Legal and policy frameworks for clinical-grade stem cell banking.

• Author: Ulmer, Elizabeth

Introduction

The potential applications of stem cell therapy and regenerative medicine make this area of research a dynamic, fast evolving field. To accommodate the considerable growth of stem cell research, banks have been created to provide researchers with access to current, high quality stem cell lines.' Banks accept and distribute stem cell lines to and from researchers, providing documentation on their use and provenance. Banks fulfill important functions to ensure the cell lines are ethically sourced and the quality of cell lines is reliable,2 helping to realize the full potential of stem cells.

While many clinical applications of stem cell research remain distant possibilities, some novel stem cell-based therapies are beginning to be developed and tested. As these efforts continue, stem cell banks will increasingly take on an important role in the distribution of clinical-grade stem cell lines that can be used to develop therapies administered to humans. In December 2011, the first clinical-grade stem cells were deposited with the United Kingdom Stem Cell Bank (UKSCB),3 marking a shift to a new era in stem cell banking. More recently, plans were announced to establish a bank of clinical-grade induced pluripotent stem cells (iPSCs) in Japan.4

As the banking of clinical-grade stem cells gains momentum, this will bring new regulatory and policy issues into play. The aim of this article is to describe the legal and policy framework relevant to stem cell banking, with a focus on clinical-grade stem cell lines, and to identify some of the issues and challenges that arise in the context of clinical-grade stem cell banking.

Stem Cell Banks

The phrase "stem cell bank" is sometimes used to refer to both stem cell registries and repositories. Registries are databases that collect and provide information on derived stem cell lines. The European Human Embryonic Stem Cell Registry and the UMass International Stem Cell Registry are examples of stem cell registries.' Repositories are facilities that process, store, and maintain the actual stem cell lines such as the UK Stem Cell Bank (UKSCB), the Spanish National Cell Bank, and the US Wisconsin International Stem Cell Bank (WISC)."Registries and repositories are not mutually exclusive and have complementary functions.' They provide researchers with information about matters such as stem cell provenance and culture methods, enabling more accurate and reliable research. Coordination among these functions is critical for the advancement of stem cell research, providing researchers with the materials and information to produce the highest quality work. This article is primarily concerned with repositories and unless otherwise indicated, the term "stem cell bank" in this article refers to banks that are acting as repositories and are actually handling human cells. Stem cell banks play a significant role in the advancement of stem cell research. Given the rapid expansion of the science, centralized stem cell banks are needed to provide researchers with access to cell lines!' By providing access to existing lines, banking reduces the need for derivation of new cell lines; in the case of human embryonic stem cells, in particular, this has ethical value because it reduces the number of human embryos that must be destroyed.' Banks also reduce unnecessary duplication in research by screening applications for use of cell lines,'" and minimize waste and errors by promoting standardization."By ensuring the maintenance of only ethically sourced cells using accepted quality conditions, stem cell banks promote consistency, safety, and ethical conduct in cell line derivation and subsequent use in research.

The benefits of using stem cell banks will also extend to clinical applications. There is general agreement that the use of centralized banks will serve the development of stem cell research, especially as it moves into clinical translation. (12) A global network of centralized banks could ensure the availability of standardized, high-quality cells for research and therapeutics. (13)

Clinical-grade Stem Cells

The ultimate goal of stem cell research is the development of therapies, treating debilitating and life-threatening conditions including, for example, neurodegenerative and cardiovascular diseases, spinal cord injuries and strokes. (14) Until recently, stem cell banking has been focused on research-grade stem cell lines, which are used for basic (preclinical) research purposes and are not administered to human patients. In the last five years there has been increasing progress in the development of clinical-grade lines; these developments call attention to the unique considerations that must be given to this type of stem cell line. (15)

Research-grade stem cell lines are derived and cultured using animal-based materials, making them uxeno-contaminated" with non-human pathogens, increasing the likelihood of infection or rejection when administered to human subjects. (16) It is important to note that although stem cells have already been used by companies in clinical trials, those were in fact "research-grade" lines that had been reclassified as "clinical-grade" for those specific trials. Given the cost and risk associated with this approach, it is not suitable for the long-term development of therapies. (17) For the future of stem cell therapies to be viable, the focus must be placed on the development of "true" clinical-grade cell lines. (18) Stricter standards apply to these cells, given that they will be used in, or in the production of, a medical product or therapy that is intended to be administered to human patients. Clinical-grade lines are, ideally, derived and maintained "independent of feeder cells and animal biologics. (19) To properly develop cell lines suitable for long-term therapeutic use, methodologies that provide "xeno-free" lines are necessary. (20) Furthermore, clinical-grade cells must be manufactured under conditions that are compliant with "Good Manufacturing Practices" (GMP). (21) In 2007, a paper was released detailing the generation of six clinical-grade hESC lines. (22) These lines were derived under strict adherence to established protocols, from the procurement of embryos to the stem cell line derivation. (23) A group of UK scientists later created animal product-free clinical-grade lines. (24)Stringent protocols are needed to help guide the derivation methods and application of clinical-grade stem cells, ensuring consistent, reproducible products. Banks must adopt these practices to provide researchers with the highest quality product possible. (25)

Clinical-grade stem cell banking will play an important role in the progression of stem cell research to the eventual production of stem cell therapies. Recent developments have brought clinical-grade stern cell banking to the forefront. In December 2011, it was announced that scientists from King's College London submitted the first clinical-grade stem cell lines, free of animal products (or "xeno-free"), to the UKSCB. (26) The stem cell lines submitted to the UKSCB will undergo rigorous review and testing before they can be banked and distributed; it is likely the bank will not approve all of the lines submitted once the tests are complete. (27) The deposit of clinical-grade lines is seen as a major step toward the eventual clinical use of stem cells, although it will be some time before they are used in clinical trials. (28)

In 2012, it was announced that the Japanese government was supporting the creation of a bank of clinical-grade iPSCs for use in clinical trials and therapies.29 The plan is to provide a supply of iPSC lines that could be compatible with 80% of the country's population."Even more recently, two UK-based companies announced plans to produce and bank GMP-compliant human iPSCs for use in clinical research, with the...