Objective To sort out the focus areas of FDA’s scientific supervision and to achieve corresponding results,so as to provide some suggestions for the scientific research and innovation of drug supervision in China.Met...Objective To sort out the focus areas of FDA’s scientific supervision and to achieve corresponding results,so as to provide some suggestions for the scientific research and innovation of drug supervision in China.Methods In-depth research was carried out in the fields of safety evaluation tools,clinical trial innovation,new methods of product quality evaluation,information science and so on.Results and Conclusion The research foundation of drug supervision related technology in China is weak,and a systematic supervision system has not been formed.Learning from the scientific experience of drug supervision in the United States,we can promote the development of the focus areas of drug supervision in China.Besides,we should improve the standard management ability while perfecting the regulations and standards system.Lastly,we should establish a system for government and industry-university-research to realize the full-cycle supervision of drugs.展开更多
Objective To study the threshold effect of export trade on internal and external R&D investment in China’s pharmaceutical industry,and to provide reference for some pharmaceutical enterprises to improve the inves...Objective To study the threshold effect of export trade on internal and external R&D investment in China’s pharmaceutical industry,and to provide reference for some pharmaceutical enterprises to improve the investment.Methods The panel data of pharmaceutical industry in 25 provinces and cities in China from 2009 to 2019 were selected to conduct empirical analysis by establishing a threshold regression model,and a better export trade interval was obtained.Results and Conclusion There is a threshold value for the effect of new product export on both internal and external R&D expenditures,and the threshold values are 845.2788 million yuan and 318.4198 million yuan,respectively.There is a single threshold effect of export trade on both internal and external R&D investment in China’s pharmaceutical industry,and the effect of export trade on internal and external R&D investment changes from negative to positive as the export trade develops from low to high.展开更多
Objective To discuss how to use social media data for post-marketing drug safety monitoring in China as soon as possible by systematically combing the text mining applications,and to provide new ideas and methods for ...Objective To discuss how to use social media data for post-marketing drug safety monitoring in China as soon as possible by systematically combing the text mining applications,and to provide new ideas and methods for pharmacovigilance.Methods Relevant domestic and foreign literature was used to explore text classification based on machine learning,text mining based on deep learning(neural networks)and adverse drug reaction(ADR)terminology.Results and Conclusion Text classification based on traditional machine learning mainly include support vector machine(SVM)algorithm,naive Bayesian(NB)classifier,decision tree,hidden Markov model(HMM)and bidirectional en-coder representations from transformers(BERT).The main neural network text mining based on deep learning are convolution neural network(CNN),recurrent neural network(RNN)and long short-term memory(LSTM).ADR terminology standardization tools mainly include“Medical Dictionary for Regulatory Activities”(MedDRA),“WHODrug”and“Systematized Nomenclature of Medicine-Clinical Terms”(SNOMED CT).展开更多
Objective To introduce the relevant big data platforms of FDA regulatory sciences and to provide reference for the construction of big data platform for China’s regulatory science under the“14th five-year plan”to d...Objective To introduce the relevant big data platforms of FDA regulatory sciences and to provide reference for the construction of big data platform for China’s regulatory science under the“14th five-year plan”to deepen the reform of medical and health system.Methods A comparative analysis was made on China’s big data for regulatory science after studying the development process,operation mode,practical significance and characteristics of the big data platform for FDA regulatory science,which would help China to establish a perfect big database.Results and Conclusion The construction of big data platform for China’s regulatory science is not comprehensive compared with that in the United States.It is necessary to build data platforms in line with China’s national conditions through efforts in law,talents,standards,and other aspects.展开更多
Objective To study the content of China’s guiding principles on multiplicity issues in clinical trials,and to provide reference for the revision of China’s relevant guiding principles.Methods Based on ICH E9,the sim...Objective To study the content of China’s guiding principles on multiplicity issues in clinical trials,and to provide reference for the revision of China’s relevant guiding principles.Methods Based on ICH E9,the similarities and differences of the guiding principles of US Food and Drug Administration(FDA),European Medicines Agency(EMA),and National Medical Products Administration(NMPA)on the multiplicity issues in clinical trials were compared one by one.Results and Conclusion In general,NMPA guidelines are based on ICH E9,but in detail,the guidelines of FDA and EMA focus differently on the multiplicity issues.Therefore,NMPA guidelines need to be detailed and comprehensive.NMPA guidelines can be refined by referring to foreign guidelines to improve the practical guiding significance for clinical research and promote the level of domestic clinical trials in line with international standards.展开更多
Objective To analyze the current situation of research and application of drug regulatory science in EU,and provide suggestions for policy-making of drug regulatory in China.Methods The policy guidelines issued by Eur...Objective To analyze the current situation of research and application of drug regulatory science in EU,and provide suggestions for policy-making of drug regulatory in China.Methods The policy guidelines issued by European Medicines Agency(EMA)and domestic and foreign literature were retrieved to summarize how to carry out drug regulation science in Europe.Results and Conclusion A strategic plan was formulated by the EMA for the implementation of drug regulatory science,and the construction of academic system and discourse system of regulatory science were improved,which played a role in promoting the progress of European drug regulatory science.It is suggested that a phased strategic plan of regulatory science should be established to clarify strategic objectives and main tasks in China as soon as possible.Besides,the construction of discipline system and discourse system should be strengthened to realize the scientific supervision of drugs.展开更多
Objective To study the research status,research hotspots and development trends in the field of real-world data(RWD)through social network analysis and knowledge graph analysis.Methods RWD of the past 10 years were re...Objective To study the research status,research hotspots and development trends in the field of real-world data(RWD)through social network analysis and knowledge graph analysis.Methods RWD of the past 10 years were retrieved,and literature metrological analysis was made by using UCINET and CiteSpace from CNKI.Results and Conclusion The frequency and centrality of related keywords such as real-world study,hospital information system(HIS),drug combination,data mining and TCM are high.The clusters labeled as clinical medication and RWD contain more keywords.In recent 4 years,there are more articles involving the keywords of data specification,data authenticity,data security and information security.Among them,compound Kushen injection,HIS database and RWD are the top three keywords.It is a long-term research hotspot for Chinese and western medicine to use HIS to study clinical medication,clinical characteristics,diseases and injections.Besides,the research of RWD database has changed from construction to standardized collection and governance,which can make RWD effective.Data authenticity,data security and information security will become the new hotspots in the research of RWD.展开更多
Objective To analyze the application of EU real-world evidence in the decision-making of new drug research and development(R&D),and to provide policy recommendations for China’s government to make new drug R&...Objective To analyze the application of EU real-world evidence in the decision-making of new drug research and development(R&D),and to provide policy recommendations for China’s government to make new drug R&D decisions.Methods The relevant policy documents of the EU on the development of new drugs and other domestic and foreign literature on the real-world evidence were analyzed to obtain the role and application of the current EU real-world evidence in the implementation of new drug development policies.Results and Conclusion At present,the EU is carrying out the national synchronous scientific advisory policy,urging the formation of a European innovation framework,and providing decision-making for new drug R&D selection and program design based on real-world evidence.It is recommended that China build a real-world medical database and design a new drug screening platform to help companies,scientific research institutions assess target drugs.In addition,a national scientific advisory platform should be set up to integrate scientific research strength and provide technical support for new drug R&D institutions.展开更多
Objective To study the use of real-world evidence by EU and its member states for establishing a strategy for rare diseases and provide references for the inclusion of orphan drugs in China’s medical insurance.Method...Objective To study the use of real-world evidence by EU and its member states for establishing a strategy for rare diseases and provide references for the inclusion of orphan drugs in China’s medical insurance.Methods A case analysis method was used to introduce the EU’s decision to include rare disease drugs in medical insurance by using real-world evidence because clinical data of rare diseases were difficult to obtain.Results and Conclusion China can use real-world evidence to make medical insurance decisions based on the experience of the EU and continue to invest more in rare diseases,which can solve the problem of few drugs for patients with rare disease.展开更多
Objective To provide references and suggestions for the application of real-world evidence in the decision-making of drug regulation in China.Methods The application of EU real-world evidence in drug regulatory decisi...Objective To provide references and suggestions for the application of real-world evidence in the decision-making of drug regulation in China.Methods The application of EU real-world evidence in drug regulatory decision support was analyzed through literature research and other methods,and the specific operation of its application was demonstrated by case studies.Results and Conclusion The application of EU real-world evidence in drug regulatory decision-making has achieved certain results and is in a stable development stage.The application of real-world evidence in China’s drug regulation is feasible.The successful application of EU real-world evidence can provide reference for China.展开更多
Objective To analyze the value of EU real-world evidence(RWE)in supporting the expanded indications for drugs and to provide reference for the decision-making of expanding drug indications supported by RWE in China.Me...Objective To analyze the value of EU real-world evidence(RWE)in supporting the expanded indications for drugs and to provide reference for the decision-making of expanding drug indications supported by RWE in China.Methods By searching relevant domestic and foreign literature and case analysis,the practice of the RWE of EU to support the expansion indications for drugs was investigated.Results and Conclusion The EU uses RWE to carry out adaptive path research,which provides a new idea for drug R&D and approval.Besides,it also provides evidence in supporting the research of expanded indications for drugs.With the increasing cognition of RWE,it will play a key role in medical and regulatory decisions in China.展开更多
Objective To study the research on real-world data and to provide new ideas and methods for the inheritance and development of empirical prescriptions of traditional Chinese medicine(TCM).Methods The disadvantages of ...Objective To study the research on real-world data and to provide new ideas and methods for the inheritance and development of empirical prescriptions of traditional Chinese medicine(TCM).Methods The disadvantages of using randomized controlled trials for empirical prescriptions of TCM and the advantages of using real-world study(RWS)were analyzed by summarizing the previous RWS and the empirical prescriptions.Meanwhile,the methods for marketing of new TCMs derived from empirical prescriptions of TCM,the data source and trial design of the RWS were discussed.Results and Conclusion RWS can provide new ideas for the listing of new TCMs.With the improvement of relevant laws and regulations,RWS will promote the development of TCM greatly.To promote the application of RWS in the inheritance and development of empirical prescriptions of TCM,the government should improve laws and regulations as soon as possible,and enterprises and research institutions should strengthen patient privacy protection and clarify the responsible parties.展开更多
Objective To analyze the application of real-world evidence(RWE)in the field of medicine in European Union,and provide suggestions for RWE supporting the review and approval of new drugs in China.Methods The European ...Objective To analyze the application of real-world evidence(RWE)in the field of medicine in European Union,and provide suggestions for RWE supporting the review and approval of new drugs in China.Methods The European Medicines Agency(EMA)and other databases were used to search relevant documents for analyzing the European Union’s new drug review and approval process with the support of RWE.Results and Conclusion The European Union carrying out new drug review and approval with the support of RWE has just begun.The decision-making process includes three stages such as new drug research and development,review,and approval.However,there are some challenges in data quality,research methods,evidence sufficiency,and research process of RWE supporting the European Union in reviewing and approving new drugs.At present,RWE can accurately grasp the clinical effects of drugs and improve the safety and effectiveness in the process of assisting the review and approval of new drugs.At the same time,RWE also can promote the development and application of Traditional Chinese Medicine(TCM)and help find out the potential value of TCM such as new indications.展开更多
Objective To establish an economic value added(EVA)performance evaluation system to maintain the competitiveness of pharmaceutical company A under the environment of fierce competition in the pharmaceutical industry.M...Objective To establish an economic value added(EVA)performance evaluation system to maintain the competitiveness of pharmaceutical company A under the environment of fierce competition in the pharmaceutical industry.Methods An EVA performance evaluation model was established by adjusting the items of EVA performance evaluation index,such as after-tax profits,total invested capital and weighted average cost of capital rate.Results and Conclusion EVA values of pharmaceutical company A from 2014 to 2018 were calculated and compared with the traditional performance evaluation method,it was found that EVA performance evaluation model reflected the real performance of pharmaceutical company A.Therefore,pharmaceutical company A is doing well,but its growth rate is unstable.展开更多
Objective To introduce the concept and plan design of pragmatic clinical trials based on real-world study(RWS)so as to provide both guidance for clinical trials and reference for relevant personnel studying RWS.Method...Objective To introduce the concept and plan design of pragmatic clinical trials based on real-world study(RWS)so as to provide both guidance for clinical trials and reference for relevant personnel studying RWS.Methods A retrospective study was made on the design of real-world clinical trials at home and abroad in recent years to summarize their design process and applications.Results and Conclusion The advantages of combining randomization and real-world data in clinical trials are important methods for evaluating medical interventions in the real clinical environment.Practical clinical trials can evaluate the therapeutic effects of interventions in real or close to real medical environments to obtain the best real-world evidence.展开更多
Objective To introduce the design of observational trials under real-world study(RWS),and to provide guidance for clinical development of new research trials and reference for real-world researchers.Methods Relevant l...Objective To introduce the design of observational trials under real-world study(RWS),and to provide guidance for clinical development of new research trials and reference for real-world researchers.Methods Relevant literature of RWS and observational experiments at home and abroad were reviewed and analyzed,and then the design of observational studies was summarized under RWS.Results and Conclusion The data and information provided in observational studies not only help to further verify the clinical study results obtained by randomized controlled trial(RCT)in clinical practice,but also objectively reflect the real situation in the process of clinical research and application.展开更多
文摘Objective To sort out the focus areas of FDA’s scientific supervision and to achieve corresponding results,so as to provide some suggestions for the scientific research and innovation of drug supervision in China.Methods In-depth research was carried out in the fields of safety evaluation tools,clinical trial innovation,new methods of product quality evaluation,information science and so on.Results and Conclusion The research foundation of drug supervision related technology in China is weak,and a systematic supervision system has not been formed.Learning from the scientific experience of drug supervision in the United States,we can promote the development of the focus areas of drug supervision in China.Besides,we should improve the standard management ability while perfecting the regulations and standards system.Lastly,we should establish a system for government and industry-university-research to realize the full-cycle supervision of drugs.
基金Research on Innovation and Development Strategy of Pharmaceutical Industry in Liaoning Province(2020lslktyb-095).
文摘Objective To study the threshold effect of export trade on internal and external R&D investment in China’s pharmaceutical industry,and to provide reference for some pharmaceutical enterprises to improve the investment.Methods The panel data of pharmaceutical industry in 25 provinces and cities in China from 2009 to 2019 were selected to conduct empirical analysis by establishing a threshold regression model,and a better export trade interval was obtained.Results and Conclusion There is a threshold value for the effect of new product export on both internal and external R&D expenditures,and the threshold values are 845.2788 million yuan and 318.4198 million yuan,respectively.There is a single threshold effect of export trade on both internal and external R&D investment in China’s pharmaceutical industry,and the effect of export trade on internal and external R&D investment changes from negative to positive as the export trade develops from low to high.
文摘Objective To discuss how to use social media data for post-marketing drug safety monitoring in China as soon as possible by systematically combing the text mining applications,and to provide new ideas and methods for pharmacovigilance.Methods Relevant domestic and foreign literature was used to explore text classification based on machine learning,text mining based on deep learning(neural networks)and adverse drug reaction(ADR)terminology.Results and Conclusion Text classification based on traditional machine learning mainly include support vector machine(SVM)algorithm,naive Bayesian(NB)classifier,decision tree,hidden Markov model(HMM)and bidirectional en-coder representations from transformers(BERT).The main neural network text mining based on deep learning are convolution neural network(CNN),recurrent neural network(RNN)and long short-term memory(LSTM).ADR terminology standardization tools mainly include“Medical Dictionary for Regulatory Activities”(MedDRA),“WHODrug”and“Systematized Nomenclature of Medicine-Clinical Terms”(SNOMED CT).
文摘Objective To introduce the relevant big data platforms of FDA regulatory sciences and to provide reference for the construction of big data platform for China’s regulatory science under the“14th five-year plan”to deepen the reform of medical and health system.Methods A comparative analysis was made on China’s big data for regulatory science after studying the development process,operation mode,practical significance and characteristics of the big data platform for FDA regulatory science,which would help China to establish a perfect big database.Results and Conclusion The construction of big data platform for China’s regulatory science is not comprehensive compared with that in the United States.It is necessary to build data platforms in line with China’s national conditions through efforts in law,talents,standards,and other aspects.
基金supported by the Special Foundation of Research Institute of Drug Regulatory Science,Shenyang Pharmaceutical University(2021jgkx004).
文摘Objective To study the content of China’s guiding principles on multiplicity issues in clinical trials,and to provide reference for the revision of China’s relevant guiding principles.Methods Based on ICH E9,the similarities and differences of the guiding principles of US Food and Drug Administration(FDA),European Medicines Agency(EMA),and National Medical Products Administration(NMPA)on the multiplicity issues in clinical trials were compared one by one.Results and Conclusion In general,NMPA guidelines are based on ICH E9,but in detail,the guidelines of FDA and EMA focus differently on the multiplicity issues.Therefore,NMPA guidelines need to be detailed and comprehensive.NMPA guidelines can be refined by referring to foreign guidelines to improve the practical guiding significance for clinical research and promote the level of domestic clinical trials in line with international standards.
基金Special Fund of the National Medical Products Administration’s Drug Regulatory Science Research Base-Shenyang Pharmaceutical University Research Institute of Drug Regulatory Science(2020jgkx005).
文摘Objective To analyze the current situation of research and application of drug regulatory science in EU,and provide suggestions for policy-making of drug regulatory in China.Methods The policy guidelines issued by European Medicines Agency(EMA)and domestic and foreign literature were retrieved to summarize how to carry out drug regulation science in Europe.Results and Conclusion A strategic plan was formulated by the EMA for the implementation of drug regulatory science,and the construction of academic system and discourse system of regulatory science were improved,which played a role in promoting the progress of European drug regulatory science.It is suggested that a phased strategic plan of regulatory science should be established to clarify strategic objectives and main tasks in China as soon as possible.Besides,the construction of discipline system and discourse system should be strengthened to realize the scientific supervision of drugs.
文摘Objective To study the research status,research hotspots and development trends in the field of real-world data(RWD)through social network analysis and knowledge graph analysis.Methods RWD of the past 10 years were retrieved,and literature metrological analysis was made by using UCINET and CiteSpace from CNKI.Results and Conclusion The frequency and centrality of related keywords such as real-world study,hospital information system(HIS),drug combination,data mining and TCM are high.The clusters labeled as clinical medication and RWD contain more keywords.In recent 4 years,there are more articles involving the keywords of data specification,data authenticity,data security and information security.Among them,compound Kushen injection,HIS database and RWD are the top three keywords.It is a long-term research hotspot for Chinese and western medicine to use HIS to study clinical medication,clinical characteristics,diseases and injections.Besides,the research of RWD database has changed from construction to standardized collection and governance,which can make RWD effective.Data authenticity,data security and information security will become the new hotspots in the research of RWD.
文摘Objective To analyze the application of EU real-world evidence in the decision-making of new drug research and development(R&D),and to provide policy recommendations for China’s government to make new drug R&D decisions.Methods The relevant policy documents of the EU on the development of new drugs and other domestic and foreign literature on the real-world evidence were analyzed to obtain the role and application of the current EU real-world evidence in the implementation of new drug development policies.Results and Conclusion At present,the EU is carrying out the national synchronous scientific advisory policy,urging the formation of a European innovation framework,and providing decision-making for new drug R&D selection and program design based on real-world evidence.It is recommended that China build a real-world medical database and design a new drug screening platform to help companies,scientific research institutions assess target drugs.In addition,a national scientific advisory platform should be set up to integrate scientific research strength and provide technical support for new drug R&D institutions.
文摘Objective To study the use of real-world evidence by EU and its member states for establishing a strategy for rare diseases and provide references for the inclusion of orphan drugs in China’s medical insurance.Methods A case analysis method was used to introduce the EU’s decision to include rare disease drugs in medical insurance by using real-world evidence because clinical data of rare diseases were difficult to obtain.Results and Conclusion China can use real-world evidence to make medical insurance decisions based on the experience of the EU and continue to invest more in rare diseases,which can solve the problem of few drugs for patients with rare disease.
文摘Objective To provide references and suggestions for the application of real-world evidence in the decision-making of drug regulation in China.Methods The application of EU real-world evidence in drug regulatory decision support was analyzed through literature research and other methods,and the specific operation of its application was demonstrated by case studies.Results and Conclusion The application of EU real-world evidence in drug regulatory decision-making has achieved certain results and is in a stable development stage.The application of real-world evidence in China’s drug regulation is feasible.The successful application of EU real-world evidence can provide reference for China.
基金Special Fund of the National Medical Products Administration’s Drug Regulatory Science Research Base-Research Institute of Drug Regulatory Science of Shenyang Pharmaceutical University(No.2020jgkx005).
文摘Objective To analyze the value of EU real-world evidence(RWE)in supporting the expanded indications for drugs and to provide reference for the decision-making of expanding drug indications supported by RWE in China.Methods By searching relevant domestic and foreign literature and case analysis,the practice of the RWE of EU to support the expansion indications for drugs was investigated.Results and Conclusion The EU uses RWE to carry out adaptive path research,which provides a new idea for drug R&D and approval.Besides,it also provides evidence in supporting the research of expanded indications for drugs.With the increasing cognition of RWE,it will play a key role in medical and regulatory decisions in China.
基金Special Fund of the National Medical Products Administration’s Drug Regulatory Science Research Base-Research Institute of Drug Regulatory Science of Shenyang Pharmaceutical University(No.2020jgkx005).
文摘Objective To study the research on real-world data and to provide new ideas and methods for the inheritance and development of empirical prescriptions of traditional Chinese medicine(TCM).Methods The disadvantages of using randomized controlled trials for empirical prescriptions of TCM and the advantages of using real-world study(RWS)were analyzed by summarizing the previous RWS and the empirical prescriptions.Meanwhile,the methods for marketing of new TCMs derived from empirical prescriptions of TCM,the data source and trial design of the RWS were discussed.Results and Conclusion RWS can provide new ideas for the listing of new TCMs.With the improvement of relevant laws and regulations,RWS will promote the development of TCM greatly.To promote the application of RWS in the inheritance and development of empirical prescriptions of TCM,the government should improve laws and regulations as soon as possible,and enterprises and research institutions should strengthen patient privacy protection and clarify the responsible parties.
基金Special Fund of the National Medical Products Administration’s Drug Regulatory Science Research Base-Research Institute of Drug Regulatory Science of Shenyang Pharmaceutical University(No.2020jgkx005).
文摘Objective To analyze the application of real-world evidence(RWE)in the field of medicine in European Union,and provide suggestions for RWE supporting the review and approval of new drugs in China.Methods The European Medicines Agency(EMA)and other databases were used to search relevant documents for analyzing the European Union’s new drug review and approval process with the support of RWE.Results and Conclusion The European Union carrying out new drug review and approval with the support of RWE has just begun.The decision-making process includes three stages such as new drug research and development,review,and approval.However,there are some challenges in data quality,research methods,evidence sufficiency,and research process of RWE supporting the European Union in reviewing and approving new drugs.At present,RWE can accurately grasp the clinical effects of drugs and improve the safety and effectiveness in the process of assisting the review and approval of new drugs.At the same time,RWE also can promote the development and application of Traditional Chinese Medicine(TCM)and help find out the potential value of TCM such as new indications.
文摘Objective To establish an economic value added(EVA)performance evaluation system to maintain the competitiveness of pharmaceutical company A under the environment of fierce competition in the pharmaceutical industry.Methods An EVA performance evaluation model was established by adjusting the items of EVA performance evaluation index,such as after-tax profits,total invested capital and weighted average cost of capital rate.Results and Conclusion EVA values of pharmaceutical company A from 2014 to 2018 were calculated and compared with the traditional performance evaluation method,it was found that EVA performance evaluation model reflected the real performance of pharmaceutical company A.Therefore,pharmaceutical company A is doing well,but its growth rate is unstable.
基金Special Fund of the National Medical Products Administration’s Drug Regulatory Science Research Base-Research Institute of Drug Regulatory Science of Shenyang Pharmaceutical University(No.2020jgkx005).
文摘Objective To introduce the concept and plan design of pragmatic clinical trials based on real-world study(RWS)so as to provide both guidance for clinical trials and reference for relevant personnel studying RWS.Methods A retrospective study was made on the design of real-world clinical trials at home and abroad in recent years to summarize their design process and applications.Results and Conclusion The advantages of combining randomization and real-world data in clinical trials are important methods for evaluating medical interventions in the real clinical environment.Practical clinical trials can evaluate the therapeutic effects of interventions in real or close to real medical environments to obtain the best real-world evidence.
文摘Objective To introduce the design of observational trials under real-world study(RWS),and to provide guidance for clinical development of new research trials and reference for real-world researchers.Methods Relevant literature of RWS and observational experiments at home and abroad were reviewed and analyzed,and then the design of observational studies was summarized under RWS.Results and Conclusion The data and information provided in observational studies not only help to further verify the clinical study results obtained by randomized controlled trial(RCT)in clinical practice,but also objectively reflect the real situation in the process of clinical research and application.
