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Orphan Indications and Clinical Trials - Why Rare Diseases Warrant Special Treatment: Part 1

Orphan Indications and Clinical Trials - Why Rare Diseases Warrant Special Treatment: Part 1
09 June 2016

By Dr. Stephan de la Motte, Chief Medical Advisor, Synteract

Rare diseases and orphan indications are gaining prominence, with funding starting to open up for clinical trials. Public incentives and facilitations are now making drug development for these health issues more financially viable.

Rare diseases are those for which effective treatments may be available but that affect a relatively small segment of the population (defined as roughly .07% in the U.S. and .05% in the European Union). Orphan indications, on the other hand, have no definitive and convincing treatment. A frequent disease can be orphan, if there is no treatment.

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
Typically, rare diseases are chronic, because in an acute disease, the medicine is given only for a very short time (meaning: very few products sold, exceptionally small market). Rare, chronic-deteriorating disease creates damages with secondary conditions and symptoms, which need additional treatments. Clinical trials for these chronic, rare diseases have some unique characteristics, including:

  • Complex case report forms are required to deal with both the primary and secondary conditions.
  • High number of study sites are needed because patients are scattered across wide regions.
  • Pro-active recruitment efforts are required because the incidence of newly diagnosed patients is extremely low; therefore, a study must rely on patients who are already known.
  • 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.

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.

Unique characteristics of clinical trials with orphan treatments

  • Use of placebo can be an issue. When there is no treatment available at all, the disease will inevitably create damage, and 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 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
  • Patients are responsive to advertisement. The challenge is to place the advertisement so that they, or a friend or relative, can see it.
  • Proactive recruitment is critical. Stabilized patients may not visit a doctor regularly. The investigator or nurse must search through the patient database and proactively call patients to inform them about the study. The patient’s current condition may not be a fit for the study, but this could change in the near future.

Check back with us for the next blog post to get some tips on how to conduct proactive recruitment and to ensure you have the right team on the job.


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