In retrospectively looking over the changes in the clinical developmentlandscape in China during the past decade, or even the past five years, you can look at it two ways. On the one hand, the pace has been slow with change hard to recognize. However, on the other hand, the 2020 initiative, put forth by the Chinese government and the CFDA’s GCP harmonization quest with ROW (rest of the world), is beginning to make a difference. I see China somewhere in the middle.
Making the Breakthrough
There is no question that one of the biggest challenges of conducting clinical research in China are the research centers, which are for the most part hospitals. The ‘key’ principal investigator is only one of many researchers working on your trial, all with different levels of training and experience. And given the fact that they are likely working on other trials, their optimal execution and genuine dedication may be hard to realize. However there are activities that can be employed to help mitigate these gaps.
It can be said that early and intermittent training involvement with your clinical site staff can make a difference. This can be orchestrated through your investigator meetings, the CRO partners that you have engaged with, and sponsor face time. Investigator meetings that make a difference include concise content, regional KOL presentations and convenient logistics. Depending on your program particulars, CRO selection will have varying aspects to consider including therapeutic experience, regional and rural reach, and upfront engagement with their upper management.
If an organization has the bandwidth to conduct ‘road shows’ personally visiting your clinical sites, you will better understand their logistical infrastructure and barriers firsthand, and begin to forge a professional relationship which will provide genuine dividends through the course of the trial. Let’s take sponsor involvement one more step. The engagement of a clinical research coordinator (CRC) at your clinical research sites is not only a plus but a necessity. The fact that the clinical site staff is overseeing multiple trials and managing numerous patients at their site on a daily basis, CRCs are trained, employed by you and placed at the site to ensure your deliverables are executed with quality and on time. They are your eyes and ears at the site that can provide oversight and continuous improvement. Although not all of these elements may be practical for every organization, they do make a difference and shouldn’t be discounted.
How often do we read and hear about the level of quality and compliance that is being exercised during the course of a clinical trial, and what is being done about it? To begin with, many of these issues are inherent of the sheer size of the country and location of the sites. There are more than 1.5 billion people in China, and this population is spread out from dense metropolitan areas to rural communities that are worlds apart. When you target your investigative site network, you will divide them into tiers, (i.e. large University Hospital setting = Tier 1, and so on).
The level of support will vary, and will ultimately define the quality that is seen. For example, rural sites have a strong interest in becoming part of your trial, as this provides medical access and care (depending on the targeted patient population) to their local community, as well has their opportunity to take part in a trial. Providing CRC support would be required as they may not have trial experience and this ensure they have a constant presence of execution and compliance. Including additional patient transportation budget allocations in the site budgets will help with patient compliance, as transportation is an obstacle for many in a country so large and dependent on public transportation. And finally, assigning a ‘truly’ regional clinical trial monitor will also provide a close connection and support to the site.
When it comes to quality and standards, there is also the issue of the capacity of a site to take on your trial and the subsequent internal contracts and financial negotiation. Historically, the administrative components of a trial within hospital settings have been inconsistent and difficult for sponsors to ensure efficiency, accountability and appropriate budgeting. In late 2014, China’s health authority released the Administrative Measures for the Clinical Study Projects of Medical Institutions with the CFDA which essentially established a code of conduct for research behaviors for hospitals and physicians.
The first requirement was the establishment of rules and SOPs for administrating trials, which included the formation of a committee to develop and manage these elements. Secondly, the centralized financial management system was needed to direct funding to a dedicated hospital account as opposed to an individual department, thereby ensuring appropriate funding. Finally, a project-based approval system requires the applying physicians to submit relevant information to the hospital for approval. The approval would be directed to ensure the qualification of the applying clinical team, and scientific basis and experience of that particular department to conduct the project.
Whether you are a multinational pharmaceutical organization filing an imported drug registration, or a domestic application filed by companies that manufactures the drug locally in China, the regulatory timeframe for registration has always been an issue and a moving target. Historically it has taken 10-12 months for registration of new chemical entities (NCEs) and 12-18 months for biologics. One of the main reasons for this delay has been the lack of resources within the CDE. Just last year the agency hired additional resources to the review teams to provide some relief to the backlog of application. However, attrition of reviewers to the private sector continues to be a chronic problem. In 2015 the CFDA issued a circular to manufacturers of pending drug registration applications that covered both local and imported drugs, to conduct self-inspection and verification on their clinical trial data.
The pending drug registrants had one month to complete the self-inspection form along with other supporting documents and submit to the CFDA. Companies were allowed to voluntarily withdraw their application if they identified any inauthentic or incomplete data through their self-inspection. If companies completed the required documentation, the CFDA would then conduct further on-site inspections without notice. If inspection reports revealed false, inauthentic or incomplete data, the companies may be banned from filing any drug registration application with the CFDA for a period of three years. Of the 1,622 pending drug registration application, 80 percent of them were withdrawn. The backlog of pending application was relieved, though the need for companies to conduct more ongoing audits and understand their level of GCP compliance was understood.
China continues to hold promise, but what next?
Overall, the environment of clinical trial development in China has improved over the last five years. A big reason for this change is this government’s effort to demonstrate to multinational pharmaceutical organizations China’s commitment to more efficient regulatory pathways. It’s also more committed demonstrating transparency within the clinical site setting, as well as the harmonization of compliant guidelines to their investigator network.
They are listening and working closely with regulators from other countries, such as the US FDA and EMA. This becomes evident when you review the content and guidance, and see the similarities with outside regulatory bodies. In 2016, for instance, the US and China held their annual Joint Commission on Commerce and Trade where they agreed on not only new commitments, but also on the further implementation of past agreements. All of these movements are critically important and can be seen as success factors to future investment in China’s clinical development arena.