Analysis And Evaluation Of Liver And Kidney Function In Clinical Trial Index Outliers

Objective:To establish a database of clinical trials of drug liver and kidney functionindicators outliers adverse reactions, analysis and evaluation of the value ofChinese medicine clinical trials liver and kidney function abnormalities, studyChinese medicine clinical trials indicators unusual significance determinationand interpretation problems in liver renal dysfunction drug relevance.Methods：By querying and collecting72clinical trials of new drugs summary reportsof Liaoning Provincial Hospital of national clinical trial from2005to2010,included in the safety evaluation report content indicators of liver and kidneyabnormalities test cases to establish entry containing the query functions indrug clinical trial database of adverse reactions, undertakeing retrospectivestudies and statistical analysis of the abnormal state.Results:First the basic situation of the clinical trial program,in the adversereaction database.Database were included in clinical trials of new drugs project involves48countries of the Food and Drug Administration for clinical test,430clinicaltrial participants in total cases,24,535cases,2051cases of abnormal liverand kidney function. The adverse reactions Indexed project involves nine system 72projects, including neuropsychiatric diseases, diseases of thecardiovascular system, endocrine system diseases, gynecological diseases,urinary system diseases, orthopedic diseases, respiratory diseases, facialsystem diseases, rheumatological The system diseases Indexed medicationincluding oral administration, injection and topical application threecategories, RECORDING formulations Maximum capsules, granules, tablets andinjection.Second, the whole situation of clinical significance of dysfunction liverand kidney value in clinical trialsOutliers database by querying the indicators of liver and kidney function,liver and kidney function abnormal values in clinical trials before treatmentin141cases judged meaningful, accounting for26.9%of the total number ofabnormal cases before treatment, and383cases determined to be meaningless,accounting treatment73.1%of the total number of abnormal cases,349casesjudged to be meaningful, accounting for22.9%of the total number of abnormalcases after treatment in the treatment of liver and kidney function abnormalvalues, and1178cases of clinical judgment as meaningless, accounting for thetreatment of abnormal cases77.1%of the total.Abnormal liver function values database, ALT abnormal data a total of1050cases, treatment of ALT in40-60U/L,60-80U/L range judged to be clinicallysignificant number of cases to18cases,17cases, accounting for ALT abnormalcases the total number of1.7%,1.6%, ALT determined within the range of40-60U /L,60-80U/L after treatment for clinically significant number of cases,34cases,25cases, respectively, of the total number of cases of abnormal ALT3.2%,2.4%, ALT clinically significant cases accounted for4.9%and4.0%of the totalnumber of cases of abnormal ALT determined within the range of40-60U/L,60-80U/L; pretreatment ALT in40-60U/L60-80U/L range determination is notclinically significant number of cases to158cases,57cases, accounting for15.0%of the total number of cases of abnormal ALT,5.4%, after treatment ALT40-60U/L,60-80U/L, determine the number of cases of no clinical significanceof452cases,133cases, accounting for the the abnormal ALT total number ofcases of43.0%,12.7%, ALT within the range of40-60U/L,60-80U/L judgedas clinical The significance of the cases accounted for58%and17.7%of thetotal number of cases of abnormal ALT.Abnormal liver function values database, AST abnormal data a total of207cases, treatment the former AST in40-60U/L,60-80U/L range judged to beclinically significant number of cases in4cases,1case, respectively, of ASTabnormal cases the total number of1.9%,0.4%, AST within the range of40-60U/L,60-80U/L after treatment determine the clinical significance of the numberof cases to16cases,11cases, respectively, of the total number of cases ofabnormal AST7.7%,5.3%, AST clinically significant cases accounted for9.6%and5.7%of the total number of cases of abnormal AST is determined within therange of40-60U/L,60-80U/L; pre-treatment AST40-60U/L60-80U/L rangedetermination is not clinically significant number of cases,30cases,5cases, accounting for14.5%of the total number of cases of abnormal AST,2.4%, ASTafter treatment in the40-60U/L,60-80U/L within the judgment is not clinicallysignificant number of cases to106cases,19cases, respectively, of the totalnumber of cases of abnormal AST51.2%,9.2%, AST within the range of40-60U/L,60-80U/L judged as clinical The significance of the cases accounted for65.7%and11.6%of the total number of cases of abnormal AST.In renal BUN outliers database, BUN abnormal cases totaled811cases,6.4-10.5mmol/L,10.5-21mmol/L within the pre-treatment BUN judged to beclinically significant number of cases to13cases,5cases, respectively.accounted for1.6%of the total number of cases of abnormal BUN,0.6%, treatmentBUN6.4-10.5mmol/L range judged to be clinically significant number of cases,21cases,8cases, accounting for2.6%of the total number of cases of BUN abnormal,0.9%, BUN6.4-10.5mmol/L,10.5-21mmol/L range judged to be clinicallysignificant cases accounted for4.2%and1.5%of the total number of BUN abnormalcases; pre-treatment BUN6.4-10.5mmol/L,10.5-21mmol/L range judged to benot clinically significant number of cases,66cases,8cases, accounting for8.1%of the total number of BUN abnormal cases,1.0%, after treatment BUN judgedas6.4-10.5mmol/L within the clinical The significance of the number of casesto360cases, accounting for BUN of44.4%of the total number of cases of abnormalBUN6.4-10.5mmol/L,10.5-21mmol/L within the range determined to be noclinically significant cases accounted for52.5%of the total number of casesof BUN abnormal and1.0%, respectively. Renal CR outliers database CR abnormal cases amounted to188cases, thetreatment of former CR in the the110-140umol/l,140-180umol/l range judgedto be clinically significant number of cases to13cases,8cases, respectively,of CR abnormal cases the total number of6.9%,4.2%, after treatment CR in thethe110-140umol/l,140-180umol/l within the scope determined to be clinicallysignificant number of cases to25cases,12cases, respectively, of the totalnumber of cases of CR abnormal13.3%,6.4%, and treatment before the CR in the110-140umol/l,140-180umol/l range judged to be not clinically significantnumber of cases were4cases,13cases, accounting for2.1%of the total numberof cases of CR abnormal,6.9%, CR is determined within the range of110-140umol/l,140-180umol/l after treatment for cases of no clinical significance were4cases,13cases, accounting for2.1%of the CR exception of the total cases,6.9%.(1) explanations of abnormal liver function cases in clinical trials beforetreatment and after treatment.Clinical trials liver function abnormal ALT interpretation of clinicalsignificance cases, liver function values in the range of40-60U/L, total54cases, the reason for the exception determination of fatty liver in33cases,combination therapy in2cases, drinking or eating one cases,8cases of otherreasons, did not determine the cause of five cases, respectively accounting for61.1%of the cases of abnormal values range,3.7%,1.9%,14.8%,9.3%; liverfunction values in the range of60-80U/L total of46cases, the reason for the exception is determined as fatty liver or alcohol for25cases,3cases ofother reasons, combination therapy, not determine reasons in17cases,accounting for54.3%of the cases the exception value range,6.5%,2.2%,37.0%; liver function values in the range of80-120U/L, a total of42cases, thereason for the exception determination of fatty liver for10cases, concomitantmedications and drinker eight cases, seven cases of other reasons, did notdetermine the cause in17cases, accounting for the range of values of theexception cases23.8%,19.0%,16.7%,40.5%.Interpretation of clinical trials liver function abnormal ALT cases ofclinical significance, liver function values in the range of40-60U/L, a totalof611cases, the reason for the exception is determined that the fatty liverand other151cases, drinking or eating14cases, did not determine the cause446cases, accounting for24.7%of the cases of the outliers range,2.3%,73.0%;liver function values in the range of60-80U/L, a total of192cases, the reasonfor the exception determination of fatty liver was69cases, drinking or eating6cases, did not determine the reason for117cases, respectively accountingfor35.9%of the cases the outliers range,3.1%,60.9%; liver function valuesin the range of80-120U/L, a total of32cases, the reason for the exceptionis determined that fatty liver or alcohol liver in17cases, three cases of thedrinker, did not determine the cause in13cases, accounting for53.1%of thecases of abnormal values range,9.3%,40.6%.Clinical trials liver function abnormal AST interpretation of clinical significance cases, abnormal liver function values are abnormal reasons toexplain the clinical trials after treatment cases the interpretation of theclinical significance of abnormal liver function AST, liver function valuesin40-60U/L range within a total of16cases, the reason for the exceptionjudged to fatty liver in6cases, did not determine the cause in10cases,accounting for37.5%of the cases of abnormal values range,62.5%; liver functionvalues in the range of60-80U/L11For example, the reason for the exceptiondetermination for fatty liver in6cases, not determined the reasons in5patients,respectively, accounted for54.5%of the cases of abnormal values range45.4%.A total of136cases, the reason for the exception judged to fatty liverand drinking22cases,114cases not determined by reason, interpretation ofclinical trials liver function abnormal AST case of no clinical significance,liver function values in the range of40-60U/L respectively of the totaloutliers range of cases16.2%,83.8%; liver function values in the range of60-80U/L total of24cases,8cases determine the reason for the exception, theremaining16patients did not determine the cause of the abnormal cases of therange of values33.3%,66.7%.(2) clinical trials before treatment and after treatment of renaldysfunction cases explanationsAbnormal clinical trials of renal BUN interpretation of cases of clinicalsignificance, BUN values in the6.4-10.5mmol/L within the total34cases, thereason for the exception determination gouty nephropathy7cases not determine the reason there were25cases respectively of the total outliers range of20.6%of the cases,73.5%; BUN value in the10.5-21mmol/L range, a total of13cases,the reason for the exception is determined to gouty nephropathy in6cases, didnot determine the cause in7cases, accounting for the outliers range46.2%ofthe cases,53.8%.Abnormal clinical trials of renal BUN no cases of clinical significanceinterpretation, BUN values in the6.4-10.5mmol/L within the scope of a totalof378cases, the reason for the exception is determined that diet and other80cases not determine the reason there were298cases, accounting for theoutliers cases in the range of21.2%,78.8%; the BUN value1.05-21mmol/L withinthe scope of a total of eight cases, the reason for the exception determinationdiabetic nephropathy in1case, the remaining seven patients did not determinethe cause.Clinical trials before treatment cases the interpretation of the clinicalsignificance of the CR value in the the70-110umol/l within the total of7cases, the reason for the exception determination gouty nephropathy, chronicrenal insufficiency in2cases, did not determine the cause abnormal renal CRcases; CR value in the the110-140umol/l within the total37cases, abnormaldetermine the reason for the gouty nephropathy in19cases, not determine thereason there were19cases; CR values the140-180umol/l within the scope ofa total of12cases, abnormal judged to gouty nephropathy as3cases, did notdetermine the cause in9cases; CR values of≥180umol/l within the scope of a total of4cases,3cases explain the cause of the exception.Clinical trials after treatment, abnormal renal function CR no clinicalsignificance in the case explained the CR value in the the70-110umol/l withinthe total54cases, the reason for the exception determination as diabeticnephropathy and other8cases, did not determine the cause in46casesrespectively of the total the total cases of abnormal values range14.8%,85.2%;CR value in the range of the110-140umol/l, a total of15cases, the reasonfor the exception is determined to gouty nephropathy in3cases, did not determinethe cause in12cases, accounting for the outliers range of20%of the cases,80%; CR value in the the140-180umol/l within the total cases, the reason forthe exception determination not determined.Third，clinical trials, liver and kidney dysfunction reason analysis andcorrelation with the test drug judgmentThe data in the database of liver and kidney function abnormalities value,causing liver and kidney dysfunction the most common causes were drinking, fattyliver, diet, leaving the indicators of liver and kidney function results inclinical trials of the main reason is as follows fatty liver, other diseases,alcohol consumption, diet and combination drug.In liver and kidney function indicators outliers database, liver and kidneydysfunction after treatment with the drug judged as may be relevant for the3cases, suspicious in26cases, accounting for1.5%of all after treatment ofabnormal cases, the rest of the abnormal cases were judged independent of the test drug.Conclusions:Firstly, clinical trials researchers are omissions in the evaluation of thesafety evaluation indicators of abnormal values, lack of awareness andexpertise of clinical trials of new drugs drug safety alertion. The data in thedatabase of clinical trials and kidney function indicators outliers, for thepre-treatment data most researchers can give adequate attention, but forsecurity evaluation for the end of the drug treatment researchers is not in fullinterpretation and evaluation can not be correctly evaluated for drug safetyof the test drug.Secondly, insufficient attention should be paid to the safety evaluationof clinical trials. safety observation and summary of clinical trials of PhaseII/III was given inadequate attention, including a description of the adverseevents detailed clinical significance determination concluded lack of properanalysis, even "adverse events has nothing to do with drugs," the conclusion,affecting a comprehensive evaluation of new drug safety and awareness.Thirdly, researchers lack of reliable basis for liver and kidney dysfunctionwithout clinical significance of determination. Explanation of loss ratio ofdysfunction of liver and kidney without clinical significance is much greaterthan the liver and kidney dysfunction which has clinical implications, on onehand the researcher has certain confusion for those parts which has no clinicalsignificance value judgement, on the other hand researchers might not give enough attention for the cases of abnormal liver function without clinical significance,neglecting its important role in new drug clinical safety evaluation, theseseriously affected the quality control of clinical trial, for the results can’treflect the real clinical trial purpose.