it affects a small percentage of the population. For example, in the U.S. any disease affecting fewer than 200,000 people is considered rare. In Europe, a disease is rare when it affects less than 1 in 2000. These numbers may seem small at first glance, but with over 7,000 rare diseases already identified and more being discovered each day, rare diseases collectively make a large impact. It is estimated that 350 million people worldwide suffer from rare diseases. 

The term “orphan” refers to a disease that lacks attention and/or has an unmet medical need. The overlapping of these two terms occurs when the cost of normal drug development is in conflict with the frequency (market size). An “orphan drug,” then, is one for a rare disease for which there are no adequate drugs available, according to the USA Orphan Drug Act definition.

Unique characteristics of clinical trials in rare diseases
An estimated 80% of rare diseases are genetic in origin, and thus present throughout a person’s life, although symptoms may not occur immediately.  Typically, rare diseases are chronic. In an acute disease, the medicine is given only for a very short time period (meaning: very few products sold, exceptionally small market). Rare, genetic, chronic-deteriorating diseases create damage with secondary conditions and symptoms, which need additional treatments. 

Clinical trials for these chronic, rare, genetic diseases have some unique characteristics, including:

  • Diagnostic odyssey - by nature, rare diseases present diagnostic challenges. On average, rare disease patients endure two to three misdiagnoses over a seven-year time period before the appropriate diagnosis is made. Precious time is lost during this process, delaying access to proper treatment and creating significant disadvantages.
  • Geographically dispersed patients - due to the rarity of the disease, a large number of clinical trial sites are often needed in order to reach patients around the globe. Enrolling one subject at one site in each country can be an inefficient model to operationalize a clinical trial without the proper models and support in place.
  • Statistical significance may be limited - due to low sample size, two studies may not be feasible.
  • True surrogate variables may not exist - accepted biomarkers may be available, but not truly validated as prognostic factors or disease course indicators. Therefore, analysis of individual patients and comparison with historical data may be acceptable.
  • Use of placebo can be an issue - when there is no treatment available, the disease will inevitably create damage, and if the new drug is the only hope (even if only theoretically), how can you justify not giving it? Giving each patient the active drug at least once (cross-over) or open-label extensions for everyone in the study can help and may create additional safety data. But this also creates difficulties for biostatistical analysis and correct interpretation of results.
  • Patient motivation can be extreme - they are willing to try something new, provided it is sound and serious. They are also willing to take on the burden of longer travels to a study site or other constraints imposed by the study. However, it is important to ensure patients are well enough to complete the journey to a study site and implement robust support mechanisms to reduce the burden of participation.
  • Enrolling family members presents unique challenges - with the majority of rare diseases being genetic in nature, it is not uncommon to see multiple family members interested in clinical trial participation. It is important that all stakeholders (patients, their extended family, sites, regulators, etc.) are clear on the acceptability of enrolling family members on the same trial on a case-by-case basis.

In working with regulatory authorities, the path to drug development and registration is highly individualized. Each situation is assessed on a case-by-case basis and deviations from a scientific “gold standard” may be acceptable. This is why clinical drug development in these cases should always be conducted based on extensive, thorough, pre-IND (US) or Scientific Advice (EU) from authorities.

Rare and orphan drug development necessitates a multi-factorial approach to support patients throughout the lifecycle of the disease. This assistance can come in the form of fostering prevention via universal screening programs to help patients gain a timely and accurate diagnosis. Only once patients are properly diagnosed and identified, can we move to the next challenges such as reducing the burden of participation on the trial and ensuring an acceptable transition off the trial onto either a newly marketed drug or back to Standard of Care. The time is now!  Before we lose another generation of rare disease patients, we must work to bring forward optimal treatment options to the rare disease patient community.   

At Synteract, we have conducted more than 130 rare and orphan clinical trials across a wide range of therapeutic indications in in the past five years alone.

Contact us for more information on drug development rare and orphan diseases.

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