9. Subject Considerations

9.1 Clinical trial subject recruitment: Are digital advertisements (including social media streams such as TikTok) allowed and, if so, what regulations govern them? 

Yes, advertisements on social media are permitted.

The U.S. National Institutes for Health (NIH) has developed guidance on “Social Media Tools” (dated February 2016) on the use of social media tools in clinical trial recruitment. The guidance reinforces the need for adequate privacy protection to protect participants and recommends that the information be provided in a controlled, PDF, or other locked format for distribution. IRB approval is needed.

The NIH guidance does not replace other guidance in relation to 21CFR56 and 45CFR46 from the FDA (see: the FDA’s “Information Sheet: Recruiting Study Subjects. Guidance for Institutional Review Boards and Clinical Investigators” (January 1998); and the Office for Human Research Protections guidance entitled “Clinical Trial Websites: When is IRB Review Required and What Should IRBs Consider with Reviewing?” (September 2005) (although note that the latter is directed at the U.S. Department of Health and Human Services (HHS) supported and conducted research, not commercial research).

9.2 Vulnerable Subjects

Vulnerable populations participating in clinical trials must be provided additional protections to safeguard their health and welfare during the informed consent process. IRBs must pay special attention to protecting such participants (see 45 CFR 46 - Protection of Human Subjects, also known as “The Common Rule”).

The U.S. Department of Health and Human Services - Office for Human Research Protections - issued some “Recommendations regarding research involving individuals with impaired decision-making” requesting new guidance on this subject to be created.

The FDA’s final guidance on “Informed Consent”, released in August 2023, includes additional recommendations throughout for clinical trials with vulnerable populations, as:

• FDA may request for the sponsor to submit the consent form for review under an IND if the study subject population is particularly vulnerable.
• IRBs must ensure that the consent process minimizes the possibility of coercion and undue influence. When a clinical investigation involves subjects who are likely to be vulnerable to coercion or undue influence, IRBs must determine that additional safeguards have been included in the clinical investigation to protect their rights and welfare (21 CFR 56.111(b)). In the event an IRB regularly reviews clinical investigations involving vulnerable subject populations, for such clinical investigations, the IRB membership should include individuals with knowledge about and/or experience working with such subjects, in order to provide expertise and identify techniques for obtaining their informed consent.
• FDA regulations authorize the IRB to observe or have a third party observe the consent process, as well as the research (21 CFR 56.109(f)). IRBs should consider using this authority when it may be appropriate or enhance the protection provided to subjects (for example, when the investigator is also the treating physician for a prospective subject, when the person conducting the consent interview is relatively inexperienced, or when the clinical investigation involves vulnerable subjects). In addition to observing a sample of consent discussions, the IRB could interview subjects to assess the consent process and evaluate the subjects’ understanding of the clinical investigation.

9.3 Pediatrics (including whether consent from a single parent is sufficient vs. requiring both parents to sign)

Where the IRB determines that permission is to be obtained from parents, both parents must give their permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child (consent from a single parent is sufficient in certain circumstances, as discussed below).

Children are covered by 21CFR50 Part D, the relevant parts of which provide that IRB may approve clinical trials involving children for:

"Clinical investigations not involving greater than minimal risk: 

Any clinical investigation within the scope described…. in which no greater than minimal risk to children is presented may involve children as subjects only if the IRB finds that: 

1. No greater than minimal risk to children is presented; and 
2. Adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.

Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects: 

Any clinical investigation…. in which more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject's well-being, may involve children as subjects only if the IRB finds that: 

1. The risk is justified by the anticipated benefit to the subjects; 
2. The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and 
3. Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians….

Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition:

Any clinical investigation…. in which more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is not likely to contribute to the well-being of the subject, may involve children as subjects only if the IRB finds that: 

1. The risk represents a minor increase over minimal risk; 
2. The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; 
3. The intervention or procedure is likely to yield generalizable knowledge about the subject's disorder or condition that is of vital importance for the understanding or amelioration of the subject's disorder or condition; and 
4. Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians.

The IRB has considerable discretion as to how consent should be provided. 21CFR50 Part D indicates the following:

1. [T]he IRB must determine that adequate provisions are made for soliciting the assent of the children when, in the judgment of the IRB, the children are capable of providing assent. 
2. In determining whether children are capable of providing assent, the IRB must take into account the age, maturity, and psychological state of the children involved. This judgment may be made for all children to be involved in clinical investigations under a particular protocol, or for each child, as the IRB deems appropriate. 
3. The assent of the children is not a necessary condition for proceeding with the clinical investigation if the IRB determines:
   1. That the capability of some or all of the children is so limited that they cannot reasonably be consulted, or
   2. That the intervention or procedure involved in the clinical investigation holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the clinical investigation.
4. Even where the IRB determines that the subjects are capable of assenting, the IRB may still waive the assent requirement if it finds and documents that: 
   1. The clinical investigation involves no more than minimal risk to the subjects; 
   2. The waiver will not adversely affect the rights and welfare of the subjects; 
   3. The clinical investigation could not practicably be carried out without the waiver; and 
   4. Whenever appropriate, the subjects will be provided with additional pertinent information after participation. 
   5. In addition to the determinations required under other applicable sections of this subpart D, the IRB must determine, in accordance with and to the extent that consent is required… that the permission of each child's parents or guardian is granted. 
      1. Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient for clinical investigations to be conducted.
      2. Where clinical investigations are covered by [this Part D] and permission is to be obtained from parents, both parents must give their permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child. 
   6. Permission by parents or guardians must be documented in accordance with and to the extent required.
   7. When the IRB determines that assent is required, it must also determine whether and how assent must be documented." 

In Sept 2022, the FDA released a DRAFT guidance titled “Ethical Considerations for Clinical Investigations of Medical Products Involving Children”. Section G - Parental/Guardian Permission and Child Assent - indicates the following:

“A clinical investigator must obtain permission from the parent(s) or guardian(s) when a child is enrolled in a clinical investigation (21 CFR 50.55(e)). The parental/guardian permission form must address the required elements of consent, as well as appropriate additional elements (see 21CFR 50.25) to allow the parent(s) or guardian to make an informed decision. Informed consent is a process. Parents, guardians, and assenting children should be given the opportunity to ask questions when considering study participation and continue to be provided information as the study progresses and as the situation requires.

Assent means a child has provided affirmative agreement to participate in a clinical investigation; mere failure to object should not be construed as assent (21 CFR 50.3(n)). Unless the IRB waives the requirement, adequate provisions must be made for soliciting assent from the children if the IRB determines that the children are capable of providing assent (21 CFR 50.55 (a)). Children 7 years of age and older are often considerably capable of assent; however, the age, maturity, and psychological state (mental capacity and developmental stage) of the child involved in the research must be considered (21 CFR 50.55 (b)).

Assent of the children is not a necessary condition for a clinical investigation to proceed if the IRB finds either 1) that the children’s capability is so limited they cannot reasonably be consulted or 2) that the intervention or procedure involved in the clinical investigation holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the clinical investigation (21 CFR 50.55(c)). Even if the IRB determines that the children are capable of assenting, assent may be waived under 21 CFR 50.55(d) if the IRB finds and documents that all the following criteria are met:

• The clinical investigation involves no more than minimal risk to the subjects; 
• The waiver will not adversely affect the rights and welfare of the subjects; 
• The clinical investigation could not practicably be carried out without the waiver; and 
• Whenever appropriate, the subjects will be provided with additional pertinent information after participation. 

Ultimately, the IRB determines whether assent is required and how assent is obtained.”

It is important to highlight, that the “age of majority” varies from state to state across the United States. For most states, the majority is 18 years old, except for Alabama (19 years old), Mississippi (21 years old), and Nebraska (19 years old).

9.4 Financial Disclosures

Financial disclosures by clinical investigators are covered by 21CFR54. As further detailed in that part, an applicant for a marketing authorization must make the appropriate certification or disclosure statement where the applicant either contracted with one or more clinical investigators to conduct the studies or submitted studies conducted by others, not under contract to the applicant. This is because one potential source of bias in clinical studies is the financial interest of the clinical investigator in the outcome of the study because of the way payment is arranged (e.g., a royalty) or because the investigator has a proprietary interest in the product (e.g., a patent) or because the investigator has an equity interest in the sponsor of the covered study.

The applicant shall submit a completed Form FDA 3454 or 3455 disclosing completely and accurately the following:

1. Any financial arrangement entered into between the sponsor of the covered study and the clinical investigator involved in the conduct of a covered clinical trial, whereby the value of the compensation to the clinical investigator for conducting the study could be influenced by the outcome of the study; 
2. Any significant payments of other sorts from the sponsor of the covered study, such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria; 
3. Any proprietary interest in the tested product held by any clinical investigator involved in a study; 
4. Any significant equity interest in the sponsor of the covered study held by any clinical investigator involved in any clinical study; and 
5. Any steps taken to minimize the potential for bias resulting from any of the disclosed arrangements, interests, or payments.

9.5 ICF translations – Are Certificates Required?

Normally, Certificate of Translations (CoTs) are not required to be submitted. However, relevant CoTs should be filed within the Trial Master File.

9.6 Subject Compensation: Is there a need for a local sponsor to be listed on the insurance certificate, the insurance certificate to cover the duration of the study, and specific minimum amounts of coverage to be specified, both for individual events occurring and in aggregate?

The U.S. regulations do not require insurance.

U.S. regulations do not require compensation for trial participants either for participation in a trial or in the event of trial-related injuries or death.