After nearly a decade, the FDA has issued final informed consent guidance. The guidance supersedes FDA’s “Guide to Informed Consent,” issued in September 1998, and finalizes draft guidance released in July 2014.

The final guidance provides new information on sponsor personnel being present for some medical device studies, emancipated children, legally authorized representatives, obtaining informed consent through electronic methods, informing subjects of new information, and discussing risks and benefits. The final guidance also includes references and links to relevant guidance issued since 2014.

The FDA noted a number of federal agencies have revised the Common Rule to “include significant changes to the provisions regarding informed consent.” While the FDA is working on rulemaking to harmonize its regulations with the revised Common Rule, the final guidance “does not address possible future changes to FDA’s informed consent regulations that may be developed as part of these harmonization efforts. FDA may amend this guidance to reflect such changes or to address new questions related to informed consent,” the agency said.

The final guidance follows the outline of the draft guidance, except that the 10 items addressed under additional considerations in the draft guidance have been made into Frequently Asked Questions in the final.

Those frequently asked questions are:

• What are some considerations for enrolling a child into a clinical investigation?
• Are there any additional protections required when enrolling children who are wards of the state?
• What are some considerations for enrolling non-English speaking subjects?
• What process should be followed when it is expected that subjects who do not understand English will be enrolled?
• What process should be followed when the enrollment of subjects who do not understand English is not expected?
• What should be considered when enrolling subjects with low literacy and numeracy?
• What should be considered when enrolling subjects with physical or sensory disabilities?
• What should be considered when enrolling adult subjects with impaired consent capacity?
• Can a subject participate in more than one clinical investigation simultaneously?
• How should data be handled when an enrolled subject decides to withdraw from a trial?
• What steps should be taken to inform subjects when a study is suspended or terminated?
• Should subjects be informed of aggregate study results at the completion of a trial?
• Is informed consent required to review patient records?

The final guidance also adds three questions on topics that were not included in the draft guidance. They are:

• Who can serve as a legally authorized representative (LAR) and what is their role?
• How can informed consent be obtained through electronic methods?
• How should subjects be informed of new information that may affect their willingness to continue participation in the research?

How To Determine LARs

Regarding LARs, the final guidance says, “the key point to consider when determining who may serve as an LAR is that the LAR must be authorized under applicable law to consent on behalf of the prospective subject to the procedure(s) involved in the clinical investigation,” which in the United States is determined by state and local law.

“Institutions, IRBs, and investigators should have the ability to access information regarding applicable laws for the clinical investigations they conduct or oversee, when necessary. If the IRB, investigator, or sponsor is uncertain about state and local laws governing who can serve as an LAR, they should consult with their institution and/or legal counsel,” the guidance advises.

The guidance also notes that some prospective subjects with profound cognitive impairment “may be able to appoint an LAR, define the limits of their own research participation, or remain actively involved in the decision to enroll and remain enrolled in the research. As such, individuals with impaired consent capacity should be included in the process of consent to the extent possible and consistent with their desires and abilities.”

In a situation in which a prospective subject is capable of providing informed consent at the beginning of a clinical investigation but is expected to become less capable of providing continued consent as the research progresses, such as in a long-term Alzheimer’s clinical trial, “consideration should be given at the start of the trial to having subjects designate an individual to serve as their LAR once the subjects’ conditions warrant it,” the guidance says.

The guidance also states that the “FDA supports the use of electronic processes to obtain informed consent.” The guidance notes “electronic processes to obtain informed consent may use an interactive interface for the informed consent process, which may facilitate the subject's ability to retain and comprehend the information. Furthermore, these electronic processes may also promote timely entry of any electronic informed consent into a study database and facilitate collection of the subject’s informed consent from remote locations.”

The guidance also notes that enrolling subjects with physical or sensory disabilities into a clinical investigation “does not require a LAR to be involved with the informed consent process or to sign the consent document unless required by state or local law.” However, “FDA recommends that investigators provide reasonable modifications and auxiliary aids and services when necessary to meet the specific needs of the study population.”

How To Inform Subjects of New Information

On the question of how to inform existing subjects of new information that may affect their willingness to continue participation in the research, the guidance says IRBs “should determine whether currently enrolled subjects should be provided with the new information and given an opportunity to affirm their willingness to continue in the research,” which is referred to as “reconsent.”

The guidance notes FDA regulations do not use or define the term “reconsent,” nor do the “regulations specify the process an IRB should use to determine the need or method to inform subjects who are already enrolled in the study of the new information. As such, IRBs have flexibility to establish procedures they think are appropriate to provide for subjects to have an opportunity to affirm their willingness to continue in the research.”

In addition, because of new information, “the investigator may need to revise the consent form to include the new information for new enrollees and obtain IRB review and approval before it is used (21 C.F.R. §50.27(a) and 21 C.F.R. §56.109). Because the consent form is being modified to reflect the new information, the IRB should determine whether the investigator should provide currently enrolled subjects with the new information either with the revised informed consent document or an alternative method such as a consent addendum or information sheet describing the new information,” the guidance says.

When a revised consent form is used to inform enrolled subjects of new information and to document their willingness to continue in the trial, the FDA says investigators may use a prepared summary of the change(s) to reduce confusion about the change(s) and aid in presenting the new information. “After the discussion of the new information and an acknowledgement of understanding by the enrolled subject, the enrolled subject should be asked to sign and date the revised consent document if they are willing to continue participating in the research,” the guidance says.

When an alternative method is used, such as a consent addendum or information sheet, the enrolled subject should be asked to sign and date the consent addendum or information sheet. “FDA recommends that a copy of the signed and dated consent addendum or information sheet be provided to the subject,” the guidance says.

However, the guidance says, “in general, FDA does not believe it is necessary for subjects who have completed their active participation in the study to be informed of new information unless the new information relates to risks that may manifest after such participation. In this situation, it may be appropriate to provide previously enrolled subjects with counseling regarding any risk that may be warranted. Similarly, FDA does not believe it is necessary to inform subjects who are still actively participating of new information when the change will not likely affect their decision to continue in the study (e.g., an increase in the number of study subjects). However, IRBs may recommend that the investigator provide the above-discussed summary to all subjects (previously and currently enrolled subjects) for their awareness.”

Guidance Discusses Risk/Benefit Concerns

In discussing risks and discomforts, the final guidance notes that “where relevant, participants should also be made aware of the possibility of unintended disclosures of private information and be provided with an explanation of measures to protect a subject’s privacy and data, and limitations to those measures.”

In addition, for clinical investigations involving the comparison of an investigational product to one or more standards of care, “it may be acceptable to describe the more common and significant risks and discomforts of the standard of care in the informed consent form and provide additional risk information, as appropriate, as part of the consent discussion,” the guidance says.

The guidance also adds that information on risks that are more likely to occur and those that are serious should be described “so that prospective subjects can understand the nature of the risk.” And “in situations where there may be a risk to others, efforts to mitigate the potential risk (e.g., using separate bathrooms) may be included in the consent document or provided in a separate document and given to the subject during the consent discussion.” Furthermore, “if unanticipated risks are reported during the investigation, the informed consent discussion and documents may need to be updated with the additional risks (21 C.F.R. §50.25(a)(2)).

As to benefits, the final guidance adds that “for clinical investigations involving the comparison of an investigational product to one or more standards of care, it may be acceptable to generally describe the benefits of the standard of care in the informed consent form and provide more specific information about the standard of care as part of the consent discussion rather than in the consent document.”

In addition, “if there is no potential for direct benefit to the prospective subject, which may be the case, for example, in a Phase 1 study in healthy volunteers, this point should be clearly stated. An example of a way in which to describe in the consent document that an investigational product does not have direct benefits to participating subjects would be to state ‘There are no direct benefits to you from taking part in this study,’” the guidance says.

Regarding alternative procedures or treatments, the final guidance adds that “prospective subjects must be informed of the appropriate alternatives available to them, including a description of the care they would be likely to receive if they choose not to participate in the research.” In addition, “when describing in the consent form an unapproved use or treatment regimen of an approved or cleared drug or device that the sponsor markets, and such use or treatment regimen is a part of the medically recognized standard of care, the consent form can provide factual information concerning the unapproved use or treatment regimen of the drug or device. However, this information should not be presented in a promotional manner. If a sponsor has questions related to this issue, they may contact FDA for feedback,” the guidance says.

“A statement identifying alternative therapies and indicating that the alternatives will be discussed by the clinical investigator in more detail, if appropriate, may be used if there is more than one alternative,” the guidance adds. “FDA recommends that treatment options lacking evidence of therapeutic value not be included.”

Further, if additional alternative procedures or courses of treatment become available during the course of the clinical investigation, the informed consent discussion and documents may need to be updated (21 C.F.R. §50.25(a)(4) and 21 C.F.R, §50.25(b)(5)).

“While the information in the consent document should be more than just a list of alternatives, a full risk/benefit explanation of alternatives may not be appropriate to include in the written document. However, the person(s) obtaining the prospective subject’s consent should be able to discuss available alternatives and answer the prospective subject’s questions,” the final guidance says.

Guidance Given on Emancipated Children and Sponsor Personnel

The guidance notes that states “may grant certain minors of a specific age the right to consent to treatments or procedures on their own behalf. These mature minors do not meet the definition of children for purposes of a clinical investigation that involves solely those ‘treatments or procedures’ for which they can give consent outside the research context and thus, the requirements of 21 C.F.R. Part 50, Subpart D, do not apply to the research with respect to these minors.”

Similarly, “minors deemed ‘emancipated’ by state law, such that they may provide consent to treatments and procedures in the clinical setting, also do not meet the definition of children under 21 C.F.R. §50.3(o), and the requirements of 21 C.F.R. Part 50, Subpart D do not apply to the research with respect to these emancipated minors. In these cases, the mature or emancipated minors can consent to participation in FDA-regulated research without the need for parental or guardian permission,” the guidance says.

For example, if a clinical trial is being conducted in a jurisdiction that has laws that explicitly allow a minor of a particular age to consent to receive specific sexually transmitted disease (STD) services in the clinical setting, these minors may be able to provide informed consent for participation in a clinical trial of a product intended to treat or diagnose an STD.”

The final guidance adds a new section on sponsor personnel saying: “Sponsor personnel (usually a field engineer) may be present during the procedure and/or follow-up visits for some medical device studies. These individuals may provide technical support and/or record study-related information for the test article. If sponsor personnel will be present during the procedure or follow-up, or if the activities of the sponsor personnel directly affect the subject, those activities should also be described in the informed consent form.”

Other Changes to Guidance Detailed

While the draft guidance “strongly” discouraged subject enrollment in multiple investigations, the final guidance states the FDA “generally” discourages the idea, noting “there are some circumstances in which co-enrollment may be appropriate (e.g., rare disease studies that are evaluating different aspects of the condition and involvement in one study does not affect the other study). In addition, this recommendation does not apply to certain appropriately designed studies, such as a clinical investigation of a novel drug and a companion in vitro diagnostic device that is essential for the safe and effective use of the drug,” the guidance says.

The final guidance states “FDA considers advertising used to recruit subjects into the clinical trial to be the start of the ongoing consent process, and the information provided in any online or hard copy recruitment materials should be consistent with the informed consent document. Generally, FDA recommends that any advertisement to recruit subjects be limited to the information the prospective subjects need to determine their interest and potential eligibility.”

In addition, “once a prospective subject is identified, and before research activities requiring prior consent occur, a person knowledgeable about the clinical investigation and capable of answering questions raised by the prospective subject should conduct a consent discussion. The consent discussion and the consent form must contain information to allow prospective subjects to make an informed decision about participation in a clinical investigation and provide an opportunity for prospective subjects to ask questions about the clinical investigation and the information in the consent document,” the guidance says.

The final guidance also notes that coercion and undue influence “can affect any population, not just subject populations seen as vulnerable to coercion or undue influence. … The possibility of undue influence could be addressed by first discussing the study with the prospective subject during a preoperative visit as part of the informed consent process. The prospective subject could be told that the study will be reviewed with them again prior to the procedure and, after all questions are resolved, they will be asked to sign a consent form acknowledging their willingness to participate in the study at that time.”

In addition, “statements that claim investigational drugs and devices are safe or effective for the purposes for which they are being investigated are prohibited (21 C.F.R. §312.7(a) and 21 C.F.R. §812.7(d)),” the guidance says. “For example, wording that refers to the clinical investigation as a ‘therapeutic trial’ could contribute to a prospective subject’s misunderstanding that the trial will offer a direct benefit for their disease or condition.”

In addition, the “FDA does not consider reimbursement for reasonable travel expenses to and from the clinical trial site (e.g., airfare, gas, tolls), and associated costs, such as parking and lodging, to raise issues related to coercion or undue influence. Reimbursement for other expenses may be considered by an IRB on a case-by-case basis, and IRBs should consider whether the proposed remuneration could be an undue influence,” the guidance says.

“Payment for participation in research should be just and fair,” the guidance says, adding “paying research subjects in exchange for their participation is a common and, in general, acceptable practice. FDA recognizes that payment to subjects for participation in clinical investigations, which is not specifically addressed by FDA regulations, may in some cases, raise difficult questions that should be addressed by IRBs. For example, an IRB should address how much money research subjects should receive, and for what subjects should receive payment (e.g., their time, inconvenience, discomfort, or some other consideration).”

However, the final guidance adds the “FDA does not consider payment to research subjects for participating in research a benefit that can be used to justify risk when IRBs evaluate whether risks to subjects are reasonable in relation to anticipated benefit as required by 21 C.F.R. §56.111(a)(2). IRBs should review both the amount of payment and the proposed method and timing of disbursement to assure that they are not coercive and do not present undue influence (21 C.F.R. §50.20),” the guidance says. “As a general rule, FDA does not believe genuine offers of payment raise questions about coercion; however, an overt threat of harm presented in the guise of an offer of payment (e.g., a threat to withhold payment that had already been promised) would still be coercive.”

In discussing confidentiality, the new guidance notes that in addition to the study sponsor, the consent process should identify all entities, such as the research team, regulatory agencies, and/or ethics committee members, who may gain access to the record relating to the clinical investigation.

The new guidance also recommends email addresses for individuals that subjects can contact with questions. The guidance also recommends that “an appropriate contact for subjects’ rights questions may be the IRB Office, the facility’s Patient Advocate Office, or other staff with training regarding the rights of clinical trial subjects.”

The final guidance also notes that “written withdrawal from the study by the subject is not a requirement [and] when possible, the site staff should document the withdrawal and the date it occurred.”

The new guidance says that to aid prospective subjects in understanding additional costs, “the consent process should describe the protocol requirements in sufficient detail (e.g., number and duration of study site visits and procedures) to enable subjects to appreciate how much time they may need to take away from work, child care, or elder care. Prospective subjects should be made aware of direct and indirect costs of participation and informed as to what extent these costs will be covered by the sponsor versus paid by the subject.”

In addition, “prospective subjects should be made aware of the number of visits and approximate time required for participation in the study to help them determine if they are able to make the commitment to complete the study. When appropriate, it may be reasonable to counsel prospective subjects that they should not participate in the trial if they do not foresee staying in the study,” the new guidance says. “The subject should also be informed as to how the data that have already been collected will be handled,” if they decide to withdraw from a trial.

The final guidance says significant new findings may include “results from interim analyses (in some cases), additional alternative procedures or courses of treatment that become available during the course of the clinical investigation, and information from other clinical trials about the effectiveness of the investigational product, the comparator, or other products for the same indication.” In addition, “where there are significant new findings, the IRB should consider whether enrolled subjects should be contacted to determine if this information impacts their decision to continue participation in the clinical investigation,” the guidance says.

The guidance notes that although the clinical investigator should consider issues regarding financial relationships and interests, “IRBs have the final responsibility of determining whether subjects should be provided with information regarding the source of funding, funding arrangements, or financial interests of parties involved in the clinical investigation as part of the informed consent process (21 C.F.R. §56.109 and 21 C.F.R. §56.111(a)(4)-(5)).”

Regarding non-English speaking subjects, the final guidance says that “when translation or interpretation is needed for written and oral information that is to be presented to subjects, FDA recommends that the IRB review, and if appropriate, approve reasonable procedures for ensuring that the translations will be prepared by a qualified individual or entity, and that interpretation assistance is available.” In addition, the “FDA recommends that whenever subjects who do not understand English are involved in research, appropriate interpreter services be made available throughout the course of the research.”

The FDA also strongly encourages stakeholders to ensure that informed consent documents are accessible to individuals with limited English proficiency. “To the extent an organization receives federal financial assistance from HHS, Title VI of the Civil Rights Act of 1964 and its implementing regulations require the organization to take reasonable steps to provide meaningful access by individuals with limited English proficiency,” the guidance says, adding the “guidance provides information to assist IRBs, clinical investigators, and sponsors in complying with FDA’s informed consent regulations for clinical investigations. It does not provide guidance on how to comply with any regulatory obligations stemming from a source outside of the statutes FDA administers and FDA’s regulations.”

The final guidance also states that the “FDA supports the return of aggregate research results and recommends that they be returned to subjects in a clear and comprehensible manner.” However, “FDA regulations do not directly address the issue of IRB review of return of aggregated results to subjects; however, when return of aggregated results is planned at the time of initial IRB review of the study, or the decision to share results is made after initial IRB approval but while the study is still open with the IRB, then the plan for communicating this information to subjects should be reviewed by the IRB. However, if the plan to share aggregated study results is developed after the study is closed with the IRB, the IRB does not need to review the sponsor’s plan to share the aggregate results,” the guidance says.