Using Real-World Evidence to Derive an External Control Arm for a Rare Disease Drug Trial

In rare disease indications, recruiting patients to clinical drug trials is challenging. Thus, it’s helpful to be able to use an external control arm in lieu of having a trial control arm, either for direct comparison or as a benchmark study (contextual – natural history study).

The client designed a prospective single treatment arm clinical trial in the US and had planned an external control arm with 3x the number of matched controls from each transplantation center. Recruitment of suitable controls proved challenging, and it was anticipated that European Union (EU) specific data would be required by the European Medicines Agency (EMA) and health technology assessment (HTA) bodies.

Advice through the combined EMA-HTA joint scientific pilots was sought.

Sample questions included:

• Relevance of existing control arm plan
• Relevance of control arm design – population, sample size, end-points, patient sub-groups etc.
• Alternate plans to generate real-world evidence
• Other evidence requirements for reimbursement submissions.

Feedback confirmed that the control arm should include European patients with specific comments on design requirements. A multi-country chart review in Europe was commissioned to derive an external control arm via a European natural history study, as well as to validate the US based external control arm.

Certara used a two-phase approach to this project.