China is the largest clinical trial market in Asia and 5th largest in the world. In recent years there was a remarkable increase in Phase I-III clinical trials. Understandably, there must be something significant happening, which brought this change.
There are recent changes in policies and regulations in China which have brought a lot of cheer from the global clinical research fraternity. It is important to understand them and see how they might be able to bring benefits to your clinical development program.
China offers a large population, rapid economic growth, and an increasing interest by the government to invest in research and development along with
- Homogenous population (92% Han Chinese)
- Over 750 global companies with research centers in China
- Regulatory framework increasingly emulating the FDA structure
- Government pledge to dedicate USD 18 billion to emerging biotechnologies in the latest five-year plan
- Over 260 million Chinese are estimated to suffer from chronic diseases and this number expected to triple by 2030.
- Hepatitis, Tuberculosis, and HIV/AIDS have been increasing rapidly. Neurodegenerative and Neuropsychiatric pharmaceutical markets are also likely to grow rapidly with only relatively recent medical recognition of CNS disorders in China. 
Highlights of Chinese clinical trial market
- An extremely dense of patients with an aging population
- A large and growing network of qualified hospitals to conduct clinical trials
- Skilled clinical trial and professional project leaders
- Support from the government for international partnerships
- Improved regulatory environment for clinical trials and new drug approvals
- 29,140 hospitals, and clinics.
- 1,04,400 independent outpatient clinics.
- An estimate of 2.2 billion hospital visits and 50 million inpatient visits every year. 
Chinese leading therapeutic areas and prevalence of the disease
When clinical trials in China were grouped by major therapeutic areas, oncology turned out to be the major therapeutic area for China. This became more dramatic after 2010, reaching nearly twice the number of trials starts compared to other therapeutic areas by 2013 and the trend continues on a rapid rise through 2018.
Now, the leading therapeutic areas in clinical trials are
- Gastrointestinal disease
- Vascular disease
- Respiratory and Lung disease
- Infectious disease. 
A total of 15,531 clinical trials were registered in clinicaltrials.gov with 5,651 ongoing trials in China. (Data as on 16-Oct-2019)
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However, despite many advantages, there are some challenges to overcome
- Large migrant populations, language, and cultural differences
- Uncontrolled use of traditional Chinese medicine
- Timely importation of study agents
- All the research sites are hospitals as a result, patients in clinical trials are treated in the same fashion as
- regular patients and patient records are amended regularly.
- Overcrowded hospitals, were a physician in a regular hospital sees about 400 patients a day.
- Heavy backlogs of drug applications and long regulatory review timelines
- Quality issues of local drugs 
The current clinical trial approval process in China
The clinical trial application review and approval or filing process is determined by the drug category in which an applicant chooses to register.
- New Drugs, Class I: Innovative new drugs that have never been marketed anywhere in the world
- New Drugs, Class II: Improved new drugs that have never been marketed anywhere in the world
- Generic Drugs, Class III: Generic drugs, with equivalent quality and efficacy to the originator’s drugs, which are marketed in other countries, but not yet in China
- Generic Drugs, Class IV: Generic drugs, with equivalent quality and efficacy to the originator’s drugs, that are already marketed in China
- Imported Drugs, Class V: Drugs that have been marketed in other countries, but not yet in China.
For Medical devices
- Class I medical devices do not require local clinical trials.
- Class II and Class III medical devices do require clinical trials unless they have exact predicates and/or are in the CFDA’s clinical trial exemption list.
China Food and Drug Administration (CFDA) requires the sponsor to obtain ethics committee (EC) approval for a clinical trial application.
If clinical trials are going to involve sampling, collection, and exportation of genetic resources (bio-sample and/or data), the sponsor is required to obtain OHGRA (Office of Human Genetic Resource Administration) approval as well. OHGRA is a governing authority under the Ministry of Science and Technology to review and approve such applications.
Some important aspects of clinical trial approval in China are as follows.
- EC approvals are the initial most steps in the approval process.
- CFDA’s approval of a clinical trial application is dependent upon obtaining proof of the EC’s approval.
- OHGRA approval process also requires the EC approval confirmation.
- Each EC has its required submission procedures, which can differ significantly regarding the application format and number of copies. However, with recent changes, regional/central EC approval should be recognized by other participating sites. [See more details below]
- Both the electronic files and a hard copy of the application in the Chinese language must be submitted to the CFDA Administrative Acceptance Service Center.
- Clinical trial applications are also considered to be drug registration applications.
- Overseas clinical trial sponsors must have an authorized representative in China to process their clinical trial application process.
- After 60 working days following IND/CTA submission, if no comments from CFDA/CDE, submission can be considered approved.
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Recent changes in clinical trial regulations
To improvise the clinical trial scenario and make china a global leader, the Chinese government has made several reforms in conducting trials and clinical trial approval processes. These changes are being considered as
- Reformist, and
Stages of changes
These major reforms were adopted in a stepwise manner across several years. It’s generally recognized to be in a period of last 10 years that changes started to appear. However, major significant changes are known to have been introduced in 3 stages recently.
Starting the year 2015, when the Chinese FDA introduced a self-inspection program for clinical data. This was followed by a priority review process in Feb 2016 to boost the clinical development program at par with the US & EU. These changes started to cleanse and improve the status of clinical data bringing more confidence in data integrity. Also, these changes started a much more clinical development program that only aided in the volume of clinical trials conducted in China.
2017 onwards, more reforms started appearing that were more influential, direct and brought significant changes. These included allowing phase I trials, easing import drug registration, along with new policies on clinical trial management, drug & medical device issues, and innovator rights. Further from Dec 2017, new reforms in OHGRA regulations were applicable, which impacted clinical trial processes significantly.
April 2018, CFDA has introduced another set of major changes. Recent government initiatives were announced at The Executive Meeting of the State Council on the 12th of April 2018.
Impact of recent changes on clinical trial scenario
Recent changes in clinical trial regulations and policies in China have impacted the scenario to bring more positivity. Here are some salient changes brought in and their impact on the clinical trial industry.
CFDA-related changes & impacts
- To reduce the backlog in drug review procedures to zero by 2018, it increased drug reviewers from 70 to 600 by 2016, with more hiring planned for 2018.
- For urgent clinical needs, Phase II data or interim analysis data can support NDA approval
- Overseas clinical trial data can be acceptable for China registration provided
- The data is reliable and authenticated (compliance with GCP)
- The data can assess the efficacy and safety for target indication
- There are no drug sensitivity to ethnic factors influencing the efficacy and safety
- The data meets China drug registration requirements
- An overseas applicant intending to conduct an international multi-center clinical trial in China can simultaneously conduct a Phase I clinical trial inside and outside China, which essentially means foreign Phase I clinical trial data can be used for the approval application of imported drugs.
- An orphan drug may get a trial exemption or patient number reduced.
- Overseas licensed orphan drugs may get NDA approval directly with conditions (PMR will be required).
- The foreign company is allowed to conduct China standalone study for innovation drug without CPP
- To crack down falsifying data, CFDA launched a self-inspection program in 2015, for clinical data. This required applicants, CRO’s and clinical sites to self-inspect 1,622 registration applications pending for approval and uncovered inauthentic and incomplete data with accompanying disapproval or investigations for appropriate cases by CFDA. CFDA reported that around 90 percent of the 1,622 applications have been withdrawn by applicants or rejected by CFDA.
Sites-related changes & impact
- CFDA will no longer accredit clinical sites with Good clinical practice (GCP). However, CFDA retains responsibility for site inspections. Most importantly, accreditation of clinical trial institutions will be subject to record-filing.
- This means all qualified hospitals may become clinical sites. Investigators will be more motivated for trials.
- The sponsor/CRO will have a much bigger site pool to select sites for their clinical trials since more sites will be able to conduct trials.
- Increased competition among sites will bring better data quality. New sites will need to have more GCP training and attention from sponsor/CRO to ensure data quality and integrity.
- Clinical trial institutions and investigators will receive support in conducting clinical trials.
- This is expected to bring positive changes in patient recruitment & data quality commitment from sites/investigators.
EC-related changes & impact
- Each province may set up a regional EC to guide EC activities and monitor trials and investigators in the region.
- Centralized EC/IRB will help in site start-up.
- For a multi-center trial, EC approval by the lead site, other sites can accept the lead site’s approval without repeating review.
- The sponsor / CRO will be able to avoid multiple EC submissions and expedite study start-up timelines.
OHGRA-related changes & impact
(Office of China Human Genetic Resource Administration) approval
- A new OHGRA review process has been set up for Phase I, Phase II, Phase III and BE studies. Phase IV, explorative study, and post-marketing research will continue to use the old process.
- The sponsor/CRO will be encouraged to use the leading site for a one-time OHGRA application for a multi-center trial.
- This will help save time in getting approvals for all sites.
- Until the leading site gets approval and submits its stamped commitment letter / EC approval / ICF to OHGRA, other sites can’t initiate the study.
- In case of any change in important aspects such as site, sponsor, study purpose, contents, term, labs, etc. during the clinical trial, the OHGRA approval on these changes is required before implementing these changes.
Having secured all necessary approval, the sponsor/CRO is authorized to initiate the trial as per global GCP norms and processes. Some additional points to be considered at this stage are
- While not an official regulatory requirement, all clinical trials approved may be registered in the Chinese Clinical Trial Registry (ChiCTR).
- It’s a mandate that the sponsor receives written confirmation of EC review and approval of the protocol before the trial’s commencement.
- Applicants should submit the research results and next-phase clinical trial protocol after completing Phase I and II studies. If there are no safety issues, the applicants can move into the next phase of the trial after communicating with CFDA’s CDE.
CFDA requires a safety reporting process for all clinical trials.
- Companies must complete a clinical evaluation report, which should include the collection of all clinical data obtained and the analysis and results of the data.
- Companies must also report any clinical risks and adverse events that occur during the clinical trials, both normal and serious (permanent injury or death) as well as suggestions for improvement and corrective actions.
- The report must be approved by all relevant Chinese authorities and should then be included in the product registration application. 
The sponsor of the trial must arrange insurance for the trial subjects to cover potential study-related losses. 
The future of clinical trials in China
It’s exciting to see, understandably, the second-largest clinical trial market to adopt such new changes. This sets the future expectations as very optimistic.
- Government reforms and CFDA regulatory flexibility is setting China on an unprecedented course to become a formidable player.
- The CFDA continues to reform and improve its regulations, showing a great approach for innovation.
- The number of clinical trials in China has been trending upward by each year and is expected to grow further with these changes.
- Its market value is forecasted to reach $200bn by 2020.[8}
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