Orphan Disease Clinical Development:

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Overcoming the Challenges Through Effective Clinical Study Design 

When developing novel therapies targeting rare diseases, a departure from classical development strategies is often required. Still, the quality of evidence generated to prove effectiveness of a new orphan disease therapy is no different to the quality expected of new therapies targeting common diseases. Marketing authorisation submission for therapies in orphan indications will be judged against the same standards as for other products. As such, treatment of rare diseases are also expected to demonstrate safety and substantial evidence of clinical benefit in adequate, well-controlled studies. Yet, enormous challenges exist for rare diseases where only a few thousand patients may exist globally and potentially only a few hundred or less in countries where studies will take place. This makes it often impossible or impractical for a drug development program in orphan indications to enrol large populations of several hundreds of thousands into multiple pivotal studies. Additionally, due to lack of prior pivotal studies being conducted in an orphan indication, widely agreed, validated, clinical endpoints to determine the effect of an intervention are often lacking. There also may not be a detailed understanding of pathophysiological mechanisms underlying the disease resulting in a lack of adequate biomarkers that can predict clinical outcome. These and other challenges exist in rare disease clinical development making traditional drug development approaches typical of common diseases, often ill-suited to rare diseases. Below list some of the challenges inherent in orphan disease drug development 

  • Small population sizes restricting design options, replication of studies and usual inferential statistics
  • Disease and phenotypic heterogeneity adds complexity to chosen endpoints and paired analysis with limited sample sizes. 
  • Well defined and validated endpoints outcome measures/tools are often lacking
  • Lack of precedent for drug development in the disease. Little reference to what types of studies (treatment duration, endpoints) have been tried before
  • Paediatric population. 50% of rare diseases affect children and significant ethical considerations exist for children as clinal trial participants

The choice of an acceptable primary endpoint for pivotal studies of common diseases can often be straight forward. In many cases such as, cancer, respiratory diseases and autoimmune disorders, specific primary endpoints for required for pivotal studies are clearly defined in regulatory guidance documents. For orphan disease drug development, choosing outcomes that are clinically relevant, important to the patient’s quality of life and acceptable by the regulators as validated endpoints will also be necessary. Yet, in comparison to more common diseases, not only do guidance documents not exist for orphan indications, often disease specific, well-characterized, clinically validated  primary and secondary efficacy endpoints are often not available. Challenges in determining the potential effect of an investigational therapy also arise when only small population exist, and that population has with large heterogeneity of physiological, cognitive, and behavioural manifestations of the disease across individuals. In such cases, choosing one suitable endpoint assessment for a highly variable patient population can be challenging as an appropriate primary endpoint should be applicable for the full range of patients involved in the analysis, including paediatric patients. The larger the variation across individuals in a study the larger the sample sizes needed to show an effect when comparing an intervention against a control group. Large samples sizes are a luxury that orphan indications do not have. 

Pivotal studies for orphan indications need to generate data that is objective, endpoints convincingly representative of a clinical effect, consider the patients’ needs and include methods to reduce the impact on variability. Design considerations including patient population, choice of comparators (external comparators where placebo arms may not be viable), treatment duration, selection of appropriate primary and secondary endpoints and regulatory agency engagement are but a few critical design inputs of an orphan indication pivotal study. Study designs for orphan drug development requires coordinated efforts from diverse disciplines in clinical development strategy, regulatory strategy, clinical study design, disease KOL’s, commercial and statistics.

It is estimated 95% of rare diseases exist are without effective treatment options. This has created a focus on treatment for rare diseases with a market estimated to reach $217 billion by 2024. With the addition US and EU commercial incentives such as 7 and 10 years (respectively) market exclusivity for first to market treatments focus on effective discernible and efficient clinical studies and development programs is necessary. Armstrong Clinical specialises in orphan indication drug development and can help ensure your studies and plans maximizes the likelihood of successfully bringing the benefits of your new medicine to patients.