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Posted 31 October 2021 | By Ellen Sem, BS (Pharmacy), RAC, Vicky Han, BPharm, MBA, Annetta C. Beauregard, MS, MBA
This rapid growth in research and development of advanced therapies in Asia-Pacific has spurred regulatory agencies to develop a regulatory framework for facilitating accelerated marketing authorizations for advanced therapies to meet unmet medical needs. This article aims to summarize the current state of the regulatory frameworks in several markets in Asia-Pacific namely, Australia, China, Hong Kong, Japan, Malaysia, Singapore, and South Korea,
Most human cell and tissue (HCT) therapy products will be regulated under Classes 2, 3, and 4.
As CAR T-cell therapy involves genetic modification of cells and the intrinsic function of the donor biological has been changed, it is classified as a Class 4 biological. The level of dossier requirements to demonstrate of efficacy, safety, and quality will depend on the level of classification. The regulatory pathway for in vivo gene therapy products (e.g., adeno-associated virus vectors) are classified as prescription medicines14 in which the sponsor will need to fulfil the requirements stipulated in the Australian Regulatory Guidelines for Prescription Medicines.15
Priority review and provisional approval are fast track approval pathways that allow certain prescription medicines for serious or life-threatening conditions accelerated access into the Australian market. For provisional approval pathway, the sponsor can apply for time-limited provisional registration for certain promising new medicines, based on preliminary clinical data where there is the potential for a substantial benefit to Australian patients. Provisional registration of prescription medicines under this pathway is limited to a maximum of 6 years.16 This pathway could make a product available for use up to 2 years earlier than normal. For priority review, TGA can complete the review up to 3 months earlier because of the more flexible evaluation process. Priority review involves the same amount and type of evidence as the standard review process.17
TGA has also adopted international guidance documents – for example, European Medicines Agency (EMA) guidelines on quality, safety, and efficacy aspects in cell and gene therapy manufacturing – which are published on the TGA’s International Scientific Guidelines followed in Australia.18 Some autologous human and cell tissue products19 may be excluded from TGA regulation or exempt from some TGA regulations. The level of regulation for autologous human and cell tissue products is based on the level of risk, level of external governance and clinical oversight, or depending on the manufacturing processes or intended use of the autologous HCT product. In May 2021, the TGA conducted a public consultation seeking feedback on a proposal to remake some of the legislative instruments relating to HCT products (including blood and blood components), which sunset in October 2021.20
Genetically modified organisms (GMOs) are also regulated by the Gene Technology Act 2000.21 The law was established to protect public health and safety and the environment by identifying risks posed by, or because of, gene technology and by managing those risks through regulating certain dealings with GMOs that include gene therapy products and certain Class 4 biologicals. The Office of the Gene Technology Regulatory (OTGR)22 is responsible for providing the regulatory oversight for the law, and applicants must apply to OTGR to handle or import such products in Australia.
Under the existing framework, cell and gene therapy products are classified as biological products and sponsors would need to fulfill the requirements for a biological product in China. Early consultation with the agency to discuss the clinical development plan is strongly encouraged. In 2020, the NMPA published the New Drug Registration Regulation, which established the four expedited review pathways for drugs used in serious life-threatening diseases to fulfill local unmet medical need: breakthrough therapy designation, conditional approval, priority review, and special emergency approval for public health emergencies.29 Most advanced therapies would qualify for these expedited pathways, which allow for quicker research and development and eventually faster product approvals.
The agency has also taken an active role in the international arena and submitted two reflection paper proposals to the International Council for Harmonisation (ICH) on cell and gene therapy product,30 which demonstrated its commitment to advocate international cooperation and harmonization in advanced therapies. In the most recent rendition of China’s 5-year plan and goals for national economic and social development, published in March 2021,31 the government has prioritized the innovation of gene and regenerative medicine to encourage research and development in advanced therapies. The hope is that having strong policy in place will provide continued support for the advanced therapy environment and eco system and that it will facilitate more multilateral collaborations between academia, biotech companies, and government.
With this new act, the industry anticipates shorter research and development time for these products of up to 4 years. The ministry will designate the advanced biopharmaceuticals as products for fast track since they should be developed swiftly. The commercialization of the products will be supported by customized and priority reviews from the early stage of development. The approval process of the products for fast track is shortened from 115 days to 90 days.43 MFDS has also issued various guidelines in cell, gene, and tissue therapy, such as guidelines on quality assessment for gene-editing based advanced therapy medicinal products,4 nonclinical assessment of gene therapy products,45 and cell-based combination products using scaffold. Sponsors will also need to fulfil the requirement stipulated in the guidelines, depending on the product category.
To enhance the competitiveness of local environment in advanced therapies, MHLW also set up the Korea Institute of Drug Safety & Risk Management. The institute serves as a regulatory science center for researching and investigating policies related advanced therapies and nurturing the experts needed for manufacturing and managing the quality of the products.
In Singapore, advanced therapeutics are known as cell, tissue, and gene therapy products (CTGTPs) and are regulated by the Health Sciences Authority (HSA). The Health Products Act (HPA) and Health Products (Cell, Tissue and Gene Therapy Products) Regulations, which came in effect on 1 March 2021, provide the main regulatory framework for CTGTPs.
The products are risk-stratified into Class 1 (low risk) and Class 2 (higher risk).46 To be classified as Class 1, the CTGTP must fulfil all the criteria: minimally manipulated; intended for homologous use and not combined; or used in conjunction with therapeutic products or medical devices and examples will include bone grafts, amniotic membrane. Other CTGTPs not classified as Class 1 will be classified as Class 2, which includes CAR-T cell therapy, gene therapy, and culture-expanded cells. The framework covers the whole lifecycle management of CTGTPs, from clinical trials to product registration, postapproval variations, dealers’ licenses, safety monitoring, and product recall.
As HSA adopts a risk-based approach, the lower-risk Class 1 CTGTP requires only prior notification to HSA. Full product registration is required for Class 2 CTGTPs, and HSA may grant conditional registration with postapproval commitments to a Class 2 CTGTPs that meet all the criteria: intended to treat an unmet medical need; product safety established in early clinical trials; and preliminary data shows meaningful evidence of therapeutic benefit (a clinically significant endpoint) compared with other available therapies (standard of care).47 Results of the confirmatory studies should be submitted within a prescribed timeline for evaluation before obtaining full marketing approval.
Research, innovation, and enterprise are cornerstones of Singapore’s national strategy to develop a knowledge-based, innovation-driven economy and society. Building on the government’s Research, Innovation and Enterprise (RIE) 2020 plan, Singapore government announced in March 2019 that it would be investing S$80 million to develop core capabilities required for cell therapy manufacturing.48 The Agency for Science, Technology and Research Singapore has dedicated teams to conduct cutting-edge discovery research in advanced therapies49 to develop expertise to contribute the development of local eco system.
Tags: Advanced therapies, Asia-Pacific, medicine', regenerative