The FDA has issued a new, final guidance on informed consent for clinical investigations – the first update since 1998. The new guidance offers recommendations for institutional review boards (IRBs), investigators and sponsors on key aspects of informed consent, significantly expanding FDA’s recommendations on several key topics, including reimbursement for research participation.
The FDA, HHS, and research and informed consent policies
- In the U.S., many types of clinical research must comply with regulations intended to protect the rights of research participants. Those protections are found at 21 CFR 50 and 56 and include concepts like informed consent, appropriate clinical trial oversight by institutional review boards (IRBs), the review of investigational research protocols by the FDA, and ensuring that test articles have been appropriately vetted prior to human use.
- Informed consent is one of the three foundational protections for research involving human subjects. The requirement stems from ethical principles of respect for persons and autonomy, as first introduced in the landmark Belmont Report on research ethics. The three main aspects of informed consent to research participation include disclosing information needed for an informed decision; ensuring understanding of the disclosed information; and ensuring that the decision regarding participation is voluntary. “The informed consent process is the critical communication link between the prospective human subject and an investigator, beginning with the initial approach of an investigator to the potential subject […] and continuing until the completion of the research study,” according to a Department of Health and Human Services (HHS) FAQ on informed consent.
- FDA and HHS have some overlapping authority in this area, but continue to work to harmonize. While the FDA regulates the conduct of clinical trials which evaluate medical products, its parent department, HHS oversees the conduct of all studies that involve human subjects. HHS incorporated the recommendations from the Belmont Report into two sets of regulations: one that pertained broadly to all human subject research, and one that was specific to research involving children. Eventually, the broader regulations would become known as the Subpart A requirements, or the “ Common Rule” (45 CFR Part 46). Likewise, considerations for research involving special populations are captured in Subpart B (Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research), Subpart C (Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects), and Subpart D (Additional Protections for Children Involved as Subjects in Research) of the HHS regulations on human subject research.
- However, HHS’ regulations only apply to research that is directly conducted or supported by the U.S. government, so FDA’s regulations are technically parallel to HHS’. As explained by the FDA previously, there are differences in scope, definitions of key terms such as “research” and “subject,” qualifying for exemptions from oversight, and more. Nonetheless, to make it easier for investigators and IRBs, and to prevent further regulatory overlap, the passage of the 21st Century Cures Act in 2016 included a new requirement that FDA must “harmonize with the Common Rule whenever permitted by law.” After some missed deadlines, the FDA published a proposed rule to harmonize its work with the Common Rule in September 2022.
- Another note on the 21st Century Cures Act requirements: Under the Cures Act, IRBs can waive or alter certain elements of informed consent for certain studies, including waivers of informed consent for certain minimal risk investigations. For now, while the 2022 rule is still in proposed form, the agency has issued interim guidance on this process. AgencyIQ notes that there has been some misunderstanding about whether the requirements are waived or whether IRBs can issue waivers. This was a key point of contention at an April 2023 advisory committee meeting in which a sponsor was under the impression that their Patient Preference Information (PPI) study met the criteria for a waiver, but did not seek said waiver from an IRB and instead assumed that the requirements would be “waived” because the PPI was “minimal risk.”
- The FDA’s guidance on informed consent was last updated in 1998. That guidance, “A Guide to Informed Consent,” has been in place since then, although the agency drafted an updated (“Informed Consent Information Sheet”) in July 2014. The proposed updates were part of a broader push from HHS at the time to “enhance[e] the regulations overseeing research on human subjects,” including through bolstered informed consent guidance.
- The 2014 draft update emphasized making informed consent documents accessible, in terms of both technical content and level of detail. This draft guidance underscored the importance of ensuring that informed consent documents would be understandable by people with “low literacy” and “low numeracy,” to help ensure their ethical inclusion in research programs and opportunities.
- While the guidance was largely well received by industry, many had questions or requests for clarification. Overall, industry and research organizations supported an overhaul of the informed consent guidance document, especially given the increasing complexity of research programs. However, many submitted comments that asked for clarifications in several key areas, including how to best present information on alternative treatments (including off-label use), what to do about multicenter trials and best practices for alternative methods for gathering informed consent.
The FDA has now updated its informed consent guidance – for the first time this century
- Up first: The new guidance itself is extensive, providing almost 70 pages of detailed recommendations for both IRBs and researchers (and research program sponsors). The new policy reflects FDA’s perspective on the informed consent regulatory requirements at 21 CFR part 50, but also references (where appropriate) the specific informed consent regulations for Investigational New Drug (IND) applications and Investigational Device Exemption (IDE) requests. The guidance offers generally the same information as the 2014 revised draft, but has been significantly expanded; while the draft was 46 pages, the new final guidance document is 66 pages. Nearly every section has been expanded, with new sentences or whole paragraphs (you can view a 1:1 direct comparison that highlights new content in green here, but we would note that the final version’s smaller font has confused the application a bit). Given the extent of the changes, AgencyIQ will not be flagging every single change; instead, we will focus on the high-impact areas and their implications. The new final guidance provides additional information on many of the key points raised in comments, including undue influence and coercion (in particular, reimbursement for participants).
- The structure of the guidance: The document is broken down into three main sections. First comes “general guidance” on FDA’s informed consent requirements (e.g., the different elements of informed consent and its documentation), responsibilities of the IRB, investigator, sponsor, and FDA in administering and overseeing informed consent, and then a series of 16 “frequently asked questions.” The FAQs, notably, are a new format for what was described as “additional considerations” in the 2014 draft guidance. Much of the content here overlaps – for example, considerations for children, non-English speaking subjects, or people with disabilities or impaired consent capacity – but also adds a variety of new topics as FAQs, including electronic methods for informed consent and information about alerting patients to new data.
- It opens with a discussion of informed consent and what, exactly, that means from the FDA’s perspective. As with the 2014 revised draft, the guidance document begins with a “summary of the informed consent process,” but the agency has amended this section to clarify the intended purpose of informed consent: To many, the term informed consent is mistakenly viewed as synonymous with obtaining a subject’s signature on the consent form; however, obtaining documentation of a subject’s informed consent is only part of the consent process,” the agency explains. The whole process involves providing the potential subject (or their legally authorized representative (LAR)) with “adequate information” to make an “informed decision,” facilitating their understanding of that information, giving them an opportunity to ask questions (and have those questions answered), and continuing to provide information as required. In general, the advertising for recruitment is the “start of the ongoing consent process.”
- A quick note on some situations in which informed consent may not be required: IVDs and minimal risk. The guidance acknowledges the changes under the 21st Century Cures Act in 2016 that allows certain minimal risk studies to seek a waiver from an IRB, directing sponsors to that guidance document. Further, there are some specific informed consent considerations for in vitro diagnostic (IVD) studies that use leftover human specimens that are not individually identifiable, per 2006 guidance from the agency. While these studies are technically subject to informed consent requirements according to the regulations, the 2006 guidance expresses the agency’s intent to exercise enforcement discretion (i.e., FDA does not enforce its existing requirements) in certain circumstances for those studies. The new guidance calls out this policy, which remains in effect – and was notably flagged by trade association AdvaMed in their comments on the draft guidance.
- Expanded information on coercion and “undue influence.” A significant element of the informed consent regulations require that sponsors minimize the possibility of either coercion or undue influence, hewing to the definitions in the aforementioned Belmont Report. The agency has updated its thinking on undue influence in the final guidance, including additional scenarios that could increase the risk of exerting coercion or undue influence.
- On the subject of reimbursement: The 2014 draft guidance included references to reimbursement only in the section on “additional costs to subjects,” which recommended that sponsors include the costs that potential subjects may be responsible for, explained as part of the informed consent process and including a note that “it may be appropriate” to refer them to a financial counselor. Notably, some commenters (e.g., Merck) found this “unnecessary” as a recommendation, and recommended amending this section. The final guidance addresses many of these concerns, and provides some new paragraphs in the section on coercion and undue influence on reimbursement, noting that FDA “does not consider” reimbursement for travel or travel-associated costs to raise coercion and undue influence issues. The final guidance does note that reimbursement for “other expenses” can be considered by the IRB on a case-by-case basis. Further, while paying research subjects is not specifically addressed in FDA regulation, it is “in general, acceptable practice.” However, given that there are not specific regulatory standards on this subject, the agency acknowledges that these issues “may in some cases, raise difficult questions that should be addressed by IRBs.” At a high level, which is what the FDA offers in its final guidance, “genuine offers of payment” do not represent coercion but “an overt threat of harm presented in the guise of an offer of payment” would. Notably, “if payments, including reimbursement for research-related expenses incurred by subjects due to participation, are provided, the consent process should not identify them as benefits” in communications about risk and benefit.
- The final guidance includes a specific emphasis making sure potential participants have enough information to “appreciate” potential indirect costs. There’s also a new note in the guidance about costs “beyond [those] directly related to participation in the research,” such as time off from work, child or elder care, or transportation costs. The agency now specifies that the consent process should include sufficient information about the protocol so that subjects can “appreciate” what these “additional costs” might be – and describe what, if any, of these “indirect costs” might be covered by the sponsor (versus paid by the subject). This subject is also flagged in the guidance section on “consequences of a subject’s decision to withdraw,” which notes that the information about the commitment the study will require should allow the participant to determine if they will have the capacity to remain in the study.
- Communicating benefits, risks, and alternatives to study participation. The final informed consent section includes a bevy of updated information about communicating several of the basic elements of informed consent. Some of these include how to describe differences between the investigational product and standard of care, and how to communicate risks – including patient data privacy risks and physical discomfort, like participants could experience from extended time in an MRI machine. The agency also expanded its section on how to describe the “potential benefits” of the research program, including benefits not only to the prospective subject but to society, as well as in comparison to the standard of care. Notably, this section also now includes some examples of what would need to be included if there is no direct benefit to the individual subjects (e.g., phase 1 studies in healthy volunteers).
- Identifying alternative procedures or treatments: the standard of care and off-label use. Per 21 CFR 20.25, informed consent needs to include a disclosure of “appropriate alternative procedures or courses of treatment.” The agency expanded this section to discuss what, precisely, those should be – including comparisons to the standard of care, and, interestingly, off-label use (and where it stands in the standard of care). While the FDA has its own framework for what different entities can and can’t say about off-label use (meaning an unapproved use of an approved or cleared drug or device), questions about how off-label use could be described were flagged in comments on the draft guidance (for example, see comments from the Biotechnology Innovation Organization (BIO), Merck’s comments here, AdvaMed’s here, Novo Nordisk’s here). The new informed consent guidance now specifically states that that off-label use information can be provided as “factual information” (contextualized in the standard of care) but “should not be presented in a promotional manner.” In general, alternative options shouldn’t be presented as a simple list of options, but a “full risk/benefit explanation of alternatives may not be appropriate” in written documents. Instead, the agency recommends that the person administering the consent process be available to discuss the options. This final updated recommendation, AgencyIQ notes, was specifically requested by Pfizer in their comments on the draft guidance.
- The section on an IRB’s responsibilities, as well as those for the clinical investigator and the FDA, are largely the same as drafted in the 2014 version. One new note: Administrative changes (e.g., “the correction of typographical and spelling errors… changes in phone numbers”) do not require formal review and approval, but the IRB should have the most current version of the form on file. Further, the agency has removed a recommendation that the clinical investigator organize information in the consent form so that the “most significant” elements are presented first.
- Considerations for sponsors: Multicenter trials and sponsor personnel. The section that specifically outlines informed consent considerations for sponsors has been expanded slightly. Likely in response to questions from industry about multicenter trials, the agency now includes some additional language on its expectations for multicenter investigations – in particular, when multicenter clinical investigations are reviewed by more than one IRB. In these situations, “it may be more efficient to share [substantive changes to the consent form] with the sites using a modified model consent form,” the agency now states in the guidance. Notably, for medical devices under an IDE, these would also need to be submitted to the FDA. The guidance also includes a new note on “sponsor personnel” responsibilities. Specifically, the guidance now says that any sponsor personnel present for a procedure or follow-up that directly affects the patient should be described in the informed consent form. AgencyIQ would note that this last point is particularly relevant for medical device studies, in which field personnel may be providing technical support, and was specifically flagged as an area that needed further clarity by AdvaMed in their comments on the draft guidance.
The biggest change in the new final guidance: The FAQs
- As noted above, the FAQ section replaces the “additional considerations” section of the 2014 draft guidance. It also now takes up about 20 pages of the document, compared to 13 in the revised draft. While many of the topics are the same (review of patient records, implications for children and people with low literacy), the guidance now includes significantly more detailed information on these subjects.
- However, many of the answers are generally the same. First, these include specific recommendations for non-English speakers, including enrollment processes. This includes the same three-step process for an approach when enrollment of non-English speakers is not expected. Further, recommendations on considerations for enrolling participants with low literacy and numeracy have largely been maintained, including that elements of informed consent could be presented orally and the involvement of a LAR as appropriate. Further, while the agency’s language about enrollment for people with disabilities or adults who have impaired consent capacity has evolved since 2014, the recommendations again remain generally the same – albeit with a specific note added to the new final guidance that “FDA strongly encourages stakeholders to ensure that informed consent documents are accessible to individuals with disabilities.” In addition, the section about what to do if a subject withdraws has been renamed (it is now in question format, per the FAQs), but the advice that FDA has for sponsors is the same. Other areas that remain unchanged include recommendations about informing subjects of the aggregate study results at the completion of a trial, and how to inform subjects that a trial has been suspended or terminated.
- The FAQs also include new information on children and LARs. While the section on enrolling children as subjects remains largely the same, the guidance includes a new section on additional protections for “children who are wards of the state,” as when children in foster care participate in a clinical trial, and a new section on who can serve as a LAR. On the latter, the agency notes that the definition of a LAR is defined in FDA regulations, but the legal authority of who can be a LAR is determined at state and local levels. This section also addresses LARs and the inclusion of individuals with disabilities, including those with “profound cognitive impairment” who may not be able to contribute to consent discussions. Overall, “individuals with impaired consent capacity should be included in the process of consent to the extent possible and consistent with their desires and abilities,” the agency explains. Further, when cognitive decline may be expected (e.g., an individual with Alzheimer’s disease may be able to provide initial consent but become less capable to do so in an ongoing way), conversations about designation of a LAR should be had at the beginning of a trial.
- New FAQ content: How sponsors should be informed of new information. If, during an investigation, new information becomes available that could impact a subject’s willingness to continue participation in that trial, an IRB may determine that the patient effectively needs to “reconsent” – a term that is not defined in FDA’s regulations. In general, “IRBs have the flexibility to establish procedures” for these scenarios, according to the final guidance, but in the new FAQ, the FDA now outlines its expectations about documentation of these processes, including revised consent documents or consent addendums or information sheets. For subjects who have already completed their active participation, the agency states that it would generally not be necessary for them to be informed of any new developments, beyond those that “may manifest” after their participation – but again notes that IRBs may recommend something different.
- Expanded FAQ content: Informed consent and patient records. In general, determinations of whether patient medical record review by sponsors and investigators would require informed consent (i.e., is part of the clinical investigation) is determined by IRBs on a case-by-case basis. The final informed consent guidance includes many points of discussion that were included in the 2014 draft version, including retrospective review of a subject who was previously enrolled and seeking “additional information” beyond existing records before enrollment. The agency now adds a new section that specifies that when additional information beyond what was originally identified in the protocol is going to be collected, that activity would typically require informed consent: “FDA recommends that the clinical investigator anticipate the need for obtaining further information and obtain consent for medical records review and data collection as part of the initial consent process.” Further, the agency has added a new FAQ topic on electronic methods for informed consent – although this simply directs sponsors to the agency’s Q&A document on this specific topic.
- Additional FAQ content: Simultaneous participation. Overall, “FDA generally discourages enrollment in such investigations,” per the final guidance – an amendment from the language in the 2014 draft that said FDA “strongly discourages these practices.” The agency now acknowledges that there are some circumstances where “co-enrollment may be appropriate,” such as rare disease studies focused on different aspects of the condition or drug and companion IVD co-development. The agency also now notes that the risks of simultaneous participation in more than one study should be discussed during the consent process – “but do not necessarily need to be included in the informed consent form.”
What’s next? The advancement of research methods is leading to a new era of informed consent policy
- What about the proposed update to informed consent under the 2022 proposed rule? The guidance acknowledges that the FDA has long been working to harmonize its own regulations with HHS’ – meaning that there is a chance that the underlying regulations will change going forward, especially if/when the FDA is ready to finalize the 2022 proposed rule. This means that the agency may need to update the guidance again when those underlying regulations are updated.
- Additional questions for novel research methods: A major issue for both industry and regulators is the advancement of research methods themselves, including leveraging technology for decentralized trials that reduce the need to travel to centralized trial sites. Best practices for these study designs are still very much under development, but their implementation has led to some concrete, practical questions for researchers and sponsors. These include questions about novel cybersecurity risks for data that is created or collected electronically during informed consent, or how to factor in reimbursement for tools like a specific smart watch or tablet needed for study participation. Going forward, these are questions that do not have firm answers, so while the 2023 final informed consent guidance does provide significant new information for sponsors and researchers, there is still work to be done in this area.
- FDA isn’t the only entity thinking about these questions. HHS’ Advisory Committee on Human Research Protections (SACHRP) provides recommendations to HHS’ Office of Human Research Protection (OHRP), the office that oversees and provides guidance to IRBs. That committee recently convened to discuss the implications of decentralized trials, with a focus specifically on what IRBs should be considering when reviewing these study proposals. As noted throughout the FDA’s informed consent guidance (and this analysis of the guidance), there are several circumstances in which IRBs have the flexibility to make case-by-case decisions, including on reimbursement for study participants. As AgencyIQ discussed, the SACHRP had significant questions about the ethics of decentralized trials, including not just clarity on the roles and responsibilities of different stakeholders throughout the research administration network but how reimbursement (or provision of digital tools) would impact diversity or health equity. These recommendations, notably, would be outside of the FDA’s policy itself, but rather be focused on the IRBs responsible for reviewing study protocols – and representing an additional layer of complexity.
- Novel methods for informed consent: The FDA is working to update its own policies about using electronic systems for core research documentation and records requirements, known as Part 11, which includes electronic informed consent. This includes a long-awaited revised draft guidance that was published in March 2023. As AgencyIQ has recently discussed, the increasing digitization of the health care system and research tools has raised new questions about where, and how, the research regulations (including informed consent) apply. For example, while the FDA has established that using electronic methods to gather and record informed consent (as described in the guidance) may be appropriate, the expansion of records that are digitized could raise additional questions about how records reviews are conducted, or what counts as “additional” review requests. The new final guidance recognizes the electronic methods for informed consent, but AgencyIQ would flag that there is additional work to be done more broadly around the use of electronic tools and records systems.