Pediatric Recruitment: What Works and What Does Not Work

Introduction

Federal regulations (45 CFR 46.402(a) of Subpart D) use the following definition of children:

“Children are persons who have not attained the legal age for consent to treatments or procedures involved in research, under the applicable law of the jurisdiction in which the research will be conducted.”

The legal age for consent is generally considered to be 18 years, although it can vary from state to state.

Children comprise a vulnerable population. They cannot make decisions for themselves. Parents, caregivers, or others must make decisions in the best interests of the child. The dependent status of children requires additional protections.

The Need for Responsible Research on Pediatric Subjects

It is important to conduct responsible pediatric research. Most products are not approved for children because their efficacy and safety have not been studied in children. Hence, these patients can be considered therapeutic “orphans.” As there are limited treatment options for children, physicians may be prescribing medications that have not been adequately tested in children and that could be harmful.

Recruitment of children for pediatric research is challenging. If the risks and benefits are not properly explained, we reduce the willingness of families to participate in research. When there are no direct benefits to the participants, it may be even more difficult to enroll children in medical studies.

“Children are not small adults,” said S.C. Denne and W.W. Hay in an article in JAMA Pediatrics (2013). Data from adult studies cannot be extrapolated to children. Children range from neonates (tiny “preemies”) to adolescents and up to pediatric subjects 18 years of age. Thus, there may be multiple and different age cohorts and heterogeneous populations within a single clinical trial.

The pediatric recruitment rate for clinical trials is low. Less than 31% of British pediatric studies between 1994 and 2002 achieved their original recruitment target number according to an article by A.M. McDonald, et al. in Trials (2006). About 46% of pediatric studies experienced delays in the recruitment timeline according to an article by ER Denhoff, et al. in PLOS ONE (2015).

Both the National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA) have taken action to increase pediatric participation in clinical trials. Researchers must provide a compelling reason why they intend to exclude children if a trial is supported by the NIH and it addresses a disease seen in both adults and children. Not inviting eligible children to participate in studies results in selection bias. This is contrary to the Belmont Report’s principle of justice, which requires equitable selection of research participants.

Conflicting Goals of Treatment and Research

The goals of treatment and research may be fundamentally different. Physicians treating pediatric patients focus on providing the best care possible for the child (beneficence and non-maleficence). The goal of researchers, however, is to ensure that the clinical trial is successful and to make scientific progress. Researchers seek to advance knowledge about what could be the best care for children as well as to serve other interests such as academic merit. Beneficence also involves benefits to others and respect for autonomy. The therapeutic benefits of research from the research perspective are secondary to the overriding goal of obtaining robust data and new knowledge.

Parents often do not understand these differences. Due to therapeutic misconception, the boundary between research and treatment may be unclear. Parents may confuse the goals of research and the goals of treatment. Also, parents may think that the participation of children is unduly risky. Due to the integration of research and clinical care, different ethical principles including those in the Belmont Report must be applied simultaneously. Academic interests must be balanced with adherence to ethical principles.

Subject/patient autonomy must be respected. Participation in research must be voluntary, and prospective subjects must enroll in the study without any pressure or coercion. Participants must be given adequate information including both the risks and the benefits of the study. They can withdraw at any time. Participants can only be enrolled after explicit consent of the parents or legal guardians and after the applicable assent is obtained. A signature on the informed consent form is not adequate consent. The informed consent process must include discussion. People with diminished autonomy, such as children, are entitled to additional protections. The contents and the discussions for assent and consent should be appropriate to the level of understanding of the participants and the use of excessive clinical terminology should be minimized. The consent should have all the regulatory elements as listed in Table 4 below to be legally effective.

Approaches to Improvements in Recruitment

Determining feasibility, identifying the appropriate setting, and selecting appropriate recruitment tools are all approaches to improving recruitment in pediatric research (Table 1). It is important to ensure that the clinical research site has enough patients to meet the inclusion criteria for a study. Investigators may overestimate this availability of subjects. Lasagna’s Law states that, “the incidence of patient availability sharply decreases when a clinical trial begins and returns to its original level as soon as the trial is completed.”

Researchers must know the target population and likely sources of participants. They must clearly define the research process and the questions that are being asked in the research. Research staff should be available onsite to directly enroll participants at any time.

In identifying the appropriate setting for recruiting children, researchers should consider schools, childcare centers, and other common settings for children. Researchers should ensure that the data collection site is safe, convenient, and child-friendly. Researchers must choose from among many possible recruitment tools in order to select the appropriate ones for the participants.

When families are approached about participating in a clinical trial, families may respond that they do not want to participate in research. Parents may not want a computer to decide which treatment their child will receive (randomization). They may not understand the research and they may not want their child to be enrolled. Researchers must educate parents about the true nature of the research.

Parents may have a preference for a certain treatment or therapy. They may believe that a certain treatment is inferior or possibly harmful. Researchers must discuss these issues with them. The language used in research, such as randomization, volunteering, and risk-benefit ratio can be confusing for some parents. Researchers should use language that parents can understand.

Providing consent for pediatric research requires parental permission (from one or both parents depending on the risk level). It also includes assent from the child (the participant) if he or she is old enough. If the parents say yes but the child says no, the child cannot be enrolled in the research. Researchers should engage the child and explain the research in language the child can understand.

The best person to introduce the research and obtain informed consent is often the family doctor. The family is more likely to agree to participate in research if there is an ongoing relationship with the health provider. However, this can create pressure to participate when the family doctor asks a family to participate in research. Hence, it may be better to say, “We are conducting a study,” rather than, “we are doing research.”

It is important to choose the right recruitment strategy and time (Table 2). The right strategy in pediatric research is proactive. Other strategies might not work for research involving children. It is also very important to choose the right time. Parents with sick children are already stressed out. Avoid asking parents about participating in research during the diagnosis visit or in emergency situations, before surgery, when an adverse event occurs, etc. Researchers should try to find the right opportunity, when parents are not overwhelmed, to engage them. They must allow adequate time for the parents to consider allowing their child to participate in a study.

Researchers must also ensure that the consent process is optimal (Table 3). They must provide parents with enough information about the study before asking for their consent, answer all of their questions, and address all of their concerns. They must ensure that families enter the study voluntarily, with adequate information and a proper understanding of the study. Researchers should try to overcome misconceptions about research and, if safety information is available, to share it with the parents.

The parents feel that they have a responsibility to protect their children. They may not understand or be able to distinguish between the goals of treatment and of research. Researchers must help parents understand the difference between treatment and research and be familiar with all aspects of the study. They must minimize the risks and maximize the benefits of the study.

Researchers must try to provide families with the right amount and type of information. Too much information, especially when it involves medical terminology and technical language, may cause information overload and hamper understanding. Researchers should talk to families at their educational level, ask if they have questions, and determine their level of understanding of the information. Table 4 includes the basics and any additional issues concerning the process of obtaining informed consent (45 CFR 46.116).

In pediatric research, along with obtaining informed consent from the parents, researchers might also obtain assent from the child based on age, IRB requirements, and any applicable law. Assent refers to the child’s affirmative agreement to participate in a research study. Researchers should present the study to the child in simple and age-appropriate language. It should be presented in concise and non-threatening language. Researchers should take the time to carefully answer all of the child’s questions, even if the child asks the same questions repeatedly.

For minimal risk studies, waiver of consent may be applicable depending on institutional review board policies. Waiver of consent may facilitate an earlier study start date and thus speed up the process of the study’s execution.

Researchers must be very careful with financial incentives in pediatric research. To a child, $20 might be a great deal of money. Such incentives may create undue pressure to participate in a study. Researchers should introduce financial reimbursement at the beginning discussion of a study. They should clearly explain that the reimbursement is for time and effort involved in participating in the study. They should also state the duration of the study. Families are more likely to participate in a pediatric study if researchers indicate how the study is relevant to them. They will also be more likely to participate if the parents and their child trust the clinical team, the research team, and the clinic or hospital.

There often are additional disparities in recruitment for pediatric studies. Minorities are under-represented, and the refusal rate is higher among African Americans (see references 8, 9, 10, 11, and 12). The informed consent document should be professionally translated into the language of the families who are expected to participate in a study.

Approaches to Maintaining Participation

Approaches to maintaining participation in pediatric studies include making participation simple, being flexible, and minimizing the burden of participating (Table 5). Flexibility might include accommodating the schedules of working parents. Reducing the burden of participating includes minimizing the length of the study, the number of visits, and the paperwork that is involved (e.g., the informed consent document should be simple and easy to understand).

Whether there is the possibility of a direct benefit to the participants is another consideration in maintaining participation in pediatric studies. If there is no known direct benefit, it may be difficult to recruit families. However, researchers should emphasize that although participation in research may not benefit the participants, they should explain that the study may possibly benefit future patients.

Sometimes, especially in cancer studies, a new treatment is only available within a research trial. There can be a sense of missed opportunity, since it may be difficult to understand that a study involves a new and potentially better therapy. Hence, when a study involves randomization, it may be difficult to enroll participants.

Table 6 highlights other approaches to maintaining participation in pediatric studies:

• Shared decision-making
• Showing ongoing concern and interest in the well-being of participants
• Open communication throughout the study (not only at the beginning).

Parents are more likely to continue in a study if they are encouraged to actively participate in the decision-making process. They may have new questions or concerns as the study progresses. Researchers should always address these new questions and concerns.

Demonstrating enthusiasm is important in motivating families to continue participating in studies. Researchers must invest time in developing and continuing relationships with parents and their children. This includes maintaining regular contact with families and communicating concern for the participants’ well-being throughout the study.

Researchers should maintain a flexible attitude. Parents may not agree to let their children participate when first asked about a study. If they indicate they would like to think it over, researchers should follow up with them and attempt to address any concerns. Researchers should develop strategies to attract parents who are considering allowing their child to participate in a study.

Transparency and honesty are always important. Even if the possibility of side effects is remote, researchers should explain them. They should explain any potential problems. Researchers should be friendly and approachable. They should be readily available to address any concerns of participants and their parents.

Researchers must keep their promises relating to a study. For example, if they promise to give $20 for compensation, they should provide it right away. If they promise to provide progress and summary reports, they should do so. Families remember very well what researchers promise to do.

Community engagement is important in most neighborhoods. Community engagement should begin early, even during the grant writing process for a study. Researchers should develop relationships with community leaders and the local representatives of community-based organizations as well as try to obtain their support for pediatric research. Members of the community tend to trust their community leaders and their community-based organizations.

It is also important to obtain input from the key stakeholders who are relevant to study recruitment and implementation. This can include physicians, clinical staff, parents, school staff, sports coaches, sports club officers, and government department/ministry officers.

Parents want to be reassured that their child will be continually monitored during a study. Researchers should explain that children will be closely monitored and that any side effects will be addressed immediately.

Researchers should consider randomization by treatment reversal. Such a design exposes both groups to the experimental treatment, but it does so in reverse order.

Summary

While research involving pediatric subjects may be challenging, the rewards can be significant. The rewards include benefits for future pediatric patients, increased medical knowledge, and benefits to society as a whole. Researchers must maintain the highest respect for pediatric participants and their families. They must protect the rights and welfare of pediatric participants as members of a vulnerable population. Due to their age range, children are a heterogeneous group. Researchers must always put the interests of the participants and their families first in all key matters. Table 7 below provides references for this article.

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TABLE 1

Improving Recruitment: Feasibility, Setting, and Recruitment Tools

• Determine feasibility:
  • Do not overestimate the pool of potential participants
  • Know the target population and likely sources for participants
  • Clearly define the research process and the questions being asked
  • Ensure that research staff are available on-site to directly enroll participants
• Identify the appropriate setting:
  • Consider:
    • Public and private schools
    • Childcare organizations
    • Sports clubs
    • Other community-based organizations
    • Community events
    • Study-tailored websites
    • Medical settings such as emergency departments or clinics
  • Understand the geographic, demographic, and socio-economic profiles of recruitment sites
  • Ensure that a site is safe, convenient, and appropriate for children, parents, and researchers
• Select appropriate recruitment tools:
  • Choose appropriate tools and identify the costs before the study begins  
  • Consider:
    • Posters and flyers in community settings, or neighborhoods
    • Advertisements
    • Direct mailings
    • Telephone screening
    • Social networks are more important in this current age
    • Local weekly newspapers

TABLE 2

The Right Recruitment Strategy and Time

• Choosing the right recruitment strategy:
  • Tailored to the research question
  • Active strategy:
    • Contact the target group of potential participants directly:
      • More successful in intervention studies
    • For an acute treatment study, investigator may present a brief study summary at department meetings, so colleagues can refer potential participants
    • Screen electronic charts for potential participants based on inclusion criteria
  • Passive strategy:
    • Spread information about studies via electronic or print media and social networks:
      • Helpful for self-motivated subjects to contact research teams
• Choosing the right time:
  • When parents are not overwhelmed or stressed
  • Avoid stressful times such as surgeries, adverse events, emergency situations, etc.
  • Do not obtain consent during the diagnosis visit
  • Allow adequate time for consideration

TABLE 3

Optimal Informed Consent

• Provide parents or LARs with enough information about the study before seeking their consent
• Ensure that participants enter the study voluntarily and with adequate information and understanding
• Address parents’ possible misconceptions about a study or about research
• Provide safety data concerning the population being studied, if available
• Recognize that parents’ or LAR’s responsibility is to protect the child:
  • Difficult to distinguish between treatment and research goal
  • Difficult to think of the research setting as detached from the best interests of their child
• Be familiar with all aspects of the research study
• Ensure that parents or LARs understand the study and that risks are minimized
• Provide the right amount and type of information:
  • Clearly explain the study
  • Medical terminology causes information overload
  • Technical language hampers understanding
  • Ask the family if they have questions
  • Determine the level of understanding

TABLE 4

Basic and Additional Elements of Informed Consent (45 CFR 46.116)

Basic elements of informed consent. Except as provided in paragraphs (d), (e), or (f) of this section of the regulations, in seeking informed consent the following information shall be provided to each subject or the legally authorized representative:

(1) A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation. It should also include a description of the procedures that will be followed, and an identification of any procedures that are experimental;

(2) A description of any reasonably foreseeable risks or discomforts to the subject;

(3) A description of any benefits to the subject or to others that may reasonably be expected from the research;

(4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject;

(5) A statement describing the extent to which confidentiality of records identifying the subject will be maintained;

(6) For research involving more than minimal risk, an explanation whether any compensation and an explanation whether any medical treatments are available if injury occurs, Also, what they might consist of, or from where further information may be obtained;

(7) An explanation of who to contact for answers to pertinent questions about the research and research subjects’ rights, These include whom to contact in the event of a research-related injury to the subject;

(8) A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled; and

(9) One of the following statements about any research that involves the collection of identifiable private information or identifiable biospecimens:

(i) A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent from the subject or the legally authorized representative, if this might be a possibility; or

(ii) A statement that the subject’s information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies.

Additional elements of informed consent. Except as provided in paragraphs (d), (e), or (f) of this section of the regulations, one or more of the following elements of information, when appropriate, shall also be provided to each subject or the legally authorized representative:

(1) A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) that are currently unforeseeable;

(2) Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s or the legally authorized representative’s consent;

(3) Any additional costs to the subject that may result from participation in the research;

(4) The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject;

(5) A statement that significant new findings developed during the course of the research that may relate to the subject’s willingness to continue participation will be provided to the subject;

(6) The approximate number of subjects involved in the study;

(7) A statement that the subject’s biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit;

(8) A statement regarding whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions; and (9) For research involving biospecimens, whether the research will (if known) or might include whole genome sequencing (i.e., sequencing of a human germline or somatic specimen with the intent to generate the genome or exome sequence of that specimen).

TABLE 5

Maintaining Participation in Pediatric Studies: Simplicity, Flexibility, and Minimizing Burden

• Make it simple:
  • Make the protocol and the informed consent document as simple and easy to understand as possible
  • Keep the study as short as possible
  • Remuneration/compensation-related issues:
    • Consider reimbursement for transportation, babysitting of siblings, etc.
  • Minimize paperwork required of the subject or responsible parties
• Be flexible:
  • Accommodate family work, or study schedules
  • Be sensitive to their feelings and attitudes or to changes that might occur as the study continues
• Minimize burden of participating:
  • Minimize the number of visits
    • Consider follow-up via telephone rather than face-to-face meetings

TABLE 6

Other Approaches to Maintaining Participation in Pediatric Studies

• Create and maintain an interest:
  • Show enthusiasm and use simple language when explaining the purpose and benefits of the study
  • Invest time in developing and continuing relationships among study partners, parents, and their children
• Maintain contact during the study:
  • Communicate concern for participant well-being
  • Welcome participant questions and concerns, and communicate willingness to address issues 
  • Share interim data analysis if available and if appropriate
• Maintain an active attitude:
  • Follow-up with parents or LARs who are considering allowing their child to participate
  • Develop strategies to attract these families
  • Demonstrate flexibility on all aspects of the study
• Be transparent, honest, and open:
  • Be sure participants and parents or LARs feel that researchers are readily available to address any concerns
  • Demonstrate consistent patience and availability throughout the study
• Keep promises:
  • Give promised incentives or rewards as soon as possible
  • Provide progress and summary reports
  • Address ongoing or new concerns during the study
  • If a study ends sooner than expected, continue providing the study drug if that was promised
  • Handle adverse events as promised

TABLE 7

References

1. Denne SC and Hay WW. “Advocacy for research that benefits children: An obligation of pediatricians and pediatric investigators.” JAMA Pediatrics. 2013. 167(9): 792–94.
2. McDonald AM, et al. “What influences recruitment to randomized controlled trials? A review of trials funded by two UK funding agencies.” Trials. 2006(7):9. 
3. Denhoff ER, Milliren CE, de Ferranti SD, Steltz SK, and Osganian SK. “Factors Associated with Clinical Research Recruitment in a Pediatric Academic Medical Center—A Web-Based Survey.” PLOS ONE 2015: 10(10): e0140768.
4. Lasagna L.Problems in publication of clinical trial methodology. Clin Pharmacol Ther 1979; 25:751-3.
5. Denhoff ER, Milliren CE, de Ferranti SD, Steltz SK, Osganian SK.Factors Associated with Clinical Research Recruitment in a Pediatric Academic Medical Center—A Web-Based Survey: PLoS One. 2015 Oct 16;10(10):e0140768.
6. Weintraub JA. Challenges, benefits and factors to enhance recruitment and inclusion of children in pediatric dental research.  Int J Paediatr Dent. 2015 Sep; 25(5): 310–316.
7. Code of Federal Regulations; 45 CFR 46.Subpart D; 21 CFR 50.54.
8. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA. 2004;291(22):2720-2726
9. Stewart JH, Bertoni AG, Staten JL, et al. Participation in surgical oncology clinical trials: gender-, race/ethnicity-, and age-based disparities. Ann Surg Oncol. 2007;14(12):3328-3334
10. Webb FJ, Khubchandani J, Striley CW, Cottler LB. Black-White Differences in Willingness to Participate and Perceptions About Health Research: Results from the Population-Based HealthStreet Study. J Immigr Minor Health. 2019 Apr;21(2):299-305 PMID:29603088
11. Minorities are underrepresented in clinical trials
12. Minorities in clinical trials