Research On Preclinical R&D Risk Management Of Humanized Monoclonal Antibody Drugs

In recent years,the development focus of the global pharmaceutical market is gradually shifting from small molecule chemical drugs to biological drugs.Biological drugs have taken up approximately 20%of the global pharmaceutical market,and the figure has a tendency to expand gradually.In the research and development of biological drugs,monoclonal antibody drugs have undoubtedly garnered the most attention.Being one of the fastest growing subdivisions,they have become one of the most important categories of biological drugs.Humanized monoclonal antibody drugs play an important role in the R&D of monoclonal antibody drugs.In the domestic R&D of monoclonal antibody drug,in particular,it is of even more significance,the reason for which is the R&D of innovative dilugs runs a high risk and takes much time and capital.As a matter of fact,the R&D of innovative drugs in China lags relatively behind.The related pharmaceutical enterprises are small in size and inadequate in independent innovation.By and large,they underestimate the risk in the R&D of innovative drugs and are incompetent to undertake the risk of R&D of new drugs.Therefore,systematic research on risk management of humanized monoclonal antibody drug R&D is of great significance to pharmaceutical enterprises in China.Based on the characteristics of the R&D of humanized monoclonal antibody drugs and the current situation of the R&D of humanized monoclonal antibody drugs in China,the risks in the pre-clinical R&D of humanized monoclonal antibody drugs are studied in this dissertation.(1)With the literature reviews,the R&D process of the humanized monoclonal antibody drugs is investigated,which includes:target selection,acquisition of mouse-derived monoclonal antibodies,construction of human monoclonal antibody cell strains,cell culture and its technology,formulation of the preparation and process design,preclinical animal experiments and clinical trials.(2)With the combination of literature review and Delphi method,accurately identify the pre-clinical R&D risk of humanized monoclonal antibody drug:cell line construction stage includes 3 target-level indexes,19 factor-level indexes and 83 index-level indexes;cell culture and process development stage includes 1 target-level index,six factor-level indexes and 58 indexes on the target level;preparation development stage includes 1 target-level index,5 factor-level indexes and 21 index-level indexes;animal experiment development stage includes 1 target-level index,3 factor-level indexes and 16 indicator-level indexes.(3)Quantify and assign the value through questionnaire,and use risk matrix method to assess the risk of pre-clinical development of humanized monoclonal antibody drugs:if the RR value of target selection is 2.74,the risk is high;if the RR value of mouse-derived monoclonal antibody acquisition is 2.08,the risk is moderate;if the RR value of humanized monoclonal antibody cell line construction research is 2.56,the risk is high;if the RR value of cell culture and technology research of humanized monoclonal antibody drug is 2.32,the risk is moderate;if the RR value of humanized monoclonal antibody drug preparation research is 2.63,the risk is high;and if the RR value of animal experiment research of humanized monoclonal antibody drug is 2.93,the risk is high.(4)Based on the results of risk assessment,the measures of risk control are put forward.Base on the research on risk management of the pre-clinical development of humanized monoclonal antibody drug,this paper provides a multi-perspective reference for Pharmaceutical businesses to reduce the risk in humanized monoclonal antibody drug development and improve themlevel of risk management of monoclonal antibody drug development in China.