Richard Irons

Driven by market forces to increase productivity and reduce the time necessary to bring new drugs to market, the global pharmaceutical industry has turned increasingly to Asia as a venue for research and development. In the last five years, China has rapidly become a favored location for outsourcing of clinical research due to the availability of a large pool of treatment-naïve patients and comparatively lower costs. 

Molecular pathology studies conducted in China to Western standards are a much less common but necessary component to pharmaceutical R&D. There are significant barriers to the export of clinical samples from China that require development of sophisticated local capabilities.  

In addition, drugs in development for the Chinese market may require new research and diagnostic characterization because some diseases in China present different features and prevalence than the same diseases in the West. Reanalysis of archival or outdated material may result in significant error and can lead to mistaken perceptions with respect to certain diseases in China. 

This is particularly the case for oncology and hematology studies. Using WHO (2001) criteria for diagnosis of hematopoietic disorders, our laboratory has identified a number of differences of therapeutic significance over the last four years

Table 1. Different patterns and prevalance of diseases in China compared to the West.			

The challenges and advantages to conducting research in China is well known, and the number of sites currently meeting Western standards, while increasing, is still comparatively low.

Through our own experience conducting research and epidemiology studies, we learned the common wisdom on the difficulties needs updating. Although much of the research coming from China in recent years has been superficial in quality, it is possible to conduct rigorous preclinical molecular-based biomedical research there with the right approach. Knowledge and understanding of the Chinese medical system, differing cultural norms, and Chinese organizational and business paradigms are required.  

Recruiting and training personnel is the foremost challenge to conducting research in China. 

The Chinese are highly educated and capable but have little familiarity with Western expectations or standards. To achieve GCP and cost effectiveness, we found it necessary to provide not only training but also continuous monitoring and guidance. Communicating Western organizational values and priorities was a challenge. 

Chinese medical training differs from the Western system in important aspects. Western educational institutions rely on the Socratic method of learning, in which discussion, dissent, and questioning play a major role. Chinese students are among the best in the world but in their Confucianism influenced educational system, learning is predominantly achieved through lecturing, listening, and memorization.

Often mischaracterized as rote learning, the system does not encourage Chinese students to solve problems and take responsibility for making decisions. As a result, exercising individual initiative, taking responsibility, and volunteering opinions are difficult behaviors for Chinese medical and research staff despite their education and competencies. 

Acquiring staff that possessed outstanding research capabilities created a good foundation for our laboratory, but ensuring uniform execution was our ultimate goal. 

Our first step was to write SOPs and protocols, as required for valid research in any venue. Deft translations into Chinese were required, as literal translations from English are sometimes not informative. The next step was to create and institute an additional system of supervision, monitoring, and verification to ensure compliance at every level in our program, from screening and triage to diagnosis. 

The system we developed utilizes a bilingual computerized database that tracks every action. Our protocols and the requirement that personnel enter findings in the computer system and respond according to its instructions  function together as a surrogate for decision making skills that may be underdeveloped in staff. It's important to note that just because Chinese personnel adopt a requested behavior doesn't mean they have adopted the Western value. Respect and trust in leadership coupled with verification is required to ensure adherence to the standards required. 

We assumed the responsibility for monitoring compliance of all involved in the studies, including staff at over 20 participating hospitals where adherence to protocols and quality control were more problematic. Hospital administration and health care delivery are not homogeneous in China; each facility has differing capabilities and a unique way of doing things. The importance of Western requirements, such as chain of custody and informed consent, were difficult to explain to the physicians as well as the patients. 

To ensure compliance with research protocols, our laboratory personnel participated at every critical step including interviewing patients, collecting samples, and transporting clinical materials from the hospitals to the laboratory. 

Traditionally, Chinese research and academia have been separated from the practice of medicine. The Western model of the university-based biomedical research center in which basic research, academic medicine, and health care delivery are fully integrated in a single institution is uncommon. Research and preclinical medical evaluation have been the pervue of Chinese universities, while clinical training and health care are provided in individual hospital settings. It was our task to integrate the research and health care systems and establish an effective clinical trial process. 

We experienced additional differences in medical systems, particularly the lack of uniform diagnostic standards in Chinese medicine. This is significant in the fields of oncology and hematology.

  Initially, we feared resistance to the WHO (2001) diagnostic classification criteria. We rapidly discovered, however, like physicians everywhere, Chinese doctors are willing to accept change that improves the prognosis and outcome for their patients (see Table 2).  

Table 2. Direct Benefit of using WHO Diagnostic Criteria			

Cultural differences in medical practice are important and may affect research design. For example, in China, access to health care often depends on a patient's ability to pay on a daily basis, and tracking outpatients can be difficult. This presents challenges for investigators who seek participation in clinical studies with long-term therapies and with requirements for patient follow-up. 

Chinese society is a network-based society.

  Success in the negotiation, design, and conduct of research requires an understanding of how organizations and individuals behave in a culture many Westerners find confusing. The time it takes to learn how to navigate regulatory, government, clinical, and business systems is a vital investment. Developing long-term relationships and well-founded networks are important preparations for any negotiations. Early discussions often center on getting to know one another, and contracts and agreements are usually achieved on a Chinese timetable that does not adhere to Western time-centered objectives. 

In the Chinese process, a signed contract may represent a midpoint in continuing discussions. Postcontractual negotiations inevitably occur. Resolving and framing issues so the principles of both systems are satisfied will depend upon understanding the differences in Chinese and Western conflict resolution styles and management systems. 

Language difficulties can pose additional problems. Producing literally identical documents in Chinese and English may be impossible, except at a superficial level. 

A literal translation of a form, such as one documenting informed consent, may not be informative to the signer and can create confusion because it does not accommodate cultural norms. Creating functionally identical versions of a contract might present ethical and regulatory issues due to differences in local interpretation. Finding a way to accommodate and harmonize the two systems is a challenge that requires great flexibility and creativity. 

The difficulties overcoming these complex logistical challenges explain why present research and development efforts in China have focused heavily on the development and not on the research. In our experience, the advantages of conducting molecular-based biomedical research in China outweigh the difficulties, once they have been addressed. 

We established our clinical research lab in Shanghai at Fudan University in 1999 and began diagnosing cases of hematopoietic disorders in 2003. In characterizing 3000 cases, we found that even when the incidence of a specific disease in China is not elevated relative to the West, the large population provides enough patients to satisfy most study requirements without resorting to multiple lab participation. 

Furthermore, though conducting molecular-based research to Western standards in China may not offer a reduced cost per patient, significant cost savings are possible in the short time frame required for adequate case accrual. 

We have shown molecular diagnostics and rigorous preclinical research are possible in China. They can be accomplished by marrying the complimentary skills and resources of a Western research model with the Chinese medical system to create an environment where both sides are comfortable with expectations and agreements. 

, PhD, is director of the Fudan-Cinpathogen Clinical and Molecular Research Center and professor of pathology at Fudan University, professor emeritus at the University of Colorado, and president and chief executive officer of Cinpathogen, Inc., email: 

1. R. Irons et al., "Prevalence of MDS subtypes in Shanghai China: A Comparison of the WHO and French American British Classifications," 

2. J. Ryder et al., "Aggressive Natural Killer Cell Leukemia: Report of a Chinese Series and Review of the Literature,"

3. L. Kong, "Clinical Trial Opportunities in China," 

http://www.appliedclinicaltrialsonline.com

4. D. Watkins, "Learning and Teaching: A Cross Cultural Perspective," 

http://www.progettodeslo.it/course/story/readings/Learning_and_Teaching_a_cross_cultural_perspective-ABSTRACT.pdf

5. L. Bao et al, "Prospective study of 174 de novo acute myelogenous leukemias according to the WHO classification: subtypes, cytogenetic features and FLT3 mutations," European J of Haematology, (77), 35-45 (2006). 

6. S.A. Gross et al, "Lymphoid neoplasms in Shanghai, China: Relative frequency of subtypes of NHL diagnosed according to the WHO classification," Proc. American Assoc. for Cancer (2006). 

7. L. Yang et al., "Statistics on Cancer in China: Cancer Registration in 2002," 

 (2W Publishing, Bretton, Peterborough, UK, 2006). 

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