Draft Guidance on Research Involving Children as Subjects and Not Otherwise Approvable by an Institutional Review Board: Process for Referrals to Food and Drug Administration and Office for Human Research Protections

On March 31, 2023, a Federal Register notice (PDF 202 KB) announced the availability of draft guidance, “Research Involving Children as Subjects and Not Otherwise Approvable by an Institutional Review Board: Process for Referrals to Food and Drug Administration and Office for Human Research Protections, Guidance for Institutional Review Boards, Investigators, and Sponsors.” The draft guidance was jointly issued by the HHS Office for Human Research Protections and the Food and Drug Administration. Comments on the draft guidance are invited through May 30, 2023, and should be made as described in the Federal Register notice, citing Docket Number FDA-2022-D-0142. The text of the draft guidance document appears below and is also available on the FDA website.

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Draft Guidance

This guidance document is being distributed for comment purposes only.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.

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

Table of Contents

I. Introduction

II. Background

III. Referral, Review, and Outcomes

A. Referral

B. Assessment of Jurisdiction

C. Referral review and acceptance

D. Referral withdrawal

IV. Preparation for Pediatric Advisory Committee (PAC) and the Pediatric Ethics Subcommittee (PES)(FDA) or Expert Panel (OHRP) Meeting

A. Federal Register Notice and Docket

B. Documents and Public Review

V. PAC/PES (FDA) or Expert Panel (OHRP) Meeting

A. Composition

B. Attendees

C. Meeting Content

D. Recommendation(s)

VI. Final Determination

VII. Process Differences Specific to joint FDA and OHRP Review

VIII. Multisite Research

IX. FDA and OHRP Review of Similar Research

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

This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP) on this topic.  It does not establish any rights for any person and is not binding on FDA, OHRP, or the public.  You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA or OHRP staff responsible for this guidance as listed on the title page. 

I. Introduction

This guidance is intended to assist institutional review boards (IRBs), institutions, investigators, and sponsors in understanding the processes used for review of research involving children as subjects that is not otherwise approvable by an IRB and has been referred to the Food and Drug Administration (FDA) under 21 CFR 50.54, the Office for Human Research Protections (OHRP) under 45 CFR 46.407, or both, for review.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s 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 Agency guidances means that something is suggested or recommended, but  not required.

II. Background

The Department of Health and Human Services (HHS) issued 45 CFR part 46, subpart D, “Additional Protections for Children Involved as Subjects in Research,” as a final rule on March 8, 1983 (48 FR 9814).  FDA issued 21 CFR part 50, subpart D, “Additional Safeguards for Children in Clinical Investigations of Food and Drug Administration-Regulated Products,” as a final rule on February 26, 2013 (78 FR 12937).  These regulations, hereinafter referred to collectively as “subpart D,” are similar, with some minor differences.¹

FDA’s subpart D regulations apply to clinical investigations² regulated by FDA as described in 21 CFR 50.1(a).   HHS’s subpart D regulations apply to all research³ involving human subjects and conducted or supported by HHS, in accordance with 45 CFR 46.101(a).  FDA-regulated clinical investigations conducted or supported by HHS are subject to both sets of regulations.  As a result, many sponsors,⁴ investigators,⁵ and IRBs need to be familiar with and comply with both FDA’s and HHS’s regulations.⁶  Under both of these regulations, an IRB must review research⁷ involving children as subjects under subpart D and may only approve research satisfying the following applicable regulations (as well as the requirements of all other applicable provisions of subpart D):

• 21 CFR 50.51 and 45 CFR 46.404:  Research not involving greater than minimal risk.
• 21 CFR 50.52 and 45 CFR 46.405:  Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects.
• 21 CFR 50.53 and 45 CFR 46.406:  Research involving no more than a minor increase over minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition.

If an IRB does not find that research involving children as subjects meets the requirements of 21 CFR 50.51, 50.52 or 50.53 (FDA regulations); 45 CFR 46.404, 46.405 or 46.406 (HHS regulations); or both as applicable, the research may proceed only if the following criteria in 21 CFR 50.54, 45 CFR 46.407, or both as applicable, are satisfied:

• The IRB finds 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; and
• The Commissioner of Food and Drugs (Commissioner), the Secretary of the Department of Health and Human Services (HHS) (Secretary),⁸ or both as applicable, 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 research in fact satisfies 21 CFR 50.51, 50.52 or 50.53; 45 CFR 46.404, 46.405, or 46.406; or both sets of regulations as applicable, or
  • The following three conditions are met:
    • 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 will be conducted in accordance with sound ethical principles; and
    • Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians as set forth in 21 CFR 50.55, 45 CFR 46.408, or both as applicable.

An IRB may refer research involving children as subjects to FDA and/or OHRP for review under 21 CFR 50.54 or 45 CFR 46.407, as applicable.  Regardless of the agency to which the referral is submitted, both FDA and OHRP intend to consult with each other on any referrals received under 21 CFR 50.54 and 45 CFR 46.407 to ensure the appropriate agency has been notified and to determine whether a joint review (i.e., a review by both FDA and OHRP) is needed.

Consistent with 21 CFR 50.1(a), the requirements of 21 CFR part 50, subpart D, apply to clinical investigations regulated under sections 505(i) and 520(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. § 355(i) and 360j(g)), as well as those that support applications for research or marketing permits for certain products regulated by FDA.  The 21 CFR part 50, subpart D requirements are separate from the investigational new drug application (IND) requirements in section 505(i) of the FD&C Act and 21 CFR part 312.  Therefore, 21 CFR part 50, subpart D, applies to all FDA-regulated clinical investigations of drug or biological products, including those that are IND-exempt per 21 CFR 312.2(b)(iv).  Similarly, 21 CFR part 50, subpart D, applies to all FDA-regulated clinical investigations of devices, including those that are exempt from most provisions of the investigational device exemption (IDE) regulations under 21 CFR 812.2(c).  Furthermore, as indicated in 21 CFR 50.1(a), part 50 also applies to certain clinical investigations of other types of FDA-regulated products (e.g., food additives, infant formulas, new dietary ingredients).  These clinical investigations are also subject to the review process under 21 CFR 50.54.

III. Referral, Review, and Outcomes

After making the required determinations (as described above), the IRB should refer the study to FDA and/or OHRP following the details described below. 

A. Referral

The following table outlines the process that should be followed when referring a study to FDA and/or OHRP for review.  Where necessary, the differences between FDA and OHRP are identified.

A referral should include:

• The IRB’s 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 IRB’s 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, investigator’s 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 investigator’s brochure (IB), and the IRB’s 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.

FDA encourages IRBs to submit referrals to FDA as soon as an IRB determines that the clinical investigation can only proceed under 21 CFR 50.54.  FDA also strongly encourages IRBs to submit all documents electronically and to submit optical character recognition (OCR)-enabled electronic versions of all documents.  For instructions on submitting documents electronically to FDA, IRBs can contact OPT at opt@fda.hhs.gov or by phone at 301-796-1397.  If an IRB is uncertain about whether to submit a clinical investigation for FDA review under 21 CFR 50.54, FDA recommends the IRB promptly consult FDA via email (opt@fda.hhs.gov).  FDA will discuss with the IRB whether the clinical investigation meets the requirements for review under 21 CFR 50.54.  FDA may request additional information from the IRB and/or contact the relevant FDA office or review division to help determine whether the requirements for review under 21 CFR 50.54 are met.

Similarly, OHRP encourages institutions or IRBs to submit referrals to OHRP as soon as an IRB determines that the  proposed research can only proceed under 45 CFR 46.407. OHRP also strongly encourages referring institutions or IRBs to submit all documents electronically and to submit OCR enabled electronic versions of all documents.  For instructions on submitting documents electronically, institutions or IRBs can contact OHRP at OHRP@hhs.gov or by phone at (240) 453-6900. If an institution or IRB is uncertain about whether to submit a research study for OHRP review under 45 CFR 46.407, OHRP recommends the institution or IRB promptly consult OHRP via email (OHRP@hhs.gov).  OHRP will discuss with the institution or IRB whether the research meets the requirements for review under 45 CFR 46.407.  OHRP may request additional information from the institution or IRB and/or contact the relevant HHS division supporting or conducting the research to help determine whether the requirements for review under 45 CFR 46.407 are met.

B. Assessment of Jurisdiction

When FDA or OHRP receives a referral, either agency will contact the other in order to jointly determine whether the study is FDA-regulated and/or HHS-supported or -conducted.  If the study is determined to be both FDA-regulated and HHS-supported or -conducted, FDA and OHRP will coordinate their assessment of the referral as needed.  In such cases, FDA and OHRP generally intend to conduct a joint review of the research and will follow the process for FDA-only assessment of referrals (See VII. Process differences specific to joint FDA and OHRP review).

C. Referral review and acceptance

Depending on to whom the referral was submitted, FDA or OHRP will conduct an initial assessment to determine whether there is adequate information to proceed with the referral. If the information submitted is insufficient to enable FDA or OHRP to conduct this initial assessment, the IRB (or institution) will be promptly notified of any needed information.

If the proposed research fulfills the criteria for consideration under the provisions of 21 CFR 50.54 (FDA) or 45 CFR 46.407 (OHRP), the referral will be accepted and the review process will be initiated.

For reviews conducted by FDA, FDA will notify the appropriate FDA office and/or review division to inform it that FDA has accepted a referral to review the clinical investigation under 21 CFR 50.54.  FDA will provide written confirmation⁹ to the referring IRB that FDA has accepted its referral.  The IRB should inform the sponsor that a referral under 21 CFR 50.54 has been accepted by FDA.

For reviews conducted by OHRP, OHRP will notify the appropriate HHS division supporting or conducting the research of the referral acceptance under 45 CFR 46.407. OHRP will provide written confirmation of acceptance to the referring IRB and/or referring institution through mail or email.   

D. Referral withdrawal

If an IRB withdraws a referral from FDA or OHRP,¹⁰ the agencies encourage the IRB (or institution) to include the reasons for withdrawal in its withdrawal request and in the IRB meeting minutes.

IV. Preparation for Pediatric Advisory Committee (PAC) and Pediatric Ethics Subcommittee (PES) Meeting (FDA) or Expert Panel Meeting (OHRP)

A. Federal Register Notice and Docket

FDA or OHRP will issue a Federal Register Notice (FRN) that will include the date and location of the public meeting, the time available during the meeting for oral presentations from the public, the establishment of a docket soliciting public comment on the referral, and instructions on how to access the docket.¹¹

• After a referral is accepted by FDA, the Office of Pediatric Therapeutics (OPT) and the relevant FDA office or review division, will prepare for presentation of the clinical investigation to a joint meeting of FDA’s Pediatric Advisory Committee (PAC) and the Pediatric Ethics Subcommitee (PES) (referred to in this guidance as the PAC/PES meeting). FDA will identify for the referring IRB and/or sponsor, as appropriate, the relevant documents (briefing materials) that the agency intends to post for the PAC/PES meeting and that may be discussed during the PAC/PES meeting.¹² FDA will post the briefing materials for the PAC/PES meeting on the FDA website. FDA intends to close the docket 24 hours after the PAC/PES meeting because consideration of public comments by the PAC/PES will have been completed.
• Review of referrals to OHRP will be conducted by an expert panel comprised of individuals selected for their expertise relevant to the specific referral. OHRP will post referral materials in a public docket, including a notice that the panelists’ individual recommendations will be publicly posted in the established docket after the expert panel meeting. OHRP will identify for the referring IRB or referring institution and HHS division supporting or conducting the research, as appropriate, the relevant documents that it intends to post in the public docket.  To allow time for public comments on the panelists’ individual recommendations, the docket will remain open for 30 days after the date of the expert panel meeting.

B. Documents and Public Review

The documents supporting the referral¹³ may include information that, under certain circumstances, could be considered confidential and exempt from public disclosure.  This information may include trade secret information (TSI), confidential commercial information (CCI), or personal privacy information (PPI) (including personally identifiable information).

After obtaining any necessary agreements and permissions from the IRB and/or sponsor, as discussed below, and documents are appropriately redacted, the agency will publicly post the referral documents (on FDA’s website, for referrals to FDA, and in a public docket, for referrals to OHRP) as soon as possible after the public announcement of the meeting in the Federal Register.

FDA-specific information: 
All FDA advisory committee members who are special government employees have access to nonpublic information in advisory committee briefing materials and are bound by the same confidentiality protections as all other government employees.  The PAC/PES members will be reminded that TSI, CCI, and PPI must not be revealed during the PAC/PES meeting.

As noted above, FDA will identify for the referring IRB and/or sponsor, as appropriate, the relevant documents that the agency intends to post for the PAC/PES meeting to meet the requirement for public review and comment and that may be discussed during the PAC/PES meeting.  As appropriate, the agency will include redactions of information that could be considered TSI, CCI, or PPI.   If the IRB and/or sponsor objects to the disclosure of any documents or information identified by FDA for public posting and discussion, FDA will work with the IRB and/or sponsor toensure that any redactions will not negatively impact either the opportunity for public review and comment that is required under the regulation or the discussion of the clinical investigation at the PAC/PES meeting. 

If redactions requested by the IRB and/or sponsor are such that either the requirement for an opportunity for public review would not be met or the discussion at the PAC/PES meeting would be significantly limited, FDA may be unable to proceed with the referral.  If this were to occur, the clinical investigation would not be authorized to proceed.  If the IRB and/or sponsor, as appropriate, agrees to the public availability of the documents or information identified by FDA (either with or without redactions), FDA will work with the IRB and/or sponsor to document the agreement. 

FDA will schedule the PAC/PES meeting based on the urgency of the request.¹⁴  FDA will schedule the PAC/PES meeting directly preceding a regularly scheduled PAC meeting or will expedite consideration of the referral by convening a separate PAC/PES meeting scheduled specifically to handle the referral.¹⁵

OHRP specific information:
All expert panel members will be bound by confidentiality agreements and informed that TSI, CCI, and PPI will not be discussed during the panel’s public deliberations.

As noted above, OHRP will identify for the referring IRB or referring institution and HHS division supporting or conducting the research, as appropriate, the relevant documents that it intends to post in the public docket.  OHRP reserves the right to permit redactions prior to including the documents supporting the referral in the public docket.  OHRP will work with the IRB or referring institution or HHS division supporting or conducting the research to ensure that the information redacted will not impact public review and discussion of the research.  If the IRB or referring institution or HHS division supporting or conducting the research objects to the disclosure of any nonpublic documents or information in the documents identified by OHRP for public posting and discussion, OHRP will work with the IRB or referring institution and/or sponsor to ensure that any redactions will not negatively impact either the opportunity for public review and comment that is required under the regulation or the discussion of the research at the expert panel meeting.

If redactions requested by the IRB or referring institution and/or HHS division supporting or conducting the research are such that either the requirement would not be met or the discussion at the expert panel meeting would be significantly limited, OHRP may be unable to proceed with the referral. In this case, the research protocol would not be authorized to proceed.  If the IRB or HHS division supporting or conducting the research, as appropriate, agrees to the public availability of the documents or information (either with or without redactions) identified by OHRP, OHRP will work with the IRB or HHS division to document the agreement.

V. PAC/PES (FDA) or Expert Panel (OHRP) Meeting

A. Composition

FDA selects the members of the PAC/PES in accordance with 21 CFR 50.54(b) and other relevant federal laws and regulations, including the Federal Advisory Committee Act (FACA) (5 U.S.C. App. 2) (1972).  FDA will invite additional individuals to participate on the PAC/PES to ensure the subcommittee consists of a “panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law).”¹⁶

OHRP will identify a panel of experts in pertinent disciplines per 45 CFR 46.407(b) (e.g., science, medicine, education, ethics, law), and child advocates with experience relevant to the protocol, to review the research.  Potential experts will be informed that they will each provide written recommendations discussing whether the proposed research satisfies the criteria at 46.407(b)(1) or (2), and that their recommendations, as well as their identity as the author of the recommendations, will be publicly available in the docket for public review and comment.

B. Attendees

The meeting will be open to the public and public participation is encouraged.  The agencies encourage the IRB, the sponsor (if appropriate), and the investigator(s) to attend the meeting to assist the members in understanding the clinical investigation or proposed research and provide an opportunity for the members to ask questions regarding the basis for the referral.

As appropriate, additional individuals (e.g., representative(s) from patient advocacy group(s), subject matter expert(s)) will be invited to make presentations regarding the referred clinical investigation/proposed research or related issues of concern.

For PAC/PES meetings, FDA will invite the referring IRB and the sponsor to present relevant information about the clinical investigation at the meeting. One or more representatives from the FDA office and/or review division responsible for reviewing the clinical investigation also may attend the PAC/PES meeting to answer questions about the clinical investigation or any related issues.

C. Meeting Content

Although an IRB (or institution) may make a referral for review because of a particular aspect of the clinical investigation or proposed research (e.g., entry criteria, planned procedure), the agencies intend to request input and recommendations on the clinical investigation or proposed research in its entirety.

The chair of the meeting will provide a summary of public comments submitted to the docket before the meeting.  

D. Recommendation(s)

For PAC/PES meetings, after deliberation and discussion of the clinical investigation, the PAC/PES will vote on whether to recommend that the proposed clinical investigation may proceed under 21 CFR 50.51, 50.52, 50.53 or 50.54.¹⁷ The PAC/PES members will not write individual recommendations regarding whether the research meets the criteria in 21 CFR 50.54(b)(1) or (2).

For OHRP expert panel meetings, after deliberation and discussion of the proposed research, each panel member will write an individual recommendation discussing whether the research meets the criteria of 45 CFR 46.407(b)(1) or (2). OHRP will post the individual panel member recommendations in the docket.  To allow time for comments on the posted expert panel recommendations, the public may continue to provide comments in the docket for 30 days after the date of the expert panel meeting.

VI. Final Determination

FDA specific information: 
After the PAC/PES meeting, FDA staff will develop and send a memorandum that outlines the PAC/PES recommendation(s) and that includes any FDA staff comments and recommendations, as well as relevant supporting documents, to the FDA Commissioner (or delegee).  The memorandum may include recommended changes to the research protocol and/or changes to the parental/guardian permission and assent forms that the PAC/PES and/or FDA staff believe are necessary for the clinical investigation to proceed under subpart D, as well as any suggested changes that might enhance the clinical investigation (e.g., strategies to ease study burden on patients and care providers, strategies to improve trial enrollment).  The memorandum will request the Commissioner (or delegee) make a final determination as to whether, and if so, under which provisions of subpart D, the clinical investigation may proceed.

After the Commissioner (or delegee) has made a final determination, FDA intends to forward the determination to the IRB and post the final determination on the FDA website within 90 days of the PAC/PES meeting or as soon as practicable thereafter.  FDA will post the PAC/PES transcripts and meeting documents on the FDA website when available.

OHRP specific information:
After the OHRP expert panel meeting, OHRP will develop a recommendation for the Assistant Secretary for Health (ASH) based on panel deliberations, reports, public comments, and its own analysis.  The recommendation may include changes to the research protocol and/or changes to the parental/guardian permission and assent forms that an expert panelist or OHRP staff believe are necessary for the research to proceed under subpart D, as well as any suggested changes that might enhance the research (e.g., strategies to ease study burden on patients and care providers, strategies to improve trial enrollment).  OHRP then will submit its recommendation and relevant documents to the ASH.  After review of the relevant materials and OHRP’s recommendation, the ASH, on behalf of the HHS Secretary, will make the final determination regarding whether the research may proceed under 45 CFR 46.404, 46.405, 46.406, or 46.407.

OHRP will inform the referring institution and/or IRB chair, the investigator, and the HHS division supporting or conducting the research of the ASH’s determination and post its recommendation to the ASH and the ASH’s final determination in the established docket within 90 days of the expert panel meeting or as soon asas practicable thereafter.

VII. Process Differences Specific to Joint FDA and OHRP Review

As noted above, for research that FDA and OHRP determine is both HHS-conducted or -supported and FDA-regulated, FDA and OHRP generally intend to conduct a joint review of the research and will follow the process for FDA-only assessment of referrals.  Unique aspects of the joint subpart D review process include:

• FDA will communicate with the IRB and sponsor, and institution if appropriate, on behalf of both FDA and OHRP.
• FDA will post documents related to the joint review to the FDA website.  OHRP will not post documents to a federal docket and will instead post a link to the FDA website on the OHRP website.
• FDA will convene a PAC/PES meeting, which will serve as the expert panel meeting for both FDA and OHRP (see Section IV).
  • OHRP will participate with FDA in the selection of members for the PAC/PES meeting;  
  • OHRP will participate with FDA in the PAC/PES meeting.
• The ASH, acting on behalf of the Secretary, will make the determination whether the research is approvable under 45 CFR 46.407 after the FDA Commissioner (or delegee) has determined whether the clinical investigation is approvable under 21 CFR 50.54.
  • After the PAC/PES makes its recommendation(s) on whether the clinical investigation may proceed under 21 CFR part 50, subpart D, and 45 CFR part 46, subpart D, FDA staff will submit a memorandum outlining the PAC/PES recommendation(s), FDA staff recommendations, and the supporting documents to the FDA Commissioner (or delegee).
  • The FDA Commissioner (or delegee) will determine whether the clinical investigation may proceed under 21 CFR 50.54.
  • FDA will forward a memorandum outlining the PAC/PES recommendation(s), FDA staff recommendations, and the Commissioner’s (or delegee’s) determination to OHRP.
  • OHRP will formulate a recommendation to the ASH based on the findings of the PAC, the FDA Commissioner’s (or delegee’s) determination, public comments, and OHRP internal review.
  • OHRP will send a memorandum with the PAC/PES recommendation(s), the FDA Commissioner’s (or delegee’s) determination, OHRP’s recommendation(s) and all supporting documents to the ASH.  The ASH, acting on behalf of the Secretary, will make the determination whether the research may proceed under 45 CFR 46.404, 46.405, 46.406, or 46.407.

Determinations of the ASH and the FDA Commissioner (or delegee) will be posted by FDA and OHRP and forwarded to the referring IRB or referring institution, investigator, and/or HHS Division, as appropriate, within 90 days of the PAC/PES meeting or as soon as practicable thereafter.

VIII. Multisite Research

In some circumstances, research referred for review under FDA and/or HHS regulations might be conducted at multiple sites or institutions, and as such, be reviewed by more than one IRB.¹⁸  If an IRBfor one or more of the clinical sites refers the research for review, the IRB should notify the sponsor or HHS division supporting or conducting the research.  In this situation, FDA and OHRP strongly encourage the sponsor or relevant HHS division to notify all other study site IRB(s) and investigator(s) of the referral.

For multisite research regulated by FDA and conducted under an IND or IDE, if an IRB makes a referral under 21 CFR 50.54, FDA will determine whether the clinical investigation may proceed (or continue, if enrollment has already begun at one or more sites) or will be placed on clinical hold.¹⁹  In the case of a referral regarding an investigation for which an IDE application (or supplement) is pending, FDA may also consider other actions.²⁰  If FDA concludes that a clinical hold is appropriate, the agency generally intends to apply that clinical hold to all sites, regardless of whether IRBs other than the one that referred the protocol have approved the protocol.  While the 21 CFR 50.54 review is underway, FDA will inform the sponsor whether the clinical investigation has been placed on clinical hold and the sponsor must then notify investigators if the clinical investigation has been placed on clinical hold.²¹ The sponsor also should inform the other study site IRBs.²²

For multisite research regulated by OHRP, that does not require, or is excepted from the requirement for, single IRB review under 45 CFR 46.114, the HHS division supporting or conducting the research may consider the implications of the 45 CFR 46.407 review process on the conduct of the research at other HHS supported sites and whether, if consistent with applicable law, to delay or suspend subject enrollment at these other sites pending the outcome of the 45 CFR 46.407 review. 

IX. FDA and OHRP Review of Similar Research

FDA and OHRP recognize that there may be situations in which it would be appropriate for the Commissioner (or delegee) and/or the ASH to rely on previous PAC/PES or expert panel consideration of a similar research protocol in order to review a newly referred protocol.  FDA and OHRP note that the subpart D regulations do not specify that the expert panel review of the research must occur after the IRB referral for review.

FDA and/or OHRP will consider reviewing research submitted to FDA and/or OHRP for subpart D review under an abbreviated process if the research is similar to research that FDA and/or OHRP has already reviewed under subpart D and determined may proceed.  This abbreviated process would necessitate that FDA and/or OHRP determine the newly referred research is sufficiently similar to the previously reviewed research such that the previous referral and review are applicable to the newly referred research; such determinations are anticipated to be rare.

If FDA and/or OHRP conduct an abbreviated review process, FDA and/or OHRP will include in the information posted to the FDA website and/or OHRP docket (see Section III.E.2 and IV.E.2) the determination by the Commissioner and/or ASH for the previous referral as well as relevant background information from the previous referral.  FDA and/or OHRP will publish an FRN to solicit public comments on the newly referred research.  For FDA subpart D reviews conducted under an abbreviated process, the FRN will include a link to the relevant documents and background information on the FDA website, notice of the establishment of a docket for comments, and directions for accessing the docket.  For OHRP subpart D reviews conducted under an abbreviated process, the FRN will include notice of the establishment of a docket for posting relevant documents and background information and comments, and directions for accessing the docket. The docket will remain open for 30 days.    

The responsible agency(ies) will review the public comments submitted to the newly established docket(s).  Based on the review of comments, FDA and/or OHRP may either decide a determination may be issued without additional PAC/PES or expert panel review, or that a new PAC/PES or expert panel review is needed.  If a new PAC/PES meeting or expert panel is convened, the review under the subpart D regulations will proceed as outlined above.  Alternatively, FDA and/or OHRP may decide that no further PAC/PES or expert panel review are necessary.  In this situation, FDA and/or OHRP will prepare a recommendation for the Commissioner (or delegee) and/or ASH and the subsequent final determination by the Commissioner (or delegee) and/or ASH regarding the newly referred protocol will be posted to the FDA website, with a reference to the FDA docket, and/or will be posted to the OHRP docket, as applicable.

Endnotes

¹ For a full discussion of the differences between the FDA and HHS human subject protection regulations, see 78 FR 12937-12947.

² FDA’s 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 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 FDA’s 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 FDA’s 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 FDA’s regulations and “research” in HHS’s regulations are different, for purposes of this guidance they are used interchangeably.

⁸ The Secretary’s 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).

⁹ FDA may communicate with the IRB via electronic mail.

¹⁰ The IRB’s 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 FDA’s 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.

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-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).

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.

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.