Balancing the science and art of clinical trials; the magic ingredient to running successful trials with the Chinese population

12th August 2015 (Last Updated July 16th, 2018 10:31)

Kai Yew, Syncore Bio, discusses his experience running trials in China

Balancing the science and art of clinical trials; the magic ingredient to running successful trials with the Chinese population

Why China?

The USA and EU execute 78.5% of all global clinical trials, while China runs only 9.4%, despite the fact that China possesses charming attractions; a fraction of expense per patient, less delay in recruitment, highly skilled researchers and clinicians, and huge treatment-naive patient pools.

China Image 1

For good and bad, the Chinese population represents about one-fifth of the world population, including 1.35 billion in China and 50 million overseas, and this population is aging rapidly. All of the above incentivizes global drug companies to swarm to China; to take advantage of the largest patient pool for the former reason, and to increase recruitment in aging degeneration diseases for the latter. Besides, the cost of clinical trials in Asia is 30-50% lower than in USA/EU . From a clinical trial perspective, this posts huge commercial interests and opportunities in this $51 billion a yea global trial market. As an industry, we look to run trials in China with this knowledge, don't we? Here come the unintuitive trends, or you may call it the "Art."

Higher upfront cost means lower overall spend
In 2012, Taiwan and Hong Kong dropped sharply in the number of newly registered clinical trials, while China increased by almost 30%. Nevertheless, many experts may suggest trials to include Singapore, Hong Kong, or Taiwan along with many trial sites within Chinese society, in order to meet the different approval schedules. This increases the complexity of the supply chain significantly. The medical data and knowledge levels in these regions tend to be more trustworthy than those obtained from China, especially if the data is not collected from the first-tier cities like Shanghai or Beijing. However, supply standards required in China may not be the same for sites elsewhere; meaning that in the end there may be a need for two supply chains; one to fulfill requirements for CFDA (used to go by SFDA), and the other one to fulfill the requirements of regulatory bodies overseas. Some trial sponsors may choose to adopt stricter standards across the board to guarantee compliance at all locations, and would therefore spend more time and money on supply from the beginning. Others may choose to passively (and economically) cooperate with the government officials in providing sufficient documentations based on requirements in each region. In the end (through lessons learned the hard way) the former strategy saves more time and cost in the long-run.

These impressions are certainly varied from speciality to speciality, for example oncology trials may be more mature and less varied than depressive disorder trials in terms of requirements. CROs who can advise based on this having done their prep and making appropriate suggestions should earn trust of the trial sponsor in the long run.

Patience is a virtue
In Australia, it takes about 3-4 months to achieve ethical and regulatory clearance, but it may take 6 times this to gain these approvals in China. Getting approval in China is a lengthy and complex process, and surprisingly, working closely with CFDA or the Center of Drug Evaluation (CDE) does not minimize the delay. This does not discourage drug developers from working closely with the CFDA, however it is advisable to prepare for the worst-case scenario. A frustrating factor to trial sponsors here is the fact that an 'inside connection' is almost certainly an advantage. Perhaps the person is a retired CFDA official, or the relative to a current official, or simply "knows someone important". There is evidence to suggest that waiting times could be shortened in these circumstances. Trial sponsors should be cautious with these assumptions, however.

Outside of regulatory approvals, operational activities can take time as well. China is famous for the lack of national infrastructure to support clinical research. For example, common issues include support for trials which require substantial commuting, enforcement of patent protection, and bureaucracy in general. Additionally, data is often registered in Chinese and must be translated into English before it can be pooled by e-systems and analyzed. In some unlucky cases where materials are in shortage and there is nowhere to source globally, be prepared to expect six months or more in delay.

A conservative estimation is a better strategy; plan for the lengthy battle, reallocate resources to where they are most valuable, and have a strong financial plan which can sustain twice the proposed length of the trial. This applies to almost everyone: sponsors, suppliers, physicians and researchers.

Building your own, intimate circle of trust
Running trials in China has brought us a lot of surprises. One of the big surprises occurred when trying to source an experienced Ophthalmologist in China for a phase II trial. I went to three trial-savvy and experienced ophthalmologists from Korea and Taiwan for the recommendation, only to receive a blank look and significant hesitation. There are certainly great doctors to work with in China, some quite famous academically, however this experience revealed how hard it is to build a circle of trust in the region. Cultural experience has demonstrated that inside the circle, the trust is strong between trial sponsors, CROs and doctors/researchers/medical centres who previously worked together, where new additions to the circle are rare and considered. Once the circle of trust is formed, those with limited knowledge and experiences in the region may be wise to keep their circle as tight as possible.

Another big surprise to us is in the fact that CRO services may not be preferred in the current atmosphere in China. For one trial we worked with a respected medical centre in the region and talked about the process of selecting a CRO to work with (our usual practice). The idea was quickly rejected, the centre wanted to instead adapt itself to perform the role of trial coordinator and gatekeeper. The medical centre stated "We follow US FDA standard to monitor the trial, and the quality is better than with a CRO". I could not help thinking that this was a business strategic decision which was fuelled by the opportunity to make money. However, a more critical reason behind this which we later discovered highlighted bad experiences the centre has had with a previous CRO. The CRO had gone through a merger during the trial, resulting in financial difficulty and discontinuation of promised services, to the detriment of the trial.

Even if everything is in place and in good hands, the deep-rooted Chinese culture tends to shop around in the beginning for trial services and suppliers, and price matching is not an uncommon approach in negotiation. After a few rounds of negotiations have passed, business is agreed and mutual trust is built, it comes the challenge of how to maintain the quality of this partnership. In China, there is always someone knocking on the door claiming to provide better yet cheaper services and products. Therefore, no matter how trustworthy you are it is important to be prepared mentally and commercially to lose a few long-term clients. From what I heard and experienced, those partners tend to come back in the middle or after bad tryouts. In some instances where partnerships have significant failures you would receive a call in the middle of the night to place a rush order of services or products. It therefore makes sense to keep positive, professional relationships across the board.

Balancing the science and art of clinical trials
The lucrative market in China comes with challenges. This demonstrates the exact beauty of balancing the science and art of running clinical trials within the Chinese population. China provides many attractions to big and small trial sponsors to plan and execute their trials. Though increased up-front spend in time, money and resource may seem hard to swallow, it is most likely to save sponsors a lot of effort in the long run. Suppliers are in a position to provide this intelligence and should be there to support trial sponsors. In the meantime, my advice would be to start to build your own, intimate circle of trust and keep it as tight as possible. With some luck, these considerations could be a good leap to successful trials in China.

References:

Clinicaltrials.gov, June, 2014
Theorem, 2012.
Economist. Jul 26th 2014