Protecting Vulnerable Populations During Research: Guidelines for safeguarding the health and welfare of children
by Yvonne Higgins, AB, CIP, Director, Quality Management
According to federal regulations regarding human research, the principal investigator holds the ultimate responsibility for protecting the safety, rights and welfare of research subjects. Of particular importance is obtaining informed consent according to strict regulatory and ethical requirements.
Complicating the issue, certain “vulnerable” populations or classes of individuals — such as children — may have limited capacity to make voluntary and informed decisions. To this end, both the Food and Drug Administration (FDA) and the Department of Health and Human Services (HHS) have adopted additional safeguards for research involving children.
Regulations define “children” as persons “who have not attained the legal age for treatments or procedures involved in the research under the applicable law of the jurisdiction in which the research is being conducted.” (Thus, the age of consent is determined by state or other local laws.)
Specifically, regulations charge the investigator with responsibilities for:
- Seeking parental permission for the child to participate in the research.
- Securing the child’s assent to participate in the research.
When research involves children, “parental permission” replaces “informed consent.” For clinical trials and other research that poses greater than minimal risk, the Institutional Review Board (IRB) is required to determine whether the parental permission form has to be signed by both parents, or if the signature of one parent is sufficient.
“Assent” is a child’s affirmative agreement to participate in the research. The capacity to make voluntary, informed decisions evolves throughout childhood and adolescence and varies among individuals of the same age. The goal of the assent process is to involve children in discussions and decisions about research participation.
Regulations require the assent of the child for certain kinds of research, but they do not elaborate on the specific elements that are required to prove the assent. In his essay on the ethical dimensions of research involving children (written in 1996 but still applicable today), William Bartholome identified the following elements of assent to guide the assent process.
According to Bartholome the investigator should:
- Help the child “achieve a developmentally appropriate understanding of the nature of her condition.”
- Disclose to the child “the nature of the proposed intervention and what she is likely to experience.”
- Assess the child’s understanding of the information provided.
- Secure “the child’s willingness to accept the proposed intervention.”
The IRB is required on a study-by-study basis to make a determination whether assent will be required. The IRB must consider a number of factors, including the characteristics of target population and the potential for direct benefit. The IRB may waive the requirement for assent in situations where the intervention is important to the health or well being of the subject, or in situations where the child is not capable of assent given his cognitive and emotional maturity and psychological state.
An Ongoing Dialogue
While IRBs and regulatory oversight agencies focus much attention on the documentation of consent, research suggests that gaining informed consent from parents and children is most effective when it occurs as an ongoing/iterative process — as opposed to the one-time act of signing the written document. When possible, parents and children should be given time to think about whether they want to enroll in the study. They should also be afforded the opportunity to speak with others before making a decision. Discussions should allow sufficient time for questions and further explanations. These discussions may take place over several visits — and should happen before presenting a parental permission or assent form.
For younger children, the investigator should focus on providing basic information about what will happen, responding to questions and concerns. For older children and teenagers, the assent process may be similar to the consent process for adults. In some cases, it may be easier for the prospective subject to ask questions of the research team without the parent present.
Regulations require a signed form from parents when the research is greater than minimal risk, as is the case with clinical trials.
In deciding whether documentation of assent will be required for studies involving children, the IRB may consider the intellectual and emotional ability of the children to comprehend the concepts involved. In most cases, IRBs require a signed form with a fully detailed explanation for older children and a shorter, simpler documentation of verbal assent for younger children. (For example, this could involve a signature by a parent assenting that the child agreed to participate and appeared to understand what they were being asked to do.)
When parents are asked for permission for a child to participate in clinical research, it is often a time of great stress and time pressure. A key ethical tension of clinical research is that some research participants — and parents who enroll their child in a study — will think that the research intervention is designed to provide a therapeutic benefit, when in actuality the intention is to gather data for the purpose of contributing to medical knowledge.
A recent publication in the journal IRB, Ethics & Human Research underscores the problem of therapeutic misconception during the consent process. The study assessed the ability of parents of critically ill neonates to recall core information provided to them before agreeing to enroll their children in a Phase II double-blind placebo-controlled trial. The clinical trial was designed to evaluate the effectiveness of azithromicin in the prevention of bronchopulmonary dysplasia in neonates who weighed less than 1,250 grams at birth and required mechanical ventilation during the first 72 hours of life. Twenty-three percent of parents interviewed for the consent process study stated that the primary purpose of the phase II clinical trial was to help their newborn’s lungs. Fewer than 10% of parents surveyed at the time of discharge could recall any of the potential risks from participation in the clinical trial.
This study underscores the importance of an investigator’s need to be sensitive to the influence of therapeutic misconception when talking with parents of ill or injured children who may misunderstand the purpose of the research.
From Minor to Adult
When the clinical investigation includes subjects who will reach the legal age of consent during the course of the study, both legal and ethical issues come into play. In this case, the subject — who is now considered an adult — must be again given the opportunity to provide informed consent before continuing in the clinical investigation. As a result, the IRB may require a statement in the parental permission and assent form to remind the subjects of their right to continue or to withdraw from the study once they become an adult.
Parental permission and a child’s assent remain critically important protections both during initial discussions with potential subjects and throughout the child’s participation in clinical research. As such, it is the responsibility of the investigator to ensure that all regulations and documentation is handled in a compliant and timely manner.
Both the FDA and the NIH provide important information and tools online to inform parents and children who are considering participation in clinical research. These tools are often used by clinical investigators to guide parents through the decision-making process.
NIH Website — Children and Clinical Studies: http://www.nhlbi.nih.gov/childrenandclinicalstudies/index.php
FDA Website — Should your child be in a clinical trial? http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm048699.htm
William Bartholome. “Ethical Issues in Pediatric Research,” in The Ethics of Research Involving Human Subjects. Frederick, MD: University Publishing Group, 1996; pages 360-361
Marilyn J. Field and Richard E. Berman, Editors. The Ethical Conduct of Clinical Research Involving Children. National Academies Press, 2004
David Ungar, Steven Joffee and Eric Kodish, “Children are Not Small Adults,” in The Journal of Pediatrics. July 2006; 149:S31-S3
Hubert Ballard, et al., “Parents Understanding and Recall of Informed Consent Information for Neonatal Research,” in IRB Ethics and Human Research. May – June 2011; 33:3, 12-17