**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 :]{.underline}**

**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:**     |
+---+-----------------------------------+--------------------------------+
| * | The type of wound that this       | Exempt from including children |
| * | device treats does not occur in   |                                |
| 1 | children and adolescents          |                                |
| * |                                   |                                |
| * |                                   |                                |
+---+-----------------------------------+--------------------------------+
| * | Similar wounds occur not only in  | PI should consider including   |
| * | adults, but also in children      | children                       |
| 2 |                                   |                                |
| * |                                   |                                |
| * |                                   |                                |
+---+-----------------------------------+--------------------------------+
| * | The device is designed to be      | PI should consider including   |
| * | operated safely only for          | children weighing more than    |
| 3 | individuals weighing more than    | 120 pounds                     |
| * | 120 pounds                        |                                |
| * |                                   |                                |
+---+-----------------------------------+--------------------------------+
| * | PI plans to enroll 100 subjects,  | PI should consider including   |
| * | but expects only 10 to be         | children:                      |
| 4 | children, which may be too few to |                                |
| * | demonstrate a statistically       | \- PI must determine if        |
| * | significant benefit in children.  | 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.                   |
+---+-----------------------------------+--------------------------------+
| * | The PI has no experience with     | If inclusion of children is    |
| * | child studies and does not work   | scientifically and ethically   |
| 5 | in a facility that sees children  | justified, PI should find      |
| * |                                   | collaborators with expertise   |
| * |                                   | regarding research with        |
|   |                                   | children.                      |
+---+-----------------------------------+--------------------------------+
| * | The device requires complicated   | PI should determine            |
| * | adjustments that must be          | educational level needed for   |
| 6 | performed by the subject of the   | device operation and limit     |
| * | study, and the PI does not        | study to those children,       |
| * | believe these can be performed    | adolescents and adults with    |
|   | correctly by children             | either sufficient knowledge or |
|   |                                   | sufficient supervision         |
+---+-----------------------------------+--------------------------------+
| * | The type of wound is very rare in | **a.** PI should consider      |
| * | childhood, and there are no other | including children.            |
| 7 | treatment studies in children.    |                                |
| * | Because it is so uncommon in      | **b.** PI should determine if  |
| * | children, PI is convinced that    | results from children and      |
|   | very few children can be found to | adults can be combined, if     |
|   | enter the trial                   | 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.                   |
+---+-----------------------------------+--------------------------------+
| * | The type of wound is very rare in | PI may request exemption from  |
| * | childhood, and there is an        | inclusion of children. Program |
| 8 | organized network of pediatric    | staff can help PIs know about  |
| * | centers defining the order in     | such networks.                 |
| * | which treatments for this         |                                |
|   | condition are being tested        |                                |
+---+-----------------------------------+--------------------------------+
| * | Another investigator is studying  | **a.** If PI is aware of       |
| * | the same device in children using | another study, PI may request  |
| 9 | an experimental design that will  | exemption from including       |
| * | determine the utility of this     | children.                      |
| * | device in 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:**       |
+---+---------------------------------+----------------------------------+
| * | The type of eye injury to be    | Exempt from including children   |
| * | studied does not occur in       |                                  |
| 1 | children and adolescents        |                                  |
| * |                                 |                                  |
| * |                                 |                                  |
+---+---------------------------------+----------------------------------+
| * | Both children and adults have   | PI should consider including     |
| * | the same sorts of traumatic     | children                         |
| 2 | injuries                        |                                  |
| * |                                 |                                  |
| * |                                 |                                  |
+---+---------------------------------+----------------------------------+
| * | None of the procedures planned  | PI should consider including     |
| * | are more than minimal risk but  | children                         |
| 3 | there is no prospect of direct  |                                  |
| * | benefit to participants.        |                                  |
| * |                                 |                                  |
+---+---------------------------------+----------------------------------+
| * | Some procedures planned are     | PI should consider including     |
| * | greater than minimal risk, but  | children. Even if some           |
| 4 | there is the prospect of direct | procedures planned are greater   |
| * | benefit to participants in this | than minimal risk, if the        |
| * | research                        | benefit outweighs the risk, the  |
|   |                                 | IRB may determine that children  |
|   |                                 | can participate in this research |
+---+---------------------------------+----------------------------------+
| * | Some procedures planned are     | Exempt from including children.  |
| * | greater than minimal risk, and  | IRB will find that children can  |
| 5 | there is no prospect of direct  | not participate in this research |
| * | benefit to participants         |                                  |
| * |                                 |                                  |
+---+---------------------------------+----------------------------------+
| * | The type of eye trauma is very  | **a.** PI should consider        |
| * | rare in childhood, but there    | including children.              |
| 6 | are no other treatment or       |                                  |
| * | observational studies in        | **b.** PI should determine if    |
| * | children and adolescents.       | results from children and adults |
|   | Because it is so uncommon in    | can be combined, or if           |
|   | children, PI is convinced that  | sufficient numbers of children   |
|   | very few children can be found  | to contribute to a meaningful    |
|   | to enter the trial              | analysis will be accrued.        |
|   |                                 |                                  |
|   |                                 | **c.** PI may need to involve    |
|   |                                 | other sites and investigators.   |
+---+---------------------------------+----------------------------------+
| * | The PI has no experience with   | If inclusion of children is      |
| * | child studies and does not work | scientifically and ethically     |
| 7 | in a facility that sees         | justified, PI should find        |
| * | children                        | collaborators with expertise     |
| * |                                 | regarding research with          |
|   |                                 | children.                        |
+---+---------------------------------+----------------------------------+
| * | Another investigator is         | **a.** If PI is aware of another |
| * | studying the same kind of eye   | study, PI may request exemption  |
| 8 | trauma in children using an     | from including children.         |
| * | experimental design that will   |                                  |
| * | determine the incidence of      | **b.** PIs should discuss with   |
|   | similar eye diseases in         | program staff whether there are  |
|   | children                        | 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     The PI should consider including
  seizures being targeted by the     children in the study.
  drug are similar in adults and     
  children.                          

  ---------------------------------- ------------------------------------

  ---------------------------------- ------------------------------------
  **2**. Experience in treating      As the study is being planned, the
  partial seizures has shown that if PI should consider including studies
  a drug is effective in treating    to develop safety and
  partial seizures in adults, it is  pharmacokinetic data on children.
  likely to be effective in          
  children. However, safety and      
  pharmacokinetic data are not       
  available in children.             

  ---------------------------------- ------------------------------------

  ---------------------------------- ------------------------------------
  **3**. The PI claims to have no    The PI should develop a
  population of children to study.   collaboration with a facility
                                     treating children with seizure
                                     disorders.

  ---------------------------------- ------------------------------------

  ---------------------------------- ------------------------------------
  **4**. The PI has safety and       The PI should consider enrolling
  pharmacokinetic data on            post-pubertal children in the
  post-pubertal children, but not on current study and developing needed
  younger children.                  data on younger children.

  ---------------------------------- ------------------------------------

  ---------------------------------- ------------------------------------
  **5**. The antiepileptic drug may  The PI should conduct a risk/benefit
  have rare but serious side         analysis to evaluate whether to
  effects.                           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  | **a.** If the PI is aware of the   |
| studying the same drug in       | other study, he/she may request an |
| children using an experimental  | exemption from including children. |
| design that will determine the  |                                    |
| utility of the drug in          | **b.** PI should check into the    |
| children.                       | 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 The study is exempt from including
  treated does not occur in          children.
  children.                          
  ---------------------------------- ------------------------------------

  ---------------------------------- ------------------------------------
  **2**. Both adults and children,   The PI should consider including
  including newborns, are infected   children of all ages in the study.
  by the organism.                   

  ---------------------------------- ------------------------------------

  ---------------------------------- ------------------------------------
  **3**. Use of the antibiotic       Because the type of infection may
  presents more than minimal risk.   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         As part of the study, the PI should
  available on children under the    establish ways to obtain safety and
  age of 18.                         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  An exemption might be granted if the
  study in which the data on         other study will provide the needed
  children are being obtained.       data on children.

  ---------------------------------- ------------------------------------

  ---------------------------------- ------------------------------------
  **6**. The PI has provided         The Institute=s program staff should
  substantial evidence that he/she   consider a program initiative (RFA)
  is unable to develop a study that  to secure the needed data on
  includes children; however the     children.
  Institute=s program staff wants to 
  proceed with the needed study on   
  adults.                            

  ---------------------------------- ------------------------------------

  ---------------------------------- ------------------------------------
  **7**. The PI has submitted a      The scientific reviewers may judge
  research application that does not the application unacceptable without
  involve children with little       further justification. Program staff
  justification.                     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]{.underline} 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:**              |
+---+--------------------------+-----------------------------------------+
| * | Available data support   | Enter children onto the adult study and |
| * | the likelihood of a      | conduct a pooled analysis of data from  |
| 1 | similar treatment effect | adult and child participants of the     |
| * | in adults and children   | treatment effect (since available data  |
| * | with the specific        | are sufficiently persuasive that the    |
|   | medical condition\*      | effect of the intervention is similar   |
|   |                          | for adults and children).               |
+---+--------------------------+-----------------------------------------+
| * | Available data indicate  | Conduct a [separate]{.underline}        |
| * | that children with the   | adequately powered analysis of data     |
| 2 | specific medical         | from child participants to reliably     |
| * | condition are likely to  | define the effect of the intervention   |
| * | respond to the           | in children (or conduct a separate      |
|   | intervention             | pediatric study with adequate power to  |
|   | qualitatively or         | reliably define the effect of the       |
|   | quantitatively           | intervention in children).              |
|   | differently than adults  |                                         |
+---+--------------------------+-----------------------------------------+
| * | There are insufficient   | **a.** Begin the study by including     |
| * | data to conclude that    | older children first, performing        |
| 3 | children with the        | interim analyses as appropriate to      |
| * | specific medical         | assess their response to and tolerance  |
| * | condition are likely to  | of the intervention. Based on that      |
|   | respond to the           | assessment, determine whether a         |
|   | intervention in a        | combined analysis or separate           |
|   | similar manner as adults | 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:**            |
+---+----------------------------+---------------------------------------+
| * | Applicable to all phase I, | May be exempt from requirement to     |
| * | II, and III studies for    | include children because the number   |
| 1 | adults with cancer.        | 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:**     |
+---+----------------------------------+--------------------------------+
| * | This disorder does not occur in  | Exempt from including children |
| * | children and adolescents         |                                |
| 1 |                                  |                                |
| * |                                  |                                |
| * |                                  |                                |
+---+----------------------------------+--------------------------------+
| * | This disorder occurs not only in | PI should consider including   |
| * | adults, but also in children     | children                       |
| 2 |                                  |                                |
| * |                                  |                                |
| * |                                  |                                |
+---+----------------------------------+--------------------------------+
| * | The disorder occurs only in      | PI should consider including   |
| * | teenagers.                       | teenagers, but not younger     |
| 3 |                                  | children                       |
| * |                                  |                                |
| * |                                  |                                |
+---+----------------------------------+--------------------------------+
| * | The PI has no experience with    | If inclusion of children is    |
| * | child studies and does not work  | scientifically and ethically   |
| 4 | in a facility that sees children | justified, PI should find      |
| * |                                  | collaborators with expertise   |
| * |                                  | regarding research with        |
|   |                                  | children.                      |
+---+----------------------------------+--------------------------------+
| * | PI plans to enroll 100 subjects, | PI should consider including   |
| * | but expects only 10 to be        | children: PI must determine if |
| 5 | children, too few to demonstrate | sufficient numbers of children |
| * | a statistically significant      | to contribute to a meaningful  |
| * | benefit in children.             | analysis will be accrued.      |
+---+----------------------------------+--------------------------------+
| * | This disorder is very rare in    | **a.** PI should consider      |
| * | childhood, and there are no      | including children.            |
| 6 | other treatment studies in       |                                |
| * | children. Because it is so       | **b.** PI should determine if  |
| * | uncommon in children, PI is      | results from children and      |
|   | convinced that very few children | adults can be combined, or if  |
|   | can be found to enter the trial  | sufficient numbers of children |
|   |                                  | to contribute to a meaningful  |
|   |                                  | analysis will be accrued.      |
|   |                                  |                                |
|   |                                  | **c.** PI may need to involve  |
|   |                                  | other sites.                   |
+---+----------------------------------+--------------------------------+
| * | The treatment has significant    | The PI and IRB must weigh the  |
| * | risks, including death. The      | risks and benefits of          |
| 8 | neurodegenerative disease is     | participation. If prior        |
| * | invariably fatal over 8 to 10    | evidence suggests the          |
| * | years.                           | 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.      |
+---+----------------------------------+--------------------------------+
| * | The treatment has significant    | The PI and IRB must weigh the  |
| * | risks, including death. The      | risks and benefits of          |
| 9 | illness is debilitating, but not | participation. If prior        |
| * | fatal.                           | 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.                      |
+---+----------------------------------+--------------------------------+