SPECIAL ARTICLE

A policy regarding research in healthy children

Samuel S. Gidd ing, MD, Dona ld C a m p , MDiv, Mary Helen F lanagan, MA, Jody A. Kowalski, BS, Laura L. Lingl, RN, BS, Bernard L. Silverman, MD, a n d Craig B. Langman, MD, for Children's Memorial Hospital Institutional Review Board

From the Children's Memorial Institute for Education and Research, Children's Memorial Hos- pital, Chicago, Illinois

Children as a group have required special consideration

with regard to participation in biomedical research. The

Belmont Report I and subsequent federal guidelines for the

protection of human subjects participating in biomedical

research 2 emphasize that children cannot participate fully

in the informed consent process because they may be unable

to evaluate the risks and benefits of participation ade-

quately. In reviewing pediatric research projects, the insti-

tutional review board must take into account developmen-

tal changes from birth to adolescence, assent to participa-

tion, response to pain or stress, and appropriateness of a

proposed intervention in addition to the worth of the

proposed research.

Balancing this need for special protection of children is

the need for well-collected clinical data useful in the treat-

ment of pediatric disease. Data collected in adults may not

be generalizable to children. Because children's diseases are

different from those of adults, because there are major de-

velopmental differences in physiology between adults and

children, and because the usefulness of certain medical

treatments may be limited to children, the exclusion of

children from medical research is inadvisable.

Associated with the dynamic ethical relationship between

the need for special protection and the need for specific

clinical research in children is the occasional need to include

healthy children in research projects. Whereas children

with a specific disease may benefit from participation in re-

search or may contribute directly to the benefit of others,

healthy children may achieve no medical benefit from

participation; the knowledge that others may benefit or

Reprint requests: Samuel S. Gidding, MD, Chairman, Institutional Review Board, Children's Memorial Institute for Education and Research, Research Administration, 2300 Children's Plaza (M/C 106), Chicago, IL 60614.

THE JOURNAL OF PEDIATRICS 1993;123:852-5. Copyright �9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/19/50215

any financial rewards for participation are the only induce-

ments.

Because of the special ethical problems confronting

research in healthy children and the simultaneously per-

ceived need for such research, the Children's Memorial

Hospital Institutional Review Board developed guidelines

for research in healthy children. A subcommittee of the re-

view board (three physicians, including the currenf and

prior chairs, a hospital ombudsman, the hospital chaplain,

the hospital risk management officer, and the review board

secretary) developed an initial draft for full board review.

The policy was heavily influenced by the known research

interests of the faculty. Following are the approved policy

and a discussion of the policy's development.

R E S E A R C H ON H E A L T H Y S U B J E C T S P O L I C Y

Because knowledge obtained from studies in adults may not al- ways be generalizable to the pediatric population, situations may arise when studies of healthy children are necessary. The purpose of this document is to provide guidelines for the development of prospective clinical trials that include healthy children. In general, children are given special consideration with regard to research studies because of their inability to participate in the informed consent process. These guidelines are not meant to replace current procedures of the institutional review board; rather, they are meant to help investigators develop protocols that conform to the review board's current opinions regarding specific ethical issues that arise in research involving healthy children. Areas to be covered in this document include an assessment of allowable risk, relationship of age to allowable risk and assent, requirements for assent of partic- ipants, and allowable reimbursement for participation.

Allowable risk. Risk may be subdivided into three areas: acute adverse effects to the well-being of the child, long-term effects to the well-being of the child, and the need for special medical ther- apy to treat complications of a research procedure. At one extreme, a research study may have neither acute nor long-term effects to the well-being of the child. At the other extreme, participation may lead to early death or to severe late complications that require sig- nificant medical therapy. In this report, risk will be categorized as minimal (with subdivisions), moderate, or high (with subdivisions).

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The Journal of Pediatrics Gidding et al. 8 5 3 Volume 123, Number 6

Tab le . Risk s t ra t i f ica t ion

Minimal risk

Level 0 Level 1 Level 2 Level 3 Moderate

risk

High risk

Level 1 Level 2

Acute effects

Long-term or late effects

Medical intervention to treat side effects

Examples

None

None

None

Office procedures that are part of routine pediatric care

Minimal None to Moderate minimal acute

effects, resolved by end of intervention

None an- Mild, None an- ticipated reversible ticipated

None or None or None or minimal minimal minimal

Moderate

Potential for mild late complica- tions

Moderate intervention may be required

Noninvasive Immuni- Tilt-table Invasive laboratory zation testing diagnostic testing, testing blood draw

Extensive, no Extensive, long- potential lasting for death effects

Potential for Potential for late corn- death plications

Exensive Medical medical intervention evaluation necessary needed to but may treat side not be effects, effective either early or late

Chemother- ECMO apy with potentially toxic agents

ECMO, Extracorporeal membrane oxygenation.

The Table summarizes these definitions of risk. As a general rule, minimal risk applies to procedures that are part of standard med- ical care such as physical examination, anthropometric measure- ment, and elicitation of the medical history. Minimal risk implies that if acute effects are present, they are no worse than moderate, there is no potential for late effects, and no-to-minimal medical in- tervention is required to treat any side effects. A moderate level of risk means that there are either acute, moderate effects or poten- tial late effects that will require some medical intervention. High risk relates to potential significant acute effects, long-lasting effects, the need for extensive medical intervention, and the risk of death.

Age. The age of a child may influence ethical judgments on pro- tocols in three areas: allowable risk, the child's perception of risk, and the child's ability to reason about participation in the protocol. This may include the child's ability to understand personal conse- quences and also the consequences for others, that is, the greater good to which such research participation may contribute. As a general rule, allowable risk can increase as the child's ability to reason and participate in the informed process develops. Children less than 8 years of age cannot meaningfully reason about the ben- efits and consequences of participation. They may also have fears related to minimally invasive procedures such as blood drawing. Conversely, adolescents may have a relatively good understanding of the consequences and benefits of participation.

Therefore the maximal allowable risk for healthy subjects by age

is minimal risk, level 0, for children from birth to age 8 years, min- imal risk levels 1 and 2 for 8- to 12-year-old children, and minimal risk level 3 for adolescents (see the Table for definition of risk lev- els). However, the institutional review board recognizes that cer- tain research projects must be conducted with healthy children at higher levels of risk than outlined above (e.g., immunizations with subsequent antibody titer testing). In preparing protocols, investi- gators should be careful to describe the level of risk to subjects. When the risk levels exceed those described above, the investigator must strongly defend the rationale for allowing a higher level of risk in the proposed research population.

Consent/assent. Informed consent must be obtained from the parents or legal guardian of all healthy children and adolescents proposed either as control subjects or primary subjects in research. The required basic elements of informed consent include the pur- pose of the study, procedures used in the study and duration of treatment, benefits, possible risks, medical treatment necessitated by injury, confidentiality, and subject assurances with regard to rights as a research participant. The complexity of the consent document depends on the risks involved in the study and the com- plexity of the study. Novel methods for informing parents about research that involves no-to-minimal risk, such as those used by the American Academy of Pediatrics for practice-based research, may be considered.

Our institutional review board expects that a research project

8 5 4 Gidding et al. The Journal of Pediatrics December 1993

should be discussed with all children older than 4 years of age in developmentally appropriate language. For children aged 4 to 12 years, the verbal explanation of the purpose of the study, the pro- cedures to be used, and the possible risks is sufficient. Assent must be obtained from those children capable of providing it. For sub- jects aged 13 years and older, a complete explanation of all required basic elements of informed consent is necessary, and adolescents must sign the consent form noting their assent to the procedure.

Inducements to participation. It is common in studies of healthy children to include an inducement to participation. The institu- tional review board supports the use of inducements and of reim- bursement to families for costs incurred during participation in the research study. The guidelines discussed below were designed to prevent excesses in the provision of inducement. Children are not allowed to receive direct monetary awards for participation in re- search studies. However, it is understood that inducements to par- ticipate in research studies should be directed to the benefit of the child as opposed to the benefit of the parent.

Costs incurred by families for participation can be reimbursed according to standard Children's Memorial Hospital reimburse- ment rates for mileage, parking, meals, other transportation, and other potential incurred costs. It is allowable to purchase meal tickets from the children's cafeteria and also to obtain and pay for parking passes from study funds. The limit on reimbursement for costs is twice the amount that can be documented either through receipts or from standard Children's Memorial Hospital reim- bursement rates (e.g., mileage rates). The institutional review board expects investigators to reimburse participants for incurred costs unless research funds are insufficient to allow such reim- bursements and parents are willing to forgo such reimbursement.

To help researchers to avoid excess financial reimbursement of study subjects, the institutional review board has established a compensation scale. The rate of reimbursement should not exceed twice the current federal minimum wage rate calculated in 4-hour (half-day) increments for the duration of participation. For exam- ple, if a child comes into the hospital for the research procedure, leaving home in the morning and returning home by midday, then the maximum allowable inducement is four times the minimum wage per hour times two. Transportation and other allowable costs to families are separate from this calculation.

Occasionally, nonmonetary inducements, such as T-shirts or toys, are given. The total value of these inducements should not ex- ceed the minimum wage standard outlined above. If both monetary and nonmonetary inducements are provided, again, the total inducement should meet the monetary standard listed above. Oc- casionaUy, group or collective prizes are considered. The total value of a group or collective prize should not exceed the reimbursement per subject multiplied by the total number of subjects. Investiga- tors should also consider providing a certificate or other acknowl- edgment of participation to research subjects as a reward.

Medical services may also be used as inducements to participa- tion. For example, additional laboratory tests such as cholesterol measurement could be offered. Completion of physical examination forms is another example. With regard to medical services, it will be important to provide the institutional review board with a plan on how abnormal findings or results will be handled.

Handling of abnormal results obtained on tests of presumably healthy subjects. A potential complication of obtaining normative data is that unanticipated abnormalities will be uncovered. In the submission of an institutional review board proposal that includes healthy subjects, the investigator must outline how potential abnormal values will be handled. What free advice or care will be provided to participants, whether arrangements will be made for referral to an appropriate treatment source, and the procedures to be followed on identification of an abnormal value should all be outlined. In studies in which data are being collected anonymously, the fact that the patient cannot be notified of an abnormal result should be included in the consent document. This situation might also occur if tissue samples are stored and analyzed at a later date. The institutiona ! review board recognizes that, in certain situations, a laboratory value may not be within the normal range but the pre- dictive value or clinical value of the abnormality is unknown. The institutional review board suggests that potential laboratory results be defined and separated into three groups: those which are unequivocally normal, those which are unequivocally pathologic and require some medical intervention, and those which are abnor- mal but carry unknown treatment implications (e.g., an increased left ventricular mass on an echocardiogram of a patient with hy- pertension). A plan for communicating abnormal results to subjects should be included in the proposal.

Conclusion. In preparing a protocol for submission to the insti- tutional review board that includes healthy children as subjects, the investigator should consider the guidelines discussed above. It is the responsibility of the investigator to demonstrate the need for col- lection of data on healthy children, to define the level of risk, and to defend the appropriateness of the age groups selected with re- gard to the need for the study and the level of risk. The informed consent process should be appropriate to the level of risk and should consider the developmental stage of the child.

D I S C U S S I O N

The policy presented in this article was designed to pro-

vide investigators with guidelines for the conduct of re-

search in healthy children. Investigators can prepare their

proposals and incorporate risk, age of participants, need for

assent, provision of inducements, and responsibility to par-

ticipants. Aspects of the study protocol that exceed the pol-

icy's definition of minimal risk, inducements, and ability to

report abnormal results back to participants would need

careful demonstration of benefit to society before the insti-

tutional review board will grant permission for the research.

Ongoing or potential research projects at the medical

center were used as models to develop scientific risk guide-

lines. This policy explicitly states the review board's defini-

tion of minimal risk for investigators. It was strongly

believed that no healthy child should be exposed to the po-

tential of late complications (moderate risk in the Table)

and that no healthy child should be exposed to a risk of in-

jury or death (high risk in the Table). It was thought that

the document should be consistent with guidelines estab-

The Journal of Pediatrics Gidding et al. 8 5 5 Volume 123, Number 6

lished by the American Academy of Pediatrics Institutional Review Board for Practice-Based Research (minutes of board meeting, July 22, 1991).

Gradations of minimal risk were established to allow for increased participation of older children and adolescents in research as they become better able to perceive risks and benefits), 4 For example, a study that involved drawing

blood from children less than 8 years of age (as opposed to taking additional blood when blood drawing is indicated for other reasons) was not considered appropriate because of the fear of painful procedures at this young age. 3 At the other end of the spectrum, it was thought that a procedure that was moderately unpleasant but had no late complica- tions, such as tilt-table testing, was allowable in adolescents for several reasons. Such studies are being done in children with syncope, and medication is being prescribed without knowledge of the normal response to tilt-table testing. 5 It was believed that an informed consent document that explains the acute risks of the procedure could be developed in age-appropriate language. The gradations of minimal risk are attempts to find levels of risk that are both accept- able ethically and explainable in the consent process at age-appropriate levels.

Implicit in these guidelines is the definition of studies that exceed the standard of minimal risk and therefore require special consideration for approval. 6 Federal guidelines require that exposure to increased risk must be justified by the "opportunity to understand, prevent, or alleviate serious problems affecting the health or welfare of children. ''2 Fed- erally funded or regulated studies with increased risk must be approved by the U.S. Department of Health and Human Services. An example of a study that would exceed minimal risk guidelines but could be justified is a trial of a new vac- cine for healthy infants. Although the immunization is painful, blood must be drawn to measure antibody titers, and there is a small but real potential risk of late effects of the immunizing agent, the infant may benefit if the immu- nization is successful. There may be demonstrable societal benefit to vaccine development. The ethics of immunization studies have been reviewed recently. 7 It is the responsibility of individual IRBs to weigh the risk and benefits of these types of studies before granting approval. Since societal benefit is claimed for vaccines, the institutional review board must also consider unintended societal harm]

Designing a formula for appropriate compensation re- quired much deliberation. We thought that children should benefit from compensation. Inadequate compensation might not be fair to participants; excessive compensation could provide too great an inducement. Setting an upper limit of twice the minimum wage for the duration of participation was considered a reasonable compromise because it was

thought that the participant was "working" with the inves- tigator on the research. Costs incurred by participants, such as the costs of meals and transportation, should be consid- ered separately from inducements. Controversy arose over the use of medical services, such as free physical examina- tions or laboratory tests, as inducements. The advantage of such inducements is that the cost to the investigator may be low and the value to the participant high. However, poten- tial risk relates to the responsibility of the physician to manage unexpected abnormalities and to accept liability for mistakes in interpretation of findings. The institutional re- view board elected to allow this type of inducement if the investigator was interested and provided a detailed descrip- tion of how abnormal findings would be managed.

Central to this policy is the ability of the investigator to author, and the institutional review board to evaluate, an informed consent document consistent with current federal and institutional guidelines. It is the institutional review board's responsibility to determine that potential research subjects are not exposed to unusual risk. 8 Further, it is the

institutional review board's responsibility to ensure that the consent document contains, in lay language, information necessary for a family to make an informed decision with regard to participation in research. The consent process may not be perfect, but we believe that policies such as the one presented in this report can be used to balance creatively the need to protect children as a special population and the need to develop appropriate scientific data for the rational prac- tice of pediatric medicine. 4

R E F E R E N C E S

1. National Commission for the Protection of Human Subjects. The Belmont Report. Federal Register 1979(April 18);44: 23192.

2. U.S. Department of Health and Human Services. Protection of human subjects [45 Code of Federal Regulations 46]. Fed- eral Register 1983(March 8);48:9814-20.

3. Jay SM, Ozolins M, Elliot CH, Caldwell S. Assessment of children's distress during painful medical procedures. Health Psychol 1983;2:133-47.

4. Susman E J, Dorn LD, Fletcher JC. Participation in biomed- ical research: the consent process as viewed by children, ado- lescents, young adults, and physicians. J PEDIATR 1992;121: 547-52.

5. Fish FA, Strasburger JF, Benson DW. Reproducibility of a symptomatic response to upright tilt in young patients with unexplained syncope. Am J Cardiol 1992;70:605-9.

6. Levine RJ. Ethics and regulation of clinical research. Balti- more: Urban & Schwarzenberg, 1986:64-5.

7. Bjune G, Gedde-Dahl T. Some problems related to risk ben- efit assessments in clinical testing of new vaccines. IRB: A Re- view of Human Subjects 1983(Jan/Feb):15:l-5.

8. Kodish E, Lantos J, Stocking C, Singer PA, Siegler M, Johnson FL. Bone marrow transplantation for sickle cell dis- ease. N Engl J Med 1991;325:1349-53.