Reflections on FDA’s Informed Consent Guidance
Introduction
The US Food and Drug Administration (FDA) published to the Federal Register on 15-Aug-2023 their Final Informed Consent Guidance for IRBs, Clinical Investigators, and Sponsors.
This 61-page document finalizes the draft issued in 2014 and supersedes previous guidance issued in September 1998. FDA states that the “revisions include significant changes to the provisions regarding informed consent.”
In this paper, 2Richards have selected salient points for further consideration by the reader.
Please note that this is our assessment of the potential impact to Study conduct. It is the responsibility of the reader to review the relevant, current regulations and guidance documents in their entirety to determine appropriate actions to be taken, if warranted.
Selected Points of Guidance
FDA states that this Guidance does not preempt any existing local laws covering informed consent and if there are differences in regulations concerning protection to human subjects then those that offer greater protection should be followed.
The document emphasizes that consent is not just about obtaining a signature on an Informed Consent Form (ICF) but is the process of providing sufficient information to a potential study participant, and/or their legally authorized representative (LAR) to allow them to decide whether it is in their own best interests to participate in a clinical study. There is also emphasis that consent is a continuous exchange of information and that study participants should be updated with new information that may impact their decision to remain in the study as the investigation progresses.
Fundamental to the consent process is that all information presented to the potential study participants should be reviewed by an IRB, although the agency clarifies that this review does not apply to publicly available basic study information, such as that posted on clinicaltrials.gov.
There is emphasis that there should be no coercion applied to potential study participants, although reasonable reimbursement and/or payment to study participants is acceptable, subject to IRB scrutiny. It is of note that this does not address potential coercion for individuals lacking medical insurance for whom participation in a clinical study may be the only feasible way to access treatment.
The Guidance notes that potential study participants should be able to understand verbal and written information presented to them. Although the Guidance doesn’t specifically state a required reading age, perhaps diligent Sponsors should consider evaluating ICF readability using, for example, the Flesch Kincaid Reading Ease scale (as used in some Australian clinical sites).
FDA requires written informed consent but also allows eConsent and the use of technology to replace face-to-face meetings for conducting consent discussions, subject to IRB approval (as allowed during the COVID pandemic). Interestingly, FDA also allows for certified photographic images of consent forms in specific cases where original documents cannot be obtained due to isolation of subjects with highly transmissible disease.
The Guidance specifically identifies that when consent and study participation occur on the same day, FDA expects that study participant’s case notes indicate that consent was obtained prior to any study procedure. Accordingly, we suggest that Sponsors consider including time, as well as date, of signature on the consent form.
In cases where vulnerable populations are participating in the study there is an expectation for IRBs to have membership with knowledge and experience working with such subjects.
IRB membership composition is not an area that receives as much scrutiny as perhaps it should, and we recommend this be considered during review of IRB approval documentation.
Our Assessment
Unsurprisingly, there is focus on ensuring protection of study participants’ rights, safety, and welfare through use of a robust informed consent process. There is particular emphasis on protection of vulnerable subjects and ensuring the consent process is well-defined, and clearly documented.
Study participants should be informed of the study, its potential risks and benefits and not face undue coercion to participate. We have seen examples of ICFs that do not accurately reflect the risks of study participation (including the risks of ionizing radiation or the toxicities of comparator products) or that imply potential therapeutic benefit from the investigational product; these are areas to include as part of the ICF development process.
Section 4 of the Guidance provides a couple of examples of language that would not be considered exculpatory by FDA, including: “If you are injured as a result of being in this study, paying for the cost of your medical care will be your responsibility or that of your health insurance company. However, signing this form does not stop you from pursuing legal action for the injury.” It will be interesting to see how this, or similar language will be assessed by reviewing IRBs given the limited options this would afford subjects with no health insurance and limited means.
The Guidance suggests that the use of charts or other tools may be used in the ICF to reduce its length, enhance its readability, and allow the consent document to focus on content related to the risks and any anticipated benefits of study participation. Having reviewed several ICFs that exceed 150-pages in length, this approach makes good sense in better ensuring that potential subjects can absorb and understand what study participation will entail.
FDA expects Investigators to have a detailed plan for the supervision and training of staff and oversight of study conduct, including the informed consent process. In our experience, this is not commonplace, and we recommend confirmation of this be sought during the site selection process and subsequent routine monitoring activities.
The guidance clarifies that “administrative” changes to ICFs can be made without IRB reapproval, although an updated copy of the ICF should be provided to the IRB. This may be an area for Sponsors to implement procedural clarification of what constitutes an “administrative” change.
In keeping with the understanding that consent is a continuous process, the Guidance requires reconsenting active study participants with any revised consent information. In our experience, this is often an area of weakness in many studies, particularly those of long duration. We have historically identified reconsent delays of many months, or total omission of reconsent, in some studies. This is something the Sponsors need to track, perhaps using the capability of EDC. In addition to providing updated risk information, another example where this becomes relevant is when a protocol is updated to include additional biological sampling. We have seen studies where delay in reconsenting has meant that additional blood samples were erroneously obtained from participants since they were not part of the original signed consent.
The Guidance makes it clear that new information that affects the rights, safety or welfare of study participants must be shared with all investigators and their IRBs. It also clarifies that any financial interests or potential conflicts of interest of the investigator should be disclosed to study participants.
The Guidance acknowledges that for multicenter clinical investigations, changes may need to be made to the consent form to address local and institutional requirements. For multicenter clinical investigations reviewed by more than one IRB, when local IRB review results in substantive modifications to the consent form, i.e., changes that affect the rights, safety, or welfare of the subjects, FDA expects the Sponsor to share the revisions with all investigators and their IRBs. This requirement should be included to relevant procedural documents.
In section C(2), the Guidance notes that a simple statement in the ICF that the investigator or sponsor may withdraw the subject from participation in the study at any time is inadequate and does not inform the subject of anticipated circumstances that may trigger their withdrawal from the clinical investigation. Again, this is an area worthy of consideration as unforeseen circumstances, for example termination of the development program, may trigger withdrawal of a subject who the investigator believes is benefiting from study participation.
The document concludes with FAQs, covering several important topics and we offer our thoughts on a few of these below:
Consenting study participants from potentially vulnerable populations
The guidance provides specifics for obtaining consent from parents/guardians/legal representatives and assent from children. It also refers to the legal rights of “mature minors” and “emancipated minors” to give consent without parental/guardian permission and to children who require advocates when they are wards of state. Additionally, the FAQ response indicates that a child cannot be used as an interpreter for the parents and that other interpreters should be used. This highlights that, in studies with pediatric study participants, there is significant complexity which will require careful review during ICF development and Sponsor monitoring.
FDA makes it clear that Sponsor should consider whether non-English speakers are expected or unexpected to participate in the study and provides guidance on approaches to ensure the adequate consent of subjects in each of these scenarios. We have seen instances of study participants that do not speak/read English signing an English-language ICF as it was the only one available at the investigational site. When required, FDA recommends IRBs review procedures for ensuring accurate translations of ICF documents by qualified personnel. This is something that should be confirmed when the Sponsor reviews the IRB approval documentation.
Legally Authorized Representatives (LARs)
FDA defines an LAR as someone with legal authority to consent on behalf of a prospective subject, and they expect institutions, IRBs, and investigators to understand and comply with local law. The response also emphasizes that consideration should also be given to study participants’ anticipated capabilities during the study and whether an LAR may be needed later (e.g., Alzheimer’s studies). FDA notes that 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. Although there is no reference to Sponsor responsibilities, we recommend Sponsors ensure that monitors confirm that there is documentation to support the standing of any LAR signing consent documents.
Participants in multiple studies
FDA discourages this except in rare circumstances where there can be no impact of one study on the other. In our experience, it is a routine protocol eligibility criterion that study participants are not enrolled in another study with an investigational product, and we recommend it remain so.
Data handling after study participant withdrawal
This response clarifies that data already collected from study participants must remain in the clinical database and that source records to support those data should remain accessible for review. It also details that investigators should determine from study participants who are withdrawing from the study whether they want to continue to be followed up after withdrawal from the interventional part of the study. We recommend that Sponsors describe clearly in the informed consent form how medical records will be accessed.
Study suspension or termination
This discusses the various options for study termination at site-level or at study-level, and consideration for when it may be in the best interests of study participants to continue receiving study drug. The reasons for study termination should be provided to study participants so that they understand any potential impact to them. We recommend that Sponsors prospectively describe in a plan and the informed consent how study termination will be managed at a site, region, or study level, including how study participants are informed of impact to their ongoing participation or subsequent medical care.
Providing study results to study participants
It has been a long-standing requirement for Sponsors to provide study results on clinicaltrials,gov within a specified timeframe. Disappointingly, in our experience this is neither done consistently by Sponsors, nor the requirement well enforced by FDA. The Agency’s response only restates this requirement although it does also reference that IRB review of any Sponsor’s pre-specific plan to share results is required.
We recommend that Sponsors consider how aggregate study data may be communicated to study participants and detail this in the informed consent document, as appropriate.
Consent to review patient records
Who can review patient records to see if they are eligible to be invited to participate in a study has been a question asked many times. Often this activity is referred to informally as “pre-screening.” The detailed FDA response expands on how records are being reviewed, whether health records have sufficient detail without additional review, whether potential participants have been involved in prior studies, etc.
We recommend that the process being used by the investigator to identify potential study participants is described in detail in the IRB submission for their review.
Reconsenting Subjects with new information
This response puts the onus on the IRB to describe how, and to whom, this should be done, based on their assessment of whether new information would impact the participant’s decision to remain in the study. It further clarifies that generally FDA does not expect completed subjects to be informed of new information unless the new information relates to risks that may manifest after study participation.
We recommend that Sponsors review changes to ICF wording that involve new information and document their evaluation regarding whom they consider should be reconsented or provided with new information, based on the potential impact to their safety or welfare.
Conclusion
With the release of the final FDA Informed Consent Guidance for IRBs, Clinical Investigators, and Sponsors the Agency has emphasized their current position regarding the protection of rights, welfare, and safety of human subjects, although this subject to future revision.
Overall, the recommendations are clear and logical and focus on advanced planning by the Sponsor, IRBs, and Clinical Investigators to understand their prospective study populations and outline processes to ensure that study participants are informed of the study and appropriately consented.
Although the Guidance does not refer to this specifically, the Sponsor has a responsibility to oversee adherence to the consent process. Noteworthy by its absence is how to deal with consent process noncompliance. Over the years we have seen inadequacies in several areas of the consent process, e.g., the use of consent forms that are expired, outdated/expired, incorrect versions, or incomplete; consent administered by inappropriate site personnel; untimely updating of consent forms and reconsents; signature of consent documents by non-legally authorized representatives. In such cases of process deficiency, we believe it appropriate that Sponsors conduct and document a review of the impact on the affected study participant(s) and implementation of corrective and preventive actions with notification to the IRB as appropriate.
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