Current challenges and opportunities in nonclinical safety testing of biologics.

Nonclinical safety testing of new biotherapeutic entities represents its own challenges and opportunities in drug development. Hot topics in this field have been discussed recently at the 2nd Annual BioSafe European General Membership Meeting. In this feature article, discussions on the challenges surrounding the use of PEGylated therapeutic proteins, selection of cynomolgus monkey as preclinical species, unexpected pharmacokinetics of biologics and the safety implications thereof are summarized. In addition, new developments in immunosafety testing of biologics, the use of transgenic mouse models and PK and safety implications of multispecific targeting approaches are discussed. Overall, the increasing complexity of new biologic modalities and formats warrants tailor-made nonclinical development strategies and experimental testing.

Safety pharmacology--a progressive approach.

Although deaths and life-threatening adverse drug reactions (ADRs) in Phase I clinical trials are extremely rare, less severe ADRs occur with an incidence of over 13%. Of the candidate drugs (CDs) that fail prior to marketing, it is generally acknowledged that about 1 in 5 do so because of ADRs in the clinic. Once new chemical entities (NCEs) are on the market, ADRs are estimated to be the fourth leading cause of death in the USA. These various statistics indicate that there is room for improvement in preclinical safety assessment, and a smarter approach to safety pharmacology (SP) can contribute to this. Rather than 'bundling' the SP studies together just prior to Phase I trials, a step-wise, streamlined approach can be adopted throughout the drug discovery process. In this way, the SP information can contribute to making informed judgements at each milestone throughout the preclinical drug discovery process: (i) to assist in series and compound selection; (ii) to assess potential risk of failure in the clinic due to ADRs; (iii) to predict potential ADRs that the clinical pharmacologists can focus on; (iv) to define a therapeutic window for acute dosing in humans. To achieve these objectives, the SP tests need to be carefully selected, adequately validated in-house, and be robust and reliable. To achieve (ii) above, outcome criteria have to be set which, for each test (in vitro and in vivo), take into account acceptable safety margins for the particular therapeutic target. Thus, highly sensitive and predictive SP tests positioned strategically and as early as possible should contribute to reducing attrition during clinical development and ultimately to marketing safer medicines more rapidly.

The application of in vitro methods to safety pharmacology.

The ICH S7A guideline defines safety pharmacology (SP) studies as those that investigate 'the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above', and permits both in vivo and in vitro techniques, as appropriate. The implementation of these ICH guidelines by the pharmaceutical industry--whilst providing a welcome and long overdue clarity into the scientific rationale, timing and regulatory requirements for SP studies--has also generated new challenges, both logistical and scientific, which have a major impact on drug development. These factors have motivated us to consider the introduction of in vitro techniques at an early stage of SP evaluation. Amongst these factors are: the expanded range of study types and physiological parameters to be assessed, the increased 'front-loading' of SP at earlier stages of the drug discovery process; the greater number of new chemical entities (NCEs) to be tested, together with limited compound supply; the condensed time frames for drug development, the higher and quicker throughput of in vitro vs. in vivo tests; the increasing predictability of in vitro tests and application of the '3Rs' rule of animal welfare (reduction, replacement and refinement). Also, there is the failure of traditional in vivo safety evaluation to predict certain clinical side-effects. The use of molecular (e.g. fluorescence and cloned ion channel), cellular (e.g. patch clamp and isolated cardiac cells) and tissue-based (e.g. microelectrodes and Purkinje fibres) methods offers a wide portfolio of novel techniques for SP evaluation of NCEs at a pre-in vivo stage. Thus, innovative in vitro techniques will contribute significantly to the early SP evaluation of NCEs.