Objective To investigate the report rate of ethical review in registered Chinese trials records.
Methods Chinese trials recorded in WHO primary registries and http://clinicaltrials.gov to 14 July 2009 were identified. The report rates of ethical review and each of the 20 items in WHO's Trial Registration Data Set were calculated. Correlation of the item's report rate with the ethical review report rate was assessed. PubMed, EMBASE, CNKI and CBM (from the establishment of each database to 14 July 2009) were also searched to collect the full texts of completed trials to calculate the report rate of ethical review in the result publications.
Results A total of 1247 records were identified, and 687 (55.1%) reported ethical review. The records reporting secondary sponsor(s), contact for public queries and key secondary outcomes were more likely to report ethical review information (66.3% vs 44.3%, 38.1% vs 28.5%, 53.9% vs 51.8%). The ethical review report rate of trials sponsored by industry was lower than those sponsored by non-industry (40.9% vs 51.9%). The report rates of ethical review for self-supported trials (83.5%) and trials with unidentified sources of monetary or material support (66.7%) were lower than the average ethical review report rate for records in the Chinese Clinical Trial Registration Center (ChiCTR). The ethical review report rate was not high in the result publications (84.3% in http://clinicaltrials.gov, 50.0% in ChiCTR).
Conclusion Registered Chinese trials records report ethical review inadequately. Incomplete registration is correlated with not reporting ethical review. Medical journals should inspect ethical review more critically.
- Clinical trial registration
- ethical review
- integration of trial registration and ethical review
- report rate
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- Clinical trial registration
- ethical review
- integration of trial registration and ethical review
- report rate
Trial registration was first proposed in the 1970s to speed President Richard Nixon's ‘War against cancer’ and to reduce bias in the reporting of trial results. In May 2007, the WHO International Clinical Trial Registration Platform (ICTRP) was established,1 and issued the minimum required 20 items for the WHO Trial Registration Data Set (TRDS),2 giving researchers an international platform and standard for trial registration. Registration was made mandatory in some nations, such as Brazil and the USA.3–6 Up to 14 July 2009, a total of 11 primary registries met the specific criteria for content, quality and validity, accessibility, unique identification, technical capacity and administration requirements of the WHO ICTRP and International Committee of Medical Journal Editors (ICMJE): International Standard Randomised Controlled Trial Number Register (ISRCTN), Australian New Zealand Clinical Trial Registry (ANCTR), Chinese Clinical Trial Registration Center (ChiCTR), Clinical Trials Registry—India (CTRI), German Clinical Trials Register (DRKS), Japan Primary Registries Network, The Netherlands National Trial Register (NTR), Sri Lanka Clinical Trials Registry (SLCTR), Iranian Registry of Clinical Trials (IRCT), Pan African Clinical Trial Registry (PACTR) and http://clinicaltrials.gov.5
The goal of WHO ICTRP was to improve the transparency of clinical trials. WHO ICTRP makes efforts to overcome potential barriers to trial registration, including differences of culture, language, economic level and conflicts of interest to keep trial registration all over the world fair and just. Without international legislation to mandate trial registration in a public registry, enforcement mechanisms can only be determined and implemented by national legislation, or through ICMJE's requirements and ethics approval.7 WHO ICTRP provides a single point of access and the unambiguous identification of clinical trials. Integration of trial registration and trial ethical review is one of the ways to improve the transparency of science and ethics of trials.8–11 One of the ways to link registration and ethical review is report the ethical review information in the trial registration records. In China, the infrastructure of ethical review is developing.12 ChiCTR established its own ethical committee to coordinate the linking of trial registration and ethical review.13
Up to now, no study has reported the completeness of ethical review of Chinese trial records in WHO ICTRP primary registries or examined the factors that affect ethical review reporting. We investigated the status of ethical review reporting in Chinese trial records to provide basic information for improving the transparency of clinical trials.
Inclusion and exclusion criteria
For a trial to be categorised as ‘Chinese’ the lead principal investigator or sponsor had to be a person or organisation in China. We assessed the registration records of all trials that met this definition, excluding trials whose participants are Chinese, but which were not Chinese led or sponsored.
We collected the registration records of 11 WHO primary registries, including ACTR, ISRCTN, ChiCTR, IRCT, DRKS, Japan Primary Registries Network, NTR, SLCTR, IRCT and http://clinicaltrials.gov, then assessed the ethical review reporting in the records of Chinese trials up to 14 July 2009.
We included all the records in ChiCTR in our initial screening, and used ‘China’ as a key word to search the other 10 registries for other records that might be eligible. We carefully read each record to identify Chinese trial records that met our criteria.
We evaluated the completeness of the records that met the minimum required 20 items for trial registration, and calculated the report rate for each item.
We recorded the ethics committee name, approval date, approval number, sponsor name, registration date and progress status of each record. Then we calculated the proportion of records that reported ethical review.
For WHO TRDS items with a report rate of less than 85%, we assessed correlation of the ethical review report rate with the item's report rate.
Ethical review reporting in the result publication
For each completed registered trial, we searched for the full text of the report of the trial in the medical literature. Sometimes the result publication information was linked in the record. Otherwise, we used English keywords to search PubMed and Embase, and Chinese keywords to search the China National Knowledge Infrastructure (CNKI, a database that includes dissertations and conference proceedings) and Chinese Biomedicine database.The search time was from the establishment of each database to 14 July 2009. Then we calculated the ethical review report rate in the result publications.
We conducted a descriptive analysis to evaluate the completeness of each WHO TRDS item and the ethical review report rate. Associations between ethical review reporting and categorical parameters were tested for significance using Pearson's χ2 test. Significance for two-tailed tests was set at p≤0.05. SPSS 11.5 software was used for statistical analysis.
We held a training workshop for the evaluators. The course content included: (1) the history of clinical trial registration and ethical review; (2) the distinction between Chinese trials and trials whose recruitment location was in China; (3) definitions of the minimum required 20 items of WHO TRDS and of ethical review information registration. The two reviewers (Song SQ and Yin SL) then pre-reviewed the completeness of 10 registration records for the minimum required 20 items for trial registration. The results showed that the two reviewers did not agree on the exact definition of secondary ID, date of first enrolment, source(s) of monetary or material support and public title. So we discussed the accurate meaning of these four items according to the definition for them by WHO minimum required 20 items for trial registration, then re-evaluated the 10 records. The re-evaluation results showed that the two reviewers did understand the meaning of the four items and the re-evaluation was correct and consistent.
Song SQ and Yin SL extracted the registration information for each trial, and Liu XM and Li YP checked the data. Differences were resolved through discussion.
A search was not available for DRKS. We did not find any trials sponsored by China in the Japan Primary Registries Network, CTRI, NTR, SLCTR, IRCT, or PACTR. We initially identified 1294 records with the keyword ‘China’ in http://clinicaltrials.gov, and finally identified 743 records that met our criteria. A further 551 records in http://clinicaltrials.gov were excluded because the trials did not meet our criteria, although the recruitment location was in China. We identified 55 eligible records in ISRCTN, 21 in ACTR and 428 records in ChiCTR. A total of 1247 Chinese trial records was identified across the four registries.
Report rate for the minimum required 20 items of WHO TRDS
For the 734 Chinese records in http://clinicaltrials.gov, 10 items of the minimum required 20 items of WHO TRDS were reported inadequately. The report rates of secondary sponsor(s), contact for public queries and key secondary outcomes were 31%, 47% and 77%, respectively. The report rates of the other seven items—contact for scientific queries, scientific title, countries of recruitment, intervention(s), date of first enrolment, target sample size and primary outcome(s)—were each more than 85% (table 1). The number of items set as well as the minimum required 20 items of WHO TRDS in http://clinicaltrials.gov reached 38, an increase of five items compared with the number we investigated on 31 December 2008.14 The appended items of current primary outcome measures, original primary outcome measures, change history, current secondary outcome measures and original secondary outcome measures reflected the dynamic process of the trial and resulted in more transparency of trial implementation. The two items of secondary ID and original study ID were merged into one item of study ID numbers, which makes the definition of secondary ID clearer and reduces redundant entries. These measures help to improve the integrity of the registration information so as to enhance the transparency of clinical trials.
In the 428 records in ChiCTR, the reporting of five entries was incomplete: secondary ID, source(s) of monetary or material support and key secondary outcomes report rates were 2%, 59% and 76%, respectively.
In the 55 records in ISRCTN, the reporting of three entries was incomplete: secondary ID, scientific title and date of first enrolment report rates were 27%, 27% and 91%, respectively. This registry has only one sponsor entry, so it does not differentiate between primary and secondary sponsors.
In the 21 records in ACTR, there were two incompletely reported entries: secondary ID and secondary sponsor(s) report rates were 10% and 71%, respectively.
The incomplete co-selection rates of items for secondary ID and secondary sponsor(s) among the four WHO primary registries were high (at 75% and 100%, respectively) compared with other items. Although the incomplete co-selection rate of primary outcome(s) was relatively high at 50%, the report rate of primary outcome(s) in the four registries was also high, at more than 85%.
Ethical review reporting of Chinese trial records in WHO primary registries
Entries of ethical review were set up in ChiCTR, ISRCTN and ANCTR but not http://clinicaltrials.gov. Ethical review information was reported in all 21 records in ANCTR. More than 80% of the records in ChiCTR and ISRCTN also reported ethical review. However, only 34.3% of the records in http://clinicaltrials.gov reported ethical review. Of 1247 total records in WHO ICTRP primary registries, 687 (55.1%) reported ethical review (table 2).
Factors affecting ethical review reporting
The number of Chinese trial records in ISRCTN and ANCTR is too small for meaningful analysis, so we included only the 1171 Chinese trials records in ChiCTR and http://clinicaltrials.gov in our analysis of factors affecting ethical review reporting.
The trial records reporting secondary sponsor(s), contact for public queries and key secondary outcomes were more likely to report ethical review (p=0.0) when compared with records without the three entries. Trials sponsored by industry were less likely to report ethical review in the registration record when compared with other trials (p=0.0) (table 3). The ethical review report rates for self-funded trials (83.5%) and trials with unidentified sources of monetary or material support (66.7%) were lower than the average report rate of ethical review (88.3%) in ChiCTR (table 4).
Ethics committee involvement
As of 14 July 2009, 13 ethical committees had reviewed 247 trials records with ethical review information posted on http://clinicaltrials.gov. The Chinese Ethics Committee (137/247, 5.3 trials each year from year 1983 to 2009), Hong Kong Ethics Committee (75/247) and JOINT CUHK–NTEC Clinical Research Ethics Committee (18/247) together reviewed 92.7% of the trials.
Meanwhile, 181 ethics committees reviewed 378 trials records with ethical review information posted on ChiCTR. Each ethics committee reviewed an average of 2.1 trials from 2005 to 14 July 2009 (0.5 trials per year). Most of the ethics committees were located in developed areas such as the Beijing–Tianjin area (30.4%) and the Shanghai/Jiangsu and neighbouring Zhejiang areas (22.1%). Moreover, the number of trials reviewed by the ethics committees in these two areas (26.5% and 35.7%) was higher than the number reviewed in the other six areas in China (table 5).
Ethical review reporting in result publications
Ethical review was reported in 15.7% (29) of the 89 trials that had result publications posted on http://clinicaltrials.gov. We obtained 38 full texts of result publications. The name of the ethics committee and the informed consent procedure were reported in 71.1% (27/38) of the full texts. Many trials obtained ethics committee approval but did not post ethical review information in their records.
Among the 40 completed trials with result publications posted on ChiCTR, we gained 24 full texts. Of these, four (16.7%) reported the name of the approving ethics committee and eight (33.3%) reported informed consent. The ethical review report rate in result publications (50%) was lower than that in the records (88.1%). All of the results were published in Chinese medical journals.
Ethical review dataset in the registries
Ethical review is included in ChiCTR, ISRCTN, and ANCTR, but not http://clinicaltrials.gov. Therefore, only 34.3% of the records in http://clinicaltrials.gov reported ethic review compared with over 85% of the records in ChiCTR ,ISRCTN and ANCTR. ANCTR asks for such details as ethics committee name, address, country, approval date and Human Research Ethics Committee number. It suggests that entry of ethical review dataset is very important for complete ethical review reporting in the record, and the registry should ask for the registers to provide data of ethical review and verify their validity.5
Location of ethical review
There are 13 ethics committees mentioned in the 256 trials in http://clinicaltrials.gov, only one of which is affiliated with a hospital. In contrast, a total of 181 ethics committees, most of them in hospitals, reviewed the 376 trials in ChiCTR, which does reflect the real situation of ethical review in China. In Chinese trials registered at http://clinicaltrials.gov, ethical reviews are performed by four ethics committees, with each reviewing an average of 5.3 trials per year, whereas in ChiCTR, ethics reviews were done by 181 ethics committees, each reviewing 0.5 trials, on average, per year. This indicates that if a trial is ethically reviewed outside the country where it is performed, it is hard to control quality, accumulate experience and check validity, especially in a nation whose mother language is not English. So location of ethics review is very important as well as location of trial registration.6 14 15
Factors affecting ethical review reporting
Our results showed that ethical review reporting was correlated with integrity of registration records, as assessed by the minimum required 20 items of WHO TRDS. The records reporting secondary sponsor(s), contact for public queries and key secondary outcomes were more likely to report ethical review when compared with the records without the three entries (p=0.0). The integrity of registration reflects the degree of transparency, especially to the public. Not reporting a direct contact for public queries impedes the ability of members of the public to obtain information on the trial. The seemingly unimportant items of secondary sponsor(s) and key secondary outcomes may also affect trial transparency. Secondary sponsor(s) may be entities that cause conflict of interest. Key secondary outcomes may include adverse events. Accordingly, missing secondary sponsor(s) and key secondary outcomes in the record reduced the transparency of trials and may have led directly to unreported ethical review.
As for the lack of reported ethical review of many trials supported by the researchers themselves, or by unidentified funders, these trials have little supervision, and may not undergo ethical review. Registries should thus pay more attention to these trials when registering the trials, and registries should also make a mandatory requirement for offering ethical review information when the researcher registers a trial.
The role of medical journals in ethical review reporting
Our study indicated that the ethical review report rate in result publications was lower than that in registration records in ChiCTR. This suggests that medical journals should be more vigilant in requiring a description of ethical review when they publish trial results. Medical journals should list the mandatory requirement for ethical review details in the instructions for the authors. From the other side, it also demonstrates the importance of ethical review reporting in registration records. Even if result publications do not report ethical review, readers could find ethical review information in the registration record.16 17
Sequence of ethical review and trial registration
According to the international ethical guidelines for biomedical research involving human subjects by WHO and the Council for International Organizations of Medical Sciences, ‘All proposals to conduct research involving human subjects must be submitted for review of their scientific merit and ethical acceptability to one or more scientific review and ethical review committees’.18 Our study showed that ethical review of some trials in http://clinicaltrials.gov and ISRCTN lagged behind registration, and some even lagged behind trial completion. Up to 14 July 2009, no ethical review information was posted in the 180 Chinese records in http://clinicaltrials.gov. Some trials may be approved by institute review boards but fail to report this approval in the registration record, whereas others without institute review board approval registered with http://clinicaltrials.gov before WHO ICTRP was established. According to the Declaration of Helsinki, 2008 version, trials should be registered and approved by an institutional review board before the first participant is recruited.
Trial registration has at least four advantages: (1) improving trust in medical research and industries, as well as public access to trial information; (2) enhancing public disclosure and dissemination of key information on design and implementation among clinicians, the public and researchers, thus promoting knowledge creation and knowledge transfer; (3) minimising bias in trial design and publication; (4) avoiding serious pitfalls in trial implementation and helping institute review boards to weigh the risks and benefits of the trial protocol and informed consent fully.19
Importance of integration of trial registration and ethical review
The goal of trial registration is to ensure trial transparency in terms of ethics and science. Ethical review is an important way to protect participants. Registration allows ethics reviewers to access trial information to aid in their review. Meanwhile, institutional ethical review supervises the process of trial to guarantee the validity and reliability of registration information.
Ethical review has been going on longer than trial registration, and many lessons learnt from ethical review implementation can be applied to trial registration. So WHO ICTRP's integration of trial registration and ethical review makes it possible for registration and ethical review to support each other, to share resources and ultimately to realise the integrity of clinical trial registration information.19–21
Registration, ethical review and standard results publication are important components of the best clinical trial practice model.22 Registration makes key information on design, intervention and outcome available to the lay public, and supervises trials at the initial stage. Transparency depends on the completeness of registration information. Including ethical review reporting in registration records contributes to the completeness of the records. It also contributes to improving the trial transparency and standardisation of the result publication by enabling editors to check the ethical review in the registration record before publishing results.
Ways to improve the ethical reporting in publication
First, ethical review institutes should not only review the ethics of a trial, but also supervise the process of a trial to result publication. Ethical review should require the researchers offering information of a trial result. If a trial result is published, the researchers should send the reference to the ethical review institute.
Second, trial registries should publish the protocol of a trial including information on ethical review, so readers can easily search it. When trial registries post the trial result, protocol including ethical review should be linked.
Third, when journal editors publish a trial result, they should require the author to provide both information registration and ethical review. If it is possible, the journal should publish the protocol of a trial or link it in the registries.
With regard to the above, journals, ethical review, trial registries and researchers come into a mutual relationship, information on ethical review is more available and open and is under the supervision of the public. Therefore, a higher ethical reporting rate may be possible.
Limitations of this study
This study only investigated the ethical review report condition of Chinese trials records in WHO ICTP primary registries. The results only reflected the ethical review reporting problems of Chinese trials records not global trial records. Further study will randomly extract the trial records in WHO ICTRP primary registries to investigate ethical review reporting status.
Although we tried our best to collect the full texts of the completed trials to calculate the report rate of the ethical review, the report rate may be underestimated due to unavailable full texts or an inadequate search. The ethical review reporting rate in full texts in this study is higher than 0.9% in Chinese journals in 2000.23
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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