Replacing the NIH test for rabies vaccine potency testing: A synopsis of drivers and barriers Marie-Jeanne Schiffelers a, * , Bas Blaauboer b , Wieger Bakker a , Coenraad Hendriksen c, d a Utrecht University School of Governance, Bijlhouwerstraat 6, 3511 ZC Utrecht, The Netherlands b Utrecht University, Institute for Risk Assessment Sciences (IRAS), P.O. Box 80.178, 3508 TD Utrecht, The Netherlands c Institute for Translational Vaccinology (InTraVacc), P.O. Box 450, 3720 AL Bilthoven, The Netherlands d Utrecht University, Faculty of Veterinary Medicine, Department Animals in Science and Society, The Netherlands article info Article history: Received 10 July 2013 Received in revised form 18 December 2013 Accepted 8 April 2014 Keywords: Rabies vaccines Potency testing 3R models Regulatory acceptance Barriers and drivers Multilevel innovation perspective abstract Approximately 70% of animal use is utilized to demonstrate quality control of vaccines. Especially rabies vaccine potency testing, using the NIH challenge test, involves objections in terms of scientific relevance, animal welfare concern and costs. Several 3R models have been proposed to refine, reduce or replace this test. Some are formally incorporated into regulatory requirements, but actual regulatory acceptance and use by industry lags behind, raising the question concerning which factors influence this process. This question is answered by a combination of literature review, interviews and a survey among 50 rabies vaccine experts. The findings are analyzed using the multilevel perspective on technology transition, which distinguishes 3 levels of factors influencing innovation acceptance. At the micro level (where 3R models are developed and validated) the dis-advantages of, and fractional experience with, 3R models, scarce data sharing and demanding validation processes exist. The meso level (existing regulatory regime) encloses the barriers of the ‘gold standard’, the lack of harmonization and the driving force of legislation stimulating 3Rs use. The macro level (the societal context) combines risk aversion and increased concern for animal welfare. Regulatory acceptance and use of 3R models requires dedicated stakeholder communication, cooperation and coordination at all three levels. Ó 2014 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved. 1. Introduction Vaccines are often produced by or derived from living micro- organisms. As a result they enclose a complex molecular struc- ture of antigens and their quality might vary from batch to batch. Other components, like preservatives and adjuvants can interfere with the quality of the product [1]. The complexity and potential variability of vaccines require that products undergo extensive characterization before being licensed. Furthermore, every vaccine batch or lot 1 has to be subjected to quality control (QC) to deter- mine its purity, safety, efficacy and potency. The requirements for this QC testing are generally described in the monographs of the European Pharmacopoeia (Ph. Eur.) and of national Pharmacopoeias such as of the U.S. or Japan. Furthermore, the guidelines of the World Health Organization (WHO) and the World Organization for Animal Health (OIE) give guidance on how to ensure to vaccine quality. Most of the tests used for the QC of classical vaccines, like rabies vaccines, are based on 1950s era technology relying heavily on live animal models [2,3]. These tests have seen little change since their adoption and, as a result, are often flawed from current scientific and ethical perspective. It is estimated that approximately 70% of all animal use for vaccine related purposes is required for batch release testing. 2 The majority of the animals are used to meet potency testing re- quirements. The strong dependency on live animal models makes * Corresponding author. Tel.: þ31 30 2539319; fax: þ31 30 2537200. E-mail address: m.j.w.a.schiffelers@uu.nl (M.-J. Schiffelers). 1 The term batch usually refers to veterinary vaccines while the term lot refers to human vaccines. This paper targets both the veterinary and the human rabies vaccine sector. A choice is made to use the term batch when speaking about rabies vaccines in general. 2 http://www.google.nl/url? sa¼t&rct¼j&q¼&esrc¼s&frm¼1&source¼web&cd¼2&ved¼0CDYQFjAB&url¼http% 3A%2F%2Fec.europa.eu%2Fenterprise%2Fepaa%2F3_events%2F3_3_workshops% 2Fwg4_pharm_5_vaccins. pps&ei¼7fMQUYuMJoKq0QX0oID4AQ&usg¼AFQjCNEylkqpbr3jWm2PwFT3cschD% 20 last accessed 1 June 2013. Contents lists available at ScienceDirect Biologicals journal homepage: www.elsevier.com/locate/biologicals http://dx.doi.org/10.1016/j.biologicals.2014.04.001 1045-1056/Ó 2014 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved. Biologicals xxx (2014) 1e13 Please cite this article in press as: Schiffelers M-J, et al., Replacing the NIH test for rabies vaccine potency testing: A synopsis of drivers and barriers, Biologicals (2014), http://dx.doi.org/10.1016/j.biologicals.2014.04.001