| Clinical comprehensive evaluation of drug refers to the process of comprehensively and systematically collecting the evidence of clinical research and usage of drug,and comprehensively analyzing the information such as safety,effectiveness,economics used in disease prevention and treatment.In order to accelerate the establishment and improvement of unified,scientific,and practical standards,implementation paths,and coordination mechanisms for clinical comprehensive evaluation of drug,coordinate the integration of drug decisionmaking evidence,scientific analysis,and accurate evaluation,and guide and standardize the conduction of clinical comprehensive evaluation of drug,the National Health Commission has issued the "Management Guidelines of Clinical Comprehensive Evaluation of Drug".In recent years,the clinical comprehensive evaluation of Chinese patent medicines(CPM)has also been conducted,but there are still some problems such as immature evaluation system,unclear evaluation methods,and non-standard evaluation process.It is imperative to establish a standardized and unified clinical comprehensive evaluation method for CPM.Evidence and Value:Impact on DEcisionMaking(EVIDEM)framework is a health technology evaluation system formed by combining health technology assessment and multi-criteria decision analysis.It combines evidence and value evaluation,qualitative and quantitative analysis,and can provide methodological guidance for the establishment of clinical comprehensive evaluation methods of CPM.In view of this,this study established a clinical comprehensive evaluation method for CPM through literature analysis,semi-structured interviews,Delphi method,and analytic hierarchy process.Then,we carried out pilot studies on Biantong capsule/tablet(BT)and Simotang oral liquid(SMT)to verify the feasibility and operability of the evaluation method,and provided new ideas for the scientific and standardized clinical comprehensive evaluation of CPM.ObjectiveThe aims of this study were to establish the clinical comprehensive evaluation method of CPM based on EVIDEM framework,and promote the scientific,systematic and standardized implementation of clinical comprehensive evaluation of CPM;To conduct pilot studies with BT and SMT as examples and verify the feasibility and operability of the evaluation method.Methods1.Establishing the clinical comprehensive evaluation method of CPM based on EVIDEM framework.After systematically searching the relevant policies,documents and literature,and discussing with expert panel,the initial evaluation system and process based on EVIDEM framework was formed.It was in accordance with the requirements of the national management guidelines and combining the characteristics of traditional Chinese medicine(TCM).Applying semi-structured interviews to further optimize the criteria,the evaluation system was developed and the evaluation process was determined.Then,using Delphi method to screen criteria and determine the evaluation system.Based on the analytic hierarchy process(AHP),we conducted a hierarchical structure model,judgment matrix,and calculated the weight of each domain and criteria.Microsoft Excel,SPSS software and Yaahp software were used to statistically analyze the data.Finally,the clinical comprehensive evaluation method of CPM based on EVIDEM framework was established.2.Conducting pilot studies on clinical comprehensive evaluation of CPM.Taking BT and SMT,which were used to treat constipation and functional dyspepsia(FD)respectively,as examples,the similar drugs were as control drugs.We used the clinical comprehensive evaluation method of CPM and comprehensively collected and analyzed the data,including published data,unpublished data provided by pharmaceutical,publicly available data,and nationwide survey data.The methods of systematic review,meta-analysis,network metaanalysis,pharmacoeconomic analysis,survey,and interviews were used to evaluate the CPM from six domains,including effectiveness,safety,economics,innovation,suitability,and accessibility,to verify the feasibility and operability of the evaluation method.Results1.Through literature review,1002 criteria from 89 evaluation systems were extracted.The criteria in the existing evaluation systems were split and standardized,with the remaining 535 criteria.Following the principles of completeness,non-redundancy,mutual independence,and operability,and combining the characteristics of TCM,the criteria were classified and summarized into six domains including effectiveness,safety,economics,innovation,suitability,and accessibility.The initial clinical comprehensive evaluation system of CPM was established.Through the discussion of the expert panels,it was determined to establish a three-level clinical comprehensive evaluation system of CPM,consisting of six domains,16 sub-domains,and 42 criteria.After semi-structured interviews with 12 experts,whom research fields included clinical medicine,clinical pharmacology,evidence-based medicine,health economics,and health management,the evaluation system was optimized.It included six domains,14 subdomains,and 28 criteria.The evaluation process was also determined,including selecting topic,establishing expert panel,selecting and structuring framework,weighting,integrating and evaluating evidence,scoring,calculating comprehensive value,ranking drugs,dealing with uncertainty,and conducting experts’ review.Then,two rounds of Delphi method were conducted to further screen and modify the evaluation system.Eighteen experts were consulted.The recall rates in the two rounds were all 100%.The degree of authority of experts was 0.90 and 0.91,respectively.The average coefficient of variation of the sub-domains were 19.47%and 12.47%,while the average coefficient of variation of the criteria were 21.67%and 14.08%,respectively.The expert coordination coefficients of the sub-domains were 0.320 and 0.411,respectively.The expert coordination coefficients for the criteria were 0.283 and 0.351,respectively.Experts had high authority and their opinions were well coordinated.Through the Delphi method,the universal clinical comprehensive evaluation system of CPM was determined from the healthcare system perspective,including six domains:effectiveness,safety,economics,innovation,suitability,and accessibility;13 sub-domains:clinical efficacy,pharmacological characteristics,pharmacotoxicology,human safety,cost analysis,incremental analysis,clinical innovation,industrial innovation,technical suitability,operational suitability,availability,affordability,and sustainability;28 criteria:clinical effectiveness,recommendation,pharmacological mechanism,acute toxicity,long term toxicity,special toxicity,adverse events/adverse reactions before marketing,adverse events/adverse reactions after marketing,direct medical cost,incremental cost effectiveness ratio,unmet need,domestic and abroad patent acquisition,usage of advanced manufacturing technology,overseas pharmaceutical market access,medicine registration category,integrity of drug label,special devices condition,special storage condition,conformity of the scope of use of the instructions,influence of duration,frequency and course,influence of dosage form,appearance and taste,drug allocation,production industry,collection of drug catalogue,cost burden,medical insurance reimbursement and patient burden,endangered animals and plants,and environmental supportability.Finally,through expert consultation,the weights of each domain,subdomain,and criteria at all levels were determined using AHP,with the domain weighing effectiveness(37.34%),safety(32.68%),economics(11.85%),innovation(5.87%),suitability(5.79%),and accessibility(6.47%).Thus,the clinical comprehensive evaluation method of CPM based on EVIDEM framework was established.2.The combination of qualitative and quantitative methods were adopted to conduct two pilot studies of clinical comprehensive evaluation on the treatment of constipation with BT and FD with SMT.The evaluation results of BT showed that compared with three control drugs:(1)In terms of effectiveness,a network meta-analysis of 31 articles showed that the ranking of single drug from high to low was control drug B(65.2),BT(52.6),control drug C(38.8),and control drug A(15.2).The ranking of the combination of usual care(UC)from high to low was control drug B+UC(96.5)>control drug A+UC(78.4)>BT+UC(66.8).The recommended number of guidelines and experts’ consensus ranked in the order of control drug A>control drug B>BT>control drug C.Based on pharmacological mechanism research,animal experiments have shown that BT could increase the number of defecation particles,increase the percentage of charcoal particles pushed forward,shorten the charcoal particles excretion time,increase the contraction intensity and intestinal segment vitality,have no significant impact on the water absorption function of the small intestine,and have improved effects on cellular and humoral immunity.(2)In terms of safety,there was no acute toxicity or long-term toxicity.Through systematic review,16 articles have mentioned adverse events/reactions of the drug,and a total of 44 adverse events/reactions occurred in 1039 participants with constipation.According to the data from the National Adverse Drug Reaction Monitoring Center,the incidence of adverse reactions is 0.076%,which is rare.(3)In terms of economics,the daily average cost of drugs ranked from low to high in the order of BT<control drug C<control drug B<control drug A.The incremental cost effectiveness analysis(ICER)showed that the economic order was control drug B>BT>control drug C>control drug A.(4)In terms of innovation,the survey showed that 2.41%(control drug A),2.23%(BT),0.00%(control drug B),and 0.00%(control drug C)of doctors believed that the drug could solve the unmet needs in the treatment of constipation.Number of domestic patents obtained were BT(n=3)>control drug C(n=2)>control drug A(n=1)=control drug B(n=1).None of the four drugs used advanced manufacturing technology and have entered the overseas pharmaceutical market.BT was listed as a new drug of three categories of TCM/ninth new drugs of TCM.(5)In terms of suitability,a survey of 580 doctors,patients,and pharmacists covering 7 major regions,18 provinces/autonomous regions/municipalities directly under the Central Government,as well as hospitals at all levels showed that,in terms of technical suitability,the contents of the drug instructions for BT were complete,clear,and easy to understand compared to the control drug;No need to use special devices,easy to carry;Storage conditions were more convenient.In terms of operational suitability,compared with the control drug,more people used BT to treat diseases other than constipation;Dosage,frequency,and course of use were more convenient and appropriate;The dosage form,specifications,and appearance characteristics were more reasonable.(6)In terms of accessibility,the supply of BT was relatively sufficient in hospitals at all levels,with widespread use and sufficient production capacity.It was included in the Chinese Pharmacopoeia and listed as Class B drugs in the National Drug Reimbursement List.The patient burden was relatively low,and it contained the second class protected plant Cistanche deserticola.And the drug had no significant environmental risk in long-term using.By assigning points and calculating the comprehensive value,the order from high to low was control drug B(84.27 points),BT(82.47 points),control drug A(70.47 points),and control drug C(59.46 points).The expert panel recommended Class A(18/18),which can be directly converted into decision-making.The evaluation results of SMT showed that compared with two control drugs:(1)In terms of effectiveness,a network meta-analysis of 98 articles showed that the ranking of single drug from high to low was SMT(56.8),control drug X(47.5),and control drug Y(25.6).The ranking of the combination of UC from high to low was control drug X+UC(92.6)>SMT+UC(87.5)>control drug Y+UC(32.3).The recommended number of guidelines and experts’ consensus ranked in the order of SMT>control drug X>control drug Y.Based on pharmacological mechanism research,animal experiments have shown that SMT can regulate gastrointestinal hormone secretion,promote gastric emptying,relieve pain,and moisten the intestines and relieve constipation.(2)In terms of safety,there was no acute toxicity or long-term toxicity.Through systematic review,25 articles have mentioned adverse events/reactions of the drug,and a total of 61 adverse events/reactions occurred in 1481 participants with FD.According to the data from the National Adverse Drug Reaction Monitoring Center,a total of 1271 adverse reactions were reported in 940 cases,with mild adverse reactions and a good prognosis.(3)In terms of economics,the daily average cost of drugs ranked from low to high in the order of control drug X<control drug Y<SMT.The ICER showed that the economic order was control drug X>SMT>control drug Y.(4)In terms of innovation,the survey showed that 6.14%(SMT),1.39%(control drug X),and 1.90%(control drug Y)of doctors believed that the drug could solve the unmet needs in the treatment of FD.Number of domestic patents obtained were control drug Y(n=9)>SMT(n=7)>control drug X(n=1).SMT used advanced manufacturing technology and achieves automated and intelligent production throughout the process.None have entered the overseas pharmaceutical market.SMT was listed as Class 1.1 innovative TCM.(5)In terms of suitability,a survey of 686 doctors,patients,and pharmacists covering 7 major regions,27 provinces/autonomous regions/municipalities directly under the Central Government,as well as hospitals at all levels showed that,in terms of technical suitability,the contents of the drug instructions for SMT were complete,clear,and easy to understand when comparing with control drugs;No need to use special devices,easy to carry;Storage conditions were relatively convenient.In terms of operational suitability,compared with the control drug,more people used SMT to treat diseases other than FD;Dosage,frequency,and course of use were more convenient and appropriate;The dosage form,specifications,and appearance characteristics were more reasonable.(6)In terms of accessibility,the supply of SMT was relatively sufficient in hospitals at all levels,with widespread use and sufficient production capacity.It was listed as Class B drugs in the National Drug Reimbursement List.The patient burden was moderate,and it did not contain the endangered animal and plant medicinal materials and had no significant environmental risk in long-term using.By assigning points and calculating the comprehensive value,the order from high to low was SMT(92.01 points),control drug X(85.11 points),and control drug Y(77.51 points).The expert panel recommended Class A(21/23),which can be directly converted into decision-making.ConclusionBy using qualitative and quantitative analysis,based on EVIDEM framework,followed the national management guideline,and combined the characteristics of TCM,we established a set of universal clinical comprehensive evaluation method of CPM.It included the evaluation process and evaluation system,involving six domains,13 sub-domains,and 28 criteria.The pilot studies on clinical comprehensive evaluation of CPM,which was carried out by taking BT for constipation and SMT for FD as examples,had comprehensive evaluation,detailed data,reliable results,and expert recognition.They have verified the feasibility and operability of the evaluation method. |
PDF Full Text Request