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Statutory regulations: Gene therapy, xenotransplantation or stem cell therapy

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Introduction

Creation of stem cells lines

The creation of embryos (human or human admixed embryo) for research, including for the development of embryonic stem cells, is regulated by the Human Fertilisation and Embryology Authority (HFEA).  The collection of adult, placental and other stem cells (including fetal and umbilical stem cells) is regulated by the Human Tissue Authority (HTA). 

The UK Stem Cell Tool Kit guides those conducting human stem cell research through the regulatory requirements (a link for the Tool Kit is provided in the resources below).  The Tool Kit was developed jointly by UK regulators as a reference tool for those who wish to develop a programme of stem cell research and manufacture, including clinical applications.

Trials of Advanced Therapy Medicinal Products (i.e. stem cell therapy, gene therapy etc) 

Clinical trials of gene therapy and stem cell therapy (i.e. studies to investigate the safety and/or efficacy of gene therapy or stem cell therapy) and other tissue engineered medicinal products (TEP), are classed as trials of Advanced Therapy Medicinal Products (ATMPs), if they are being presented as exerting principally a pharmacological, immunological or metabolic action.  As such they must be conducted in compliance with the Advanced Therapy Medicinal Products Regulations (EC) No 1394/2007, and must be approved by the Competent Authority (the MHRA).  Both the MHRA and EMA provide guidance on Advanced Therapy Medicinal Products (see resources below), and further information on what constitutes a medicine or medicinal function is given on the MHRA Borderline Medicines pages (available from resources below). 

Further guidance is also available on this Tool Kit, at 'Statutory requirements: Gene therapy, xenotransplantation and stem cell therapy' and 'Statutory requirements: Collecting and using human tissue' (information on trials of tissue engineered products).

Xenotransplantation 

The UK Xenotransplantation Interim Regulatory Authority (UKXIRA) ceased to exist in 2006.

The Home Office released Guidance on the use of Human Material in Animals in January 2016 (see below). The guidance classifies experiments involving animals containing human material (ACHM) into three categories:

Category 1 covers the great majority of ACHM experiments which do not present issues beyond those of the general use of animals in research. These experiments are subject to the same oversight and regulation under the Animals (Scientific Procedures) Act (ASPA) as other animal research.

All Category 1 experiments currently carried out in vivo are regulated under the ASPA either due to the effect on the animal source of the cells/tissues; on the recipient animal; or on the potential animal offspring.

Category 2 would currently include research involving:

  • substantial modification of an animal’s brain that may make the brain function potentially more ‘human-like’, particularly in large animals;
  • experiments that may lead to the generation or propagation of functional human germ cells in animals;
  • experiments that could be expected to significantly alter the appearance or behaviour of animals, affecting those characteristics that are perceived to contribute most to distinguishing our species from our close evolutionary relatives; and
  • experiments involving the addition of human genes or cells to non-human primates.

Category 2 experiments are regulated solely under ASPA if they do not involve human embryos, or human gametes. Experiments involving human embryos, human gametes that will be used to create an embryo, or human admixed embryos in which the human component is predominant will also require authorisation by the HFEA. Where the necessary authorisation is unclear or uncertain, advice should be sought from both the HFEA and Home Office. In such cases, the HFEA and Home Office will liaise to determine what regulatory framework(s) are appropriate and advise accordingly.

In all cases advice will also be sought from the Animals in Science Committee.

Note that, where human tissues and cells are being stored for the purposes of research ‘in connection with disorders, or the functioning, of the human body’, before they are transplanted into a recipient species, an HTA licence may also be required.

Category 3 covers a very narrow range of experiments which, for now, will not be licensed because they either lack compelling scientific justification or raise very strong ethical concerns. The list of such experiments, at present, includes:

  • allowing the development of an embryo, formed by pre-implantation mixing of non-human primates and human embryonic or pluripotent stem cells, beyond 14 days of development or the first signs of primitive streak development (whichever occurs first); unless there is persuasive evidence that the fate of the implanted (human) cells will not lead to ‘sensitive’ phenotypic changes in the developing fetus;
  • transplantation of sufficient human-derived neural cells into an non-human primate as to make it possible, in the judgement of the Animals in Science Committee, that there could be substantial functional modification of the non-human primate brain, such as to engender ‘human-like’ behaviour. Assessing the likely phenotypic effect of such experiments will be informed by prior work on other species (possibly including stem cell transfer between non-human primates) or by data on the effects of ‘graded’ transplantation of human cells into non-human primates; and
  • breeding of animals that have, or may develop, human derived germ cells in their gonads, where this could lead to the production of human embryos or true hybrid embryos within an animal.

The list of Category 3 experiments will be kept under continuous review by the Animals in Science Committee.

Research which falls into Category 3, or could do so, will always undergo detailed scrutiny by the Home Office and the HFEA and advice will also be sought from the Animals in Science Committee.

Human tissue xenografts

Human tissue xenografts are the transplantation of human cells, tissue or organs into another species and as such they are subject to the requirements of the Human Tissue Act 2004.  What this means in practice is:

  • Consent – If it is known at the time of obtaining consent that the intention is to transfer the individual’s cells, tissue or organs into an animal model, then this should be explained to the individual and consent should be obtained for this.
  • Licensing - The application of human tissue xenografts in itself does not require a licence.  However, where human tissue and cells are being stored for the purposes of research ‘in connection with disorders, or the functioning, of the human body’ before being transplanted into a recipient species, a licence may be required.

Ethics approval of gene therapy, xenotransplantation or stem cell therapy trials

If you are proposing to undertake a research study involving gene therapy, embryonic stem cell therapy, the therapeutic use of genetically modified stem cells, or therapeutic xenotransplantation, you may need to apply to an NHS Research Ethics Committee (REC) which has been flagged to review 'Gene Therapy or Stem Cell Clinical Trials' (see Gene Therapy Advisory Committee resource below for information on how to apply).

These specially flagged NHS RECs also have responsibility for providing ethical review for studies involving the delivery of synthetic or recombinant nucleic acids into humans, such as:

  • Genetically modified biological vectors (e.g. viruses or plasmids)
  • Genetically modified stem cells
  • Oncolytic viruses
  • Nucleic acids associated with delivery vehicles
  • Naked nucleic acids
  • Antisense techniques (for example, gene silencing, gene correction or gene modification)
  • Genetic vaccines
  • DNA or RNA technologies such as RNA interference
  • Xenotransplantation of animal cells (but not solid organs)

Further guidance is provided on the Ethical Approval page of this Tool Kit.

Resources

  • 1. HFEA (Human Fertilisation and Embryology Authority)

    The independent regulator overseeing the use of gametes and embryos in fertility treatment and research. The HFEA license human embryo research and provide details on how to apply for a research licence, current ongoing research as well as codes of practices and other guidance.

    Legal Requirement for some em studies (not applicable for all) Date added: 28 October 2008
  • 2. HTA (Human Tissue Authority)

    The Human Tissue Authority (HTA) is the regulatory authority with responsibility for licensing, inspecting and defining codes of practice, with respect to research use and therapeutic use of human tissue (apart from human embryos or fertilisation).

    Legal Requirement for some em studies (not applicable for all) Date added: 23 October 2008
  • 3. UK Stem Cell Tool Kit

    A regulatory tool for those conducting human stem cell research in the UK.

    Legal Requirement for some em studies (not applicable for all) Date added: 18 January 2010
  • 4. NIHR Clinical Trials Toolkit

    This web-based resource is designed to support clinical trialists and regulators in ensuring clinical trials of investigational medicinal products are conducted in accordance with the Medicines for Human Use (Clinical Trials) Regulations.

    Legal Requirement for some em studies (not applicable for all) Date added: 29 October 2008
  • 5. ATMP: Advanced Therapy Medicinal Product Regulations (EC) No 1394/2007

    European Regulations for the conduct of clinical trials of Advanced Therapy Medicinal Products (ATMPs). These include trials of gene therapies, stem cell therapy, and tissue engineered therapy. The Regulations include a working definition of trials covered.

    Legal Requirement for some em studies (not applicable for all) Date added: 18 November 2008
  • 6. EMA: Advanced Therapy Medicinal Products

    European Medicines Agency (EMA) guidance on Advanced Therapy Medicinal Products (ATMPs) i.e. medicines for human use that are based on gene therapy, somatic-cell therapy or tissue engineering.

    Legal Requirement for some em studies (not applicable for all) Date added: 18 November 2008
  • 7. MHRA: Advanced Therapy Medicinal Products

    MHRA guidance on how advanced therapy medicinal product trials (ATMPs) are regulated in the UK (including tissue engineering, gene therapy and stem cell therapy).

    Legal Requirement for some em studies (not applicable for all) Date added: 18 November 2008
  • 8. MHRA: Borderline Products

    MHRA Borderline Products pages provide definitions of what constitutes a medicine / medicinal function.

    Legal Requirement for some em studies (not applicable for all) Date added: 18 November 2008
  • 9. IRAS (Integrated Research Application System)

    The Integrated Research Application System (IRAS) is a single system for applying for approvals for health and social/community care research in the UK.

    Standard Process for all research Date added: 29 October 2008
  • 10. HRA Gene Therapy Advisory Committee

    The Gene Therapy Advisory Committee (GTAC) is the UK national Research Ethics Committee (REC) for gene therapy clinical research according to regulation 14(5) of the Medicines for Human Use (Clinical Trials) Regulations 2004. Since 2012, the Health Research Authority has taken responsibility for reviewing these applications via NHS RECs flagged as 'Gene Therapy or Stem Cell Clinical Trials'.

    Legal Requirement for some em studies (not applicable for all) Date added: 23 October 2008
  • 11. HRA guidance on applying for research approvals

    Guidance on approvals provided by the Health Research Authority.

    Good Practice for all research Date added: 29 October 2008
  • 12. Nuffield Council on Bioethics

    The Nuffield Council on Bioethics examines ethical issues raised by new developments in biology and medicine. Reports are available on the ethics of xenotransplantion, stem cell research and genetic screening etc.

    Good Practice for some em studies (not applicable for all) Date added: 29 October 2008