Justifying the lack of incurred sample reproducibility in a study: considerations and strategies

In 2012 with the issuance of its Guideline on Bioanalytical Method Validation, the European Medicine Agency (EMA) made the incurred sample reproducibility (ISR) assessment a requirement for studies to be submitted to European authorities. Since then 2012, European agencies have started to issue deficiencies to pharmaceutical companies for lack of ISRs in studies submitted recently but performed prior to the issuance of the 2012 Guideline. It now becomes the applicant's responsibility to justify scientifically the departure from the new guideline even for less recent studies. This article details the different strategies to provide an adequate justification for the absence of ISR data in studies performed prior to February 2012 but submitted to European agencies after that date.