Ethical Challenges with the Informed Consent Process in Pediatric Research Studies

Abstract

Background:

Informed Consent (IC) is crucial in pediatric research, aligning with the National Research Act of 1974 and the Belmont Report's principles. Current regulations, particularly 45 CFR 46, provide additional safeguards for children in research.

Objective:

This article explores ethical challenges in pediatric research IC, drawing from PubMed literature and regulatory guidelines to understand historical context, legislative milestones, and contemporary issues.

Methods:

A literature review, primarily sourced from PubMed, informed the examination of pediatric research and IC, referencing guidelines from the American Academy of Pediatrics and regulations from the FDA and HHS.

Results:

The study underscores the need for increased pediatric research due to the prevalence of drugs studied on adults. Despite legislative efforts like the FDAMA and Pediatric Research Equity Act, ethical challenges persist in obtaining IC in pediatric studies.

Conclusion:

Pediatric research necessitates nuanced IC approaches, involving parents, guardians, and children. Ethical challenges such as coercion and compensation require attention, with recommendations emphasizing guideline adherence and increased public engagement for trust-building and pediatric health advancement.

1. BACKGROUND

Informed Consent is an integral part of conducting research involving human participants. Particularly when pediatric population is involved. Informed consent can be ethically challenging. The National Research Act was enacted in 1974, leading to the establishment of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The goal was to identify the basic principles for protection of human subjects involved in research. The Belmont Report came to life in the Belmont Conference Center at the Smithsonian Institution. The Report identified three basic principles: Respect for persons, Beneficence, and Justice (1). Nowadays, The Belmont Report Principles are embedded within the Code of Federal Regulations titled Protection of Human Subjects 45 CFR 46. Sections within this regulation are designed to protect vulnerable populations. Subpart D of this section is designed for additional protection in research involving children (2).

2. WHY PEDIATRIC RESEARCH?

According to American Academy of Pediatrics, almost 80% of drugs that are prescribed to children are studied on adults and not labeled for children use (3). More research on pediatric pharmacology, and as a whole, pediatric health is needed. Pediatricians believe that this population needs more achievements in biomedicine.

To address this problem, Congress issued the Food and Drug Administration Modernization Act (FDAMA) in 1997, and The Best Pharmaceuticals for Children Act (BPCA) in 2002 to encourage the companies to do more research on pediatrics and provide an additional six months of market exclusivity for conducting research in Pediatrics. Unfortunately, this incentive didn’t produce the response from pharmaceutical companies to bridge the wide gap in pediatric pharmacology as it was intended to do so. So, Congress enacted the Pediatric Research Equity Act in 2003 (4), as to force the inclusion of pediatric assessments data unless a waiver was obtained in all applications for new active ingredients, new indications, new dosage forms, dosage regimen, and new routes for administration. However, regulatory burden and poor pediatric pharmacology infrastructure still limit the progress of pediatric research (5).

3. INFORMED CONSENT IN PEDIATRIC RESEARCH

Informed consent is an important safeguard for the protection of human participants (6). The ICH-GCP define the informed consent as “A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form” (6). The informed consent (IC) is a regulatory requirement by FDA (21 CFR 50), a guideline in ICH-GCP (4.8 Informed Consent of Trial Subjects) and it is an important element of the research process. Obtaining the IC from a potential participant says that he read and understood the nature of the study and he is voluntarily participating in the study, by his own will. All IC forms must include complete and accurate information regarding the nature of the study and the nature of subject participation, the ability to read and understand by potential participant, and contain all the required elements of 21 CFR 50. It should be noted that IC must be approved by IRB and be obtained from participants before entering a study.

The process of IC process in pediatric research is special. The IC should be obtained from parents/guardians, and the assent from the child when required. Assent is a form of consent designed for children. The purpose of assent is to inform the child of a certain age about the study in a language that the child understands, and to get his approval to participate in research. The FDA and HHS have put forth regulations obtaining consent and assent. These regulations can be found in 21 CFR 50§d, and 45 CFR 46§d, respectively.

4. ETHICAL CHALLENGES

IRB Role

Within the Code of Federal Regulations titled Protection of Human Subjects 45 CFR 46, there is a subpart that focuses on research involving children (2). The 45 CFR 46§d provides additional regulation for additional protection of children involved in research.

In this part, the IRB will review all research pertaining to this subpart, in regard to risk level, and only approve research that satisfies those conditions of applicable subpart of this section and determine the state of parents/guardian consent and child assent. These risk levels can be simplified as follows:

* Research that does not entail risks beyond the minimum level.

* Research that entails risks beyond the minimum level but offers the potential for direct benefit to the participating individuals.

* Research that entails risks beyond the minimum level and does not provide direct benefits to the individual subjects, but is likely to generate knowledge applicable to the disorder or condition under investigation.

* Research that is otherwise not permissible but provides an opportunity to comprehend, prevent, or alleviate a significant issue impacting the health or well-being of children.

Minimal risk is defined by the FDA and HHS as the likelihood or degree of harm or discomfort to the research participant is no greater than the risks they typically encounter in their everyday life (7). The IRB will ensure that appropriate measures are taken to obtain the agreement of children, if, in the assessment of the IRB, they are capable of giving their agreement, and how it should be documented. When considering the assent, participants’ falls into the following:

• Infants unable to enter any discussion and parental consent are a must.

• Children who understand some or all aspects of research but are still vulnerable to coercion, parental consent is always required but assent is sometimes required with parental consent.

• Mature children that can give consent and parental consent can be waived.

• On some occasions when a child refuses to assent but there is a net benefit to the child’s participation it appropriate to proceed after parental consent obtained (8).

Parental/Guardian Permission and Child Assent

The challenge in conducting research in children, drug research in particular, is based on adults deciding on the best interests of children. Ethicists maintain that it is inappropriate to physically interact with human beings unless they are able to provide consent for such contact. Ramsey’s argument asserts the prohibition of involving non-consenting subjects, such as children, in research, even when there is no associated risk (9). However, opposing viewpoints suggest that in various situations, if a child is capable, they would likely give consent (10). When considering the regulations, the assent can’t be obtained unless parent/guardian permission is obtained. Before the assent, an explanation of the nature of the study to the child in a level considered appropriate. Huge efforts should be made so the child can understand the nature of the research and express her/his willingness to participate. As per the recommendations of the American Academy of Pediatrics, children who are 7 years old or above should be provided with the chance to decline participation in research, and it is important to honor their decision (3). Over the last decade, the scope of this debate has broadened to encompass the issue of including healthy children in non-therapeutic drug research. This is driven by the objective of gaining knowledge about the pharmacokinetic properties of drugs in healthy children, which is essential for understanding how specific disease conditions can alter these values.

Coercion

Coercion can’t be obvious all the time. Parents may feel pressurized if the pediatrician, taking care of their child, approached them for a study that the child is a potential candidate. They feel if they didn’t enroll their child, the quality of care can be affected or the relationship between the parents and doctor will be affected. Researchers should make it clear when approaching parents/guardians and the child about a study that refusal to consent or withdraw later will not affect the quality of care. They should emphasize this and include it in the consent form. Some suggest that staff not directly in contact with the child should take the initial approach to eliminate this concern (11).

Also, being involved in pediatric research can be consuming for both parents/guardians and the child. This can affect the enrollment or continuing participation. It is agreeable that families should be compensated for their time and effort. However, it is of equal importance that the compensation doesn’t reach the coercion level as to force someone to enroll or stay in the study (11).

5. CONSENT BY ADOLESCENTS

In addition to the standard safeguards implemented to safeguard children participating in research, there are specific legal and ethical factors that pertain specifically to adolescents. In most cases, researchers should respect an adolescent’s decision and safeguard their rights. It is important to provide the adolescent with a comprehensive overview of the study, clarify expectations of participation, and obtain their agreement separately from their parent or guardian, allowing them to freely ask questions or decline involvement.

The American Academy of Pediatrics asserts that a waiver of parental permission should be contemplated only if the risks are minimal, if the research tackles inquiries that can solely be addressed within this age group, and if the treatment for the medical condition can be administered to minors based solely on their own consent (12, 13).

6. THE IMPACT OF IC ON RESEARCH AND PUBLIC HEALTH

With the recent advances of research, crafting IC language at the mandatory 8th grade reading level is getting increasingly difficult (14). When the IC is clear and understandable, potential participants can decide confidently and this will reflect on the researcher and the research community. It will ensure enrollment and maybe retention of participants, which will reflect on the research outcome. Gaining the trust of the public is the first step to progress in research, and researchers should work with the public community to influence the progress of research and general health.

7. RECOMMENDATIONS FOR FUTURE

In moving forward, fostering ethically sound pediatric research requires a collective effort from all stakeholders. The research community must not only be well-versed in existing guidelines and regulations but also actively adhere to them. To bridge the gap between the scientific realm and the public, there is a vital need for increased interaction. This involves engaging with the community to underscore the significance of pediatric research in advancing children's health. Exploring innovative strategies for public involvement, such as forums, educational initiatives, and collaborations with advocacy groups, can further enhance the impact of these efforts. Additionally, addressing potential challenges in implementation and proposing viable solutions will contribute to the effectiveness of these recommendations.

8. CONCLUSION

The trajectory of pediatric health hinges on a foundation of public trust and understanding. As we navigate the complexities of pediatric research, educating the public becomes a cornerstone for progress. By instilling confidence and knowledge within the community, we pave the way for increased participation in research endeavors. This collaborative approach not only upholds ethical standards but also ensures that advancements in pediatric health are shared, appreciated, and embraced by the very individuals they seek to benefit. Through this symbiotic relationship between the research community and the public, we embark on a promising journey toward better pediatric health outcomes..

Author's contribution:

The author was involved in all steps of preparation this article including final proofreading.

Conflicts of interest:

There are no conflicts of interest.

Financial support and sponsorship:

Nil.