Research Involving Children as 
Subjects and Not Otherwise 
Approvable by an IRB:  Process 
for Referrals to FDA and OHRP 
Guidance for Institutional Review 
Boards, Institutions, Investigators, and 
Sponsors 
 
DRAFT GUIDANCE 
 
 This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft guidances.  
Submit electronic comments to http://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.  Comments also may be submitted to the Office for Human Research Protections, Division of 
Policy and Assurances (1101 Wootton Parkway, Suite 200, 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 FDA (Office of Pediatric Therapeutics, Donna 
Snyder) at 301-796-1397, or the Office for Human Research Protections, Natalie Klein, at 240-453-6900 
or 866-447-4777.  
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration (FDA) 
Office of Pediatric Therapeutics (OPT) 
 
U.S. Department of Health and Human Services 
Office for Human Research Protections (OHRP) 
 
 
March 2023 
Procedural 
 
   
 
Research Involving Children as 
Subjects and Not Otherwise 
Approvable by an IRB:  Process 
for Referrals to FDA and OHRP 
Guidance for Institutional Review 
Boards, Institutions, Investigators, and 
Sponsors 
   
   Additional copies are available from:
Office of Pediatric Therapeutics 
Office of Clinical Policy and Programs, Office of the Commissioner 
Food and Drug Administration 
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
(Tel) 301-796-1397 
and/or 
Division of Policy and Assurances 
Office for Human Research Protections 
1101 Wootton Parkway, Suite 200 
Rockville, MD  20852 
Phone: 240-453-6900  688-447-4777 
http://www.hhs.gov/ohrp/newsroom/rfc/index.html 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration (FDA) 
Office of Pediatric Therapeutics (OPT) 
 
U.S. Department of Health and Human Services 
Office for Human Research Protections (OHRP) 
 
 
March 2023 
  
   
Procedural 
  
   
1 
2  TI.a  blIeN ToRfO CDoUnCTtIeOnNt ..s.. ........................................................................................................................................ 2 
3  II.  BACKGROUND .............................................................................................................................................. 2 
4  III.  REFERRAL, REVIEW, AND OUTCOMES ................................................................................................ 4 
5  A.  Referral ........................................................................................................................................................ 5 
6  B.  Assessment of Jurisdiction .......................................................................................................................... 6 
7  C.  Referral review and acceptance ................................................................................................................. 6 
8  D.  Referral withdrawal .................................................................................................................................... 7 
9  IV.  Preparation for Pediatric Advisory Committee (PAC) and the Pediatric Ethics Subcommittee 
10  (PES)(FDA) or Expert Panel (OHRP) meeting .............................................................................................. 7 
11  A.  Federal Register Notice and Docket........................................................................................................... 7 
12  B.  Documents and Public Review ................................................................................................................... 8 
13  V.  PAC/PES (FDA) or Expert Panel (OHRP) Meeting ..................................................................................... 9 
14  A.  Composition ................................................................................................................................................. 9 
15  B.  Attendees .................................................................................................................................................... 10 
16  C.  Meeting Content ........................................................................................................................................ 10 
17  D.  Recommendation(s) ................................................................................................................................... 10 
18  VI.  Final Determination ....................................................................................................................................... 11 
19  VII.  PROCESS DIFFERENCES SPECIFIC TO JOINT FDA AND OHRP REVIEW .................................. 11 
20  VIII. MULTISITE RESEARCH ............................................................................................................................ 12 
21  IX.  FDA AND OHRP REVIEW OF SIMILAR RESEARCH .......................................................................... 13 
22   
2 3 
24     
1 
   
2 5 
Research Involving Children as Subjects and Not Otherwise 
26 
Approvable by an IRB: 
27 
Process for Referrals to FDA and OHRP 
28 
29  Guidance for Institutional Review Boards, Institutions, Investigators, and Sponsors 
30   
31   
32  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
33  Administration (FDA) and the Office for Human Research Protections (OHRP) on this topic.  It does not 
34  establish any rights for any person and is not binding on FDA, OHRP, or the public.  You can use an 
35  alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To discuss 
36  an alternative approach, contact the FDA or OHRP staff responsible for this guidance as listed on the title 
37  page.   
38   
39   
40  I.  INTRODUCTION 
41   
42  This guidance is intended to assist institutional review boards (IRBs), institutions, investigators, 
43  and sponsors in understanding the processes used for review of research involving children as 
44  subjects that is not otherwise approvable by an IRB and has been referred to the Food and Drug 
45  Administration (FDA) under 21 CFR 50.54, the Office for Human Research Protections (OHRP) 
46  under 45 CFR 46.407, or both, for review.  
47   
48  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
49  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
50  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
51  the word should in Agency guidances means that something is suggested or recommended, but  
52  not required. 
53   
54  II.  BACKGROUND 
55   
56  The Department of Health and Human Services (HHS) issued 45 CFR part 46, subpart D, 
57  Additional Protections for Children Involved as Subjects in Research, as a final rule on 
58  March 8, 1983 (48 FR 9814).  FDA issued 21 CFR part 50, subpart D, Additional 
59  Safeguards for Children in Clinical Investigations of Food and Drug Administration-
60  Regulated Products, as a final rule on February 26, 2013 (78 FR 12937).  These regulations, 
61  hereinafter referred to collectively as subpart D, are similar, with some minor differences.1   
62   
63  FDAs subpart D regulations apply to clinical investigations2 regulated by FDA as described 
 
1 For a full discussion of the differences between the FDA and HHS human subject protection regulations, see 78 FR 
12937-12947.  
2 FDAs regulations at 21 CFR 50.3(c) define 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 
 
2 
   
64  in 21 CFR 50.1(a).   HHSs subpart D regulations apply to all research3 involving human 
65  subjects and conducted or supported by HHS, in accordance with 45 CFR 46.101(a).  FDA-
66  regulated clinical investigations conducted or supported by HHS are subject to both sets of 
67  regulations.  As a result, many sponsors,4 investigators,5 and IRBs need to be familiar with 
68  and comply with both FDAs and HHSs regulations.6  Under both of these regulations, an 
69  IRB must review research7 involving children as subjects under subpart D and may only 
70  approve research satisfying the following applicable regulations (as well as the requirements 
71  of all other applicable provisions of subpart D): 
72    
73    21 CFR 50.51 and 45 CFR 46.404:  Research not involving greater than minimal risk. 
74    21 CFR 50.52 and 45 CFR 46.405:  Research involving greater than minimal risk but 
75  presenting the prospect of direct benefit to the individual subjects.  
76    21 CFR 50.53 and 45 CFR 46.406:  Research involving no more than a minor increase 
77  over minimal risk and no prospect of direct benefit to individual subjects, but likely to 
78  yield generalizable knowledge about the subjects disorder or condition.  
79   
80  If an IRB does not find that research involving children as subjects meets the requirements of 
81  21 CFR 50.51, 50.52 or 50.53 (FDA regulations); 45 CFR 46.404, 46.405 or 46.406 (HHS 
82  regulations); or both as applicable, the research may proceed only if the following criteria in 
83  21 CFR 50.54, 45 CFR 46.407, or both as applicable, are satisfied: 
84   
85    The IRB finds that the research presents a reasonable opportunity to further the 
86  understanding, prevention, or alleviation of a serious problem affecting the health or 
87  welfare of children; and 
 
later to, or held for inspection by, the Food and Drug Administration as part of an application for a research or 
marketing permit.  The term does not include experiments that are subject to the provisions of part 58 of this 
chapter, regarding nonclinical laboratory studies. 
3 HHS regulations at 45 CFR 46.102(l) of the 2018 Requirements and 45 CFR 46.102(d) of the pre-2018 
Requirements define research as a systematic investigation, including research development, testing, and 
evaluation, designed to develop or contribute to generalizable knowledge. The 2018 Requirements at 45 CFR 
102(l)(1)-(4) deem certain activities not to be research. 
4 FDAs regulations at 21 CFR 50.3(e) define sponsor as a person who initiates a clinical investigation, but who 
does not actually conduct the investigation, i.e., the test article is administered or dispensed to or used involving, a 
subject under the immediate direction of another individual.  A person other than an individual (e.g., corporation or 
agency) that uses one or more of its own employees to conduct a clinical investigation it has initiated is considered 
to be a sponsor (not a sponsor-investigator), and the employees are considered to be investigators. 
5 FDAs regulations at 21 CFR 50.3(d) define investigator as an individual who actually conducts a clinical 
investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used 
involving, a subject, or, in the event of an investigation conducted by a team of individuals, is the responsible leader 
of that team. 
6 The HHS regulations do not define the term investigator, however OHRP interprets an investigator to be any 
individual who is involved in conducting human subjects research studies. See 
https://www.hhs.gov/ohrp/regulations-and-policy/guidance/faq/investigator-responsibilities/index.html. 
Due to the scope of the HHS regulations, this guidance refers to the HHS division supporting or conducting the 
research instead of sponsor when discussing HHS-conducted or -supported research. 
7 Although the definitions of clinical investigation in FDAs regulations and research in HHSs regulations are 
different, for purposes of this guidance they are used interchangeably. 
3 
   
88    The Commissioner of Food and Drugs (Commissioner), the Secretary of the Department 
89  of Health and Human Services (HHS) (Secretary),8 or both as applicable, after 
90  consultation with a panel of experts in pertinent disciplines (e.g., science, medicine, 
91  education, ethics, law) and following opportunity for public review and comment, 
92  determines either: 
93    The research in fact satisfies 21 CFR 50.51, 50.52 or 50.53; 45 CFR 46.404, 46.405, 
94  or 46.406; or both sets of regulations as applicable, or 
95    The following three conditions are met: 
96  1.  The research presents a reasonable opportunity to further the understanding, 
97  prevention, or alleviation of a serious problem affecting the health or welfare of 
98  children; 
99  2.  The research will be conducted in accordance with sound ethical principles; 
100  and 
101  3.  Adequate provisions are made for soliciting the assent of children and 
102  the permission of their parents or guardians as set forth in 21 CFR 
103  50.55, 45 CFR 46.408, or both as applicable. 
104   
105  An IRB may refer research involving children as subjects to FDA and/or OHRP for review 
106  under 21 CFR 50.54 or 45 CFR 46.407, as applicable.  Regardless of the agency to which the 
107  referral is submitted, both FDA and OHRP intend to consult with each other on any referrals 
108  received under 21 CFR 50.54 and 45 CFR 46.407 to ensure the appropriate agency has been 
109  notified and to determine whether a joint review (i.e., a review by both FDA and OHRP) is 
110  needed. 
111   
112  Consistent with 21 CFR 50.1(a), the requirements of 21 CFR part 50, subpart D, apply to 
113  clinical investigations regulated under sections 505(i) and 520(g) of the Federal Food, Drug, 
114  and Cosmetic Act (FD&C Act) (21 U.S.C.  355(i) and 360j(g)), as well as those that support 
115  applications for research or marketing permits for certain products regulated by FDA.  The 21 
116  CFR part 50, subpart D requirements are separate from the investigational new drug 
117  application (IND) requirements in section 505(i) of the FD&C Act and 21 CFR part 312.  
118  Therefore, 21 CFR part 50, subpart D, applies to all FDA-regulated clinical investigations of 
119  drug or biological products, including those that are IND-exempt per 21 CFR 312.2(b)(iv).  
120  Similarly, 21 CFR part 50, subpart D, applies to all FDA-regulated clinical investigations of 
121  devices, including those that are exempt from most provisions of the investigational device 
122  exemption (IDE) regulations under 21 CFR 812.2(c).  Furthermore, as indicated in 21 CFR 
123  50.1(a), part 50 also applies to certain clinical investigations of other types of FDA-regulated 
124  products (e.g., food additives, infant formulas, new dietary ingredients).  These clinical 
125  investigations are also subject to the review process under 21 CFR 50.54. 
126   
127  III.  REFERRAL, REVIEW, AND OUTCOMES 
128   
129  After making the required determinations (as described above), the IRB should refer the study 
130  to FDA and/or OHRP following the details described below.   
 
8 The Secretarys authority under Title IV of the Public Health Service Act (42 U.S.C. 281, et seq.) has been 
delegated to the Assistant Secretary for Health (ASH), 44 FR 46318 (August 7, 1979); see 67 FR 10216 (March 6, 
2002). 
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131   
132  . 
133   
134  A.  Referral 
135  The following table outlines the process that should be followed when referring a study to FDA 
136  and/or OHRP for review.  Where necessary, the differences between FDA and OHRP are 
137  identified.   
138   
FDA  OHRP 
Address for referral:  Address for referral: 
opt@fda.hhs.gov or   OHRP@hhs.gov or 
Office of Pediatric Therapeutics (OPT)   Division of Policy and Assurances 
Office of the Commissioner   Office for Human Research Protections 
Food and Drug Administration   Department of Health and Human Services 
10903 New Hampshire Avenue   1101 Wootton Parkway, Suite 200 
Silver Spring, MD, 20993  Rockville, MD 20852 
A referral should include: 
  The IRBs explanation of why the clinical investigation or proposed research does not meet 
the requirements of 21 CFR 50.51, 50.52, or 50.53 for FDA referrals; 45 CFR 46.404, 
46.405, or 46.406 for OHRP referrals;  
  The IRBs finding that the research presents a reasonable opportunity to further the 
understanding, prevention, or alleviation of a serious problem affecting the health or 
welfare of children;  
  The research protocol, investigators name, current informed consent documents, 
including the parental/guardian permission form and, if being used, the assent form(s) 
and/or a description of the assent process; 
  Other informative supporting documents, such as the IRB minutes pertinent to the clinical 
investigation or proposed research, correspondence between the IRB and the investigator, 
investigational product labeling, the investigators brochure (IB), and the IRBs 
assessment of investigator qualifications and research site adequacy; 
  IRB names and contact information (also include institution name for OHRP referrals) 
  For FDA referrals only:  Investigational New Drug application (IND) or Investigational 
Device Exemption (IDE) numbers assigned by FDA if applicable and known  
  For OHRP referrals only:   HHS application number (if applicable) and name of the 
HHS division conducting or supporting the research.  Note: For HHS-supported research, 
OHRP will notify the relevant HHS division supporting the research of the request for 
review of the research under 45 CFR 46.407. 
139   
140  FDA encourages IRBs to submit referrals to FDA as soon as an IRB determines that the clinical 
141  investigation can only proceed under 21 CFR 50.54.  FDA also strongly encourages IRBs to 
142  submit all documents electronically and to submit optical character recognition (OCR)-enabled 
143  electronic versions of all documents.  For instructions on submitting documents electronically to 
144  FDA, IRBs can contact OPT at opt@fda.hhs.gov or by phone at 301-796-1397.  If an IRB is 
145  uncertain about whether to submit a clinical investigation for FDA review under 21 CFR 50.54, 
146  FDA recommends the IRB promptly consult FDA via email (opt@fda.hhs.gov).  FDA will 
147  discuss with the IRB whether the clinical investigation meets the requirements for review under 
5 
   
148  21 CFR 50.54.  FDA may request additional information from the IRB and/or contact the 
149  relevant FDA office or review division to help determine whether the requirements for review 
150  under 21 CFR 50.54 are met. 
151   
152  Similarly, OHRP encourages institutions or IRBs to submit referrals to OHRP as soon as an IRB 
153  determines that the  proposed research can only proceed under 45 CFR 46.407. OHRP also 
154  strongly encourages referring institutions or IRBs to submit all documents electronically and to 
155  submit OCR enabled electronic versions of all documents.  For instructions on submitting 
156  documents electronically, institutions or IRBs can contact OHRP at OHRP@hhs.gov or by 
157  phone at (240) 453-6900. If an institution or IRB is uncertain about whether to submit a research 
158  study for OHRP review under 45 CFR 46.407, OHRP recommends the institution or IRB 
159  promptly consult OHRP via email (OHRP@hhs.gov).  OHRP will discuss with the institution or 
160  IRB whether the research meets the requirements for review under 45 CFR 46.407.  OHRP may 
161  request additional information from the institution or IRB and/or contact the relevant HHS 
162  division supporting or conducting the research to help determine whether the requirements for 
163  review under 45 CFR 46.407 are met. 
164   
165  B.  Assessment of Jurisdiction 
166   
167  When FDA or OHRP receives a referral, either agency will contact the other in order to jointly 
168  determine whether the study is FDA-regulated and/or HHS-supported or -conducted.  If the 
169  study is determined to be both FDA-regulated and HHS-supported or -conducted, FDA and 
170  OHRP will coordinate their assessment of the referral as needed.  In such cases, FDA and 
171  OHRP generally intend to conduct a joint review of the research and will follow the process for 
172  FDA-only assessment of referrals (See VII. PROCESS DIFFERENCES SPECIFIC TO JOINT 
173  FDA AND OHRP REVIEW). 
174   
175  C.  Referral review and acceptance 
176   
177  Depending on to whom the referral was submitted, FDA or OHRP will conduct an initial 
178  assessment to determine whether there is adequate information to proceed with the referral. If the 
179  information submitted is insufficient to enable FDA or OHRP to conduct this initial assessment, 
180  the IRB (or institution) will be promptly notified of any needed information.  
181   
182  If the proposed research fulfills the criteria for consideration under the provisions of 21 CFR 
183  50.54 (FDA) or 45 CFR 46.407 (OHRP), the referral will be accepted and the review process 
184  will be initiated. 
185   
186  For reviews conducted by FDA, FDA will notify the appropriate FDA office and/or review 
187  division to inform it that FDA has accepted a referral to review the clinical investigation under 
188  21 CFR 50.54.  FDA will provide written confirmation9 to the referring IRB that FDA has 
189  accepted its referral.  The IRB should inform the sponsor that a referral under 21 CFR 50.54 
190  has been accepted by FDA. 
191   
192  For reviews conducted by OHRP, OHRP will notify the appropriate HHS division supporting 
 
9 FDA may communicate with the IRB via electronic mail. 
6 
   
193  or conducting the research of the referral acceptance under 45 CFR 46.407. OHRP will provide 
194  written confirmation of acceptance to the referring IRB and/or referring institution through mail 
195  or email.    
196   
197  D.  Referral withdrawal 
198   
199  If an IRB withdraws a referral from FDA or OHRP,10 the agencies encourage the IRB (or 
200  institution) to include the reasons for withdrawal in its withdrawal request and in the IRB 
201  meeting minutes. 
202   
203  IV.  Preparation for Pediatric Advisory Committee (PAC) and Pediatric Ethics 
204  Subcommittee (PES) Meeting (FDA) or Expert Panel Meeting (OHRP) 
205   
206  A.  Federal Register Notice and Docket  
207   
208  FDA or OHRP will issue a Federal Register Notice (FRN) that will include the date and location 
209  of the public meeting, the time available during the meeting for oral presentations from the public, 
210  the establishment of a docket soliciting public comment on the referral, and instructions on how 
211  to access the docket.11    
212   
213    After a referral is accepted by FDA, the Office of Pediatric Therapeutics (OPT) and the 
214  relevant FDA office or review division, will prepare for presentation of the clinical 
215  investigation to a joint meeting of FDAs Pediatric Advisory Committee (PAC) and the 
216  Pediatric Ethics Subcommitee (PES) (referred to in this guidance as the PAC/PES 
217  meeting). FDA will identify for the referring IRB and/or sponsor, as appropriate, the 
218  relevant documents (briefing materials) that the agency intends to post for the PAC/PES 
219  meeting and that may be discussed during the PAC/PES meeting.12 FDA will post the 
220  briefing materials for the PAC/PES meeting on the FDA website. FDA intends to close 
221  the docket 24 hours after the PAC/PES meeting because consideration of public comments 
222  by the PAC/PES will have been completed.  
223    Review of referrals to OHRP will be conducted by an expert panel comprised of 
224  individuals selected for their expertise relevant to the specific referral. OHRP will post 
225  referral materials in a public docket, including a notice that the panelists individual 
226  recommendations will be publicly posted in the established docket after the expert panel 
227  meeting. OHRP will identify for the referring IRB or referring institution and HHS 
228  division supporting or conducting the research, as appropriate, the relevant documents 
 
10 The IRBs reasons for withdrawal of the referral could include, but are not limited to, a misunderstanding of the 
requirements of the subpart D regulations, a misinterpretation of the applicability of 21 CFR 50.54 or 45 CFR 
46.407 to the clinical investigation, or submission of a protocol modification by the sponsor to the IRB such that the 
IRB determines the clinical investigation is approvable under another subpart D provision (i.e., 21 CFR 50.51, 50.52 
or 50.53 or 45 CFR 46.404, 46.405 or 46.406).  
11 OHRP and FDA will post information about how to access the docket on their respective websites. 
12 For further information on the preparation of advisory committee briefing materials for FDA advisory committee 
meetings and the timelines for preparing and posting such materials, see FDAs Guidance for Industry, Advisory 
Committee Meetings  Preparation and Public Availability of Information Given to Advisory Committee Members, 
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/preparation-and-public-
availability-information-given-advisory-committee-members.  
7 
   
229  that it intends to post in the public docket.  To allow time for public comments on the 
230  panelists individual recommendations, the docket will remain open for 30 days after the 
231  date of the expert panel meeting. 
232   
233  B.  Documents and Public Review 
234   
235  The documents supporting the referral13 may include information that, under certain 
236  circumstances, could be considered confidential and exempt from public disclosure.  This 
237  information may include trade secret information (TSI), confidential commercial information 
238  (CCI), or personal privacy information (PPI) (including personally identifiable information).  
239   
240  After obtaining any necessary agreements and permissions from the IRB and/or sponsor, as 
241  discussed below, and documents are appropriately redacted, the agency will publicly post the 
242  referral documents (on FDAs website, for referrals to FDA, and in a public docket, for 
243  referrals to OHRP) as soon as possible after the public announcement of the meeting in the 
244  Federal Register.  
245   
246  FDA-specific information:  
247  All FDA advisory committee members who are special government employees have access to 
248  nonpublic information in advisory committee briefing materials and are bound by the same 
249  confidentiality protections as all other government employees.  The PAC/PES members will be 
250  reminded that TSI, CCI, and PPI must not be revealed during the PAC/PES meeting. 
251   
252  As noted above, FDA will identify for the referring IRB and/or sponsor, as appropriate, the 
253  relevant documents that the agency intends to post for the PAC/PES meeting to meet the 
254  requirement for public review and comment and that may be discussed during the PAC/PES 
255  meeting.  As appropriate, the agency will include redactions of information that could be 
256  considered TSI, CCI, or PPI.   If the IRB and/or sponsor objects to the disclosure of any 
257  documents or information identified by FDA for public posting and discussion, FDA will work 
258  with the IRB and/or sponsor toensure that any redactions will not negatively impact either the 
259  opportunity for public review and comment that is required under the regulation or the 
260  discussion of the clinical investigation at the PAC/PES meeting.   
261   
262  If redactions requested by the IRB and/or sponsor are such that either the requirement for an 
263  opportunity for public review would not be met or the discussion at the PAC/PES meeting 
264  would be significantly limited, FDA may be unable to proceed with the referral.  If this were to 
265  occur, the clinical investigation would not be authorized to proceed.  If the IRB and/or sponsor, 
266  as appropriate, agrees to the public availability of the documents or information identified by 
267  FDA (either with or without redactions), FDA will work with the IRB and/or sponsor to 
268  document the agreement.   
269   
270  FDA will schedule the PAC/PES meeting based on the urgency of the request.14  FDA will 
 
13 Documents supporting the referral include, e.g., the research protocol, parental/guardian permission and assent 
forms, and IRB meeting minutes. 
14 The PAC is currently scheduled to meet approximately two times per year. The PES is convened on an as-
 
8 
   
271  schedule the PAC/PES meeting directly preceding a regularly scheduled PAC meeting or will 
272  expedite consideration of the referral by convening a separate PAC/PES meeting scheduled 
273  specifically to handle the referral.15   
274   
275   
276  OHRP specific information: 
277  All expert panel members will be bound by confidentiality agreements and informed that TSI, 
278  CCI, and PPI will not be discussed during the panels public deliberations.  
279   
280  As noted above, OHRP will identify for the referring IRB or referring institution and HHS 
281  division supporting or conducting the research, as appropriate, the relevant documents that it 
282  intends to post in the public docket.  OHRP reserves the right to permit redactions prior to 
283  including the documents supporting the referral in the public docket.  OHRP will work with the 
284  IRB or referring institution or HHS division supporting or conducting the research to ensure 
285  that the information redacted will not impact public review and discussion of the research.  If 
286  the IRB or referring institution or HHS division supporting or conducting the research objects 
287  to the disclosure of any nonpublic documents or information in the documents identified by 
288  OHRP for public posting and discussion, OHRP will work with the IRB or referring institution 
289  and/or sponsor to ensure that any redactions will not negatively impact either the opportunity 
290  for public review and comment that is required under the regulation or the discussion of the 
291  research at the expert panel meeting.  
292   
293  If redactions requested by the IRB or referring institution and/or HHS division supporting or 
294  conducting the research are such that either the requirement would not be met or the discussion 
295  at the expert panel meeting would be significantly limited, OHRP may be unable to proceed 
296  with the referral. In this case, the research protocol would not be authorized to proceed.  If the 
297  IRB or HHS division supporting or conducting the research, as appropriate, agrees to the public 
298  availability of the documents or information (either with or without redactions) identified by 
299  OHRP, OHRP will work with the IRB or HHS division to document the agreement.  
300   
301  V.  PAC/PES (FDA) or Expert Panel (OHRP) Meeting 
302   
303  A.  Composition  
304   
305  FDA selects the members of the PAC/PES in accordance with 21 CFR 50.54(b) and other 
306  relevant federal laws and regulations, including the Federal Advisory Committee Act (FACA) 
307  (5 U.S.C. App. 2) (1972).  FDA will invite additional individuals to participate on the PAC/PES 
308  to ensure the subcommittee consists of a panel of experts in pertinent disciplines (for example: 
309  science, medicine, education, ethics, law).16  
 
needed basis to address ethics issues as they arise. For the purposes of a 21 CFR 50.54 review, the meeting will 
always be a held as a joint PAC/PES meeting. 
15 A minimum of 8 to 10 weeks is generally necessary between the acceptance of the referral and the PAC/PES 
meeting date because of the time needed to issue the FRN announcing the meeting and prepare the relevant 
materials (see Sections III.E.4 and III.E.5). Thus, unless a referral is submitted more than 8-10 weeks in advance of 
an already scheduled PAC meeting, it generally will not be possible to add the referral to the agenda for that 
meeting. 
16 See 21 CFR 50.54(b).    
9 
   
310   
311  OHRP will identify a panel of experts in pertinent disciplines per 45 CFR 46.407(b) (e.g., 
312  science, medicine, education, ethics, law), and child advocates with experience relevant to the 
313  protocol, to review the research.  Potential experts will be informed that they will each provide 
314  written recommendations discussing whether the proposed research satisfies the criteria at 
315  46.407(b)(1) or (2), and that their recommendations, as well as their identity as the author of the 
316  recommendations, will be publicly available in the docket for public review and comment. 
317   
318  B.  Attendees 
319   
320  The meeting will be open to the public and public participation is encouraged.  The agencies 
321  encourage the IRB, the sponsor (if appropriate), and the investigator(s) to attend the meeting to 
322  assist the members in understanding the clinical investigation or proposed research and provide 
323  an opportunity for the members to ask questions regarding the basis for the referral.  
324   
325  As appropriate, additional individuals (e.g., representative(s) from patient advocacy group(s), 
326  subject matter expert(s)) will be invited to make presentations regarding the referred clinical 
327  investigation/proposed research or related issues of concern. 
328   
329  For PAC/PES meetings, FDA will invite the referring IRB and the sponsor to present relevant 
330  information about the clinical investigation at the meeting. One or more representatives from the 
331  FDA office and/or review division responsible for reviewing the clinical investigation also may 
332  attend the PAC/PES meeting to answer questions about the clinical investigation or any related 
333  issues. 
334   
335  C.  Meeting Content 
336   
337  Although an IRB (or institution) may make a referral for review because of a particular aspect 
338  of the clinical investigation or proposed research (e.g., entry criteria, planned procedure), the 
339  agencies intend to request input and recommendations on the clinical investigation or proposed 
340  research in its entirety. 
341   
342  The chair of the meeting will provide a summary of public comments submitted to the docket 
343  before the meeting.   
344   
345  D.  Recommendation(s) 
346   
347  For PAC/PES meetings, after deliberation and discussion of the clinical investigation, the 
348  PAC/PES will vote on whether to recommend that the proposed clinical investigation may 
349  proceed under 21 CFR 50.51, 50.52, 50.53 or 50.54.17 The PAC/PES members will not write 
350  individual recommendations regarding whether the research meets the criteria in 21 CFR 
351  50.54(b)(1) or (2).  
352   
 
17 Although the PAC/PES meeting will focus on whether the clinical investigation is approvable under 21 CFR part 
50 subpart D, the clinical investigation also must comply with all other applicable requirements, including but not 
limited to those in 21 CFR part 50, subparts A and B, and in 21 CFR part 56. 
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353  For OHRP expert panel meetings, after deliberation and discussion of the proposed research, 
354  each panel member will write an individual recommendation discussing whether the research 
355  meets the criteria of 45 CFR 46.407(b)(1) or (2). OHRP will post the individual panel member 
356  recommendations in the docket.  To allow time for comments on the posted expert panel 
357  recommendations, the public may continue to provide comments in the docket for 30 days after 
358  the date of the expert panel meeting. 
359   
360   
361  VI.  Final Determination 
362   
363  FDA specific information:  
364  After the PAC/PES meeting, FDA staff will develop and send a memorandum that outlines the 
365  PAC/PES recommendation(s) and that includes any FDA staff comments and 
366  recommendations, as well as relevant supporting documents, to the FDA Commissioner (or 
367  delegee).  The memorandum may include recommended changes to the research protocol and/or 
368  changes to the parental/guardian permission and assent forms that the PAC/PES and/or FDA 
369  staff believe are necessary for the clinical investigation to proceed under subpart D, as well as 
370  any suggested changes that might enhance the clinical investigation (e.g., strategies to ease study 
371  burden on patients and care providers, strategies to improve trial enrollment).  The 
372  memorandum will request the Commissioner (or delegee) make a final determination as to 
373  whether, and if so, under which provisions of subpart D, the clinical investigation may 
374  proceed.  
375   
376  After the Commissioner (or delegee) has made a final determination, FDA intends to forward 
377  the determination to the IRB and post the final determination on the FDA website within 90 
378  days of the PAC/PES meeting or as soon as practicable thereafter.  FDA will post the 
379  PAC/PES transcripts and meeting documents on the FDA website when available. 
380   
381  OHRP specific information:  
382  After the OHRP expert panel meeting, OHRP will develop a recommendation for the Assistant 
383  Secretary for Health (ASH) based on panel deliberations, reports, public comments, and its own 
384  analysis.  The recommendation may include changes to the research protocol and/or changes to 
385  the parental/guardian permission and assent forms that an expert panelist or OHRP staff believe 
386  are necessary for the research to proceed under subpart D, as well as any suggested changes that 
387  might enhance the research (e.g., strategies to ease study burden on patients and care providers, 
388  strategies to improve trial enrollment).  OHRP then will submit its recommendation and relevant 
389  documents to the ASH.  After review of the relevant materials and OHRPs recommendation, the 
390  ASH, on behalf of the HHS Secretary, will make the final determination regarding whether the 
391  research may proceed under 45 CFR 46.404, 46.405, 46.406, or 46.407. 
392   
393  OHRP will inform the referring institution and/or IRB chair, the investigator, and the HHS 
394  division supporting or conducting the research of the ASHs determination and post its 
395  recommendation to the ASH and the ASHs final determination in the established docket within 
396  90 days of the expert panel meeting or as soon asas practicable thereafter.  
397   
398  VII.  PROCESS DIFFERENCES SPECIFIC TO JOINT FDA AND OHRP REVIEW  
399   
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400  As noted above, for research that FDA and OHRP determine is both HHS-conducted or -
401  supported and FDA-regulated, FDA and OHRP generally intend to conduct a joint review of the 
402  research and will follow the process for FDA-only assessment of referrals.  Unique aspects of 
403  the joint subpart D review process include: 
404    FDA will communicate with the IRB and sponsor, and institution if appropriate, on 
405  behalf of both FDA and OHRP. 
406    FDA will post documents related to the joint review to the FDA website.  OHRP will not 
407  post documents to a federal docket and will instead post a link to the FDA website on the 
408  OHRP website. 
409    FDA will convene a PAC/PES meeting, which will serve as the expert panel meeting for 
410  both FDA and OHRP (see Section IV). 
411    OHRP will participate with FDA in the selection of members for the PAC/PES meeting;   
412    OHRP will participate with FDA in the PAC/PES meeting. 
413    The ASH, acting on behalf of the Secretary, will make the determination whether the 
414  research is approvable under 45 CFR 46.407 after the FDA Commissioner (or delegee) 
415  has determined whether the clinical investigation is approvable under 21 CFR 50.54. 
416    After the PAC/PES makes its recommendation(s) on whether the clinical 
417  investigation may proceed under 21 CFR part 50, subpart D, and 45 CFR part 46, 
418  subpart D, FDA staff will submit a memorandum outlining the PAC/PES 
419  recommendation(s), FDA staff recommendations, and the supporting documents to 
420  the FDA Commissioner (or delegee). 
421    The FDA Commissioner (or delegee) will determine whether the clinical 
422  investigation may proceed under 21 CFR 50.54.  
423    FDA will forward a memorandum outlining the PAC/PES recommendation(s), FDA 
424  staff recommendations, and the Commissioners (or delegees) determination to 
425  OHRP. 
426    OHRP will formulate a recommendation to the ASH based on the findings of the 
427  PAC, the FDA Commissioners (or delegees) determination, public comments, and 
428  OHRP internal review. 
429    OHRP will send a memorandum with the PAC/PES recommendation(s), the FDA 
430  Commissioners (or delegees) determination, OHRPs recommendation(s) and all 
431  supporting documents to the ASH.  The ASH, acting on behalf of the Secretary, will 
432  make the determination whether the research may proceed under 45 CFR 46.404, 
433  46.405, 46.406, or 46.407.  
434   
435  Determinations of the ASH and the FDA Commissioner (or delegee) will be posted by FDA 
436  and OHRP and forwarded to the referring IRB or referring institution, investigator, and/or HHS 
437  Division, as appropriate, within 90 days of the PAC/PES meeting or as soon as practicable 
438  thereafter. 
439   
440  VIII.  MULTISITE RESEARCH 
441   
442  In some circumstances, research referred for review under FDA and/or HHS regulations might 
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443  be conducted at multiple sites or institutions, and as such, be reviewed by more than one IRB.18  
444  If an IRBfor one or more of the clinical sites refers the research for review, the IRB should 
445  notify the sponsor or HHS division supporting or conducting the research.  In this situation, 
446  FDA and OHRP strongly encourage the sponsor or relevant HHS division to notify all other 
447  study site IRB(s) and investigator(s) of the referral.  
448   
449  For multisite research regulated by FDA and conducted under an IND or IDE, if an IRB makes 
450  a referral under 21 CFR 50.54, FDA will determine whether the clinical investigation may 
451  proceed (or continue, if enrollment has already begun at one or more sites) or will be placed on 
452  clinical hold.19  In the case of a referral regarding an investigation for which an IDE application 
453  (or supplement) is pending, FDA may also consider other actions.20  If FDA concludes that a 
454  clinical hold is appropriate, the agency generally intends to apply that clinical hold to all sites, 
455  regardless of whether IRBs other than the one that referred the protocol have approved the 
456  protocol.  While the 21 CFR 50.54 review is underway, FDA will inform the sponsor whether 
457  the clinical investigation has been placed on clinical hold and the sponsor must then notify 
458  investigators if the clinical investigation has been placed on clinical hold.21 The sponsor also 
459  should inform the other study site IRBs.22 
460   
461  For multisite research regulated by OHRP, that does not require, or is excepted from the 
462  requirement for, single IRB review under 45 CFR 46.114, the HHS division supporting or 
463  conducting the research may consider the implications of the 45 CFR 46.407 review process on 
464  the conduct of the research at other HHS supported sites and whether, if consistent with 
465  applicable law, to delay or suspend subject enrollment at these other sites pending the outcome 
466  of the 45 CFR 46.407 review.   
467   
468   
469  IX.  FDA AND OHRP REVIEW OF SIMILAR RESEARCH  
470   
471  FDA and OHRP recognize that there may be situations in which it would be appropriate for the 
472  Commissioner (or delegee) and/or the ASH to rely on previous PAC/PES or expert panel 
473  consideration of a similar research protocol in order to review a newly referred protocol.  FDA 
474  and OHRP note that the subpart D regulations do not specify that the expert panel review of the 
475  research must occur after the IRB referral for review.  
476   
477  FDA and/or OHRP will consider reviewing research submitted to FDA and/or OHRP for subpart 
478  D review under an abbreviated process if the research is similar to research that FDA and/or 
479  OHRP has already reviewed under subpart D and determined may proceed.  This abbreviated 
 
18 Under 45 CFR 46.114, any institution located in the United States that is engaged in cooperative research (i.e., 
research that involves more than one institution) must rely upon approval by a single IRB for that portion of the 
research that is conducted in the United States (45 CFR 46.114(b)(1)) unless one of the exceptions at 45 CFR 
46.114(b)(2) applies. 
19 For clinical investigations being conducted under an IND, see 21 CFR 312.42(b).  For clinical investigations 
being conducted under an IDE, see section 520(g)(8) of the FD&C Act.  
20 FDA may approve, approve with conditions, or disapprove a pending IDE application. See 21 CFR 812.30. 
21 21 CFR 312.42(a), 312.50, and 812.40. 
22 For device investigations that require submission of an IDE application, sponsors must ensure that any reviewing 
IRB is promptly informed of significant new information about an investigation. 21 CFR 812.40. 
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480  process would necessitate that FDA and/or OHRP determine the newly referred research is 
481  sufficiently similar to the previously reviewed research such that the previous referral and review 
482  are applicable to the newly referred research; such determinations are anticipated to be rare. 
483   
484  If FDA and/or OHRP conduct an abbreviated review process, FDA and/or OHRP will include in 
485  the information posted to the FDA website and/or OHRP docket (see Section III.E.2 and IV.E.2) 
486  the determination by the Commissioner and/or ASH for the previous referral as well as relevant 
487  background information from the previous referral.  FDA and/or OHRP will publish an FRN to 
488  solicit public comments on the newly referred research.  For FDA subpart D reviews conducted 
489  under an abbreviated process, the FRN will include a link to the relevant documents and 
490  background information on the FDA website, notice of the establishment of a docket for 
491  comments, and directions for accessing the docket.  For OHRP subpart D reviews conducted 
492  under an abbreviated process, the FRN will include notice of the establishment of a docket for 
493  posting relevant documents and background information and comments, and directions for 
494  accessing the docket. The docket will remain open for 30 days.     
495   
496  The responsible agency(ies) will review the public comments submitted to the newly established 
497  docket(s).  Based on the review of comments, FDA and/or OHRP may either decide a 
498  determination may be issued without additional PAC/PES or expert panel review, or that a new 
499  PAC/PES or expert panel review is needed.  If a new PAC/PES meeting or expert panel is 
500  convened, the review under the subpart D regulations will proceed as outlined above.  
501  Alternatively, FDA and/or OHRP may decide that no further PAC/PES or expert panel review 
502  are necessary.  In this situation, FDA and/or OHRP will prepare a recommendation for the 
503  Commissioner (or delegee) and/or ASH and the subsequent final determination by the 
504  Commissioner (or delegee) and/or ASH regarding the newly referred protocol will be posted to 
505  the FDA website, with a reference to the FDA docket, and/or will be posted to the OHRP docket, 
506  as applicable.  
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