Inspection Report for Drug Clinical Trial Data
On Jul. 22, 2015, CFDA issued the Announcement of Self-Examination and Inspection of Drug Clinical Trial Data (No.117, 2015). According to the requirement of “the most rigorous standard, the most strict supervision, the severe penalization and the most serious accountability and to safeguard the food and drug safety of the broad masses of the people, CFDA conducted drug clinical trial data inspection for the registration applications of the 1622 pending productions or imported drugs. The inspection work for drug clinical trial data was henceforth started, till now, a whole year has passed.
According to spirit of the State Council’s Comments on the reform of the review and approval system of medical devices for drugs(state issue〔2015〕No. 44), to improve the transparency and impartiality of the inspection work for drug clinical trial data, implement the three openness principals of open standards, open procedures and open results, the Center for Food and Drug Inspection of CFDA(hereinafter referred to as CFDI) carefully summarized the on-site inspection work for clinical trials of all the involving drugs in announcement No.117. Detailed conditions are as follows:
I. The issuing situation of the announcement
From Jul. 22, 2015, CFDA issued a series of announcements to guide and bulletin the conduction situation of the inspection work for clinical trial data. Please see table 1.
Table 1 Relevant Announcement on Self-Examination and Inspection Work for Drug Clinical Trial Data
II. Report of the drugs and Clinical Trial Institutions
Among the 1,622 drugs in Announcement No.117 (2015), a total of 1,094 drugs that filled the self-examination system need on-site inspection, with 948 drugs being domestic products and 146 drugs being imported products. A total of 82 clinical trial institutions undertook Human bio-equivalence trials and phase I clinical trials, among the 82 clinical trial institutions, 7 institutions undertook more than 20 Human bio-equivalence trials and phase I clinical trials; a total of 383 clinical trial institutions undertook phase II/III clinical trials, among the 383 institutions, 13 undertook more than 60 phase II/III clinical trials; a total of 126 contract research organizations (CROs) undertook the clinical trial, among the 126 CROs, 6 undertook more than 20 clinical trials. The top 10 clinical trial institutions that undertook the clinical trials are listed in figure1, the top 19 CROs that undertook the drug clinical trials are listed in figure2, and the distribution situations among provinces are described in figure3.
Figure 1: The Top 10 CROs that Undertook the Drug Clinical Trials
Figure 2: The Top 19 CROs that Undertook the Drug Clinical Trials
Figure 3: The Distribution Situations among Provinces
III. Withdraw situations of drugs
On Aug. 28, 2015, CFDA issued the Announcement of Situations of the Self-Examination for the Drug Clinical Trial Data (No.169, 2015). Among the 1,622 drugs published, the applicants of a total of 1,094 registration applications submitted self-examination documents, accounting for 67%; 317 registration applications were withdrawn, accounting for 20%; 193 registration applications applied to reduce or remit to submit the clinical trials, accounting for 12%, please see table 4. The applicants of 10 registration applications did not submit self-examination documents not actively withdraw the applications, the withdraw opinions of 8 registration applications with multiple applicants were inconsistent.
Figure 4: Statistical Situation of the Self-Examination and Reporting of the Drug Clinical Trial Data
Up to Jun. 30, 2016, a total of 174 drugs in Announcement No.117 haven’t yet received inspection, the distribution among provinces of the un-inspected varieties were demonstrated in figure 5.
Figure 5: The Distribution among Provinces of the Un-Inspected Varieties
IV. Preparations of the Inspection Work for Drug Clinical Trial Data
(i) Inspection work procedures
According to the requirement of Announcement of Printing and Distributing the Inspection Procedures(Provisional) for the Drug Clinical Trial Data（S.Y.J.Y.H.G. No.34 ）, the procedures of the inspection work for drug clinical trial data are as follows. (See figure 6):
1. CFDI will determine the inspection drugs and publish on website according to the Review progress and assess requirement provided by drug trial site. The publicity period is 10 working days.
2. When the online publicity period has finished, for the application drugs that has not withdrawn, CFDI will notify the drug registration applicants, clinical trial institutions and the corresponding provincial level food and drug regulatory authorities the on-site inspection dates. On that occasion, withdraw applications from the registration applicants will not be accepted any more.
3. CFDI will send out inspection team to conduct on-site inspection. Before every team setting out, the inspection personnel will be trained in Beijing, the construction of a clean government will be emphasized and relevant knowledge of key points in the inspection, inspection procedures and report writing will be trained.
4. CFDI will convoke expert review meeting within 10 days after the launch of on-site inspection. On that occasion, expert review comments will be formed.
5. CFDI will convoke communication meeting, to give feedback to and communicate with the drug registration application and principal investigators regarding the inspection opinions.
6. Synthesizing the inspection opinions and communication situations, CFDI will form the explicit inspection opinions to the drug study site to carry out comprehensive inspection.
CFDI has established Procedures of the On-Site Inspection Work for Drug Clinical Trial Data, Communication Procedures of the Inspection for Drug Clinical Trial Data, and multiple report templates have formed to make the execution standardized and the reports unified.
Figure 6: Procedures of the Inspection Work for Drug Clinical Trial Data
(ii) The procedures of the on-site inspection are as follows (See table 7)
1. Preparatory meeting
Before the inspection, the team leader will organize the preparatory meeting which emphasizes integrity and work disciplines, the inspector commitment and statement of no interest conflict will be signed; the inspectors will acknowledge the basic information of the drugs and the inspection project, detailed on-site inspection plan and division of labor will be discussed and determined.
2. First meeting.
Before the inspection of every institution, the team leader will organize and convoke the first meeting:
(1) Read the on-site inspection announcement.
(2) Introduce the inspection team members and the major personnel of the to-be-inspected institutions.
(3) Introduce the integrity and work disciplines.
(4) Introduce the inspection procedures and the requirements of the to-be-inspected institutions.
3. On-site inspection
The inspection team will inspect the drug clinical trial data according to the CFDA issues the Announcement of Key Points in the On-Site Inspection of the Drug Clinical Trial Data (No. 228).
4. Comprehensive meeting of the inspection team
The comprehensive meeting will be chaired by the team leader. The inspector will report the problems they found, for the uncertain problems, further on-site confirmation will be conducted; the Unqualified Items in the On-Site Inspection for Drug Clinical Trial Data will be formed.
5. Last meeting
After the completion of the inspection for every institution, the team leader will organize and convoke the last meeting and report the on-site inspection situations; the Unqualified Items in the On-Site Inspection for Drug Clinical Trial Data will be read out; if the inspected institution has no objection, then the inspection team, the inspector and the inspected institution will signed to confirm. The Unqualified Items in the On-Site Inspection for Drug Clinical Trial Data is quadruplicated for the inspection center, registration applicant, the inspected institution and the corresponding provincial Food and Drug Administrative department, respectively.
6. Synthesizing the on-site inspection situation and identified problems, the inspection team will form Report of the On-site Inspection for Drug Clinical Trials.
Figure 7: Procedures of the On-Site Inspection for Drug Clinical Trial Data
(iii) Inspection standards
The standard of the on-site inspection for drug clinical trial data will be according to Announcement of Key Points in the On-Site Inspection of the Drug Clinical Trial Data issued by CFDA on Nov. 10, 2015.
The announcement has regulated the key points in the on-site inspection regarding the following issues: the clinical trial condition and compliance; the completeness of the subject screening/inclusion relevant data chain; the authenticity and completeness of the signature of informed consent and the clinical trial procedure; the traceability of the clinical trial procedure record and data of clinical examination and test; the key data such as the violation of project in the CRF and numbers of serious adverse events(SAE); the management procedure and record of the investigational drugs/vaccines; the record of the collection, preservation, transportation and connection of the bio-samples in clinical trial. Additionally, the announcement also specifies the inspection key points of the bio-sample tests in the BE/PK trial and phase II/III clinical trials. Unified inspection standard and consistent scale should be obtained for every clinical trial.
(iv)Principles during Inspection:
Every classification should be inspected in every inspection work. For BE clinical trial, clinical trial and bio-sample test should be inspected; for phase II/III clinical trial, the institution of the team leader, the institution that included especially many subjects, the institution with especially many cases of AE/SAE should be focused in the inspection.
(v) The training of the inspectors
The inspectors are the safeguard of the inspection work for the drug clinical trial data, therefore, the training of the inspectors becomes one of the important works of CFDI for the year.
CFDI has drafted Inspector Training System. Since the issuing of Announcement No.117, the inspection has launched a total of 3 training classes for the inspector of the country. The training classes employed overseas and domestic experts in clinical trials, bio-sample test, statistical analysis and auditing, to give systemic training for the inspector; in Mar. 2016, the “ key points for BE trial procedures and practice” lecture was hold according to the BE study principle issued by CFDA; in April, CFDI invited DIA experts to conduct discussion regarding the global GCP regulatory focus and development trend; in July, hold the global multi-center clinical trial and drug clinical trial quality management and regulatory training class jointly with Peking University, Asia Pacific Economic Cooperation Organization and supervision center of excellence.
Besides special training course, CFDI conduct centralized training for the inspectors before they set out, with actual case analysis, further on-site inspection requirement, report drafting and problems drafting requirement being trained.
Currently, more than 170 inspectors participated inspection work for the drug clinical trial data, the inspectors are from CFDI, NIFDP, CDE, CHP, provincial inspectorate, Colleges and Universities and hospitals. After training, the inspectors’ abilities improved, thus the smooth development of the inspection work for the drug clinical trial data could be obtained.
(vi)Data management system for the self-examination report of drug clinical trial data
To accomplish the task of on-site inspection for drug clinical trial data, CFDI designed and developed the report data management system for the inspection of drug clinical trial data. The system has been opened since Aug. 3, 2015. The registration applicants report the clinical trial situations by varieties, such as, basic information of the drug, clinical trial institutions, starting and ending time of the clinical trial, situations of the subjects, medication situations, AE/SAE situations, and problems found during self-examination. Up to the closing date of the system on Aug. 25, 2015, a total of 1,513 electric data and 2,100 paper materials were received.
On Jun. 13, 2016, the self-examination reporting system was opened for the drug registration applicants whose products are involved in the Announcement No.81, 2016. From now on, the system will be open for all the drugs that need inspection for the drug clinical trial data.
V. Situations of the inspection for drug clinical trial data
(i) Basic situation of the inspection
From Oct. 2015, CFDI has started conducting inspection for the drug clinical trial data involved in the Announcement No. 117. Up to Jun. 30, 2016, 6 clinical trial data inspections were conducted, a total of 46 inspection teams with 366 inspectors were sent out and 68 varieties have been inspected (35 BE trials, 33 phase II and III clinical trials; among the 68 varieties, 64 have completed inspection reports and have been transferred to CDE), 119 drug clinical trial institutions and 23 bio-sample analysis institutions were inspected, with their locations covering 25 provinces and municipalities. Please see figure 8.
Figure 8 The distribution of the inspected institutions of the drug clinical trial data
(ii) Public situations of the inspection results
CFDA issued three Announcements to notify the on-site inspection results of the first to third batches of clinical trial data. A total of 30 registration drugs were disapproved, among which 26 were BE trials, and 4 were phase II and III clinical trials. A total of 11 institutions were registered and investigated. Please see table 2.
Table 2 Result of the On-Site Inspection for Clinical Trial Data
(iii) Public situation of the inspection plan
According to the requirement of Announcement of Printing and Distributing the Work Procedures of Inspection for Drug Clinical Trial Data (Provisions) (Food and Drug Administration No. 34(2016)), from Mar. 2016, CFDI will publish the to-be-inspected drugs on the internet, the publicity period is 10 working days. Starting from the third Announcement, the application companies, team leader institution of the clinical trial, contract research organizations (CRO), phase I/BE clinical trial institutions, phase I/BE analysis test institutions and corresponding investigators will be published to the public together. Currently, 4 Announcements of inspection plans have been issued, with a total of 69 publicity drugs, 16 withdraw drugs (23%), and 22 inspected drugs. The publicity period of the fourth Announcement will be finished by Jul. 21, 2016. For Notice situations, please see table 3.
Table 3: Publicity Situations of the Inspection Plan for Drug Clinical Trial
(vi) Convoke situation of the communication meeting
Up to now, 3 communication meetings on inspection situations have been convoked, near 200 persons of drug registration applicants and principal investigators attended the meeting. In the meeting, the expert review comments were read to the drug registration applicants and principal investigators, and the drug registration applicants and principal investigators explained the problems that need further explication. More than 90 problems were communicated in the three meetings; adequate communications were made with the drug registration applicants and principal investigators.
VI. Major problems found in the on-site inspection
(i) The typical problems of the BE and PK trials are as follows:
1. Unauthenticated investigational drug, for example, the test preparations were directly used as reference preparations; therefore, false conclusions that the test preparations were equivalent with the reference preparations were obtained.
2. Original records were missing. Such as, original record of the clinical trial subjects identification code table, blood sampling time, vital signs monitoring table, plasma transport and processing record, record of the sample analysis procedures, records of distribution and storage of the samples, relevant records were re-arranged afterwards; the records of analysis procedure and records of distribution and storage of the samples were re-arranged afterwards, there was no original analysis record.
3. Questionable clinical trial records. Such as, the recording personnel of the 2008 Drug Storage Room Temperature Humidity, Temperature and Humidity of Refrigerator Record started to work in the hospital from Aug. 2008, whereas the record of the drug storage room temperature humidity since Jan. 2008 was recorded by him (her).
4. Questionable analytic test data. Such as, the completion time of the analytic test was Apr. 2010-Jul. 2010, whereas the factory qualified report time of gas chromatograph was Mar. 2, 2011.
5. Modified and exchanged of the data. Such as, the sample number of multiple time points of the subjects were reversed in sequence with the file number in the figure from small to large, there were no explanations in the original record and summary report.
6. Concealing and modifying the clinical trial data. Such as, the record in the original record book and the record in the audit trail record were inconsistent, multiple analytic test system dates were repeatedly modified, same file name was used for multiple tests and the original spectrum was covered, only one file was submitted in the summary report of the audit trail record of the methodological validation and bio-sample test.
7. Unreliable clinical trial data. Such as, in the record of the control solution preparation, concentration calculation of the stock solution was wrong, therefore, the actual concentration could not be confirmed.
8. Modification of the data. Such as, the trail file showed the system times during study period were modified for several times.
9. Selectively application of the data. Such as, the test numbers showed in the trail file was more than the test numbers showed in the study record.
(ii) The typical problems found in the phase II and III clinical trial were as follows:
1. Modifications of the data to enable the subjects meet the inclusion criteria or include the subjects into the Per Protocol Set. Such as: after modification of the medication doses, the subject was included in the Per Protocol Set; Modify the chief complains of subjects, modify or add symptoms description conforms to the inclusion criteria to enable the subjects conform to the inclusion criteria.
2. Missed report or failed to report the serious adverse events (SAE) according to relevant procedures.
3. Untraceable of the test result. Such as: the primary efficacy parameters i.e. pulmonary function test results of all the subjects were untraceable.
4. The data in the CRF were inconsistent with the original data.
5. The data in the statistical analytic report or in the summary report were inconsistent with that in CRF.
6. Concomitant medications that were prohibited in the study protocol were used.
7. The patient’s diary cards (which should be filled by the subjects) were all filled by the investigators.
8. Violation of study protocol
VII. Summary and prospection
For the past one year, the Drug Clinical Trial Data Self Reporting System has been established by CFDI under the leadership of the CFDA. Hence, the reliable collection of the basic data and statistical report were guaranteed; after ceaseless summary, the inspection program and key points become more and more scientific, the inspection procedures more and more standardized, the inspections measures more and more diversified, and the affirmation of the inspection result more and more emphasize on objective facts and scientific decision-making. After inspection, the efficacy uncertain drugs with hidden risks were disapproved, this measure safeguarded the people’s health; the inspection found some chaos in the past clinical trials, some of the falsifications were horrifying; the inspection shaped a good image for the inspectors and the prestige of the CFDA, which vigorously promoted the construction of the professional inspector team; the inspection improved the cognitive levels of the drug registration applicants and investigators to clinical trials, strengthened the subject responsibilities, which played a role in promotion of the adjustment of the industry, and enable the clinical trial go back to the normal track; the inspection explored the scientific inspection method and revolutionized the inspection modes of the clinical trial.
The clinical data is the basis of the drug inspection and approval, the authenticity of clinical data is the guarantee of the drug safety and efficacy, therefore, the inspection work for drug clinical trial data will continue to carry out. Every trial will be checked with strict requirements according to the Key Points of On-Site Inspection in the Drug Clinical Trial Data. CFDI will enlarge the inspector team from now on, it is predicted that in 2020, the number of professional clinical trial inspector will be more than 200. The training for the inspectors will be strengthened to accelerate the inspection work; the transparency and fair work style will be maintained, publicity of the inspection plan before inspection, supplementary communication after inspection and conduct the inspection work with one measurement should be implemented. To further strengthen the communication and connection with the Center for Drug Evaluation, standardize the key points and judgment standards of inspection to keep in consistency with the international specifications and technical standards, and to ultimately establish the scientific and high-efficiency inspection system; for the falsifications found in the on-site inspection, serious punishment should be made and the responsibilities of the relevant responsible persons will be investigated thoroughly. To put the “four most strictness” into practice, improve the safety standards of the drug quality and safeguard the health of the public.