Trial results disclosure in Asia

China, Japan, South Korea and Taiwan each require a trial to be registered on a national registry, and they differ in whether its results have to be posted there, on what timetable, in what form and language, whether the public can read what is posted, and what other routes carry results to the public.

China

ChinaDrugTrials.org.cn, the national registry launched in 2013, takes every interventional trial conducted in China, including bioequivalence studies, pharmacokinetic studies and trials of every phase. ^{1, 2, 3} Registration is mandatory before subject enrolment, and as of April 2023 observational studies did not have to be registered. ^{2, 3, 4} The Center for Drug Evaluation's draft guidance, in effect from 1 July 2020, requires every trial approved by the National Medical Products Administration and conducted in China to be registered, bioequivalence and phase 4 or post-marketing surveillance studies included (Article 6), before subject enrolment (Article 14). ^{5, 6}

After the trial completes, the sponsor must post results on the same platform within twelve months of completion or before a new drug application, whichever comes first. ² The second limit is worded three ways: as before an application, as a recommendation in Article 15 of the guidance to post results before submission for trials supporting a new drug application, and, in a 2023 overview table, as before marketing authorisation. ^{2, 6, 7} Trials completed before 1 July 2020 stay on the same timetable unless an application had already been submitted, in which case posting is optional and at the sponsor's discretion. ^{2, 8}

In China and in Japan alike, what "study completion" means depends on how the individual study defined it in the protocol. The common understanding is the date of the last subject's last visit, but a study with an exceptionally long follow-up period may define it as the last visit of the treatment period instead. ^{9, 3}

The results go up as a separate summary or overview document which, under Article 15 of the guidance, should at least contain the content of the CSR synopsis as described in ICH E3. ^{2, 7, 3, 6} The uploaded results are not accessible to the public. ^{2, 3, 7} The registry is operated in Mandarin only, in simplified script. ^{10, 7}

Under the Drug Registration Regulation, in force from July 2020, sponsors should register the protocol and trial information before the trial starts, keep it updated and add the results after completion, and they are responsible for the authenticity of that information (Article 33). ⁵ A sponsor that fails to register a trial or to provide its results is warned and ordered to take corrective action, and failure to correct within the given time may result in a penalty of 10,000 to 30,000 Chinese yuan (Article 116). ⁵

The older voluntary registries

Several older registries in China, registered in the WHO Registry Network, are still in use but now serve only as voluntary registries. ^{10, 3, 7} The Chinese Clinical Trial Registry (ChiCTR), established in 2005, accepts trials from China and elsewhere, is operated in Mandarin and English, and has been a WHO ICTRP primary registry since 2007. It was the primary registry for Chinese trials until the national platform launched, and its role in relation to the regulation has been unclear since. ¹¹ The Centre for Clinical Research and Biostatistics registry, a ChiCTR partner since 2009, accepts trials globally and is operated in English, with only the study title bilingual. ⁶ Two registries for traditional medicine were established after 2013. ¹² The Acupuncture-Moxibustion Clinical Trial Registry, established in 2014 for trials using acupuncture-moxibustion as interventions, has been a ChiCTR partner since 2016, is a WHO ICTRP partner registry and complies with WHO ICTRP registration requirements. ¹³ The International Traditional Medicine Clinical Trial Registry has taken trials from China and elsewhere since 2019 across Chinese medicine, acupuncture, tuina massage, herbal medicine, ayurveda, homeopathy and complementary medicine. It is operated in Mandarin and English, complies with WHO ICTRP registration requirements and has been a WHO ICTRP primary registry since March 2023. ⁶

Registry overlap and missing results

As of 25 June 2023 more than 70,000 trials were registered on ChiCTR and just under 21,000 on ChinaDrugTrials.org.cn, which leaves open how many trials are registered on both platforms and maintained equally, and how many on only one. ⁶ A quick look at trials completed between 2020 and 2022 on the national platform found that not all had posted results. ^{8, 6} In one 2023 assessment, the registries potentially have issues of redundancy, inadequate maintenance and missing information, as many other major registries worldwide have. ⁶ The same assessment holds that imposing a penalty for failing to provide results is only the first step, and that effective and consistent oversight of registration and results posting must not be overlooked. ⁶ Data exchange and mutual recognition between the two platforms have been suggested for consideration, to improve the transparency and sharing of trial information. ⁶

Results on the Center for Drug Evaluation's website

Separately from the registries, results for approved drugs are disclosed on the Center for Drug Evaluation's website, typically as review reports and drug instruction manuals. ^{10, 3, 7}

How the national registry arose

In November 2012 the Center for Drug Evaluation began a trial run of a registration and information disclosure platform on its website. ⁵ In September 2013 Notification No. 28 of the then China Food and Drug Administration required every trial conducted in China, whether bioequivalence, pharmacokinetic or phase 1 to 4, to be registered and its information disclosed. ^{14, 5} Pre-registration for the trial's identifier had to be completed within one month of approval and the rest before first enrolment, and registration was to be seen as a prerequisite for later communication and consultation with the authority during the trial. ^{14, 12} In October 2013 the Center released further information following the notification, announcing the effort to complete a new trial disclosure platform, and ChinaDrugTrials.org.cn launched as an independent platform in November 2013. ^{12, 5} The trial run on the Center's website was then terminated. ⁵ Notification No. 257 of December 2015, on the management of bioequivalence trials of chemical drugs, indicated the integration of the registry for generic drugs and bioequivalence trials into the platform. In 2020, with the Drug Administration Law of 2019 and the Drug Registration Regulation, the platform was upgraded and formally merged with that registry. ⁵

Japan

Japan had three trial registries until September 2020, when they were unified into a single registry, the Japan Registry of Clinical Trials. ^{10, 3} Every interventional and observational trial conducted in Japan except bioequivalence studies is legally required to be registered on it before subject enrolment. ^{10, 9, 3} The sponsor must post results within one year of study completion. ^{9, 7, 3}

Unlike China's, the Japanese results are accessible to the public. They take the form of a synoptic summary, mostly covering only the primary endpoints and the key secondary endpoints, and they may also be posted as links to publications. ^{9, 15, 3, 7} The registry is a primary registry in the WHO Registry Network and is operated in both Japanese and English, and since the unification no other Japanese registry is known to be in use. ^{15, 7}

What the PMDA publishes once a drug is approved

For an approved drug, the Pharmaceuticals and Medical Devices Agency (PMDA) publishes on its website certain sections of Modules 1 and 2 of the common technical document, its own review reports and summaries of data. ^{15, 3, 7, 16, 17} The clinical study reports sit in Module 5 and are not disclosed. ¹⁶

As of March 2019 the PMDA did not require individual clinical study reports to be made publicly available. ^{18, 19} Individual study results were instead disclosed in other documents the PMDA made available. ¹⁹ With few exceptions, all of the disclosed information was in Japanese. The individual study results were available in Modules 2.5, 2.7.3 and 2.7.4, and the synopses of individual studies at 2.7.6 in a Japanese application included more data than the standard ICH E3 synopsis to comply with the PMDA's preferences. ¹⁸

Registries, publications and company websites before the unification

Besides the PMDA's website, results reached the public in Japan in March 2019 through clinical trial registries, publications and pharmaceutical companies' websites. ¹⁹ After three registries were jointly named the Japan Primary Registries Network in 2008, registrations rose sharply, and by 2013 there were more than five times as many a year. The rise came after journals generally began requiring registration before study start as a condition of publication. Another factor was a 2008 update of the national ethical guidelines, enacted in 2009, that added a requirement to register interventional trials. The guidelines that superseded it in 2014 required, as of 2019, interventional studies to be registered in one of the three Japanese registries. Registration information was required in Japanese and English, and the English could be in an English-language registry. As more global and fewer local studies were run in Japan, the share registered on ClinicalTrials.gov might increase. ²⁰

The registries made summary results available in Japanese and English, and English summaries could also be provided elsewhere, such as on ClinicalTrials.gov. They generally carried limited results: those for the primary endpoint and perhaps the main secondary endpoints. In the registry where most industry-sponsored studies sat, they took the form of a brief synoptic summary. On the university hospital and medical association registries, they were most often a link to a publication, or else a small text-box summary without tables or figures. Despite the requirement to disclose results, many registered studies had no results posted after completion. ²⁰

In Japan, as globally, the publication rate of registered studies was low. Of more than 3,000 studies registered during the first five years of the university hospital registry, results were published for only 10%. A survey of 179 lung cancer studies in the same registry found results published for approximately half, and more likely to be published if positive. Results of local studies in Japanese patients were sometimes published in Japanese-language journals to inform local healthcare professionals of evidence relevant to treating Japanese patients. The emerging trend toward plain language summaries accompanying publications or abstracts to inform lay people had not yet caught on in Japan. ²¹

In January 2018 the member companies of the Japan Pharmaceutical Manufacturers Association committed to clinical trial data sharing based on the IFPMA Principles for Responsible Clinical Trial Data Sharing. The commitment has five parts: enhancing data sharing with researchers, enhancing public access to clinical study information after approval of a medicine or a new indication, sharing results with patients who take part in trials, certifying procedures for sharing trial information, and reaffirming commitments to publish trial results. It was expected to promote data sharing by all companies. ²² Some large companies had also built their own Japanese websites for their clinical study data. These usually post a public disclosure synopsis written for the general public rather than a full study report, or else links to registry entries, and the documents are usually in English. ²²

Undisclosed study reports and the outlook

Because Module 5 is not disclosed, detailed study information is limited, particularly on study conduct, statistical analysis methods and the results of secondary or exploratory endpoints, which are typically described only in the study report. That information could help guide further research and clinical practice. ²² Many investigators, healthcare professionals and trial participants believe that sharing data from individual trials might help inform other patients with the same diseases and those who treat them, but in Japan the study data are mainly used in the application dossier and not otherwise. ²²

As of March 2019 the number of Japanese study reports publicly disclosed seemed certain to be increasing, because reports are often used for applications in several countries and regions. Other routes, such as trial registration websites and publications, were also being promoted in Japan. Some data may still remain undisclosed, perhaps for studies not used for an application and for drugs whose approval was not obtained or whose development was terminated. Writers on the Japanese landscape hoped then that disclosure would be promoted in Japan, to fulfil an ethical commitment to patients and researchers and to advance medical treatment. ²³

Because reports of Japanese studies might be used for marketing applications in other countries and regions, Japanese pharmaceutical companies that would like to expand their market internationally need to prepare clinical study reports that can be used for global applications and disclosure. ¹⁸

South Korea

Every interventional trial conducted in South Korea must be registered before subject enrolment on the official registry of the Ministry of Food and Drug Safety, a platform launched only in 2019. ²⁴ As of April 2023 it covered phase 0 to 4 interventional trials, registered after the ministry's approval, and observational studies did not have to be registered. ^{3, 4} Its results timetable is more clearly defined, as within one year of the last subject's last visit. ^{24, 7} Results are posted within the registry as a brief synoptic summary covering mainly the primary and key secondary endpoints, and the public can read them. ^{24, 3, 7} The registry is operated in Korean only. ^{24, 7}

An older registry, the Clinical Research Information Service, has been in use since 2010, is a primary registry in the WHO Registry Network, and is operated in both English and Korean. It may carry more comprehensive trial information and results than the ministry's registry does, but since the newer platform launched, registration and results posting on it are voluntary only. ^{25, 7}

As of 2023 it was not known whether results were also disclosed on any official Korean government website. ^{25, 7}

Taiwan

The Taiwan Clinical Trial Registry takes every trial conducted in the country, interventional and observational alike, registered before subject enrolment. ^{25, 26} Unlike the other three national registries, it serves only as a repository that lets the public search for trials they might be eligible to join, and no trial results are posted on it. ^{26, 7} As of April 2023 it covered phase 1 to 4 interventional trials and observational studies, registered after approval by Taiwan's regulator, and it is operated in Mandarin in traditional script. ^{3, 7}

Many trials conducted in Taiwan are also registered on ClinicalTrials.gov, but many of those do not provide results where the trial was not conducted in the US, and those that do mostly provide them as links to publications. ^{26, 7} The website of the Taiwan Food and Drug Administration provides package inserts for approved drugs and no other detailed results summary. ^{26, 7}

Across the four countries

All four countries follow ICH E3 for developing the clinical study report, mostly with their own additional requirements. ^{27, 3, 7} Disclosure of the report is not a requirement in any of the four. ^{27, 3, 7}

China requires specific title-page and appendix content in the report, and Japan requires a separate comparison of Japanese and non-Japanese data for Module 5.3.7. For multinational trials, Taiwan expects a summary of Taiwanese safety and efficacy data in an appendix, while for South Korea no additional requirement is given. ⁷

Results may also be published, but many may appear only in local journals in the country's own language. ²⁷

Trial regulations in these countries can change rapidly. ²⁸