Regulation of stem cell lines
Before the transposition of the European Union Tissue and Cells Directive (EUTCD), cell lines derived from human embryos were subject to regulation by two regulatory bodies: the Human Fertilisation and Embryology Authority (HFEA) and the Medicines and Healthcare products Regulatory Agency (MHRA). The HFEA regulates the creation and use of embryos prior to the derivation of human embryonic stem (hES) cell lines for research. The MHRA regulates the use of investigational medicinal products (IMPs) in clinical trials in the UK – this would include the use of cell lines as a component of an IMP. Eventual authorisation of a medicinal product in the UK falls under the remit of the MHRA or the European Medicines Agency (EMA).
It is widely acknowledged that the intention underlying the creation of cell lines is that they will eventually be used as a medicinal product. However, at the point of creation of any particular cell line it is not possible to predict whether it will eventually result in being used for patient treatment in a medicinal product or whether it will remain purely as a resource for research.
Since the 5 July 2007, any human tissue that is used in patient treatment must comply with all the requirements of the EUTCD. In view of this it is imperative that a cell line created with the intention that it will at some point in the future be used in patient treatment, can be shown to comply with the EUTCD. Failure to comply with the EUTCD requirements could in the future adversely affect an application for authorisation of a medicinal product.
An online tool-kit has been developed by the Department of Health and the Medical Research Council in conjunction with regulatory authorities, including the HTA. It describes the necessary arrangements to be made following choices specific to each project.
The Human Fertilisation and Embryology Authority (HFEA) regulates the use of gametes and embryos for use in fertility treatments and research. An HFEA research licence is required for any activity involving the use of an embryo for research. Therefore, an HFEA research licence must be in place before an embryo can be used for the purpose of creating cell lines. Once a cell line has been created it is a condition of an HFEA research licence that a sample line is deposited in the UK Stem Cell Bank. At this point the HFEA’s regulatory remit ceases.
The HTA’s regulatory authority commences at the point the embryo is disorganised and cells are grown to create cell lines with the intention that the lines may at some future time be used in human application. Therefore, any organisation processing, testing, storing and distributing human embryonic stem cell lines with the intention that they may be used in patient treatment may only do so under the authority of an HTA licence.
Under the Regulations, the HTA is responsible for ensuring that any tissues or cells intended for patient treatment conform to the requirements of the EUTCD. A consequence of this is that the HTA will require evidence to show that a human embryonic cell line intended for patient treatment was procured in accordance with the Directives, and that the environment in which the source materials (i.e. the gametes and resultant embryo) were processed, complied with the technical requirements of the Directives.
At the time of procurement the primary intention is to procure gametes to create viable embryos for use in fertility treatment. However, if a cell line from a donated embryo is created with the intention that it will be used in human application, the HTA requires evidence that the procurement of the source materials (i.e. the gametes) complied with the requirements of the Directives. Therefore, compliance with standards for the consent, donor selection criteria, parental viral screening and traceability will ensure that procurement has taken place in accordance with the Directives. A failure to comply with the procurement requirements of the Directives may prevent the future use of the cells in patient treatment.
The EUTCDs set very specific standards regarding the environment within which human tissues and cells must be processed if they are to meet the standards of quality and safety required for use in human application. These standards apply to any processing carried out on a cell line created from an embryo and also to the source materials from which the cell line was created i.e. the gametes and embryo.
In particular, if tissues or cells are exposed to the environment during processing, the air quality must meet particle count and microbial colony count standards that are equivalent to those of Grade A, with a background environment at least equivalent to Grade D (see HTA Directions 002/2018 paragraph 40). Tissues or cells not processed in a Grade A against D background must be stored separately and a risk assessment carried out to ensure that they meet suitable standards of quality and safety for use in patient treatment.
The Human Tissue Act 2004 licenses (amongst other activities) the storage of relevant material for use for research. The Human Tissue Act explicitly excludes from its remit the licensing of material if it is created outside the human body. Therefore, the regulation of cell lines for research falls outside of the HTA’s remit.
Cell lines that are European Union Tissue and Cells Directive (EUTCD) compliant should be stored separately from those that are not to avoid any potential contamination issues.
Any establishment in the UK that carries out certain activities in relation to cell lines for patient treatment requires either a licence from the HTA under the Quality and Safety Regulations 2007 or have a third party agreement (TPA) in place with an establishment that is licensed by the HTA. Procurement is one of these activities, but for human embryonic stem cell lines this activity is licensed by the HFEA. The other activities that require either a licence or TPA are:
- import / export; and
Any establishment storing cell lines in the UK for human application may only lawfully carry out this activity if licensed to do so by the HTA under the Regulations. Storage, unlike the above activities cannot be carried out under a third party agreement.