Conducting clinical trials can be inherently complex, but the challenges multiply when these trials extend across multiple regions. Global clinical trials are vital for including diverse populations, which can lead to more comprehensive and generalizable results. As the demand for such diversity increases, many Contract Research Organizations (CROs) and sponsors are increasingly conducting trials in the Asia-Pacific (APAC) region. However, the different countries, regions, and populations within APAC present unique challenges, laws, and regulatory landscapes. Understanding these differences is crucial for effectively conducting clinical trials that draw participants from both the U.S. and APAC regions.

Countries of the Asia Pacific (APAC) region are diverse in population, health needs, and capacity of healthcare and regulatory systems. The regulatory environment is heterogeneous, and authorities are at varying stages of development and implementation of regulatory frameworks that ultimately impact drug development and the biopharmaceutical industry. While there are country-specific regulations and requirements, the overall trend in the Asia Pacific is towards international harmonization and global convergence, with markets participating in the International Council on Harmonization (ICH) and actively working on learning best practices such as expedited pathways to improve access to new drugs and reduce drug lag.

This article will explore key differences between clinical trial regulations in the United States and the Asia Pacific (APAC) region, highlighting implications for sponsors, investigators, and patients.

 

Clinical Trials in Asia Pacific (APAC)

The Asia Pacific region offers advantages to sponsors seeking to expand their clinical trial site locations with a diverse patient population encompassing various ethnicities, demographics, and medical conditions. According to the Clinical Leader, the APAC CRO market is expected to grow to US$12 billion by 2025. 

The Asia Pacific regulatory bodies promote a high standard of care and clinical research that meets international expectations for ethical protocols. From a regulatory standpoint, many Asia Pacific countries, e.g., Japan, Korea, China, and Australia, require local data from clinical trials for regulatory approval. Aside from offering a large and diverse population, trial data from the Asia Pacific region is recognized to be of high quality, facilitating drug approval in other markets as well.

 

Regulatory Authorities and Frameworks

United States:

In the U.S., the Food and Drug Administration (FDA) oversees clinical trials. The regulatory framework is well-defined, with a structured process for drug development and approval. Key regulations include the Code of Federal Regulations (CFR), specifically Title 21, which outlines the guidelines for Good Clinical Practice (GCP), Institutional Review Boards (IRBs), and Investigational New Drug (IND) applications.

APAC:

The APAC region encompasses diverse regulatory environments, each with its own governing bodies and frameworks. Major markets like Japan, China, and South Korea have their regulatory agencies – the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, the National Medical Products Administration (NMPA) in China, and the Ministry of Food and Drug Safety (MFDS) in South Korea. While there is an ongoing effort to harmonize regulations through initiatives like the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), each country retains distinct requirements.

 

Clinical Trial Approval Processes

United States:

In the U.S., the clinical trial approval process begins with evidence from early tests and preclinical research demonstrating the safety and effectiveness of an intervention to be conducted on human subjects. Then, an IND application must be completed and submitted to the FDA before initiating investigational drug trials. The FDA reviews the application to ensure that the proposed studies are scientifically sound and that patient safety is prioritized. Once approved, sponsors must also obtain IRB approval at the trial sites. The entire process is streamlined yet stringent, ensuring robust oversight.

Once clinical trials have been conducted and are moving toward the market, a New Drug Application (NDA) will need to be submitted, which aims to demonstrate the safety and effectiveness of a drug for its intended use in the population studied. All information and data (from preclinical to Phase III trial data) must be included. In addition to the clinical results, developers must include proposed labeling, safety updates, drug abuse information, patent information, any data from studies that may have been conducted outside the U.S., Institutional Review Board (IRB) compliance information, and directions for use.

APAC:

Approval processes in the APAC region can be more varied. For instance, Japan’s PMDA conducts a detailed review similar to the FDA’s IND process, while China’s NMPA has recently undergone significant reforms to expedite drug approvals, aligning more closely with international standards. In South Korea, the MFDS requires clinical trial authorization, with an emphasis on both local and global data. These differences necessitate tailored strategies for sponsors to navigate each regulatory body effectively.

Japan has comparatively fewer regulations than the U.S. FDA. The Clinical Trials Act of 2018 in Japan created a streamlined and time-saving approval process. After obtaining IRB approval, which takes four to eight weeks, sponsors submit an application to the Japanese regulatory agency, the Pharmaceuticals and Medical Devices Agency (PMDA), which responds within 30 days.

In China, regulatory reforms have significantly reduced the time needed for approval from years to months. Sponsors submit a Clinical Trial Application (CTA) with clinical trial data to the National Medical Products Administration (NMPA) and can expect a response within 60 business days. Without a response by this time, the application is automatically approved, and sponsors must conduct the trial within three years of approval. The clinical trial data must follow Good Clinical Practice (GCP) guidelines and be submitted to the NMPA in the NDA package. Submitted data must include detailed information on the trial design, patient demographics, adverse events, and efficacy outcomes. 

 

Phase I Trial Data

United States:

The purpose of Phase I trials in the U.S. is to determine safety and dosage. According to the FDA, these trials typically involve 20 to 100 healthy volunteers or people with the condition being studied. Approximately 70% of drugs in the U.S. successfully move from Phase I to Phase II. Clinical development lag, which significantly contributes to drug lag (the drug approval interval between countries), is a concern, especially for conditions with a substantial disease burden.

APAC:

In Japan, the issue of drug lag is more pronounced compared to Europe and the U.S. To address this, the Ministry of Health, Labour, and Welfare announced in 2023 that Phase I clinical studies are not generally required before late-stage global studies. However, Phase I studies remain necessary in certain circumstances, such as when many Japanese patients will use the drug.

In China, the National Medical Products Administration (NMPA) requires local population data for Phase I trials before approving the next phase. However, it may consider Phase I results from ethnically Chinese patients living in other countries. Recent regulatory reforms in China, including accepting global studies as a basis for marketing approval, have facilitated earlier entry of imported drugs. A study indicated that drugs with China-based sites in FDA pivotal trials were five times more likely to obtain NMPA approval.

In Australia, the Therapeutic Goods Administration (TGA) oversees clinical trials. The TGA encourages early-phase clinical trials and has established streamlined processes to support this. Sponsors can use the Clinical Trial Notification (CTN) scheme, where trials are approved by human research ethics committees (HRECs) rather than the TGA itself. This process accelerates trial commencement and reduces regulatory burden, promoting Australia as a favorable destination for Phase I studies.

Electronic Submission

United States:

The FDA has adopted the Clinical Data Interchange Standards Consortium (CDISC) standards for electronic submissions. These standards streamline the submission process but come with specific regulatory validation rules, including severity categories that sponsors must adhere to.

APAC:

The Pharmaceuticals and Medical Devices Agency (PMDA) in Japan also follows CDISC standards for electronic submissions. However, the regulatory validation rules, including severity categories, differ from those of the FDA. As a result, what is acceptable to the FDA may not be acceptable to the PMDA. Sponsors should conduct validation checks using rules from both agencies. Additional considerations include differences in the requirement to implement a version of standards from their respective Data Standards Catalog, the severity of the validation rules, and file naming conventions.

In China, the NMPA has made strides in adopting electronic submission standards, aiming to align with international practices. However, local adaptations and specific requirements still exist, necessitating careful preparation and validation by sponsors.

Australia’s TGA also follows CDISC standards, and like the FDA and PMDA, has its specific validation rules. Sponsors must ensure compliance with TGA’s electronic submission requirements, which include detailed guidelines on data format, validation checks, and documentation standards. The TGA’s streamlined processes for early-phase trials also extend to electronic submissions, facilitating faster approvals and efficient regulatory interactions.

 

Ethical and Safety Standards

United States:

The U.S. adheres to GCP guidelines, ensuring ethical and scientific quality standards in clinical trials. IRBs’ crucial role is providing independent review and oversight to protect participants’ rights and well-being. The FDA mandates comprehensive reporting of adverse events and has strict protocols for monitoring and inspections.

APAC:

Ethical standards in the APAC region are also guided by GCP, with each country adopting its specific adaptations. Japan, for example, has stringent ethical review processes, often requiring multiple layers of approval. China has strengthened its ethical review system, emphasizing transparency and participant protection. South Korea maintains rigorous standards, with continuous efforts to align with global practices. Despite these efforts, variability remains, necessitating local expertise to ensure compliance.

 

Patient Recruitment and Diversity

United States:

Patient recruitment in the U.S. benefits from a large, diverse population. However, achieving adequate enrollment can still be challenging due to strict inclusion/exclusion criteria and regulatory requirements. The FDA encourages diversity in clinical trials, recognizing the importance of representing various demographics to ensure generalizable results.

APAC:

The APAC region offers a vast patient pool, with some countries like China and India having large populations that facilitate rapid enrollment. However, socio-cultural factors and varying healthcare infrastructures can impact recruitment efforts. Sponsors must be culturally sensitive and aware of local practices to engage effectively with participants. Moreover, regional diversity can provide valuable data on drug efficacy across different ethnic groups.

 

Cellular Therapies & the Heterogeneity of Regulatory Oversight 

Due to the heterogeneity of regulatory oversight in Asia Pacific, we explore their differences and similarities by focusing on one type of treatment: advanced cellular therapies. Cellular therapy products are an emerging medical product class experiencing rapid growth in research and development (R&D) and clinical innovation and posing unique regulatory challenges worldwide. Cellular therapies include cancer vaccines, cellular immunotherapies, and other types of autologous and allogeneic cells for specific therapeutic indications, including hematopoietic stem cells and adult and embryonic stem cells.

In the U.S., the Center for Biologics Evaluation and Research (CBER), a center within the FDA, regulates cellular therapy products, human gene therapy products, and certain cell and gene therapy devices under applicable federal laws.

In Asia Pacific countries, regulatory oversight of cellular therapies reflects the heterogeneity of the region’s regulatory environment. Classification of such therapies differs, with Australia classifying them as biologicals/prescription medicines, China as therapeutic biological products, Hong Kong as advanced therapy products, Japan as regenerative medicine products, South Korea as advanced regenerative medicine, and Singapore as cell therapy and gene therapy products.

In 2020, the NMPA published the New Drug Registration Regulation in China. Four expedited review pathways were established for drugs to treat serious life-threatening diseases. Most advanced therapies qualify for expedited pathways, allowing quicker R&D and subsequent product approvals. In the same year, South Korea enacted the Advanced Regenerative-Bio Act to improve access to advanced regenerative medicine and advanced biopharma products. While the Ministry of Health and Welfare (MHoW) has regulatory oversight of clinical practice and research use of regenerative medicine in South Korea, the Ministry of Food and Drug Safety (MFDS) oversees the commercial use and manufacturing of cell and gene therapy.

In Singapore, advanced therapeutics are regulated by the Health Sciences Authority (HSA) under the Health Products Act and Health Products (Cell, Tissue, and Gene Therapy Products) Regulations, which provide the main regulatory framework for cell, tissue, and gene therapies.

The Act on the Safety of Regenerative Medicine provides regulatory oversight in Japan on all med tech using processed cells in medical care or academic research. On the other hand, the Act on Pharmaceuticals and Medical Devices regulates the marketing authorization and commercialization of a regenerative medicinal product. In Japan, regenerative medical products include cellular and tissue-based products used in the reconstruction, repair, or formation of structures or functions of the human body, the treatment or prevention of human diseases, and gene therapy.

Okamoto et al. emphasize the need to harmonize the activity and data collection between cellular therapies, especially in the field of hematopoietic cell transplantation (HCT). They recommend multi-stakeholder collaboration to strengthen the R&D capacity, promote early patient access, and harmonize decision-makers to reinforce consistency and improve efficiencies of the regulatory process.

 

Impact on Sponsors and Investigators

For sponsors and investigators, understanding the regulatory landscapes in the U.S. and APAC is crucial for successful trial execution. The U.S. offers a relatively predictable regulatory environment with clear guidelines, but navigating the FDA’s stringent requirements demands thorough preparation and robust compliance mechanisms. In contrast, the APAC region presents opportunities for faster recruitment and diverse data, but the variability in regulations requires strategic planning and local expertise.

 

Conclusion

Comparing clinical trial regulations between the USA and the APAC region highlights the complexities and opportunities inherent in global drug development. While the U.S. offers a well-established, stringent regulatory framework, the APAC region provides a dynamic landscape with diverse regulatory environments. For sponsors and investigators, leveraging the strengths of each region while mitigating the challenges is key to advancing clinical research and bringing new therapies to patients worldwide. Understanding these regulatory nuances ensures that clinical trials are conducted efficiently, ethically, and in a manner that maximizes their potential to improve global health outcomes.

 

TFS – Your trusted Regulatory Services Partner 

TFS HealthScience (TFS) is a global mid-size Contract Research Organization (CRO) servicing clinical researchers to advance medical innovation and bring treatments to patients faster. With nearly 30 years of experience, TFS has extensive expertise in managing global clinical trials, providing comprehensive services from regulatory affairs and study coordination to medical writing. TFS has business locations in multiple countries within North America, Europe, and recently expanded into the APAC region with an operational base in Melbourne, Australia. This expansion highlights our commitment to supporting partners with a broader reach to patients, fostering innovative solutions, and facilitating global collaboration.

Need help managing your next global clinical trial? Contact a TFS team member today!