Development And Application Of The Standard For Evaluation Of Placebo Simulation Effect Of Chinese Patent Medicine

1 PurposeCombined with the characteristics of traditional Chinese medicine,the standardized evaluation method of placebo simulation effect of Chinese patent medicine was studied,and corresponding guidance document was formed to provide standardized process and demonstration method for the evaluation of placebo simulation effect in double-blind clinical studies of Chinese medicine.2 MethodsThe formulation of the Standard for Evaluation of the Simulation Effect of Chinese Patent Medicine Placebo(hereinafter referred to as the Standard)adopts quantitative and qualitative research methods.Quantitative research includes literature research and electronic questionnaire survey.Qualitative research includes semistructured expert interview and expert consensus meeting.As for the application of the Standard,a Chinese patent medicine was taken as an example,followed the relevant principles in the Standard.The simulation effect of placebo in a clinical trial was evaluated by independent evaluation and comparative evaluation respectively.3 Results3.1 Establishment of evaluation method databaseIt has included 12 academic papers,4 principal documentations and 1 national standard.The 1 7 sensory attributes were summarized,and appearance,color,odor and taste were ranked with frequency ≥10.Other details include decomposition of the drug,evaluation against the package insert of drug,and evaluation of the granules before and after dissolution.The evaluation methods could be divided into independent evaluation and comparative evaluation,which were subdivided into 7 methods.There are 7 requirements related to placebo simulation effect in the standards included.The research questions include eight aspects:basic principles,sensory attributes,evaluation methods,eligibility criteria,evaluators,drug decomposition,participants’ judgment on grouping,and the characteristics of traditional Chinese medicine in the Standard.3.2 Questionnaire survey of expertsAccording to the question list,a total of 3 rounds of surveys were conducted,40 valid questionnaires were collected,and a total of 29 experts participated,who are from 15 organizations across 9 provinces,cities and special administrative region,including universities,hospitals of traditional Chinese medicine,pharmaceutical companies and Center for Drug Evaluation.Experts recommend evaluation should be based on vision(external shape,color,lustre and texture),gustatory(taste and mouthfeel),smell,and touch(soft,hard,elastic,sticky,etc.).The evaluation method combining independent evaluation and comparative evaluation was recommended,and the evaluation method and eligibility criteria should be selected according to the subjectivity and objectivity of the primary endpoint of the clinical trial,as well as whether participants are likely to be exposed to the investigational drug and placebo at the same time.For independent evaluation,only one of the investigational drug or placebo is evaluated,and the ratio of the proportion of investigational drug judged to be genuine to the proportion of placebo judged to be genuine(hereinafter referred to as RR)is used as the judgment index for the qualification of simulation.Experts generally believed that RR was at least 75%,which could be regarded as qualified.If the primary endpoint of clinical trial is subjective indicators,RR should be increased to 80%.When it is objective,experts suggested that the RR can be lowered appropriately to 60%.Comparative evaluation is conducted on a 10-point scale.The higher the score,the more consistent the sensory properties of the two drugs evaluated,and the better the placebo simulation effect.When the primary endpoint is subjective,the minimum scores of qualified simulation of sensory attributes such as vision,taste,smell and touch were 8,7,7 and 8,respectively.When it is an objective endpoint,the lowest score is 7.Evaluators should include at least patients and clinical researchers.More experts believe that independent evaluation should be at least 30 people and comparative evaluation should be at least 20 people.Evaluators are free to decide whether to break down the drug for evaluation with no hints from researchers.The placebo simulation is evaluated immediately after follow-up(when patients are discharged from the group)by collecting patients’judgments of their group.3.3 Semi-structured expert interviewConsidering the current placebo preparation technology,the three experts involved in the interview suggested paying attention to the operability of the Standard and avoiding exorbitant criterion of acceptability,with a score of 7-8 being appropriate for comparative evaluation.Chinese patent medicine placebo should be defined differently from western medicine,allowing to add low dose of investigational drug.The acceptability of sponsors and subsequent data analysis methods should be considered before collecting patients’judgments on grouping.Pay attention to the evaluation of special dosage forms in different physical states.The number of evaluators should not be too large,but include at least patients and personnel with medical background.3.4 Expert Consensus MeetingWhen redefining the placebo of Chinese patent medicine,it should reflect that the low dose addition of whole prescription is allowed,and when a medicine has a special sensory attribute and is too difficult to simulate,specific medicine ingredient can be selected for low dose simulation.No less than 20 people are included at a time,and majorities should be healthy volunteers,with less involvement of professionals.There are no functional abnormalities in their vision,smell,taste and touch of the administration site,and no conflicts of interest with the study.Independent evaluation should be a primary evaluation method,and comparative evaluation is used based on the likelihood of exposure to both the investigational drug and placebo.The eligibility criteria for independent evaluation is RR≥60%.In the comparative evaluation,the qualification criteria of external shape(shape,size and thickness),color and lustre,texture,taste,mouthfeel,smell and touch(soft and hard,elasticity and stickiness,etc.)are 7,7,7,6,6,6,7,7,respectively.It was decided not to collect the grouping judgement data,because patients’ judgments are more likely to be based on efficacy and can not objectively reflect the simulated effect of placebo.In addition,it is necessary to clarify whether to decompose the drug during evaluation process,and internal contents should at least be considered as a drug in visual sense.3.5 Collect experts’ opinions on the Standard35 questionnaires was distributed,25 of which were collected,with 116 opinions in total.The most opinions were about language logic,sensory attributes,and questions in the evaluation questionnaire templates.Sixty-five opinions were adopted,36 were not,and 13 were partially adopted.According to the feedback form,the Standard was improved to form the final version.3.6 Application of the Standard4 males and 16 females participated in independent evaluation,and there were 10 patients in the placebo group and the investigational drug group respectively.The mean age of each group was 42.6 and 38.6 years,respectively.There were 3 patients in the investigational drug group who had taken or been exposed to the drug in the past,all of whom were in the investigational drug group.No statistical difference was found in the distribution of the investigational drug and placebo among medical background personnel,patients and healthy individuals(P>0.05).The judgment on the simulation effect was divided into five grades:definitely the real drug,possibly the real drug,uncertain,possible placebo,and definitely the placebo.Among them,3 people thought it might be real,10 people were not sure that the sample was the real drug or placebo,7 people thought it might be placebo,and no one made the judgment of definitely the real drug or placebo.10 of them were not sure whether the sample was investigational drug or placebo,7 thought it might be placebo,3 thought it might be investigational drug,and no one made the judgment that it was investigational drug or placebo.After unblinding,1 person in the investigational drug group was correct,2 were wrong and 7 were uncertain.In the placebo group,five were correct,two were wrong and three were unsure.Statistical analysis indicates that RR=62.5%(>60%)and P=0.3317(>0.05),therefore it can be considered the investigational drug is consistent with placebo,and the independent evaluation is passed.A total of 72 evaluators participated in comparative evaluation,including 24 people with medical background,24 patients and 24 healthy people,with a malefemale ratio of 1:1,an average age of 38.81,and a master degree accounting for the highest proportion.All evaluators opened the capsule shells for evaluation,and 3 people had taken Zhizhu Kuanzhong Capsule in the past.By using three-point test,17,18 and 14 participants of medical background,outpatients and general healthy people were correctly judged,respectively,which failed to meet the eligibility standard of the correct number less than 13.It can be considered that there are significant differences between the investigational drug and placebo in the three groups.No correlation was found between age,gender,educational background and time.Color,taste and odor were the top 3 sensory attributes in their judgement reasons.4 ConclusionThe artificial evaluation methods of placebo simulation effect of Chinese patent medicine have some problems,such as non-standard evaluation process and uncertain qualification criteria,which affect the scientific results of clinical evaluation of Chinese patent medicines.In the face of the difficulties in the preparation of Chinese medicine placebo,it is doubtful whether the blindness can be successfully implemented in clinical trials.From the aspects of evaluators,sensory attributes,evaluation methods,judgment methods,qualification criteria,result reports and other details,this study standardized the process and requirements of artificial evaluation methods,and formed a standard with strong process,operability and industry consensus,so as to provide a reference for the clinical evaluation of Chinese patent medicine.The conclusions of this study are as follows:The Standard was established,which includes 6 parts:scope of application,definition of terms,evaluation requirements(including the category and number of evaluators,evaluation methods,judgement methods and qualification criteria),a recommendation table of sensory attributes,evaluation report,and other requirements and appendix including evaluation questionnaire templates and correct response critical value table suitable for judging the evaluation results of the three-point test.It is the first normative document since the industry advocated to standardize the evaluation of the simulation effect of Chinese medicine placebo,so as to provide reference for reasonable evaluation of Chinese medicine placebo.Through the demonstration evaluation of a Chinese patent medicine,combined with the consideration of clinical trial design,the target patients are from the outpatient department,and it is not easy for these patients to communicate with each other and open the capsule shells for comparison.Therefore,the placebo can be applied in clinical trial.At the same time,special attention should be paid to drug management,so as to prevent the comparison causing blindness.This evaluation showed that the Standard has the characteristics of reasonable requirements,clear interpretation and simple operation,which can be used by professionals in clinical evaluation of Chinese patent medicine.From the perspective of placebo,the study provides quality control measures conducive to the success of blindness,and also provides practical experience for the application of the Standard,and lay a foundation for the popularization and application of the Standard.