Perspective


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.


The incurred sample reanalysis (or ISR) to assess a method reproducibility has been an important focus in regulated bio- analysis for several years now. After being abandoned as a mandatory test by Health Canada in the early years 2000, it was re-introduced as a recommendation for drug submissions directed to the US mar- ket in the mid 2000s. This comeback was communicated through different scien- tific meetings, with the publication of the Viswanathan et al. [1] white paper in 2007 after which it became a good practice for studies submitted to the US FDA. It was recently confirmed as a requirement for the FDA in the draft Guidance for Industry [2] published in September 2013. In July 2011, with the introduction of its


draft Guideline on Bioanalytical Method Validation and in 2012 with the enforce- ment of the official document [3], the Euro- pean Medicine Agency (EMA) also made the ISR a requirement for studies to be sub- mitted to European authorities. Repeating samples to show that bioanalytical assays are reproducible therefore became required for most new bioanalytical studies performed around the world. It is with the issuance of the EMA Guideline,


that the acceptance 10.4155/BIO.14.258 © 2015 Future Science Ltd


criteria for ISR got better defined and when the test outlines clearer. Since the late 2012, however, European


agencies have started to issue deficiency letters to pharmaceutical companies for the lack of ISRs in studies submitted recently but performed prior to the issuance of the 2012 Guideline. It now becomes the applicant responsibility to justify scientifi- cally the departure from the new guideline even for older 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.


EMA’s position on the justification In December of 2012, the EMA published a paper entitled ‘Questions & Answers: Posi- tions on specific questions addressed to the pharmacokinetics (PKs) working party [4]’ which discusses, among other topics, the issue of the absence of ISRs for studies per- formed prior to 2012. The document pro- vides considerations to take into account when justifying the lack of ISRs in a study. These considerations are divided into five main topics entitled:


Bioanalysis (2015) 7(2), 221–227 ISSN 1757-6180


Sofi Gagnon-Carignan, Sylvain Lachance*,1 Saint-Laurent1 Gendron1


, Audrey , Mariève & Ann Lévesque1 1inVentiv Health Clinical, Québec, Canada


*Author for correspondence: sylvain.lachance@inventivhealth.com


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