Clinical Research: Phase 1 - Phase 4

Natural History Studies: A Growing Force in Treating Rare Diseases

Knowledge of a disease’s natural history is essential to building the scientific foundation for an effective clinical development program. That’s especially the case when developing drugs to treat rare diseases, which by their very nature are poorly understood.

Natural history studies don’t just track the course of diseases over time, but identify demographic, genetic, environmental, and other variables that shape the drug development process. Among other things, they can:

  • Better estimate the prevalence of a disease, which can be very important to initial orphan drug designation applications.
  • Identify, evaluate, and validate potential biomarkers for specific indications.
  • Evaluate or create new clinical outcome assessments.
  • Determine the feasibility of specific assessment batteries.

Regarding that last point, we have an ongoing trial whose patient population has cognitive and physical disabilities, is easily fatigued, and thus cannot complete some burdensome evaluations. As part of the natural history study, we are judging whether the defined set of assessments is feasible for this group, and that determination will help design the clinical interventional studies that follow.

Two of our leading rare disease experts discussed these and other aspects of natural history studies in our webinar available online.

Case study: Asfotase alfa

A prominent example of natural history data’s use as a historical control is asfotase alfa, an enzyme replacement therapy to treat hypophosphatasia — a very critical condition that, in severe form, causes stillbirth and short life expectancy among perinatal and infant patients.

Given the severe nature of the disease and the impracticality of using randomized control groups, the biologic license application was submitted on seven open-label studies (including three critical studies in perinatal, infantile, and juvenile patients) with FDA division agreement to use a natural history cohort for efficacy. The sponsor and the FDA had detailed dialogue regarding study design and how (and indeed, if) retrospective patient data might be used.

The division advised the sponsor to establish a natural history cohort for use as a comparator in efficacy analyses, and agreement was reached that the endpoints of overall survival and ventilator-free survival were acceptable for the perinatal/infantile HPP population. There was no formal agreement for the juvenile-onset population, though a comparison to a natural history group was determined to be potentially acceptable.

The drug received orphan designation in 2008 and fast track designation less than a year later. The agency accorded it breakthrough status in 2013. The BLA received FDA priority review, and the product was approved in 2015.

This example represents an exception to the well-controlled trials we encourage and help our customers design and execute. Our webinar, Natural History vs. Registry Studies in Rare Disease, speaks extensively to this goal and examines many facets of natural history studies, along with the role of registry studies in seeking treatments for rare afflictions. Watch or download it now.