Cellular Therapies: Regulating Uncertainty in Asia’s Biomedical Hubs

International Regulatory Approaches to CTPs

Cell therapy products (CTPs) are a class of therapeutics based on human cells and/or biological derivatives of human cells.¹ According to an international regulatory review, these products are generally regulated within frameworks that impose restrictions on the sale and distribution of CTPs depending on their level of risk. With this framework, CTPs that are assessed as being high-risk are regulated more stringently than those that are categorised as low-risk.² This approach is aimed at allowing patients to access low-risk products under the supervision of their doctor while providing an evidence-based pathway for CTPs that are regulated as medicinal or biological drugs.³ However, the framework may have also created structural weaknesses that are being exploited by networks of clinicians, businesses and healthcare providers who are offering CTPs without establishing clinical evidence of their safety and efficacy.

This article examines the regulatory frameworks that oversee the use of CTPs in Japan, Singapore and South Korea, and the introduction of new provisions that provide sponsors with rapid approvals to market their product before evidence of efficacy has been established in clinical trials. For this examination, the analysis is set out in parts. The first provides a conceptual overview of the risk-based framework and identifies problems associated with the current classification systems for CTPs. The second part describes how this framework has been applied in Singapore, Japan and South Korea, and discusses the advantages and disadvantages of the new rapid approval provisions. It is argued that while these rapid approval systems provide sponsors with early access to the market, they have the potential to discourage investment in large-scale efficacy trials.

Risk Classification of CTPs

Within risk-based frameworks, CTPs are generally classified according to four criteria: the source of the donor cells; their intended use; degree of manipulation or processing that they are exposed to; and whether they are administered in the same surgical procedure. Donor cells and tissues may be sourced either from the recipient (autologous) or from another person (allogeneic).⁴ Autologous cells are typically regarded as having lower risks than allogeneic cells because the donor and recipient is the same person. Thus, autologous cells do not raise an immune response, and related complications, such as graft-versus-host disease, are avoided.

Whether the CTP is intended for homologous use in the same or functionally-compatible tissues can also affect its risk profile. For example, injecting cells derived from the bone marrow into the brain would not be considered as homologous use and so would not be classified as low-risk. However, this criterion is difficult to assess where the CTP involves early progenitor cells that may be differentiated into multiple tissue-types that are functionally compatible. Whether cells are administered in a single procedure can also be difficult to assess where samples are banked in storage facilities for a time until they are administered to a patient. Given these difficulties, the key classification criterion usually falls onto the degree of cellular manipulation.

Cellular manipulation is the most important criterion because the more cells are altered from their original state, the harder it is to predict how they will behave when transplanted in vivo. The processes that constitute minimal manipulation vary in different countries but there is a general consensus that as cells undergo successive manipulations, the more they start to look like a manufactured drug product than cells that are simply isolated and transplanted from one part of the patient to another. Hence, autologous CTPs that are minimally manipulated and intended only for homologous use are usually regarded as carrying lower risks. These products are subject to fewer regulatory controls than allogeneic CTPs or cells that have been subjected to extensive manipulations and should be exposed to greater regulatory oversight.

Based on this classification, CTPs that are excluded from regulation as medical or biological drug products are considered medical procedures. For example, while whole organs for transplant are excluded from regulation as a medical procedure, organs that are synthetically engineered are regulated as combined drugs/devices.⁵ Autologous skin and bone...