Ethical Considerations for  
Clinical Investigations of 
Medical Products 
Involving Children 
Guidance for Industry, Sponsors, and 
IRBs 
 
DRAFT GUIDANCE 
 
 
This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 90 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance. Submit electronic comments to https://www.regulations.gov. Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (OPT) Donna Snyder at 301-796-1397. 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Pediatric Therapeutics (OPT) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 
 
September 2022 
Clinical/Medical   
 
   
Ethical Considerations for  
Clinical Investigations of Medical 
Products Involving Children 
Guidance for Industry, Sponsors, and IRBs 
 
Additional copies are available from: 
Office of Pediatric Therapeutics 
Office of Clinical Policy and Programs, Office of the Commissioner, FDA 
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
(Tel) 301-796-1397 
 and/or: 
Office of Communications, Division of Drug Information, CDER, FDA 
10001 New Hampshire Ave., 
Silver Spring, MD 20993-0002 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
and/or: 
Office of Communication, Outreach, and Development, CBER, FDA  
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-
biologics/biologics-guidances 
and/or: 
Office of Policy, Guidance and Policy Development, CDRH, FDA 
10903 New Hampshire Ave., Bldg. 66, Room 5431 
Silver Spring, MD 20993-0002 
Email: CDRH-Guidance@fda.hhs.gov 
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-
assistance/guidance-documents-medical-devices-and-radiation-emitting-products 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Pediatric Therapeutics (OPT)  
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 
September 2022 
Clinical/Medical   
  Contains Nonbinding Recommendations 
  Draft  Not for Implementation    
Table of Contents 
 
I.  INTRODUCTION ................................................................................................................. 1 
II.  BACKGROUND .................................................................................................................... 2 
III. ETHICAL FRAMEWORK .................................................................................................. 2 
A.  Principle of Scientific Necessity ........................................................................................ 3 
B.  Risk Categories for Interventions or Procedures without Prospect of Direct Benefit 4 
C.  Prospect of Direct Benefit ................................................................................................. 5 
D.  Assessment of Risk for Interventions or Procedures with a Prospect of Direct Benefit
  ............................................................................................................6 
E.  Component Analysis .......................................................................................................... 7 
F.  Potential for Review per 21 CFR 50.54 ............................................................................ 8 
G.  Parental/Guardian Permission and Child Assent ........................................................... 9 
IV. APPLICATION OF SUBPART D TO PEDIATRIC CLINICAL INVESTIGATIONS
  ............................................................................................................10 
A.  Data to Support Conducting Pediatric Clinical Investigations ................................... 10 
B.  Design Considerations for Clinical Investigations ........................................................ 11 
1.  Clinical Investigations of Drugs .................................................................................... 11 
2.  Clinical Investigations of Medical Devices .................................................................... 12 
C.  Study Procedures in Pediatric Clinical Investigations ................................................. 13 
1.  Procedural Sedation in Pediatric Clinical Investigations ............................................. 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Contains Nonbinding Recommendations 
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Ethical Considerations for Clinical Investigations of Medical 
Products Involving Children 
Guidance for Industry, Sponsors, and IRBs 
1   
2   
3  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
4  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
5  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
6  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
7  for this guidance as listed on the title page. 
8   
 
 
9  I.  INTRODUCTION 
10   
11  Clinical investigations1 in children are essential for obtaining data on the safety and effectiveness 
12  of drugs, biological products,2 and medical devices (collectively referred to as medical 
13  products herein) in children and to protect children from the risks associated with exposure to 
14  medical products that may be unsafe or ineffective.  Children3 are a vulnerable population who 
15  cannot consent for themselves and who therefore are afforded additional safeguards when 
16  participating in a clinical investigation.  Such safeguards are an essential requirement for the 
17  initiation and conduct of pediatric investigations as part of a medical product development 
18  program.  This guidance describes the FDAs current thinking regarding ethical considerations 
19  for clinical investigations of medical products in children.4  Clinical investigations involving 
20  FDA-regulated products that are not medical products may have similar ethical considerations to 
21  those discussed in this guidance but are outside the scope of this guidance.  
22   
23  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
24  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
25  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
26  the word should in Agency guidances means that something is suggested or recommended, but 
27  not required.    
 
1 FDAs regulations at 21 CFR 50.3(c) define the term clinical investigation as any experiment that involves a test 
article and one or more human subjects and that either is subject to requirements for prior submission to the Food 
and Drug Administration under section 505(i) or 520(g) of the Act, or is not subject to requirements for prior 
submission to the Food and Drug Administration under these sections of the Act, but the results of which are 
intended to be submitted later to, or held for inspection by, the Food and Drug Administration as part of an 
application for a research or marketing permit. See also 21 CFR 56.102(c).  In this guidance, the terms trial, 
clinical trial, and study have the same meaning as the term clinical investigation. 
2 For purposes of this guidance, references to drugs include drug products approved under section 505 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 355) and biological products licensed under section 351 of the Public 
Health Service Act (42 U.S.C. 262). 
3 FDAs regulations at 21 CFR 50.3(o) define children as persons who have not attained the legal age for consent to 
treatments or procedures involved in clinical investigations, under the applicable law of the jurisdiction in which the 
clinical investigation will be conducted.  For the purposes of this guidance, children include neonates, infants, 
children, and adolescents who have not reached the legal age of consent in their local jurisdiction. 
4 See section II for information regarding the regulatory requirements.   
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28  II.  BACKGROUND  
29   
30  The ethical principles for the protection of human subjects in FDA-regulated clinical 
31  investigations are reflected in the requirements in 21 CFR parts 50 and 56; additional safeguards 
32  for children are included in 21 CFR part 50, subpart D (Additional Safeguards for Children in 
33  Clinical Investigations).  Institutional review boards (IRBs) are required to follow these 
34  regulations when reviewing clinical investigations of FDA-regulated medical products that are 
35  intended to enroll children.  21 CFR part 50, subpart D parallels the Department of Health and 
36  Human Services regulations found in 45 CFR part 46, subpart D, Additional Protections for 
37  Children Involved as Subjects in Research. 
38   
39  All FDA-regulated clinical investigations of medical products are subject to the requirements in 
40  parts 50 and 56 regardless of whether they require an investigational device exemption (IDE) or 
41  an investigational new drug application (IND).5  For studies requiring an IDE or an IND, 
42  sponsors are encouraged to discuss their investigational plan, including plans for pediatric drug 
43  development, with the relevant review division prior to submitting a protocol to the IDE or 
44  IND.6  
45   
46   
47  III.  ETHICAL FRAMEWORK  
48   
49  In accordance with 21 CFR 50.50, IRBs must review clinical investigations involving children as 
50  subjects and approve only those clinical investigations that satisfy the criteria described in 21 
51  CFR 50.51, 50.52, or 50.53 and the conditions of all other applicable sections of subpart D. 
52   
53    21 CFR 50.51 (clinical investigations not involving greater than minimal risk) requires 
54  that the IRB find that no greater than minimal risk to children is presented (see section 
55  III.B) and adequate provisions are made for soliciting the assent of the children and the 
56  permission of their parents or guardians (see section III.G). 
57   
58    21 CFR 50.52 (clinical investigations involving greater than minimal risk but presenting 
59  the prospect of direct benefit to individual subjects) requires that the IRB find that the 
60  risk is justified by the anticipated benefit to subjects (see section III.C), the relation of the 
61  anticipated benefit to the risk is at least as favorable to the subjects as that presented by 
62  available alternative approaches (see section III.C), and adequate provisions are made for 
63  soliciting the assent of the children and the permission of their parents or guardians (see 
64  section III.G).  
65   
 
5 21 CFR 50.1 and 56.101. 
6 For additional information regarding clinical investigations of drugs involving children, see the ICH guidance for 
industry E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population (April 2018). 
See also the FDA guidance for industry Pediatric Study Plans: Content of and Process for Submitting Initial 
Pediatric Study Plans and Amended Initial Pediatric Study Plans (July 2020).  We update guidances periodically. 
For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. 
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66    21 CFR 50.53 (clinical investigations involving greater than minimal risk and no 
67  prospect of direct benefit to individual subjects, but likely to yield generalizable 
68  knowledge about the subjects disorder or condition7) requires that the IRB finds that: 
69   
70    The risk represents a minor increase over minimal risk (see section III.B);  
o
71   
72    The intervention or procedure presents experiences to subjects that are reasonably 
o
73  commensurate with those inherent in their actual or expected medical, dental, 
74  physiological, social, or educational situations (see section III.B);  
75   
76    The intervention or procedure is likely to yield generalizable knowledge about the 
o
77  subjects disorder or condition that is of vital importance for the understanding or 
78  amelioration of the subjects disorder or condition; and  
79   
80    Adequate provisions are made for soliciting the assent of the children and the 
o
81  permission of their parents or guardians (see section III.G).  
82   
83  For children to be exposed to the level of risk described in 21 CFR 50.53, the children 
84  should either have or be at risk for the specific disorder or condition that will be studied 
85  in the clinical investigation.8  Objective or empiric data should support that the condition 
86  proposed for study has the potential to negatively impact the childs health and well-
87  being or increase the risk of developing a health problem in the future, as well as that 
88  collection of the data will enhance understanding towards prevention, diagnosis, 
89  improvement, or treatment of the condition.  
90   
91  The following are the fundamental concepts for the ethical framework in 21 CFR part 50, 
92  including subpart D, and 21 CFR part 56, and that IRBs should consider when reviewing clinical 
93  investigations that include children. 
94   
95  A.  Principle of Scientific Necessity  
96   
97  The principle of scientific necessity9 is encompassed in two regulatory requirements:  the 
98  equitable selection of subjects (21 CFR 56.111(a)(3)) and minimization of risk (21 CFR 
99  56.111(a)(1)).  The concept is also grounded in the ethical principles of the Belmont Report,10 
100  specifically that of justice.  IRBs should consider the scientific necessity of conducting a clinical 
101  investigation in children.  It may be more efficient to consider scientific necessity prior to 
 
7 For the purposes of this guidance, references to disorder and condition include diseases.  
8 Institute of Medicine (2004); Committee on Clinical Research Involving Children, Ethical Conduct of Clinical 
Research Involving Children; Field MJ, Behrman RE, editors. Washington DC: National Academies Press. 
Recommendation 4.3.  Available at https://www.ncbi.nlm.nih.gov/books/NBK25542/ (accessed September 19, 
2022). 
9 Roth-Cline M, Nelson R.  The ethical principle of scientific necessity in pediatric research.  Am J Bioeth. 
2014;14(12):1415. 
10 The Belmont Report, Ethical Principles and Guidelines for the Protection of Human Subjects of Research, 1979, 
The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, available 
at https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html (accessed 
September 19, 2022). 
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102  assessing risk and benefit under 21 CFR part 50, subpart D.  Children should not be enrolled into 
103  a clinical investigation unless their participation is necessary to answer an important scientific 
104  and/or public health question directly relevant to the health and welfare of children.  For 
105  example, for products that are being developed for use in adults and children, if effectiveness in 
106  adults can be extrapolated to children, then effectiveness studies in adults should be conducted to 
107  minimize the need to collect effectiveness data in children.11  
108   
109  Regarding the equitable selection of subjects, IRBs should consider the purposes of the research 
110  and the setting where the research will be conducted and should be aware of the unique 
111  challenges of research involving children.12  Regarding minimization of risk, research 
112  procedures should be consistent with sound research design and should not expose subjects to 
113  risk unnecessarily.  When appropriate, procedures already being performed as part of clinical 
114  care should be used to meet research needs.  
115   
116  When it is considered scientifically necessary to conduct a clinical investigation in children, it is 
117  imperative that the clinical investigation be well-designed to collect interpretable data.  Key 
118  elements of well-designed clinical investigations include the selection of appropriate control 
119  groups and study endpoints relevant in the pediatric population.  Studies that are not well-
120  designed expose children to unnecessary risks, are unlikely to yield informative study results and 
121  as a result may be considered unethical.  In pediatric drug development, randomized, placebo-
122  controlled trials may be necessary to establish safety and effectiveness. 
123   
124  B.  Risk Categories for Interventions or Procedures without Prospect of Direct 
125  Benefit 
126    
127  Any intervention or procedure, including the administration of an investigational drug or use of 
128  an investigational medical device, undertaken as part of a clinical investigation in children may 
129  be associated with risk.  The regulations at 21 CFR part 50, subpart D include two categories of 
130  risk for procedures or interventions in a clinical investigation that do not offer a prospect of 
131  direct benefit: 
132   
133    Minimal risk means that the probability and magnitude of harm or discomfort anticipated 
134  in the research are not greater in and of themselves than those ordinarily encountered in 
135  daily life or during the performance of routine physical or psychological examinations or 
136  tests (21 CFR 56.102(i)).  The standard of minimal risk should be interpreted as those 
137  risks encountered in the daily life of normal, average, healthy children living in safe 
138  environments and indexed to the experiences of children of the same age and 
139  developmental stage as the subject population.  The experiences of a normal 2-year-old 
140  may be very different than the experiences of a normal 16-year-old.  The duration of the 
141  exposure to the risk, the characteristics of the risk, and the reversibility of harm should 
 
11 See the guidance for industry and FDA staff Leveraging Existing Clinical Data for Extrapolation to Pediatric 
Uses of Medical Devices (June 2016) and the ICH guidance for industry E11(R1).  For additional information on 
pediatric extrapolation, see the ICH draft guidance for industry E11A Pediatric Extrapolation (August 2022) (when 
final, this guidance will represent the FDAs current thinking on this topic). 
12 See the guidance for industry Enhancing the Diversity of Clinical Trial Populations  Eligibility Criteria, 
Enrollment Practices, and Trial Designs (November 2020). 
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142  also be considered. Examples of minimal risk interventions or procedures may include a 
143  single blood draw, physical exam, chest x-ray,13 or surveys.14  Given that investigational 
144  drugs generally are considered to have the potential to cause harm, the use of an 
145  investigational drug in a clinical investigation that includes children is unlikely to be 
146  considered minimal risk under 21 CFR part 50, subpart D.  Investigational devices, 
147  however, can vary significantly in design and intended use (e.g., monitoring, diagnostic, 
148  or therapeutic devices).  Depending on the investigational device (e.g., diagnostic versus 
149  therapeutic) and how it is used in the investigation, there could be device investigations 
150  that meet the criteria for minimal risk under 21 CFR part 50, subpart D.  
151   
152    Minor increase over minimal risk should be understood to mean a slight increase over 
153  minimal risk that poses no significant threat to the childs overall health or well-being.15 
154  Any potential harms with the intervention or procedure should be expected to be transient 
155  and reversible and the probability for severe pain, discomfort, or harm should be 
156  extremely small or nonexistent.  The setting and the experience level of the investigator 
157  are important factors to consider when making an assessment as to whether an 
158  intervention or procedure meets criteria as a minor increase over minimal risk.16 
159  Examples of interventions or procedures that might be considered a minor increase over 
160  minimal risk are a urine collection via a catheter, or bone marrow aspirate with topical 
161  pain relief,17 or administering a single dose of an investigational drug with adequate 
162  safety information (see section IV.B). 
163   
164  See section IV for additional information regarding risk categories related to the design of the 
165  clinical investigation and research related procedures.18 
166   
167  C.  Prospect of Direct Benefit  
168   
169  The level of certainty required for determining that a prospect of direct benefit exists is not 
170  commensurate with the rigorous standards for confirming effectiveness.19  Consequently, 
171  effectiveness in adults does not need to be established before studies in children may begin. 
172  Prospect of direct benefit refers to the potential benefit to the individual child from exposure to 
 
13 Institute of Medicine (2004); Committee on Clinical Research Involving Children, Ethical Conduct of Clinical 
Research Involving Children; Field MJ, Behrman RE, editors. Washington DC: National Academies Press.  Table 
4.1, page 135. 
14 See the Federal Register of November 9, 1998 (63 FR 60353 at 60355).   
15 Department of Health Education and Welfare, Research Involving Children: Report and Recommendations of the 
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.  See the 
Federal Register of January 13, 1978 (43 FR 2084 at 2112).  
16 For information on reviewing the qualifications of investigators, see the guidance for IRBs, Clinical Investigators, 
and Sponsors on IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, 
and the Determination of Whether an IND/IDE is Needed (August 2013). 
17 See footnote 13.  
18 Additional recommendations related to risk are included in The Secretarys Advisory Committee on Human 
Research Protections (SACHRP): Appendix B: Recommendations regarding risk in research involving children, July 
28, 2005. Available at https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2005-july-28-letter-appendix-
b/index.html (accessed September 19, 2022). 
19 Bhatnagar M, Sheehan S, Sharma I, Baer G, Green D, McCune S, Joffe S, Snyder D, 2021, Prospect of Direct 
Benefit in Pediatric Clinical Trials: Practical Challenges and Potential Solutions, Pediatrics, 147(5) e2020049602. 
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173  the research intervention or procedure in the clinical investigation in question (21 CFR 50.52). 
174  Prospect of direct benefit should result from the research intervention or procedure being studied 
175  (e.g., the investigational drug or medical device) and not from ancillary interventions or 
176  procedures, such as physical exams done as part of the trial.  For research interventions or 
177  procedures that are considered to offer prospect of direct benefit, the IRB must find not only that 
178  the risk is justified by the anticipated benefit to the child, but the relation of the anticipated 
179  benefit to the risk is at least as favorable as any available alternatives (21 CFR 50.52).  When 
180  evaluating if an intervention or procedure offers a prospect of direct benefit, the IRB should 
181  consider whether the evidence establishing proof of concept about a potential beneficial effect is 
182  sufficient, and whether the proposed dose (particularly for drugs) and duration of exposure to the 
183  intervention or procedure are adequate to offer a potential clinical benefit to the individual child. 
184  For a medical device clinical investigation, the device characteristics should be compatible with 
185  the childs age and developmental stage such that a benefit is anticipated.20  
186   
187  The necessary evidence to determine prospect of direct benefit for a pediatric clinical 
188  investigation may be based on one or more sources of information.  When adult data are 
189  available in conditions that exist both in adults and children, evidence of clinical benefit from the 
190  drug or device in adults can provide support for prospect of direct benefit before clinical 
191  investigations are initiated in children.  Animal or relevant device modeling and simulation data 
192  may provide evidence of prospect of direct benefit; and, in conditions that exist in both pediatric 
193  and adult populations, may preclude or mitigate the need to preliminarily collect relevant adult 
194  data.  For pediatric conditions with a phenotype that extends into adulthood, demonstration of a 
195  drugs favorable effect on a biomarker(s) or surrogate endpoint(s) linked to the causal pathway 
196  of the disease in adults may also support prospect of direct benefit in children.  For conditions 
197  with manifestations that occur exclusively in children, collection of adult data evaluating the 
198  drug or device may not be available or feasible, and nonclinical data obtained in a relevant 
199  animal or in vitro model for the condition of interest may often be the only source of information 
200  to support prospect of direct benefit.  
201   
202  See section IV for additional information regarding prospect of direct benefit related to the 
203  design of the clinical investigation and research related procedures. 
204   
205  D.  Assessment of Risk for Interventions or Procedures with a Prospect of Direct 
206  Benefit 
207   
208   21 CFR 50.52(a) requires that the IRBs find that the risk is justified by the anticipated benefit to 
209  subjects.  Assessment of the risk is predicated on adequate safety data.  All available clinical 
210  safety datasuch as data collected from healthy adults, if appropriate; adults with the same 
211  condition; or adults or children treated with the same drug or device for a different indication
212  should be included in the risk analysis.  However, if such information is not available, as may be 
213  the case for pediatric conditions that present solely or primarily in childhood, safety information    
 
20 See the guidance for industry and FDA staff Leveraging Existing Clinical Data for Extrapolation to Pediatric 
Uses of Medical Devices. 
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214  may be limited to nonclinical studies,21 which could include:  
215   
216    Nonclinical studies to evaluate maximum tolerated doses or device performance and 
217  safety, 
218    Juvenile animal studies to support the pediatric age groups being studied, and/or 
219    Nonclinical studies of sufficient duration to support treatment for chronic conditions. 
220   
221  E.  Component Analysis  
222   
223  A research protocol, including a protocol studying a pediatric condition, may, and usually does, 
224  include multiple research-related interventions or procedures, some that offer prospect of direct 
225  benefit and some that do not.  Any intervention or procedure conducted solely for research 
226  purposes and not needed for clinical management or routine clinical care should be evaluated 
227  separately to determine whether it offers prospect of direct benefit to the enrolled child (known 
228  as a component analysis of risk).22  If a specific intervention or procedure does not offer 
229  prospect of direct benefit, the risk of the intervention or procedure should be limited to a minor 
230  increase over minimal risk, and meet the other conditions outlined under 21 CFR 50.53 unless 
231  the protocol is referred for review, as per 21 CFR 50.54 (see section III.F).  
232   
233  Failure to carefully evaluate the different components of a clinical investigation may result in an 
234  intervention or procedure that does not offer prospect of direct benefit exceeding the allowable 
235  ceiling of a minor increase over minimal risk.  For example, for children enrolled in the active 
236  study arm of a placebo-controlled clinical investigation, there is prospect of direct benefit offered 
237  by the investigational medical product.  For children in the placebo arm, however, there is no 
238  prospect of direct benefit from the placebo intervention or procedure.  Factors to consider when 
239  assessing risk to children in the placebo arm of the trial (evaluated under 21 CFR 50.51 as 
240  minimal risk or 21 CFR 50.53, as a minor increase over minimal risk) are:  
241    The placebo intervention (e.g., sugar pill, saline);   
242    Routes of administration (e.g., oral, infusion, topical) or procedures used for 
243  administration (e.g., placement of peripheral catheter);  
244    Frequency and duration of administration of the placebo;  
245    Risk of withholding known effective therapy, if such therapy exists and will be withheld; 
246  and  
247    Use of rescue therapy, if appropriate.23  
 
21 For information on the design and conduct of nonclinical studies, see guidance for industry Investigational 
Enzyme Replacement Therapy Products: Nonclinical Assessment (October 2019); guidance for industry Nonclinical 
Safety Evaluation of Pediatric Drug Products (February 2006); guidance for industry Severely Debilitating or Life-
Threatening Hematologic Disorders: Nonclinical Development of Pharmaceuticals (March 2019); ICH guidance for 
industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals (March 2010); ICH guidance for industry S9 
Nonclinical Evaluation for Anticancer Pharmaceuticals Questions and Answers (June 2018); ICH guidance for 
industry S11 Nonclinical Safety Testing in Support of Development of Paediatric Medicines (May 2021); and draft 
guidance for industry and FDA staff General Considerations for Animal Studies for Medical Devices (October 
2015) (when final, this guidance will represent the FDAs current thinking on this topic). 
22 Final Rule, Additional Safeguards for Children in Clinical Investigations of Food and Drug Administration-
Regulated Products, 78 FR 12937 at 12942 (February 26, 2013) and 43 FR 2084 at 2086 (January 13, 1978). 
23 Momper JD, DJ Green, K Park, GJ Burckart, DL Snyder, 2021, Ethical Considerations for Pediatric Placebo-
Controlled Trials: FDA Outcomes and Perspectives. TIRS, 55(2): 282-303.  
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248  The risks associated with administration of a placebo in a clinical investigation should be part of 
249  the component analysis of risk.  For example, if an intravenous catheter will be placed solely to 
250  administer placebo and is not needed for clinical management or is not needed for routine 
251  clinical care, the risk of the insertion and management of the catheter should be considered as 
252  part of the risk assessment.  A peripheral intravenous catheter should generally be considered as 
253  minimal risk or a minor increase over minimal risk, whereas a central intravenous catheter 
254  should generally be considered to exceed the minor increase over minimal risk threshold.24  Oral 
255  administration of a placebo for a short time period should generally be considered minimal risk. 
256  A placebo administered by a single injection could be considered minimal risk; it is possible that 
257  multiple injections or infusions could be considered as a minor increase over minimal risk, but in 
258  other circumstances multiple injections or infusions would exceed the minor increase over 
259  minimal risk threshold.  If known effective therapy is withheld, the risk associated with 
260  withholding therapy should not exceed a minor increase over minimal risk.  If withholding or 
261  withdrawing a known effective therapy may result in significant harm to the child, the risk may 
262  exceed the minor increase over minimal risk threshold, and the use of a placebo may not be 
263  justified.25, 26  In some cases, placebo-controlled drug trials requiring injections or infusions 
264  administered over the course of one or two years have been justified as a minor increase over 
265  minimal risk depending on whether appropriate risk mitigation strategies are included as part of 
266  the protocol.27  
267   
268  F.  Potential for Review per 21 CFR 50.54 
269   
270  If an intervention or a procedure in a pediatric protocol exceeds a minor increase over minimal 
271  risk and does not offer prospect of direct benefit, the protocol is not approvable by an IRB under 
272  21 CFR 50.51, 50.52, or 50.53.  FDA regulations include provisions under which a clinical 
273  investigation that is not otherwise approvable by an IRB may proceed if the following criteria are 
274  met28: 
 
24 As an example, in 2017 an IRB referred a protocol involving placebo administration via a central access venous 
device to FDA for review per 21 CFR 50.54.  FDA consulted with its Pediatric Advisory Committee and Pediatric 
Ethics Subcommittee (PAC/PES).  A summary of the deliberations of the PAC/PES, the recommendation from 
FDAs Office of Pediatric Therapeutics to the Deputy Commissioner for Medical Products and Tobacco, and the 
decision by the Deputy Commissioner is available at https://www.fda.gov/media/105555/download (accessed 
September 19, 2022). 
25 ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical Trials (May 2001), page 
15. 
26 World Medical Association.  (2013).  Declaration of Helsinki: Ethical Principles for Medical Research Involving 
Human Subjects. First adopted in Helsinki, Finland, in 1964.  Available at https://www.wma.net/policies-post/wma-
declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ (accessed September 19, 
2022). 
27 For examples, see Minutes from the May 11, 2018 joint meeting of the Pediatric Advisory Committee and the 
Endocrinologic and Metabolic Drugs Advisory Committee, regarding the use of randomized, blinded placebo-
controlled trials for products intended for the treatment of achondroplasia, available at 
https://www.fda.gov/media/114640/download (accessed September 19, 2022); Meeting Minutes from the May 18, 
2017 joint meeting of the Pediatric Advisory Committee and Pediatric Ethics Subcommittee, regarding a clinical 
investigation of a product intended to treat Duchenne Muscular Dystrophy, available at 
https://www.fda.gov/media/107320/download (accessed September 19, 2022); and footnote 23. 
28 For additional information see the guidance for clinical investigators, institutional review boards, and sponsors 
Process for Handling Referrals to FDA Under 21 CFR 50.54 Additional Safeguards for Children in Clinical 
Investigations (December 2006).  
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275    The IRB finds that the research presents a reasonable opportunity to further the 
276  understanding, prevention, or alleviation of a problem affecting the health or welfare of 
277  children; and 
278   
279    The Commissioner, after consultation with a panel of experts in pertinent disciplines 
280  (e.g., science, medicine, education, ethics, law) and following opportunity for public 
281  review and comment, determines either: 
282   
283    The research in fact satisfies 21 CFR 50.51, 50.52, or 50.53; or 
284   
285    The following three conditions described in 21 CFR 50.54 are met: 
286   
287  1)  The research presents a reasonable opportunity to further the understanding, 
288  prevention, or alleviation of a serious problem affecting the health or welfare of 
289  children; 
290   
291  2)  The research will be conducted in accordance with sound ethical principles; 
292  and 
293   
294  3)  Adequate provisions are made for soliciting the assent of children and 
295  the permission of their parents or guardians as set forth in 21 CFR 
296  50.55. 
297   
298  G.  Parental/Guardian Permission and Child Assent 
299   
300  A clinical investigator must obtain permission from the parent(s) or guardian(s) when a child is 
301  enrolled in a clinical investigation (21 CFR 50.55(e)).29  The parental/guardian permission form 
302  must address the required elements of consent, as well as appropriate additional elements (see 21 
303  CFR 50.25) to allow the parent(s) or guardian to make an informed decision.  Informed consent 
304  is a process.  Parents, guardians, and assenting children should be given the opportunity to ask 
305  questions when considering study participation, and continue to be provided information as the 
306  study progresses and as the situation requires.30  
307   
308  Assent means a child has provided affirmative agreement to participate in a clinical 
309  investigation; mere failure to object should not be construed as assent (21 CFR 50.3(n)).  Unless 
310  the IRB waives the requirement, adequate provisions must be made for soliciting assent from the 
311  children if the IRB determines that the children are capable of providing assent (21 CFR 
 
29 FDAs regulations include limited exceptions from the general requirements for informed consent.  See 21 CFR 
50.23 and 50.24 and guidance for institutional review boards, clinical investigators, and sponsors Exception from 
Informed Consent Requirements for Emergency Research (April 2013).  Of note, FDA does not intend to object to 
an IRB waiving or altering informed consent requirements for certain minimal risk clinical investigations involving 
children, as described in guidance for sponsors, investigators, and institutional review boards IRB Waiver or 
Alteration of Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to Human 
Subjects (July 2017). 
30 For additional information on the informed consent process, see draft guidance for IRBs, clinical investigators, 
and sponsors Informed Consent Information Sheet (July 2014).  When final, this guidance will represent the FDAs 
current thinking on this topic. 
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312  50.55(a)).  Children 7 years of age and older are often considered capable of assent;31 however, 
313  the age, maturity, and psychological state (mental capacity and developmental stage) of the child 
314  involved in the research must be considered (21 CFR 50.55(b)).  
315   
316  Assent of the children is not a necessary condition for a clinical investigation to proceed if the 
317  IRB finds either 1) that the childrens capability is so limited they cannot reasonably be 
318  consulted or 2) that the intervention or procedure involved in the clinical investigation holds out 
319  a prospect of direct benefit that is important to the health or well-being of the children and is 
320  available only in the context of the clinical investigation (21 CFR 50.55(c)).  Even if the IRB 
321  determines that the children are capable of assenting, assent may be waived under 21 CFR 
322  50.55(d) if the IRB finds and documents that all the following criteria are met: 
323   
324    The clinical investigation involves no more than minimal risk to the subjects;  
325    The waiver will not adversely affect the rights and welfare of the subjects;  
326    The clinical investigation could not practicably be carried out without the waiver; and  
327    Whenever appropriate, the subjects will be provided with additional pertinent information 
328  after participation. 
329   
330  Ultimately, the IRB determines whether assent is required and how assent is obtained. 
331   
332   
333  IV.  APPLICATION OF SUBPART D TO PEDIATRIC CLINICAL 
334  INVESTIGATIONS 
335   
336  IRBs should consider the following when determining if the regulatory criteria for clinical 
337  investigations involving children have been met. 
338   
339  A.  Data to Support Conducting Pediatric Clinical Investigations 
340   
341  Multiple sources of information may be used to inform the design of an acceptable pediatric 
342  clinical investigation.  Information from nonclinical studies, bench testing or modeling and 
343  simulation (especially in the case of devices), and literature may be used to assess the potential 
344  risks and benefits of initiating the investigation in children.  Depending on the quality and 
345  applicability of these data, collection of relevant adult data prior to initiation of a trial in pediatric 
346  subjects may not always be necessary.  If relevant adult data are available, those data may inform 
347  the trial design for pediatric subjects (see Principle of Scientific Necessity, section III.A).  Early 
348  inclusion of children in medical product development or initiation of clinical trials directly in 
349  children may be appropriate.  
350   
351  In some cases, adult studies may not be ethical or feasible.  For example, for a rare disease with 
352  high pediatric mortality, there may be few adults with the disease, or adults may have a less 
353  severe form with limited applicability to the more severe pediatric form.  
354   
 
31 See the Federal Register of January 13, 1978 (43 FR 2084 at 2110).  
 
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355  B.  Design Considerations for Clinical Investigations 
356   
357  Clinical investigations involving children should be designed to maximize the amount of 
358  information gained and minimize the number of subjects involved. 
359   
360  The risks posed by the drug or device in a pediatric clinical investigation may vary depending on 
361  the particular subgroup of pediatric patients.  Factors to consider when designing a clinical 
362  investigation and assessing the potential risks to children involved in the study include the:  
363   
364    Age and degree of physiological maturity of the child;  
365    Nature and natural history of the clinical condition to be treated;  
366    Current severity of the condition to be treated in the child;  
367    Presence of other complicating clinical conditions;  
368    Safety and effectiveness of the drug or device that may have been demonstrated in older 
369  subjects, or that is expected based on other clinical or nonclinical investigations; and  
370    Likely duration of drug or device use and its impact on the growth and development of 
371  the child, including behavioral and psychosocial effects.   
372   
373  The following sections provide additional design considerations for clinical investigations of 
374  drugs and clinical investigations of medical devices. 
375   
376  1.  Clinical Investigations of Drugs 
377   
378  To offer a prospect of direct benefit, any dose planned for use in a pediatric clinical investigation 
379  should have the potential to have a therapeutic effect based on available scientific information.32 
380  If there are adults with the disease, pharmacokinetic (PK) and pharmacodynamic (PD) data in 
381  adults may provide useful information to help establish a potentially effective dose for use in 
382  children.  
383   
384  If there are a limited number of adults with the condition, PK and PD data from clinical trials in 
385  healthy adult volunteers33 or in adults or children using the product for other indications may be 
386  informative in helping to establish initial dosing for children with the condition under study. 
387  Such information may also provide some evidence of drug activity to support prospect of direct 
388  benefit if the activity assessment is relevant to the pediatric population of interest.  Extending a 
389  dose for a product from another patient population (or different indication) to the new pediatric 
390  population should be based on a sound scientific assessment, particularly addressing how the 
391  exposure-response for effectiveness and safety in the other population was used to predict the 
392  exposure-response relationship in the pediatric population of interest.  
393   
394  Nonclinical studies in disease-specific animal models of a pediatric condition or in vitro data 
395  could be used to support an initial pediatric dose if the PD effect on important aspects of the 
 
32 These considerations also apply to investigational gene therapies. For these trials, a single dose of vector is 
generally administered, with the possibility of a long-lasting duration of action and resulting benefit; the study dose 
will need to be in the potentially therapeutic range.  
33 Testing in adult normal, healthy volunteers is generally not acceptable for gene therapy trials.  See the guidance 
for industry Human Gene Therapy for Rare Diseases (January 2020).  
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396  condition in question can be translated into an equivalent human dose that is anticipated to be 
397  effective and offers prospect of direct benefit.  This should be based on scientific criteria that 
398  estimate the relationship between the PD effect in the nonclinical model and human physiology. 
399   
400  Clinical investigations should be of sufficient duration to offer a potential clinical benefit to the 
401  individual child.  This judgement is similar to that made when exposing children to a treatment 
402  in clinical practice.  Of note, most single-dose studies intended to collect PK data in children do 
403  not offer prospect of direct benefit because the study duration is too short to offer a clinical 
404  benefit.  A study intended to collect single-dose PK data might be considered under 21 CFR 
405  50.53 as a minor increase over minimal risk if there is adequate safety information to 
406  characterize the risk from exposure to the investigational drug and any additional study 
407  procedures as no more than a minor increase over minimal risk.34, 35  In this case, the study 
408  intervention does not offer benefit but may contribute to generalizable knowledge about the 
409  childs disorder or condition.  
410   
411  Multiple-dose studies36 intended to collect PK data may offer prospect of direct benefit, but the 
412  dose and duration of exposure to the study intervention should be sufficient to have the potential 
413  to result in a clinical benefit or to effect some change in a surrogate of clinical benefit.  To 
414  provide studies of adequate duration to offer prospect of direct benefit, adaptive study designs 
415  should be considered when additional dose finding is required within the context of the clinical 
416  investigation.  Such adaptive designs could combine prospectively planned dose ranging or dose 
417  titration with continued dosing after a dose is established.37  
418   
419  2.  Clinical Investigations of Medical Devices 
420   
421  Compared to drugs, devices present different challenges due to the range of technology they 
422  incorporate and their varying applications.  The available clinical data for the device (e.g., 
423  published studies and reports and actual use information) should be considered when designing 
424  the clinical trial to maximize the amount of information gained and minimize the number of 
425  subjects involved.  For indications involving both adults and children, it may be possible to 
426  design a single pivotal study that includes both pediatric and adult subjects to reduce the burden 
427  of multiple studies and to optimize the sample sizes for both the pediatric and adult study 
428  populations.  Further, while every effort should be made to gather data that adequately address 
429  each targeted pediatric subgroup for the proposed indication for use, in some cases, the expected 
430  benefit and safety can be determined without separate studies in each subgroup.  That is, it may 
 
34 See the draft guidance for industry General Clinical Pharmacology Considerations for Pediatric Studies of 
Drugs, Including Biological Products (September 2022).  When final, this guidance will represent the FDAs 
current thinking on this topic. 
35 Roth-Cline M, Nelson RM. Microdosing Studies in Children: A US Regulatory Perspective. Clinical 
Pharmacology and Therapeutics. 2015; 98(3): 232-233.  
36 Given the complexity of gene therapy products, multiple dose PK studies are unlikely to be conducted.  Please 
contact CBER for additional considerations that may apply. 
37 Guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics (November 2019).  
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431  be extrapolated from one age group to another.38  In other cases, such as with neonates, clinical 
432  data gathered specifically in that subgroup will likely be needed.39 
433    
434  C.  Study Procedures in Pediatric Clinical Investigations 
435   
436  In the context of a clinical investigation, procedures that are carried out as part of routine clinical 
437  care of a child generally are considered to offer a clinical benefit and do not require evaluation as 
438  a research intervention under the regulations.  Procedures that are carried out solely for research 
439  purposes and do not offer prospect of direct benefit must meet the minimal risk criteria (21 CFR 
440  50.51) or no more than a minor increase over minimal risk criteria (21 CFR 50.53) in order to be 
441  included in a clinical investigation unless referred for review under 21 CFR 50.54 (see section 
442  III.F).  
443   
444  The potential for harm and the invasiveness and frequency of the planned procedures should be 
445  considered when assessing the risk.  A single lumbar puncture or a single muscle biopsy have 
446  been considered, in many circumstances, to constitute a minor increase over minimal risk.40 
447  However, large organ biopsiessuch as liver or kidney biopsieswhen done for research 
448  purposes only have generally been considered to exceed a minor increase over minimal risk, and 
449  should not be done in children unless the procedure is performed as part of the routine clinical 
450  care for that child in the treatment of their condition.  When considering the risk of a procedure, 
451  the risk of any sedation not needed for the childs clinical care (i.e., non-therapeutic procedural 
452  sedation, see section IV.C.1) or the risk of use of a contrast agent should also be considered.  For 
453  example, a single MRI without contrast could be considered minimal risk, but the addition of 
454  contrast or sedation to the procedure is likely to constitute at least a minor increase over minimal 
455  risk, depending on the type of contrast being used and the risk of the sedation.   
456   
457  1.  Procedural Sedation in Pediatric Clinical Investigations 
458   
459  Procedures in children in a clinical trial may require sedation and the risks of sedation needed for 
460  non-beneficial research-only (non-therapeutic) procedures should be considered.  The Pediatric 
461  Ethics Subcommittee of FDAs Pediatric Advisory Committee met in March 2015 to discuss the 
462  use of non-therapeutic procedural sedation and came to the following areas of agreement when 
463  considering the use of sedation for a non-therapeutic procedure:41   
464   
465    Procedures should be performed at a high-volume center with a dedicated pediatric 
466  sedation service; 
467   
 
38 See footnote 20.  
39 For additional information, see the guidance for industry and FDA staff Premarket Assessment of Pediatric 
Medical Devices (March 2014). 
40 Snyder D, Lee C, and Nelson R. (2018). Invasive Placebos, Patient Burdens and Community Advocacy: A 
Federal Ethics Panel Protocol Review.  In Kodish, E and Nelson, R. (Eds).  Ethics and Research with Children, A 
Case-Based Approach (2nd ed.).  New York, NY: Oxford University Press. 
41 Minutes of the Pediatric Ethics Subcommittee of FDAs Pediatric Advisory Committee, March 23, 2015. 
http://wayback.archive-
it.org/7993/20180127092544/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/P
ediatricAdvisoryCommittee/UCM510177.pdf (accessed September 19, 2022). 
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468    There should be rigorous scientific justification for the need for the non-therapeutic 
469  procedures; 
470    The approach to procedural sedation and risk minimization procedures should be 
471  described in the protocol;  
472   
473    Children with chronic conditions that may place them at higher risk from procedural 
474  sedation should be carefully evaluated and potentially excluded from the protocol;  
475   
476    The non-therapeutic procedure should be terminated if complications of sedation arise or 
477  the level of sedation is inadequate, as it would be inappropriate to escalate the approach 
478  to procedural sedation beyond what would be considered a minor increase over minimal 
479  risk rather than to stop the procedure;  
480   
481    If a particular procedure in a particular patient population is normally accompanied by 
482  sedation when performed for clinical reasons, sedation should not be withheld in the non-
483  therapeutic research setting to avoid its risks and thereby attempt to enhance the 
484  procedures approvability under federal research regulations; and  
485   
486    There should be clear communication with potential subjects (and their parents/guardians) 
487  regarding the non-therapeutic nature of the procedures and procedural sedation in child assent 
488  and parental permission documents. 
489   
490  FDA recommends that sponsors use these recommendations for minimizing risk in designing and 
491  implementing protocols that include non-therapeutic procedural sedation.  These 
492  recommendations will also aid IRBs when assessing the risk to children.  The IRB should 
493  consider the cumulative risk if more than one procedure with non-therapeutic procedural 
494  sedation is planned.  If the IRB determines that the procedure(s) is integral to answering the 
495  scientific question and ethical to perform, but that it constitutes more than a minor increase over 
496  minimal risk, review under 21 CFR 50.54 will be required before the clinical investigation may 
497  proceed.  
14