Insider Analysis From Fountain Medical Development: Clinical Development in China - Current Status And Future Trends

By Joanne Jiang, Ph.D, Fountain Medical Development Ltd.

Soaring drug development costs - coupled with slim prospects for obtaining blockbuster products - have driven pharmaceutical companies to look for cost-reduction strategies in nearly every area of their businesses. One of the leading initiatives for cost reduction is the mobilization of more clinical trials to Asia and Latin America.

In the current environment, China has become an increasingly attractive place to host global-standard clinical studies. Not only does China provide the vast number of patients suitable for a variety of therapeutic areas pursued by global pharmaceutical companies and medium- and small-scale biotechnology firms, but it also provides the fastest-growing pharmaceutical market worldwide. This scenario allows ample commercial return stemming from successful registration in China using Chinese clinical study results.

Benefits Of Conducting Research In China

Opening Chinese study sites is likely the best insurance policy for the timely completion of ongoing or planned clinical studies for almost all drug development programs. Indeed, timeline delays have been a major issue for many drug development programs. Statistics have demonstrated that more than 70 percent of trials drag beyond the expected completion deadline. "Last patient enrolled" becomes an ever-demanding milestone for many clinical study teams to reach.

Incorporating China into a company's global development program often allows the project team to boost patient enrollment mid-way into the study, enabling enrollment to ramp up quickly and achieve recruitment goals in advance of the expected timeline. This time savings frees up additional resources for both the clinical team and the development team. In addition, an advanced development timeline usually leads to faster registration, which translates into a highly significant commercial advantage. For example, a blockbuster product entering the market one day earlier than planned can result in hundreds of thousands of dollars in sales worldwide.

Acceptance of Chinese clinical study data has been demonstrated by both verbal communications and actions taken by the U.S. FDA, the European Medicines Agency and Japanese regulatory agencies. There have been seven audits performed in trial sites in seven different cities throughout China by the FDA since 1999, which yielded no major citations. The FDA also has granted label changes based on a large outcome study solely performed in China.

The EMEA repeatedly has accepted Phase II and Phase III studies with Chinese patients as a significant component of the studies. Moreover, Japan's regulatory agency recently has acknowledged a willingness to accept data generated from clinical studies in China (PharmAsia News, April 17, 2008).

Finding Right Chinese Partner Is Key

Naturally, driven by increasing market demand and supported by a positive regulatory landscape, moving clinical studies to China already is occurring. To date, most of the Western-standard clinical studies are conducted by contract research organizations and Chinese subsidiaries of global biotech or pharmaceutical companies. One important aspect of making these studies successful is identifying the right partner in China. For a typical clinical trial, sponsors usually work through a Chinese CRO or an internal clinical operational group in China.

In either case, it is important for a pharmaceutical or biotechnology company to establish a well-thought out communication plan. This plan not only must support communication within the operational team, but also has to adequately manage communications with investigators and the clinical research associates. For companies that do not have a division in China, choosing the right CRO to implement projects is the most important decision.

In terms of evaluating different CROs in China, sponsors often are impressed by lower-price quotations and sometimes overly positive promises, which can be both misleading and inaccurate. To avoid common CRO selection pitfalls, sponsors should interview key personnel on the project team, such as the project manager and the lead CRA, as well as the data manager.

Questions focusing on the trial's details usually can identify potential weaknesses early in the interview process. In addition, the communication and working style of these key team members are very important. CRO staff should be able to communicate effectively, using English, in oral and written forms. They also should value and practice basic teamwork tenets, such as honesty, openness, the ability to work independently and taking responsibility for their deliverables.

One unique aspect of conducting clinical studies in China is that CRAs spend more hours at the investigator sites compared to time spent for studies performed in the United States or the European Union. Because the clinical research experience levels are different among the Chinese investigators, it is critical that CRAs set appropriate levels of monitoring for each site. Prior to study initiation, CRAs need to properly gauge the level of experience at each particular site and work with the investigator and site coordinator to address all details required by the protocol during initiation and subsequent study visits.

Although additional time is spent at each study site, it is worth noting that these extra hours rarely result in higher cost of clinical studies, because the number of sites required in China is much lower than those needed in the United States. This decrease in sites in China is attributed to the number of patients enrolled per site - typically 10 to 20 times higher than those in the United States. China has a highly concentrated hospital system in metropolitan areas and Chinese hospitals are usually large, with 1,500 to 3,000 beds per hospital. Due to a lower number of sites and a robust patient enrollment rate, it is highly feasible for each CRA to focus on two-to-three key sites in the same city for a particular study. This allows more consistency in monitoring and controlling study implementation processes.

Clinical Trial Offerings In China To Increase

As China hosts more and more global-standard clinical studies, it is not hard to imagine that the scope of supporting services also will expand. For example, global central laboratories have begun to put their footprints in China by opening subsidiaries in cities like Beijing and Shanghai. Related pharmacogenomic as well as biomarker analytical capabilities also are being established in China. Leading CROs in China already have expanded into this area and are expediting blood sample analysis by conducting assays locally during and after clinical studies.

In the near future, the central lab business will grow tremendously as a result of both an increasing number of trials and a lack of alternatives. It is a well-known fact that the Chinese government purposefully restricts shipping blood samples outside of China due to concerns over leaked genetic information. This makes it necessary to analyze blood samples for Chinese research subjects locally.

Challenges To Consider

In the midst of a booming clinical studies surge in China, there are a few challenges that need to be overcome to improve the overall environment for clinical study there. One of the biggest challenges is the investigational new drug review timeline. Currently, it takes at least eight-to-10 months to open an IND in China. China's State FDA is rolling out a "green-channel" concept, which could accelerate the review timeline to six-to-eight months. Review priorities will be given to compounds or biologicals that are novel, first-in-class and address significant, unmet medical needs in China through their commercialization.

In light of the long regulatory approval time, to fully benefit from the excellent patient enrollment in China it is critically important to have a well-planned global development program that includes China early in the process. If China is only an afterthought or a last resort due to a delayed trial, the long IND review timeline is likely to undermine the clear benefit of high Chinese trial enrollment rates to the global development program.

Many study sites in Beijing and Shanghai host at least four ongoing clinical studies. The majority of the Chinese divisions of global pharma companies also are located in these two cities. As a result of this concentration, hospitals in these areas were the first to be accessed by the Chinese divisions of the top 10 players in the industry.

Although experienced investigators may be occupied with several therapeutic areas in the top hospitals in first-tier cities, companies must recognize that there are numerous SFDA-certified hospitals in second-tier cities that are willing to cooperate with sponsors to conduct early- or late-phase clinical trials. These investigators already have passed good clinical practice training and have been audited by the SFDA; they are very cooperative, eager to learn and willing to follow procedures. With the proper training and monitoring, these sites can and will deliver the same quality of clinical trial conduct as provided by the top sites in Beijing or Shanghai.

In summary, China has proven to be capable of delivering high-quality clinical studies with moderate cost; increasingly supportive and associated services for clinical development also are being established in China. As such, these factors are driving most of the top 20 pharmaceutical and biotech companies worldwide to incorporate China into their routine drug development programs.

However, there are new challenges to face as more clinical studies make their way into China. Improving IND review timelines and clinical study expertise at more clinical trial sites, especially those in secondary cities, are two of the most important priorities to ensure China's continued success and allow it to be the preferred country for clinical research.

Dr. Joanne Jiang, Ph.D., MBA, is the co-founder of Fountain Medical Development, a contract research organization offering a full range of ICH GCP-compliant clinical research services in China for multinational clients. In the pharmaceutical industry for 12 years, Dr. Jiang started her career in the preclinical pharmacology area at Bayer Pharmaceutical and at Eli Lilly, working as research scientist, lab head and project leader, and furthered her expertise in drug development and project management as a global project manager. She has worked for Aventis and Daiichi Sankyo, managing drug development and life cycle management projects, encompassing preclinical to Phase IV activities, with a particular focus on clinical trial planning and management, and the integration of marketing plans and regulatory strategy to enable optimal trial design. Dr. Jiang can be reached at [email protected]