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Enacting regulation: tissue in practice
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well as the foundation of innovation and medical advance.7,8 Human tissue and its use is a matter of interest not only to pathologists and scientists, but to lawyers, philosophers, policy makers, clinicians and the public e whether patients or currently healthy individuals. Not least because of the multiple interests of these various parties and the special status of human biological material, its use in research is closely regulated. What does this mean for those intending to undertake research? Some have commented on e and objected to e the legislative burdens they experience, while others are bemused, confused or deterred from entering research by what they see to be a hazy labyrinth of red tape.6,9 There is also concern that regulation has reduced collection of and access to samples, thus threatening to impede medical advance.10 This paper steps to the side of the usual discussion of the status of tissue in ethics and law to consider instead the enactment of regulation in the daily practice of researchers. This is a separate and often overlooked area between regulation as drafted by legislators and policy makers, and as experienced by those who work within that regulatory frame. The paper considers the governance and procedures put in place and the expertise made available in one research centre, in order for researchers to proceed with their specialized work without first needing an advanced degree in law or ethics. The paper focuses on the bridging, facilitation activity of a research tissue bank at the University of Oxford by providing an on-the-ground account of how ethical and legal requirements related to the use of human tissue in research in the United Kingdom work out in day to day practice of collecting, storing and providing tissue for research. After a description of the regulatory and research contexts within which the tissue bank and its research facilitation service operate, a series of scenarios illustrate issues that arise with tissue in practice: in the governance of its collection, storage and provision to researchers.
Enacting regulation: tissue in practice Karen Melham Gemma Marsden Joy Wiles Divija Jatavallabhula
Abstract This paper steps to the side of the usual discussions of the status of tissue in ethics and law to consider instead the enactment of regulation in the daily practice of researchers. This is a separate and often overlooked area between regulation as drafted by legislators and policy makers, and as experienced by those who work within that regulatory frame. The paper considers the governance and procedures put in place and the expertise made available in one research centre. Focus on the bridging, facilitation activity of a particular research tissue bank affords an on-the-ground account of how ethical and legal requirements related to the use of human tissue in research in the United Kingdom work out in the everyday practice of collecting, storing and providing tissue for research.
Keywords consent; Human Tissue Act; human tissue research; research governance in practice; tissue banking
The status and use of human tissue in research is complex, at times contested, and an area of ongoing ethical and legal discussion. Companion articles in this issue’s symposium address some of the areas of current debate. The use of human tissue in research has been the source of scandal1e3 and litigation4e6 as
Regulatory context Karen Melham PhD Ethicist, Centre for Health Law and Emerging Technologies, University of Oxford, Oxford, UK. Conflicts of interest: Ethicist for bioresources in the NIHR Oxford Biomedical Research Centre, including ORB and OCHRe. She is also chair of National Research Ethics Committee South Central e Oxford A, and member of STRATUM (Strategic Tissue Repository Alliances Through Unified Methods).
Within the England, Wales and Northern Ireland, the requirements for research involving human biological material are primarily based on two pieces of legislation: the Human Tissue Act 2004 (HTA 2004) with its accompanying Codes of Practice,11 and the Medicines for Human Use (Clinical Trials) Regulations (2004).12 In addition, if researchers intend to use identifying patient data, this information is subject to the common law duty of confidentiality and the requirements of the Data Protection Act (1998).13 In circumstances where individuals lack capacity to consent, the provisions of the Mental Capacity Act (2005) may also be relevant.14 The Human Tissue Act 2004 (HT Act) consolidated previous legislation and created the Human Tissue Authority (HTA) to “regulate the removal, storage, use and disposal of human bodies, organs and tissue.”11 The HTA describes itself as “a watchdog that supports public confidence by licensing organisations that store and use human tissue for purposes such as research, patient treatment, post-mortem examination, teaching, and public exhibitions”.15 The HTA conducts regular inspections to assess whether licenced establishments follow required procedures and maintain good standards and appropriate records.
Gemma Marsden BSc Hons Biobank Manager, Oxford Radcliffe Biobank, NIHR Oxford Biomedical Research Centre, Oxford, UK. Conflicts of interest: Manager of the Oxford Radcliffe BIobank (ORB). Joy Wiles BSc Hons Research Coordinator, Oxford Centre for Histopathology Research, NIHR Oxford Biomedical Research Centre, Oxford, UK. Conflicts of interest: Research coordinator within the Oxford Centre for Histopathology Research (OCHRe). Divija Jatavallabhula BSc Hons Research Coordinator, Oxford Centre for Histopathology Research, NIHR Oxford Biomedical Research Centre, Oxford, UK. Conflicts of interest: Research coordinator within the Oxford Centre for Histopathology Research (OCHRe).
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While the HTA concerns itself with procurement and storage of human tissue, its remit does not include the ethical approval of the research undertaken with that tissue. This comes under the purview of the National Research Ethics Service (NRES) and its Research Ethics Committees. These committees, in turn, tend to the provisions of Clinical Trials Regulations. The EU Clinical Trials Directive16 was transposed into UK law in May 2004 in the form of the Clinical Trials Regulations.12 The Regulations were intended to apply only to clinical trials and not medical research more broadly, but it is UK Department of Health policy that the operating procedures required by the Directive and the Regulations “should also apply in general to the review by RECs (Research Ethics Committees) in the UK of all other research involving human participants within the NHS”.17 With one body taking responsibility for storage and another for research use of human biological material, it is necessary for the HTA and NRES to work in close alignment. They issued a Joint Statement in 2009, outlining their working arrangements.18 These include agreement that while human biological material is being used in a research project for which ethics approval has been given, it does not require registration under an HTA licence. Such an arrangement allows researchers who collect samples from participants as part of their ethically approved research to proceed without reference to the HTA. At such time as ethical approval for a research project expires, materials still held for which there is consent for storage and further use must be transferred to a licenced facility. They can be accessed again subject to ethics approval. Renewed access to previously collected samples need not entail return to a REC for every research project proposed. The HTA and NRES also arranged for Research Ethics Committees to be able to give generic ethical approval for a research tissue bank. A research tissue bank is defined as “A collection of human tissue or other biological material, which is stored for potential research use beyond the life of a specific project with ethical approval or for which ethical approval is pending.”19 A tissue bank storing human tissue for use in as yet unspecified research must obtain a licence from the HTA. It may then apply to an REC for generic ethical approval for its arrangements for collection, storage and release of tissue, in keeping with the programme of research it is designed to support. Research tissue bank approval can thus extend to specific projects requiring non-identifiable tissue from the bank.18,20 In this way, the REC devolves governance for its collections to the research tissue bank itself. The bank submits annual reports to the REC, renews its ethical approval every five years, and is subject to the licencing requirements of the HTA. The result is that researchers can access tissue from a central place with the brunt of regulatory administration being handled by the bank. Researchers will need to satisfy the access requirements of the tissue bank, but these are less involved and can be facilitated in a shorter time frame than is possible with REC review.
participants. The Nuremberg code, developed following the post WW2 Nuremberg trials, articulated clearly the principle of voluntary, informed consent for research.21 This has been developed further in the various versions of the World Medical Association’s Declaration of Helsinki.22 Informed consent as described in the Declaration of Helsinki in turn forms the basis for the consent requirements in the EU Clinical Trials Directive. Consequently, it is an area of Research Ethics Committee review in the UK context. In addition to biological material being collected specifically for research purposes, including biobanking, tissue may be available as a clinical by-product. Consent for research, including biobanking, is sought before any intervention. Tissue obtained in the course of diagnosis, such as a blood or urine sample or a tissue biopsy, or as a result of treatment, such as when an organ or tumour is removed, can also be used in research under certain conditions. Trusts have policies in place to obtain consent for investigation or treatment, and their consent provisions may include an option for patients to give permission for the use of removed material in research. This material will be stored in a diagnostic archive; the samples form part of a patient’s medical record. In some instances, and when a patient has consented, additional surplus material may be stored in a research tissue bank. Consent can be broad in both time and scope: it does not need to be project-specific. Where individuals are consenting to use of tissue in further research without knowing the nature of that research, they are instead consenting to governance. Information provided to support their decision explains how and by whom decisions will be made about the use of their tissue. Since the consent requirements of the HT Act are not retrospective, it is not necessary to obtain or confirm consent for use of material that was already stored e whether in a research or archival setting e when the HT Act came into force on 1 Sept 2006. These are considered ‘existing holdings.’ Tissue for which consent has not been sought for research use (other than existing holdings) can only be released if it is 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; there are research ethics approval provisions in place, such that material is either: released by a research tissue bank with generic ethical approval from a REC for research within the terms of its approval or to be used for a specific research project approved by a REC.18,23 These regulatory requirements, even with their arrangements to align responsibility and governance, are still some distance from the work done by pathologists and researchers with tissue itself. Between the regulation and the research there is need for a facilitating gateway where requirements are enacted in order to facilitate proper lawful and ethical use of human tissue for research. What follows is a description of one such gateway, and instances in which it enables sound research practice.
Consent A central tenet of both the Human Tissue Act and research ethics is consent. The importance of obtaining and recording consent from individuals for the use of their biological material underpins Human Tissue Legislation. Consent is a similarly fundamental concern running through the ethics of research involving human
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Oxford Radcliffe Biobank The Oxford Radcliffe Biobank (ORB) is a research facility of the Oxford University Hospitals NHS Trust (OUH) and the University
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of Oxford. It is the subject of a service level agreement between these two institutions, which forms part of their strategic partnership.24 ORB provides infrastructure to underpin biobanking activities and delivers a portfolio of integrated services to users, from tissue acquisition, storage and distribution, through to the governance, ethical and regulatory cover that come with its research tissue bank status. The specimens and associated information managed by ORB are used for research studies that may contribute to increasing the knowledge and understanding of disease in order to improve diagnosis and treatment, and aims ultimately to contribute to improvements in patient care. A primary focus of ORB is maintenance of a generic, open-access resource of tissue donated by patients and research participants for use in medical research and provision of a simple and efficient system to collect, store, curate, and distribute these specimens and associated information. This includes having a Sample Access Committee that meets fortnightly to consider in detail all requests. ORB was established in 2006 when a number of active and legacy collections within the University of Oxford and the Oxford University Hospitals NHS Trust were brought together for licencing by the Human Tissue Authority (HTA). This was in response to the Human Tissue Act (2004), when it came into effect on 1 September 2006. In 2007, substantial support was awarded by the Oxford Biomedical Research Centre (funded by the National Institute for Health Research) to enable further integration and expansion of biobanking activity. This centralized approach complements the various funding streams that support individual collections. In response to the requirements of the Human Tissue Act, ORB operates a multi-site Human Tissue Authority Research Licence with policies and procedures in place to ensure registered collections comply with the legislation.25 ORB also provides storage facilities according to HTA guidelines. It is recognized that access to large numbers of high-quality, clinically annotated biomaterials is vital for the advancement of medical research and healthcare delivery. ORB facilitates this access and enhances the research infrastructure by working with all stakeholders to ensure effective sharing of information, resources and best practice. Custodians of collections engage with ORB as part of a federated model. In order to manage the requirements of the legislation across all the collections within ORB, central NIHR funding ensures that there is sufficient support for centralized management. However each discrete collection is set up with a Person Designated (PD) and a Principal Investigator (PI) at the particular site. The PD assists in the governance of the activities authorized by the licence. In practice, the PD is responsible for reporting annual collection and usage statistics to the centralized ORB management team in time for the ethics annual report and HTA selfassessment, as well as overseeing the day to day operational management of the samples. The PI of each collection is responsible for approval of all sample usage from their collection; which entails a formal review and approval process. Audits are carried out to ensure that each collection is managed according to ORB policies and that all activities are carried out according to standard operating procedures (SOPs). In practice, managing a biobank is about being the interface between the patient, the care givers and the researchers. To the patient, a biobanker is an individual who comes to one of their
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hospital appointments to speak to them about the use of their tissue for research. Gaining consent is a balancing act of getting the amount and quality of information right, pitched at the right level and delivered at a suitable time. It is about engaging with individuals, earning their trust in research and its governance, and completing the consent form properly, as an indication of this process of discussion, understanding and agreement.
Oxford Centre for Histopathology Research Working closely with ORB is the Oxford Centre for Histopathology Research (OCHRe), a University of Oxford Small Research Facility (SRF) which operates on a cost recovery basis. OCHRe is an integrated service-driven facility which enables access to equipment and methodologies for research, and importantly the expertise essential for the generation and interpretation of reliable and reproducible results. OCHRe acts as a gateway for access to myriad specimen collections held in Oxford in addition ORB, including some diagnostic archives of the Oxford University Hospitals NHS Trust. It is important to note that, although OCHRe facilitates this access, the Trust’s diagnostic archive is not at present a research tissue bank. In keeping with the Joint Statement by the HTA and NRES, it does not in any way advertise itself as a research resource.18 The archive itself forms part of a patient’s medical record, with samples necessarily retained in case of second opinion, further clinical investigation, or legal action. The archive holds a vast array of formalin fixed paraffin embedded (FFPE) tissue which can be made available for the purpose of research when there is patient consent for its use in research and a favourable opinion from a research ethics committee. Historically, the access to this tissue was not as clearly structured compared to that of a research tissue bank. OCHRe provides the structure and acts as the bridge between researchers and cellular pathology. In practice this means that consent provisions are checked before samples are approved for the use in projects, and those projects and the terms of their ethical approval are scrutinized as part of the sample access application process. The use of each sample is approved by the reporting pathologist who acts on behalf of the Trust and the patient. A major benefit of having a formalized process in place is that the curation of the diagnostic archive is organized and tracked, therefore enabling the Trust to fulfil its obligations as the custodian of this particular part of the patient record. Use of tissue blocks from the archive is carefully monitored by OCHRe, such that no one particular block is allowed to be used to extinction, thereby maintaining the patient record in case it needs to be re-visited for clinical or legal reasons. OCHRe safeguards samples by offering a sectioning service for researchers; cutting sections from the blocks and ensuring that there is sufficient material left in them for return to the archive. Tissue blocks themselves are not released for research projects unless there are exceptional circumstances. As a further safeguard, OCHRe staff are trained to the standards of the diagnostic lab and are signed as competent before being allowed to cut diagnostic material. OCHRe is recognized by the Oxford University Hospitals NHS Trust R&D Department as a facilitating body for research. In practice and as part of its approval, R&D directs researchers to OCHRe if their projects involve the use of human tissue. This
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means that a clinical trial can gain approval in principle to access the necessary tissues before the stage of recruiting the first patient. There is sometimes confusion on the part of people setting up new projects and trials, where an R&D approval is seen as an overall approval on behalf of all parties in the Trust for the project to go ahead. This means that we sometimes encounter resistance when they are setting up a project with OCHRe as it is seen as an unnecessary layer. The difference between the two governance processes is that OCHRe looks at the feasibility and operational factors that will impact on the ability of the project to go ahead. The function of R&D approval is to ensure that the host organization as the sponsor can take legal responsibility for initiation and management of the study and to ensure the provision of insurance for the study.
Some researchers prefer to give a brief to OCHRe of the types of samples required and the selection of cases and tissue blocks is completed by a pathologist for the disease speciality. This adds an element of quality control to the project. In the last year the average number of pathologists involved in research projects has increased by ten percent.
Case study: quality management incidents As recommended by the HTA, the Oxford Radcliffe Biobank uses a quality management system for document management, version control, maintaining a record of staff training and for managing quality issues. An example of an active process of quality management for ORB is the reporting of incidents. A matrix is used which grades incidents in severity from mild to catastrophic, such as equipment failure which did not result in the loss of samples, through to the use of the wrong sample, right through to the DNA analysis of a sample without consent. In the UK, genetic analysis without consent is an offence. An example in practice of the type of incident that we actively manage is a failure to guarantee patient anonymity. The Biobank received a phone call from a patient ringing the phone number provided on the top of his biobank consent form. He was calling to say that he’d been sent home with someone else’s consent form. He wasn’t interested in blame or finger pointing; he just wanted to make sure that it was returned to the correct person. He returned the form to the Biobank by post. Biobank staff wrote back to the patient, thanking him for the safe return of the form, apologizing for the mix up and including some first class stamps for the inconvenience. This event subsequently triggered an impact assessment in which the ORB manager and team examined the event, its impact, and the contributing causes. This resulted in an action plan, which was carried out in order to reduce the likelihood of a repeat occurrence. It is common practice to use a label on consent forms which contains standard patient identifiers such as their name, address, post code, date of birth, hospital and NHS numbers. This is to be able to identify correctly the consent form, which is then coded with a unique patient number. It is the unique number that is then used on all other labels and documentation and provides a mechanism for linked-anonymization. In this case, a serious breach of confidentially had been avoided as the form only contained the initials, signature and printed name of the patient, and no address or date of birth. The researcher involved had seen many of patients in a succession and had not reached the point of labelling when the mix up occurred. The person gaining consent had the copies of the consent form from the previous patient in her hand when she moved on to obtain consent from the next patient. A copy of the previous patient’s form was inadvertently mixed with the paperwork for the second patient. Contributing causes were identified as lack of concentration, time pressures, a busy clinic and a gap in staff training. The incident was classed as severe but ranked as low impact. The immediate action plan was to check the copy consent forms in the medical notes and the research file for both patients to ensure that these were filed correctly. Follow-up actions included the review of the SOP (standard operating procedure) for consent and to carry out staff training covering good practice when dealing with confidential information.
Working with pathologists: coordination and trust ORB has a small team of biobankers who are based within the department of Cellular Pathology. This staff has found this close proximity to pathologists to be very helpful getting to know and gaining the trust of the pathologists with whom they work so closely. The vast majority of the samples collected are surplus to diagnostic requirements following a major resection, and therefore biobankers rely heavily on pathologists being on hand to dissect specimens and allocate samples to the biobank. Recently there has been an increase in the number of researchers requesting fresh tissue for their work. This means there is an added level of coordination work to ensure the tissue gets to the applicants as soon as possible. There are a number of possible impediments, over which biobankers have very little control. Sometimes consent for research has not in fact been obtained. Sometimes theatres are slow to bleep and alert following resection, or the correct paperwork has not been completed when we arrive at theatres. Since procedures may happen at another site, there may be traffic to contend with. With all these factors working against the collection of fresh tissue, the availability of the pathologists is paramount. On the other hand, biobankers and OCHRe staff work together with the pathologists to prevent multiple different researchers asking them directly for tissue. Researchers seeking tissue are directed to OCHRe to ensure the correct approvals are in place for them to work with human tissue. OCHRe is then the point of contact between the pathologist and the researcher. This removes from pathologists the clamour of researchers at their doors and, with a transparent and rigorous process in place, pathologists can be assured that all the tissue donated to research is being used in accordance with the regulations. In addition, the value of introducing the process of research governance has been shown in the increased awareness of biomedical research within the diagnostic department. Because of their interactions with biobank and OCHRe staff, pathologists are better informed about the governance involved in using tissue for research. Further, because they have become an essential part of the application process, they have an awareness of the research being carried out in Oxford. Researchers are seeing the benefits of involving pathology when designing and carrying out their work. The Sample Access Committee will generally recommend pathology review of an H&E slide of any sample used for a project so that the researcher knows what they are getting.
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Case study: checking consent
A material transfer agreement (MTA) was also put in place to document and establish the custodianship of the tissue and data as they were being provided to another institution for research purposes. This was not just to establish who is free to publish the results gained through the use of the materials transferred but also to retain the right to use any results created for future research purposes. As is standard practice, checks and balances were also made during the negotiation of the MTA to ensure that the terms and conditions did not conflict with any grant terms and conditions which may govern the overall programme of research in which the material transferred will be used. These exceptional circumstances lead to OCHRe working with the Trust to create a Block Release Committee, consisting of pathology management, consultant pathologists, the Trust HTA representative, and OCHRe management whose terms of reference include decision making for the release of tissue blocks from the diagnostic archive in exceptional circumstances. In this way, ORB and OCHRe are serving to facilitate access to tissues for research, allowing Oxford to participate in a wider diversity of projects.
An OCHRe customer requested 31 patient samples from the diagnostic archive for a project for which he had obtained project-specific ethics approval which included a patient consent form and information sheet. The Sample Access Committee had requested sight of the completed consent forms as part of the approvals process. On review, it was found that not one of the forms had been completed to the appropriate standard. Some were signed but no clauses were initialled: on others the consent clauses had an ambiguous line through them but there was no signature or name on the form. It was not clear from looking at the forms what the wishes of each patient were. The committee ethicist met with the researcher, discussed at length the problems with consent, and how to ensure better practice in future. Since it was decided that these forms could not be used as a record of patient consent, it was suggested that the researcher provide an alternative record of consent in the form of the research inclusion section of each ‘Patient Consent to Treatment or Investigation’ form. Every patient attending the Oxford University Hospitals NHS Trust for treatment or investigation is asked to complete one of these forms with a person competent to undertake the procedure that they are undergoing. This consent form includes an option to allow tissue to be used for research, and is supported by an information leaflet.26 The researcher did provide this alternative information. The need to do so led to delay to the project and to a reduced cohort size, as some forms were unavailable to view. At the same time, the researcher noted that he now better appreciated what was involved in obtaining consent, and has sought advice since. He also recognized that the service sought to find a way to make his research possible through another, compatible regulatory avenue.
Help or hindrance, facilitation or frustration? From the point of view of the researchers for whom ORB and OCHRe provide a service, we are sometimes seen as a barrier to research, or at least a necessary evil. For each application for tissue staff ask for information so that those with governance responsibility can be satisfied that the chain of trust between initial contact and the patient is perpetuated and in order to maintain that trust through continued research governance. The individual obtaining consent for sample use in research will have assured the patient in the consent discussion and in writing on the consent form that their samples will only be used for research that has been given a favourable opinion by an ethics committee. In those instances where the request for samples is outside the scope of the research that ORB supports with its generic research tissue bank approval, the Sample Access Committee will expect to see the details of the ethical approval and sometimes the application that the researcher presented to the ethics committee. The approval letter from the ethics committee gives little information about the scope of the approval, so it is often necessary, in order to determine the terms of that approval, to look at the information on which the committee based their decision. This may at first make OCHRe staff and Sample Access Committee members look like obsessives at play, but the process has in the past identified applications for tissue not in fact covered by the ethics approval details given. These were not deliberate attempts to gain access to tissue unlawfully, but rather oversights when projects had morphed slightly from what was initially envisaged, and amendments had not been made, or there was an inaccurate understanding of what a research ethics approval might allow. These issues can also arise with researchers inexperienced in preparing ethics applications and who may not have ‘future proofed’ the terms of consent. OCHRe staff also ask all applicants for information regarding the aims and objectives of the project and the intended use of the sample requested. This information is presented to the Sample
Case study: safeguarding material A request was received from a multi-centre study for samples from the diagnostic archive for the purpose of incorporating into a large scale tissue micro array (TMA) where the samples will remain anonymous to the researcher. The array would bring together material from many more patients than would be possible from one hospital alone and so would be an invaluable resource for future projects. This is an example of an exceptional circumstance wherein a block might be released instead of only slides or sections, since the tissue block is required so that a small core of material can be removed for incorporation into the array. The project was retrospective, and thus designed to make use of archival material. This means that the individuals who donated the tissue would not know of this specific purpose but because of the consent provisions of the Human Tissue Act would have been asked if their tissue could be used for research approved by a research ethics committee. There was a perceived element of risk to the Trust and the patients for this project as the tissue blocks would be shipped elsewhere for the TMA construction. It was agreed that only cases with more than one block of representative tissue would be included, thereby safeguarding against loss of tissue e and its information e from the patient record. An arrangement was put in place to ship the samples in batches, with careful tracking and inventory at each stage.
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Access Committee to make the case for the use of the sample for this particular research project. At times, the committee requests further information from the researcher and this can extend the timeline for the application process. It is possible to see that researchers could think of this governance as a barrier to research, but as the honest broker in the middle, we have a duty of care to get the details right. In contrast to this viewpoint, other researchers are clearly pleased and grateful that the service is available to guide them through the ethical and regulatory minefield associated with using human tissue for research. ORB and OCHRe have formalized the process of accessing human samples. Prior to the inception of ORB and OCHRe, this was solely the responsibility of the PI of each collection (or the reporting pathologist in terms of the diagnostic archive). This often led to a culture of “it’s not what you know but who you know.” Although the PI/pathologist gives approval for the use of the samples, OCHRe aims to provide a common access point and application process. To some this extends the process e if they were previously used to speaking directly to the PI/pathologist they can be somewhat put out by the formal application process. To these researchers, governance is seen as a block to research and has frequently been referred to as such. There is a sizable contingent of researchers and pathologists, however, who are worried and often baffled by the regulations surrounding the use of human tissue in research. They are glad and feel comforted that OCHRe can relieve this burden either by practically dealing with these issues or by providing clear advice and guidance. This particularly applies to pathologists, who are often overrun with clinical responsibilities and who are to varying degrees detached from the world of research and its associated regulations. ORB and OCHRe staff also uphold and communicate their policies and procedures as the public face of pathology to the research world in Oxford.
research infrastructure and support the efficient best use of tissue in research for the common goal of patient benefit. A
REFERENCES 1 The Redfern Inquiry into human tissue analysis in UK nuclear facilities http://www.official-documents.gov.uk/document/hc1011/hc05/0571/ 0571_i.pdf (accessed 07/2013). 2 Hall D. Reflecting on Redfern: what can we learn from the Alder Hey story? Arch Dis Child 2001; 84: 455e6. 3 Skloot R. The immortal life of Henrietta lacks. New York: Crown Publishing, Random House, 2010. 4 Moore v regents of the University of California, 793P2d479 (Cal Rptr 146 1990). 5 Greenberg v Miami children’s hospital research institute, 264 F Supp 2d 1064 (SD Fla 2003). 6 Washington University v Catalona, 400F3d667 (8thCir 2007). 7 Armstrong S. A matter of life and death. Canongate, 2010. 8 http://www.mrc.ac.uk/Ourresearch/Ethicsresearchguidance/ Useofhumantissue/index.htm (accessed 07/2013). 9 Conversations with pathologists. http://www.pathsoc.org/ conversations/(accessed 07/2013). 10 Corfield JE, Yuille M, et al, STRATUM (Strategic Tissue Repository Alliances through Unified Methods): a project to deliver the building blocks for a UK Biobanking Network. Available for download at: http://stratumbiobanking.org/materials.html STRATUM overview (accessed 07/2013). 11 www.legislation.gov.uk/ukpga/2004/30/contents (accessed 07/2013). 12 Medicines for human use (clinical trials) regulations 2004, SI 2004/1031. http://www.legislation.gov.uk/uksi/2004/1031/made (accessed 07/2013). 13 www.legislation.gov.uk/ukpga/1998/29/contents (accessed 07/2013). 14 http://www.legislation.gov.uk/ukpga/2005/9/contents (accessed 07/2013). 15 www.hta.gov.uk/aboutus.cfm (accessed 07/2013). 16 Directive 2001/20/EC of the European Parliament and Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use 2001. OJ L121/34 http:// eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri¼OJ: L:2001:121: 0034:0044:en:PDF (accessed 07/2013). 17 Standard operating procedures for research ethics committees Version 5.1, March 2012, http://nres.nhs.uk/nres-publications/ publications/standard-operating-procedures/ (accessed 07/2013). 18 Joint statement from the HTA and National Research Ethics Service (NRES) Issued 29 July 2009 www.hta.gov.uk/ legislationpoliciesandcodesofpractice/ positionstatementondiagnosticarchivesreleasingtissueforresearch. cfm (accessed 07/2013). 19 Section 11.19 Standard operating procedures for research ethics committees Version 5.1, March 2012 http://nres.nhs.uk/nrespublications/publications/standard-operating-procedures/ (accessed 07/2013). 20 Section 11.20 Standard operating procedures for research ethics committees Version 5.1, March 2012, http://nres.nhs.uk/nrespublications/publications/standard-operating-procedures/.
Conclusion The regulations surrounding the use of human tissue in research can seem complex and the requirements for compliance, labyrinthine. The research facilitation provided by ORB and OCHRe bridges the gap between regulation and research, setting out clear processes to ensure legally and ethically compliant use of tissue for research. Staff have frequently been told that they are entirely trusted by the pathologists who know that the important information will have been checked rigorously. Staff are now a valuable part of cellular pathology through their governance and histopathology services. This has eased the pressure on the diagnostic service in terms of technical and administrative capacity. The overall function of a research tissue bank is to act as a matchmaker between patients and their samples, and researchers and their hypotheses. Its role is to facilitate research and to act as a platform upon which projects can be designed and carried out. Use of tissue in research e and thus its procurement, curation and appropriate provision e is essential to translational health research and sustainable clinical care. By working to establish tissue banking for research as a routine and integral part of the provision of healthcare, ORB and OCHRe seek to facilitate access and enhance
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21 Article 1, Trials of war criminals before the Nuremberg Military Tribunals under control council law No. 10, vol. 2. US Government Printing Office, 1949. 22 Paragraph 24. Declaration of Helsinki e ethical principles for medical research involving human subjects. World Medical Association. www.wma.net/en/30publications/10policies/b3/ (accessed 07/2013). 23 HTA code of practice 1, part 3, article 115 www.hta.gov.uk/ legislationpoliciesandcodesofpractice/codesofpractice/ code1consent.cfm (accessed 07/2013). 24 www.medsci.ox.ac.uk/news/university-of-oxford-and-the-oxfordradcliffe-hospitals-nhs-trust (accessed 07/2013). 25 http://orb.ndcls.ox.ac.uk.
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26 http://www.ouh.nhs.uk/patient-guide/leaflets/files/tissue.pdf (accessed 07/2013).
Acknowledgements All authors are funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
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well as the foundation of innovation and medical advance.7,8 Human tissue and its use is a matter of interest not only to pathologists and scientists, but to lawyers, philosophers, policy makers, clinicians and the public e whether patients or currently healthy individuals. Not least because of the multiple interests of these various parties and the special status of human biological material, its use in research is closely regulated. What does this mean for those intending to undertake research? Some have commented on e and objected to e the legislative burdens they experience, while others are bemused, confused or deterred from entering research by what they see to be a hazy labyrinth of red tape.6,9 There is also concern that regulation has reduced collection of and access to samples, thus threatening to impede medical advance.10 This paper steps to the side of the usual discussion of the status of tissue in ethics and law to consider instead the enactment of regulation in the daily practice of researchers. This is a separate and often overlooked area between regulation as drafted by legislators and policy makers, and as experienced by those who work within that regulatory frame. The paper considers the governance and procedures put in place and the expertise made available in one research centre, in order for researchers to proceed with their specialized work without first needing an advanced degree in law or ethics. The paper focuses on the bridging, facilitation activity of a research tissue bank at the University of Oxford by providing an on-the-ground account of how ethical and legal requirements related to the use of human tissue in research in the United Kingdom work out in day to day practice of collecting, storing and providing tissue for research. After a description of the regulatory and research contexts within which the tissue bank and its research facilitation service operate, a series of scenarios illustrate issues that arise with tissue in practice: in the governance of its collection, storage and provision to researchers.
Enacting regulation: tissue in practice Karen Melham Gemma Marsden Joy Wiles Divija Jatavallabhula
Abstract This paper steps to the side of the usual discussions of the status of tissue in ethics and law to consider instead the enactment of regulation in the daily practice of researchers. This is a separate and often overlooked area between regulation as drafted by legislators and policy makers, and as experienced by those who work within that regulatory frame. The paper considers the governance and procedures put in place and the expertise made available in one research centre. Focus on the bridging, facilitation activity of a particular research tissue bank affords an on-the-ground account of how ethical and legal requirements related to the use of human tissue in research in the United Kingdom work out in the everyday practice of collecting, storing and providing tissue for research.
Keywords consent; Human Tissue Act; human tissue research; research governance in practice; tissue banking
The status and use of human tissue in research is complex, at times contested, and an area of ongoing ethical and legal discussion. Companion articles in this issue’s symposium address some of the areas of current debate. The use of human tissue in research has been the source of scandal1e3 and litigation4e6 as
Regulatory context Karen Melham PhD Ethicist, Centre for Health Law and Emerging Technologies, University of Oxford, Oxford, UK. Conflicts of interest: Ethicist for bioresources in the NIHR Oxford Biomedical Research Centre, including ORB and OCHRe. She is also chair of National Research Ethics Committee South Central e Oxford A, and member of STRATUM (Strategic Tissue Repository Alliances Through Unified Methods).
Within the England, Wales and Northern Ireland, the requirements for research involving human biological material are primarily based on two pieces of legislation: the Human Tissue Act 2004 (HTA 2004) with its accompanying Codes of Practice,11 and the Medicines for Human Use (Clinical Trials) Regulations (2004).12 In addition, if researchers intend to use identifying patient data, this information is subject to the common law duty of confidentiality and the requirements of the Data Protection Act (1998).13 In circumstances where individuals lack capacity to consent, the provisions of the Mental Capacity Act (2005) may also be relevant.14 The Human Tissue Act 2004 (HT Act) consolidated previous legislation and created the Human Tissue Authority (HTA) to “regulate the removal, storage, use and disposal of human bodies, organs and tissue.”11 The HTA describes itself as “a watchdog that supports public confidence by licensing organisations that store and use human tissue for purposes such as research, patient treatment, post-mortem examination, teaching, and public exhibitions”.15 The HTA conducts regular inspections to assess whether licenced establishments follow required procedures and maintain good standards and appropriate records.
Gemma Marsden BSc Hons Biobank Manager, Oxford Radcliffe Biobank, NIHR Oxford Biomedical Research Centre, Oxford, UK. Conflicts of interest: Manager of the Oxford Radcliffe BIobank (ORB). Joy Wiles BSc Hons Research Coordinator, Oxford Centre for Histopathology Research, NIHR Oxford Biomedical Research Centre, Oxford, UK. Conflicts of interest: Research coordinator within the Oxford Centre for Histopathology Research (OCHRe). Divija Jatavallabhula BSc Hons Research Coordinator, Oxford Centre for Histopathology Research, NIHR Oxford Biomedical Research Centre, Oxford, UK. Conflicts of interest: Research coordinator within the Oxford Centre for Histopathology Research (OCHRe).
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While the HTA concerns itself with procurement and storage of human tissue, its remit does not include the ethical approval of the research undertaken with that tissue. This comes under the purview of the National Research Ethics Service (NRES) and its Research Ethics Committees. These committees, in turn, tend to the provisions of Clinical Trials Regulations. The EU Clinical Trials Directive16 was transposed into UK law in May 2004 in the form of the Clinical Trials Regulations.12 The Regulations were intended to apply only to clinical trials and not medical research more broadly, but it is UK Department of Health policy that the operating procedures required by the Directive and the Regulations “should also apply in general to the review by RECs (Research Ethics Committees) in the UK of all other research involving human participants within the NHS”.17 With one body taking responsibility for storage and another for research use of human biological material, it is necessary for the HTA and NRES to work in close alignment. They issued a Joint Statement in 2009, outlining their working arrangements.18 These include agreement that while human biological material is being used in a research project for which ethics approval has been given, it does not require registration under an HTA licence. Such an arrangement allows researchers who collect samples from participants as part of their ethically approved research to proceed without reference to the HTA. At such time as ethical approval for a research project expires, materials still held for which there is consent for storage and further use must be transferred to a licenced facility. They can be accessed again subject to ethics approval. Renewed access to previously collected samples need not entail return to a REC for every research project proposed. The HTA and NRES also arranged for Research Ethics Committees to be able to give generic ethical approval for a research tissue bank. A research tissue bank is defined as “A collection of human tissue or other biological material, which is stored for potential research use beyond the life of a specific project with ethical approval or for which ethical approval is pending.”19 A tissue bank storing human tissue for use in as yet unspecified research must obtain a licence from the HTA. It may then apply to an REC for generic ethical approval for its arrangements for collection, storage and release of tissue, in keeping with the programme of research it is designed to support. Research tissue bank approval can thus extend to specific projects requiring non-identifiable tissue from the bank.18,20 In this way, the REC devolves governance for its collections to the research tissue bank itself. The bank submits annual reports to the REC, renews its ethical approval every five years, and is subject to the licencing requirements of the HTA. The result is that researchers can access tissue from a central place with the brunt of regulatory administration being handled by the bank. Researchers will need to satisfy the access requirements of the tissue bank, but these are less involved and can be facilitated in a shorter time frame than is possible with REC review.
participants. The Nuremberg code, developed following the post WW2 Nuremberg trials, articulated clearly the principle of voluntary, informed consent for research.21 This has been developed further in the various versions of the World Medical Association’s Declaration of Helsinki.22 Informed consent as described in the Declaration of Helsinki in turn forms the basis for the consent requirements in the EU Clinical Trials Directive. Consequently, it is an area of Research Ethics Committee review in the UK context. In addition to biological material being collected specifically for research purposes, including biobanking, tissue may be available as a clinical by-product. Consent for research, including biobanking, is sought before any intervention. Tissue obtained in the course of diagnosis, such as a blood or urine sample or a tissue biopsy, or as a result of treatment, such as when an organ or tumour is removed, can also be used in research under certain conditions. Trusts have policies in place to obtain consent for investigation or treatment, and their consent provisions may include an option for patients to give permission for the use of removed material in research. This material will be stored in a diagnostic archive; the samples form part of a patient’s medical record. In some instances, and when a patient has consented, additional surplus material may be stored in a research tissue bank. Consent can be broad in both time and scope: it does not need to be project-specific. Where individuals are consenting to use of tissue in further research without knowing the nature of that research, they are instead consenting to governance. Information provided to support their decision explains how and by whom decisions will be made about the use of their tissue. Since the consent requirements of the HT Act are not retrospective, it is not necessary to obtain or confirm consent for use of material that was already stored e whether in a research or archival setting e when the HT Act came into force on 1 Sept 2006. These are considered ‘existing holdings.’ Tissue for which consent has not been sought for research use (other than existing holdings) can only be released if it is 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; there are research ethics approval provisions in place, such that material is either: released by a research tissue bank with generic ethical approval from a REC for research within the terms of its approval or to be used for a specific research project approved by a REC.18,23 These regulatory requirements, even with their arrangements to align responsibility and governance, are still some distance from the work done by pathologists and researchers with tissue itself. Between the regulation and the research there is need for a facilitating gateway where requirements are enacted in order to facilitate proper lawful and ethical use of human tissue for research. What follows is a description of one such gateway, and instances in which it enables sound research practice.
Consent A central tenet of both the Human Tissue Act and research ethics is consent. The importance of obtaining and recording consent from individuals for the use of their biological material underpins Human Tissue Legislation. Consent is a similarly fundamental concern running through the ethics of research involving human
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Oxford Radcliffe Biobank The Oxford Radcliffe Biobank (ORB) is a research facility of the Oxford University Hospitals NHS Trust (OUH) and the University
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of Oxford. It is the subject of a service level agreement between these two institutions, which forms part of their strategic partnership.24 ORB provides infrastructure to underpin biobanking activities and delivers a portfolio of integrated services to users, from tissue acquisition, storage and distribution, through to the governance, ethical and regulatory cover that come with its research tissue bank status. The specimens and associated information managed by ORB are used for research studies that may contribute to increasing the knowledge and understanding of disease in order to improve diagnosis and treatment, and aims ultimately to contribute to improvements in patient care. A primary focus of ORB is maintenance of a generic, open-access resource of tissue donated by patients and research participants for use in medical research and provision of a simple and efficient system to collect, store, curate, and distribute these specimens and associated information. This includes having a Sample Access Committee that meets fortnightly to consider in detail all requests. ORB was established in 2006 when a number of active and legacy collections within the University of Oxford and the Oxford University Hospitals NHS Trust were brought together for licencing by the Human Tissue Authority (HTA). This was in response to the Human Tissue Act (2004), when it came into effect on 1 September 2006. In 2007, substantial support was awarded by the Oxford Biomedical Research Centre (funded by the National Institute for Health Research) to enable further integration and expansion of biobanking activity. This centralized approach complements the various funding streams that support individual collections. In response to the requirements of the Human Tissue Act, ORB operates a multi-site Human Tissue Authority Research Licence with policies and procedures in place to ensure registered collections comply with the legislation.25 ORB also provides storage facilities according to HTA guidelines. It is recognized that access to large numbers of high-quality, clinically annotated biomaterials is vital for the advancement of medical research and healthcare delivery. ORB facilitates this access and enhances the research infrastructure by working with all stakeholders to ensure effective sharing of information, resources and best practice. Custodians of collections engage with ORB as part of a federated model. In order to manage the requirements of the legislation across all the collections within ORB, central NIHR funding ensures that there is sufficient support for centralized management. However each discrete collection is set up with a Person Designated (PD) and a Principal Investigator (PI) at the particular site. The PD assists in the governance of the activities authorized by the licence. In practice, the PD is responsible for reporting annual collection and usage statistics to the centralized ORB management team in time for the ethics annual report and HTA selfassessment, as well as overseeing the day to day operational management of the samples. The PI of each collection is responsible for approval of all sample usage from their collection; which entails a formal review and approval process. Audits are carried out to ensure that each collection is managed according to ORB policies and that all activities are carried out according to standard operating procedures (SOPs). In practice, managing a biobank is about being the interface between the patient, the care givers and the researchers. To the patient, a biobanker is an individual who comes to one of their
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hospital appointments to speak to them about the use of their tissue for research. Gaining consent is a balancing act of getting the amount and quality of information right, pitched at the right level and delivered at a suitable time. It is about engaging with individuals, earning their trust in research and its governance, and completing the consent form properly, as an indication of this process of discussion, understanding and agreement.
Oxford Centre for Histopathology Research Working closely with ORB is the Oxford Centre for Histopathology Research (OCHRe), a University of Oxford Small Research Facility (SRF) which operates on a cost recovery basis. OCHRe is an integrated service-driven facility which enables access to equipment and methodologies for research, and importantly the expertise essential for the generation and interpretation of reliable and reproducible results. OCHRe acts as a gateway for access to myriad specimen collections held in Oxford in addition ORB, including some diagnostic archives of the Oxford University Hospitals NHS Trust. It is important to note that, although OCHRe facilitates this access, the Trust’s diagnostic archive is not at present a research tissue bank. In keeping with the Joint Statement by the HTA and NRES, it does not in any way advertise itself as a research resource.18 The archive itself forms part of a patient’s medical record, with samples necessarily retained in case of second opinion, further clinical investigation, or legal action. The archive holds a vast array of formalin fixed paraffin embedded (FFPE) tissue which can be made available for the purpose of research when there is patient consent for its use in research and a favourable opinion from a research ethics committee. Historically, the access to this tissue was not as clearly structured compared to that of a research tissue bank. OCHRe provides the structure and acts as the bridge between researchers and cellular pathology. In practice this means that consent provisions are checked before samples are approved for the use in projects, and those projects and the terms of their ethical approval are scrutinized as part of the sample access application process. The use of each sample is approved by the reporting pathologist who acts on behalf of the Trust and the patient. A major benefit of having a formalized process in place is that the curation of the diagnostic archive is organized and tracked, therefore enabling the Trust to fulfil its obligations as the custodian of this particular part of the patient record. Use of tissue blocks from the archive is carefully monitored by OCHRe, such that no one particular block is allowed to be used to extinction, thereby maintaining the patient record in case it needs to be re-visited for clinical or legal reasons. OCHRe safeguards samples by offering a sectioning service for researchers; cutting sections from the blocks and ensuring that there is sufficient material left in them for return to the archive. Tissue blocks themselves are not released for research projects unless there are exceptional circumstances. As a further safeguard, OCHRe staff are trained to the standards of the diagnostic lab and are signed as competent before being allowed to cut diagnostic material. OCHRe is recognized by the Oxford University Hospitals NHS Trust R&D Department as a facilitating body for research. In practice and as part of its approval, R&D directs researchers to OCHRe if their projects involve the use of human tissue. This
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means that a clinical trial can gain approval in principle to access the necessary tissues before the stage of recruiting the first patient. There is sometimes confusion on the part of people setting up new projects and trials, where an R&D approval is seen as an overall approval on behalf of all parties in the Trust for the project to go ahead. This means that we sometimes encounter resistance when they are setting up a project with OCHRe as it is seen as an unnecessary layer. The difference between the two governance processes is that OCHRe looks at the feasibility and operational factors that will impact on the ability of the project to go ahead. The function of R&D approval is to ensure that the host organization as the sponsor can take legal responsibility for initiation and management of the study and to ensure the provision of insurance for the study.
Some researchers prefer to give a brief to OCHRe of the types of samples required and the selection of cases and tissue blocks is completed by a pathologist for the disease speciality. This adds an element of quality control to the project. In the last year the average number of pathologists involved in research projects has increased by ten percent.
Case study: quality management incidents As recommended by the HTA, the Oxford Radcliffe Biobank uses a quality management system for document management, version control, maintaining a record of staff training and for managing quality issues. An example of an active process of quality management for ORB is the reporting of incidents. A matrix is used which grades incidents in severity from mild to catastrophic, such as equipment failure which did not result in the loss of samples, through to the use of the wrong sample, right through to the DNA analysis of a sample without consent. In the UK, genetic analysis without consent is an offence. An example in practice of the type of incident that we actively manage is a failure to guarantee patient anonymity. The Biobank received a phone call from a patient ringing the phone number provided on the top of his biobank consent form. He was calling to say that he’d been sent home with someone else’s consent form. He wasn’t interested in blame or finger pointing; he just wanted to make sure that it was returned to the correct person. He returned the form to the Biobank by post. Biobank staff wrote back to the patient, thanking him for the safe return of the form, apologizing for the mix up and including some first class stamps for the inconvenience. This event subsequently triggered an impact assessment in which the ORB manager and team examined the event, its impact, and the contributing causes. This resulted in an action plan, which was carried out in order to reduce the likelihood of a repeat occurrence. It is common practice to use a label on consent forms which contains standard patient identifiers such as their name, address, post code, date of birth, hospital and NHS numbers. This is to be able to identify correctly the consent form, which is then coded with a unique patient number. It is the unique number that is then used on all other labels and documentation and provides a mechanism for linked-anonymization. In this case, a serious breach of confidentially had been avoided as the form only contained the initials, signature and printed name of the patient, and no address or date of birth. The researcher involved had seen many of patients in a succession and had not reached the point of labelling when the mix up occurred. The person gaining consent had the copies of the consent form from the previous patient in her hand when she moved on to obtain consent from the next patient. A copy of the previous patient’s form was inadvertently mixed with the paperwork for the second patient. Contributing causes were identified as lack of concentration, time pressures, a busy clinic and a gap in staff training. The incident was classed as severe but ranked as low impact. The immediate action plan was to check the copy consent forms in the medical notes and the research file for both patients to ensure that these were filed correctly. Follow-up actions included the review of the SOP (standard operating procedure) for consent and to carry out staff training covering good practice when dealing with confidential information.
Working with pathologists: coordination and trust ORB has a small team of biobankers who are based within the department of Cellular Pathology. This staff has found this close proximity to pathologists to be very helpful getting to know and gaining the trust of the pathologists with whom they work so closely. The vast majority of the samples collected are surplus to diagnostic requirements following a major resection, and therefore biobankers rely heavily on pathologists being on hand to dissect specimens and allocate samples to the biobank. Recently there has been an increase in the number of researchers requesting fresh tissue for their work. This means there is an added level of coordination work to ensure the tissue gets to the applicants as soon as possible. There are a number of possible impediments, over which biobankers have very little control. Sometimes consent for research has not in fact been obtained. Sometimes theatres are slow to bleep and alert following resection, or the correct paperwork has not been completed when we arrive at theatres. Since procedures may happen at another site, there may be traffic to contend with. With all these factors working against the collection of fresh tissue, the availability of the pathologists is paramount. On the other hand, biobankers and OCHRe staff work together with the pathologists to prevent multiple different researchers asking them directly for tissue. Researchers seeking tissue are directed to OCHRe to ensure the correct approvals are in place for them to work with human tissue. OCHRe is then the point of contact between the pathologist and the researcher. This removes from pathologists the clamour of researchers at their doors and, with a transparent and rigorous process in place, pathologists can be assured that all the tissue donated to research is being used in accordance with the regulations. In addition, the value of introducing the process of research governance has been shown in the increased awareness of biomedical research within the diagnostic department. Because of their interactions with biobank and OCHRe staff, pathologists are better informed about the governance involved in using tissue for research. Further, because they have become an essential part of the application process, they have an awareness of the research being carried out in Oxford. Researchers are seeing the benefits of involving pathology when designing and carrying out their work. The Sample Access Committee will generally recommend pathology review of an H&E slide of any sample used for a project so that the researcher knows what they are getting.
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Case study: checking consent
A material transfer agreement (MTA) was also put in place to document and establish the custodianship of the tissue and data as they were being provided to another institution for research purposes. This was not just to establish who is free to publish the results gained through the use of the materials transferred but also to retain the right to use any results created for future research purposes. As is standard practice, checks and balances were also made during the negotiation of the MTA to ensure that the terms and conditions did not conflict with any grant terms and conditions which may govern the overall programme of research in which the material transferred will be used. These exceptional circumstances lead to OCHRe working with the Trust to create a Block Release Committee, consisting of pathology management, consultant pathologists, the Trust HTA representative, and OCHRe management whose terms of reference include decision making for the release of tissue blocks from the diagnostic archive in exceptional circumstances. In this way, ORB and OCHRe are serving to facilitate access to tissues for research, allowing Oxford to participate in a wider diversity of projects.
An OCHRe customer requested 31 patient samples from the diagnostic archive for a project for which he had obtained project-specific ethics approval which included a patient consent form and information sheet. The Sample Access Committee had requested sight of the completed consent forms as part of the approvals process. On review, it was found that not one of the forms had been completed to the appropriate standard. Some were signed but no clauses were initialled: on others the consent clauses had an ambiguous line through them but there was no signature or name on the form. It was not clear from looking at the forms what the wishes of each patient were. The committee ethicist met with the researcher, discussed at length the problems with consent, and how to ensure better practice in future. Since it was decided that these forms could not be used as a record of patient consent, it was suggested that the researcher provide an alternative record of consent in the form of the research inclusion section of each ‘Patient Consent to Treatment or Investigation’ form. Every patient attending the Oxford University Hospitals NHS Trust for treatment or investigation is asked to complete one of these forms with a person competent to undertake the procedure that they are undergoing. This consent form includes an option to allow tissue to be used for research, and is supported by an information leaflet.26 The researcher did provide this alternative information. The need to do so led to delay to the project and to a reduced cohort size, as some forms were unavailable to view. At the same time, the researcher noted that he now better appreciated what was involved in obtaining consent, and has sought advice since. He also recognized that the service sought to find a way to make his research possible through another, compatible regulatory avenue.
Help or hindrance, facilitation or frustration? From the point of view of the researchers for whom ORB and OCHRe provide a service, we are sometimes seen as a barrier to research, or at least a necessary evil. For each application for tissue staff ask for information so that those with governance responsibility can be satisfied that the chain of trust between initial contact and the patient is perpetuated and in order to maintain that trust through continued research governance. The individual obtaining consent for sample use in research will have assured the patient in the consent discussion and in writing on the consent form that their samples will only be used for research that has been given a favourable opinion by an ethics committee. In those instances where the request for samples is outside the scope of the research that ORB supports with its generic research tissue bank approval, the Sample Access Committee will expect to see the details of the ethical approval and sometimes the application that the researcher presented to the ethics committee. The approval letter from the ethics committee gives little information about the scope of the approval, so it is often necessary, in order to determine the terms of that approval, to look at the information on which the committee based their decision. This may at first make OCHRe staff and Sample Access Committee members look like obsessives at play, but the process has in the past identified applications for tissue not in fact covered by the ethics approval details given. These were not deliberate attempts to gain access to tissue unlawfully, but rather oversights when projects had morphed slightly from what was initially envisaged, and amendments had not been made, or there was an inaccurate understanding of what a research ethics approval might allow. These issues can also arise with researchers inexperienced in preparing ethics applications and who may not have ‘future proofed’ the terms of consent. OCHRe staff also ask all applicants for information regarding the aims and objectives of the project and the intended use of the sample requested. This information is presented to the Sample
Case study: safeguarding material A request was received from a multi-centre study for samples from the diagnostic archive for the purpose of incorporating into a large scale tissue micro array (TMA) where the samples will remain anonymous to the researcher. The array would bring together material from many more patients than would be possible from one hospital alone and so would be an invaluable resource for future projects. This is an example of an exceptional circumstance wherein a block might be released instead of only slides or sections, since the tissue block is required so that a small core of material can be removed for incorporation into the array. The project was retrospective, and thus designed to make use of archival material. This means that the individuals who donated the tissue would not know of this specific purpose but because of the consent provisions of the Human Tissue Act would have been asked if their tissue could be used for research approved by a research ethics committee. There was a perceived element of risk to the Trust and the patients for this project as the tissue blocks would be shipped elsewhere for the TMA construction. It was agreed that only cases with more than one block of representative tissue would be included, thereby safeguarding against loss of tissue e and its information e from the patient record. An arrangement was put in place to ship the samples in batches, with careful tracking and inventory at each stage.
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Access Committee to make the case for the use of the sample for this particular research project. At times, the committee requests further information from the researcher and this can extend the timeline for the application process. It is possible to see that researchers could think of this governance as a barrier to research, but as the honest broker in the middle, we have a duty of care to get the details right. In contrast to this viewpoint, other researchers are clearly pleased and grateful that the service is available to guide them through the ethical and regulatory minefield associated with using human tissue for research. ORB and OCHRe have formalized the process of accessing human samples. Prior to the inception of ORB and OCHRe, this was solely the responsibility of the PI of each collection (or the reporting pathologist in terms of the diagnostic archive). This often led to a culture of “it’s not what you know but who you know.” Although the PI/pathologist gives approval for the use of the samples, OCHRe aims to provide a common access point and application process. To some this extends the process e if they were previously used to speaking directly to the PI/pathologist they can be somewhat put out by the formal application process. To these researchers, governance is seen as a block to research and has frequently been referred to as such. There is a sizable contingent of researchers and pathologists, however, who are worried and often baffled by the regulations surrounding the use of human tissue in research. They are glad and feel comforted that OCHRe can relieve this burden either by practically dealing with these issues or by providing clear advice and guidance. This particularly applies to pathologists, who are often overrun with clinical responsibilities and who are to varying degrees detached from the world of research and its associated regulations. ORB and OCHRe staff also uphold and communicate their policies and procedures as the public face of pathology to the research world in Oxford.
research infrastructure and support the efficient best use of tissue in research for the common goal of patient benefit. A
REFERENCES 1 The Redfern Inquiry into human tissue analysis in UK nuclear facilities http://www.official-documents.gov.uk/document/hc1011/hc05/0571/ 0571_i.pdf (accessed 07/2013). 2 Hall D. Reflecting on Redfern: what can we learn from the Alder Hey story? Arch Dis Child 2001; 84: 455e6. 3 Skloot R. The immortal life of Henrietta lacks. New York: Crown Publishing, Random House, 2010. 4 Moore v regents of the University of California, 793P2d479 (Cal Rptr 146 1990). 5 Greenberg v Miami children’s hospital research institute, 264 F Supp 2d 1064 (SD Fla 2003). 6 Washington University v Catalona, 400F3d667 (8thCir 2007). 7 Armstrong S. A matter of life and death. Canongate, 2010. 8 http://www.mrc.ac.uk/Ourresearch/Ethicsresearchguidance/ Useofhumantissue/index.htm (accessed 07/2013). 9 Conversations with pathologists. http://www.pathsoc.org/ conversations/(accessed 07/2013). 10 Corfield JE, Yuille M, et al, STRATUM (Strategic Tissue Repository Alliances through Unified Methods): a project to deliver the building blocks for a UK Biobanking Network. Available for download at: http://stratumbiobanking.org/materials.html STRATUM overview (accessed 07/2013). 11 www.legislation.gov.uk/ukpga/2004/30/contents (accessed 07/2013). 12 Medicines for human use (clinical trials) regulations 2004, SI 2004/1031. http://www.legislation.gov.uk/uksi/2004/1031/made (accessed 07/2013). 13 www.legislation.gov.uk/ukpga/1998/29/contents (accessed 07/2013). 14 http://www.legislation.gov.uk/ukpga/2005/9/contents (accessed 07/2013). 15 www.hta.gov.uk/aboutus.cfm (accessed 07/2013). 16 Directive 2001/20/EC of the European Parliament and Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use 2001. OJ L121/34 http:// eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri¼OJ: L:2001:121: 0034:0044:en:PDF (accessed 07/2013). 17 Standard operating procedures for research ethics committees Version 5.1, March 2012, http://nres.nhs.uk/nres-publications/ publications/standard-operating-procedures/ (accessed 07/2013). 18 Joint statement from the HTA and National Research Ethics Service (NRES) Issued 29 July 2009 www.hta.gov.uk/ legislationpoliciesandcodesofpractice/ positionstatementondiagnosticarchivesreleasingtissueforresearch. cfm (accessed 07/2013). 19 Section 11.19 Standard operating procedures for research ethics committees Version 5.1, March 2012 http://nres.nhs.uk/nrespublications/publications/standard-operating-procedures/ (accessed 07/2013). 20 Section 11.20 Standard operating procedures for research ethics committees Version 5.1, March 2012, http://nres.nhs.uk/nrespublications/publications/standard-operating-procedures/.
Conclusion The regulations surrounding the use of human tissue in research can seem complex and the requirements for compliance, labyrinthine. The research facilitation provided by ORB and OCHRe bridges the gap between regulation and research, setting out clear processes to ensure legally and ethically compliant use of tissue for research. Staff have frequently been told that they are entirely trusted by the pathologists who know that the important information will have been checked rigorously. Staff are now a valuable part of cellular pathology through their governance and histopathology services. This has eased the pressure on the diagnostic service in terms of technical and administrative capacity. The overall function of a research tissue bank is to act as a matchmaker between patients and their samples, and researchers and their hypotheses. Its role is to facilitate research and to act as a platform upon which projects can be designed and carried out. Use of tissue in research e and thus its procurement, curation and appropriate provision e is essential to translational health research and sustainable clinical care. By working to establish tissue banking for research as a routine and integral part of the provision of healthcare, ORB and OCHRe seek to facilitate access and enhance
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21 Article 1, Trials of war criminals before the Nuremberg Military Tribunals under control council law No. 10, vol. 2. US Government Printing Office, 1949. 22 Paragraph 24. Declaration of Helsinki e ethical principles for medical research involving human subjects. World Medical Association. www.wma.net/en/30publications/10policies/b3/ (accessed 07/2013). 23 HTA code of practice 1, part 3, article 115 www.hta.gov.uk/ legislationpoliciesandcodesofpractice/codesofpractice/ code1consent.cfm (accessed 07/2013). 24 www.medsci.ox.ac.uk/news/university-of-oxford-and-the-oxfordradcliffe-hospitals-nhs-trust (accessed 07/2013). 25 http://orb.ndcls.ox.ac.uk.
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26 http://www.ouh.nhs.uk/patient-guide/leaflets/files/tissue.pdf (accessed 07/2013).
Acknowledgements All authors are funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
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