Informed Consent

C.2.1.1.

DHHS-conducted or -supported research on human research participants is regulated by 45 CFR Part 46 [70].

The DHHS regulations describe both when informed consent is required and what elements must be in an informed consent process and document. The biospecimen resource should track whether appropriate informed consent is present or the reason why informed consent is not necessary and should seek to resolve any discrepancies in the consent status for stored biospecimens (See the Office for Human Research Protections [OHRP] Web site for guidance on informed consent [77]).

C.2.1.2.

The OHRP has issued guidance on regulatory requirements that must be satisfied by biospecimen resources (available at [78]). The OHRP recommends that the following be included in informed consent documents for biospecimen collection:

• A clear description of the operation of the biospecimen resource. This description could include details that may be of interest to human research participants, such as whether identifiable information will be maintained by the biospecimen resource and/or whether research results will be linked to the biospecimen (See Section C.1, Principles for Responsible Custodianship, for NCI recommendations).
• The conditions under which samples and data will be released to recipient investigators (See Section C.4, Access to Biospecimens and Data, for NCI recommendations).
• Procedures for protecting the privacy of human research participants and confidentiality of data (See Section C.3, Privacy and Confidentiality Protections, for NCI recommendations).
• Specific descriptions of the nature and purpose of the research.
• Information about the consequences of DNA typing if human genetic research is anticipated. NHGRI has developed an online Web resource with the goal of providing the research community with the information needed to develop informed consent materials for genomics-related research projects, such as genome-wide association studies (GWAS) and gene sequencing studies. See the NHGRI online consent information Web resource [79].

C.2.1.3.

FDA regulations regarding informed consent should be considered when applicable, particularly when human specimens are used for in vitro diagnostic device studies (See 21 CFR Part 812 [80], 21 CFR Part 50 [81], and 21 CFR Part 56 [82]). The FDA may exercise enforcement discretion as to the requirement for informed consent for in vitro diagnostic device studies that utilize “leftover” biospecimens (e.g., remnants of biospecimens collected for routine clinical care or analysis or biospecimens previously collected for another research purpose) that are not individually identifiable if certain conditions have been met.

C.2.1.4.

For samples collected on or after the effective date of the NIH GDS Policy (January 25, 2015), NIH expects that research participants have given consent for their genomic and phenotypic data to be used for future research purposes and shared broadly, in order for the data to be submitted to an NIH-designated repository. Consent is required even for cell lines or clinical samples which are de-identified. If there is consent which is not consistent with the NIH GDS Policy, then the samples cannot be used for research falling under the Policy unless an exception applies. NIH Guidance on the GDS Policy consent requirements are available: [83]

The NIH GDS Policy consent requirements are consistent with the NCI Best Practices at C.2.3 that informed consent address:

• How the biospecimens will be used and whether they may be used in secondary research.
• How data collected or generated in the research will be shared.
• Who may access biospecimens and associated data, including whether for-profit research may seek access.

The NIH GDS Policy endorses biospecimen resources utilizing a “one-time general consent” strategy [see C.2.3.9].

C.2.2.1.

The NCI recommends seeking the informed consent of research participants who provide biospecimens and associated data whenever such consent is required by regulation, and also when consent is ethically appropriate and can practicably be obtained. Respect for individuals who have provided data and/or biospecimens for research is of paramount importance; therefore, their preferences should be considered when deciding whether informed consent should be sought or waived. Some individuals may prefer to be actively engaged in future research, while others may be opposed to being re-contacted to consent for additional research or future uses. The biospecimen resource should have transparent policies concerning the informed consent process, including when consent is sought from human research participants or from the next of kin of deceased biospecimen contributors. Electronic consent (e-consent) or mobile consent strategies may streamline the consent process and improve participant understanding of consent information.

C.2.2.2.

Personal, religious, and culturally held beliefs and traditions should be respected in biomedical research using biospecimens. For example, some cultures believe that the body is sacred and should not be disturbed [84, 85]. Investigators should consider the beliefs and traditions of the community when planning a research study that will include collection of biospecimens and whether any of the following issues should be addressed for the population under study during the informed consent process:

• Whether there are any religious, cultural, or personal restrictions regarding the biospecimen.
• What are the instructions for disposal or return, if practicable, of the biospecimen?
• What is the participant’s primary language and whether the consent is explained in that language?

The biospecimen resource should track any relevant restrictions or instructions based on these types of beliefs in order to ensure that the human research participant’s wishes are upheld.

C.2.2.3.

For biospecimens collected during the course of medical care, the timing of consent (e.g., before or after a medical procedure) to use biospecimens for research purposes should not be imposed rigidly but instead informed by a number of important considerations, including ethical guidelines and logistical constraints.

Generally, consent should be obtained prior to the medical procedure, but post-medical procedure consent may be appropriate in some circumstances [86]. These decisions should be made on a case-by-case basis with sensitivity to the situation a patient faces when undergoing a medical procedure or a test for a serious disease. For example, post-medical procedure consent may be acceptable for the use of remnant biospecimens beyond what is needed for diagnostic purposes if it was not practicable to previously consent the patient because of considerations about illness, undue stress, or the ability of the patient to fully comprehend what was being asked. However, prior informed consent would be required in cases where biospecimens are collected from human research participants for research purposes or when the procedure for collecting biospecimens for clinical purposes is changed to meet a research need unless an IRB grants a waiver of the requirements for obtaining informed consent.

C.2.2.4.

Information about policies governing the retention of biospecimens, placement of research data in clinical records, documentation pertaining to informed consent, and protections for the privacy of human research participants and the confidentiality of their data should be provided to participants either in the informed consent document or in supporting materials (Also see Section C.1, Principles for Responsible Custodianship).

C.2.2.5.

The informed consent document should disclose whether biospecimens may at some point be de-identified and/or subsequently used for secondary research purposes beyond those described in the original informed consent. Human research participants deciding whether to contribute biospecimens for research should understand how their tissue may be used in the future, including any potential anonymous use. The NIH GDS Policy requires that data submitted to an NIH-designated repository be de-identified according to standards set forth under the regulations for the protection of human subjects at 45 CFR 46, as well as the requirements of the HIPAA Privacy Rule. In addition, NIH has obtained a Certificate of Confidentiality as an additional precaution because genomic data can be re-identified.

C.2.2.6.

New concepts that strengthen the informed consent process by facilitating community engagement in the research are under development and being piloted. These efforts include biospecimen resource community advisory boards, community consultation, and community based participatory research projects. These governance models [87-89] view participants as partners in the research and promote the underlying ethical values of informed consent, including respect and autonomy.

C.2.3.1.

For the benefit of human research participants, an informed consent document outlining important issues and risks in straightforward language should be developed and implemented. The informed consent document should specify the following:

• That patients have the right to refuse biospecimen donation, and that this will in no way influence their treatment or eligibility to participate in research studies or clinical trials.
• Why particular biospecimens and data are being sought and why human research participants are being asked to participate.
• The source of the biospecimens that will be collected for research; for example, whether the biospecimen will come from leftover tissue from a surgical procedure or from an additional procedure (e.g., an extra blood draw).
• Who will be the custodian of the biospecimens and what will be the custodian’s role.
• How the obtained biospecimens will be used and whether they may be used in secondary research.
• How data collected or generated in the research will be shared.
• Whether biospecimens will continue to be stored in an identifiable or non-identifiable manner, and shared as long as they are potentially useful for research, respectfully destroyed when no longer useful for research, or transferred to another established resource in accordance with the terms of the informed consent.
• Who may access biospecimens and associated data, including whether for-profit researchers may seek access and, if so, any policies regarding disposition of potential commercial profits.
• Whether there is a policy or plan for producing a lay summary of the aggregate study findings.
• Whether there is a policy or plan for offering the return of any individual research results, and whether these results will be placed in the medical record.
• The nature of any special risks associated with proposed genomic research technologies such as whole genome or exome sequencing

C.2.3.2.

The informed consent document should describe what types of data will be collected and how the data will be used and stored. Where applicable, the informed consent document should state whether identifiable or coded information will be maintained in the biospecimen resource and if research results will be linked to other data about the human research participant, such as clinical data obtained from anatomic pathology and clinical pathology laboratory information systems and cancer registries (Refer to Section B.5.3, Longitudinal Clinical Data, for further recommendations on the integration of informatics systems). If longitudinal data will be collected by accessing the participant’s medical records, the informed consent document should clearly state this. The informed consent document also should describe whether the biospecimens and/or the data associated with or derived from biospecimens will be shared with other investigators and, if so, the oversight mechanisms for such sharing.

C.2.3.3.

If appropriate, the informed consent document may include an option that allows human research participants to select whether they would be willing to be re-contacted about the use of their biospecimens and/or data in future research studies.

C.2.3.4.

The informed consent document should state whether research participation could benefit or potentially negatively impact participants’ families and communities; e.g., if there is a risk of stigmatization and discrimination based on research results.

C.2.3.5.

If a study involves genetic sequencing or analysis, the informed consent document should include information about the types of genetic sequencing or analysis that will be conducted (e.g., somatic, familial, or whole genome analysis) and the potential risks to the human research participant posed by such research, if applicable. NHGRI has several consent form examples and model consent form language [90]. The Genetic Information Nondiscrimination Act (GINA, [91]) of 2008 may reduce some of these risks by prohibiting employment and health-insurance discrimination on the basis of genetic information. GINA does not protect against potential discrimination on the basis of genetic information for disability or long-term care insurance. For more information on GINA, please refer to the guidance from the OHRP [92] and the discussion of genetic discrimination and GINA on the NHGRI website [93].

C.2.3.6.

The informed consent document should address the use of biospecimens and/or data by private or for-profit entities and the possibility of research leading to future development of commercial products, as appropriate. The document should describe whether human research participants, their families, or communities will receive any financial or nonfinancial benefits from the products, tests, or discoveries resulting from the research.

C.2.3.7.

The informed consent document should state whether individual or aggregate research results will be released to the human research participant, the participant’s healthcare provider, or the participant’s family and, if so, the mechanism for communicating such results; e.g., e-mail, newsletter, telephone call, genetic counselor, etc. Individual research results may range from primary diagnostic findings or discrepancies to secondary “incidental” findings unrelated to diagnosis or even to study aims. Any procedure for opting out of the receipt of research results should be clearly indicated. The HIPAA Privacy Rule [94] and the Clinical Laboratory Improvements Amendments (CLIA, [95] ) may affect whether research results should be offered or disclosed.

NCI recommends that in developing policies pertaining to the return of individual research results, institutions consider whether these findings are analytically validated, medically significant, and clinically actionable to research participants and/or their relatives.

C.2.3.8.

General information about COIs, institutional policies for sharing samples with other investigators or companies, the financial implications of sharing, and any known or likely benefit to the institution or investigator should be easily found online at the resource’s or institution’s Web site or provided in a brochure that accompanies the informed consent document (Also see Section C.6, Conflicts of Interest).

C.2.3.9.

Biospecimen resources may utilize a “one-time general consent” strategy [96] whereby biological specimens and data are collected for broad use in future research studies that will subsequently be approved by institutional review boards or other panels of scientific and ethical experts.

C.2.3.10.

A tiered system of consent may be considered where human research participants could specify the types of research for which their contributed biospecimens will be used.

While a tiered system of consent will provide the human research participant with greater specificity about secondary research, it also can lead to ambiguities in terms of how to classify certain types of interdisciplinary or multidisciplinary research. If the purpose of the biospecimen resource is to provide biospecimens for a broad range of research, tiered consent may be burdensome and uninformative. Tiered consent may be considered if consent categories are well defined and relatively constant over time and if an informatics system capable of tracking the levels of consent for each human research participant is already in place. Whenever tiered consent is utilized, biospecimen resources should adhere to the human research participant’s choices in order to ensure that his or her wishes are honored.

Examples of tiered consent categories are as follows:

• My tissue may be kept for use in research to learn about, prevent, or treat cancer.
• My tissue may be kept for use in secondary research to learn about, prevent, or treat other health problems; e.g., diabetes, Alzheimer’s disease, or heart disease.
• My tissue may be associated with my medical record and history.
• I am willing to be contacted about future research studies.

C.2.3.11.

Biospecimen resources should consider whether, in addition to the informed consent document, more detailed supplementary materials should be made available to interested human research participants. If supplementary materials are provided, protocols should be in place to ensure that such materials are consistently offered to human research participants and that the content does not conflict with the informed consent document. These materials may include the following:

• A one-page graphic or written summary outlining the biospecimen resource’s governance, with an emphasis on oversight and access protocols.
• An accompanying brochure that provides more detailed information about the biospecimen resource, either directly or by referencing the resource’s Web site, and covers any other issues that could not be addressed in the informed consent document.