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Draft 2nd Edition of the TCPS (December 2008)

Chapter 12

HUMAN TISSUE

The use of human tissue for research contributes greatly to the advance of biomedical science. Ethical considerations raised by such research centre on acceptable access and consent to the use of tissue and potential privacy concerns arising from the disclosure of information derived from donor tissue.

Human tissue here refers to any biological material and includes blood or other body fluids. The status accorded the human body and its parts varies among individuals and cultures. This variation, in part, reflects how people perceive, identify with, and relate to their bodies. It is important, then, to assess the ethics of research involving human tissue with an awareness of, and sensitivity to, the relevant cultural context.

A. Identifiability of Tissue

Five categories of human tissue can be distinguished, based on the extent to which they are identifiable. These categories, with minor variations, are also found in Chapter 5 (“Privacy and Confidentiality”) with respect to the identifiability of personal information:

  • Identified tissue: Tissue donors can be identified through direct identifiers associated with the sample (e.g., name, address, social insurance number or personal health number);
  • Identifiable tissue: Tissue donors can be identified by a combination of indirect identifiers (e.g., date of birth, place of residence, or unique personal characteristic) using reasonably foreseeable means;
  • De-identified/coded tissue: Identifiers are removed from tissue samples and replaced with a code that permits individual donors to be identified only by use of that code, access to which may be restricted;
  • Anonymized tissue: Tissue is irrevocably stripped of any means of identification and a code is not kept to allow future re-linkage; and
  • Anonymous tissue: Information that never had identifiers associated with it.

These categories, however, are not fixed. Identified, identifiable and de-identified tissue can be anonymized by well-accepted technical or administrative means. For purposes of assessing privacy, identified and identifiable tissue may be treated in much the same way, since these categories of tissue can be straightforwardly associated with a particular individual. Likewise, anonymous and anonymized tissue also may generally be treated the same, since they cannot be associated with an individual.

However, due to continuing technological development in genetics, individuals with access to stored tissue are increasingly able to discover the identity of individual donors using genetic markers. For this reason, genetic testing has made it more difficult to categorize tissue as anonymous or anonymized. Researchers and research ethics boards (REBs) should be aware of, and guard against, this potential threat to donors’ privacy.

From the perspective of confidentiality, it may seem desirable to anonymize or de-identify collected tissue to the extent possible. However, there are considerations that may justify retaining some identifiers, which include the scientific requirements of some studies and the need to avoid using different samples from the same donor. Anonymity may not always be desirable for other reasons as well. Rendering tissue anonymous has the disadvantage of making it impossible to offer the benefits of research findings to donors and their families or to alert them to relevant clinical findings. This is particularly significant when research may disclose a previously undiagnosed condition, such as HIV infection or an inherited predisposition to breast cancer, for which potentially effective treatments are available.

B. Tissue Collection

Tissues samples may be obtained in different ways:

  1. They may be collected expressly for a specific research purpose;
  2. They may be collected incidentally to medical or diagnostic procedures with no initial intent to be used in research; or
  3. They may be collected for research or medical or diagnostic purposes with some expectation that they may or will also be used in future research, although the precise research project(s) may not be known at the time.

The first category above refers to the initial collection of tissue for research, which is described in this section. The latter two categories are relevant to subsequent, secondary uses of tissue for research that may not have been conceived at the time the tissue was taken. These are described in Section D (“Secondary Use of Previously Collected Tissue”), below.

Article 12.1 Research proposing the initial collection and use of human tissue requires ethics review by a research ethics board and consent of the tissue donor.

  1. The collection and use of human tissue for research purposes should be undertaken with the free and informed consent of the donor;
  2. In the case of donors who lack capacity, consent may be given by advance directive or by an authorized third party; and
  3. In the case of deceased donors, consent may be given by advance directive or by an authorized third party.

Application Article 12.1 applies prospectively - that is, prior to the collection of tissue intended for research purposes. It applies the general elements of free and informed consent in Chapter 3 (“Free and Informed Consent”) to tissue donation. The consent process permits individuals to protect themselves against unwanted or potentially harmful invasions of privacy. Individuals who do not wish to contribute tissue to particular research projects should be free to withhold consent without penalty and without prejudicing access to any treatment they would otherwise receive. For individuals unable to give consent, the principles developed in Chapter 3 regarding third-party authorization should be observed.

When informed consent to the research use of tissue is being discussed, a clear distinction should be made between consent to research use and that for any clinical procedure or test. In practice, this may mean separate consent forms, but in any event, the different uses must be clearly explained and understood by donors.

Advance directives may include instructions relating to the future donation of tissue, and they should be respected. However, post-mortem donation of tissue can be an extraordinarily sensitive topic in some families. In such cases, if serious objections or divisions within a donor’s family become known, researchers should be aware of family members’ concerns, and they should respond in a way that respects that sensitivity. REBs and researchers should be aware that provincial human tissue gift laws often make specific provision for research use and should be consulted.

Consent for Future Use

Article 12.2 To facilitate the appropriate subsequent use of human tissue, consent forms should provide potential participants with a range of choices relating to the future use of their tissue.

Application Where secondary use of donated tissue is anticipated, it is desirable that individuals approached to donate be given a realistic opportunity to express the specific nature and scope of the consent they wish to give. Accordingly, offering a variety of choices, as suggested in Article 12.2, permits donors flexibility in shaping the acceptable secondary use of their tissue. Options might include, for example:

  • Refusing any future use of their tissue in research;
  • Permitting only anonymous or anonymized use of their tissue in research;
  • Permitting identified, identifiable or coded use of tissue for one particular study only;
  • Permitting identified, identifiable or coded use of their tissue for any study relating to the condition for which the sample was originally collected;
  • Permitting future contact by researchers to seek consent for other studies; or
  • Permitting coded use of their biological materials for any kind of future study.

At the same time, donors should be advised that, once given, their consent may be difficult to withdraw. They should also be advised of the potential for subsequent identification, including identification by means of increasingly sophisticated genetic technologies.

Article 12.3 For the purpose of obtaining free and informed consent, the full range of information set out in Article 3.2 in Chapter 3 (“Free and Informed Consent”) should be provided. In addition, researchers who seek to collect human tissue for research should provide potential donors or authorized third parties with the following information:

  1. The type and amount of tissue to be taken;
  2. The manner in which tissue will be taken, and the safety and invasiveness of the procedures for acquisition;
  3. Potential uses of the tissue, including any commercial uses;
  4. Measures to protect the privacy of individual donors, ensure confidentiality of the data, and minimize harms to donors;
  5. The length of time the tissue will be kept, how it will be preserved, and any limits on its use; and
  6. Where applicable, the researchers’ plan for disclosure of clinically relevant information derived from the tissue.

Application Free and informed consent to tissue donation requires that all currently known relevant information be provided to potential donors. In general, consent must be based on an understanding of the specific uses of tissue for research anticipated at the time. Potential research participants should also be advised if there is the possibility that future studies, the nature of which is currently unknown, may be undertaken using the donated tissue. Researchers should submit to the REB an acceptable plan for maintaining the duty of confidentiality in regard to tissue donors. Reasonably anticipated harms, such as the possibility of future identification, must also be disclosed. This includes information on any identifying information to be attached to the tissue, its potential traceability, and how the use of the tissue could affect the donor’s privacy.

In general, tissue samples should be used only for the agreed-on research project. The law in some jurisdictions requires that research be restricted to these purposes. Subject to Articles 12.5 and 12.6, if tissue is to be used for any other research purpose, the individual’s prior consent should be obtained.

The research protocol and consent form should describe any incidental findings that may be anticipated, as well as the way they will be managed. Incidental findings are unanticipated discoveries, which may not have been within the original focus of the research, that may have clinical, psychological, social or other health-related significance. If incidental findings are made, the question may arise whether, and how, they should be communicated to the affected donor. The management of incidental findings is more fully discussed in Article 3.4 in Chapter 3 (“Free and Informed Consent”).

While all the basic guidelines of Chapter 3 regarding free and informed consent apply to research involving human tissue, some deserve special attention. Explaining the purpose of the research is of particular importance, since the tissue donor will not be directly involved in the research. Explaining the potential for financial conflict of interest is also important, as there may be the potential for significant commercial gain.

C. Tissue Storage and Banking

This section applies to any storage of tissue. It includes tissue stored only for the duration of a study as well as that which is stored or banked for future research use.

Collection and retention of tissue in biological banks (“biobanks”) creates an increasingly important resource for research. Biobanks vary widely in their characteristics. Different types of biological materials may be stored in biobanks, including blood and tissue samples, such as tissues from tumours or organs. Biobanks may include or be linked with databases of identifiable or non-identifiable information; they may be disease-specific or contain genetic material from a wide population base; they may be established prospectively for use in a specific research study or to provide biological materials for numerous studies.

The creation of biobanks presents risk to individuals whose genetic and other personal information may be accessed, used, retained and disclosed, and they also present risk to those individuals’ biological relatives and others with whom they have shared genetic characteristics.

Article 12.4 Institutions and researchers that maintain collections or repositories of tissue:

  1. Should ensure that they have or use appropriate facilities, policies and procedures to ensure that tissue is stored safely and in accordance with applicable standards; and
  2. Should establish appropriate physical, administrative and technical safeguards to ensure that the privacy of tissue donors is protected.

Application Institutions and researchers must ensure that their facilities, equipment and procedures permit tissue to be stored safely so that its scientific value is maintained. Procedures for storage and record-keeping must include effective measures to ensure that donors’ identities are protected. Such measures include the security of facilities and effective procedures for data handling, record-keeping and regulating access to tissue and associated information by outside researchers and others.

Organizations that maintain biobanks may have their own policies on privacy, confidentiality and access to materials. Researchers should be aware of requirements for compliance with such policies. For example, researchers may be required to apply to the organization for permission to access biological samples, and they may be required to enter into an agreement with the organization that sets out conditions for research access and use of materials in the biobank.

Identified data derived from tissue may be linked to other research or public databases. Such data linking can be a powerful research tool and valuable resource for monitoring the health of populations, understanding factors influencing disease, and evaluating health services and interventions. Data linkage raises separate privacy issues, discussed in Section E (“Data Linkage”) of Chapter 5 (“Privacy and Confidentiality”).

D. Secondary Use of Previously Collected Tissue

A researcher may want to use tissue left over from earlier research, from a diagnostic examination or surgical procedure, or from an established tissue repository. At the time tissue was collected, individuals may have consented to a particular research purpose or otherwise expressed a preference about future uses, such as an advance directive made in accordance with laws governing gifts of human tissue for research or other purposes, or by an instruction contained in a consent form, as described in Article 12.2. Researchers and REBs should respect known preferences or instructions. Alternatively, future use of tissues may not have been discussed with or even contemplated by the individual. It can be difficult then to determine individual wishes regarding future uses of tissue for research. A proportionate assessment of risks and benefits will help guide the research ethics process in these cases.

Chapter 5 (“Privacy and Confidentiality”) provides detailed guidance on secondary use of personal information for research purposes (in particular, see Articles 5.5 and 5.6). The following section adapts the provisions in Chapter 5 to the specific context of research involving secondary use of tissue.

Article 12.5 Researchers should seek research ethics board (REB) approval for the secondary use of tissue. Researchers must satisfy the REB that:

  1. Use of the tissue is essential to the research;
  2. They will take appropriate measures to protect the privacy of and minimize harms to the individuals from whom tissue was collected, and to ensure confidentiality; and
  3. Individuals from whom the tissue was collected did not object to secondary use at the initial stage of collection or otherwise make known their objection.

Application For research involving the secondary use of tissue that is anonymous, anonymized, and de-identified or coded where no member of the research team has access to the code that permits re-identification of individuals, the REB may proceed by delegated review. (Under some circumstances, delegated review may be available for secondary use of identifiable tissue.) Researchers and REBs should be aware, however, that risks may arise even in research involving anonymized or anonymous tissue. The research may reveal potentially harmful information about groups or communities, even though it may not be possible to identify the individuals who provided the tissue. For example, as more fully described in Section E (“Genetic Research Involving Communities”) of Chapter 13 (“Human Genetic Research”), research on human tissue may involve an exploration of genetic variation within specific groups or communities. Such research may raise ethical concerns about stigmatization and exploitation of groups and social disruption in communities. For this reason, researchers may have an obligation to seek the engagement of community members or leaders in the design, conduct and reporting of such research (see Article 12.6, below). Should any of these concerns arise during the conduct of a study, the researchers should bring such concerns to the REB for guidance and direction.

Subject to Article 12.6, if a researcher satisfies the conditions in Article 12.5 (a) to (c), the REB may approve the research without requiring the consent of individuals from whom tissue was collected. Established tissue repositories may have their own policies and procedures governing access to tissue for research purposes. For example, repositories may release only anonymized samples and may require researchers to sign material transfer agreements or secure REB approval. Researchers should be aware of and abide by such policies and procedures and obtain any other required permission.

Article 12.6 In highly sensitive situations involving secondary research use of tissue, the research ethics board (REB) may require that a researcher’s secondary use of the tissue be dependent on the informed consent of the individuals from whom the tissue was collected or from authorized third parties, unless it is impossible or impracticable to obtain consent. If the REB is satisfied that consent is impossible or impracticable, access for secondary use may require either:

  1. An appropriate strategy for notifying individuals or groups that tissue is intended to be used for a specified research purpose; or
  2. Consultation with representatives of individuals or groups from whom tissue was collected.

Application In considering the applicability of this article, REBs should apply a proportionate approach to ethical assessment of research that considers the likelihood and magnitude of harms for individuals from whom tissue was collected, as well as the potential benefits of the research. Highly sensitive situations may arise when identifying or identifiable results of the research will be published or when the tissue was originally collected from individuals or groups who may have special interests in regard to tissues, such as groups with specific medical conditions or who attribute particular cultural or religious significance to tissue. For this reason, according to the Canadian Institutes of Health Research Guidelines for Health Research Involving Aboriginal People,[13] secondary research use of tissue samples known to have originated with Aboriginal people requires the specific consent of the individual donor and, where appropriate, consultation with the community if the sample can be traced back to the individual or the community. REBs should also be particularly cautious when individuals or groups from whom the tissue was collected may be significantly harmed by accidental or intentional disclosure.

Article 12.6 provides that the REB may require researchers to seek consent from individuals or their authorized third parties. It may, however, be impossible or impracticable to contact all individuals or authorized third parties to obtain informed consent, particularly when the group is large or its members are likely to be deceased, geographically dispersed or difficult to track. Attempting to locate and contact members of the group may raise additional privacy concerns, especially when a relationship with individuals has not been maintained. Seeking consent from only a partial set of group members may introduce undesirable bias into the research. Financial, human and other resources required to contact individuals and obtain consent may be so burdensome as to impose undue hardship that jeopardizes the research.

Where an REB is satisfied that consent is impossible or impracticable, Article 12.6(a) requires that the researcher propose an appropriate strategy for giving notice to individuals or groups about the proposed research or, where such notification is impossible or impracticable, that there be consultation with representatives of the individuals or group, in accordance with Article 12.6(b). For example, researchers may develop a way to sample the opinions of a subset of individuals in the group or contact one or more organizations that are likely to represent the views and interests of the individuals from whom tissue was collected. The goal of notice or consultation is to provide an opportunity for input regarding the proposed research.

If researchers seek access to tissue in an established repository, the organization that manages the repository may have already taken steps to obtain consent from or notify individuals or authorized third parties, or to engage in consultation with representative groups. The researcher should inform the REB of the extent to which the repository organization has addressed these issues. If the REB is satisfied that issues of consent, notification or consultation have already been addressed by the repository organization, it may be unnecessary for the researcher to duplicate steps that have already been undertaken.

Article 12.7 In the context of secondary research with tissue, researchers who wish to contact individuals from whom tissue was previously collected must obtain research ethics board approval prior to contact.

Application Sometimes a research goal may be achieved only by follow-up contact with individuals to collect additional information or biological samples. However, contact with individuals whose previously collected tissue is sought for use in secondary research raises privacy concerns, especially if a relationship with these individuals has not been maintained. Individuals might not want to be contacted by researchers. The research benefits of follow-up contact must clearly outweigh the potential harms to individuals of follow-up contact, and the REB must be satisfied that the proposed manner of follow-up contact is respectful and minimizes potential harms to individuals.

E. Human Reproductive Tissue

This section sets out ethical guidelines relating to research involving human fetuses and fetal tissue, embryos, stem cells and gametes. While research involving human reproductive tissue has great promise for assisting the development of healthy pregnancies, curing illness, and repairing or rebuilding tissue, some such research is objectionable to many. Accordingly, this research has provoked vigorous debate. Discussion and reflection should continue as our scientific understanding develops.

Significant ethical issues include consent to research involving reproductive tissue, privacy concerns of donors and research participants, and the potential for harm to an embryo or fetus. Researchers and REBs have a continuing duty to remain mindful of the public interest in these issues, and to respect policy, legal and regulatory requirements. In particular, researchers and REBs should be aware of the detailed requirements and prohibitions found in the Assisted Human Reproduction Act.[14]

Article 12.8 In addition to Articles 12.1 to 12.7 that apply to all research involving human tissue, the following guidelines apply to research involving human reproductive tissue.

  1. Research using reproductive tissue or cells, in the context of an anticipated or ongoing pregnancy, should not be undertaken if the knowledge sought can reasonably be obtained by alternative methods.
  2. No reproductive tissue should be obtained, for research use, through commercial transaction.

Application Because of the potential for harm to the woman or the fetus, Article 12.8(a) recommends that the use of such reproductive tissue should be avoided where pregnancy is anticipated or ongoing, if research goals may be accomplished in some other way.

Article 12.8(b) reflects concerns about the commercialization or commodification of human reproduction. The purchase or sale, directly or indirectly, of any human tissue for the purpose of creating a human being, including any gamete or in vitro human embryo, is ethically unacceptable.

Research Involving Human Embryos

An embryo is a human organism during the initial period of its development following fertilization or creation. It includes any cell derived from such an organism that is used for the purpose of creating a human being. Any research in which fertilization occurs should be regarded as research on embryos. The Assisted Human Reproduction Act prohibits the creation of a human embryo specifically for research purposes.

Article 12.9 Research on embryos intended for implantation to achieve pregnancy is acceptable if intended to benefit the embryo or to advance knowledge if:

  1. Research interventions will not compromise the care of the mother, or the subsequent fetus; and
  2. Researchers closely monitor the safety and comfort of the mother and the safety of the embryo.

Application Research potentially altering the embryo by chemical or physical manipulation should be distinguished from research directed at ensuring normal fetal development. For example, the evaluation of potential teratogens and their effects on certain cell lineages may use early embryos, but those embryos must not be implanted for an ongoing pregnancy.

Article 12.10 Research involving human embryos that have been created for reproductive purposes, but are no longer required by their donors for this purpose, may be ethically acceptable if:

  1. The ova and sperm from which they are formed were obtained in accordance with Article 12.8;
  2. Where the embryo was created using donor gametes, free and informed consent was provided by the gamete donors; and
  3. Embryos exposed to manipulations not directed specifically to their ongoing normal development will not be transferred for continuing pregnancy.

Application Research on embryos requires the consent of the gamete donors. The REB may not waive the requirement for such consent. In particular, researchers and REBs should be aware of the Consent Regulation under the Assisted Human Reproduction Act.[15]

Research Involving Fetuses and Fetal Tissue

The term “fetus” applies to the developing human being from fertilization to delivery, whether alive or dead at delivery. Fetal tissue includes membranes, placenta, umbilical cord, amniotic fluid and other tissue that contains the genetic information of the fetus.

Research may be undertaken on methods to treat, in utero, a fetus that is suffering from genetic or congenital disorders. Because the fetus and the woman cannot be treated separately, any intervention to one involves an intervention to the other.

Article 12.11 With respect to fetal research:

  1. Consistent with the requirements of Chapter 3 (“Free and Informed Consent”), research involving a human fetus requires the free and informed consent of the woman.
  2. Research interventions should not compromise the woman’s ability to decide whether to continue her pregnancy.

Application Research involving a human fetus requires the free and informed consent of the woman. Accordingly, research involving the use of fetal tissue should be guided by respect for the woman’s dignity. Research methods on the treatment of fetuses in utero thus pose no issues that are not addressed elsewhere in this Policy. Researchers should ensure that a clear distinction is made between consent to research use and consent for any clinical procedures or testing. In practice, this may mean separate consent forms, but in any event, the different uses must be clearly explained and understood by participant-donors.

Pluripotent Stem Cell Research

Article 12.12 Researchers who intend to conduct research to derive or use pluripotent stem cells should follow the Canadian Institutes of Health Research Guidelines for Human Pluripotent Stem Cell Research,[16] as amended from time to time.

Hybrids and Chimeras

Research involving the creation of hybrids and chimeras raise serious ethical concerns, and federal legislation prohibits certain activities relating to their creation. Researchers and REBs are referred to the Assisted Human Reproduction Act for guidance in this area.


Endnotes

[13] http://www.cihr-irsc.gc.ca/e/29134.html

[14] (2004, c. 2) http://laws.justice.gc.ca/en/A-13.4/.

[15] Assisted Human Reproduction (Section 8 Consent) Regulations (SOR 2007-137) http://canadagazette.gc.ca/partII/2007/20070627/html/sor137-e.html .

[16] The Guidelines for Human Pluripotent Stem Cell Research can be found at http://www.cihr-irsc.gc.ca/e/15255.html.