Code of practice for consultation
Research Code 9
This code of practice is for consultation purposes only and has not received Parliamentary approval. You should continue to use the current versions of the codes (available at: www.hta.gov.uk/guidance/codes_of_practice.cfm) until this revised code has been approved.
Contents Paragraphs Introduction
1–24
•
About the Human Tissue Authority
1–6
•
Legislation and statutory framework
7–14
•
Codes of practice
15–24
Scope of this code
25–30
Structure and navigation
31
Status of this code
32
Scheduled purposes
33–36
Consent
37–54
•
Obtaining consent
37–43
•
Exceptions to the need for consent
44–54
Licensing
55–71
•
When a licence is, and is not, needed
55–63
•
Ethical approval of research projects
64–71
Relevant material and research
72–85
•
Acellular material
72–73
•
Relevant material in the context of diagnosis and post-mortem examination
74–79
•
Tissue blocks and sections on slides
80–81
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•
Cells cultured from relevant material
82–83
•
Genetic research on relevant material
84–85
Relevant material and human application
86–90
•
Cell lines and stem cells
86–87
•
Clinical trials
88–90
HTA licensing standards
91–124
•
Standards for research
94–96
•
Governance and quality systems
97–112
•
Premises, facilities and equipment
113–124
Appendix Appendix A: Licensing and consent flowcharts
References
Glossary
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Introduction About the Human Tissue Authority Role of the Human Tissue Authority 1.
The Human Tissue Act 2004 (HT Act) [www.opsi.gov.uk/acts/acts2004/ukpga_20040030_en_6#sch1] established the Human Tissue Authority (HTA) to regulate activities concerning the removal, storage, use and disposal of human tissue (referred to as relevant material in the HT Act). Activities covered by the HT Act are referred to as scheduled purposes.
2.
The HTA has several statutory functions. One is to inform the public, professionals and the Secretary of State for Health about issues within our remit. We meet this requirement for professionals by providing guidance, including codes of practice, to support good practice.
Regulation through licensing 3.
Another statutory function is to regulate, through licensing, a number of sectors and to carry out inspections to ensure licence conditions are being met. The HTA publishes standards that licensed establishments must meet: on consent; governance and quality systems; premises; facilities and equipment; and disposal. The sectors licensed under the HT Act are: • • • • •
4.
Anatomy Post-mortem services Human application (transplantation of tissues and cells; see below) Research Public display
The HTA is the Competent Authority in the UK responsible for ensuring the safety of human tissues and cells that are used for transplantation in compliance with the European Union Tissues and Cells Directives (EUTCD).
Regulation of living and deceased donation 5.
A third statutory function is the regulation, through a system of approvals, of the donation from living people of solid organs, bone marrow and peripheral blood stem cells for transplantation into others. The HTA, Independent Assessors and Accredited Assessors who work on behalf of the HTA, assess whether consent
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requirements for donation have been met, and act as representatives for the donors. The HTA also regulates living donation on behalf of the Scottish Government. 6.
The HTA also oversees the consent requirements of the HT Act for deceased organ donation.
Legislation and statutory framework Human Tissue Act 2004 [www.opsi.gov.uk/acts/acts2004/ukpga_20040030_en_1] 7.
8.
9.
Consent is the fundamental principle of the HT Act. The legislation covers England, Wales and Northern Ireland, and sets out the legal framework for: •
the storage and use of human tissue from living people.
•
the removal, storage, and use of tissue from the deceased.
Regulations made under the HT Act, which provide more detail, include: •
The Human Tissue Act 2004 (Persons who Lack Capacity to Consent and Transplant) Regulations 2006 [www.opsi.gov.uk/si/si2006/draft/20064576.htm]
•
The Human Tissue Act 2004 (Ethical Approval, Exceptions from Licensing and Supply of Information about Transplants) Regulations 2006 [www.opsi.gov.uk/si/si2006/20061260.htm]
Consent for diagnosis or treatment is not in the scope of the HT Act.
Human Tissue (Scotland) Act 2006 [www.opsi.gov.uk/legislation/scotland/acts2006/asp_20060004_en_1] 10. The HT Act 2004 covers England, Wales and Northern Ireland, and there is separate legislation for Scotland, the Human Tissue (Scotland) Act 2006. 11. The HT (Scotland) Act is based on authorisation, rather than consent, but both are expressions of the same principle. 12. Guidance on the Human Tissue (Scotland) Act 2006 is available in the Scottish Health Department Letter: HT (Scotland) Act 2006: A Guide to its Implications for
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NHS Scotland [www.hta.gov.uk/_db/_documents/Information_about_HT_(Scotland)_Act.pdf] and practitioners working in Scotland should ensure they are familiar with this guidance. Human Tissue (Quality and Safety for Human Application) Regulations 2007 13. The Human Tissue (Quality and Safety for Human Application) Regulations 2007 (Q&S Regulations) govern the quality and safety of tissues and cells (not including solid organs) used for transplantation. The Q&S Regulations brought the EUTCD into force in the UK, including Scotland [www.opsi.gov.uk/si/si2007/uksi_20071523_en_1] 14. There is no code of practice for establishments using tissues and cells for transplantation. However, the HTA issues Directions for these establishments which set out expected standards. Directions 001/2006 summarise the requirements of the parent and first technical Directive of the EUTCD (Directives 2004/23/EC and Directive 2006/17/EC). Directions 002/2007 set out the requirements of the Regulations 2007 and the second technical Directive (Directives 2004/86/EC), and supplement and amend Directions 001/2006. [link to Directions page of website]
Codes of practice About the codes 15. The codes of practice give practical guidance to professionals carrying out activities which lie within the HTA’s remit. They may also be of interest to members of the public. The first editions of the codes have been revised to reflect our experience of regulation. We have made the codes more relevant to the sectors we regulate by including case studies and examples; and have restructured them in a way that makes them more user-friendly. 16. They are supplemented by other more detailed guidance, for example on licensing standards, which can be found on the HTA website. 17. Failure to follow a code of practice is not in itself a criminal offence under the HT Act, but the HTA may take a breach into account when carrying out its regulatory responsibilities. For licensed establishments, adherence to the HTA’s codes of practice is assessed as part of the licensing and inspection activities.
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18. The HTA has now published nine codes of practice, which are listed below: [www.hta.gov.uk/guidance/codes_of_practice.cfm] 1.
Consent
2.
Donation of solid organs for transplantation
3.
Post-mortem examination
4.
Anatomical examination
5.
Disposal of human tissue
6.
Donation of allogeneic bone marrow and peripheral blood stem cells for transplantation
7.
Public display
8.
Import and export of human bodies, body parts and tissue
9.
Research
19. All nine codes of practice have been brought info force by HTA Directions and are either new or replace the codes previously published by the HTA. [www.hta.gov.uk/guidance/licensing_guidance/expected_standards_directions.cf m] Using the codes 20. The codes complement each other and should be read alongside other relevant guidance, either referenced in the text or provided on the HTA website. 21. The codes of practice are available in pdf form for printing, and in HTML format, which allows the reader to navigate through the codes more easily when viewed online. 22. The HTA will update these codes from time to time, and will issue Directions to bring them into force following the appropriate approval process. Other advice and guidance 23. The HTA website provides extensive guidance to help ensure that the sectors we regulate comply with the law and embrace best practice. This includes guidance
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for licensed sectors and the transplant community, patient and public leaflets, and an e-newsletter. 24. A number of other organisations have also produced guidance on issues in the HTA’s remit. Where this has been produced in collaboration with the HTA, it will appear on our website. But as a general rule, we would always advise that the HTA’s codes of practice and other guidance are used as the definitive source of information for issues within our remit. If you are in any doubt, please contact the HTA, or seek your own legal advice. Regulated sectors should also keep up to date with other relevant legislation.
Scope of this code 25. The HT Act introduced a regulatory framework within which the use of human tissue in research in connection with disorders or the functioning of the human body must now take place. The framework requires research using relevant material from either living or deceased people to be regulated through licensing of the storage of the relevant material; and research using relevant material can only be done where there is appropriate consent, subject to the exceptions set out in paragraphs 44–54. It is the storage of the material to be used for research which is the licensable activity. The consent provisions refer however to its use for research. 26. This is the first HTA code of practice covering the storage of relevant material for use in research. It addresses research in the context of the HT Act and covers research using relevant material conducted in England, Wales and Northern Ireland. 27. The HTA’s remit and licensing requirements in relation to research do not extend to Scotland, but researchers in Scotland may find this code a useful reference for good practice. 28. This code explains the consent and licensing requirements relevant to the research sector and provides guidance for people removing, using and storing relevant material for use for research, to aid compliance with the HT Act and with the HTA’s standards on governance, quality systems, premises, facilities and equipment. 29. A number of other organisations have also produced guidance on issues in the HTA’s remit. This code should be read in conjunction with guidance issued by the General Medical Council (GMC) [www.gmc-uk.org/], UK Clinical Research
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collaboration (UKCRC) [www.ukcrcrgadvice.org/bestpracticeguidance/Pages/default.aspx], Medical Research Council (MRC) [www.mrc.ac.uk/PolicyGuidance/EthicsAndGovernance/index.htm] and National Research Ethics Service (NRES) [www.nres.npsa.nhs.uk] on the use of human tissue in research. 30. For guidance on how to comply with the HTA’s consent and disposal standards, please also refer to the code of practice on Consent and code of practice on Disposal of human tissue [link]. Further guidance about licensing under the HT Act is set out in the Guide to Licensing for Designated Individuals and Licence Holders [www.hta.gov.uk/licensing/designated_individuals_and_licence_holders/dls_unde r_the_ht_act.cfm].
Structure and navigation 31. This code begins by explaining what scheduled purposes and defines research. It then covers the consent and licensing requirements relevant to the research community and offers guidance on what tissue falls under the remit of the HTA. The latter part of the code sets out guidance on how to comply with the HTA licensing standards on governance and quality systems and premises, facilities and equipment.
Status of this code 32. Research falls within the HTA’s statutory remit. This code on research is a new code of practice and has received Parliamentary approval.
Scheduled purposes 33. To understand the provisions of the HT Act as they apply to research, an understanding of what the HT Act calls scheduled purposes is required. Research is one of a number of scheduled purposes under the HT Act. 34. The HT Act does not contain a definition of research but the HTA regards research using relevant material as: A study which addresses clearly defined questions, aims and objectives in order to discover and interpret new information or reach new understanding of the structure, function and disorders of the human body. Research attempts
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to derive new knowledge and includes studies that aim to generate hypotheses, as well as studies that aim to test them or develop practical applications of new knowledge. 35. The HT Act differentiates between scheduled purposes, for which consent is required and activities for scheduled purposes, which require a HTA licence. Research is a scheduled purpose. Consent is needed therefore for research whether the relevant material is from the living or the deceased, subject to the exceptions set out in paragraphs 44–54. The activity that requires a licence is the storage for use for the scheduled purpose of research as opposed to the undertaking of the research itself. 36. Detailed guidance about the consent and licensing requirements of the HT Act and the remit of the HTA are set out below and in the flowchart in Appendix A.
Consent Obtaining consent 37. The giving of consent is a positive act. The HT Act requires that consent must be obtained for the removal, storage and use of relevant material for certain scheduled purposes, including research subject to the exceptions set out in paragraphs 44–54. 38. The general principle applying to consent for the storage and use of relevant material for research and other scheduled purposes is that, for consent to be valid it must be given voluntarily, by an appropriately informed person who has the capacity to agree to the activity in question. Adults and children (under 18 years) have capacity to consent if they can: • • •
understand the nature and purpose of the proposed procedure understand and retain information relevant to the decision consider the necessary information to arrive at a choice
39. Anyone using relevant material for research must have the necessary assurance that valid consent has been given, although they do not need to have taken or recorded the consent personally. 40. It is good practice for those people taking consent to keep a record that the person giving their consent has full knowledge and understanding of what they are consenting to.
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41. Special procedures will be needed in cases involving donors unable to give consent themselves, i.e. children who do not have sufficient understanding and intelligence to understand fully what is proposed (i.e. are not Gillick competent) and adults who lack capacity to consent. The Mental Capacity Act 2005 [www.opsi.gov.uk/ACTS/acts2005/ukpga_20050009_en_1] provides a statutory framework to empower and protect people who may lack capacity to make decisions for themselves. More detailed guidance on consent and questions of capacity are explored in the HTA’s code of practice on Consent [link] and in the code of practice to the MC Act [www.publicguardian.gov.uk/mca/code-ofpractice.htm]. 42. Researchers intending to undertake analysis of DNA must ensure that qualifying consent is in place subject to certain exemptions. Further information is given in paragraphs 84 and 85 of this code as well as the code of practice on Consent [link]. 43. Researchers should note that removal of tissue for research from the living always requires consent under common law as opposed to the HT Act. Exceptions to the need for consent 44. This section explains where exceptions to the consent requirements apply. 45. The consent requirements of the HT Act are not retrospective. This means that it is not necessary to obtain consent for material that was already held in possession at the time the HT Act came into force, that is 1 September 2006 [www.opsi.gov.uk/acts/acts2004/ukpga_20040030_en_2#pt1-l1g9] 46. Although consent is not needed to carry out research on relevant material obtained before 1 September 2006, the views of the deceased person or of their family must be respected. Where a family has expressed a wish to claim such tissue, it is good practice to seek consent. The HTA’s code of practice on the Disposal of human tissue [link] provides further information on how to dispose of existing holdings. 47. If more than 100 years have elapsed since the date of a person’s death, consent to undertake research on relevant material from that person is not required. 48. The consent provisions of the HT Act do not apply to material that has been imported. Nonetheless, the HTA considers it good practice for mechanisms to be
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in place which provide assurance that human tissue which is to be imported is obtained with valid consent. Guidance for importers wishing to import human bodies, body parts and tissue from abroad into England, Wales and Northern Ireland, is set out in the code of practice on the Import and export of human bodies, body parts and tissue [link]. Directions which bring into force the first edition of this code, as provided for under Section 26 of the HT Act, may be found at [www.hta.gov.uk/guidance/licensing_guidance/expected_standards.cfm]. 49. Consent for storage and use for research is not needed where relevant material has been taken from a living person and the researcher is not in possession, and not likely to come into possession of information that identifies the person from whom it has come; and where the material is part of research approved by a research ethics authority. 50. A research ethics authority is either: •
an NHS (or Health and Social Care in Northern Ireland) Research Ethics Committee (REC), established under and operating to the governance arrangements issued by the Department of Health [www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPo licyAndGuidance/DH_4005727]; or
•
an ethics committee recognised by United Kingdom Ethics Committee Authority (UKECA), to review clinical trials of investigational medicinal products under the Medicines for Human Use (Clinical Trials) Regulations 2004 [www.opsi.gov.uk/si/si2004/20041031.htm].
Details of all recognised committees are on the NRES website [www.nres.npsa.nhs.uk/contacts.htm].
51. Where approval for a specific research project is pending, the consent exception applies. An application for ethical approval is pending from when it has been submitted to a research ethics authority until the decision of the authority has been communicated to the applicant. 52. Providing the person carrying out the research is not in possession (and not likely to come into possession) of information identifying the participant, the data do not have to be permanently or irrevocably unlinked.
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53. To facilitate the use of valuable relevant material in research, the HTA advises that consent should not be taken solely for use in a specific research project: if consent is given for a broad range of research, this removes the need to go back to the participant following completion of the specific project, and is preferable to developing complex systems for keeping the samples unlinked. Researchers should attempt to anticipate and explain the purpose for which tissue could be used to avoid the need for seeking repeated consents. 54. Although it does not have an explicit role in the ethical approval of research on relevant material, the HTA endorses the guidance produced by NRES [www.nres.npsa.nhs.uk] and the GMC [www.gmc-uk.org].
Licensing When a licence is, and is not, needed 55.
This section explains where a licence from the HTA is needed and where exceptions to licensing apply.
56.
Relevant material for use in research will need to be stored on licensed premises and with valid consent, whether the material is from the living or the deceased, subject to certain exceptions set out below.
57.
It is important to note that an HTA licence should not be viewed as an alternative to ethical approval. The HTA strongly advises researchers to gain ethical approval before embarking on any research.
58.
Existing holdings of relevant material for use in research that were obtained prior to 1 September 2006 must be stored on licensed premises, subject to certain exceptions set out in paragraphs 60–71. However a licence is not required for storage for research on relevant material from a person if more than 100 years have elapsed since the date of the person’s death.
59.
The HT Act does not define the term storage. Neither does it give any minimum or maximum term for storage of relevant material if the purpose of storing this material is for use in research. However, some examples of what the HTA considers to be storage in the context of research are given below, so that researchers can assess whether the HTA would regard the relevant material in their possession as being stored and therefore licensable.
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60.
Generally, relevant material is being stored once it is kept on premises for use for research. However, there are some exceptional circumstances where a licence is not needed. Essentially, relevant material does not need to be held under a licence where it is being held temporarily. The following paragraphs explain the exception in more detail.
61.
Under the HT Act, where relevant material is in storage pending transfer elsewhere, providing it is held for a matter of hours or days (but never more than a week) the storage is incidental to transportation and a HTA licence is not required. Example – skin biopsies for use in research are collected across a number of sites and batched prior to being sent to an establishment licensed by HTA for the storage of relevant material for use for scheduled purposes (research). The multiple sites collecting the biopsies do not need to be licensed as the storage is pending transportation. However, if the biopsies are kept for longer than a week, a storage licence would be required.
62.
Where relevant material is being held whilst it is processed to render it acellular, HTA views this as analogous to the incidental to transportation exception and a licence is not required providing the processing takes place within hours, days and no more than a week. Example – a researcher wants to undertake a study looking into immunological responses to breast cancer. To do this clotted blood samples will be collected from breast cancer patients in ten hospitals. The blood is collected and batched and sent to a laboratory to be spun down to collect the serum. As the blood will be sent to the laboratory within a matter of days to leave acellular serum, and the cells will be disposed of, a HTA licence is not required. In this case, the researchers using the serum should have evidence to ensure that the laboratory process rendered the relevant material acellular.
63.
In addition to the exceptions to licensing covered in the preceding paragraphs, there is a broader exception set out in the HT Act 2004 (Ethical Approval, Exceptions from Licensing and Supply of Information about Transplantation) Regulations 2006 [www.opsi.gov.uk/si/si2006/20061260.htm]. This exception is set out in the section below.
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Ethical approval of research projects 64.
The 2006 Regulations set out an exception to licensing if relevant material is held for the purpose of HTA qualifying research, in that it is approved by a research ethics authority (see paragraph 50 for further details). It is important to note that this exception does not allow for approval of projects by RECs other than those recognised by UK Health Departments or UKECA, e.g. those approved only by a university ethics committee.
65.
A licence from the HTA should not be viewed as an alternative to ethical approval. The HTA strongly advises researchers to gain ethical approval before embarking on any research.
66.
Once relevant material is no longer being stored as part of a research ethics authority approved project (or one where such approval is pending), the relevant material must be held on premises licensed by the HTA if it is to be used for a scheduled purpose. Where it is to be used for further research the researcher must ensure that that research is in accordance with the initial consent obtained.
67.
The disposal of relevant material should only take place as a last resort if it is no longer valuable for use in research.
68.
The HTA has worked with NRES on a system of ethical approval for certain types of tissue bank which store relevant material for use in research. These tissue banks hold a HTA licence and the relevant material is also held under REC approval; researchers receiving relevant material from such a bank will not need a licence from the HTA or their own REC approval to store the relevant material on their own premises. Further information is available in section 11 of the NRES standard operating procedures (SOPs) [www.nres.npsa.nhs.uk]. The research must be carried out in accordance with the tissue bank’s ethical approval. If this is not the case, separate REC approval or a HTA licence will be required.
69.
Research tissue bank approval under the NRES SOPs confers ethical approval for projects receiving tissue from the bank within the conditions agreed by the REC; for example, tissue is supplied in non-identifiable form, projects have received appropriate scientific critique and fall within the scope of the broad consent given by donors.
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70.
If the research tissue bank holds a HTA licence but does not have ethical approval under the NRES SOPs, each researcher receiving the relevant material will have to either apply to the HTA for a licence to store relevant material or apply for their own REC approval.
71.
On completion of research using relevant material from a REC-approved research tissue bank, the individual researcher will need to either transfer the relevant material to a licensed establishment, apply for their own HTA licence; apply for REC approval of a new research project, or dispose of the relevant material.
Relevant material and research Acellular material 72.
Relevant material is material that consists of or contains cells. Acellular material is therefore not relevant material. Guidance on how to apply the definition of relevant material is provided on the HTA website [www.hta.gov.uk/guidance/licensing_guidance/definition_of_relevant_material.c fm].
73.
As demonstrated in paragraph 62, the separation of relevant material to leave it acellular does not need to take place on premises where a HTA licence is in place, providing the processing takes place within hours or days of receipt and never longer than a week.
Relevant material in the context of diagnosis and post-mortem examination 74.
Consent and licensing requirements apply if relevant material is removed and stored with the prime intent of research.
75.
Additional relevant material for use in research may be obtained with consent from a patient at the same time as diagnostic material. As the main reason for storing the tissue is for use for research and not diagnosis, the storage must be under the authority of a HTA licence, subject to the exceptions set out in paragraphs 55–71.
76.
Relevant material removed as part of a post mortem examination may only be retained for use in research if appropriate consent has been given and must be
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stored under a HTA licence subject to the exceptions set out in paragraphs 55– 71. For more information about the post-mortem sector you can refer to the code of practice on Post-mortem examination [link] 77.
If material is removed as part of a surgical treatment or transplant but can not be used for the intended purpose, it can be used for research providing appropriate consent is obtained and it is stored on HTA licensed premises, subject to the exceptions set out in paragraphs 54–71.
78.
The HTA understands that on occasion researchers may request to use samples that are stored in hospitals for diagnosis, for use for research. Samples can be released providing the patient has given consent for the use of their tissue in research, or the samples are released in non-identifiable form and there is no evidence that the patient has not given consent, and the research is REC-approved. Once released, the samples must be stored under a HTA licence, subject to exceptions set out in paragraphs 55–71.
79.
The HTA has included a storage licence covering scheduled purposes on the post mortem licence application form, so that establishments undertaking postmortems can also store tissue for research. This means that diagnostic material could be stored under the licence negating the need for the samples to be stored on alternative licensed premises.
Tissue blocks and sections on slides 80.
Relevant material that is contained in tissue blocks or sectioned onto microscope slides and stored or used for research, must be held on licensed premises, subject to certain exceptions set out in paragraphs 55–71.
81.
If the relevant material was obtained after 1 September 2006, appropriate consent must be in place for its use in research subject to the exceptions set out in paragraphs 44–54.
Cells cultured from relevant material 82.
Material that is created outside the human body does not fall under the remit of the HTA.
83.
Cell cultures are relevant material if they contain cells that have been removed directly from the human body, e.g. if the culture contains original cells from a biopsy or blood sample. A cell culture would no longer contain relevant material
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where only daughter cells, derived from the original cells by division in culture, remain – these daughter cells are not regarded as originating from a human body. Individual researchers will need to make a judgment as to when this point is reached. If the research involves cell lines or daughter cells (regardless of where they are purchased from) a HTA storage licence is not required. Example – a researcher is working on a study using cultured cells which originated from cervical cancer biopsies. None of the original biopsy cells remain intact and all the cells to be used have been created outside the human body. The cultured cells do not need to be stored on licensed premises. Genetic research on relevant material 84.
A licence is not required to store DNA although the storage of tissue before extraction of the DNA will require a licence subject to the exceptions set out in paragraphs 55–71.
85.
It is an offence under the HT Act to have any human material with intent to analyse the DNA in it and use the results for non-excepted purposes, unless there is qualifying consent. Qualifying consent is referred to in paragraph 42 of this code and explained in detail in the code of practice on Consent [link]. Use of the results of DNA analysis for research is an excepted purpose if the material is from the body of a living person and the researcher is not in possession, and not likely to come into possession, of information that identifies the person from whom it has come, and where the research is approved by a REC. Where these conditions do not apply, it is an offence to use DNA in research without qualifying consent unless the results of the analysis of the DNA are to be used for the purpose of detecting crime, or where the results are required under regulations made by the Secretary of State. Example – a researcher is analysing DNA which will be extracted from tissue biopsies over the course of 24 hours and the tissue will subsequently be discarded. The DNA will be used for research and the researcher will have access to clinical data identifying the donor, so qualifying consent will be needed. Provided the process of extracting the DNA takes a matter of hours or days and any remaining tissue is moved to licensed premises or discarded, the extraction can take place on non-licensed premises.
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Relevant material and human application Cell lines and stem cells 86.
The storage of stem cells must take place on licensed premises subject to the exceptions set out in paragraphs 55–71. However, the storage of cell lines which will only ever be used for research does not need to be on licensed premises as they are created outside the human body. If the stem cells or cell lines may be used in future for human application they must be procured, processed, tested and stored under a licence under the Q&S Regulations [www.opsi.gov.uk/si/si2007/uksi_20071523_en_1]
87.
Human embryonic stem cell lines are regulated by three regulatory bodies; the Human Fertilisation and Embryology Authority (HFEA) [www.hfea.gov.uk], the HTA [www.hta.gov.uk] and the Medicines and Healthcare products Regulatory Agency (MHRA) [www.mhra.gov.uk/index.htm]. More information about the regulatory remit of the HFEA and the MHRA can be found on the HTA website.
Clinical trials 88.
The storage of relevant material for a clinical trial which will not be used in human application must be stored on licensed premises subject to the exception set out in paragraphs 55–71. Relevant material that is used as part of a clinical trial and will be used in human application needs to be licensed under the Q&S Regulations [www.opsi.gov.uk/si/si2007/uksi_20071523_en_1] It is important to note that where tissue is used for human application which is part of a medicinal trial approved by a UKECA-recognised ethics committee, licensing under the Q&S Regulations still applies.
89.
The HTA has produced a statement in conjunction with the MHRA [www.mhra.gov.uk/index.htm] which explains the regulatory remits of the HTA and MHRA in regulating Advanced Therapy Medicinal Products which contain relevant material [www.hta.gov.uk/guidance/licensing_guidance/atmp_regulation_and_quality_a nd_safety_regulations.cfm]
90.
The use of stem cells and cell lines in human application as well as the use of relevant material in clinical trials is a field that is developing significantly. To ensure that you are up to date with the regulatory requirements, you are advised to keep abreast of information provided by the HTA via the enewsletter and website.
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HTA licensing standards 91.
In order to obtain a HTA licence, an establishment must demonstrate that it meets a number of core standards. These relate to the consent provisions of the HT Act and the regulatory requirements for governance and quality systems, suitable premises and appropriate arrangements for disposal.
92.
The HTA undertakes inspection of HTA licensed establishments and will assess the suitability of the Licence Holder (LH), the Designated Individual (DI), the practices and the premises during these inspections.
93.
The HTA code of practice on Consent and code of practice on Disposal of human tissue provide advice and guidance on how to meet the requirements of the HT Act and licensing standards in these areas. Help in understanding the requirements relating to the HTA standards on governance and quality systems and premises, facilities and equipment is provided below.
Standards for research 94.
Where the storage of relevant material is for research, the storage of relevant material must be carried out on premises licensed by the HTA (subject to the exceptions set out in paragraphs 55–71). The storage should also be carried out in accordance with the conditions of the licence. The person with statutory responsibility under the HT Act, the DI, has a duty to ensure that people working under the licence are suitable and that they follow suitable practices. The DI must also ensure that the conditions of the licence are being complied with [www.hta.gov.uk/licensing/designated_individuals_and_licence_holders/dls_un der_the_ht_act.cfm]
95.
In order to assess suitability, the HTA has developed a number of standards with which the establishment must comply. [www.hta.gov.uk/guidance/licensing_guidance/expected_standards_directions. cfm] The standards were developed in consultation with representatives from the research sector.
96.
The standards are grouped under the headings: consent; governance and quality systems; premises, facilities and equipment; and disposal.
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Governance and quality systems 97. The HTA standards on governance and quality focus on the establishment’s internal systems and processes that are in place to support staff in the delivery of high quality services. 98. Some establishments will have reviewed their working practices more frequently than others. The HTA regulatory process encourages those involved in research to regularly review their procedures and make improvements where areas of deficiency are identified. 99. The work of the staff at the establishment undertaking research must be subject to a system of governance. That means that there must be clear reporting lines and accountability, (particularly with regard to the individual researchers and the DI), documented roles and responsibilities, a system of staff appraisal, and training and development. 100. All staff working under the HTA licence should be aware of the governance arrangements in place, and they should be represented at governance meetings. Evidence for HTA inspection purposes could include team meeting minutes. 101.
There must be documented policies and procedures covering all aspects of activity relating to the storage of relevant material for use for research, i.e. how to obtain consent. These should be up-to-date, subject to regular review and reflective of best practice, including guidance from the GMC [www.gmc-uk.org], local ethics committees and NRES [www.nres.npsa.nhs.uk].
102.
All establishments should identify the risks inherent in the critical procedures and procedures should be developed in consideration of and to mitigate these potential risks where appropriate.
103.
Risk assessments should be undertaken by a suitably trained person who is able to take an objective view. In any event, the results of risk assessments should be shared with staff so that they have an understanding of the issues identified.
104.
The HTA expects DIs to be committed to improving quality, demonstrated by for example, a programme of audit, and staff being given training and development opportunities to update their skills.
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105.
Access to advice and guidance from organisations such as the HTA, GMC [www.gmc-uk.org] and NRES [www.nres.npsa.nhs.uk] should be freely available, and there should be commitment from management to provide the means by which improvements can be made.
106.
Records must be kept that document consent and allow traceability to the relevant material stored for use in research. The procedures relating to recordkeeping should reference the establishment’s system of labelling relevant material for research.
107.
The HTA standards require a unique identification number to be assigned to the relevant material to facilitate traceability.
108.
The system of record-keeping must include the location of relevant material stored under the licence at the establishment i.e. which cupboard / fridge / freezer the relevant material is stored in and the name of the researcher. The records may include a description of the relevant material, the project it is currently being used for and who the lead researcher is, and whether consent is specific for the project or for wider use in research.
109.
Once relevant material is no longer being stored as part of a specific project approved by a research ethics authority or a specific project where approval is pending, it must be stored under the authority of a HTA licence subject to the exceptions set out in paragraphs 55–71. If relevant material is stored for use in a specific research project, it is advisable that the DI has a log of the relevant material so that he / she is aware of when the relevant material will need to be stored under a HTA licence.
110.
The DI must be aware of the need to ensure the safety of staff undertaking research. This should be covered by a documented risk assessment.
111.
All establishments licensed by the HTA are required to have an internal system for reporting adverse events and, where necessary, instigating an investigation or root cause analysis. In a research environment, the focus may be on noncompliance with the HT Act and codes of practice or damage to the tissue integrity; for example, through theft or inappropriate storage.
112.
Staff working under the HTA licence must understand what is meant by an adverse event and the procedure to follow when such an event occurs. Adverse events classified by the DI as severe in nature must be reported to the HTA.
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Premises, facilities and equipment 113.
The HTA seeks to work with establishments through its inspection process, to help them make improvements where improvements can be made, and takes a proportionate and risk-based approach where scope for improvement has been exhausted.
114.
Premises must be ‘fit for purpose’. This means that areas used for storage of relevant material for use in research must provide an environment that is safe for those working under the licence and preserves the integrity of the tissue.
115.
Relevant material must be stored in such a way that it minimises the risk of contamination to those working under the licence. If necessary, the DI should also put in place environmental controls and appropriate equipment to reduce the risk of contamination.
116. The DI must also consider risks to the relevant material such as theft or damage. Security measures should include the use of lockable storage facilities, alarm systems and indelible identification marking of relevant material if appropriate. Consideration should also be given to mitigating damage caused by the relevant material being handled by those working under the licence. For example, storage environments may require continuous temperature monitoring and heating and cooling systems. 117. Where chemicals are used for preservation of relevant material, the area must be adequately ventilated to control exposure. Control of Substances Hazardous to Health (COSHH) [www.hse.gov.uk/coshh] requires the exposure of formaldehyde to be controlled as low as possible and below the maximum exposure limit (2 ppm). This may include monitoring of levels and continuous operating extract ventilation. 118. The establishment must be clean, well maintained and subject to a programme of planned preventative maintenance. 119. If applicable, staff should have access to the protective clothing, materials and equipment they need. Equipment must be regularly maintained to ensure that it is suitable for use. Equipment should be made of material that is easy to clean, impervious, non-rusting, non-decaying and non-staining. There should be a system for renewing items that are no longer suitable through wear and tear.
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120. If applicable, staff working under the licence should be aware of and have access to guidance from the Health and Safety Executive (HSE) [www.hse.gov.uk] on safe working and the prevention of infection. 121. If relevant material is transferred between establishments consideration must be given to minimising the likelihood of theft or damage during transport. Material Transfer Agreements (MTA) should define how the relevant material is preserved, any potential contamination risks associated with it and who is responsible for disposal if applicable. 122. The establishment must have contingency arrangements in place should there be an emergency situation that renders the premises unusable for the storage of relevant material for use for research. 123. The HTA expects compliance with all its standards, even if relevant material is to be held only for a short period of time or if only a few items are held under the authority of a licence. 124. The HTA has published a guide to licensing for Designated Individuals and Licence Holders [www.hta.gov.uk/licensing/designated_individuals_and_licence_holders/dls_un der_the_ht_act.cfm] which sets out in detail the licensing arrangements under the HT Act. Included is a description of the role of the DI, which is of fundamental importance to the HT Act’s scheme of regulatory control and the HTA’s licensing framework.
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Appendix A: Licensing and consent flowcharts Licensing and consent requirements for human tissue for research from the living Storage of human tissue from the living Consent required?
•
•
Licence required?
Yes, unless: obtained before 1 September 2006 or is non-identifiable and is for a specific RECapproved project
• •
•
•
Yes, unless it is: more than 100 years old or for a specific RECapproved project or stored with intent to render acellular or storage is incidental to transportation
Licensing and consent requirements for human tissue for research from the deceased Storage of human tissue from the deceased Consent required? Yes, unless obtained before 1 September 2006
Licence required?
• •
•
•
Yes, unless it is: more than 100 years old or to be stored as part of a specific REC-approved project or stored with intent to render acellular or storage is incidental to transportation
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References Guide to licensing for Designated Individuals and Licence Holders www.hta.gov.uk/licensing/designated_individuals_and_licence_holders/dls_under_the _ht_act.cfm Guidance to applying for a licence www.hta.gov.uk/licensing/guide_to_licensing_and_application.cfm Model consent forms www.hta.gov.uk/guidance/model_consent_forms.cfms E-learning training course for Designated Individuals www.hta.gov.uk/licensing/designated_individuals_and_licence_holders.cfm Mental Capacity Act (MC Act) 2005 www.opsi.gov.uk/ACTS/acts2005/ukpga_20050009_en_1 Human Tissue (Quality and Safety for Human Application) Regulations 2007 www.opsi.gov.uk/si/si2007/uksi_20071523_en_1 The Medicines for Human Use (Clinical Trials) Regulations 2004 www.opsi.gov.uk/si/si2004/20041031.htm Human Tissue Act 2004 (Ethical Approval, Exceptions from Licensing and Supply of Information about Transplantation) Regulations 2006 www.opsi.gov.uk/si/si2006/20061260.htm General Medical Council (GMC) www.gmc-uk.org UK Clinical Research collaboration (UKCRC) www.ukcrc-rgadvice.org/bestpracticeguidance/Pages/default.aspx Medical Research Council (MRC) guidance on the use of human tissue in research www.mrc.ac.uk/PolicyGuidance/EthicsAndGovernance/index.htm National Institute for Health and Clinical Excellence (NICE) www.nice.org.uk/otherpublications/bestpracticeinclinicalaudit/principles_for_best_prac tice_in_clinical_audit.jsp
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Healthcare Commission www.healthcarecommission.org.uk/healthcareproviders/serviceproviderinformation/nat ionalclinicalaudit.cfm National Research Ethics Service (NRES) www.nres.npsa.nhs.uk Health and Safety Executive (HSE) www.hse.gov.uk Human Fertilisation and Embryology Authority (HFEA) www.hfea.gov.uk Medicines and Healthcare products Regulatory Agency (MHRA) www.mhra.gov.uk/index.htm Control of Substances Hazardous to Health (COSHH) www.hse.gov.uk/coshh
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Glossary
Accredited Assessor: A person trained and accredited by the HTA to act as a representative of both the donor and the HTA to ensure the relevant requirements of the HT Act and HT Act (Ethical Approval, Exceptions from Licensing and Supply of Information about Transplants) Regulations 2006 are met, in cases of potential bone marrow or PBSC donations. Allogeneic: Cells, tissue, organs or part organs removed from one person and applied or transplanted into another. Anatomical examination: Examination by dissection for the purpose of teaching, studying or conducting research into the structure of the human body. Appropriate consent: Defined in the HT Act by reference to the person who may give consent. This is broadly either the consent of the person concerned, their nominated representative or (in the absence of either of these) that of a person in a qualifying relationship to him immediately before he died. Biopsy: A procedure where tissue is removed from the human body for examination. Bone marrow: The soft, spongy tissue found in the centre of most large bones that produces the cellular components of blood: white cells, red cells and platelets. Cells: individual human cells or a collection of human cells when not bound by any form of connective tissue. For establishments licensed for human application this includes cell lines grown outside the human body but not gametes, embryos outside the human body, or blood and blood components. Designated individual (DI): The individual designated on the licence to supervise the licensable activities carried out. DIs are trained by the HTA to carry out this important role and they have statutory responsibilities they must fulfil. Diagnosis: A process where a disease is identified. DNA (deoxyribonucleic acid): The genetic material of humans which is located in the cell nucleus and controls heredity.
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Donation: The act of donating human tissue, cells, organs or part organs for a scheduled purpose either during life or after death. Donor: Every human source, whether living or deceased, of tissue, cells, organs or part organs. Ethical approval: Approval by a research ethics authority which is either: a Research Ethics Committee (REC) established under and operating to the governance arrangements for NHS Research Ethics Committees; or an ethics committee recognised by the UK Ethics Committees Authority (UKECA) to review clinical trials of investigational medicinal products. Gillick competent: In the case of Gillick v West Norfolk and Wisbech Area Health Authority [1986] 1 AC 112 the court found that a child below 16 years of age will be competent to consent to medical treatment if they have sufficient intelligence and understanding to understand what is proposed. This test applies in relation to all people under 18 where there is no presumption of competence in relation to the procedure. Human application: In relation to tissue or cells, means use on or in a human recipient, including use in applications situated or occurring outside the body, but not including use for autologous graft (tissue or cells removed from and applied in the same person within the same surgical procedure). Independent Assessor (IA): A person trained and accredited by the HTA to act as a representative of both the donor and the HTA to ensure the relevant requirements of the HT Act and HT Act (Ethical Approval, Exceptions from Licensing and Supply of Information about Transplants) Regulations 2006 are met, for certain types of living organ transplantations. Licensing: A number of activities can only be carried out where the establishment is licensed under the HT Act by the HTA. Organisations whose activities involve the removal, storage or use of relevant material may need to work under an HTA licence. All establishments working under an HTA licence must work to specified standards set by the HTA. Licence Holder (LH): The person who holds a licence and is responsible for the payment of any fees charged by the HTA. Under the Human Tissue (Quality and Safety for Human Application) Regulations 2007 the LH is also responsible for complying with HTA Directions. The LH can be a corporate body. Where the
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applicant is not the proposed Dl, the HTA must be satisfied that the applicant is a suitable person to be the holder of the licence. Licensed premises: Where the licensed activity (e.g. storage, or public display) takes place. If the licensed activity will take place at more than one place, a separate licence will need to be issued. Premises in different streets or with different postal codes will be considered as being in different places. In contrast, different buildings on a hospital site could be regarded as the same place. Living donor: The person donating tissue, cells or organs for transplantation. The most common forms are live kidney donation (where one kidney is removed), or live bone marrow donation. Nominated representative: A person appointed by a deceased person who is empowered to consent to the carrying out of a post mortem examination and to the removal, storage and use of the body or tissue for any of the scheduled purposes, other than anatomical examination or public display. Non-identifiable: Ensuring that if relevant material is removed from a human body, all necessary steps are taken to prevent the person from whose body the material has come from being identified. Organ: Defined by the HT Act (Ethical Approval, Exceptions from Licensing and Supply of Information about Transplants) Regulations 2006. A differentiated and vital part of the human body, formed by different tissues, that maintains its structure, vascularisation and capacity to develop physiological functions with an important level of autonomy. Part organ: For the purposes of the HT Act and the HT Act (Ethical Approval, Exceptions from Licensing and Supply of Information about Transplants) Regulations 2006, material is part of an organ if it is to be used for the same purpose as the entire organ in the human body. Post-mortem examination: Dissection and examination of a body after death, principally in order to determine the cause of death or the presence of disease processes. A hospital post-mortem examination is carried out with appropriate consent to gain a fuller understanding of the deceased person’s illness or the cause of death, and to enhance future medical care. Coroners’ post-mortem examinations are carried out under the authority of the coroner and without consent to assist coroners in carrying out their functions.
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Processing: All operations involved in the preparation, manipulation, preservation and packaging of tissues or cells intended for human applications. Qualifying relationship: Person/s who can give consent for the deceased person if the deceased person has not indicated their consent nor appointed a nominated representative. Relevant material: Defined by the HT Act as material other than gametes, which consists of or includes human cells. In the HT Act, references to relevant material from a human body do not include: (a) embryos outside the human body, or (b) hair and nail from the body of a living person. See policy guidance on how to apply this definition on the HTA website by following the links to guidance/ licensing guidance/ definition of relevant material [www.hta.gov.uk/guidance/licensing_guidance/definition_of_relevant_material.cf m]. Research: A study which addresses clearly defined questions, aims and objectives in order to discover and interpret new information or reach new understanding of the structure, function and disorders of the human body. Research attempts to derive new knowledge and includes studies that aim to generate hypotheses, as well as studies that aim to test them or develop practical applications of new knowledge. Research Ethics Committee (REC): An ethics committee established and recognised to advise on matters which include the ethics of research investigations on relevant material which has come from a human body. Scheduled purposes: Scheduled purposes specify where the use of relevant material requires consent. In addition, the licensed activities of removal and storage relate to scheduled purposes. The purposes are divided into 2 parts: Part 1: Purposes requiring consent: General – anatomical examination; determining the cause of death; establishing after a person’s death the efficacy of any drug or other treatment administered to him; obtaining scientific or medical information about a living or deceased person which may be relevant to any other person (including a future person); public display; research in connection with disorders; or the functioning; of the human body, transplantation. Part 2: Purposes requiring consent: Deceased persons – clinical audit, education or training relating to human health, performance assessment, public health monitoring, quality assurance.
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Stem cell: A precursor cell that can develop into more than one kind of cell. For example, early bone marrow cells can develop into red blood cells, white blood cells or platelets. Tissue: Any and all constituent part/s of the human body formed by cells. Transplantation: An implant of an organ or part organ, tissue or cells either from and into the same body or from one person to another. Valid consent: Is consent which has been given voluntarily, by an appropriately informed person who has the capacity to agree to the activity in question.
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