Volume 20, No. 1 February, 2013
Current Regulatory Development of Somatic Cell Therapy Products in Taiwan
Division of Drugs & New Biotechnology Products,
Food and Drug Administration, Department of Health,
Executive Yuan, Taiwan, R.O.C.
Introduction
The improvement of human life quality is often the driving force of the development of newly innovative technologies. Biotechnology has been regarded as the key industry of the 21st century, which can be applied into medicine, food, agriculture, and even environmental protection and industrial process. It has made important impact to human life. As the cuttingedge medical technologies develop continuously, the applications to cell- and gene-based therapy products and recombinant DNA technologies are becoming more mature and offer more patients with the hope of fighting untreatable diseases.
Scope and Features of New Biotechnology Products in Taiwan
The successful bone marrow transplantation in 1968 has opened the door to cell therapy in clinical applications. Recently with more advanced studies on the molecular characteristics of stem cells, there have been over 500 companies involved in cell therapy studies and hundreds of clinical trials conducted annually in the USA and Europe. Some cell therapeutic products have already gone through non-clinical and clinical studies to get their product license.
In Taiwan, somatic cell therapies have been taken as the new medical technologies in the early times (1996~2006). For the adaption to this rapid development, somatic cell therapy products are redefined as new biotechnology products and governed by both the regulations of
Pharmaceutical Affairs Act and Medical care Act. The agency for taking the responsible for the regulations or oversight of somatic cell and gene therapy products was switched from Bureau of
Medical Affairs, Department of Health to Food and Drug Administration, Department of Health,
Executive Yuan, Taiwan (TFDA) on Jan. 1st, 2010.
Currently TFDA has not yet approved any human cell or gene therapy product for marketing use. The amount of cell- and gene-related research and development including autologous chondrocytes, autologous skin fibroblasts, autologous and allogeneic mesenchymal stem cells, dendritic cells…etc. are still in clinical developmental stage. More than 90% somatic cell therapy and gene therapy studies in Taiwan are academic and medical center-initiated clinical trials. TFDA has found that during 1999 to 2010, only 15 to 20 somatic cell product applications for clinical trials were submitted annually, and those for gene therapy were fewer.
The major areas for disease treatment are neurology (stroke), gynecology (carcinoma of uterus), oncology (liver and lung cancer), ophthalmology (cornea damage) and orthopaedic disease (cartilage repairs).
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Volume 20, No. 1 February, 2013
Challenge and Critics for the Somatic Cell Therapy Products Applications
The greatest challenge for the development of somatic cell therapy products is how to prevent the potential risks from cell therapy treatment. Will cells survive and integrate into the surrounding tissues after implantation of the cell therapeutic products to patient? Is there any risk for malignancy after implantation of the stem cell therapy products? Will gene transfer vector migrate and integrate into germ-line and affect the next generation? Many questions still need further studies to identify scientific answers.
Currently, the new biotechnology product developments in Taiwan are mostly in early clinical trial stages. In order to deliver a safe and effective cell and gene therapy products, they need to follow Investigational New Drug (IND) application process to prove the product safety and effectiveness. The investigator should provide the sufficient information for IND application.
In general, safety is the primary concern for the regulatory agency in phase I human clinical studies.
Development of Somatic Cell Therapy Regulations
In response to the variety and rapid development of novel cellular and gene-based products, the regulatory agency shall establish regulations for clinical trials and new drug approval for the new biotechnology products in many countries.
In Taiwan, somatic cell therapies products should also fulfill the regulations, such as Good
Tissue Practice (GTP), Good Laboratory Practice (GLP), and Good Clinical Practice (GCP). The manufacturing needs to follow the Good Manufacturing Practice (GMP) when the products are matured for marketing. Additionally, TFDA has announced two draft guidance for cell therapy products: “Guidance for sponsors and TFDA reviewers: Content and Format of investigational new drug applications for human somatic cell and gene therapy products” and “Guidance on
Investigational human somatic cell products” on Feb. 22, 2011. The guidance provides the recommendations for an investigational new drug application of a human somatic cell therapy.
According to the draft Guidance, the term somatic cell therapy refers to the administration of autologous, allogeneic, or xenogeneic somatic or stem cells to human with the aim of disease therapy, diagnostics or prevention. The principle of somatic cell therapy applies to those patients with life-threatening or serious defects in life quality. The reproductive cells which could affect the genetic-to-genetic or reproductive functions, such as the somatic cell nuclear transfer
(SCNT) or other methods of human replication are totally forbidden.
The cell therapy product contains living cells and the cells can be cultured in-vitro and gene modified ex-vivo for subsequent administration to humans. They present many manufacturing challenges. In order to deliver a safe and effective somatic cellular product, sponsors should assess the safety, identity, purity and potency of the investigational product and demonstrate the quality of product. Therefore, documents regarding the information of product manufacturing and characterization and quality testing should be provided for IND application including (1)
Control of starting and raw materials: donor screening and testing of infection virus should be applied to those autologous, allogeneic, or xenogeneic cells to exclude the pathogen or
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Volume 20, No. 1 February, 2013 immunedeficiency and follow the principle of “Subjects Protection”. (2) Manufacturing process and in process control: Highly quarantine procedures to prevent the pathogen contamination during culturing, preservation, or delivering which should follow the GTP and/or GMP guidance.
(3) Release testing for final product and stability; (4) Product traceability and labeling; (5) Biosafety: public health and biohazard concern should be addressed.
Besides quality data, non-clinical studies or published scientific papers are needed to provide for IND application for supporting further clinical use. The principles of these studies are to provide information including (1) To select a safe starting doses and dose escalation scheme for clinical trials; (2) To support the route of administration and the application schedule; (3) To identify target organs for toxicity and parameters to monitor in patients receiving these therapies;. (4) To support the duration of exposure and the duration of the follow-up time to detect adverse reactions.
In the future, TFDA will continue to work together with industries, academic researchers, medical and research centers to improve the regulatory framework for the new biotechnology products, held seminars and training courses, and offer regulation consultation and assistance.
Hope that these actions of improvement will help investigators who develop these innovative products better understanding the regulatory requirements and compliance with the regulations of clinical trial application, product registration for marketing to benefit patients in need.
Conclusion
Currently, the new biotechnology products in Taiwan are still under development. However,
Taiwan government has identified biotechnology as one of the key issues for the country. This target encourages many research institutes to allocate human and financial resources for developing of the cell therapy conducting clinical trials or commercializing products. TFDA in
Taiwan has promised to cooperate with the industry, research institutes, medical hospitals and other government organizations to promote and provide the environment for these products’ development.
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