- Email: [email protected]
Development of Regulatory Capacity in Monitoring, Oversight, Enforcement, and Approval of Clinical Trials
CHAPTER
12
Development of Regulatory Capacity in Monitoring, Oversight, Enforcement, and Approval of Clinical Trials Taiwan’s Experience as an Example Herng-Der Chern Center for Drug Evaluation, Taipei, Taiwan 129
CHAPTER OUTLINE Drug Regulation: An Instrument for Public Assurance of Drug Safety and Efficacy 129 Conceptual Spheres of Investigational New Drug Regulations 130 Evolution of Clinical Research Regulations 130
Dimensions of Regulatory Capacity
131
Structure 131 Human Resources 131 Financial Resources 133 Planning, Monitoring, and Evaluating Implementation 133 Political Influence and Accountability 134
Transparency 135 Inspections and Surveillance 135 Evaluating Regulatory Capacity and Performance 135
Globalization of Clinical Research and International Conference on Harmonisation: Sharing Expertise for Capacity Building 136 Regulation of Clinical Trials in Developing Countries 136 Ethics Committees as Co-regulators 137 Conclusion 138 References 138
DRUG REGULATION: AN INSTRUMENT FOR PUBLIC ASSURANCE OF DRUG SAFETY AND EFFICACY The products of the biopharmaceutical industry, drugs, often have a profound impact on public health. To protect public health, every step in the development of a new drug is highly Global Clinical Trials Playbook. DOI: 10.1016/B978-0-12-415787-3.00012-6 Copyright Ó 2012 Elsevier Inc. All rights reserved.
SECTION 3 Regulatory Capacity
regulated based not only on best international practice, such as International Conference on Harmonisation (ICH) guidelines and good science, but also on special local regulatory requirements of national regulatory authorities (NRAs) so that they can be held accountable to their congress and citizens for their regulatory actions. However, most NRAs also recognize that early access to innovative medicinal products by patients can promote public health. To assure the general public of the safety and efficacy of the drugs at the same time supporting new drug development, such as H1N1 vaccine or therapies for acquired immunodeficiency syndrome (AIDS), the development of the capacity and capability of the NRA becomes a critical priority for many countries. Since all approved drugs are likely to be used globally, i.e. in a large human population, clinical trials have become indispensable and important steps in new drug development.
Conceptual Spheres of Investigational New Drug Regulations
130
Regulation for investigational new drugs (INDs) should be stated in the law, order, guidance, or points to consider. The review process should be transparent, efficient, and responsive, and run under standard operating procedures (SOPs) with a good quality assurance and control system in place. The review principles should be consistent and fair to all stakeholders. There should be no conflict of interest in regulatory evaluation and the information submitted to the NRA must be kept confidential. For the NRA to approve a specific indication carrying specific labeling, a large amount of clinical data needs to be submitted through a series of INDs during clinical development. As all INDs have different levels of built-in risk for trial subjects, the NRA has dual responsibilities to both protect public health and promote public health in the IND review. The first role of the NRA is to protect public health. All individual INDs should be carefully reviewed by the NRA based on sound study design with good risk/benefit ratio, preclinical data, ethical concerns, informed consent, and safety measures to decide whether it is safe to proceed. Good IND study design aiming for an NDA is mainly the responsibility of the sponsor. This is why the US Food and Drug Administration (FDA) does not use wording such as “this IND is approved by the FDA”, to avoid any implication that the scientific merit of the sponsor’s study design was endorsed by the FDA. The second role of the NRA is to promote public health. The sponsor is encouraged to seek early regulatory advice, such as through a preIND or an end of Phase II meeting with the FDA, or scientific advice from the European Medicines Agency (EMA) or Japanese Pharmaceuticals and Medical Devices Agency (PMDA), before making critical decisions for the drug development plan, to avoid potential regulatory surprises during the final NDA review.
Evolution of Clinical Research Regulations The evolution of clinical research regulations can be briefly summarized in the following milestones: l
l
l
1938: Following the death of 107 people from sulfanilamide, the US Food, Drug and Cosmetic Act enforced the need for manufacturers to demonstrate safety. 1947: Following inhumane experiments on prisoners of war in World War II, the Nuremberg Code was implemented, with the following key points: e The concept of informed consent was first proposed, so that informed consent of volunteers must be obtained without coercion in any form. e Human experiments should be based on prior animal experimentation. e Anticipated scientific results should justify the experiment. e Only qualified scientists should conduct medical research. e Physical, mental suffering, and injury should be avoided. e There should be no expectation of death or disabling injury from the experiment. 1962: The USA passed the Kefauver-Harris Drug Amendment, meaning that proof of efficacy was required for NDA approval.
CHAPTER 12 Development of Regulatory Capacity in Monitoring, Oversight, Enforcement
l
l l
1964: The Declaration of Helsinki was developed by the World Medical Association. These ethical codes provide principles for medical research involving human subjects. 1989: Good Clinical Practice (GCP) of the European Community. 1996: ICH-GCP was first accepted in the USA, the European Union (EU), and Japan. The ICH-GCP was followed by many non-ICH countries. GCP defines the basic principles used to protect trial subjects and data integrity in clinical trials.
Following the spirit of the FDA’s IND process, the Center for Drug Evaluation (CDE) in Taiwan offers free regulatory consultations throughout the new drug development process. Of 600 consultations requested by sponsors in 2010, face-to-face meetings were granted in 20 percent. Taiwan FDA/CDE review INDs using the concept of “safe to proceed” and make regulatory recommendations for regulatory requirements for potential NDAs.
DIMENSIONS OF REGULATORY CAPACITY Structure The main components of regulatory capacity are a legal regulatory administrator, in-house full time technical staff, and an external advisory committee. Under the concept of risk-based evaluation, different review processes were set up with different levels of regulatory intensity, such as full review, abbreviated review, and clinical trial notification system. In Taiwan, the CDE/Taiwan Food and Drug Administration (TFDA) were set up as an innovative model for regulatory review.1 The CDE was established in 1998 as a non-profit, non-governmental organization (NGO), fully sponsored and authorized by the Taiwan government to conduct regulatory consultation and evaluation for INDs, NDAs, guidance drafting, and international affairs. This special set-up has given the CDE the flexibility to recruit professionals in terms of increased headcount, competitive salary scales, and the ability to avoid many of the limitations applied to civil servants. The CDE/TFDA Integrated Medicinal Products Review Office (iMPRO) was established on June 1, 2011, with reviewers from both the CDE and the TFDA sharing an office and following the same SOPs for reviewing. The combination of legal authority and accountability with the capacity for in-house technical expertise under a streamlined process is the cornerstone in taking complicated regulatory action based on good regulatory science. In the early 2000s, when the capacity and capability of the CDE and TFDA were inadequately provided, the advisory committee played an important role in sharing the review work and serving as a quality check for the CDE’s recommendations. Since the establishment of the iMPRO, the CDE/TFDA’s in-house review team has been independently responsible for most IND and NDA reviews (Figure 12.1). The role of the advisory committee has been transformed into a real advisory one, to serve the NRA only on complicated regulatory challenges. The evolution of this regulatory structure has streamlined the review process significantly.
Human Resources Regulatory science is both an art and a science involving many disciplines, such as biomedical science, ethics, law, management, and communication skills. The best way to learn it is through hands-on review experience supervised by experienced staff in a multidisciplinary review team. It takes time and a carefully planned training program to nurture good reviewers. To maintain qualified human resources, we need to create a learning organization, career path development, passion in their work in protecting and promoting public health, organizational prestige recognized by their peer groups and the general public, a good working environment, and competitive pay. Since 1998, the CDE has nurtured an experienced review team, with 170 full-time staff as of February 2012, working on step-by-step coverage of the review of INDs, NDAs, some new medical devices, and health technology assessment. The CDE has 25 fulltime medical doctors, seven statisticians, 35 PhDs, and 48 with a master’s degree (two of whom are lawyers), making it a major thinktank for the TFDA (Figure 12.2). A dedicated IND
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FIGURE 12.1 Excellence in regulatory science: in-house review capacity of the Center for Drug Evaluation/Taiwan Food and Drug Administration (CDE/TFDA). The Integrated Medicinal Product Review Office (iMPRO) has integrated reviewers and project managers from TFDA and CDE since June 1, 2011. AC: Advisory Committee; IVD: in vitro diagnostics; PMA: premarket approval; IDE: investigational device exemption; IND: investigational new drug; BABE: bioavailability and bioequivalence; NDA: new drug application. (Please refer to color plate section)
132
FIGURE 12.2 Full-time employees in the Center for Drug Evaluation (CDE), March 2011. (Please refer to color plate section)
review team is mainly composed of full-time medical doctors and statisticians, with preclinical review supported by the preclinical division, including chemistry, manufacturing, and control (CMC), pharmacology/toxicology, pharmacokinetics, and biological reviewers. The team leader of an IND review team will be the medical reviewer, so he or she can make a clinical judgment as to whether an IND is safe to proceed based on the clinical risk/benefit ratio. The
CHAPTER 12 Development of Regulatory Capacity in Monitoring, Oversight, Enforcement
CDE has project managers serving as the main contact to manage the whole IND review according to SOPs.
Financial Resources Stable and sufficient financial resources are a critical element in building and maintaining regulatory capacity. The financial resources can normally either be allocated a budget from the government or receive a user fee from the sponsors, mostly pharmaceutical companies. For example, NRAs such as the EMA, the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK, and the Therapeutic Goods Administration (TGA) in Australia are fully supported by the user fee, while the US FDA and Japanese PMDA are only partially supported by the user fee. The magnitude of NRAs’ annual budget can vary even though they have similar responsibilities and regulatory challenges. However, almost all NRAs have problems of inadequate financial resources, from the well-resourced US FDA to the NRAs in most developing countries. Unfortunately, significant increases in resources usually only come after a safety disaster with a product under the NRA’s jurisdiction, with the aim of fixing the system for better public health protection. As NRAs also have a role in public health promotion, some NRAs have been relatively successful in justifying their budgets as investment expenditure, as a critical component of the infrastructure in the development of innovative medicinal products. As the CDE is a non-profit NGO, it was 100 percent supported by Taiwanese government funding under grants from different government sectors, including the Ministry of Economic Affairs, the National Translational Medicine Research Program, and the Ministry of Health, without any application fee for the products evaluated by the CDE. The nominal application fee goes to the TFDA, not the CDE. Over the years, the CDE has been relatively successful in securing financial support, about US $10 million in 2012, from different government sectors in Taiwan for the concept of public health promotion. Other than review work entrusted by the TFDA, the CDE provides regulatory consultations, grant reviews for clinical research, and regulatory training programs to serve stakeholders under different government projects. Although all projects need to be reviewed annually and there is some financial instability, this special working model links the CDE’s performance and the satisfaction of all stakeholders via the annual budget review process. Since the CDE and TFDA have recently been functionally integrated under the iMPRO, the next step will be the formal establishment of an expanded iMPRO as an independent administrative agency, with both a legal basis for regulatory authority and flexibility in management, similar to the PMDA in Japan.
Planning, Monitoring, and Evaluating Implementation To nurture the capacity and capability of a reputable NRA requires (1) careful stepwise planning based on the correct principles of regulatory science, (2) a good quality assurance and quality control system to monitor its performance by benchmarking other reputable NRAs, and (3) periodical evaluation of its overall implementation based on the vision, mission, goal, objectives, action plans, and roadmap, via a high-level advisory committee. In the following section, the CDE/TFDA model will be used as an experimental model of regulatory science in Asia to illustrate the importance of the approaches stated above.
PLANNING In 1997, Taiwan chose the biopharmaceutical industry as one of its national priorities for economic development. As the biopharmaceutical industry is a regulation-intensive industry involving human health, many experts recommended upgrading the capacity of local NRAs to best international practice. The CDE was set up in 1998 (see Structure, above, for more details) to conduct regulatory consultation and evaluation of medicinal products with good regulatory science to support the final decision of the legal authority, now the TFDA.
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From the beginning, the strategy of the CDE has been to follow the spirit of the FDA in regulatory science and the EMA format in reviews, to harmonize with the ICH guidance, and to network with reputable NRAs. Both the CDE and the TFDA have strived to be the leader in regulatory challenges related to Asia, by thinking globally but acting locally. Some highlights of its achievements are: l
l l
l
l
the implementation of the ICH E5 in accepting foreign clinical data via Bridging Study Evaluation (BSE), since 2000 setting up an IND process and providing free regulatory consultation initiating critical path projects for in-depth regulatory consultation for the index cases selected2 setting up a Clinical Trial Notification (CTN) system following the spirit of TGA Australia, in which a qualifying IND (the same protocol has been approved by at least one of the 10 reference NRAs) can be approved within an average regulatory time of only 17.3 calendar days from submission to receipt of an approval letter leading international projects, e.g. the APEC Network of Regulatory Science since 2000 and APEC Good Regulatory Practice, including hosting the Good Pharmaceutical Review Practice workshop on drugs/devices and promoting the exchange of regulatory information among NRAs in 2011e2012.
MONITORING Building quality into the decision-making process of the assessment requires good quality assurance and quality control systems to monitor the performance and improve consistency, transparency, timeliness, and competency in the review process. Good monitoring measures can improve stakeholder satisfaction and communication within the NRA, and serve as a guide for the allocation of regulatory resources. 134
The CDE/TFDA has a good internal quality assurance/quality control tracking system to monitor the IND review in terms of efficiency (regulatory time and sponsor time compared with the target time in SOPs), quantity (number of new protocols and clinical sites) and composition of INDs (number of Phase I, II, III, or multiregional trial), reasons for any delay in review, approval rate, and reasons for non-approval. External experts from different review disciplines (CMC, pharmacology and toxicology, statistics, medical, clinical pharmacology, etc.), many with US FDA review experience, periodically perform external quality audits on the CDE’s assessment reports. Feedback from stakeholders is carefully reviewed through complaints, annual meetings, workshops, and surveys. Regulatory capacity and capability have been gradually improved since the establishment of the CDE in 1998. Progress is planned and monitored annually by the biotechnology committee at cabinet level, and by the TFDA on an almost daily basis.
Political Influence and Accountability A clinical trial involves testing a new drug, with some unpredictable risks, in human subjects who volunteer not only for their own benefit but also to advance public health. If clinical trial conduct were treated lightly, without due respect and with no precautions regarding ethical trial conduct, the political repercussions from society may cause major setbacks to the future recruitment of subjects. Consumer groups and many politicians have been very active and concerned about the safe and ethical conduct of clinical trials. A lot of legislation relating to the conduct of clinical trials, informed consent, qualification of the principal investigators, accreditation of the hospitals, handling of genetic material, and guidance for cell and gene therapy has been stipulated. If there is major violation of a clinical trial protocol, the TFDA can take strong regulatory action, and even ban the whole hospital from submitting new INDs before a risk management plan is submitted. The principal investigator may face criminal charges for major misconduct in the clinical trial. Another kind of political pressure may come
CHAPTER 12 Development of Regulatory Capacity in Monitoring, Oversight, Enforcement
from lobbying of the sponsors. To avoid potential undue political influence in the independent evaluation of NRAs, the CDE/TFDA has set up an internal quality audit system with primary and secondary reviewers and supervisors from different disciplines to ensure consistent and impartial review. All reviewers’ assessment reports will be signed and archived without any internal changes. The reviewers will be accountable for their own assessment reports only. If a higher manager wishes to overrule a recommendation from the primary reviewers, he or she will be accountable for the decision and his or her points documented. There is also an ombudsman system to investigate any significant issues efficiently and fairly.
Transparency Transparency for an NRA refers to the ability and willingness of the agency to allocate time and resources, and to provide information on its activities to both the informed public (which includes health professionals) and industry. Transparency may provide assurance on safety safeguards to the public, and increase confidence in the system and predictability for the industry. Information provided may include the approval basis of a product, approval time, summary of approval for the product, advisory committee members, and meeting dates. The information may be made available through an official journal, a periodical publication, or an official website. For the CDE/TFDA, any disapproval of an IND should give clear reasons to the sponsor. The sponsor can check the progress of their IND review on the Internet. If the sponsor has questions about the reasons for IND disapproval, they can request a free face-to-face consultation with the CDE to clarify any questions. The request for a meeting will normally be granted within one month. Periodically, the CDE/TFDA will invite stakeholders to discuss topics of concern and the performance index of the review efficiency, and conduct anonymous satisfaction surveys. The CDE’s performance will be reviewed during the budget application process by many key opinion leaders in the country.
Inspections and Surveillance The integrity of clinical trial data will be the presumption for all NDA approval. Thus, it is very important to ensure the integrity of clinical trial conduct and data management through GCP inspection. Since 1997, the TFDA has been conducting GCP inspection on at least one clinical site for all INDs in Taiwan. About 10 percent of the trials were disqualified for major GCP violation. The inspection team is composed of senior physicians and experienced statistical experts from the medical centers and TFDA staff. So far, no overseas GCP inspection has been conducted, but this aspect is being seriously considered. The CDE sent senior clinical reviewers to the EMA for GCP inspector training in 2010e2011. There are many accreditation schemes that can serve as a model of surveillance for personnel conducting clinical trials, e.g. the Association of Clinical Research Professionals (ACRP); for institutional review boards (IRBs), e.g. the Forum for Ethical Review Committee in the Asian and Western Pacific Region (FERCAP); and for clinical trial sites, e.g. the Association for the Accreditation of Human Research Protection Programs (AAHRPP).
Evaluating Regulatory Capacity and Performance The capacity of an NRA can be evaluated by its annual budget, size, scope, and remit, the number and qualifications of its reviewers, and the type of the data assessment used (full review, abbreviated review, abridged review by reference to the approval of recognized NRAs, role of the external advisory committee).3 The performance of an NRA can be evaluated by good review practice (GRP). GRP concerns the process and documentation of review procedures, and aims to standardize and improve the overall documentation, and ensure the timeliness, predictability, consistency, and high quality of the review and any reports. GRP also refers to whether the reviewers have good qualifications and on-the-job training programs, and
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perform the review based on good regulatory science. Another indicator for GRP is whether the regulatory action of the NRA is recognized by other NRAs. The CDE/TFDA is one of the few Asian NRAs to have an in-house review team that conducts a full review for a new molecular entity. For example, in 2009, the CDE/TFDA approved an H1N1 vaccine IND and NDA developed by a local company under a rolling review approach. Five million doses of vaccine were administered, which controlled the H1N1 epidemic successfully.
GLOBALIZATION OF CLINICAL RESEARCH AND INTERNATIONAL CONFERENCE ON HARMONISATION: SHARING EXPERTISE FOR CAPACITY BUILDING The ICH has been relatively successful in harmonizing major scientific guidance for new drug development and common technical dossier (CTD) for global regulatory submission. The EMA has been known for creating a closed regulatory club that involved NRAs sharing their expertise and regulatory information among themselves. The dilemma of the inadequate capacity and capability of many small NRAs has been resolved by EMA’s model of “compare and contrast” for GRP. Not only is the review process streamlined by coordinated collective regulatory effort, but the goal of protecting and promoting public health is also achieved. There are many regulatory harmonization initiatives with different levels of success ongoing worldwide. For example, the Association of Southeast Asian Nations (ASEAN), the Asia-Pacific Economic Cooperation (APEC), the Life Science Innovation Forum (LSIF), the Regulatory Harmonization Steering Committee (RHSC), the KoreaeJapaneChina Tripartite Clinical Trial Collaboration, the Cross Strait Agreement on Medicine and Public Health Affairs between China and Taiwan4, and many other bilateral agreements in regulatory cooperation all indicate the future trend towards the globalization of clinical research and the sharing of regulatory expertise and information. 136
The TFDA/CDE has been routinely participating in the regulatory forum of ICH-GCG for several years. The TFDA/CDE is leading an APEC Best Regulatory Practice project in 2011e2012. Besides hosting the Good Review Practice (GRP) Workshop for Drugs and Medical Devices, another highlight is the Pharmaceutical Evaluation Report among APEC member economies (APEC PER Scheme). With help from the Center for Innovation in Regulatory Science (CIRS), Taiwan completed a survey for gap analysis of GRP among APEC NRAs in 2011.
REGULATION OF CLINICAL TRIALS IN DEVELOPING COUNTRIES Six major essential elements of clinical trial infrastructure are required to attract global clinical trials to a particular country: l l l l l l
quality of trial conduct up to ICH-GCP standard efficiency, including IND review of NRA and IRB efficiency of clinical trial conduct in hospitals regulatory requirements for local clinical trial or bridging study for NDAs cost of the trial, including whether there are any government incentives potential market size.
Using the evolving clinical trial status in Taiwan as an example for other developing countries,5,6 it is obvious that the regulatory infrastructure is the driver for the rapid improvement in clinical trials in Taiwan in terms of both quantity and quality. Five phases of clinical trial regulatory infrastructure may be identified: l
1993e1996: There was an administrative requirement that all NDAs to be approved in Taiwan would need to conduct a clinical trial involving a minimum of 40 Taiwanese subjects. This regulatory requirement was simple and clear and brought some trials, mostly Phase IV trials of drugs already marketed in other countries, to Taiwan.
CHAPTER 12 Development of Regulatory Capacity in Monitoring, Oversight, Enforcement
FIGURE 12.3 Built-up regulatory infrastructure: investigational new drugs (INDs) from 1994 to 2010 in Taiwan. GCP: good clinical practice; CDE: Center for Drug Evaluation. (Please refer to color plate section) l
l
l
l
1997e2000: Taiwan GCP was promulgated with GCP inspection and the CDE was set up for IND review. These measures guaranteed the quality of clinical trial conduct in Taiwan, so about 50 percent of the trials were Phase IeIII trials conducted together with other countries. 2000e2006: The 40 case regulatory requirement was gradually replaced by the BSE for potential ethnic sensitivity in accepting foreign clinical trial data.7 Ninety-five percent of the trials were Phase IeIII trials and Taiwan became the preferred site for multiregional clinical trials in Asia. This means that most companies decided to include Taiwan in their global clinical development so they could better determine whether the NDA was ethnically sensitive at the time of BSE, before NDA. 2006e2010: The number of the clinical trials increased by 12e15 percent per year, which reflected the continuous improvement in the efficiency of regulatory IND review and clinical trial conduct in more qualified sites, including the five National Centers of Excellence for Clinical Trials and Research8 and a dozen General Clinical Research Centers supported by government funding. 2011epresent: The CDE/TFDA announced the CTN scheme on August 18, 2010. The average regulatory review time was 17.3 calendar days for CTN cases (26 cases, about 19 percent of all INDs submitted) compared with 38.3 days for non-CTN cases (112 cases) (data from August 18, 2010 to March 31, 2011). Among these 26 CTN cases, 12 (46 percent) were Phase I and II trials, compared with only 25 percent of the non-CTN cases. This means that CTN schemes can attract early phase trials to Taiwan by improving the efficiency of the review time.
The regulatory infrastructure for INDs in Taiwan from 1994 to 2010 is shown in Figure 12.3.
ETHICS COMMITTEES AS CO-REGULATORS Ethics committee or IRB approval is needed for the IND to be conducted at the site that bestows them with the role of co-regulators of INDs. Although the minimum requirements for IRB structure and operation are stipulated in the ICH-GCP, there are still many challenges in establishing a robust IRB. Many IRBs face the following challenges: l
Members may not have adequate training for ethical review and may insist on something that is “nice to know” and/or “scientifically interesting” but not necessarily needed for protocol modification.
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l l
l
There may be a lack of administrative support and SOPs. For a multicenter trial, different IRBs may make different comments on the same IND protocol. There may be a lack of resources to monitor the progress of the INDs.
To target these challenges, in 1997 Taiwan established a Joint IRB, composed of members from five medical centers, the National Health Research Institute, and laypeople. At one time, the Joint IRB’s decision was honored by two-thirds of medical centers in Taiwan for multicenter clinical trials. The Taiwan Association of IRBs was established in 2009 to serve as an open platform for all IRBs in terms of education, research, policy recommendations, and international interaction. More than 20 IRBs in Taiwan have passed the FERCAP IRB accreditation and the country has the highest number of accredited IRBs in Asia.
CONCLUSION The past decade has witnessed the rapid development of the methodology of study design and related regulation, ethical principles for clinical trials as a critical component of new drug development, and marketing registration. During the trend towards simultaneous global drug development and regulatory convergence, there has been a focus on bringing the quality of the clinical trial conduct and its regulatory capacity up to best international practice, especially in many emerging countries. Taiwan has come a long way over the past 20 years, although there is room for improvement, considering all the new challenges to reach its current capacity and capability in regulatory science. This experience can serve as a good reference for other NRAs in developing a best fit regulatory system to protect and promote public health in their own jurisdiction.
References 138
1. Chern H-D, Gau Chen C-S, H-MH, Liao C-C. An experimental model of regulatory science in Asia: Center for Drug Evaluation in Taiwan. Drug Information Journal 2009;43:301e4. 2. Lin B-B, Lin C-H, Chern H-D. The Critical Path Program in Taiwan. Drug Information Journal 2009;43:311e7. 3. McAuslane N, Cone M, Collins J, Walker S. Emerging markets and emerging agencies: a comparative study of how key regulatory agencies in Asia, Latin America, the Middle East, and Africa are developing regulatory processes and review models for new medicinal products. Drug Information Journal 2009;43:349e59. 4. Cross Strait Cooperation Agreement on Medicine and Public Health Affairs. http://www.cde.org.tw/SubLink/ CSCA/cross_strait_Cooperation_Agreement.pdf [accessed 25.01.12]. 5. Wong ECK. Clinical trials in Southeast Asia: an update. Drug Information Journal 2009;43:57e61. 6. Liao J-J, Liao C-C, On A, Chern H-D, Lin M-S. Updates on IND process and clinical trials status in Taiwan. Drug Information Journal 2009;43:63e8. 7. Su L-L, Chern H-D, Ryan Lee I-L, Lin C-L, Lin M-S. An overview of bridging study evaluation in Taiwan. Drug Information Journal 2009;43:371e6. 8. Lin C-C, Yang C-H, Cheng A-L, Chan W-K, Ho H-N. National Center of Excellence for Clinical Trials and Research at National Taiwan University. Drug Information Journal 2009;43:361e3.
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Development of Regulatory Capacity in Monitoring, Oversight, Enforcement, and Approval of Clinical Trials Taiwan’s Experience as an Example Herng-Der Chern Center for Drug Evaluation, Taipei, Taiwan 129
CHAPTER OUTLINE Drug Regulation: An Instrument for Public Assurance of Drug Safety and Efficacy 129 Conceptual Spheres of Investigational New Drug Regulations 130 Evolution of Clinical Research Regulations 130
Dimensions of Regulatory Capacity
131
Structure 131 Human Resources 131 Financial Resources 133 Planning, Monitoring, and Evaluating Implementation 133 Political Influence and Accountability 134
Transparency 135 Inspections and Surveillance 135 Evaluating Regulatory Capacity and Performance 135
Globalization of Clinical Research and International Conference on Harmonisation: Sharing Expertise for Capacity Building 136 Regulation of Clinical Trials in Developing Countries 136 Ethics Committees as Co-regulators 137 Conclusion 138 References 138
DRUG REGULATION: AN INSTRUMENT FOR PUBLIC ASSURANCE OF DRUG SAFETY AND EFFICACY The products of the biopharmaceutical industry, drugs, often have a profound impact on public health. To protect public health, every step in the development of a new drug is highly Global Clinical Trials Playbook. DOI: 10.1016/B978-0-12-415787-3.00012-6 Copyright Ó 2012 Elsevier Inc. All rights reserved.
SECTION 3 Regulatory Capacity
regulated based not only on best international practice, such as International Conference on Harmonisation (ICH) guidelines and good science, but also on special local regulatory requirements of national regulatory authorities (NRAs) so that they can be held accountable to their congress and citizens for their regulatory actions. However, most NRAs also recognize that early access to innovative medicinal products by patients can promote public health. To assure the general public of the safety and efficacy of the drugs at the same time supporting new drug development, such as H1N1 vaccine or therapies for acquired immunodeficiency syndrome (AIDS), the development of the capacity and capability of the NRA becomes a critical priority for many countries. Since all approved drugs are likely to be used globally, i.e. in a large human population, clinical trials have become indispensable and important steps in new drug development.
Conceptual Spheres of Investigational New Drug Regulations
130
Regulation for investigational new drugs (INDs) should be stated in the law, order, guidance, or points to consider. The review process should be transparent, efficient, and responsive, and run under standard operating procedures (SOPs) with a good quality assurance and control system in place. The review principles should be consistent and fair to all stakeholders. There should be no conflict of interest in regulatory evaluation and the information submitted to the NRA must be kept confidential. For the NRA to approve a specific indication carrying specific labeling, a large amount of clinical data needs to be submitted through a series of INDs during clinical development. As all INDs have different levels of built-in risk for trial subjects, the NRA has dual responsibilities to both protect public health and promote public health in the IND review. The first role of the NRA is to protect public health. All individual INDs should be carefully reviewed by the NRA based on sound study design with good risk/benefit ratio, preclinical data, ethical concerns, informed consent, and safety measures to decide whether it is safe to proceed. Good IND study design aiming for an NDA is mainly the responsibility of the sponsor. This is why the US Food and Drug Administration (FDA) does not use wording such as “this IND is approved by the FDA”, to avoid any implication that the scientific merit of the sponsor’s study design was endorsed by the FDA. The second role of the NRA is to promote public health. The sponsor is encouraged to seek early regulatory advice, such as through a preIND or an end of Phase II meeting with the FDA, or scientific advice from the European Medicines Agency (EMA) or Japanese Pharmaceuticals and Medical Devices Agency (PMDA), before making critical decisions for the drug development plan, to avoid potential regulatory surprises during the final NDA review.
Evolution of Clinical Research Regulations The evolution of clinical research regulations can be briefly summarized in the following milestones: l
l
l
1938: Following the death of 107 people from sulfanilamide, the US Food, Drug and Cosmetic Act enforced the need for manufacturers to demonstrate safety. 1947: Following inhumane experiments on prisoners of war in World War II, the Nuremberg Code was implemented, with the following key points: e The concept of informed consent was first proposed, so that informed consent of volunteers must be obtained without coercion in any form. e Human experiments should be based on prior animal experimentation. e Anticipated scientific results should justify the experiment. e Only qualified scientists should conduct medical research. e Physical, mental suffering, and injury should be avoided. e There should be no expectation of death or disabling injury from the experiment. 1962: The USA passed the Kefauver-Harris Drug Amendment, meaning that proof of efficacy was required for NDA approval.
CHAPTER 12 Development of Regulatory Capacity in Monitoring, Oversight, Enforcement
l
l l
1964: The Declaration of Helsinki was developed by the World Medical Association. These ethical codes provide principles for medical research involving human subjects. 1989: Good Clinical Practice (GCP) of the European Community. 1996: ICH-GCP was first accepted in the USA, the European Union (EU), and Japan. The ICH-GCP was followed by many non-ICH countries. GCP defines the basic principles used to protect trial subjects and data integrity in clinical trials.
Following the spirit of the FDA’s IND process, the Center for Drug Evaluation (CDE) in Taiwan offers free regulatory consultations throughout the new drug development process. Of 600 consultations requested by sponsors in 2010, face-to-face meetings were granted in 20 percent. Taiwan FDA/CDE review INDs using the concept of “safe to proceed” and make regulatory recommendations for regulatory requirements for potential NDAs.
DIMENSIONS OF REGULATORY CAPACITY Structure The main components of regulatory capacity are a legal regulatory administrator, in-house full time technical staff, and an external advisory committee. Under the concept of risk-based evaluation, different review processes were set up with different levels of regulatory intensity, such as full review, abbreviated review, and clinical trial notification system. In Taiwan, the CDE/Taiwan Food and Drug Administration (TFDA) were set up as an innovative model for regulatory review.1 The CDE was established in 1998 as a non-profit, non-governmental organization (NGO), fully sponsored and authorized by the Taiwan government to conduct regulatory consultation and evaluation for INDs, NDAs, guidance drafting, and international affairs. This special set-up has given the CDE the flexibility to recruit professionals in terms of increased headcount, competitive salary scales, and the ability to avoid many of the limitations applied to civil servants. The CDE/TFDA Integrated Medicinal Products Review Office (iMPRO) was established on June 1, 2011, with reviewers from both the CDE and the TFDA sharing an office and following the same SOPs for reviewing. The combination of legal authority and accountability with the capacity for in-house technical expertise under a streamlined process is the cornerstone in taking complicated regulatory action based on good regulatory science. In the early 2000s, when the capacity and capability of the CDE and TFDA were inadequately provided, the advisory committee played an important role in sharing the review work and serving as a quality check for the CDE’s recommendations. Since the establishment of the iMPRO, the CDE/TFDA’s in-house review team has been independently responsible for most IND and NDA reviews (Figure 12.1). The role of the advisory committee has been transformed into a real advisory one, to serve the NRA only on complicated regulatory challenges. The evolution of this regulatory structure has streamlined the review process significantly.
Human Resources Regulatory science is both an art and a science involving many disciplines, such as biomedical science, ethics, law, management, and communication skills. The best way to learn it is through hands-on review experience supervised by experienced staff in a multidisciplinary review team. It takes time and a carefully planned training program to nurture good reviewers. To maintain qualified human resources, we need to create a learning organization, career path development, passion in their work in protecting and promoting public health, organizational prestige recognized by their peer groups and the general public, a good working environment, and competitive pay. Since 1998, the CDE has nurtured an experienced review team, with 170 full-time staff as of February 2012, working on step-by-step coverage of the review of INDs, NDAs, some new medical devices, and health technology assessment. The CDE has 25 fulltime medical doctors, seven statisticians, 35 PhDs, and 48 with a master’s degree (two of whom are lawyers), making it a major thinktank for the TFDA (Figure 12.2). A dedicated IND
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FIGURE 12.1 Excellence in regulatory science: in-house review capacity of the Center for Drug Evaluation/Taiwan Food and Drug Administration (CDE/TFDA). The Integrated Medicinal Product Review Office (iMPRO) has integrated reviewers and project managers from TFDA and CDE since June 1, 2011. AC: Advisory Committee; IVD: in vitro diagnostics; PMA: premarket approval; IDE: investigational device exemption; IND: investigational new drug; BABE: bioavailability and bioequivalence; NDA: new drug application. (Please refer to color plate section)
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FIGURE 12.2 Full-time employees in the Center for Drug Evaluation (CDE), March 2011. (Please refer to color plate section)
review team is mainly composed of full-time medical doctors and statisticians, with preclinical review supported by the preclinical division, including chemistry, manufacturing, and control (CMC), pharmacology/toxicology, pharmacokinetics, and biological reviewers. The team leader of an IND review team will be the medical reviewer, so he or she can make a clinical judgment as to whether an IND is safe to proceed based on the clinical risk/benefit ratio. The
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CDE has project managers serving as the main contact to manage the whole IND review according to SOPs.
Financial Resources Stable and sufficient financial resources are a critical element in building and maintaining regulatory capacity. The financial resources can normally either be allocated a budget from the government or receive a user fee from the sponsors, mostly pharmaceutical companies. For example, NRAs such as the EMA, the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK, and the Therapeutic Goods Administration (TGA) in Australia are fully supported by the user fee, while the US FDA and Japanese PMDA are only partially supported by the user fee. The magnitude of NRAs’ annual budget can vary even though they have similar responsibilities and regulatory challenges. However, almost all NRAs have problems of inadequate financial resources, from the well-resourced US FDA to the NRAs in most developing countries. Unfortunately, significant increases in resources usually only come after a safety disaster with a product under the NRA’s jurisdiction, with the aim of fixing the system for better public health protection. As NRAs also have a role in public health promotion, some NRAs have been relatively successful in justifying their budgets as investment expenditure, as a critical component of the infrastructure in the development of innovative medicinal products. As the CDE is a non-profit NGO, it was 100 percent supported by Taiwanese government funding under grants from different government sectors, including the Ministry of Economic Affairs, the National Translational Medicine Research Program, and the Ministry of Health, without any application fee for the products evaluated by the CDE. The nominal application fee goes to the TFDA, not the CDE. Over the years, the CDE has been relatively successful in securing financial support, about US $10 million in 2012, from different government sectors in Taiwan for the concept of public health promotion. Other than review work entrusted by the TFDA, the CDE provides regulatory consultations, grant reviews for clinical research, and regulatory training programs to serve stakeholders under different government projects. Although all projects need to be reviewed annually and there is some financial instability, this special working model links the CDE’s performance and the satisfaction of all stakeholders via the annual budget review process. Since the CDE and TFDA have recently been functionally integrated under the iMPRO, the next step will be the formal establishment of an expanded iMPRO as an independent administrative agency, with both a legal basis for regulatory authority and flexibility in management, similar to the PMDA in Japan.
Planning, Monitoring, and Evaluating Implementation To nurture the capacity and capability of a reputable NRA requires (1) careful stepwise planning based on the correct principles of regulatory science, (2) a good quality assurance and quality control system to monitor its performance by benchmarking other reputable NRAs, and (3) periodical evaluation of its overall implementation based on the vision, mission, goal, objectives, action plans, and roadmap, via a high-level advisory committee. In the following section, the CDE/TFDA model will be used as an experimental model of regulatory science in Asia to illustrate the importance of the approaches stated above.
PLANNING In 1997, Taiwan chose the biopharmaceutical industry as one of its national priorities for economic development. As the biopharmaceutical industry is a regulation-intensive industry involving human health, many experts recommended upgrading the capacity of local NRAs to best international practice. The CDE was set up in 1998 (see Structure, above, for more details) to conduct regulatory consultation and evaluation of medicinal products with good regulatory science to support the final decision of the legal authority, now the TFDA.
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From the beginning, the strategy of the CDE has been to follow the spirit of the FDA in regulatory science and the EMA format in reviews, to harmonize with the ICH guidance, and to network with reputable NRAs. Both the CDE and the TFDA have strived to be the leader in regulatory challenges related to Asia, by thinking globally but acting locally. Some highlights of its achievements are: l
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the implementation of the ICH E5 in accepting foreign clinical data via Bridging Study Evaluation (BSE), since 2000 setting up an IND process and providing free regulatory consultation initiating critical path projects for in-depth regulatory consultation for the index cases selected2 setting up a Clinical Trial Notification (CTN) system following the spirit of TGA Australia, in which a qualifying IND (the same protocol has been approved by at least one of the 10 reference NRAs) can be approved within an average regulatory time of only 17.3 calendar days from submission to receipt of an approval letter leading international projects, e.g. the APEC Network of Regulatory Science since 2000 and APEC Good Regulatory Practice, including hosting the Good Pharmaceutical Review Practice workshop on drugs/devices and promoting the exchange of regulatory information among NRAs in 2011e2012.
MONITORING Building quality into the decision-making process of the assessment requires good quality assurance and quality control systems to monitor the performance and improve consistency, transparency, timeliness, and competency in the review process. Good monitoring measures can improve stakeholder satisfaction and communication within the NRA, and serve as a guide for the allocation of regulatory resources. 134
The CDE/TFDA has a good internal quality assurance/quality control tracking system to monitor the IND review in terms of efficiency (regulatory time and sponsor time compared with the target time in SOPs), quantity (number of new protocols and clinical sites) and composition of INDs (number of Phase I, II, III, or multiregional trial), reasons for any delay in review, approval rate, and reasons for non-approval. External experts from different review disciplines (CMC, pharmacology and toxicology, statistics, medical, clinical pharmacology, etc.), many with US FDA review experience, periodically perform external quality audits on the CDE’s assessment reports. Feedback from stakeholders is carefully reviewed through complaints, annual meetings, workshops, and surveys. Regulatory capacity and capability have been gradually improved since the establishment of the CDE in 1998. Progress is planned and monitored annually by the biotechnology committee at cabinet level, and by the TFDA on an almost daily basis.
Political Influence and Accountability A clinical trial involves testing a new drug, with some unpredictable risks, in human subjects who volunteer not only for their own benefit but also to advance public health. If clinical trial conduct were treated lightly, without due respect and with no precautions regarding ethical trial conduct, the political repercussions from society may cause major setbacks to the future recruitment of subjects. Consumer groups and many politicians have been very active and concerned about the safe and ethical conduct of clinical trials. A lot of legislation relating to the conduct of clinical trials, informed consent, qualification of the principal investigators, accreditation of the hospitals, handling of genetic material, and guidance for cell and gene therapy has been stipulated. If there is major violation of a clinical trial protocol, the TFDA can take strong regulatory action, and even ban the whole hospital from submitting new INDs before a risk management plan is submitted. The principal investigator may face criminal charges for major misconduct in the clinical trial. Another kind of political pressure may come
CHAPTER 12 Development of Regulatory Capacity in Monitoring, Oversight, Enforcement
from lobbying of the sponsors. To avoid potential undue political influence in the independent evaluation of NRAs, the CDE/TFDA has set up an internal quality audit system with primary and secondary reviewers and supervisors from different disciplines to ensure consistent and impartial review. All reviewers’ assessment reports will be signed and archived without any internal changes. The reviewers will be accountable for their own assessment reports only. If a higher manager wishes to overrule a recommendation from the primary reviewers, he or she will be accountable for the decision and his or her points documented. There is also an ombudsman system to investigate any significant issues efficiently and fairly.
Transparency Transparency for an NRA refers to the ability and willingness of the agency to allocate time and resources, and to provide information on its activities to both the informed public (which includes health professionals) and industry. Transparency may provide assurance on safety safeguards to the public, and increase confidence in the system and predictability for the industry. Information provided may include the approval basis of a product, approval time, summary of approval for the product, advisory committee members, and meeting dates. The information may be made available through an official journal, a periodical publication, or an official website. For the CDE/TFDA, any disapproval of an IND should give clear reasons to the sponsor. The sponsor can check the progress of their IND review on the Internet. If the sponsor has questions about the reasons for IND disapproval, they can request a free face-to-face consultation with the CDE to clarify any questions. The request for a meeting will normally be granted within one month. Periodically, the CDE/TFDA will invite stakeholders to discuss topics of concern and the performance index of the review efficiency, and conduct anonymous satisfaction surveys. The CDE’s performance will be reviewed during the budget application process by many key opinion leaders in the country.
Inspections and Surveillance The integrity of clinical trial data will be the presumption for all NDA approval. Thus, it is very important to ensure the integrity of clinical trial conduct and data management through GCP inspection. Since 1997, the TFDA has been conducting GCP inspection on at least one clinical site for all INDs in Taiwan. About 10 percent of the trials were disqualified for major GCP violation. The inspection team is composed of senior physicians and experienced statistical experts from the medical centers and TFDA staff. So far, no overseas GCP inspection has been conducted, but this aspect is being seriously considered. The CDE sent senior clinical reviewers to the EMA for GCP inspector training in 2010e2011. There are many accreditation schemes that can serve as a model of surveillance for personnel conducting clinical trials, e.g. the Association of Clinical Research Professionals (ACRP); for institutional review boards (IRBs), e.g. the Forum for Ethical Review Committee in the Asian and Western Pacific Region (FERCAP); and for clinical trial sites, e.g. the Association for the Accreditation of Human Research Protection Programs (AAHRPP).
Evaluating Regulatory Capacity and Performance The capacity of an NRA can be evaluated by its annual budget, size, scope, and remit, the number and qualifications of its reviewers, and the type of the data assessment used (full review, abbreviated review, abridged review by reference to the approval of recognized NRAs, role of the external advisory committee).3 The performance of an NRA can be evaluated by good review practice (GRP). GRP concerns the process and documentation of review procedures, and aims to standardize and improve the overall documentation, and ensure the timeliness, predictability, consistency, and high quality of the review and any reports. GRP also refers to whether the reviewers have good qualifications and on-the-job training programs, and
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perform the review based on good regulatory science. Another indicator for GRP is whether the regulatory action of the NRA is recognized by other NRAs. The CDE/TFDA is one of the few Asian NRAs to have an in-house review team that conducts a full review for a new molecular entity. For example, in 2009, the CDE/TFDA approved an H1N1 vaccine IND and NDA developed by a local company under a rolling review approach. Five million doses of vaccine were administered, which controlled the H1N1 epidemic successfully.
GLOBALIZATION OF CLINICAL RESEARCH AND INTERNATIONAL CONFERENCE ON HARMONISATION: SHARING EXPERTISE FOR CAPACITY BUILDING The ICH has been relatively successful in harmonizing major scientific guidance for new drug development and common technical dossier (CTD) for global regulatory submission. The EMA has been known for creating a closed regulatory club that involved NRAs sharing their expertise and regulatory information among themselves. The dilemma of the inadequate capacity and capability of many small NRAs has been resolved by EMA’s model of “compare and contrast” for GRP. Not only is the review process streamlined by coordinated collective regulatory effort, but the goal of protecting and promoting public health is also achieved. There are many regulatory harmonization initiatives with different levels of success ongoing worldwide. For example, the Association of Southeast Asian Nations (ASEAN), the Asia-Pacific Economic Cooperation (APEC), the Life Science Innovation Forum (LSIF), the Regulatory Harmonization Steering Committee (RHSC), the KoreaeJapaneChina Tripartite Clinical Trial Collaboration, the Cross Strait Agreement on Medicine and Public Health Affairs between China and Taiwan4, and many other bilateral agreements in regulatory cooperation all indicate the future trend towards the globalization of clinical research and the sharing of regulatory expertise and information. 136
The TFDA/CDE has been routinely participating in the regulatory forum of ICH-GCG for several years. The TFDA/CDE is leading an APEC Best Regulatory Practice project in 2011e2012. Besides hosting the Good Review Practice (GRP) Workshop for Drugs and Medical Devices, another highlight is the Pharmaceutical Evaluation Report among APEC member economies (APEC PER Scheme). With help from the Center for Innovation in Regulatory Science (CIRS), Taiwan completed a survey for gap analysis of GRP among APEC NRAs in 2011.
REGULATION OF CLINICAL TRIALS IN DEVELOPING COUNTRIES Six major essential elements of clinical trial infrastructure are required to attract global clinical trials to a particular country: l l l l l l
quality of trial conduct up to ICH-GCP standard efficiency, including IND review of NRA and IRB efficiency of clinical trial conduct in hospitals regulatory requirements for local clinical trial or bridging study for NDAs cost of the trial, including whether there are any government incentives potential market size.
Using the evolving clinical trial status in Taiwan as an example for other developing countries,5,6 it is obvious that the regulatory infrastructure is the driver for the rapid improvement in clinical trials in Taiwan in terms of both quantity and quality. Five phases of clinical trial regulatory infrastructure may be identified: l
1993e1996: There was an administrative requirement that all NDAs to be approved in Taiwan would need to conduct a clinical trial involving a minimum of 40 Taiwanese subjects. This regulatory requirement was simple and clear and brought some trials, mostly Phase IV trials of drugs already marketed in other countries, to Taiwan.
CHAPTER 12 Development of Regulatory Capacity in Monitoring, Oversight, Enforcement
FIGURE 12.3 Built-up regulatory infrastructure: investigational new drugs (INDs) from 1994 to 2010 in Taiwan. GCP: good clinical practice; CDE: Center for Drug Evaluation. (Please refer to color plate section) l
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1997e2000: Taiwan GCP was promulgated with GCP inspection and the CDE was set up for IND review. These measures guaranteed the quality of clinical trial conduct in Taiwan, so about 50 percent of the trials were Phase IeIII trials conducted together with other countries. 2000e2006: The 40 case regulatory requirement was gradually replaced by the BSE for potential ethnic sensitivity in accepting foreign clinical trial data.7 Ninety-five percent of the trials were Phase IeIII trials and Taiwan became the preferred site for multiregional clinical trials in Asia. This means that most companies decided to include Taiwan in their global clinical development so they could better determine whether the NDA was ethnically sensitive at the time of BSE, before NDA. 2006e2010: The number of the clinical trials increased by 12e15 percent per year, which reflected the continuous improvement in the efficiency of regulatory IND review and clinical trial conduct in more qualified sites, including the five National Centers of Excellence for Clinical Trials and Research8 and a dozen General Clinical Research Centers supported by government funding. 2011epresent: The CDE/TFDA announced the CTN scheme on August 18, 2010. The average regulatory review time was 17.3 calendar days for CTN cases (26 cases, about 19 percent of all INDs submitted) compared with 38.3 days for non-CTN cases (112 cases) (data from August 18, 2010 to March 31, 2011). Among these 26 CTN cases, 12 (46 percent) were Phase I and II trials, compared with only 25 percent of the non-CTN cases. This means that CTN schemes can attract early phase trials to Taiwan by improving the efficiency of the review time.
The regulatory infrastructure for INDs in Taiwan from 1994 to 2010 is shown in Figure 12.3.
ETHICS COMMITTEES AS CO-REGULATORS Ethics committee or IRB approval is needed for the IND to be conducted at the site that bestows them with the role of co-regulators of INDs. Although the minimum requirements for IRB structure and operation are stipulated in the ICH-GCP, there are still many challenges in establishing a robust IRB. Many IRBs face the following challenges: l
Members may not have adequate training for ethical review and may insist on something that is “nice to know” and/or “scientifically interesting” but not necessarily needed for protocol modification.
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There may be a lack of administrative support and SOPs. For a multicenter trial, different IRBs may make different comments on the same IND protocol. There may be a lack of resources to monitor the progress of the INDs.
To target these challenges, in 1997 Taiwan established a Joint IRB, composed of members from five medical centers, the National Health Research Institute, and laypeople. At one time, the Joint IRB’s decision was honored by two-thirds of medical centers in Taiwan for multicenter clinical trials. The Taiwan Association of IRBs was established in 2009 to serve as an open platform for all IRBs in terms of education, research, policy recommendations, and international interaction. More than 20 IRBs in Taiwan have passed the FERCAP IRB accreditation and the country has the highest number of accredited IRBs in Asia.
CONCLUSION The past decade has witnessed the rapid development of the methodology of study design and related regulation, ethical principles for clinical trials as a critical component of new drug development, and marketing registration. During the trend towards simultaneous global drug development and regulatory convergence, there has been a focus on bringing the quality of the clinical trial conduct and its regulatory capacity up to best international practice, especially in many emerging countries. Taiwan has come a long way over the past 20 years, although there is room for improvement, considering all the new challenges to reach its current capacity and capability in regulatory science. This experience can serve as a good reference for other NRAs in developing a best fit regulatory system to protect and promote public health in their own jurisdiction.
References 138
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