Announcement of the State Food and Drug Administration on the disapproval of 13 drug registration applications of 14 enterprises (No. 260, 2015)

Source: CFDA 2015-12-8 according to the announcement of the State Food and Drug Administration on the self inspection and verification of drug clinical trial data (No 117 in 2015) According to the requirements of the announcement on self inspection of drug clinical trial institutions (No 197, 2015) issued by the State Food and drug administration, the national health and Family Planning Commission and the Ministry of health of the General Logistics Department of the people's Liberation Army, the State Food and Drug Administration conducted on-site inspection on some drug registration applications that have submitted self inspection data The relevant information is hereby announced as follows: 1 After verification, the aspirin sustained-release tablets (Acceptance Number: cyhs1190075) declared by Changzhou Pharmaceutical Factory Co., Ltd., the rebaudit dispersible tablets (Acceptance Number: cxhs120067) declared by Suzhou Sinochem Pharmaceutical Industry Co., Ltd., and the cefdinir suspension (Acceptance Number: cxhs1200057) declared by Xi'an Enzi Pharmaceutical Co., Ltd ）, letrozole tablets (acceptance No.: cyhs1290097) declared by Chongqing shenghuaxi Pharmaceutical Co., Ltd., ipridone tablets (acceptance No.: cxhs1400017) and ipridone capsules (acceptance No.: cxhs140001) declared by Shenzhen Nanfang Yingxin Pharmaceutical Co., Ltd and Hefei Jiunuo Pharmaceutical Technology Co., Ltd ）, paracetamol tramadol capsule (acceptance No.: cxhs1200035) declared by Wuxi Fuqi Pharmaceutical Co., Ltd and Guangdong Aimin Pharmaceutical Co., Ltd., agomeladine tablet (acceptance No.: cyhs1490053) declared by Fuan Pharmaceutical Group qingyutang Pharmaceutical Co., Ltd., thiocaproic acid dispersible tablet (acceptance No.: cxhs1400243) declared by Jiangsu Shenlong Pharmaceutical Co., Ltd ）, L-amlodipine besylate tablets (acceptance No.: cyhs1290126) declared by Anhui Xingxing Pharmaceutical Co., Ltd., donepezil hydrochloride orally disintegrating tablets (acceptance No.: cxhs1400294) declared by Shaanxi Fangzhou Pharmaceutical Co., Ltd., donepezil hydrochloride dispersible tablets (acceptance No.: cxhs1100096) declared by Guangdong bidi Pharmaceutical Co., Ltd ）13 drug registration applications submitted by Huayu (Wuxi) Pharmaceutical Co., Ltd., including quetiapine fumarate tablets (acceptance No.: cyhs1290042), have the problems of untrue and incomplete clinical trial data The State Food and drug administration shall not approve the above 13 drug registration applications in accordance with the relevant provisions of the measures for the administration of drug registration 2、 The main problems existing in the above clinical trial data of drug registration application are as follows: (1) aspirin sustained release tablets (acceptance No.: cyhs1190075), the applicant is Changzhou Pharmaceutical Factory Co., Ltd., the clinical trial organization and biological sample analysis unit are the Second Affiliated Hospital of Suzhou University, and the contract research organization is Shanghai Keris Biotechnology Co., Ltd 1 The test drug is not authentic Both the test preparation and the reference preparation are test preparation, the package specification is 20 pieces / plate, and the commercial package specification of the reference preparation is 24 pieces / plate However, the sample retained on site shows that the package specification and the tablet appearance of the reference preparation are completely consistent with the test preparation 2 Selective use of data On November 9, 2010, the trace file showed that sample 13-Ⅱ-8-0 (steady-state trough value of multiple administration) was tested twice in the same batch, and the data difference between the two times was large, so the second test data was used, without explanation; on November 7, 2010, the trace file showed that there were 15-i-1-0-2 in the blood sample test of subject 15 The test record of the sample, but the data is not used, and there is no relevant original record （2） The applicant is Suzhou Sinochem Pharmaceutical Industry Co., Ltd and the clinical trial institution is the Second Affiliated Hospital of Suzhou University 1 False data 9-Ⅱ-0 in 20120401-9 analysis batch and Q3 in 20120402-12 analysis batch have only test atlas, and no corresponding trace file is found 2 modify the data The track file of March 22, 2012 shows that the system time has been modified twice, which is March 13 and March 16 respectively; the analysis batch track file of 20120402-12 shows that the sample ID of 20120402-001-049 has been modified 3 Selective use of data The track file of 20120328 analysis batch shows that 66 sample tests have no report and corresponding atlas, and the records of blood sample collection and sample processing are missing The same problem exists in the 20120402-04 analysis batch （3） Cefdinir dry suspension (acceptance No.: cxhs1200057), the applicant is Xi'an Enzi Pharmaceutical Co., Ltd., the clinical trial organization and biological sample analysis unit are the Second Affiliated Hospital of Suzhou University, and the contract research organization is Shanghai Zhuolian Pharmaceutical Technology Co., Ltd 1 Modify data The track file shows that the system time was modified many times during the experiment For example, on October 7, 2011, 5:35 PM was revised to 3:50 PM; on October 29, 2011, 8:14 am was revised to 1:20 am, and then 2:24 am was revised to 9:25 am; on October 31, 2011, it was revised to October 11, and then from October 14 to November 1 2 Selective use of data From October 24 to 29, 2011, a total of 5 batches of sample tests were carried out, with 1049 tests and 910 experimental records shown in the track file; on October 7, 2011, 19 samples were tested, but no report and corresponding atlas were found, and the sample processing records were missing （4） Letrozole tablets (acceptance No.: cyhs1290097), the applicant is Chongqing shenghuaxi Pharmaceutical Co., Ltd., the clinical trial organization and biological sample analysis unit are the Second Affiliated Hospital of Suzhou University, and the contract research organization is Chongqing pharmaceutical industry Research Institute Co., Ltd Selective use of data The paper-based atlas information shows that the sample detection is not continuous, indicating that some samples have been tested but not used, the data of the mass spectrometer source computer has been deleted, no sample information not used above is found, and the data of the mass spectrometer source computer is less than the information data of the archived electronic disc; the standard curve and quality control samples that meet the requirements are selectively used from the mass spectrum, and they are found in the audit It is found in the trail that the serial number (sample ID) of the adopted sample is modified into a continuous sequence （5） Eplidone tablet (acceptance No.: cxhs1400017), the applicant is Shenzhen Nanfang Yingxin Pharmaceutical Co., Ltd and Hefei Jiunuo Pharmaceutical Technology Co., Ltd., the drug clinical trial institution is 458 Hospital of the people's Liberation Army, the biological sample analysis unit is Guangzhou Psychiatric Hospital, and the contract research organization is Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd 1 The clinical trial work is entrusted by Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd The main links of the clinical process of the project are all implemented by the staff of Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd., such as physical examination, clinical process observation, blood collection, sample processing, transfer and distribution of experimental drugs, blood sample in and out of the warehouse, etc The signature form of the researcher of the project shows that except for the main researcher Zhang Mou (who denies participating in the project) and a clinical observer Cheng Mou, the other participants are all the staff of Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd., while the clinical observer does not know the process of the test, but the original test records of all the subjects are signed by them; most of the clinical test records Display: the clinical trial drug administration and blood collection record form, sample in and out of warehouse registration form, trial drug registration form, trial drug requisition registration form, etc are all signed by the staff of Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd 2 The original record is missing The receiving records of biological samples lack information such as sample identification, quantity, transportation mode and condition, sample status, etc.; the stored biological samples have no original records of receiving and storing; the original experimental records of biological sample detection lack information such as conditions, process and experimental results of each batch of experiments 3 The analysis and test process is incomplete There is no relevant maintenance record for the key experimental equipment and instruments for analysis and test; the use record of the instrument is incomplete, and there is no key information such as the name and quantity of the test sample 4 Data is not traceable The test data cannot be traced; the original record is missing during the clinical trial; the X-ray examination data cannot be traced; the name of the atlas file has no correlation with the corresponding blood sample number 5 Conceal the abandoned test data Check according to the sequence of map file coding from small to large It is found that 31 maps are missing between coding sequences Retrieve 31 maps in the source computer Put the recovered maps back to the original sequence, then Cmax exceeds the upper limit of standard curve quantification Conduct 24 hours at room temperature In the stability assessment, the deviation of discarded map data exceeds the acceptance standard, so the researcher rejects it and does not include it in the methodology assessment calculation; all discarded map data are not used, nor described in the summary report and original record 6 Modify data During the test, the test Atlas of the study was checked in the order of file coding from small to large, and it was found that 19 atlas were exchanged in the coding sequence; 13 of 30 subjects The sequence of sample number and file code in the corresponding atlas was changed in multiple time points of subjects, which made the fluctuation state of the original drug time curve tend to be smooth; the reasons for unauthorized modification and adjustment of data were not explained in the original record and summary report of the experiment （6） Eplidone capsule (acceptance No.: cxhs1400018), the applicant is Shenzhen Nanfang Yingxin Pharmaceutical Co., Ltd and Hefei Jiunuo Pharmaceutical Technology Co., Ltd., the drug clinical trial organization is 458 Hospital of the people's Liberation Army, the biological sample analysis unit is Guangzhou Psychiatric Hospital, and the contract research organization is Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd 1 The clinical trial work is entrusted by Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd., which is the same as eplidone tablets (acceptance No.: cxhs1400017) 2 Clinical trial data cannot be traced The original records of the clinical trial process are missing; the X-ray examination data cannot be traced; the inspection data cannot be traced; the handover records of the experimental drugs cannot be traced; the name of the atlas file has no correlation with the corresponding blood sample number 3 The original record is missing The analysis process records and sample in and out records provided on site are the results of post sorting and cannot reflect the real process 4 Conceal the abandoned test data According to the sequence of map file coding from small to large, it is found that 30 maps are missing between coding sequences, 22 maps are retrieved in the source computer, the recovered maps are put back to the original sequence, the drug time curve will show significant fluctuation; all the discarded map data are not used, nor described in the general summary report and the original record 5 Modify data In 5 of 20 subjects, the sequence of multi-point sample number and file name code in corresponding atlas was reversed from small to large For example, the researcher randomly inserted 4 points in the first cycle and 2 points in the second cycle of subject 34 into the map sequence, and the sequence was disordered The original record and summary report of the experiment did not explain the reasons for the unauthorized modification and adjustment of the data （7） Paracetamol tramadol capsule (acceptance No.: cxhs1200035), the applicant is Wuxi Fuji Pharmaceutical Co., Ltd and Guangdong Aimin Pharmaceutical Co., Ltd., and the clinical trial organization and biological sample analysis unit are Guangzhou psychiatric hospital