Grants and Funding
Inclusion of Children Policy: Case Studies
March 1999

The following Case Studies have been developed to assist investigators in evaluating when children should be included in research studies supported by the NIH.

Examples of Issues in Designing Scientific Studies:

Case A: Should Children and Adult Subjects Both be Included in a Trial to Study a Medical Device?

Case B: Should Children and Adult Subjects Both be Included in a Natural History Study?

Case C: Should Both Children and Adult Subjects be Included in the Same Study of an Antiepileptic Drug?

Case D: Should Children be Included in Clinical Studies Evaluating a New Antibiotic Drug for Resistant Streptococcal Infection?

Case E: What Evidence is Needed to Determine Whether a Pooled or Separate Analysis of Data is Appropriate?

Case F: Should Children and Adult Subjects Both be Included in a Trial to Study a New Anti-Cancer Drug?

Case G: When Should Children be Included in a Study of a Fatal vs. a Non-Fatal Disease?


Case A: Should Children and Adult Subjects Both be Included in a Trial to Study a Medical Device?

A novel device to speed wound healing is being studied. Phase 1 studies in adults have found it to be safe and to have some efficacy. A large scale, placebo-controlled, multicenter study is planned.

Possible Conditions: Possible Consequences:

1. The type of wound that this device treats does not occur in children and adolescents

Exempt from including children

2. Similar wounds occur not only in adults, but also in children

PI should consider including children

3. The device is designed to be operated safely only for individuals weighing more than 120 pounds

PI should consider including children weighing more than 120 pounds

4. PI plans to enroll 100 subjects, but expects only 10 to be children, which may be too few to demonstrate a statistically significant benefit in children.

PI should consider including children:

  • PI must determine if sufficient numbers of children to contribute to a meaningful analysis will be accrued.

  • If there is insufficient information to determine the number of children needed, pilot data or a separate pilot study in children may be appropriate.

5. The PI has no experience with child studies and does not work in a facility that sees children

If inclusion of children is scientifically and ethically justified, PI should find collaborators with expertise regarding research with children.

6. The device requires complicated adjustments that must be performed by the subject of the study, and the PI does not believe these can be performed correctly by children

PI should determine educational level needed for device operation and limit study to those children, adolescents and adults with either sufficient knowledge or sufficient supervision

7. The type of wound is very rare in childhood, and there are no other treatment studies in children. Because it is so uncommon in children, PI is convinced that very few children can be found to enter the trial

a. PI should consider including children.

b. PI should determine if results from children and adults can be combined, if sufficient numbers of children to contribute to a meaningful analysis will be accrued, or if pilot data will be of value.

c. PI may need to involve other sites.

8. The type of wound is very rare in childhood, and there is an organized network of pediatric centers defining the order in which treatments for this condition are being tested

PI may request exemption from inclusion of children. Program staff can help PIs know about such networks.

9. Another investigator is studying the same device in children using an experimental design that will determine the utility of this device in children

a. If PI is aware of another study, PI may request exemption from including children.

b. PIs should discuss with program staff whether there are other funded studies on the topic, in their portfolios, that include children.




Case B: Should Children and Adult Subjects Both be Included in a Natural History Study?

An ophthalmologist wants to study whether the incidence of certain eye diseases increases after a unique sort of eye trauma. No experimental treatment will be offered.

Possible Conditions: Possible Consequences:

1. The type of eye injury to be studied does not occur in children and adolescents

Exempt from including children

2. Both children and adults have the same sorts of traumatic injuries

PI should consider including children

3. None of the procedures planned are more than minimal risk but there is no prospect of direct benefit to participants.

PI should consider including children

4. Some procedures planned are greater than minimal risk, but there is the prospect of direct benefit to participants in this research

PI should consider including children. Even if some procedures planned are greater than minimal risk, if the benefit outweighs the risk, the IRB may determine that children can participate in this research

5. Some procedures planned are greater than minimal risk, and there is no prospect of direct benefit to participants

Exempt from including children. IRB will find that children can not participate in this research

6. The type of eye trauma is very rare in childhood, but there are no other treatment or observational studies in children and adolescents. Because it is so uncommon in children, PI is convinced that very few children can be found to enter the trial

a. PI should consider including children.

b. PI should determine if results from children and adults can be combined, or if sufficient numbers of children to contribute to a meaningful analysis will be accrued.

c. PI may need to involve other sites and investigators.

7. The PI has no experience with child studies and does not work in a facility that sees children

If inclusion of children is scientifically and ethically justified, PI should find collaborators with expertise regarding research with children.

8. Another investigator is studying the same kind of eye trauma in children using an experimental design that will determine the incidence of similar eye diseases in children

a. If PI is aware of another study, PI may request exemption from including children.

b. PIs should discuss with program staff whether there are other funded studies on the topic, in their portfolios, that include children.




Case C: Should Both Children and Adult Subjects be Included in the Same Study of an Antiepileptic Drug?

Clinical studies have demonstrated in adults that a new antiepileptic drug for the treatment of partial seizures should be evaluated in a randomized controlled clinical trial. Such a trial is being planned.

Possible Conditions: Possible Consequences:

1. In general, the type of seizures being targeted by the drug are similar in adults and children.

The PI should consider including children in the study.

2. Experience in treating partial seizures has shown that if a drug is effective in treating partial seizures in adults, it is likely to be effective in children. However, safety and pharmacokinetic data are not available in children.

As the study is being planned, the PI should consider including studies to develop safety and pharmacokinetic data on children.

3. The PI claims to have no population of children to study.

The PI should develop a collaboration with a facility treating children with seizure disorders.

4. The PI has safety and pharmacokinetic data on post-pubertal children, but not on younger children

The PI should consider enrolling post-pubertal children in the current study and developing needed data on younger children.

5. The antiepileptic drug may have rare but serious side effects.

The PI should conduct a risk/benefit analysis to evaluate whether to include children in the study. The analysis should consider the risk due to side effects, the severity of the seizures, and the extent to which current drugs and the new drug can or cannot control the seizures.

6. Another investigator is studying the same drug in children using an experimental design that will determine the utility of the drug in children.

a. If the PI is aware of the other study, he/she may request an exemption from including children.

b. PI should check into the existence of other funded studies on the research topic that include children, and should discuss with program staff whether there are other funded studies on the topic that include children.




Case D: Should Children be Included in Clinical Studies Evaluating a New Antibiotic Drug for Resistant Streptococcal Infection?

A new antibiotic has been developed that shows promise against certain toxic and virulent strains of antibiotic-resistant streptococcus. This new antibiotic is going to be made available for a clinical study to evaluate efficacy in adults with a life-threatening streptococcal infection.

Possible Conditions: Possible Consequences:

1. The type of infection being treated does not occur in children.

The study is exempt from including children.

2. Both adults and children, including newborns, are infected by the organism.

The PI should consider including children of all ages in the study.

3. Use of the antibiotic presents more than minimal risk.

Because the type of infection may well be fatal, especially in newborns, a risk/benefit analysis would be needed as the basis for the inclusion of newborns and older children.

4. Safety data are not available on children under the age of 18.

As part of the study, the PI should establish ways to obtain safety and dosage data in younger children with such infections. Once these data are available, it may be possible to include age-appropriate children in the study.

5. The PI is aware of another study in which the data on children are being obtained.

An exemption might be granted if the other study will provide the needed data on children.

6. The PI has provided substantial evidence that he/she is unable to develop a study that includes children; however the Institute's program staff wants to proceed with the needed study on adults.

The Institute's program staff should consider a program initiative (RFA) to secure the needed data on children.

7. The PI has submitted a research application that does not involve children with little justification.

The scientific reviewers may judge the application unacceptable without further justification. Program staff will have to resolve the issue of compliance before the study can be considered for funding.




Case E: What Evidence is Needed to Determine Whether a Pooled or Separate Analysis of Data is Appropriate?

An experimental treatment approach is being evaluated for adults with a specific medical condition. Should the investigators include children in a combined analysis with adult patients, or should a separate analysis be done for children (either as an individual stratum of the adult study or as an entirely separate study)?

Possible Conditions: Possible Consequences:

1. Available data support the likelihood of a similar treatment effect in adults and children with the specific medical condition*

Enter children onto the adult study and conduct a pooled analysis of data from adult and child participants of the treatment effect (since available data are sufficiently persuasive that the effect of the intervention is similar for adults and children).

2. Available data indicate that children with the specific medical condition are likely to respond to the intervention qualitatively or quantitatively differently than adults

Conduct a separate adequately powered analysis of data from child participants to reliably define the effect of the intervention in children (or conduct a separate pediatric study with adequate power to reliably define the effect of the intervention in children).

3. There are insufficient data to conclude that children with the specific medical condition are likely to respond to the intervention in a similar manner as adults

a. Begin the study by including older children first, performing interim analyses as appropriate to assess their response to and tolerance of the intervention. Based on that assessment, determine whether a combined analysis or separate adequately powered analysis should be done, and the number and ages of children to include.

b. Alternatively, begin by conducting a separate pediatric study with adequate power to reliably define the effect of the intervention in children. Note: data from this separate pediatric analysis (or study) may indicate a similar treatment effect for the intervention in adults and children, so that future studies of the intervention may be able to use combined analyses of data from adult and pediatric study participants.


In determining whether children and adults with a specific medical condition are likely to respond similarly to the intervention, investigators may consider: (1) data concerning the cellular/physiological similarities of the underlying disease process in adults and children; (2) data concerning the physiological response of adults and children to the intervention (e.g., tolerability and toxicities associated with the intervention). For drug studies, pharmacokinetic and pharmacodynamic data may be used to demonstrate similarities in physiological response to the intervention for adults and children.



Case F: Should Children and Adult Subjects Both be Included in a Trial to Study a New Anti-Cancer Drug

An investigator is proposing a phase I (dose-seeking), phase II (activity determining), or phase III (definitive, randomized) clinical trial of a new agent for adults with cancer. Should the investigator include children in the proposed research project?

Possible Conditions: Possible Consequences:

1. Applicable to all phase I, II, and III studies for adults with cancer.

May be exempt from requirement to include children because the number of children is limited and because the majority are already accessed by a nationwide pediatric cancer research network (Exclusion 4b).

The PI is encouraged to discuss his/her agent with investigators having expertise in treating children with cancer, so that development of the agent in children can occur at an appropriate time.

Explanation: The malignant conditions of childhood are often biologically different from those occurring in adults, and the response of children to anti-cancer treatments may be qualitatively and quantitatively different from the response of adults. In recognition of this, the National Cancer Institute (NCI) has established a nationwide clinical research infrastructure that focuses specifically on clinical trials to study new treatments for children with cancer (see J Clin Oncol 16:966-78, 1998). Since more anti-cancer agents can be evaluated in adults than in children (given the larger numbers of adults with cancer), an important function of these NCI-supported pediatric oncology research teams is to prioritize agents for evaluation so that agents with the greatest promise are expeditiously tested in children. Inclusion of children in adult trials would diminish accrual to pediatric studies (due to competition from adult studies), thereby delaying obtaining answers to important questions of therapy for children.

Therefore, investigators evaluating new treatments in adults with cancer need not propose inclusion of children for those cancers that NCI-supported pediatric oncology research teams already prioritize for evaluation. Instead, academic and pharmaceutical sponsors of new cancer treatments are encouraged to work with NCI staff and pediatric oncologists to assure timely and appropriate evaluations of these treatment approaches in children.

In addition to the long-established NCI network for oncology clinical trials in children, some other Institutes have or are establishing comparable networks in other fields. Investigators are encouraged to contact Institute staff to discuss this possibility.



Case G: When Should Children be Included in a Study of a Fatal vs a NonFatal Disease?

An investigator wishes to study a novel agent for the treatment of a progressive neurodegenerative disorder. The agent under study has been associated with fatal bone marrow suppression, which happens in 1 of 100 cases. Should the investigator include children in this study, even if there is substantially less experience (or even no experience) in the use of the medication with children?

Possible Conditions: Possible Consequences:

1. This disorder does not occur in children and adolescents

Exempt from including children

2. This disorder occurs not only in adults, but also in children

PI should consider including children

3. The disorder occurs only in teenagers.

PI should consider including teenagers, but not younger children

4. The PI has no experience with child studies and does not work in a facility that sees children

If inclusion of children is scientifically and ethically justified, PI should find collaborators with expertise regarding research with children.

5. PI plans to enroll 100 subjects, but expects only 10 to be children, too few to demonstrate a statistically significant benefit in children.

PI should consider including children: PI must determine if sufficient numbers of children to contribute to a meaningful analysis will be accrued.

6. This disorder is very rare in childhood, and there are no other treatment studies in children. Because it is so uncommon in children, PI is convinced that very few children can be found to enter the trial

a. PI should consider including children.

b. PI should determine if results from children and adults can be combined, or if sufficient numbers of children to contribute to a meaningful analysis will be accrued.

c. PI may need to involve other sites.

7. The treatment has significant risks, including death. The neurodegenerative disease is invariably fatal over 8 to 10 years.

The PI and IRB must weigh the risks and benefits of participation. If prior evidence suggests the potential benefits outweigh risks, the IRB may allow child participation. In a 100% fatal disease, a treatment with significant risk may be approved for child study.

8. The treatment has significant risks, including death. The illness is debilitating, but not fatal.

The PI and IRB must weigh the risks and benefits of participation. If prior evidence suggests the potential benefits outweigh risks, the IRB may allow child participation. In a nonfatal disease, much more evidence of efficacy may be required before child participation is approved.



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