Author: Terence Myles Eagleton, MBBS, BSc, Senior Medical Director, Medical Affairs, Rare Diseases
In May 2017, I had the privilege of speaking at the 7th Annual Outsourcing in Clinical Trials Europe conference in Barcelona, Spain. I spoke on the topic of rare diseases and orphan drug development, which is a field in which I have been privileged to work for many years and remain passionate about.
Though I have experience working in a wide variety of therapeutic areas, most of my work as a pharmaceutical physician has largely been in the development of innovative medicines for rare and ultra-rare metabolic and endocrine diseases. My presentation at the OCT Europe Conference was entitled “Leveraging Research Networks to Accelerate Orphan Drug Development”, during which I highlighted the growing interest in the development of products in the rare disease space, the unique challenges involved, and strategies for leveraging rare disease research networks to accelerate drug development. A summary of this presentation follows.
Rare Diseases by the Numbers
The definition of orphan diseases varies from country to country. In the US, it is any disease that affects less than 200,000 persons, whilst in the EU it is any disease that affects less than five per 10,000 inhabitants. According to the National Organization for Rare Disorders, there are nearly 7,000 known diseases classified as being rare or ultra-rare in the United States. Each year, there are approximately 200 newly rare or ultra-rare indications that are described principally through genetic analysis. Even though these diseases are individually rare, they affect a large part of the population. In the US, a rare disease is estimated to affect approximately 30 million people in total. In fact, it has been estimated that approximately 350 million people have rare diseases around the world, which if looked at in terms of population by country would constitute the third most populous country finishing just behind China and India.
Moreover, 50% of these rare diseases are present in childhood and represent serious unmet medical need. A third will die before their first birthday, another 30% of children with rare diseases will not live to see their fifth birthday.
These numbers are staggering. But there is good news. The passing of the Orphan Drug Act of 1983 in the US and similar legislation in the EU in 1999 helped incentivize companies to develop products for rare diseases (to include measures such as extended patent protection, tax credits on clinical research cost, expedited regulatory assistance and review, annual grant funding, waiver in PDUFA filing fees, and the attraction, in many cases, of premium pricing.)
Combined with these incentives and a revolution in bioengineering, there has been a dramatic upsurge in the development and commercialization of a number of orphan medicines. For example, prior to the 1983 Orphan Drug Act, there were fewer than 10 products that had been approved for rare diseases. In 2013 alone, 33 orphan drugs were approved in the US. In 2016, 41% of all products that were approved in the United States were for rare diseases. That number is comparable in Europe as well which hit 37%.
Clinical trials in rare disease have similar requirements to those of general clinical trials to include a regulatory strategy, appropriate study design (sample size, endpoints), site selection, patient recruitment, data collection and measurements, and allotted funds and study personnel. However, there are a number of unique challenges in orphan drug development that I would like to turn to now.
Challenges in Orphan Drug Development
The inherent characteristics of rare diseases means they have their own unique challenges. These include:
- Small and heterogeneous populations often spread across large geographical distances posing challenges to recruitment
- Poor knowledge and awareness of the natural history of the disease and therefore potential ambiguity or absence of appropriate validated end points resulting in poor outcome assessment in clinical trials
- Many of these diseases are progressive, heterogeneous, severe, and life threatening making these studies very operationally complex
For example, in orphan drug development, each and every data point is precious. To mitigate the sample size limitations, a number of strategies can be utilized to make the most of a relatively small data package in a clinical trial setting. These include utilization of alternative trial designs and statistical techniques such as crossover and or various adaptive designs, as well as possible “all-inclusive” strategies (companion or extension protocols, natural history or observational studies to utilize as a “comparator” database for future interventional studies, expanded access programs for excluded patients that may benefit from use, etc.) and so forth.
How to Leverage Research Networks to Accelerate Orphan Drug Development
With these considerations in mind, let’s turn to rare disease clinical research networks and how these might be leveraged to accelerate orphan drug development. First, let’s define a Rare Disease Clinical Research Network. For the purpose of this discussion, I would suggest that these are either formal or informal research networks in which medical research in rare diseases can be advanced by providing support for clinical studies through collaboration, study enrollment and data sharing. Typically, these are physician scientists and multidisciplinary teams that may work together with many stakeholders. For example, the European Commission’s 24 Research Networks focusing on rare diseases consisting of over 900 highly specialized medical teams which works closely with the EURODIS European Patient Advocacy Groups to advance research in rare diseases across Europe.
However, there are a number of other types of research networks with which industry may wish to collaborate to include established rare disease clinical research networks such as the International Rare Diseases Research Consortium or IRDiRC (a collaboration between government, academia, industry and patient organizations); the Rare Diseases Clinical Research Network or RDCRN (a collaboration between the NCATS and the NIH); The NIHR Clinical Research Networks (NIHR CRN)-especially the NIHR UK Rare Genetic Disease Research Consortium; as well as Patient Advocacy Registries (such as the NORD-FDA Natural History Study Project which has created 19 rare diseases registries) or the TREAT-DMD-patient registry (a consortium to define and collect longitudinal data by clinicians, researchers and industry), which established a ‘network of excellence’ with the remit of ‘reshaping the research environment’ in the neuromuscular field. The network has developed from its European roots to become a global organization bringing together leading specialists, patient groups and industry representatives to ensure preparedness for the trials and therapies of the future while promoting best practice today.
In addition, there are many other types of Commercial Databases (eg. Citeline.com) or industry sponsored patient registries that might potentially be utilized to advance clinical research. Some of these include the Hunter Outcome Survey (which collects data in patients with mucopolysaccaharidosis Type II (supported by Shire) or the International Collaborative Gaucher Group (ICGG) Gaucher Registry for Gaucher Disease (supported by Sanofi/Genzyme) and the Global aHUS Registry for atypical haemolytic uremic syndrome (sponsored by Alexion). Finally, Contract Research Organizations such as Medpace have established “virtual” research networks for rare diseases. Indeed, recently Medpace has formalized these in an initiative for drug development in a wide variety of different therapeutic areas including rare diseases in an initiative called the Medpace Navigate and Flagship Site Strategy. Visit our website to learn more about our experienced, multi-functional project team and patient recruitment support group for rare diseases.