In August of 2023, the FDA released a guidance document on Informed consent. The information in the guidance is intended to inform clinical investigators, sponsors, institutional review boards (IRBs) on the basic requirements of informed consent as well as what basic and ancillary elements can comprise informed consent processes and documents. This blog summarizes these guidelines but is by no means an exhaustive description of its contents.
Currently, FDA describes its requirements for informed consent in its regulations on Protection of Human Subjects (21 CFR part 50).
The FDA distinguishes in this latest guidance that informed consent is not the act of merely obtaining a signature. It is the process of making sure potential participants understand the research, as well as their role in it. The agency also notes that a big part of informed consent means giving prospects ample opportunity to ask questions of investigators and their study team to gain adequate knowledge and confidence in participating in the study. This is also seen as an ongoing process whereby participants should be able to ask questions throughout the study to support their informedness.
Recruitment is considered a vital part of the consent process. The agency’s reasoning here is that recruitment conveys the initial information that potential participants use to gauge their interest in the study. As such, the information provided in initial recruitment advertisement needs to be minimal while serving this purpose of generating interest.
The FDA distinguishes in this latest guidance that informed consent is not the act of merely obtaining a signature. It is the process of making sure potential participants understand the research, as well as their role in it.
One of the main potential risks identified by the FDA is that of undue coercion. As such, the agency recommends that investigators do not overstate the benefits of a particular treatment or diagnostic tool being studied, and do not make unsubstantiated claims to this or any other effect to spur consent. Conversely, the agency does not consider any sort of incentive, whether financial or otherwise, to be considered undue influence, unless under some overt or covert threat of withholding it.
Overall, the consent form should contain information presented in language that an average person can understand. If medical or scientific terms are used, they must be explained. Exculpatory language that waives participants of their legal rights is prohibited.
The FDA defined eight basic elements of consent:
The consent form should note that participation is for research purposes, and while preliminary data may exist, the study is investigational, observational, or experimental in nature. The description should contain a list of procedures done in the study, what typical elements of clinical care may be included or excluded as part of the study, how the participants will be involved, how long the study will be for participants, and what may be involved in follow-up from the initial study timeframe.
Any reasonably foreseeable risks or discomforts must be documented in the consent (sidenote: video consent can be considerably useful for this). Procedures or tests that may carry risks or discomfort must be documented, especially those with considerable risk for morbidity and/or mortality. ‘Risks’ entails not just physical harm, but also the possibility of unintended disclosures of private/sensitive information of participants.
Accordingly, the agency recommends describing ways in which personal health information and personally identifiable information will be secured/protected to the best of the study team’s ability, while disclosing limitations to these efforts. While all possible risks don’t need to be described, it’s important to provide some detail on how the most likely risks may impact participants. Probability as well as reversibility can be considered in these risk disclosures.
Reliable information on potential benefits to the participants as well as others (such as patients with a particular condition) can be described. The FDA cautions against overly optimistic benefits or descriptions of benefits. If there are no direct benefits, this must be clearly stated. Payments/incentives/reimbursement are not considered benefits as part of the consent process.
Participants must be made aware of the care or treatments they could receive in place of participating in the study. If there is more than one alternative, there should be language indicating that investigators can follow up with the participant to describe these in more detail. If additional treatments or procedures become available during the course of the treatment, this may warrant the updating of the consent document. The document can also refer patients to their primary care doctor or another healthcare professional to discuss alternatives in more detail.
Alternative considerations are also in play when considering participation in other research studies. The consent process should also detail whether participation In other studies affects a person’s ability to participate in the study for which the consent process is intended.
The consent process should describe the measures by which confidential information will be safeguarded. The FDA maintains the right to inspect confidential information as it pertains to the research without permission and holds this right per stipulations set forth in the Health Insurance Portability and Accountability Act (HIPAA).
If a study poses any significant risks, it’s important to disclose any compensation and medical treatments available should injury occur. If no compensation is available, the informed consent should specify this, while also making it clear that this does not require the person to waive any legal rights.
The consent form should have information on who to contact for questions regarding the study, the participant’s rights, as well as who to contact in case of injury as a result of the study activities. It should include names, telephone numbers, and email addresses. The FDA advises against listing a study contact for participant’s rights as it may discourage participants from seeking out information from biased parties, and instead recommends contact information for a member of the study’s IRB office. It should also disclose who to contact in the case of an emergency, including 24-hour contact information where applicable. Correct contact information should be provided to participants as it gets updated.
Participants must be informed of their right to stop participation at any time, and that their participation is completely voluntary. Should the research require special procedures to ensure safe, secure withdrawal from the study, these procedures must be outlined in the consent. The consent document should clarify if the information the participants provide during their course of the study will remain part of the study’s database or not.
The FDA defines six additional elements of informed consent:
A document containing the signature of a participant and the date is required for the consent process, and digital signatures and documents can be used provided they are in accordance with 21 CFR Part 11, which regulates the use of electronic records and signatures.
While paper consent is the traditional form of obtaining consent, other methods can be used. Technologies for obtaining consent must be discussed with the study’s appropriate IRB, or investigators can contact the FDA for advice as needed. If written consent is required, consent may not be obtained via telephone. The general guidance suggests that any alternative method for consent is adequate if it allows for the “adequate exchange of information and documentation, and a method to ensure the signer of the consent form is the person who plans to enroll as a subject in the clinical investigation or is the legally authorized representative (LAR) of the subject.”
If a telephone conversation is used to provide information to the participant or their LAR for the consent process, there must be a means obtaining signature. This can be done by email, fax, or via a secure web address. Another way to ensure signature is for participants to bring in a signed copy of the form to their next scheduled visit to the research site. The signed consent form must be maintained as part of a participant’s case history per 21 CFR 312.62(b) and 812.140(a)(3), and the participant/LAR must receive a copy of their form per 21 CFR 50.27(a). While the copy provided to participants does not need to be signed, it is recommended per these guidelines.
A document provided to the participant, or their LAR, should either contain all the information regarding the consent, or be a short form summary and acknowledgement of an oral explanation of the entire consent documentation. All IRBs need to approve of the written form of the oral summary to be stated exactly as written to potential participants.
The FDA maintains that institutional review boards review all consent materials to request modifications and approve/disapprove of the materials. This includes advertisements and other recruitment materials.
The central responsibility for review boards is to ensure that materials are compliant with 21 CFR part 50, and to ensure that participants are well-informed of their rights as it pertains to the study in question. They must ensure that consent materials minimize the incidence of undue coercion.
As far as content, IRBs should consider whether to disclose sources of funding for the study, the adequacy and appropriateness of all wording in the consent materials to facilitate informedness, supplemental media to inform understanding, and the use of standardized language as it relates to their institution. As far as form, they should weigh how well alternative forms of consent that differ from face-to-face interactions such as telephonic interviewing supports informedness. By extension, investigators should also consider these factors.
IRBs have the authority to observe (or have a third party observe) the consent process to ensure adequate compliance with their guidance as well as with regulatory requirements. They may also interview participants to ensure the consent process ensures adequate informedness. If any information or element of the consent materials and process is updated, IRBs need to be able to review these materials in a timely manner. Small administrative changes such as telephone numbers or typographical errors do not require re-approval, however, IRBs should be sent an updated copy on consent forms for their records. The FDA recommends that IRBs have a way of keeping track of up-to-date forms so that previously approved forms are not used in the consent process.
According to the guidance, “the clinical investigator is responsible for protecting the rights, safety, and welfare of subjects during a clinical investigation, and for ensuring that, unless an exception applies, legally effective informed consent is obtained from each subject or the subject’s LAR before that subject takes part in the clinical investigation.” The informed consent must meet all federal, local, and state requirements—in addition to what the FDA may require.
The clinical investigator must inform their IRB of the consent process and materials they will use, as well as who will conduct the consent discussion. They are required to obtain IRB approval for the clinical investigation, the consent form, and any other information given to participants before beginning the consent process. They must obtain approval from their respective IRB for revisions to the consent material or process that may affect the willingness of participants to continue in the study or for prospects’ willingness to initially consent. The IRB will determine whether investigators need to inform previously enrolled participants of the new information and whether the research team should obtain consent to further continue in the study.
Clinical investigators have the authority to delegate the responsibility of the consent discussion to their study staff members. In which case, the FDA expects these staff to be adequately educated, trained and experienced to perform this activity. Whoever is delegated to obtain informed consent should have adequate knowledge of the investigation and be able to address concerns or questions from participants pertaining to the study. An investigator should have a detailed plan for supervising and training staff as it relates to informed consent and other study processes. The investigator remains responsible for all tasks delegated to their team as it relates to obtaining legally effective, informed consent.
Investigators also need to consider whether to disclose financial relationships/interests. This includes things like sources of funding or funding arrangements. As such, special measures can be considered to mitigate financial conflicts of interest such as having unbiased individuals involved in the consent process or using independent monitoring of the consent process.
A sponsor generally gives investigators a standard consent form that can be adapted for local site needs. They should provide any updates of this standard form to investigators to ensure that these forms are up-to-date across sites. Sponsors should work closely with a study’s investigator to ensure IRB approval and should provide a copy of their form—approved by the sponsor’s IRB—to the investigator.
When review from local IRBs result in substantial modifications to the consent form, the FDA expects the sponsor to share these revisions with all investigators and their IRBs. These revisions should be shared with a central IRB if there is one, and central IRBs can also address local issues as needed. Medical device studies may call for additional considerations.
Sponsors may be required to submit different materials as it pertains to drug or device studies. The FDA does not require sponsors to submit consent materials for review for all types of investigations. The agency will generally assess the adequacy of the content, most notably as it relates to the communication of foreseeable risks or discomfort to participants. The FDA reserves the right to require revisions to consent materials that they find to be misleading, inaccurate, or incomplete insofar as it would make participant consent inadequate or otherwise non-compliant with 21 CFR part 50.
The FDA’s review does not substitute for an IRB’s review and approval of the consent form and processes. New drug and biologics do not require the submission of consent materials to the FDA, except in instance where it is deemed necessary to evaluate study safety. If consent forms call for specific exceptions from requirements, these are reviewed on a case-by-case basis.
Medical device studies that require an IDE application require the submission of all forms and materials in the process for consent. The FDA reviews the consent to ensure it complies with 21 CFR part 50 and sends a letter citing any deficiencies to the sponsor. The study may not begin until the sponsor corrects the deficiencies. If an IRB calls for substantial changes to the informed consent document after IDE approval, the sponsor is required to obtain additional approval from the FDA prior to implementing these changes in their study.
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