Use of animal efficacy, pharmacokinetic/pharmacodynamic and first in human data for regulatory approval of treatment options against chemical, biological, radiological and nuclear threats

Chemical, biological, radiological and nuclear (CBRN) agents can pose a significant risk to public health. Concerningly, for many of the CBRN threats there are no treatment options available. Conducting pivotal randomized controlled trials (RCTs) usually required for regulatory approval of medicinal products may not be feasible for medical countermeasures (MCM) intended for the treatment of CBRN threats because of the low prevalence and case numbers and ethical concerns on conducting RCTs, considering the potential serious health outcomes associated with CBRN threats. This is concerning, as it hampers the development and availability of new treatments against CBRN threats, which are needed for preparedness to ensure appropriate response to an outbreak. This review outlines alternative, regulatory flexible approaches that were used for the approval under exceptional circumstances of therapeutic MCMs against biological threats in the European Union. Considerations on the requirements of using animal efficacy data as key evidence for inferring efficacy from animals to humans, on using animal pharmacokinetic/pharmacodynamic data including pharmacometric modelling and simulation approaches to predict the human dose and on generating safety data in healthy humans are discussed. Challenges and advantages of this approach are highlighted, including the lessons learned based on the examples of tecovirimat, zanamivir and obiltoxaximab. This article is part of the Theo Murphy meeting issue 'Evaluating anti-infective drugs'.