Research with Respect: Advocacy in Pediatric Clinical Trials

Lauren Bird, RN, BSN, CCRC
Clinical Research Nurse

Mallory Rowell, MS, CCRC
Clinical Research Coordinator

The Research Institute at Nationwide Children’s Hospital

Abstract: Maintaining respect for the autonomy of families enrolled in pediatric clinical trials is a vital aspect in achieving the best outcomes. This article highlights ethical considerations in working with families enrolled in pediatric clinical trials, with a focus on appreciating the difficulty that families face in deciding whether to participate in a clinical trial as well as the importance of advocating for the special needs of family units. The significance of providing valuable resources to families and how this can positively affect recruitment and retention rates is also covered, along with the need to incorporate an ethical mindset into daily practice.

Introduction

It is normal for a parent to have conflicting feelings about enrolling a child in a research study. Clinical research professionals must put themselves in the shoes of parents, and they must ensure that they respect parents’ decisions and make the parents comfortable when they are enrolling their child in a research study.

Ethics impacts everything that is done in pediatric clinical research. It is not an abstract concept. Ethics is ubiquitous in the day-to-day work of clinical research professionals who constantly face challenges that require them to use an ethical mindset.

In practice, ethics is dynamic. Although there are many regulations and laws that require certain behavior in certain situations, there are also an infinite number of situations that are not covered by any regulation or law. Handling these situations requires critical thinking and an ethical mindset.

History of Human Subjects Research and the Era of Bioethics

Historically, there have been many failures to inform, protect, and respect research participants. A great deal of fear and mistrust of clinical research still exists today. Historic failures have ranged from a complete disregard for human life to deception to issues as seemingly innocuous as failing to provide any benefit to the community from which the participants are recruited. Ethical failures vary in the degree of extremity. Clinical research professionals must continually be aware of their obligation to the community, individuals, and society overall.

Within the last 40 years, during what is referred to as the era of bioethics, ethics in medicine has evolved significantly. This has been an important time for humanistic principles to take hold in medicine and research. Although the early idea of introducing values into research may have seemed like a lofty goal, this remains a vital tool for conducting good research today.

Focusing on the vast philosophical opinions that surround bioethics sometimes makes bioethics seem less accessible to those who are not bioethicists. There is sometimes a disconnect between the philosophical and practical aspects of bioethics. For example, how do healthcare providers such as nurses and physicians align their actions to the code of ethics, or philosophy, which includes principles such as beneficence and autonomy? This article focuses on respect as well as some of the challenges clinical research professionals face in their work in upholding this ideal. Situations where being able to act ethically is critical are highlighted.

Special Considerations and Current Issues in Pediatric Clinical Research

Table 1 highlights special considerations in pediatric clinical research at Nationwide Children’s Hospital. Children are considered a vulnerable group and have special protections under the law. The institutional review board (IRB) at Nationwide Children’s Hospital is especially careful in deciding which studies should or should not be undertaken. Most IRBs include a variety of different experts and laypersons to ensure that different interests are represented. Nationwide Children’s Hospital has a pediatric expert on the IRB.

The IRB at Nationwide Children’s Hospital also assigns risk levels from 1 to 4 to pediatric research studies. The risk levels are related to requirements for enrollment, consent, and study conduct.

Another special consideration when enrolling a child into a study is that the entire family is essentially being enrolled. In some instances, only one parent and the child come to the study visits. Many times, however, extra family members come to the study visits. This can place an incredible burden on families when they are deciding whether to enroll in a study. Clinical research professionals must be sensitive to this.

The last special consideration is maintaining the balance between not wanting to put children through pain and discomfort and the obligation to continue conducting research. Children are still considered therapeutic orphans for many drugs, devices, and other therapies, which means that there is no good research to tell physicians how to treat their pediatric patients. As much as clinical research professionals might struggle emotionally with their role in working with children in research, it is their duty to help ensure that adequate research is available to safely treat children.

Prevalent Ethical Dilemmas in Pediatric Clinical Research

There are four areas that have especially prevalent ethical dilemmas:

• Informed consent
• Therapeutic misconception
• Spectrum of health status (healthy control versus chronically ill)
• Social media and technology.

Table 2 highlights each of these areas.

The issues around informed consent have been well documented in the literature. This is an area where continual improvements are likely to be needed. Appropriate informed consent requires a strong understanding of the practicality of ethics. When clinical research professionals at Nationwide Children’s Hospital conduct the informed consent process, they look at things such as who is deciding to participate and whether they understand what is involved in the research study.

In pediatric research, the parent or guardian signs the consent form, which can lead to complications. For example, what happens if the parent wants the child to participate in the study but the child does not want to participate? At Nationwide Children’s Hospital, assent starts at age nine. If a child age 9 or older does not sign the assent form, clinical research professionals do not enroll the child in the study.

The following situation, which occurred at Nationwide Children’s Hospital, illustrates this ethical issue. A parent and child came in to enroll in a device study for an investigational product. The device had been shown to be helpful in providing patients and their families with feedback about the child’s illness. The child is seven years old, which is old enough to generally understand the study but not old enough to provide assent. The mother is very excited about the study and readily signed the informed consent form; however, the child does not want to wear the device for a few days. Based on the regulations, the mother technically has the right to enroll the child into the study. This is the type of situation that clinical research professionals face regularly.

Therapeutic misconception is almost as pervasive in the bioethics literature as informed consent. This occurs when research participants are unable to fully understand the difference between medical care and research. Typically, these families believe that they will be given special treatment or that the child will benefit from participating in a study. It is very important for the family and child to understand the difference between standard medical care and research. The goal of standard medical care is to treat the individual and resolve the illness, whereas the goal of research is to learn something and hopefully provide generalizable information to the broader population.

Clinical research professionals must understand the factors that contribute to therapeutic misconception in order to determine the changes that they can make to daily practice. One factor is the person who explains the research to the patient. If the investigator is also the patient’s physician, the family might confuse the roles of doctor and researcher. The information covered in the discussion is another contributing factor. The discussion should include an explanation of the difference between standard clinical care and research and what the patient and family can expect from the research process. If the enrollment takes place during a clinical visit in the clinic room, this can send mixed signals and contribute to therapeutic misconception.

Nationwide Children’s Hospital enrolls patients who range from healthy controls to the chronically ill. Different approaches are needed to enroll healthy controls and chronically ill participants. Enrolling healthy controls can be challenging, as the research provides no direct benefit to them, and typically, clinical research professionals do not have a long-term relationship with the family. With rare diseases on the other hand, the families typically seek out research and are often desperate to enroll in these studies. They form relationships with study coordinators because they are often enrolled in studies for years.

There may be different ethical issues depending on when and where patients are enrolled. For example, enrolling patients in the Emergency Room (ER) setting can be difficult and challenging. One study at Nationwide Children’s Hospital required obtaining consent from children who were coming into the ER in cardiac arrest. What worked best was having one of the clinical investigators who was an attending physician in the ER go in and consent the family, since the principal investigator had already formed relationships with that family.

Children enrolling in “compassionate use” clinical trials usually have a fatal diagnosis, and the study is the only hope that they have left. The families are often desperate to get the child into such a study. Clinical research professionals must inform them that the study has risks even though the study drug may be the only treatment that can treat the child.

Typically, chronically ill children and their families have tried everything that is available clinically, and they see clinical research as their last hope. It is heartbreaking to see what these families go through, especially when conducting research in rare diseases. Choosing which children with rare diseases to enroll in clinical trials is difficult. At Nationwide Children’s Hospital, clinical research professionals and the clinical investigators review the list of patients and families who would like to participate, and they evaluate which patients will be most compliant with the requirements of the study. Open and honest communication with the parents that their child may not be selected for a study is crucial.

When parents are sharing their stories, such as moving from another country to the city where the children’s hospital is located in the hope of enrolling in the trial, it can be difficult to separate emotion from the role of researcher. Clinical research professionals must treat every family equally, and they must adhere to the protocol in order to obtain the necessary unbiased high-quality data.

Social media and technology can sometimes be a hot topic in research. Parents are networking online through social media, and clinical research professionals must ensure that this does not affect the study data. At Nationwide Children’s Hospital, for example, parents of twelve children participating in a double-blind study had created a private Facebook group and were sharing information such as the side effects that they were seeing in their children, the color of the drug dripping off the IV pole, and physical therapy data. The clinical investigator had to talk to each of the parents and explain about how sharing these data could have a negative outcome on the study.

For high-profile studies at Nationwide Children’s Hospital, the informed consent form includes a paragraph about not discussing details of the study with anyone outside the family, and it mentions Facebook and Twitter. It states that the child could be removed from the study at the clinical investigator’s discretion if the family does this.

Technology is ever changing, and clinical research professionals must learn to adapt. It is important to always be aware of potential problems related to social media and technology, to share ideas for dealing with this within the institution, and to have policies in place to protect the institution.

Respect in Clinical Research and Good Ethical Standards

Respecting children and families in clinical research includes remembering that every patient is unique. Clinical research professionals must adapt to different personalities in order to form better relationships with patients, and they must remember that children are capable of making some decisions. For example, when working with small children, the study coordinator can ask the child to choose a type of Band-Aid or which arm the IV will go in. This makes the child feel important and empowered, shows respect, and embraces the child’s autonomy. It shows the parents that clinical research professionals are respecting their child’s wishes and gives them a sense of having some control over the situation. 

Part of practicing respect in research is ensuring that participants are fully informed. Clinical research professionals must ensure that the family has the information necessary to make the best decision for the child and the family. This includes answering all of their questions, giving the family ample time to review the informed consent form, and informing the family that participation is voluntary and they can withdraw at any time. Participants must be protected from unnecessary harm by following all aspects of the protocol and having strong oversight by the clinical investigator.

Treating participants and their families as collaborators in the research process helps show that clinical research professionals value them and that they are an important part of the process. When clinical research professionals and families work together as a team toward the same goal, families feel more involved and invested in a study.

By ingraining good ethical standards into the way every situation is viewed, ethical standards become part of everyday practice. In order to empathize with patients, clinical research professionals must focus on humanizing, advocating, empowering, and educating pediatric research participants and their families. Clinical research professionals should empower the children and their families to be their own advocates, and clinical research professionals should also ensure that the children and their families understand what participating in the study involves. Clinical research professionals should also learn as much about the study as possible so that they can answer questions and convey confidence. Having an open mind and a questioning attitude is important.

The benefits of treating families with respect include better compliance and retention rates for clinical trials and developing a positive reputation in the community. If families feel valued, they will continue to come back and will be compliant. Clinical research professionals should show that they will go the extra mile for the families. At Nationwide Children’s Hospital, small things, such as using good distraction techniques for painful procedures, help put the parents at ease and establish trust. Doing all of this helps the families develop a long-term relationship with research. Families share good experiences, and the clinical research site develops a positive reputation in the community.

Conclusion

Most clinical research professionals may never face the specific ethical quandaries covered in this article. The key takeaway messages about conducting pediatric clinical research with respect (Table 3) are relevant for all clinical research. Ethics is not just something for the theoretical world to debate. It affects everything that clinical research professionals do, and it is a responsibility that they must embrace.

Along with considering possible ethical situations that could occur, an ethical mindset is necessary in daily practice. Clinical research professionals should also know the resources that are available in the event of an ethical dilemma, such as who to turn to for help when faced with an ethical issue.

The essence of conducting pediatric research with respect is to try to understand the difficulties that the participants and their families face and to serve as an advocate for them. Clinical research professionals must also help give clinical research a good name. They have the power to positively influence relationships with participants and their families and with the community, thereby helping to advance research.

---

TABLE 1

Special Considerations in Pediatric Clinical Research at Nationwide Children’s Hospital

• Vulnerable group:
  • Special protections
• Internal IRB:
  • Must have a pediatric expert
  • Assign a risk level (1-4) to each study
• Consideration of the family unit:
  • How will participation affect the family as a whole?
• Therapeutic orphans:
  • U.S. Food and Drug Administration pediatric rule

TABLE 2

Current Issues in Pediatric Clinical Research

• Consent:
  • Who decides to participate?
    • Parent or child?
  • Does the child understand what he/she is signing?
    • Some institutions begin assent at age 5
  • If the parent consents and child declines, where is the line drawn?
• Therapeutic misconception:
  • Parent or participant believes that the participant will directly benefit from trial participation
  • Lack of understanding of the different goals of therapeutic medicine and research
  • How do clinical research professionals know if a patient/family is experiencing this misconception?
• Spectrum of health status (healthy control vs. chronically ill):
  • Spectrum of health status at consent
  • Different approaches:
    • Healthy control:
      • No long-term relationship and no direct benefit
    • Rare disease:
      • Families seek out research and may be enrolled for years
  • Different ethical issues:
    • Enrolling from the ER (consenting under stress)
    • Compassionate use (fatal diagnosis)
• Social media and technology:
  • Parents networking through social media
  • Use of technology to quickly and easily obtain private study information

TABLE 3

Key Takeaway Messages About Conducting Pediatric Clinical Research with Respect

• Be aware that ethics affects everything clinical research professionals do (big and small):
  • An ethical mindset is necessary in daily practice
• Know the available resources in the event of an ethical dilemma
• Understand what the participant and family is facing:
  • Imagine how difficult decisions about pediatric clinical research can be
  • Consider the possible struggles of the individual or family
• Help give research a good name