Contains Nonbinding Recommendations 
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  

For single copies of this guidance, please contact: Office of Policy, Food and Drug 
Administration, 5600 Fishers Lane, rm. 14-101, HF-11, Rockville, MD 20857, (301) 827-3360. 
For questions on the content of this guidance, contact Erik Mettler, Office of Policy, (301) 827- 
3360. 
U.S. Department of Health and Human Services 
Food and Drug Administration 
December 2006 
Final Guidance  Contains Nonbinding Recommendations 
 
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  
 
 
 
 
 
 
 
 
 
 
Additional copies are available from: 
Office of Policy, Office of the Commissioner 
Food and Drug Administration 
5600 Fishers Lane 
Rockville, MD 20857 
(301)827-3360 
http://www.fda.gov/ 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
December 2006 
Final Guidance     
  Contains Nonbinding Recommendations 
 
Table of Contents 
 
I.  INTRODUCTION..............................................................................................................................................1 
II.  BACKGROUND................................................................................................................................................1 
III.  REVIEW PROCESS.....................................................................................................................................2 
A.  OVERVIEW OF PROCESS.................................................................................................................................2 
B.  PUBLIC PARTICIPATION.................................................................................................................................3 
C.  SCHEDULING THE SUBCOMMITTEE AND ADVISORY COMMITTEE MEETINGS.............................................3 
D.  SUBMITTING A REFERRAL..............................................................................................................................3 
E.  DOCUMENTS TO INCLUDE IN THE REFERRAL................................................................................................4 
F.  ASSESSMENT OF REFERRAL...........................................................................................................................5 
G.  ACCEPTANCE OF REFERRAL..........................................................................................................................5 
H.  MULTI-SITE CLINICAL INVESTIGATIONS......................................................................................................6 
I.  FEDERAL REGISTER NOTICES........................................................................................................................6 
J.  COMPOSITION OF THE PEDIATRIC ETHICS SUBCOMMITTEE........................................................................6 
K.  THE SUBCOMMITTEE MEETING.....................................................................................................................7 
L.  PAC MEETING................................................................................................................................................7 
M.  TRANSMITTAL MEMORANDUM......................................................................................................................8 
N.  REFERRAL PROCESS TIMING.........................................................................................................................8 
O.  FDA-DHHS JOINT REVIEW UNDER 21 CFR 50.54 AND 45 CFR 46.407.......................................................8 
Final Guidance  i   
  Contains Nonbinding Recommendations 
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  
  
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the appropriate FDA staff.  If you cannot identify the appropriate FDA staff, 
call the appropriate number listed on the title page of this guidance. 
 
 
I.  INTRODUCTION 
 
This guidance is intended to assist clinical investigators, Institutional Review Boards (IRBs), 
sponsors, and other interested parties in understanding the Food and Drug Administrations 
(FDA or agency) process for handling clinical investigations that include children as subjects and 
that have been referred to FDA for review under 21 CFR 50.54.  This guidance describes the 
procedures FDA generally intends to follow in handling such clinical investigations and in 
reaching final determinations pursuant to that regulation.  It is based in part on FDAs experience 
to date with such referrals.  The Department of Health and Human Services (HHS) has human 
subject protection regulations that also govern research involving children and supported or 
conducted by HHS.  (See 45 CFR Part 46 Subpart D.)  This guidance also addresses situations in 
which a clinical investigation is subject to both 21 CFR 50.54 and 45 CFR 46.407.1  
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in FDAs guidances means that something is suggested or 
recommended, but not required.  
 
 
II.  BACKGROUND 
 
FDA adopted 21 CFR Part 50 Subpart D, Additional Safeguards for Children in Clinical 
Investigations, as an interim final rule in April 2001 (21 CFR Part 50, Subpart D) (Subpart D) 
                                                 
1 The HHS Subpart D regulations are implemented and interpreted by HHSs Office for Human Research 
Protections (OHRP) and are nearly identical to FDAs regulations.  OHRP has posted on its website information 
pertaining to its process for handling clinical protocols that are subject to 45 CFR 46.407, and to 45 CFR 46.407 as 
well as FDAs Subpart D regulations.  See www.hhs.gov/ohrp/children/guidance_407process.html.  
  1 Contains Nonbinding Recommendations 
(See 66 FR 20598, April 24, 2001).  Under these regulations an IRB must review clinical 
investigations that involve children as subjects and are covered by Subpart D and must approve 
only those clinical investigations that satisfy the criteria described in 21 CFR 50.51, 50.52 or 
50.53, and the conditions of all other applicable sections of Subpart D.  If an IRB does not 
believe that a clinical investigation within the scope described in 21 CFR 50.1 and 56.101 and 
involving children as subjects meets the requirements of 21 CFR 50.51, 50.52 or 50.53, the 
clinical investigation may proceed only if: 
  The IRB finds and documents that the clinical investigation presents a reasonable 
opportunity to further the understanding, prevention, or alleviation of a serious problem 
affecting the health or welfare of children; and 
  The Commissioner of Food and Drugs (Commissioner), after consultation with a panel of 
experts in pertinent disciplines (e.g., science, medicine, education, ethics, law) and 
following opportunity for public review and comment, determines either: 
- 
The clinical investigation in fact satisfies 21 CFR 50.51, 50.52 or 50.53, or 
- 
The following three conditions described in 21 CFR 50.54 are met: 
1.  The clinical investigation presents a reasonable opportunity to further the 
understanding, prevention, or alleviation of a serious problem affecting the health 
or welfare of children. 
2.  The clinical investigation will be conducted in accordance with sound ethical 
principles; and 
3.  Adequate provisions are made for soliciting the assent of children and the 
permission of their parents or guardians as set forth in 50.55. 
 
 
III.  REVIEW PROCESS 
 
In FDA-regulated clinical investigations involving children, the agency makes every effort to 
protect the rights, safety, and welfare of those children.  In addition, the agency strives to achieve 
the basic goals of adherence to sound ethical principles, transparency through public and expert 
input, efficiency, timeliness, clarity, and consistency.  These goals are also endorsed by the 
Subcommittee on Research Involving Children of the Secretarys Advisory Committee on 
Human Research Protections (SACHRP).2  FDA believes that these goals are best served by 
having a clear, efficient, and comprehensive process for referrals by IRBs under 21 CFR 50.54.  
 
A.  Overview of Process 
 
FDA will use its advisory committee process to evaluate clinical investigations referred for 
review under 21 CFR 50.54.  This process will provide transparency and help ensure expert input 
as well as public participation.  When FDA receives a referral from an IRB, the agency will 
determine if the clinical investigation described in the protocol is regulated by FDA as described 
in 21 CFR 50.1(a).  If so, the agency will determine whether the referral is complete and can be 
                                                 
2 See Recommendations for OHRP/FDA Harmonization Subcommittee on Research Involving Children of 
SACHRP, January 29, 2004 minutes, page 9. 
 
  2 Contains Nonbinding Recommendations 
accepted for processing.  If the referral is accepted, the agency generally will call a meeting of 
the Pediatric Ethics Subcommittee (the Subcommittee) of the Pediatric Advisory Committee 
(PAC) and present the referral to the Subcommittee for its consideration.  At the next open 
meeting of the PAC, the Subcommittee chair (or another member of the Subcommittee, if the 
chair is unavailable) will present to the PAC the Subcommittees recommendation(s) regarding 
the referred clinical investigation.  After discussion and deliberation, the PAC will make its 
recommendation(s) regarding the referral to the Commissioner of Food and Drugs.  The 
Commissioner will then make the final determination as to whether the clinical investigation 
meets the requirements of FDAs Subpart D regulations.  This process is discussed in greater 
detail below.  
 
B.  Public Participation  
 
Public review and comment is required under 21 CFR 50.54.  Furthermore, FDA believes that 
public participation is important to help ensure the comprehensiveness and integrity of the 
review of clinical investigations referred under that regulation and the protection of the children 
who may be enrolled in the investigations.  In order to encourage public participation, FDA 
intends to establish an agency docket for each accepted referral and solicit public comment on 
the proposed investigation.  The materials in the docket for each investigation will include the 
referral documents sent by the IRB, related agency correspondence, public comments on the 
referral, the transcripts of both the Subcommittee meeting and the PAC meeting, and the final 
determination of the Commissioner regarding the referral under 21 CFR 50.54.  Materials 
submitted to the docket will be available through FDAs Division of Dockets Management or 
through FDA's Division of Freedom of Information. 
 
In addition, the Subcommittee and PAC meetings will be open to the public.  At the 
Subcommittee meeting, the chair will also present a summary of the public comments received.   
 
C.  Scheduling the Subcommittee and Advisory Committee Meetings 
 
When FDA receives an appropriate and complete referral3 from an IRB under 21 CFR 50.54, the 
Office of Pediatric Therapeutics (OPT) will coordinate with the Executive Secretary4 of the PAC 
regarding the scheduling of the Subcommittee and PAC meetings.  FDA generally expects to 
schedule Subcommittee meetings directly preceding a PAC meeting.  The PAC is currently 
scheduled to meet approximately three times per year, but FDA will consider calling additional 
meetings as necessary. 
 
D.  Submitting a Referral  
 
The agency encourages IRBs considering referring a clinical investigation under  50.54 first to 
discuss with the sponsor whether there are appropriate modifications to the protocol that would 
allow the clinical investigation to be approved under another provision of Subpart D. 
 
                                                 
3 See discussion of the joint review process with OHRP in section III.O 
4 The Executive Secretary is the Designated Federal Official (DFO) who coordinates the activities of the advisory 
committee and serves as the link between committee members, FDA, industry and the public. 
  3 Contains Nonbinding Recommendations 
IRBs should send referrals under 21 CFR 50.54 of clinical investigations regulated by FDA, as 
described in 21 CFR 50.1(a), to FDAs OPT at opt@fda.gov, or Office of Pediatric Therapeutics, 
Office of the Commissioner, FDA, 5600 Fishers Lane, RM 13B-45, HFG-2, Rockville, MD  
20857.  FDA may also receive copies of referrals from OHRP in situations where an IRB has 
referred a clinical investigation to OHRP but not to FDA.  Similarly, if an IRB submits a clinical 
investigation to FDA but not to OHRP, FDA will usually send it to OHRP so that OHRP can 
determine whether the clinical investigation is also subject to HHS jurisdiction.  If a clinical 
investigation is subject to both HHS and FDA jurisdiction, then, as discussed below in Section 
III.O., the referral process will be conducted jointly by FDA and OHRP under 21 CFR 50.54 and 
45 CFR 46.407.  
 
E.  Documents to Include in the Referral  
 
If an IRB decides to refer a clinical investigation for consideration under 21 CFR 50.54, the IRB 
should submit its finding (required under 21 CFR 50.54(a)) that the clinical investigation 
presents a reasonable opportunity to further the understanding, prevention, or alleviation of a 
serious problem affecting the health or welfare of children.     
 
The referral should also include the following:   
  An explanation as to why the IRB does not believe that the clinical investigation meets 
the requirements of 21 CFR 50.51, 50.52, or 50.53.  FDA believes that in most cases this 
probably will be explained in the IRB's minutes from its discussions of the protocol at 
issue. 
  The research protocol and, if the clinical investigation is being conducted under an 
Investigational New Drug application (IND) or Investigational Device Exemption (IDE), 
the IND or IDE number assigned by FDA; 
  All informed consent documents, including the parental permission form and, if being 
used, the assent forms and/or a description of the assent process; and 
  Any other informative supporting documents, such as IRB minutes pertinent to the 
clinical investigation, correspondence between the IRB and the investigator, product 
labeling, and the investigators brochure.  
 
In addition, the IRB should ensure that the submitted documents consistently describe the 
clinical investigation. We strongly encourage IRBs to submit electronic versions of all 
documents.  
 
These documents are needed to allow FDA to complete its initial assessment of the clinical 
investigation to determine if the study is subject to FDA jurisdiction, and to provide the 
Subcommittee and the PAC with complete information regarding the referral.  The referring IRB 
should provide these documents in a form the IRB would find approvable, but for the issue(s) 
that prompted the referral under 21 CFR 50.54.  Providing these documents in "IRB-approvable" 
condition will allow the Subcommittee and the PAC to focus on the issue(s) that prompted the 
referral, and not on other matters that the IRB is able to resolve itself.  
 
When OPT receives a referral, it will contact the referring IRB to confirm receipt of the referral.  
This will begin the process of exchanging information about the referral process between OPT, 
  4 Contains Nonbinding Recommendations 
the IRB, and the investigator.  Either in that initial contact or subsequently, OPT will advise the 
IRB as to whether the clinical investigation is subject to FDA jurisdiction and, if it is, whether 
the referral is complete, and thus acceptable for review, or whether any information is missing 
from the submission.  Depending on the circumstances of the research, OPT may ask for 
additional information, which may include, for example, information regarding the past use of 
the investigational article in children or adults, documents regarding continuing review, drug 
preparation protocol, or the certificate of analysis for the chemical being studied.  During this 
exchange OPT will explain the procedures the agency intends to follow and will encourage the 
IRB to ask any questions it might have about the requirements of 21 CFR 50.54. 
 
Following this exchange, the IRB may decide to withdraw the referral from consideration.  The 
reasons for withdrawal could include, for example, a misunderstanding of the requirements of 
the Subpart D regulations and the applicability of 50.54 to the clinical investigation at issue, i.e., 
a determination by the IRB after further analysis that the clinical investigation can in fact 
proceed under another provision in the Subpart D regulations. The agency encourages the IRB to 
document the reasons for withdrawal of the referral in its request to do so.  FDA suggests that an 
IRB in doubt about whether to refer a clinical investigation under 50.54 consult with OPT as 
soon as possible via email at opt@fda.gov. 
 
F.  Assessment of Referral 
 
Following receipt of the referral, FDA will determine whether the protocol is FDA-regulated 
(generally within 2 weeks after receipt) and inform the referring IRB in writing of the 
determination.  If the clinical investigation was referred to FDA by OHRP, FDA will also inform 
OHRP of that determination. 
 
The considerations under FDAs IND regulations (see 21 CFR Part 312) and IDE regulations 
(see 21 CFR Part 812) that are used to determine whether an IND or IDE can go into effect are 
related to, but distinct from, the considerations under Part 50 regarding the protection of human 
subjects.    Therefore, IRBs should note that, although some clinical investigations are exempt 
from the requirement that they need be conducted under an IND (see 21 CFR 312.2(b)), those 
that are exempt are still subject to 21 CFR Parts 50 and 56 and thus may trigger the Subpart D 
process under section 50.54. Similarly, a clinical investigation of a medical device may be 
exempt under 21 CFR 812.2(c) from the requirement that it be conducted under an IDE, but the 
clinical investigation may still be subject to the Subpart D process.  Furthermore, as indicated in 
21 CFR 50.1(a), Part 50 also applies to certain investigations that are not subject to sections 
505(i) or 520(g) of the Federal Food, Drug, and Cosmetic Act (21 USC  355(i), 360j(g)).  
 
G. Acceptance of Referral  
 
Following receipt of the referral, OPT will then ask the referring IRB for any other relevant 
documents and inform the IRB that FDA intends to post the documents in the docket created for 
the referral, and on the agencys website.  If the IRB believes that any documents it has included 
in its referral may be considered confidential by the sponsor, the IRB will be responsible for 
obtaining any necessary permission from the sponsor to post the documents.  If an IRB (or 
  5 Contains Nonbinding Recommendations 
sponsor) objects to the public posting of the documents, the agency will be unable to proceed 
with the referral. 
 
H. Multi-Site Clinical Investigations 
 
In some circumstances clinical investigations referred for review under 21 CFR 50.54 may be 
conducted at multiple sites.  In the event that an IRB at one or more of the clinical sites refers the 
investigation for review, it should notify the sponsor.  In such a situation, FDA strongly 
encourages the sponsor to notify the IRB(s) and investigator(s) at all of the other sites of the 
referral.  Once an IRB has made a referral under 50.54, pursuant to that regulation the 
investigation may not proceed (i.e., no subjects may be recruited or enrolled in the investigation) 
at any site for which that IRB has responsibility.   
 
Once IRBs at other sites have been notified by the sponsor of the referral, they may choose to 
allow the clinical investigation to proceed at their sites, or they may choose to await the outcome 
of the 50.54 referral.  In making this determination, FDA encourages IRBs to consider the 
implications of continuing the investigation during the pendency of the review and determination 
under 21 CFR 50.54.  For example, at the conclusion of the review, it is possible that the 
Commissioner could determine that the investigation cannot proceed because one or more of the 
criteria in 21 CFR 50.54(b) are not met.  Alternatively, the Commissioner might determine that 
the investigation can proceed but only with modifications of the protocol or the informed consent 
documents and procedures.  At the sites where the clinical investigation goes forward, the IRBs 
of record retain all normal responsibilities for review and oversight.  
 
I.  Federal Register Notices 
 
Following a referral, FDA generally will issue three Federal Register notices: 
  A solicitation of public comments on the referral, along with background information for 
the referral, notice of the establishment of a docket for the referral, and directions for how 
to access the docket.  Generally, FDA will provide approximately 4 weeks for submission 
of comments to the docket; 
  The announcement of the Pediatric Ethics Subcommittee meeting; and 
  The announcement of the Pediatric Advisory Committee meeting. 
 
J.  Composition of the Pediatric Ethics Subcommittee  
 
FDA will select the members of the Subcommittee in accordance with 21 CFR 50.54(b) and 
other relevant federal laws, including the Federal Advisory Committee Act (FACA) (5 U.S.C. 
App. 2)(1972).  The Subcommittee will include at least two members of the PAC.  Whenever 
possible, the selected members of the PAC will have clinical expertise relevant to the subject 
matter under discussion.  FDA will also invite individuals to serve on the Subcommittee who 
have expertise and/or experience relevant to the clinical investigation being discussed.  As a 
general matter, OPT will make these selections in collaboration with the relevant FDA Center(s) 
and review division(s).  Additional individuals will be invited according to the principles set 
forth in 21 CFR 50.54(b), such that the Subcommittee consists of a panel of experts in pertinent 
disciplines (for example: science, medicine, education, ethics, law) (21 CFR 50.54(b)).  As a 
  6 Contains Nonbinding Recommendations 
general matter, FDA also believes that usually it will be helpful to include a patient 
advocate/community representative and a statistician on the Subcommittee.  
 
The agency notes that there will be no cap on the number of members of the Subcommittee, and 
the agency will include as many members as necessary to ensure that the relevant expertise is 
represented.   
 
K. The Subcommittee Meeting 
 
FDA intends to invite a representative of the referring IRB (to be selected by the IRB) and the 
investigator to attend the Subcommittee meeting and to make a presentation to the Subcommittee 
regarding the referred protocol.  The agency encourages the IRB representative and the 
investigator to attend the meeting to help the Subcommittee understand the clinical investigation 
and basis for the referral.  One or more representatives from the FDA review division responsible 
for reviewing the clinical investigation may also attend to answer questions from the 
Subcommittee.  As appropriate, the agency may invite additional individuals to make 
presentations to the Subcommittee regarding either the referred protocol or issues raised in it (for 
example, the sponsor of the clinical investigation, or, in a situation involving a multi-site trial, a 
representative from an IRB that has approved the protocol). Although a referral may be made 
because of a particular aspect of the clinical investigation, the Subcommittee and the PAC, as 
well as FDA (and OHRP if they are involved5), usually will consider the clinical investigation in 
its entirety.   
 
FDA anticipates that a Subcommittee meeting usually will last for one day and a typical agenda 
will include: 
  Call to order 
  Meeting statement 
  Description of Subpart D expert panel process 
  Overview, charge to panel 
  Background of clinical investigation and protocol-specific scientific/medical issues 
  Investigator comments 
  IRB comments, including identification of specific ethical issues which led to the referral 
  Summary of public comments 
  Open public hearing 
  Presentation of questions 
  Expert panel discussion 
  Discussion, agreement, and vote on recommendation(s) (summary of deliberations) that 
will be presented to PAC. 
 
The Subcommittee will operate by majority vote.  Meeting transcripts and recommendations 
from the Subcommittee meeting will be made available to the public in the docket established for 
the referral and on the agencys website. 
 
L.  PAC Meeting 
                                                 
5 See discussion of joint review process with OHRP in section III.O. 
  7 Contains Nonbinding Recommendations 
 
At the next meeting of the PAC (usually shortly after the Subcommittee meeting), the chair of 
the Subcommittee (or another member of the Subcommittee, if the chair is unavailable) will 
present the Subcommittees recommendation(s) regarding whether the clinical investigation 
meets the requirements of Subpart D and other relevant requirements of Part 50.  The agency 
also encourages the IRB representative and the investigator to attend the PAC meeting such that 
they are available to answer questions about the referred protocol.  After discussion of the 
clinical investigation and the recommendation(s), the PAC will vote on its recommendation(s) to 
the Commissioner regarding whether the proposed clinical investigation may proceed under 21 
CFR Part 50 Subpart D.  The PAC's recommendations may include changes that the PAC 
believes are necessary for the clinical investigation to proceed as well as other suggested changes 
to improve the investigation.  In cases where FDA and OHRP are working jointly to review a 
clinical investigation subject to both FDA's and HHS' regulations, the PAC recommendation(s) 
also will be made to the Secretary.  (See Section III.O., for more details on studies subject to 
joint FDA-HHS reviews.) 
 
The PAC will operate by majority vote.  Meeting transcripts and recommendation(s) from the 
PAC meeting will be made available to the public in the docket established for the referral and 
on the agencys website.  After the PAC meeting, the chair will usually summarize the 
recommendation(s) of the PAC in a letter to OPT.    
 
M. Transmittal Memorandum 
 
OPT will draft and send a transmittal memorandum to the Commissioner outlining the PAC and 
Subcommittee recommendation(s), and including any recommendations/comments that FDA 
may have. The transmittal memorandum also will include any other necessary supporting 
documentation.  The transmittal memorandum will request that the Commissioner make a final 
determination as to whether, and if so, under what provisions of Subpart D, the clinical 
investigation may proceed.  After the Commissioner has made a final determination, OPT will 
forward that determination to the referring IRB and will post it in the docket created for the 
referral and on the agencys website.   
 
N.  Referral Process Timing 
 
OPT projects that this referral process will take approximately six months to complete; complex 
submissions may take longer to process (e.g., protocols involving a joint referral with OHRP). 
 
O. FDA-DHHS joint review under 21 CFR 50.54 and 45 CFR 46.407 
 
In light of the need for both consistency and efficiency, the process for IRB referrals of proposed 
clinical investigations that are both HHS-conducted or supported and FDA-regulated will 
function in essentially the same manner as the process for FDA-only referrals. In such cases: 
  HHS, through OHRP, will participate in the selection of members for the Subcommittee. 
  After the Subcommittee makes a recommendation to the PAC, the PAC will make its 
recommendation(s) to both the Secretary of HHS and the Commissioner of Food and 
Drugs. 
  8 Contains Nonbinding Recommendations 
  OPT will forward the Commissioner's determination to OHRP. 
  OHRP will send a transmittal memo with its recommendation, the Commissioner's 
determination, and all supporting documents, including the recommendation(s) of the 
PAC and the summary of the Subcommittee meeting, to the Secretary for a determination 
as to whether the clinical investigation may be conducted or supported by HHS.   
 
 
 
  9