Nonclinical Aspects of Biopharmaceutical Development: Discussion of Case Studies at a PhRMA-FDA Workshop

Robust assessments of the nonclinical safety profile of biopharmaceuticals are best developed on a scientifically justified, case-by-case basis, with consideration of the therapeutic molecule, molecular target, and differences/similarities between nonclinical species and humans (ICH S6). Significant experience has been gained in the 10 years ensuing since publication of the ICH S6 guidance. In a PhRMA-FDA–sponsored workshop, “Nonclinical Aspects of Biopharmaceutical Development,” industry and US regulatory representatives engaged in exploration of current scientific and regulatory issues relating to the nonclinical development of biopharmaceuticals in order to share scientific learning and experience and to work towards establishing consistency in application of general principles and approaches. The proceedings and discussions of this workshop confirm general alignment of strategy and tactics in development of biopharmaceuticals with regard to such areas as species selection, selection of high doses in toxicology studies, selection of clinical doses, the conduct of developmental and reproductive toxicity (DART) studies, and assessment of carcinogenic potential. However, several important aspects, including, for example, appropriate use of homologues, nonhuman primates, and/or in vitro models in the assessment of risk for potential developmental and carcinogenic effects, were identified as requiring further scientific exploration and discussion.

[1]  Joy A. Cavagnaro,et al.  Preclinical safety evaluation of biotechnology-derived pharmaceuticals , 2002, Nature Reviews Drug Discovery.

[2]  W. Pardridge Drug Targeting to the Brain , 2007, Pharmaceutical Research.

[3]  M. Tabrizi,et al.  Elimination mechanisms of therapeutic monoclonal antibodies. , 2006, Drug discovery today.

[4]  G. Remuzzi,et al.  Cellular responses to protein overload: key event in renal disease progression , 2004, Current opinion in nephrology and hypertension.

[5]  G. Shopp,et al.  Short communication: renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins. , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[6]  Kathryn L Chapman,et al.  Preclinical safety testing of monoclonal antibodies: the significance of species relevance , 2007, Nature Reviews Drug Discovery.

[7]  P. Bugelski,et al.  Myeloma-like cast nephropathy caused by human recombinant soluble CD4 (sCD4) in monkeys. , 1992, The American journal of pathology.

[8]  Nicki Panoskaltsis,et al.  Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. , 2006, The New England journal of medicine.

[9]  Liudmila Polonchuk,et al.  Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics. , 2008, Journal of pharmacological and toxicological methods.

[10]  K. Aldape,et al.  Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. , 2003, Blood.

[11]  N. Simister Placental transport of immunoglobulin G. , 2003, Vaccine.

[12]  R. Rodewald,et al.  Isolation and characterization of the Fc receptor from the fetal yolk sac of the rat , 1990, The Journal of cell biology.

[13]  M. Tabrizi,et al.  Preclinical and clinical safety of monoclonal antibodies. , 2007, Drug discovery today.

[14]  W. Schwieterman Regulating biopharmaceuticals under CDER versus CBER: an insider's perspective. , 2006, Drug discovery today.

[15]  G. A. Lazar,et al.  Optimizing engagement of the immune system by anti-tumor antibodies: an engineer's perspective. , 2007, Drug discovery today.

[16]  R. Ober,et al.  Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies. , 2001, International immunology.

[17]  Oprs Alert Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers , 2005 .