Informed Consent In Clinical Trials: Understanding The FDA's And OHRP's Joint Draft Guidance

By Liz Oestreich, JD, and Thomas R. Berry, PharmD, Eliquent Life Sciences

Obtaining informed consent from participants in FDA regulated clinical investigations of drugs, devices, and biologics, and nonexempt human subjects research is a key tool in protecting the rights of study participants. When consent is obtained incorrectly it can be an impediment to the overall success of a trial and, more importantly, can endanger the subjects.

FDA and the Health and Human Services’ Office of Human Research Protections (OHRP) both have regulations designed to protect human subjects participating in clinical trials, including on how to provide informed consent. 21 CFR Parts 50 and 56 articulate FDA’s regulations intended to protect the rights, safety, and welfare of human subjects participating in FDA-regulated clinical investigations. OHRP, on the other hand, has issued the Federal Policy for the Protection of Human Subjects, also known as the “Common Rule,” which applies to research conducted or supported by a broader array of federal government departments and agencies that have adopted the Common Rule.

When OHRP revised the Common Rule in 2018, it added a requirement for informed consent that was not specified in FDA’s regulations. Specifically, the revised Common Rule requires consent information to “begin with a concise and focused presentation of the key information that is most likely to assist a prospective subject or legally authorized representative in understanding the reasons why one might or might not want to participate in the research” (45 CFR 46.116(a)(5)(i)). FDA’s newly proposed rule would add the identical language to 21 CFR 50.20(e)(1).

Thus, FDA and OHRP have jointly issued draft guidance titled Key Information and Facilitating Understanding in Informed Consent with their current thinking on how sponsors, investigators, and IRBs should structure and present informed consent documents to provide the key information in a way that is easily understood.1

How To Provide Key Information

Key information should be presented at the beginning of the consent process in a concise manner and can be reiterated throughout the consent form. FDA outlines multiple strategies for providing key information to prospective research subjects that would be consistent with both the revised Common Rule and FDA’s proposed rule and emphasizes flexibility. The agency notes that the key information section may vary depending on the distinctive attributes and design of the study as well as the prospective subject population, the condition being examined, and other relevant factors.1

The communication is the important part – how the key information is to be communicated is not prescribed. The information does not need to be printed on a piece of paper; rather, it can be presented using alternative media such as illustrations, video, or on an electronic tablet as long as it meets the goal of ensuring the prospective subject understands. No matter the delivery mechanism, key information should be linked to corresponding sections of the consent form that contain comprehensive information or cross referenced where appropriate to ensure information is presented in an organized and digestible manner.

The key message is to ensure key information is presented in a simple and concise format that is both easy to read and understand. FDA suggests utilizing a presentation format that groups ideas into “bubbles” or sections of text contained in a circular shape or bullet points to simplify long explanations. Ample space surrounding text is also recommended to separate the relevant sections. The draft guidance allows a certain level of creativity to ensure each key topic here can be communicated and understood prior to enrollment.

While some creativity is allowed between different forms of presentation, FDA strongly advises beginning the chosen form with a key information section. Key information should also be presented first when informing participants in emergency research and for study of expanded access use of an investigational drug.1

Who Can Give Informed Consent?

Informed consent is usually provided by the subject participating in the study. A legally authorized representative (LAR) may also provide informed consent when required. A LAR is “an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in the research.”2

What Should Be Considered Key Information?

At the beginning of the consent process, investigators should provide key information to inform prospective subjects of the trial.

This section of a consent document should be relatively short and to the point (a few pages at most) and should allow the prospective participant to consider whether enrollment in the trial is appropriate. Topics to be considered for inclusion in the key information section are as follows:3

1. Voluntary participation and the right to discontinue participation

This statement should explain participants’ ability to join and leave the study (withdraw their consent) at any time with no penalty or loss of benefits to which the prospective study subject is otherwise entitled.

2. Purpose of the research, expected duration, and procedures to be followed

This statement should convey the purpose of the study and identify not only why the study is being conducted but also why the prospective subject is being asked to participate. This can include specific reference to inclusion criteria or factors such as the prospective subject’s lack of response to previous treatments, gender identity, or socioeconomic status. This statement should also explain the protocol in language plain enough for the prospective subject to understand. This might include:

• the expected duration of the prospective subject’s participation,
• a high-level description of the major procedures involved,
• a brief description of any investigational medical product and its marketing authorization status, and
• identification of any experimental procedures (this may include nonclinical research).

This section should also include information about how placebos will be used and whether or not subjects will be assigned a specific regimen and what intervention options would be available following the study, if any.

3. Key reasonably foreseeable risks and discomforts

This section should include information about the most common and serious risks and discomforts associated with participation in the study. This information is typically the most important to prospective subjects and therefore should be included on the first page of the key information section. If only a select number of risks and discomforts are chosen for inclusion in the key information section (for example those most frequently observed), it should be noted that additional risks and discomforts are listed in another section and the document should include a cross reference or hyperlink to a complete listing of such information. Where appropriate, the key information section may include actions that will be taken to monitor and mitigate risks, such as dose adjustments, etc.

4. Reasonably expected benefit

This section could be a major determinant of whether or not a prospective subject decides to participate in the study and thus should be conveyed in a clear and truthful manner. This section should acknowledge if there is no potential for direct benefit to the prospective subject. This section should also include any benefits anticipated for overall public health, if not for the specific participant. Sponsors, investigators, and IRBs should be careful not to convey potential benefits in an inappropriate or overly optimistic manner.

5. Appropriate alternative procedures

The goal of this section is to ensure the prospective subject understands the alternative non-research-based treatment options available to them. If applicable, key information should also include a description of alternative procedures or courses of treatment that may be appropriate for the prospective subject. For example, this section may include a description of care that could be received through standard treatment rather than within the context of clinical research and explain the differences in treatment.

6. Compensation and medical treatments for research-related injuries

This information should be included for research involving more than minimal risk to ensure prospective subjects understand any compensation available to them if injury occurs as a result of participation. FDA specifically recommends including a statement regarding compensation if there are no plans to compensate prospective subjects for the cost of treatment for research-related injuries.

7. Costs related to subject participation

This section should inform prospective participants on the costs they may incur while participating in the study. This may include coverage of costs related to tests, procedures, products, or interventions during the study. Specifically, this section should detail what will be covered by the study and what costs will be the responsibility of the participant and whether health insurance can be charged. Policies relating to reimbursement of expenses such as parking, air travel, lodging, and other personal expenses should also be explained. Finally, this section should clearly state information relating to incentives for participation.

8. Other key information to provide

Key information should also include any additional information relating to the risks or benefits of the study or background on information being collected from participants and how it will be used. Information describing the potential for continued study should also be included if relevant.

Why Is This Draft Guidance Important?

Informed consent is required for the protection of study participants. Failure to comply with regulations requiring informed consent can impact study compliance. During inspections conducted as part of FDA’s Bioresearch Monitoring Program (BIMO), FDA may review informed consent documents for study participants to ensure an effective process for obtaining informed consent is in place and that each study participant gave appropriate informed consent. In FY2023, 11 warning letters were issued to clinical investigators or sponsors following BIMO inspections. Two of the 11 warning letters included findings of failure to conduct a study in compliance with informed consent requirements.

• A warning letter issued to an IRB included a finding that the IRB failed to ensure that information given to subjects as part of informed consent was in accordance with 21 CFR Part 50.25.4 Specifically, the IRB failed to ensure that the IRB-approved informed consent documents for two clinical trials contained a statement notifying the subject that clinical trial information has been or will be submitted for inclusion in the clinical trial registry databank (as required by 21 CFR 50.25(c)). FDA explained, “Failure to ensure that IRB-approved informed consent documents for applicable clinical trials contain the statement notifying subjects that clinical trial information has been or will be submitted for inclusion in the clinical trial registry databank may result in subjects not being provided appropriate human subject research protections or pertinent information about the clinical investigation.”
• The second warning letter found that an investigator “failed to obtain informed consent that identifies any procedures which are experimental and that describes reasonably foreseeable risks, as required under 50.25(a)(1) and (2). The informed consent form used in your clinical investigation does not identify any procedures which are experimental.” FDA explained, “Failure to obtain informed consent in accordance with 21 CFR Part 50 involving subjects in research jeopardizes the safety and welfare of subjects by denying them an opportunity to fully assess the risks and benefits of their participation in the clinical investigation.”5

Where study participants are enrolled en masse using the same informed consent approach, the risk to the study could be great should that informed consent process be found ineffective. It is the responsibility of the sponsor, investigator, and IRB to protect the health and safety of enrolled participants and ensure they have given appropriate informed consent to participate in research. Following FDA’s new guidance on how to convey key information to study participants is an important step to ensuring informed consent.

References

1. Key Information and Facilitating Understanding in Informed Consent, Guidance for Sponsors, Investigators, and Institutional Review Boards, Draft Guidance, March 1, 2024, available at https://www.fda.gov/media/176663/download
2. FDA guidance on informed consent. 21 CFR 50.3(l).
3. An example of a key information document is included in the appendix of the draft guidance
4. Larkin Community Hospital Institutional Review Board, Warning Letter, Jan. 11, 2023, available at https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/larkin-community-hospital-institutional-review-board-638146-01112023
5. FDA warning letter, March 3, 2023, Maggie Jeffries, MD/Avanti Anesthesiology, LLC, available at https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/maggie-jeffries-md-avanti-anesthesiology-llc-646498-03032023

About The Authors:

Liz Oestreich, J.D., is senior vice president of regulatory compliance at Eliquent Life Sciences (Greenleaf Health). She brings more than ten years of regulatory experience and a diverse background of legal, public policy, and non-profit sector knowledge to her position. As a consultant, Oestreich provides strategic guidance on premarket and postmarket issues to drug, medical device, tobacco, and cannabis companies. She earned her J.D. from the University of the District of Columbia, David A. Clarke School of Law, and her B.A. from the University of Arizona.

Thomas R. Berry, Pharm.D., is senior vice president of regulatory compliance at Eliquent Life Sciences (Greenleaf Health). In this role, he leverages more than 20 years of experience at the U.S. FDA to assist clients on quality and compliance matters, inspection readiness, and pharmacovigilance, among other areas. He is a retired Captain with 23 years in the U.S. Public Health Service (USPHS) and six years as an Army Pharmacy Officer. Berry received a B.S. in pharmacy and a Pharm.D. from Creighton University, and completed an ASHP-certified residency at Fitzsimons Army Medical Center.

Greenleaf Health has joined forces with Eliquent Life Sciences.