Study Design Considerations for the Evaluation of Pancreatic Enzyme Replacement Therapy (PERT) Products in People with Cystic Fibrosis: An Update

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PURPOSE: In 2013, the Cystic Fibrosis Foundation (CFF) published recommendations regarding study design considerations for the evaluation of porcine derived pancreatic exocrine replacement therapy (PERT) products in people with CF and exocrine pancreatic insufficiency (EPI). The purpose of this report is to provide an updated guidance with an emphasis on the design and conduct of non-inferiority (NI) trials of non-porcine derived PERT products. METHODS: A CFF PERT Working Group comprised of gastroenterologists, statisticians, and authors of the 2013 publication was established to produce an updated guidance document based on their expertise in clinical trial design and outcome measures in people with CF and EPI. FINDINGS: For the evaluation of non-porcine PERT products, we recommend a parallel withdrawal design to demonstrate the non-inferiority of the investigational product to an active comparator (an approved porcine PERT product). Sample size calculations and other statistical considerations for NI studies are provided. To determine EPI eligibility, we recommend fecal elastase-1 (FE-1) testing rather than an off-PERT period. For assessing efficacy, we recommend including a substrate absorption challenge test (SACT) for comparison to the currently accepted coefficient of fat absorption (CFA) to further advance an alternative, more feasible primary outcome measure. A patient reported outcome measure (PROM) specific to CF-EPI and acceptable to regulatory agencies needs to be defined, several are under investigation. IMPLICATIONS: Observations and recommendations provided in this updated report should benefit clinical investigators, drug developers, and regulatory agencies as they consider the issues and nuances of evaluating PERT products for cystic fibrosis.

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