Considerations for Informed Consent in Clinical Trials Involving Neurologic Disorders
Informed consent is a cornerstone of ethical clinical research. As stated in the Belmont Report, a foundational research ethics document, true informed consent must have three components: information, comprehension and voluntariness.
Delivering information is the most straightforward part of informed consent. In addition to the informed consent document, research teams, sponsors, CROs and/or study monitors can provide other written documents, verbal explanations and supplementary materials about the clinical trial.
However, in clinical trials involving participants with neurological disorders, the participants’ ability to comprehend the information provided as part of the informed consent process is where ethical challenges can arise. Participants must receive and understand the information, which requires clear communication and opportunities to ask questions. Without genuine comprehension, voluntariness is at risk, as individuals may not be able to make a truly informed choice about participation in a study. Therefore, it is essential to consider the appropriate ethical considerations when developing informed consent documents and related processes to ensure participants grasp the implications of their decision and are free from coercion or undue influence.
What Sponsors Should Consider When Enrolling Participants with Neurologic Disorders
Comprehension is often a challenge in clinical trials involving participants with neurologic disorders that may affect the participant’s comprehension, such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease. The nature of the condition may impair the potential participant’s ability to fully understand and process the information being given. This impacts their ability to make informed decisions, which is often referred to as “decisional impairment” or “loss of decisional capacity.”
When developing neurological disorder clinical trials, industry sponsors and institutional review boards will assess the factors that determine a participant’s capacity to give consent, who can provide consent if the participant is unable and how to address consent and/or assent of participants whose decisional capacity may change or decline over time.
How Is Capacity to Consent Determined?
There are several useful sources which provide detailed information about determining the capacity of a potential participant to give consent for research. Impairment of the ability to consent may be temporary, fluctuating or permanent. The research investigator is responsible for determining whether a participant has the capacity to give informed consent based on their assessment of the participant’s response and comprehension, in consultation with the participant’s caregiver or family as appropriate. When industry sponsors develop research protocols, they may also consider providing guidelines in the protocol to assist investigators on determining a participant’s capacity to consent. The proposed process for assessing capacity should be clearly outlined for the IRB’s consideration, including who will be responsible for the assessment and how it will be documented.
There are instruments and assessment tools which can be administered, and which should be used if that is part of the process for determining the ability to consent for clinical care, but generally the assessment is less formal and relies on the investigator’s expertise to make the determination.
Who Can Give Consent for Participation in a Clinical Trial When the Participant Can’t?
It is important that sponsors and investigators understand the legal parameters for when relying on a Legally Authorized Representative may be appropriate when participants may not have the ability to consent for themselves.
State and local laws have provisions that determine who should act as the Legally Authorized Representative (LAR) for an adult who does not have the capacity to make their own health care decisions. The LAR for research consent will be the same as the LAR for clinical care decisions.
The LAR may be a court-appointed guardian if one is in place, or it may be a person previously identified and documented by the patient as their Health Care Proxy or the Healthcare Power of Attorney. If none of these are in place, there is a hierarchy of relationships defined by local laws, which usually includes a spouse, adult children, parents, adult siblings, grandparents or grandchildren.
Remember that the patient’s primary caregiver may not necessarily be their LAR. Therefore, it may be necessary to ask questions about relationships and legal documentation before assuming that the person who brings the patient to study visits can also legally provide consent for research, even if it feels intrusive. Sometimes, complex relationships (long estranged spouses or children, etc.) can also make the determination of the appropriate LAR unclear, and the site may need to involve legal guidance to help determine the best way to proceed.
Also, keep in mind that the role of LAR does not begin unless and until the patient loses decisional capacity. The LAR makes decisions only when someone can no longer make those decisions for themselves. Even if someone has a progressive condition and it is reasonable to expect that they may eventually lose decisional capacity.
What If the Capacity to Consent Is Lost During the Course of the Study?
While informed consent for research must be obtained before any research procedures are performed, consent is not a one-time activity – it is ongoing throughout the duration of the study. It is not sufficient or appropriate to say that if consent to participate has been provided before the start of the study, that consent remains valid through the duration of the study, no matter what.
In most situations, the participant’s active involvement is taken as an indication of their continued consent (taking the study drug, coming to study visits, etc.). However, in certain circumstances, it is essential to formally make sure there is agreement to continue the study. For example, when new information becomes available about the study or study drug (e.g., a previously unknown safety risk) there is usually a process of “re-consent” to continue participation. Institutional Review Boards will often indicate when re-consent is required. When monitoring visits are conducted by the sponsor/CRO, the study monitor will also look to confirm that active participants have been re-consented.
For neurologic studies, where loss of decisional capacity is likely, it is important for sponsors and investigators to plan for such an event. Sponsors can include specific instructions in the protocol for how to manage such situations.
The general best practice for ensuring that informed consent is valid for the duration of the study and that the participant’s autonomy is respected includes three steps:
- Obtain consent from the participant at the start of the study
- Identify and document who will become the future LAR
- Ensure the LAR is aware of the participant’s study participation
During the study, when the participant loses decisional capacity, a “re-consent” should occur, with the LAR providing consent for study continuation and the participant providing assent to continue. It’s generally acceptable to use the same informed consent document currently being used (i.e., it is not necessary to have a special “continuation consent”). The re-consent discussion should be documented in the study records so it is clear why the LAR’s consent is dated mid-study.
The FDA’s Guidance on Informed Consent also addresses this circumstance in the FAQs, stating:
“In a situation in which a prospective subject is capable of providing informed consent at the onset of a clinical investigation but is expected to become less capable of providing continued consent as the research progresses (e.g., a long-term clinical trial for Alzheimer’s), consideration should be given at the start of the trial to having subjects designate an individual to serve as their LAR once the subjects’ condition warrants it.”
Adult Participant Assent in Clinical Trials
The practice of assent – written or oral agreement to participate in research activities – is usually seen in pediatric clinical trials as children are legally prevented from providing consent for research. In these studies, the parent/guardian(s) give “parental permission” for participation, and assent is obtained from the child, with modifications in each study based on the age (physical age and/or developmental age) and capacity of the child.
This practice is followed because even if the child cannot legally give or refuse consent for research, it is respectful of the child’s autonomy to ensure they understand and agree to the research activities they will be part of to the degree that their cognitive ability allows.
It is less common to hear of assent in non-pediatric studies but the ethical concepts underlying the practice can also apply in neurologic studies where decisional capacity is in question. Even if someone lacks the legal ability to give consent, asking for their assent to the degree that they can provide it treats the participant with respect for their autonomy. Therefore, requiring assent from research participants with decisional impairment is becoming an increasingly common practice and it is required by many IRBs.
There are no regulations that specifically require obtaining assent from adults who lack the capacity to provide consent, but there is support for this practice in the regulatory language and guidance. This approach is supported by the FDA Guidance on Informed Consent, which states:
“While some prospective subjects, such as those with profound cognitive impairment, will not be able to contribute to the consent decisions, others may be able to appoint an LAR, define the limits of their own research participation, or remain actively involved in the decision to enroll and remain enrolled in the research. As such, individuals with impaired consent capacity should be included in the process of consent to the extent possible and consistent with their desires and abilities.”
Advancing Ethical & Inclusive Research
As the volume of clinical trials for neurologic disorders grows, institutional review boards, investigators, sponsors, CROs and ClinOps must be diligent about enforcing informed consent processes that provide sufficient protection for vulnerable participants. For participants to feel confident about participating in clinical trials, it is essential to communicate with the participant and their legally authorized representatives how they will be protected throughout the course of the clinical trial.
Looking ahead, the following factors will shape the advancement of informed consent in this field:
- Proactive Planning for Decisional Capacity Changes: Given that many neurologic disorders are progressive, trial designs should integrate structured plans for transitioning consent responsibilities to LARs. Establishing these contingencies early can prevent ethical and operational challenges later in the study.
- Incorporating Ongoing Consent & Assent Practices: Ethical research requires more than a one-time consent process. Investigators should integrate periodic reassessments of participants’ willingness to continue, ensuring their autonomy is respected throughout the trial. Expanding adult assent practices will further reinforce patient-centered research.
- Strengthening Regulatory Alignment & Best Practices: Collaboration with IRBs, regulatory agencies and patient advocacy groups can help establish standardized approaches for consent in neurologic research. Sharing insights and lessons learned will drive continuous improvement in ethical trial design.
- Fostering Inclusive Research Participation: By strengthening informed consent strategies, IRBs, investigators, sponsors, CROs and ClinOps can reduce barriers to participation, ensuring diverse patient populations – including those with fluctuating decisional capacity – have equitable access to clinical trials.
The future of innovative clinical research involving neurologic disorders depends on maintaining rigorous ethical standards that ensure the protection of those participating in these trials. With IRBs, investigators, and sponsors working to develop informed consent forms and processes that are informative, clear, understandable, allow for questions, and include details on what can be expected in situations when a participants decision-making ability may be impaired or lost, clinical trials will be more inclusive, patient-centered and lead to meaningful advancements in neurologic care.
About the Author:
Linda Reuter is the Sr. IRB Director at BRANY. Her responsibilities include supervising the IRB staff and maintaining compliance with the IRB Standard Operating Procedures as well as applicable regulations. This includes supervising pre and post IRB meeting activities, expedited reviews, continuing reviews, protocol monitoring, continuing education, development of short and long term strategic goals for the organization, maintaining AAHRPP accreditation standards, policy maintenance and development, and training and mentoring of IRB staff.
Ms. Reuter began her career in IRB Administration at North Shore University Hospital Manhasset, currently part of Northwell Health. She held various positions within the Health System’s IRB program over a 20-year period. Linda formed IRB Consulting, LLC in 2012, providing IRB administrative services, training and education, audit services, and general consulting to numerous IRB programs, including BRANY and HRP Consulting Group, as well as several local institutions.
Ms. Reuter graduated with honors from SUNY Stony Brook with a M.S. in Health Sciences. She holds a B.S. in Biology from SUNY Stony Brook, and an advanced certificate in Health Care Management. She published work related to her Master’s thesis on Lyme disease in the Journal of Immunology, is a contributing author for a book on How to Work With and Within IRBs and has been a certified IRB professional since 2001.
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