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Abstracts / Toxicology
ontinuing Education Courses (CEC)
EC 1: Scientific and Regulatory Approaches for the Preclinicalafety Evaluation of Biologics
01-01cientific and regulatory approaches for the preclinical safetyvaluation of biologics
laudio Bernardi
Accelera Srl, Compliance & Administration, Nerviano (Milan), Italy
ince the origin and development of biotechnology-derived phar-aceuticals several guidelines and points-to-consider have been
ssued to identify the most appropriate scientific and regulatorypproaches for the preclinical safety evaluation of new biologicalntities (NBEs) in support to their clinical development. Regula-ory standards for the preclinical safety assessment, outlined in theCH S6 guidance are comparable among geographic Regions (EU,SA, and Japan) and a flexible science-based approach to nonclin-
cal safety evaluation of biologics has been agreed. The selectionf the most relevant models and the responsiveness of differentpecies for toxicity testing are crucial. Best practices include initro studies in mammalian cell lines to predict in vivo activitynd to assess the sensitivity in various species, including humans.hese studies are generally designed to evaluate receptor occu-ancy, affinity and pharmacological effects assisting in the selectionf the most appropriate models for further investigations in inivo pharmacology and toxicity studies. Whenever possible, tox-city studies should be performed in two animal species relevantor the prediction of human safety. The duration of treatment,oute of administration and study design should support the tar-eted clinical indication, and special attention should be giveno the potential immunogenicity/immunotoxicity of the productnd its impact on the pharmacodynamics, pharmacokinetics andoxicity.
Finally, also the criteria adopted to assess the safety ofiotechnology-derived pharmaceuticals may significantly deviaterom those generally used for standard chemical small moleculesi.e. MABEL vs. NOAEL).
oi:10.1016/j.toxlet.2009.06.186
01-02reclinical evaluation of the immunological safety of biologics
acques Descotes
Lyon Poison Center, Lyon, France
iologics are mostly large molecules, e.g. therapeutic proteins thatre often intended to bind to specific targets expressed on themmune system, or to counteract immunopathological processesesulting in human diseases. Therefore, biologics have a high poten-ial for immunotoxicity, which is reflected in the clinical experienceccumulated so far on their adverse effects related to immunosup-ression, immunostimulation, hypersensitivity (immunogenicity)nd/or autoimmunity. The preclinical evaluation of the immuno-
ogical safety of biologics should focus individually on each broadype of immunotoxic effects using dedicated animal models or initro assays. However, only a small number of standardized andalidated procedures are available, and none for the evaluation ofarticular aspects, such as hypersensitivity and autoimmunity. Ascoser
s 189S (2009) S3–S13 S3
iologics are either increasingly humanized or intended to bindo human-specific targets, the selection of relevant species, andhe induction of specific and often neutralizing antibodies are
ajor limitations to be overcome. Only limited guidance is offeredy currently available regulatory documents. More adequate ani-al models and biomarkers of immunotoxicity are needed to
mprove the preclinical immunotoxicity evaluation of biologics ando ensure a better transition from preclinical to clinical evaluation.
oi:10.1016/j.toxlet.2009.06.187
01-03European perspective on nonclinical development of biologics
eatriz Silva Lima
Laboratorio de Farmacologia, Faculdade de Farmacia, Lisboa,ortugal
he value of the nonclinical studies for proof of concept, kinet-cs or safety evaluation of therapeutic candidates depends on theuman predictability of experimental approaches. When designinghese studies, the experimental models should be carefully chosennd justified. For biopharmaceuticals the choice of in vitro or inivo models is a difficulty as these products mostly correspond e.g.o human molecules obtained by DNA recombinant technology oro molecules (e.g. monoclonal antibodies) designed to specificallynteract with human targets/receptors/epitopes. It is recognisedhat subtle structural differences between the human and animalquivalent molecules/targets lead to differences on the activity andheir pharmacological response. However, even if the homologyf human vs animal target is high, aspects like cellular cascades,heir interrelated mechanisms and the type of target-related cel-ular responses may influence the human/animal responsiveness.hese aspects, in addition to pharmacokinetics, need considera-ion and integration for species selection for nonclinical evaluationf (bio)candidates. Additionally, the development of neutralis-ng antibodies by animals against the human molecules may
odify their responsiveness and needs investigation. The rel-vance of the animal species chosen for nonclinical studies isherefore fundamental to warrant its human predictability, espe-ially concerning the safe use in the earliest phases of clinicalnvestigation. The CHMP/ICH/302/95 (ICH-S6) guideline discussesrinciples for biopharmaceuticals nonclinical testing. One adden-um with clarifications/updates is being produced in ICH. AlsoMEA/CHMP/SWP/28367/07 guideline for risk mitigation in firstn man clinical trials is relevant in this context.
oi:10.1016/j.toxlet.2009.06.188
01-04egulatory approach to first-in-human trials with monoclonalntibodies
abriele Reichmann
Paul-Ehrlich-Institute, Immunology, Langen, Germany
onoclonal antibodies (mAbs) are in many cases effective pharma-
euticals and, in general, have proved to be safe. However, on rareccasions mAbs can be highly toxic. For this reason, pre-clinicalafety assessment is a crucial step in the development programspecially prior to the first application in humans and should beegarded as a tool for pro-active risk identification.