Taiwan s Strategy in the Establishment of Clinical Trial Infrastructure Chei-Hsiang Chen, Ph. D. Director, Biotechnology and Pharmaceutical Industries Program Office, Ministry of Economic Affairs, Taiwan I. Introduction In order to achieve the rapid growth and development of the biotechnology and pharmaceutical industries in Taiwan, to enter and compete in the global markets, it is necessary to improve the quality and quantity of new pharmaceutical products approval system through combined wisdom and efforts of the government, the industry and the general public. In addition, as the pharmaceutical products affect the public health greatly, advanced nations in the world all have considered and devoted a great deal of human and monetary resources to establish a regulatory agency with professional and technical proficiency, and to strengthen the function and efficiency of the drug review and approval system as a national top priority.. The Needs for the Establishment of Clinical Trial Infrastructure in Taiwan Since nearly a half of the global population is in Asia, Taiwan has a vital role in the future of global clinical trial business for pharmaceutical development. Taiwan also has an own need for the clinical trial business due to the facts that: (1) the promotion of public health via global new drug development and registration; (2) the possibility of ethnic sensitivity in drug response; (3) the requirement to meet the local registration and marketing; (4) Taiwan clinical sites can conduct clinical trials with good quality, efficiency and less cost, and (5) a solution for Taiwan to the Partnership in Harmonization with ICH. The total number of investigational new drug (IND) and multinational clinical trial applications in Taiwan from 2001 to 2005 are listed in Table 1 and 2. 1205
Table 1. 2001-2005 IND Applications in Taiwan Clinical trial Year I I IV Total 2001 7 25 107 8 147 2002 4 26 101 12 143 2003 7 28 103 5 143 2004 15 29 67 3 114 2005 9 48 94 5 156 Source: Bureau of Pharmaceutical Affairs, Department of Health, Taiwan 2006 Table 2. 2001-2005 Multinational Clinical Applications in Taiwan Year I Clinical trial Total In order to ensure the safety of pharmaceutical usage of the consumers, to promote public health and welfare, and to develop the nation s biotechnology and pharmaceutical industries, the government of Taiwan amended Executive Yuan s Promotion Program for Biotechnology Industry in 1997 and directed the Department of Health (DOH) to establish a specific organization for the evaluation of new drugs. Furthermore, in order to establish a regulatory system to encourage pharmaceutical research and development, to assure protection for discoveries and intellectual property, to improve the quality of domestic clinical trials and to ensure drug safety, DOH made revision in 1998 to the existing regulations for safety monitoring of new drugs. In accordance with the existing regulations announced on July 7, 1993 for a new drug application (NDA) in Taiwan, it is mandatory to conduct a domestic clinical trial with a minimum of 40 human subjects with the submission of relevant documents. However, a sample size of 40 as required would be difficult to demonstrate significant importance statistically or clinically. The study design of the local clinical trial usually only repeated the study that has been conducted in other countries but in a smaller sample size. In addition, the study has not been designed based upon the medical situation in Taiwan. Therefore, the existing requirements for clinical trials were amended to include Bridging Study provisions, which became effective on January 1, 2001. Bridging study can generate data on pharmacokinetics/pharmaco- dynamics, efficacy, safety and dosage in Taiwanese populations, thus enabling the extrapolation of foreign clinical trial data to relevant domestic population. Conduct necessary meaningful clinical study based upon differences of diseases, ethnic difference and the results of study. A I 2001 1 14 54 5 74 2002 0 12 52 7 71 2003 0 8 46 2 56 2004 3 16 53 0 72 2005 3 22 58 1 84 Source: Center for Drug Evaluation, Taiwan, 2006 IV 1206
dosage adjustment can be done for the local study. Bridging study can reduce clinical trial duplication and avoid wasting resources for drug research and development. Later, the evaluation and verification of Bridging Study Data Package shall be conducted in accordance with ICH E5 Guidance. Compared the clinical trial system with other Asia Pacific countries, Taiwan has the advantages of: (1) good regulatory infrastructure upto ICH level; (2) well GCP-trained clinical professionals (3) experienced CROs; (4) adequate patient pool; (5) established General Clinical research center (6) IRB/Joint IRB- simple process of application and review, and (7) establishment of multi-center research, such as Taiwan Cooperative Oncology Group (TCOG). Note: In Taiwan, Institutional Review Board (IRB) is formed in accordance with rules governing good clinical trial practices (GCP) as promulgated by the Department of Health in 1997. It is stipulated that the board shall consist of a certain number of non-medical practitioners, and one third of the board members shall be recruited from experts in legal, social and theological fields. The application and approval process of clinical trial in Taiwan is shown in Fig. 1. Sponsor CRO Hospitals Clinical trial application IRB/J-IRB CDE technical review Review Committee recommendation BPA/DO Advisory Board Fig. 1: Application and Approval Process of Clinical Trial in Taiwan BPA: Bureau of Pharmaceutical Affairs; DOH: Department of Heath CDE: Center for Drug Evaluation; IRB: Institutional Review Board J-IRB: Jointed Institutional Review Board I. Center for Drug Evaluation (CDE) To balance between consumer protection and industry development, and to bypass the constraint of the administrative system and solve the problem of lack of professional reviewers for drug evaluation, the Department of Health (DOH) founded the Center for Drug Evaluation (CDE) as a non-governmental and non-profit organization on July 13, 1998. The Center would be entrusted by the Bureau of Pharmaceutical Affairs (BPA) to assist in the technical review of new drugs and new biological products, establish regulatory requirements that comply with international standards, provide consultations on plans of pertinent clinical trials for the purpose of new drug application and other matters related to new drug registration. 1207
1. Mission of CDE The mission of CDE is: (1) to establish a transparent, efficient and responsive system for regulatory applications in Taiwan; (2) to facilitate Taiwan s participation in global new drug development process by establishing guidelines in line with ICH requirements for clinical protocol and drug approvals and (3) to lay a leading role in building up regulatory expertise with educational efforts as well as examining the need for special regulatory requirements for the region. 2. Principal Functions of CDE The principal functions of CDE are: (1) to help BPA to set up the review system and enhance the ability to review new drug applications; (2) to support DOH to establish a mechanism in drafting guidelines; (3) to provide consultation service to local biotechnology and pharmaceutical industries and (4) to upgrade Taiwan s ability to review the new drug applications of products developed domestically and those have not been approved in any other advanced countries. The function of CDE is shown in Fig. 2. Function of CDE Pre - IND IND ( I-I) NDA Post - Marketing 1. New Drug Development Consultation 2. Gene transfer study 3. Regulatory Consultation 4. Herbal medicine development Regulatory Consultation 1. Clinical trial Protocol Review 2. Bridging Study Evaluation 3. Clinical Trial Waiving 4. Clinical trial Inspection 5. Clinical trial adverse events evaluation 1. New Drug Review 2. Regulatory Consultation 1. Post-marketing adverse drug reaction evaluation 2. Legitimate Drug Usage and Drug Safety 6. Regulatory Consultation Fig. 2: The Function of Center for Drug evaluation (CDE), Taiwan Since CDE is a non-governmental and non-profit organization, therefore, communication with worldwide regulatory agencies through active participation in international convention is necessary. In order to keep path with current international trends, CDE coordinates with DOH to communicate and exchange experiences with international experts. In addition, other major functions of CDE include introduction of Taiwan s progress to international communities and further strengthen international cooperation. In recent years, through the development of biotechnology and pharmaceutical industries, the related research has been enthusiastically conducted. The government devotes many resources and efforts to upgrading the pharmaceutical industry and the 1208
development of emerging biotechnology industry. Because of these reasons, CDE began to plan and set up procedures to review biotechnology products. In the era of globalization, the goal of the development of biotechnology industry is to target global marketing, The development of biotechnology industry, in addition to the local guidelines, as well as the quality, efficacy and, safety, has to meet the international standard. Traditional Chinese medicine is a very important natural resource in Taiwan. Because of thousands years of Chinese doctors experiences and vast documents, Taiwan has leading edge compared to other nations in conducting research of Chinese medicine. However, its value is difficult to be recognized internationally due to lacking of welldesigned clinical experiments and scientific data. Like other industry, Chinese medicine industry must have sufficient large market, in order to survive. If Taiwan intends to develop the Chinese medicine industry, globalization is the choice and no other alternative can be substituted. In order to enhance the competitiveness of domestic Chinese medicine industry, CDE cooperates with the Chinese Herbal Medicine Committee, DOH to establish a modernized mechanism in reviewing clinical trial protocols and new Chinese medicine registration. CDE aims to build up an innovative technology platform through integration of regulations and successful marketing experiences regarding Chinese medicine development worldwide. CDE provides consultation to sponsors in line with the rapid growth of Chinese medicine market worldwide. One of the present government s goals is to promote Taiwan as a major research and development center for Chinese medicine. At the present, reviewers at CDE are capable of reviewing the new drugs that are not yet approved for marketing in other countries in the world, and are also devoting their efforts to the promotion and improvement in clinical trial environment. However, in order to meet the challenge of the dynamic change of the regulatory environment, CDE not only has to maintain the present competitiveness, but also to enhance the professional capability in reviewing to gradually keep up with the international standards. In the future, CDE will be actively in providing various evaluation and consultation services based on a professional review and service system with the best quality, high efficiency, transparence and consistency to the government and the industry. IV. Conclusion Many multinational pharmaceutical companies used to seek human clinical trials in other Asian countries, such as Singapore and Hong Kong. It is important that Taiwan has such an infrastructure of clinical trial to attract global clinical trial business. However, Taiwan cannot become the sponsor s first choice for clinical trial unless start taking proactive measures to: 1) further improve the efficiency of clinical trial review process; 2) strengthen the proper function and administrative flow of IRB/J-IRB; 3) ensure appropriate internal and external expertise during review process; 4) offer one-stop and streamline regulatory process for all medical products and 5) have more GCP-qualified investigators and study coordinators. Contact Details: Contact Person: Dr Chei-Hsiang Chen Director, Biotechnology and Pharmaceutical Industries Program Office, Ministry of Economic Affairs, Taiwan Email: chchenj@biopharm.org.tw 1209