eIC Regulations Considerations

Presenting information to potential participants or their LARs (henceforth collectively ‘“participants”) in an electronic format meets the definition of eIC in the 2016 Office for Human Research Protections (OHRP) and FDA joint guidance (henceforth “OHRP/FDA guidance”) [20], which outline an expansive view of eIC, stating it encompasses: “the use of electronic systems and processes that may employ multiple electronic media, including text, graphics, audio, video, podcasts, passive and interactive web sites, biological recognition devices, and card readers, to convey information related to the study and to obtain and document informed consent.”

This definition emphasizes that eIC is more than obtaining an electronic signature: the learning experience is an integral part of the IC process. As part of our development process, it was crucial to identify which regulations applied to the ADRC studies to ensure compliance and because of important differences between the major US federal regulations that apply to human research. For example, the Common Rule and FDA regulations governing human subjects research differ regarding the requirements for electronic signature. The Common Rule simply communicates that consent forms may be signed electronically (45 CFR 46.117)]. In comparison, FDA regulations (21 CFR 11 aka “Part 11”) include detailed requirements that must be met to ensure electronic signatures are “trustworthy, reliable, and generally equivalent to a handwritten signature executed on paper” [21]. Part 11 includes requirements for any system capturing an electronic signature to be secure with restricted access, include a method for validation, and produce an audit trail. The ADRC studies for which the eIC tool was developed were not subject to FDA regulations and thus were not required to comply with Part 11. Nonetheless, we highlight areas where compliance with FDA regulations differs from the Common Rule and those we determined applied to the ADRC studies (Table 1).

Table 1. Key regulations that should be considered when developing an electronic informed consent (eIC) process

ARDC = Alzheimer’s Disease Research Center.

Another regulation to consider is whether the HIPAA Privacy Rule applies and, if so, whether a separate authorization to use protected health information will be required. Additional examples of regulations that may apply to some research and affect the eIC process include the Children’s Online Privacy Protection Act (COPPA) [22] and Family Education Rights and Privacy Act (FERPA) [Reference Gilbert23], which may influence from whom permission must be obtained and documented.

eIC Tool Features

This project presented the team the opportunity not only to reformat the current paper IC version into an eIC but also to add key features to create a participant-centered IC experience by:

• Simplifying the language and presenting information in modules.

• Representing themes with iconography.

• Allowing participants to choose the order they view the modules.

• Providing optional (tiered) information about specific concepts.

• Concluding each module with questions to reinforce learning and allow self-assessment of comprehension of the material.

The eIC we developed employed best practices for the presentation of information in an online format as implemented in Apple ResearchKit, the National Institutes of Health All of Us Research Program [Reference Doerr, Moore and Barone24], and the HHS and the US General Services Administration’s Research-Based Web Design & Usability Guidelines [25]. Figure 1 illustrates the navigation through our eIC.

Fig. 1. Electronic informed consent flow and features. IRB, institutional review board.

In accordance with the revised Common Rule, our eIC tool starts with a concise summary of the study, followed by study details grouped into a table of contents presented in a 3 × 3 grid. Each “tile” represents a module and includes a title and icon that conveys the section’s content. The modules represent essential sections of an IC, such as risks and benefits; privacy; costs and compensation. The reader must click on all modules, moving through the content and answering questions to assess understanding before being allowed to access the signature section. In each module, optional information is available about key concepts via hyperlinks in popup windows. After reviewing each module’s information and answering the comprehension questions, a summary of main concepts reinforced by the iconography used throughout the eIC is shown so readers can verify their understanding and consolidate their decision on whether to join the study.

Because ADRC researchers enroll individuals with memory deficits, an important feature of the eIC tool is the addition of multiple-choice questions after each module rather than at the end of the IC interaction; this deliberate design feature assesses comprehension of each module’s concepts rather than overall recall. It is a well-accepted approach in AD research used to address comprehension of individual elements in competency assessment [Reference Jefferson, Lambe and Moser26] and can function as a “cognitive prosthetic” to help potential research participants, especially those with mild cognitive impairments, stay focused on the IC session [Reference Rubright, Sankar and Casarett27]. When participants select a response, the tool provides feedback on whether the response was correct and, if not, what the correct response was and why. Questions were designed to be engaging and reinforce learning. Asking questions about specific study concepts and providing corrective feedback is an effective way to determine if participants comprehend the information [Reference Festinger, Dugosh, Croft, Arabia and Marlowe28]. Answers can help identify misunderstandings and lead to conversations to address knowledge gaps, which is especially important when working with individuals with potential memory and cognitive deficits, but also a best practice for IC generally.

eIC Regulatory Oversight and Logistical Challenges

Federal regulations do not directly describe the specific information an IRB must obtain to review an eIC process. One reason for this lack of specificity is that IRBs must make their determinations independent of format when they review the IC process and any information provided to participants. A key IRB responsibility is to ensure participants receive any information, including the basic elements of consent and any relevant additional details, in “understandable language.” The 2018 Common Rule obligates IRBs to ensure the IC process facilitates comprehension and includes information that a reasonable person would want to have to make an informed decision about whether to participate. Additionally, federal regulations require IRBs to maintain documentation of their reviews, including any study changes or IC revisions.

During the development of the eIC tool, ADRC researchers, in conjunction with their local IRBs, worked through regulatory and operational issues that the review of an eIC process presented. Not all IRBs have the bandwidth for such close collaboration. Consequently, Table 2 provides practical recommendations for IRBs and research teams considering eIC with interactive features, focusing on four areas:

1. 1) Presenting the eIC experience to the IRB and tracking changes.

2. 2) Retaining records

3. 3) Documenting the IC

4. 4) Providing a copy of the IC

Table 2. Key considerations and recommended practices for electronic informed consent (eIC) approaches

IRBs and study teams should work together to develop a plan that addresses each of these areas. For example, research teams should discuss with the IRB what constitutes the “copy” of the IC when it includes interactive elements and how the copy should be provided (e.g., on an electronic storage device, via email, or another method). We recommend research teams provide participants with a summary that highlights key information about the research study and which participants can either print in tangible form or save electronically for easy reference. This approach mirrors the concise and focused summary requirement in the Common Rule (45 CFR 46.116(a)(5)) and is similar to the short form approach often used to document IC when the contents of the IC are presented orally to a participant. When using the short form, the study team must create and provide a written summary of what is to be said to the prospective participant and include an acknowledgment that all applicable elements of IC were presented. For an interactive eIC experience, this “written summary” of key information with the link to the eIC process could be given to participants in paper format for the participant record.

One consideration not driven by federal regulations is the common practice of IC form stamping. IRBs often add approval stamps on IC forms to assist study teams with tracking approved document versions. Stamps frequently identify the IRB, IC version, approval date, and study expiration date. Some platforms (e.g., REDCap) can generate a static capture of IC document screens and convert them to PDF files. Many IRB systems can stamp PDFs. IRBs and study teams need to be flexible and develop procedures, such as the REDCap alternative method, to identifying IRB-approved documents. The eIC approach with interactive features that our team developed, for example, cannot be stamped in the same way as traditional IC forms, but text within our online forms could show the version and IRB approval date, essentially recreating the information in an IRB stamp. Additionally, study teams can describe in standard operating procedures their process for a) tracking changes and versions of interactive eIC forms and b) presenting the correct versions to participants. If IRBs do not require written representation of IC information to be stamped, this challenge is completely avoided.

Core Versus Optional Information

The revised Common Rule placed IC front and center, reemphasizing the need for study teams and IRBs to carefully consider IC content and presentation. An interactive eIC tool can better meet some of the expectations outlined in the Common Rule for IC compared with a paper-based or eIC approach alone because the interactive features give participants more agency in determining the level of detail and order in which to consume the information. An interactive eIC is responsive to two key requirements in the Common Rule:

1. 1) Prospective participants must be given information that a reasonable person would want to evaluate to make an informed decision about participating and an opportunity to discuss that information.

2. 2) The information given should be in a language understandable to participants.

Although being able to tailor the level of detail and complexity of information is not unique to an eIC approach, eIC facilitates it through hyperlinks and pop-ups.

The Common Rule uses the reasonable person standard to guide IC content, but does not define reasonable person. Operationalizing this standard is challenging because individuals differ in what information they want about research [Reference Odwazny and Berkman29]. The challenge of defining what a reasonable person would want to know is compounded by the fact that participants differ in the information they consider to be important about research studies. For example, one study showed most potential participants wanted to know information about the return of research results (91%) [Reference Kirkby, Calvert, Draper, Keeley and Wilson30], yet federal regulations do not prioritize disclosure of clinically relevant results either as a concept that should be included in the concise and focused summary or even as a basic element of IC. Additionally, the Common Rule requires that for a reasonable person to make a decision, an IC must be presented in language understandable to them—but ensuring all IC language is understandable to every possible participant is a difficult standard to meet [Reference Ethicist31]. As the FDA notes, “understandable” means the information is presented to potential participants “in a language and at a level the participants can comprehend (including an explanation of scientific and medical terms)” [32].

The ADRC eIC experience was responsive to the reasonable person standard and providing information in language understandable in two key ways. Specifically, the ADRC eIC incorporated:

1. 1. A tiered-information approach that ensured individuals received core information about the research and allowed them to access supplemental information as desired.

2. 2. A modular approach, iconography, simplified language (middle-school reading level), definitions, and glossary of terms such that individuals of varied educational levels could learn about the study.

Further, grouping information into logical modules that met the Common Rule requirement for IC organization presentation.

A decision our team made in collaboration with the local IRBs was determining what information could be tiered, resulting in some information being presented to all (i.e., core information), while supplementary information would be accessible on-demand via a pop-up window if the reader clicked the hyperlink (i.e., optional information). Core information included required basic and applicable additional elements of IC per the Common Rule. A simple example of the tiered approach appears in the IC section that describes study visits: “We will ask you to return for follow-up visits every one or two years for as long as you can.” This statement meets the basic element of IC to inform individuals of the expected duration of their study participation. One could click on the phrase “as long as you can” to read details about long-term participation, and a pop-up window appeared that provided details (i.e., the possibility that if participants can no longer attend visits in person, they may be able to participate via telephone and their information would be collected from a surrogate if they became too ill to continue via telephone). The IRB required the estimation of study duration (“as long as you can”) to appear within the body of the IC materials as a required basic element of IC, while the detail about how participation might change from in-person to remote visits was viewed as of interest to some individuals but not essential to decision-making. For the tiered approach, each module starts with core information and includes links to pop-up screens for optional information (Figure 2); this approach allows individuals to tailor the IC process to the level of information they need and how they prefer to access it.

Fig. 2. Electronic informed consent tiered information feature

Other Considerations

Several additional factors can affect the development of eIC, such as:

• State laws: Some states have restrictions on what platforms may be used to capture electronic signatures, which can limit what platforms or approaches can be considered for eIC, or dictate specific requirements for IC language and font size (e.g., California’s Protection of Human Subjects in Medical Experimentation Act that requires the “Experimental Participants Bill of Rights” be provided to all participants in medical research and be in a specific format).

• Single IRB: As of January 20, 2020, most federally supported, multi-site research must be overseen by a single IRB (45 CFR 46.114(b)). If a single IRB will be used for the study, any local context requirements related to eIC will need to be communicated to the reviewing IRB [Reference Cobb, Witte and Cervone33]. The process for including site-specific language within an eIC should be considered and discussed with the single IRB.

• Posting Clinical Trial Consent Forms: The revised Common Rule includes a new provision that a copy of the final version of the consent form is posted on a publicly available federal website for each clinical trial conducted or supported by a Common Rule department or agency (45 CFR 56.116(h)).

• Non-English Speakers: The Common Rule requirement for research teams to provide information to participants in language understandable to them does not just speak to readability but also whether what language a participant may comprehend. Translation and interpretation needs should be factored into the development of any IC process, whether paper- or electronic-based.

• Assent: For studies involving children that use an eIC process, the research team will need to consider the development of age-appropriate materials if an assent process is required. Use of any IC materials aimed at parents or guardians may only be suitable for older children.

Research teams developing eIC processes should consult with their IRB early on to ensure the team addresses applicable regulations, understands IRB review requirements, and factors in tracking, versioning, and maintaining materials involved in an eIC process. To facilitate collaboration, we developed questions to help research teams and IRBs anticipate and address regulatory and other issues that innovative eIC processes can present (Table 3).

Table 3. Key operational and regulatory questions to ask when developing an electronic informed consent (eIC) approach