中药新药临床试验的风险—效益评价研究
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摘要
目的：通过阐明风险—效益评价理念对中药新药临床试验的重要性,初步建立基于风险—效益评价理念的中药新药临床试验设计与结果评价的思路与方法,并进行示范研究。
方法：①文献及理论研究：通过文献研究,分析目前中药新药临床试验设计及有效性和安全性评价的现状。整理、归纳与风险—效益评价相关的理论知识,在此基础上提炼出基于风险—效益评价理念的中药新药临床试验设计与结果评价的思路与方法。②示范研究：示范研究1：运用提出的思路和方法,设计中药新药芪明颗粒治疗糖尿病性视网膜病变的临床试验方案,并对其进行分析与评价。示范研究2：对已完成的中药新药某中药复方冻干注射液Ⅲ期临床试验结果进行效益与风险分析及综合评价。
结果：①基于风险—效益评价理念的中药新药临床试验设计与结果评价思路与方法的提出：首先在遵循临床试验设计一般原则的基础上,重点应考虑适应病证的选择、疗效指标的选择、对照药物的选择、安全性数据库及安全性指标的选择与考查以及临床试验的质量控制等方面,从而为试验药物进行效益—风险评价提供充分的证据。其次在中药新药临床试验结果分析时,提出了效益分析时主要考虑的问题及相关证据、进行风险分析主要考虑的指标或证据。②示范研究：示范研究1：分析芪明颗粒可能存在的效益和风险.认为芪明颗粒治疗糖尿病性视网膜病变的临床试验方案完全遵循GCP原则,并体现出了中医药的优势和特点。因此该方案对上市前中药新药临床试验方案的设计具有非常高的借鉴作用。示范研究2：对某中药复方冻干注射液Ⅲ期临床试验结果进行了风险、效益分析与评价,认为由于所选适应症存在较大风险因素,休克可能本身的死亡率与药物关系难以判别,实施过程中质量控制不严格等问题而致其支持安全性的证据不充分,故风险—获益评价不够理想,难以说服管理部门批准注册。
结论：①药品的“风险—效益”评价贯穿于药物的研发、上市、并最终从市场上消失的全过程,研发者及临床研究者应具有“风险—效益”评价的意识,在新药临床试验过程中应强调风险效益的动态评估。除了充分考虑试验药物存在的疗效及安全性风险之外,还应考虑其它各种风险,如方案设计风险、伦理学风险、研究质量风险等方面。
②作为新药的研发者及临床研究者,以基于风险—效益评价理念的中药新药临床试验设计思路与方法进行方案设计,既能体现临床试验的科学性,又能体现中医药的优势和特点,从而为临床试验的实施及结果评价提供良好保障,体现出“以人为本”的临床试验精髓。
⑧作为新药研发者及临床研究者,基于风险—效益评价理念的中药新药临床试验结果分析与评价的思路与方法可对完成的临床试验及时进行效益—风险评价,以做出是否有可能被批准注册的初步判断、或及时更改研发策略、以及做出提早停止一些风险过大产品研发的决策。
Objective:To establish initially the ideas and methods of design and results evaluation on clinical trials of newly-developed drug of Chinese material medica based on the concept of risk-benefit assessment through clarifying the concept of the importance of the risk-benefit assessment for clinical trials of newly-developed drug of Chinese material medical, and show a demonstration.
Methods:①the literature and theoretical research:To analyze the status about clinical trials of newly-developed drug of Chinese material medica. arrange and summarize the relevant theoretical knowledge about the risk-benefit assessment, and extract the ideas and methods of design and results evaluation on clinical trials of newly-developed drug of Chinese material medica based on the concept of risk benefit assessment.②Demonstration research:study 1:To design the clinical trial protocol of newly-developed drug of Chinese material medical-Qiming granula. which will be used in treating diabetic retinopathy. Then analyze and evaluate the protocol by the ideas and methods. Study 2:To analyze and comprehensive evaluate the risk and benefit of the results of the completed PhaseⅢclinical trial of newly-developed drug of Chinese material medica which is compound freeze-dried injection.
Results:①Put forward the ideas and methods of design and result evaluation on clinical trials of newly-developed drug of Chinese material medica based on the concept of risk-benefit assessment:First, appropriate diseases and syndromes of adaptation, index of effect, control drugs, safety database, safety index and quality control measurement should be selected carefully based on the general principle of design on clinical trials of newly-developed drug of Chinese material medical, then the sufficient evidence could be provided. Second, propose the major issues and correlated evidence about benefit assessment, and important index or evidence about risk assessment during the course of result analysis about clinical trials.②Demonstration research:Study 1:Analyze the potential benefits and risks of the Qiming granula, and consider that the protocol of Qiming granula which will be used in treating diabetic retinopathy is in line with GCP principles, and reflect the advantages and characteristics of traditional Chinese medicine. Therefore the protocol has a very high reference effect for the design about clinical trials of newly-developed drug of Chinese material medica. Study 2:Analyze and comprehensive evaluate the risk and benefit of the results of the completed PhaseⅢclinical trials of the compound freeze-dried injection and discovered that the selected syndrome of adaptation is not appropriate. the relationship between the drug and shock's mortality rate is difficult to judge, and the quality control is not strict etc. All of these can't provide sufficient support for the security of the clinical trial. The risk-benefit assessment of this drug is not enough ideal, therefore it is difficult to convince the regulatory to approve registration.
Conclusion:①The concept of "risk-benefit" assessment should be throughout the whole process, including research, market, and eventually disappear from the market. Sponsor and clinical investigator should have the consciousness of the "risk-benefit" assessment, and the concept of dynamic risk-benefit assessment should be emphasized in clinical trails. In addition to efficacy and safety risks, we should consider other risks, such as design risk, ethics risk, research quality risks etc.②The sponsor or clinical investigator should have the ideas and methods when they design the clinical trials of newly-developed drug of Chinese material medica, which based on the concept of risk-benefit assessment. The ideas and methods can reflect the scientific nature, embody the advantages and characteristic of traditional Chinese medicine, and provide a sufficient safeguard for implementation and the results evaluation of the clinical trials. It also reflects the "people-oriented" essence of the clinical trials.③As a sponsor or clinical investigator, the ideas and methods of results evaluation on clinical trials of newly-developed drug of Chinese material medica based on the concept of risk-benefit assessment could be used to analyze and assess the benefit and risk of the completed clinical trials. And make preliminary judgments on the possibility of a newly-developed drug should be registered, or change the R & D strategy, or to stop the clinical trials in time which have large risk.
方法：①文献及理论研究：通过文献研究,分析目前中药新药临床试验设计及有效性和安全性评价的现状。整理、归纳与风险—效益评价相关的理论知识,在此基础上提炼出基于风险—效益评价理念的中药新药临床试验设计与结果评价的思路与方法。②示范研究：示范研究1：运用提出的思路和方法,设计中药新药芪明颗粒治疗糖尿病性视网膜病变的临床试验方案,并对其进行分析与评价。示范研究2：对已完成的中药新药某中药复方冻干注射液Ⅲ期临床试验结果进行效益与风险分析及综合评价。
结果：①基于风险—效益评价理念的中药新药临床试验设计与结果评价思路与方法的提出：首先在遵循临床试验设计一般原则的基础上,重点应考虑适应病证的选择、疗效指标的选择、对照药物的选择、安全性数据库及安全性指标的选择与考查以及临床试验的质量控制等方面,从而为试验药物进行效益—风险评价提供充分的证据。其次在中药新药临床试验结果分析时,提出了效益分析时主要考虑的问题及相关证据、进行风险分析主要考虑的指标或证据。②示范研究：示范研究1：分析芪明颗粒可能存在的效益和风险.认为芪明颗粒治疗糖尿病性视网膜病变的临床试验方案完全遵循GCP原则,并体现出了中医药的优势和特点。因此该方案对上市前中药新药临床试验方案的设计具有非常高的借鉴作用。示范研究2：对某中药复方冻干注射液Ⅲ期临床试验结果进行了风险、效益分析与评价,认为由于所选适应症存在较大风险因素,休克可能本身的死亡率与药物关系难以判别,实施过程中质量控制不严格等问题而致其支持安全性的证据不充分,故风险—获益评价不够理想,难以说服管理部门批准注册。
结论：①药品的“风险—效益”评价贯穿于药物的研发、上市、并最终从市场上消失的全过程,研发者及临床研究者应具有“风险—效益”评价的意识,在新药临床试验过程中应强调风险效益的动态评估。除了充分考虑试验药物存在的疗效及安全性风险之外,还应考虑其它各种风险,如方案设计风险、伦理学风险、研究质量风险等方面。
②作为新药的研发者及临床研究者,以基于风险—效益评价理念的中药新药临床试验设计思路与方法进行方案设计,既能体现临床试验的科学性,又能体现中医药的优势和特点,从而为临床试验的实施及结果评价提供良好保障,体现出“以人为本”的临床试验精髓。
⑧作为新药研发者及临床研究者,基于风险—效益评价理念的中药新药临床试验结果分析与评价的思路与方法可对完成的临床试验及时进行效益—风险评价,以做出是否有可能被批准注册的初步判断、或及时更改研发策略、以及做出提早停止一些风险过大产品研发的决策。
Objective:To establish initially the ideas and methods of design and results evaluation on clinical trials of newly-developed drug of Chinese material medica based on the concept of risk-benefit assessment through clarifying the concept of the importance of the risk-benefit assessment for clinical trials of newly-developed drug of Chinese material medical, and show a demonstration.
Methods:①the literature and theoretical research:To analyze the status about clinical trials of newly-developed drug of Chinese material medica. arrange and summarize the relevant theoretical knowledge about the risk-benefit assessment, and extract the ideas and methods of design and results evaluation on clinical trials of newly-developed drug of Chinese material medica based on the concept of risk benefit assessment.②Demonstration research:study 1:To design the clinical trial protocol of newly-developed drug of Chinese material medical-Qiming granula. which will be used in treating diabetic retinopathy. Then analyze and evaluate the protocol by the ideas and methods. Study 2:To analyze and comprehensive evaluate the risk and benefit of the results of the completed PhaseⅢclinical trial of newly-developed drug of Chinese material medica which is compound freeze-dried injection.
Results:①Put forward the ideas and methods of design and result evaluation on clinical trials of newly-developed drug of Chinese material medica based on the concept of risk-benefit assessment:First, appropriate diseases and syndromes of adaptation, index of effect, control drugs, safety database, safety index and quality control measurement should be selected carefully based on the general principle of design on clinical trials of newly-developed drug of Chinese material medical, then the sufficient evidence could be provided. Second, propose the major issues and correlated evidence about benefit assessment, and important index or evidence about risk assessment during the course of result analysis about clinical trials.②Demonstration research:Study 1:Analyze the potential benefits and risks of the Qiming granula, and consider that the protocol of Qiming granula which will be used in treating diabetic retinopathy is in line with GCP principles, and reflect the advantages and characteristics of traditional Chinese medicine. Therefore the protocol has a very high reference effect for the design about clinical trials of newly-developed drug of Chinese material medica. Study 2:Analyze and comprehensive evaluate the risk and benefit of the results of the completed PhaseⅢclinical trials of the compound freeze-dried injection and discovered that the selected syndrome of adaptation is not appropriate. the relationship between the drug and shock's mortality rate is difficult to judge, and the quality control is not strict etc. All of these can't provide sufficient support for the security of the clinical trial. The risk-benefit assessment of this drug is not enough ideal, therefore it is difficult to convince the regulatory to approve registration.
Conclusion:①The concept of "risk-benefit" assessment should be throughout the whole process, including research, market, and eventually disappear from the market. Sponsor and clinical investigator should have the consciousness of the "risk-benefit" assessment, and the concept of dynamic risk-benefit assessment should be emphasized in clinical trails. In addition to efficacy and safety risks, we should consider other risks, such as design risk, ethics risk, research quality risks etc.②The sponsor or clinical investigator should have the ideas and methods when they design the clinical trials of newly-developed drug of Chinese material medica, which based on the concept of risk-benefit assessment. The ideas and methods can reflect the scientific nature, embody the advantages and characteristic of traditional Chinese medicine, and provide a sufficient safeguard for implementation and the results evaluation of the clinical trials. It also reflects the "people-oriented" essence of the clinical trials.③As a sponsor or clinical investigator, the ideas and methods of results evaluation on clinical trials of newly-developed drug of Chinese material medica based on the concept of risk-benefit assessment could be used to analyze and assess the benefit and risk of the completed clinical trials. And make preliminary judgments on the possibility of a newly-developed drug should be registered, or change the R & D strategy, or to stop the clinical trials in time which have large risk.
引文
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