OBJECTIVES

Randomized clinical trials (RCTs) are the gold standard in drug development but are often not feasible in Rare Diseases (RD) due to small patient population. EMA has, therefore, allowed for alternative options, such as cross-over designs. However, only a minority of EMA registered studies in RD were based only on pivotal cross-over trials. This research aimed to develop key hypothesis around payer perspective on cross-over trial designs based on historical HTA evaluations.

METHODS

A list of cross-over trials within RDs or Oncology (as a proxy) was gathered from targeted searches of clinical trial databases and HTA websites in EU. A detailed review of clinical and economic critique related to cross-over pivotal studies in HTA decisions was undertaken to conclude on the impact of such designs in payer decisions, supplemented by secondary research of agency policies and research articles.

RESULTS

We uncovered a small number of payer assessments of cross-over studies of ODDs, since AMNOG implementation (~10%), which include Kalydeco and TOBI in Cystic Fibrosis and Enpaxiq in Myelofibrosis. Views may differ between agencies when discussing methodology and results. In addition, there is a general lack of updated guidance by payers vs. regulatory bodies and critical review of the payer perspective is confined to treatment switching within Oncology. From our analysis, we outline the main payer challenges (e.g. OS extrapolation bias in Oncology, critique to assumptions of statistical methods) and recommendations for manufacturers submitting cross-over study evidence for pricing and reimbursement of RD Products in EU.

CONCLUSIONS

With increasing payer pressure around budget impact of orphan drug, manufacturers should undertake a robust payer education strategy to highlight the pros & cons of such designs. Engaging payers in the discussion to identify the main challenges and solutions can help tailor clinical development and analyses to match expectations across EU to improve patient access.