In the cold winter of "double 11" in the pharmaceutical industry, 11 drug registration applications were not approved and 5 institutions were put on file for investigation

In the "double 11" national carnival, the medical industry is both hot and cold On the same day, the sales of tmall pharmacy increased by 340% year on year, while CFDA released the on-site verification results of clinical trial data of some drug registration applications that had submitted self-examination data: 11 drug registration applications of 8 enterprises were not approved, and 5 related clinical research institutions were put on file for investigation 11 drug registration applications not approved The announcement shows that: Clozapine orally disintegrating tablets (acceptance No.: cxhs15000028) declared by Hainan Sinochem United Pharmaceutical Co., Ltd., candesartan ester tablets (acceptance No.: cyhs1390059, cyhs1390060) declared by Zhejiang Huahai Pharmaceutical Co., Ltd., nifedipine controlled-release tablets (acceptance No.: cyhs1390020) declared by Qingdao Baiyang Pharmaceutical Co., Ltd., manufactured by Zhejiang onlycom Clopidogrel bisulfate tablets (acceptance No.: cyhs1190072) declared by pharmaceutical Co., Ltd., racecadotril dry suspension (acceptance No.: cxhs1190001) declared by Hainan Kangzhi Pharmaceutical Co., Ltd., isosorbide mononitrate sustained release tablets (acceptance No.: cyhs1190129) declared by Guangdong bidi Pharmaceutical Co., Ltd., and Bullo declared by Shandong dyne marine biopharmaceutical Co., Ltd The clinical trial data of 11 registration applications, such as Fen suspension (acceptance No.: cyhs11900061) and ibuprofen suspension (acceptance No.: cyhs11900062), azithromycin capsule (acceptance No.: cyhs11900070) and amlodipine besylate tablet (acceptance No.: cyhs1290102) declared by Hebei Yuansen Pharmaceutical Co., Ltd., are untrue and incomplete The State Food and drug administration shall not approve the above 11 drug registration applications in accordance with the relevant provisions of the measures for the administration of drug registration 5 related institutions put on file for investigation In view of the problems existing in the above clinical trial data, the State Food and drug administration also decided to investigate the drug clinical trial data of Guangzhou psychiatric hospital and the Second Affiliated Hospital of Liaoning University of traditional Chinese medicine suspected of falsification, carry out extended inspection on the other drug clinical trial data it undertook, and carry out extended inspection on the relevant contract research organizations Investigation: the drug clinical trial data of Tongji Medical College Affiliated Concord Hospital, Bengbu Medical College Affiliated Hospital and Qilu Hospital of Shandong University were suspected of falsification, which were investigated by Hubei, Anhui and Shandong food and drug administration respectively The State Food and Drug Administration will, on the basis of finding out the facts, clarify the responsibilities of the registration applicant, the relevant personnel of the drug clinical trial institution and the contract research organization The relevant responsible personnel involved in the medical institution shall be handled by the health and family planning department, and those suspected of crimes shall be transferred to the public security organ The State Administration of food and Drug Administration said that all declared enterprises, clinical trial institutions and clinical trial contract research organizations that have applied for production and are awaiting examination should continue to carry out self-examination, and those varieties with untrue problems found in the self-examination should take the initiative to report to the State Administration of food and Drug Administration and withdraw relevant applications The clinical trial institutions or clinical trial contract research organizations that actively report the problematic varieties will be exempted from punishment At the same time, the CFDA will continue to check the application to be reviewed, and will severely punish the falsifications that are found to have problems in the authenticity, so as to ensure the authenticity and effectiveness of the approved drugs The main problems existing in the clinical trial data of the above drug registration application (I) clozapine orally disintegrating tablets (acceptance No.: cxhs15000028), the applicant is Hainan Sinochem United Pharmaceutical Industry Co., Ltd., the clinical trial organization is Guangzhou Psychiatric Hospital, and the contract research organization is Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd 1 The original record is missing The original records of the clinical trial subjects, such as the identification code table, blood sampling schedule, vital signs monitoring table, plasma transportation and processing record table, disintegration time, sample analysis process record, sample in and out of storage record, are missing, and the relevant records are filled in after the event; the analysis process record, sample in and out of storage record, etc are obtained after the post event, without the original analysis record 2 Multiple cases of disobedience of the plan combined with medication 23 subjects in the trial used other drugs in combination during the trial, 20 of them used other drugs in violation of the clinical trial plan 3 Analyze the audit trail of the test system During this study, the biological sample analysis and test instrument can check the track and work log without any records, and can modify or delete the data at will 4 Conceal the abandoned test data The original record book lacks the information of the second batch, but it is verified that the analysis batch exists; 18 maps are missing between the coding sequences of the map file, and 9 maps are found back after verification, and the data of 9 maps are not used, nor described in the summary report and the original record 5 Modify the exchange test data The report data is inconsistent with the original record data, for example, the calculation results of matrix effect data and source map data are inconsistent, and the fourth batch of standard curve data in the original record is inconsistent with the map; the sequence of sample number of multiple time points of 8 subjects and the file name code in the corresponding map is reversed from small to large, and the reasons are not reflected in the original record and summary report 6 The analysis and test process is incomplete There is no correlation between the atlas file and the blood sample, and the relationship between them can be changed at will and cannot be traced; the sample number cannot be traced to the actual blood sample point of the subject （2） Candesartan tablets (acceptance No.: cyhs1390059, cyhs1390060), the applicant is Zhejiang Huahai Pharmaceutical Co., Ltd., the drug clinical trial institution is Guangzhou Psychiatric Hospital, and the contract research organization is Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd 1 The original record is missing The original records of the clinical trial subjects, such as the identification code table, blood sampling schedule, vital signs monitoring table, plasma transport and processing record table, sample analysis process record, sample in and out of the warehouse record, are missing, and the relevant records are filled in after the event; the analysis process record, sample in and out of the warehouse record, etc are obtained after the later stage, without the original analysis record 2 Analyze the audit trail of the test system During this study, the biological sample analysis and test instrument can check the track and work log without any records, and can modify or delete the data at will 3 No sample was left for the test drug, and some blood samples were lost The test preparation and reference preparation of this variety were not preserved according to the requirements of the clinical trial approval documents; the zero blood sample of all subjects was lost before administration, and the rest blood samples were preserved 4 The authenticity of some atlas is highly questionable The baseline noise of 90 pre administration zero blood samples of 30 subjects in three cycles was very consistent, but the baseline noise of these pre administration zero blood samples was quite different from that of the first blood samples after their own administration 5 Conceal the abandoned test data There are 28 maps missing from the coding sequence of the map file, 9 of which are found by the core, and none of the 9 map data has been used, nor described in the summary report and the original record; there are two 81 maps missing after the coding of the 12 file names, and the experimental operator explained that the 81 position of the instrument sample tray is the position of the needle washing bottle, but it was found that "candesartan5181" is actually the quality control sample 6 Modify the exchange test data The sequence of sample number and file name code in the corresponding atlas was reversed from small to large in multiple time points of three subjects, and the reasons were not reflected in the original record and summary report 7 Incomplete analysis and test process There is no correlation between the atlas file and the blood sample The connection between the two can be changed at will and cannot be traced The sample number cannot be traced to the actual blood sample point of the subject （3） Nifedipine controlled-release tablets (acceptance No.: cyhs1390020), the applicant is Qingdao Baiyang Pharmaceutical Co., Ltd., and the clinical trial institution is the Affiliated Union Hospital of Tongji Medical College, Huazhong University of science and technology 1 Multiple violations of the clinical trial protocol According to the scheme and informed consent, 48 subjects were enrolled in the group, 24 for single administration and 24 for multiple administration, but the same batch of subjects were used for single administration and multiple administration in the actual clinical trial; some subjects were enrolled in the group in violation of the inclusion exclusion criteria 2 The original record is missing In the clinical trial, there was only case report form (CRF), no original medical record, and the time of entry and exit of subjects as well as the management and diet control during their stay could not be traced 3 Conceal and modify test data The records in the original test record book are inconsistent with the audit trail records In the audit trail of methodology verification and biological sample test, the analysis and test system date is changed repeatedly, and the same file name is used to name and cover the original map after repeated test Only one file in the report is submitted For example: (1) change system date and repeat detection in methodology validation On August 15, 2012, the system date was adjusted to July 4, 2012 to investigate the matrix effect and repeat the injection for at least 11 times and cover the original map; on August 17, 2012, the system date was adjusted to July 4, 2012 to investigate the matrix effect again and repeat the injection for at least 17 times and cover the original map (2) Change the system date and repeat the test in the biological sample test On August 24, 2012, the system date was adjusted to August 16, 2012, and the samples of all subjects 4 and 5 were analyzed again Among them, all biological samples of subjects 4 were analyzed three times, all biological samples of subjects 5 were analyzed two times, and the final report only showed the results of the last analysis （4） Clopidogrel bisulfate tablets (acceptance No.: cyhs1190072), the applicant is Zhejiang anglikang Pharmaceutical Co., Ltd., the clinical trial institution is the Union Hospital Affiliated to Tongji Medical College of Huazhong University of science and technology, and the contract research organization is Beijing Levi Biotechnology Co., Ltd 1 The original record is missing In the clinical trial, there is only case report form, without original medical record, the time of subjects entering and leaving the hospital, management during their stay, diet control, etc cannot be traced The "actual time" of blood collection in the blood collection record form and case report form is the theoretical time calculated based on the time of taking medicine, not the actual time of blood collection 2 The adverse event record is incomplete The laboratory examination results of the subjects were obviously abnormal, but they were not included in the adverse events and were not followed up 3 Conceal and modify test data The records in the original inspection record book are inconsistent with those in the audit trail In many places of the audit trail, the date of the analysis and test system is changed repeatedly After repeated inspection, the same file name is used to name, overwrite or select data For example: (1) the analysis process of metabolite clopidogrelic acid shown in the original record book is as follows: method exploration was carried out on November 22, 26 and 29, 2010, methodology validation was carried out on January 12, 13 and 14, 2011, biological samples were detected on January 15, 2011, and analysis was completed on January 20 Check the corresponding trajectory: during the analysis of biological samples on January 20, 2011, there were three times of repeated time modification between January 19 and 20, and then returned to January 19 for accompanying quality control sample analysis; on January 20, the date was changed back to January 12, 2011 for methodology validation analysis (2) On January 19, 2011, in an analysis batch, a total of 16 analytical quality control samples were tested, including 7 unqualified samples, but only one unqualified quality control and 8 qualified quality control results were selected In the two analytical batches of January 26, 2011 and January 28, 2011, there were multiple biological sample determination maps with the same number, but only one of them was submitted in the report （5） Racecadotril suspension (acceptance No.: cxhs1190001), applicant: Hainan Kangzhi Pharmaceutical Co., Ltd., drug clinical