For Chinese-Foreign cooperation clinical trials，the HGRAC is an integral part of the initiation process, even if you are not planning to export any of the below-mentioned genetic materials or “export” of information related to such materials.
So, what is the HGRAC Process?
The Human Genetic Resources Administration of China (HGRAC) has actually been around since 1998, put in place to manage the export of genetic materials such as human organs, tissues, cells, blood specimens, preparations of any types or recombinant DNA constructs, which contain human genome, genes or gene products as well as information related to such genetic materials. And if I’m being honest with you, since CROs are not usually involved in the business of exporting (usually outsourced to a logistics vendor or handled by Sponsor), I had never even heard of the HGRAC prior 2014, it was never part of our day-to-day. But all that has changed for a few years already.
For a fully translated version of the official document, check out this link.
On June 10, 2019, the “Regulations of the People’s Republic of China on the Management of Human Genetic Resources” was issued and came into effect on July 01, 2019. The regulations are aimed at effectively protecting and using Chinese human genetic resources to preserve public health, national security and social interest.
The scope of human genetic resources management includes human genetic resource materials, genetic materials like organs, tissues, and cells containing genetic material such as the human genome, genes, human genetic resource information, and data generated using human genetic resource materials. The information types include clinical data, such as:
general laboratory information;
imaging data like B-mode, CT, MRI, X-ray, PET-CT;
biomarker data, such as diagnostic biomarkers monitoring biomarkers, pharmacodynamics / response biomarkers, predictive biomarkers, prognostic biomarkers, safety biomarkers, susceptibility / risk biomarkers;
genetic numbers / data like total genome sequencing, exome sequencing, target region sequencing, human mitochondrial sequencing, whole genome methylation sequencing (incl. RNA sequencing), transcriptome sequencing, single cell transcriptome sequencing, sequencing;
At the same time, activities like clinical diagnosis, treatment, blood collection and supply services, investigation and punishment of illegal crimes, stimulant testing, funerals and other activities involving human substances and related activities are excluded.
Improving research & Development
China encourages scientific research institutions, universities, medical institutions, and enterprises to make use our human genetic resources to carry out international cooperative scientific research and improve overall research and development capabilities. The premises being that:
there is no harm to China’s public health, national security and social public interests;
the two partners are Chinese and foreign units with a legal entity and have the foundation and ability to carry out related work;
the purpose and content of the cooperative research are clear and legal;
a reasonable duration and cooperative research plan;
the source of human genetic resources to be used is legal, and the type and quantity are consistent with the research content;
the research results of the ethical review of the respective countries (regions) of the two partners are clear, and there is a reasonable and clear beneficial distribution plan;
and, in order to obtain the approval of international cooperation, the legal entity established in China shall go through the application and approval procedures.
Note: for the process Chinese units should refer to Chinese scientific research institutions, universities, medical institutions, and enterprises. And foreign parties should refer to organizations established or actually controlled by foreign organizations and foreign organizations and individuals. (Among them are Hong Kong, Macao, and Taiwanese organizations and various other organizations, individuals established or actually controlled by reference to foreign units for management.)
Clinical Trial Requirements
In order to obtain marketing authorization for these innovative drugs and medical devices in China, the clinical trials are required to be carried out in the qualified clinical trial sites. Also, a filing system needs to be implemented for international cooperative trials that involve the human genetic resources materials. Provided that:
human genetic resources are collected, tested, analyzed, and the remaining sample processed in the clinical sites only; or
the human genetic resources involved are collected in the clinical sites, and the the third-party central laboratory are contracted by the trial sites for the analysis and the remaining processe.
If the third-party central laboratory is not contracted by the trial sites, the approval is required.
China Human Genetic Resources Management Office
Within 6 months after completing international cooperation activities, the two parties are required to submit a joint report on the results of their research to the science and technology administration department of the State Council.
In general, the China Human Genetic Resources Management Office is responsible for the administration, and adopts the approval system for the collection, preservation, international cooperation of scientific research, and the export of genetic resources materials of Chinese human genetic resources.
Specifically, the time frame for approval is- a decision on approval or disapproval within 20 working days from the date of application. If it is extended for another 10 working days for special reasons and is not approved, the reason is explained.
In order to help applicants to better understand and implement the relevant regulations, the Office of Human Genetic Resources organizes human genetic resource management training sessions every year, the most recent of which was in Shanghai on November 20, 2019.
Improving the process
The next step will be to speed up the issuance of documents like the detailed rules for implementation of regulations on the management of human genetic resources to further improve constantly optimize the process. Two examples:
For the renewal of the definition of foreign units, a ” was drafted to improve on the lack of corresponding punishment provisions for the acts and events of biotechnology misuse in the previous period. The draft clarifies the corresponding responsibilities and penalties and completes this legal gap.
Another illustration is the notice on simplifying the approval process for some administrative approval projects issued on January 7 this year. Its purpose is to further shorten the time of administrative examination and approval, which is applicable to (1) changes in international cooperation scientific research activities of human genetic resources and (2) the export of human genetic resource materials.
Practical implications regarding the HGRAC process and working with genetic materials in China
Who does the HGRAC Process effect?
Any Sponsor looking to conduct a clinical trial in China that is classed as a Wholly Foreign-Owned Enterprise (WFOE) or Foreign-Invested Enterprise (FIE) – regardless of the size of that investment – must adhere to this process. NB: ‘Foreign’ includes Hong Kong, Taiwan and Macao.
Even if a Sponsor is classed as a Local Entity (LE), if said Sponsor hires a CRO that is classed as a WFOE or FIE to conduct their clinical trial in China, they must too adhere to the HGRAC process.
And…even if a WFOE/FIE sets up a Joint Venture with an LE – or any other partnership for that matter – allowing said LE to conduct the clinical trial on their behalf, the HGRAC Process must still be adhered to as there will inevitably be data transfer between the two companies.
There really is no getting around it.
How does the HGRAC Process work?
The HGRAC Process is primarily conducted online, though, being China, there is still a lot of leg-work, signing and stamping to be done. Only once approval is obtained from a Site’s Ethics Committee (EC) may an online application be made. If your Study includes multiple Sites, each individual Sites’ EC approval must be obtained before they can go through the HGRAC Process. The good news is there is no need to wait until all Sites’ EC approvals are in place before you make the first application. Applications can be done in ‘batches.’
For example, if you have 10 Sites, and the first 3 Sites’ EC approvals have been obtained, you may take those 3 Sites through the HGRAC Process first. The other 7 can also be handled in the same fashion until all Sites have been taken through the process.
Who takes Sponsor through the HGRAC Process?
An online application must be led by a Site. Your CRO/SMO will guide them through the process accordingly.
NB: Not all Sites are willing to go through this process and will therefore need to be ‘batched’ under another Site’s application. A single Site may lead multiple ‘batches.’
How much does the HGRAC Process cost?
Monetary costs are negligible and vary between Sites but in general, each application will cost between 10,000 – 20,000 CNY (~1,500 – 3000 USD). The real cost is in the time lost due to this process…
How long does the HGRAC Process take?
Since conception (late 2014) timelines have fluctuated back and forth. The process has been revised multiple times resulting in different answers to this question at different points in time. As I’m writing this (May, 2018) current timelines are between 2-4 months. This is subject to change.
Once the HGRAC Process is complete, what then?
Once HGRAC approval is obtained, the Site(s) may enter in to Clinical Study Agreement(s) (CSA).
Note: Some Sites are willing to enter CSA negotiations before HGRAC approval is obtained but will not sign until approval is in place. This can help shave a few weeks off your timeline.
Very few Sites will sign a CSA before HGRAC approval is obtained but will usually insist there is a clause in the contract stating very clearly that it will not come in to effect until HGRAC approval is obtained.