March 11, 2020 Secretary’s Advisory Committee on Human Research Protections New Information Provided to Previously Enrolled Research Subjects Informed consent to research participation is a fundamental requirement for research and the embodiment of the principle of respect for persons. Individuals or their surrogates have the right to receive information and ask questions about research participation so that they can make informed decisions about participation in research. The process of informed consent occurs when communication between a potential subject and a researcher results in the individual’s authorization or agreement to participate in a research study or their refusal to participate. Central to this process is the informed consent document, which contains extensive written information about the proposed research. The IRB community has long held that the decision-making process begins before potential subjects are handed a consent document, e.g., extending to advertising and recruitment, and that voluntariness (and hence continued consent) must be part of any ongoing research. In some research studies, circumstances arise in which new information becomes available that needs to be shared with subjects as part of this ongoing consent process. OHRP has asked the SACHRP subcommittees to comment on circumstances in which subjects already enrolled in a study should be provided with relevant new information and have the opportunity to either withdraw from the research or to affirm and document their willingness to continue in the research. In the research community this process is colloquially referred to as “re-consent.” Neither the Common Rule regulations nor the FDA regulations use the term “re-consent” or otherwise describe a process for approving the mechanism for providing new information to subjects who are already enrolled in a research study. There is, however, a regulatory provision that when appropriate, significant new findings developed during the course of the research “that may relate to the subject's willingness to continue participation will be provided to the subject”. (§46.116(c)(5)) However, providing new findings is not the same as asking an individual to explicitly review their consent to participate in research and confirm their willingness to continue participation. The intent of this document is to identify mechanisms for providing new information to subjects in a manner that is both consistent with the principle of respect for persons and compliant with the requirements of the 2018 Common Rule. Re-consent versus General Provision of New Information – Key Terms In this document, the term re-consent is used it to mean that subjects will go through a complete consent process that supersedes the original consent using a document that contains all required elements of consent and is documented in accordance with the federal regulations. When new information is provided through other mechanisms, such as a consent addendum or an information sheet, there is no expectation that this information is presented in a manner that would be considered legal informed consent. Rather, it signifies that there is information that should be provided to subjects who then have an opportunity to consider the information and reaffirm their willingness to continue participating in the research. In all cases, the researchers and the IRB must work to ensure that respect for persons is maintained throughout the duration of an individual’s participation in research by implementing a robust consent process that allows for the ongoing provision of information relevant to participation. When there is a need to present subjects with new information, IRBs should encourage use of the least burdensome approach for the subject. For example, the provision of new information should not automatically result in a process whereby subjects are expected to review and initial every page of the revised consent form every time there is a minor change. U.S. Regulatory Requirements The regulations include the following sections , which are relevant to the discussion of “re-consent”: “Informed consent will be sought from each prospective subject or the subject's legally representative, in accordance with, and to the extent required by, §46.116.” (§46.111(a)(4)) “An investigator shall seek informed consent only under circumstances that provide the subject or the legally authorized representative sufficient opportunity to discuss and consider whether or not to participate and that minimize the possibility of coercion or undue influence.” (§46.115(a)(2)) “An institution, or when appropriate an IRB, shall prepare and maintain adequate documentation of IRB activities, including the following: … Statements of significant new findings provided to subjects, as required by §46.116(c)(5).” (§46.115(a)(7)) “The prospective subject or the legally authorized representative must be provided with the information that a reasonable person would want to have in order to make an informed decision about whether to participate, and an opportunity to discuss that information.” (§46.116(a)(4)) “the following elements of information, when appropriate, shall also be provided to each subject or the legally authorized representative: … A statement that significant new findings developed during the course of the research that may relate to the subject's willingness to continue participation will be provided to the subject” (§46.116(c)(5)) Ex-US Perspectives European Union From the European Union (EU) perspective, before a decision is made to ask subjects to re-consent, there must be a determination of whether a protocol amendment or change to a study’s risk profile is “substantial.” The EU Regulation on Clinical Trial defines a substantial modification as “any change to any aspect of the clinical trial which “is likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial.” (REGULATION (EU) No 536/2014). Although the Regulation is clear that substantial modifications must be approved by the IRB, the Regulation does not provide guidance on when an IRB should require re-consent. CIOMS Guidelines The 2016 CIOMS International Ethical Guidelines for Health-related Research Involving Humans state the following in Guideline 9: “With the approval of the research ethics committee, researchers must renew the informed consent of each participant if there is a substantive change in the conditions or procedures of the research, or if new information becomes available that could affect the willingness of participants to continue.” The corresponding commentary for Guideline 9 adds additional context: “When substantive changes occur in any aspect of a study, the researcher must again seek informed consent from the participants. For example, new information may have come to light, either from the study itself or other sources, about the risks or benefits of products being tested or about alternatives to them. Participants must be given such information promptly. In most clinical trials, interim results are not disclosed to researchers or participants until the study has been concluded. In long-term studies, the willingness of each paticipant to continue in the study must be ensured.” Current IRB practices: While there is known variability in IRB approaches to requiring explicit renewal of consent during the course of a research study, there are a few pathways that are used most often in regular practice. Frequently sponsors, clinical research organizations, and investigators submit a revised consent document with an accompanying recommendation of reconsent for all enrolled subjects. However, data is lacking regarding what ultimately happens with that request. Do IRBs question whether re-consent is required or to they accept the request and approve the proposed process? Little is also known regarding how an IRB requirement to obtain new consent is implemented at sites, but it is likely that there is high variability in approach. The choice of pathway may be influenced by factors including the nature of the new information, its perceived impact on currently enrolled subjects, or the status of the research (e.g., enrolling, long term follow-up only, near completion). Possible approaches to providing new information include: • Require researchers to repeat the informed consent process with the revised informed consent document(s) and document consent following the requirements for documenting consent at 45 CFR 46.117. • Require that researchers present the new information through the use of an addendum to the original informed consent document and either obtain documentation directly or describe the communication process in the subject’s research records. • Allow researchers to orally communicate the new information and document the communication process in each subject’s research records. With each of these options, the timing may vary depending on the perceived urgency of the new information. Depending on the specific circumstances, including whether any subjects are at immediate risk, the IRB may instruct the researchers to bring subjects back immediately or provide information by telephone, or wait until the next scheduled subject visit. The requirements for use of any revised consent materials (e.g., consent document, addendum or notification) may be adapted to the population of subjects the changes affect. For example, an addendum or notification may be appropriate for current subjects or a subset of current subjects, while a revised consent document would usually be the appropriate document for use with new subjects. Questions for SACHRP: 1. When new information requires revisions to the informed consent document for research that was approved under the pre-2018 Common Rule, is it necessary to transition a protocol and informed consent document to the revised rule when the new information results in a change in the consent document? Response: The requirement to provide new information to research subjects should not require a protocol to transition to the revised rule. When an informed consent document that was approved under the pre-2018 rule is revised, it is grandfathered under the pre-2018 rule. There is no requirement to add either the additional elements of consent or the key information requirements to the consent document, even when information is being revised in other sections of the consent document. 2. When do the regulations require re-consent? Response: Re-consent is not a concept that is described or defined in the regulations. The regulations require that researchers provide subjects with significant new findings developed during the course of the research when those findings may impact a subject's willingness to continue participation in the research. In other words, the regulations are clear that new information must be provided to subjects, but do not suggest a threshold for the significance of the information or prescribe a specific mechanism for implementing the requirement. Significant new information could include revised risk information or information related to an unanticipated problem, such as a data breach. Potential subjects must be provided with sufficient information to allow them to make an informed, voluntary decision to participate in a research study. But the consent process does not end with that initial decision. Consent is an expression of voluntary participation and is an ongoing process that continues throughout a study, keeping subjects informed until their participation is complete. The provision of significant new information in the context of a given study will depend upon factors including the nature of the study, the nature and urgency of the new information, and the status of subjects e.g., in screening phase, receiving an intervention, long term-follow-up, etc. Providing the new information creates an explicit opportunity for subjects to exercise their ongoing right to continue their participation or withdraw from the research. 3. Is re-consent a concept that should be considered under the regulations? Or is the idea that under the regulations you are only required to seek and obtain consent once, and anything else is above and beyond the regulatory requirements? Response: Although the term “re-consent” is not defined as a regulatory term or concept, §46.116(c)(5) is clear that researchers have an obligation to provide subjects with new findings, and that the information may lead to a subject’s reconsideration of their initial consent. In general, the idea of re-consent is understood at a high level by the research and IRB communities. However, specific internal IRB definitions of re-consent and requirements for obtaining re-consent are variable. This should not be regarded as a regulatory problem, as the circumstances that create the need to provide new information will be variable, and IRBs should have the flexibility to calibrate the mechanism for re-consent to the facts of the situation in which the need arises. Guidance for sponsors, researchers and IRBs may help foster a consistent approach to providing subjects with new information and documenting how the information was provided. Given the lack of evidence / concern that subjects are not being provided with this information, a regulatory solution does not seem appropriate or necessary. When developing guidance, consideration should be given to incorporating the models endorsed by CIOMS (expressed as “renewing” informed consent) and the EU model (need for re-consent triggered when “substantial modifications” to research are implemented). 4. When might an IRB determine that re-consent is advisable or an ethically appropriate thing to do? Response: The existing regulatory requirement to provide subjects with significant new findings that may impact the subject's willingness to continue in the research is an appropriate threshold. The most frequently cited examples of such findings are the identification of new or increased risks to subjects and modifications to the study design to increase duration or other burdens on subjects. When considering this issue for a specific study, IRBs should consider the nature of the new information, and the likelihood that the nature of the new information would be considered important by a reasonable person , such as a significant new risk that has been identified. Appendix 1 provides examples of information that would warrant a timely notification to research subjects. The IRB may also consider the status of the study with respect to subjects (e.g., currently enrolling, closed to enrollment but intervention incomplete, long term follow-up only). Appendix II provides a framework for when information should be disseminated, taking into account the nature of the information and study’s status with respect to enrollment. 5. When is it appropriate to just provide individuals with additional information (but not necessarily obtain consent again)? Response: In addition to the existing regulatory requirement related to significant new findings, there are other types of information that may impact the subject’s interest and ability to continue their participation that must be shared from a practical standpoint. Examples of such information include the need to extend follow-up for an additional period of time, or an increased frequency of visits to the research site for minimal risk data collection activities. How additional information is communicated to subjects will depend upon many factors including the type of study, the complexity and/or urgency of the new information and the population. In some cases, a subject who continues to attend study visits and actively participate in a study after receiving additional information may signify continuing consent. In other situations, it is desirable to explicitly document a subject’s receipt of new information and their consent to continue their participation. IRBs, sponsors and investigators should balance the need for documentation with respect for the subjects and choose the least burdensome method of providing new information and/or obtaining and documenting re-consent consistent with the circumstances. There is also information that does not need to be communicated to research subjects. Examples include changes to the inclusion criteria that have no impact on previously enrolled subjects (e.g., increase to upper age limit from 60 to 70) or an increase in the overall number of subjects. Due to the multiple factors that must be considered by the IRB, there will be variability with respect to the format for presenting information to current subjects. This can include: oral presentation of new information; a written addendum to the original informed consent document that describes the new information; an edited version of the consent document that clearly identifies any changes (e.g., redlining), or; a revised consent document with changes incorporated. Irrespective of the written format, the investigator must employ an appropriate process for providing subjects with the new information and ascertaining their willingness to continue. Ongoing consent should be documented, either through documentation of the process in the subjects’ study records or by having subjects sign a written document. The requirements for documentation of initial consent and waivers of documentation may provide a useful framework for deciding when to formally document that subjects have received new information and gave consent for their ongoing participation. In certain low risk cases, it may be acceptable not to ascertain the subjects’ willingness to continue participation. However, in such cases it is probably also acceptable not to provide the subjects with the new information. Appendix 2 provides a framework for evaluating new information considering the nature of the information, the status of the research and the perceived urgency of disseminating the information, and what mechanisms may be used to disseminate the information and documenting that the information was provided. Additional questions not asked of SACHRP, but believed to be useful to the regulated community: 6. Does the act of transitioning a study from the pre-2018 Common Rule to the 2018 Common Rule by itself require re-consent? SACHRP recommends that solely the act of transitioning a study from the pre-2018 Common Rule to the 2018 Common Rule does not by itself create the requirement to obtain re-consent from the subjects. The subjects provided their consent using a consent form that was valid under the pre-2018 Common Rule. In other words, the additional requirements under 45 CFR 46.116(a)(5)(i), 116(b)(9), and 116(c)(7), (8) and (9) of the 2018 Common Rule does not require subjects to re-consent. SACHRP confirmed that OHRP agrees with this interpretation. While the mere act of transitioning does not transition result in a requirement to bring the consent document up to 2018 rule requirements, an IRB has the discretion to determine that the additional disclosures required by the 2018 rule should be provided to subjects. Moreover, future versions of the consent form would need to comply with the 2018 Common Rule requirements and the IRB would need to determine if and how previously enrolled subjects should be given any new information contained in the revised consent document. 7. Can an IRB decide that re-consent of previously enrolled subjects with a new, 2018 Common Rule-compliant Informed consent document is required when a study is transitioned to the 2018 Common Rule? An IRB always has the authority to determine whether subjects need to be provided with additional information and, if so, the mechanism of dissemination. Examples of current IRB practices are described earlier in this document. This could include the use of a consent document that is compliant with the 2018 Common Rule, or through an addendum or other type of document. IRBs have flexibility when deciding what would be the optimal approach.