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Navigating the Complexities of Exception from Informed Consent (EFIC) in Research

A growing area of research involves exception from informed consent, also known as planned emergency research. Under certain conditions, in an emergency setting, participants can be enrolled in a trial without their consent. This article summarizes the podcast hosted by CITI Program with guest Michael Linke, PhD from the University of Cincinnati and the host Justin Osborne from The HRP Consulting Group where they discussed the regulations and ethical considerations around this important area of research.

In the dynamic landscape of medical research, certain situations arise where obtaining informed consent from participants becomes impractical. In these instances, researchers may turn to a mechanism known as Exception from Informed Consent (EFIC) to conduct studies aimed at addressing urgent medical needs. A recent discussion sheds light on the intricacies of EFIC and its role in advancing medical knowledge.

EFICinvolves conducting research without obtaining prospective informed consent from participants. The regulations governing EFIC, outlined in 50.24 CFR 40, set strict criteria for its approval. Central to EFIC is the need for studies to address life-threatening conditions with no acceptable treatments, offering potential benefits to participants. Additionally, there must be a limited timeframe to find a legally authorized representative (LAR) for surrogate consent.

One of the key elements of EFIC studies is community consultation and public disclosure. Before initiating a study, investigators engage with the local community to inform them about the research, address concerns, and seek feedback. This process ensures transparency and community involvement in research activities, although challenges exist in effectively implementing it, particularly in diverse and dynamic communities.

Despite the regulatory framework established in 1986, recent discussions have highlighted the need for continued review and potential updates to EFIC guidelines. A meeting hosted by the National Institutes of Health (NIH) brought together stakeholders to discuss current practices, challenges, and potential improvements in EFIC implementation.

One notable topic of discussion was the distinction between EFIC studies and waivers of informed consent, with EFIC presenting a higher threshold due to its stringent criteria and community engagement requirements. The meeting also addressed the evolving definition of “minimal risk” and the scope of conditions eligible for EFIC studies.

While no immediate regulatory changes are anticipated, ongoing dialogue and collaboration among researchers, regulatory agencies, and institutional review boards (IRBs) are essential to ensure the ethical conduct of EFIC studies. Additionally, advancements in technology, such as remote community engagement through social media, offer new avenues for conducting community consultation activities.

The ultimate goal of EFIC research remains unchanged: to advance medical knowledge and improve patient outcomes in emergency situations where traditional consent procedures are not feasible. With careful consideration of ethical principles, rigorous oversight, and ongoing dialogue, EFIC studies can continue to contribute meaningfully to medical research while upholding participant welfare and community engagement.

Listen to the podcast here: On Research Podcast on Exception from Informed Consent (citiprogram.org)

Interested in learning more about Exception from Informed Consent?  Set up a conversation with one of our consultants info@thehrpconsultinggroup.com.

FDA Final Rule – Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations

FDA Final Rule – Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations

Fast Facts

  • On December 21, 2023, the Food and Drug Administration (FDA) published a Final Rule “Institutional Review Board Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations” (Federal Register: Institutional Review Board Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations).
  • Background: The rule implements changes from Section 3024 of the Cures Act ( L. 114–255) to allow for a waiver or alteration of informed consent when a clinical investigation poses no more than minimal risk to the human subject and includes appropriate safeguards to protect the rights, safety, and welfare of human subjects.
  • Summary: The rule amends FDA’s regulations to allow IRBs to approve an informed consent procedure that does not include or that alters certain informed consent elements, or to waive the requirement to obtain informed consent, for certain minimal risk clinical investigations.
    • The rule harmonizes FDA’s requirements for waiver or alteration of informed consent with the revised Common Rule’s requirements under 45 CFR 46.116(f)(3).
    • Amendments to FDA’s regulations include:
      • Adding a new § 50.22, “Exception from informed consent requirements for minimal risk clinical investigations” to part 50.
      • Making three conforming amendments to §§ 50.20, 312.60, and 812.2 to reflect the exception from informed consent for certain minimal risk clinical investigations.
    • Effective Date: The rule is effective January 22, 2024.
    • Applicability: The rule will apply to IRB review at any stage of an FDA-regulated clinical investigation conducted on or after the effective date, including initial IRB approval or review of any changes to a previously approved clinical investigation.
    • Plans for FDA Guidance: FDA plans on issuing further guidance to assist IRBs in applying these criteria to clinical investigations. Guidance will include additional information on:
      • The types of FDA-regulated clinical investigations that may qualify for a waiver or alteration of consent under § 50.22.
      • The types of research activities that may involve no more than minimal risk to the subjects and therefore might qualify for a waiver or alteration of informed consent.

In Response 21, FDA notes that clarification of specific terms and phrases are provided “throughout this document”. For example, FDA discusses interpretation of “minimal risk” and “practicably” (see below).

Secondary Research Involving Leftover Biospecimens

According to the section titled “Comments on Secondary Research Involving Leftover Biospecimens” Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable will remain in effect.

  • “We believe that most IVD device investigations falling within the scope of the policy described in section IV of the Leftover Specimen Guidance will satisfy the criteria at § 50.22. However, to the extent that there are IVD device investigations that fall within the scope of the Leftover Specimen Guidance but do not satisfy the waiver criteria in § 50.22, FDA is retaining the Leftover Specimen Guidance at this time to help avoid potential disruption to IVD device investigations as IRBs gain experience implementing the new waiver provision in § 50.22 for FDA-regulated clinical investigations.”

Considerations for HRPPs and IRBs

  • Review existing materials to identify where changes need to be made to reflect the final rule.This may include SOPs, IRB submission forms, reviewer checklists, guidance documents, website content, educational materials, etc.
  • For institutions that use electronic IRB management systems: Depending on the system that you use, updates may need to be made to conditioning and actions, instructional text, options that display, etc.

Summary and Interpretation of the Informed Consent Exception Criteria

(Emphasis added by HRP)

  • The Clinical Investigation Involves No More Than Minimal Risk to the Subjects

“Minimal risk” is defined in § 50.3(k) to mean that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

In Response 10, FDA also notes the following:

  • “FDA is not revising the definition of minimal risk in this rule. Retaining the current definition of minimal risk will avoid confusion in the research community and maintain harmonization with the revised Common Rule. The Common Rule and FDA regulations have shared the same definition of minimal risk since 1991, and the definition of minimal risk was not changed in the revised Common Rule. Because of the longstanding consistency in the definitions of minimal risk provided in both FDA regulations and the Common Rule, IRBs have experience in applying the term “minimal risk” to research involving human subjects, including determining when a clinical investigation involves no more than minimal risk.”
  • The Waiver or Alteration Will Not Adversely Affect the Rights and Welfare of the Subjects

“FDA stated in the preamble of the proposed rule that, to make this finding, IRBs may consider, for example, whether the waiver or alteration has the potential to negatively affect the subjects’ well-being or whether the subject population in general would likely object to a waiver or alteration being granted for the research in question (83 FR 57378 at 57381 to 57382). It would not be necessary for an IRB to find that obtaining informed consent would be harmful or contrary to the best interests of subjects in order to satisfy this criterion.”

  • If the Clinical Investigation Involves Using Identifiable Private Information or Identifiable Biospecimens, the Clinical Investigation Could Not Practicably Be Carried Out Without Using Such Information or Biospecimens in an Identifiable Format

“To match the structure of the revised Common Rule’s general waiver provision ( i.e.,45 CFR 46.116(f)), this criterion has been incorporated into the codified text at § 50.22(c).”

In Responses 15 & 16, FDA also notes the following:

  • “Definitions of “identifiable private information” and “identifiable biospecimen” are included in FDA’s proposed rule to amend part 50, Protection of Human Subjects, and part 56, Institutional Review Boards (87 FR 58733, September 28, 2022).”
  • “Additionally, the revised Common Rule includes provisions at 45 CFR 46.102(e)(7)(i) and 102(e)(7)(ii) that require Federal departments and Agencies implementing the revised Common Rule, regularly and upon consultation with appropriate experts, to (i) reexamine the meaning of “identifiable private information” and “identifiable biospecimen”  and (ii) assess whether there are analytic technologies or techniques that should be considered to generate identifiable private information or identifiable biospecimens. FDA intends to participate in these efforts with HHS and the other Federal departments and Agencies, providing input on FDA-regulated research and promoting consistent and appropriate interpretation of these terms across HHS and FDA human subject research regulations. Including a new requirement in FDA’s regulations for FDA to consider issues relating to the meaning of “identifiable,” on a periodic basis and in light of evolving technology, is thus unnecessary and could result in duplicative efforts and additional burden on the Agency without added benefit.”
  • The Clinical Investigation Could Not Practicably Be Carried Out Without the Waiver or Alteration

“In the preamble to the proposed rule, FDA stated that, if scientifically sound research can practicably be carried out using only consenting subjects, FDA believes it should be carried out without involving nonconsenting subjects. FDA also provided an example of what practicable means ( i.e., (1) that recruitment of consenting subjects does not bias the science and the science is no less rigorous as a result of restricting it to consenting subjects or (2) that the research is not unduly delayed by restricting it to consenting subjects) (83 FR 57378 at 57382). As noted in our response to comment 7, the emphasis is on situations where it is impracticable to carry out the clinical investigation, as designed, without the waiver or alteration, rather than on situations where it is not feasible to obtain informed consent from subjects.”

Further discussion on FDA interpretation of the term “practicably” can be found in Response 13 .

  • “With respect to the interpretation of the term “practicably,” we reiterate that the emphasis is on situations where it is impracticable—not necessarily impossible—to carry out the clinical investigation, as designed, without the waiver or alteration.”
  • “Practicability should be assessed on a case-by-case basis considering the unique factors associated with the clinical investigation, such as its aims, its population(s), and the impact on its scientific validity if informed consent were required ( g., introduction of bias).”
  • “The relevant considerations, and the weight given to each consideration, should reflect the unique circumstances of the clinical investigation for which a waiver or alteration of informed consent is being sought.”
  • “If an IRB finds that a clinical investigation can be practicably carried out using only consenting subjects, then FDA believes it should be carried out without involving nonconsenting subjects.However, we agree that, under this final rule, an IRB can approve a clinical investigation falling within the scope of part 50 in which investigators will have access to and utilize data and/or biospecimens that have already been collected without having to obtain informed consent, provided the IRB finds and documents that the criteria under § 50.22 are met.”
  • “In addition, we agree that IRBs may find under § 50.22(b) (§ 50.22(c) in the proposed rule) that a clinical investigation could not practicably be carried out without a waiver or alteration of informed consent based on the unavailability of certain subjects in an investigation to give consent for a new investigation ( g.,subjects lost to follow up), when restricting the research to the subjects available to provide consent would compromise the scientific or ethical integrity, or cause undue delay of, the investigation.”
  • “As some comments point out, SACHRP made recommendations in 2008 related to waivers of informed consent and the interpretation of minimal risk under the Common Rule, including the Common Rule waiver criterion that corresponds to § 50.22(b). In its recommendations, SACHRP emphasized that the criterion “states that the research could not practicably be carried out without the waiver or alteration. Put another way, it would not be practicable to perform the research (as it has been defined in the protocol by its specific aims and objectives) if consent was required” (Ref. 2). SACHRP also offered the following concepts to help an IRB determine whether the research could not be practicably carried out without the waiver or alteration of consent: (1) the scientific validity of the research would be compromised if consent were required; (2) ethical concerns would be raised if consent were required; (3) there is a scientifically and ethically justifiable rationale why the research could not be conducted with a population from whom consent can be obtained; and (4) practicability should not be determined solely by considerations of convenience, cost, or speed.

Although SACHRP’s recommendations regarding the “practicably” waiver criterion were developed for research that is regulated under the Common Rule, they are consistent with FDA’s interpretationof the corresponding waiver criterion in this rule ( i.e., § 50.22(b)). It thus may be appropriate for an IRB to find that a clinical investigation could not practicably be carried out without a waiver or alteration of informed consent on the grounds that ethical concerns would be raised if consent were required ( e.g., an investigation using previously collected biospecimens where obtaining subjects’ consent for secondary research use of the biospecimens may expose individuals to new privacy risks by linking the biospecimens with nominal identifiers in order to contact the individuals to seek consent). In some cases, these ethical concerns could justify a finding of impracticability under § 50.22(b) even if the scientific validity of the clinical investigation would not be compromised by asking the individuals to provide informed consent.”

  • “In addition, as stated in the preamble to the proposed rule, FDA interprets the term “practicably” in § 50.22(b) to mean, for example, that the research is not unduly delayed by restricting it to consenting subjects (83 FR 57378 at 57382). The phrase “unduly delayed” refers to more than just considerations of speed. By “unduly delayed,” we mean a delay in the initiation of a clinical investigation that is so lengthy as to raise ethical or scientific concerns given the benefit, or value, potentially gained by the research ( g.,delaying the initiation of an investigation of a rare disease treatment by several years in order to allow for collection of new biospecimens from consenting subjects with the rare disease, when biospecimens from individuals with the disease are available from a repository but the biospecimens have no accompanying current contact information). Accordingly, an IRB may make a finding that the research could not practicably be carried out without the requested waiver or alteration because requiring consent would unduly delay the research.”
  • “We note that it would be inappropriate for an IRB to find that a clinical investigation could not practicably be carried out without a waiver or alteration of informed consent based solely on a clinical investigator being resistant to obtaining informed consent. We do not consider investigator resistance to obtaining informed consent to be a scientifically or ethically valid reason for finding under § 50.22(b) that a clinical investigation could not practicably be carried out without a requested waiver or alteration of informed consent.”
  • Whenever Appropriate, the Subjects Will Be Provided With Additional Pertinent Information After Participation

“FDA proposed that, whenever appropriate, the subjects will be provided with additional pertinent information after participation. For example, an IRB may find that information that had been previously withheld about the clinical investigation to prevent bias must be provided to subjects following their participation.”

Revisions to Part 50 – Protection of Human Subjects

PART 50—PROTECTION OF HUMAN SUBJECTS

  1. The authority citation for part 50 is revised to read as follows:

Authority: 21 U.S.C. 321, 343, 346, 346a, 348, 350a, 350b, 352, 353, 355, 360, 360c–360f, 360h–360j, 371, 379e, 381; 42 U.S.C. 216, 241, 262, 263b–263n.

  1. In § 50.20 revise the first sentence to read as follows:
  •  50.20

General requirements for informed consent.

Except as provided in §§ 50.22, 50.23, and 50.24, no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative. * * *

  1. Add § 50.22 to subpart B to read as follows:
  •  50.22

Exception from informed consent requirements for minimal risk clinical investigations.

The IRB responsible for the review, approval, and continuing review of the clinical investigation described in this section may approve an informed consent procedure that does not include or that alters some or all of the elements of informed consent set forth in § 50.25(a) and (b), or may waive the requirement to obtain informed consent, provided the IRB finds and documents the following:

(a) The clinical investigation involves no more than minimal risk to the subjects;

(b) The clinical investigation could not practicably be carried out without the requested waiver or alteration;

(c) If the clinical investigation involves using identifiable private information or identifiable biospecimens, the clinical investigation could not practicably be carried out without using such information or biospecimens in an identifiable format;

(d) The waiver or alteration will not adversely affect the rights and welfare of the subjects; and

(e) Whenever appropriate, the subjects or legally authorized representatives will be provided with additional pertinent information after participation.

Revisions to Part 312 – Investigational New Drug Application

PART 312—INVESTIGATIONAL NEW DRUG APPLICATION

  1. The authority citation for part 312 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360bbb, 371; 42 U.S.C. 262.

  1. Revise § 312.60 to read as follows:
  •  312.60

General responsibilities of investigators.

An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation. An investigator shall in accordance with the provisions of part 50 of this chapter, obtain the informed consent of each human subject to whom the drug is administered, in accordance with part 50 of this chapter except as provided in §§ 50.23 or 50.24 of this chapter. Additional specific responsibilities of clinical investigators are set forth in this part and in parts 50 and 56 of this chapter.

Revisions to Part 812 – Investigational Device Exemptions

PART 812—INVESTIGATIONAL DEVICE EXEMPTIONS

  1. The authority citation for part 812 is revised to read as follows:

Authority: 21 U.S.C. 331, 351, 352, 353, 355, 360, 360c–360f, 360h–360j, 360hh–360pp, 360rr–360ss, 360bbb–8b, 371, 372, 374, 379e, 381, 382; 42 U.S.C. 216, 241, 262, 263b–263n.

21 U.S.C. 331, 351, 352, 353, 355, 360, 360c–360f, 360h–360j, 360bbb–8b, 371, 372, 374, 379e, 379k–1, 381, 382, 383; 42 U.S.C. 216, 241, 262,.

  1. Revise § 812.2 (b)(1)(iii) to read as follows:
  •  812.2

Applicability.

* * * * *

(b) * * *

(1) * * *

(iii) Ensures that each investigator participating in an investigation of the device obtains from each subject under the investigator’s care, informed consent in accordance with part 50 of this chapter and documents it, unless documentation is waived by an IRB under § 56.109(c).

Single IRB Update

HRP recently had a very helpful email dialogue with OHRP regarding the cooperative review (single IRB) provisions in the revised Common Rule. OHRP has graciously provided permission for us to disseminate the information they provided and have asked that we remind everyone to please check in with the funding agency when uncertain whether the mandate applies because the funding agency may have a definition of support that is more strict or different than OHRP’s.

From: OS OPHS OHRP (HHS/OPHS) <OHRP@hhs.gov>
Sent: Tuesday, October 31, 2023 1:15 PM
To: OS OPHS OHRP (HHS/OPHS) <OHRP@hhs.gov>; Karen Christianson <ChristiansonK@thehrpconsultinggroup.com>
Subject: RE: Cooperative Research Question

Karen,

Thank you so much for your patience.  Please see your questions with my answers in purple below. 

You asked: I’m writing with a few questions that come up from time to time related to the cooperative research provisions and single IRB.

Jaime Hernandez: A preliminary question that I’d like to answer first relates to when a study has to comply with the single IRB requirement.  The single IRB requirement applies to institutions engaged in cooperative research (see 45 CFR 46.114(b)).  Cooperative research is defined as non-exempt, human subjects research conducted or supported by HHS in which two or more institutions are involved or cooperating in (see 46.114(a)).  If the research activities of only one researcher are non-exempt, human subjects research conducted or supported by HHS, then the study is not cooperative research, and it doesn’t have to comply with the single IRB requirement (but it can if the institutions want to do so).  If the research activities of two or more of researchers are non-exempt, human subjects research conducted or supported by HHS, then only those researchers are involved in cooperative research and must comply with the single IRB requirement.  The other researchers who are NOT engaged in non-exempt, human subjects research conducted or supported by HHS don’t have to rely on the single IRB together with the two or more researchers who are engaged (although they all can use the single IRB if they want to).

Therefore, to answer the scenarios below, the main issue is whether the different participants in a study are engaged in non-exempt, human subjects research conducted or supported by HHS.  For all the scenarios, I assume the research studies are all non-exempt, human subjects research.  So the remaining issue is whether they are supported by HHS under the different grant mechanisms you describe in each scenario.

  1. When a cooperative research project is not itself conducted or supported by HHS (or other Common Rule Department or Agency) funds, but one or more members of the research teams are supported, for example, by a career development, training, or fellowship award, would the cooperative research project be subject to the single IRB requirement?

Jaime Hernandez: We can’t speak for other Common Rule agencies since they may have a different approach to “support.”  But, for HHS funded research, OHRP generally looks at the career development, training, or fellowship award to see if the specific human subjects study in question was described in the award.  For example, if an award doesn’t describe any specific research study, and the awardee joins the research team of a senior PI, that PI’s research does not become supported by HHS even if the salary of the new team member is covered by a training or fellowship grant.  On the other hand, if the study was initiated by the awardee and proposed to NIH (either in the original grant or subsequent submission), and NIH approves the conduct of the specific study under the award, then OHRP would consider it to be supported by HHS.

These are only two examples, of course, and often it is not so simple.  I would suggest looking at the awards to see if it describes the specific research study.  Also, I would look at the terms and condition of the award or reach out to the award administrator at the funding agency to see if the funding agency would consider the study supported by them.    

  • When a Center or Institute is supported by HHS (or other Common Rule Department or Agency) funds, and the Center/Institute in turn funds cooperative research projects, would those research projects be subject to the single IRB requirement?

Jaime Hernandez: In this scenario too, OHRP looks at whether a specific research project was identified in the grant that HHS supported.  If so, then the center or institute would be considered engaged.

  • When an organization is considered engaged in research by virtue of being the awardee institution but all activities involving human subjects are carried out by another organization, and the research is not exempt, would the cooperative research provisions apply and would IRB reliance need to be documented in accordance with .103(e)?

Jaime Hernandez: Consistently with 1 and 2, and as I said in my prior email, OHRP usually looks at whether the grant includes plans for specific human subjects research or just un-specified, future research.  Note that for grants for the conduct of non-exempt human subjects research in which the primary awardee only “passes the money,” OHRP asks that institutions send the grant to us for a case-by-case determination (see, https://www.hhs.gov/ohrp/regulations-and-policy/guidance/september-22-2011-non-engaged-scenarios/index.html).  This is different than for a center or institute grant in scenario 2, for example.  But in any of the 3 scenarios, feel free to send us the grant if you need a more specific answer. It may take us a while to review it, but we are here to help.

I hope this answers your question,    

Jaime O. Hernandez, J.D., M.Be.
Pronouns: he/him/his

Office for Human Research Protection (OHRP)

Is it time to rethink the IRB roster?

We’re all eagerly watching the evolving ethical and regulatory landscape in research, with updated guidance from several agencies and organizations, the unknown implications of AI and the increasing dependency on technology to conduct our trials.

For those who have been in the research industry for a while, this is a lot of change in a short amount of time, and it often feels like we’re being reactive rather than proactive.

So, let’s be proactive about something that hasn’t changed much in the past 30 years – the composition of the IRB Roster.

IRB Committee Composition Goals

To take a step back, let’s talk through the purpose of the IRB composition. The goal is to minimize the risk for human subjects in research, right? We all know an IRB must have at least 5 members with varying backgrounds, expertise and diversity, including at least one scientific, one non-scientific and one unaffiliated member.

Varying Background and Expertise – Future Needs

The question is, with this quickly evolving landscape, are we meeting the “varying backgrounds and expertise” mandate? Our focus is generally on having the appropriate scientific or scholarly expertise to review the research. That will always be essential in properly protecting human subjects.

However, with the growth of AI and technology, how many IT experts are on our boards? With the recruitment strategies increasingly using social media and such, how about a marketing expert on our board? With protocol designs and logistical considerations becoming more and more complicated, how many boards include an expert in project management?

Recommendation: Be Proactive

Being proactive means staying in front of the problem. We don’t want to look back on our board roster composition and realize we may have missed potential risks in a research study because we focused so heavily on the scientific aspects and ignored the social and logistical aspects of a research study.

 

Looking for IRB consulting around your roster, services or operations? Contact your friends at The HRP Consulting Group.

IND Safety Reports and IRBs

HRP recently engaged in extensive correspondence with the FDA regarding the following statements that appeared in one of the later iteration’s of the FDA’s guidance document “Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency”:

Where an IND safety report is required to be submitted to FDA under 21 CFR 312.32, the investigator must [emphasis added] also send that IND safety report to the IRB. The IRB may have additional reporting requirements regarding COVID-19 during the clinical trial.

And

In addition, investigators are required under 21 CFR 312.66 to report all “unanticipated problems involving risk to human subjects or others” to the IRB. FDA considers a serious and unexpected adverse event that meets the criteria for sponsor reporting to FDA and all investigators in an IND safety report under 21 CFR 312.32, and would generally consider a serious adverse event that meets the criteria for safety reporting for an IND-exempt bioavailability/bioequivalence study under 21 CFR 320.31(d)(3), to be an “unanticipated problem[ ] involving risk to human subjects or others” that therefore must [emphasis added] be reported to the IRB by the investigator.

We discussed the disconnect between the above statements and the information provided in FDA’s still-active 2009 guidance document: “Adverse Event Reporting to IRBs – Improving Human Subject Protection” including the following:

In general, an AE observed during the conduct of a study should be considered an unanticipated problem involving risk to human subjects, and reported to the IRB, only if it were unexpected, serious, and would have implications for the conduct of the study (e.g., requiring a significant, and usually safety-related, change in the protocol such as revising inclusion/exclusion criteria or including a new monitoring requirement, informed consent, or investigator’s brochure).An individual AE occurrence ordinarily does not meet these criteria because, as an isolated event, its implications for the study cannot be understood [emphasis added].

While recognizing that the AE reporting to IRBs guidance remains active, FDA pointed to changes that were made to the IND Safety Reporting Regulations in 2010 and the subsequent 2012 guidance “Guidance for Industry and Investigators – Safety Reporting Requirements for INDs and BA/BE Studies” which states:

Although the rule on IND safety reporting does not directly address safety reporting by investigators to IRBs, questions have arisen about its impact on adverse event reports to IRBs, particularly with respect to the specific adverse events considered to be “unanticipated problems” that must be reported to the IRB. In general, a report that meets the criteria for reporting in an IND safety report should also be considered an “unanticipated problem” and reported to the IRB by the investigator.

We discussed the implications for IRBs, including the volume of IND Safety Reports, safety reports that do not involve or impact “local” subjects or the conduct of the research, and whether IRBs are expected to report these IND Safety Reports as unanticipated problems to “appropriate institutional officials, and the Food and Drug Administration” per 21 CFR 56.108(b).

FDA reiterated their position that IND Safety Reports submitted to the FDA should also be submitted to IRBs as unanticipated problems noting that the IRB “may decide to take action to safeguard participants that was not taken by the sponsor (e.g., stop administering an investigational drug, revise informed consent form).”  Because of the changes made to the IND regulations regarding what must be submitted to the FDA in an IND Safety Report, FDA does not believe that many of these reports will be uninformative.

Regarding reporting to the FDA, the FDA offered that an IRB could include in its written procedures that sponsor submission of the IND Safety Report to the FDA fulfills the prompt reporting requirement as long as the IRB confirms that the sponsor has submitted the report.  Regarding reporting to institutional officials, the FDA offered that the IRB could also address in its procedures when and to whom IND Safety Reports will be reported.

To that end, HRP has modified our SOPs, forms, and checklists accordingly and incorporated procedures for Chair or designee review and acknowledgment of these reports, when the reports do not involve or impact local subjects, or significantly impact the conduct of the research, and additional actions are not needed to ensure the protection of subjects enrolled at sites overseen by an IRB.

 

Exception Process for Revised Common Rule Single IRB Requirement

HRP recently sought clarification from NIH and OHRP regarding the process for organizations to request exceptions from the revised Common Rule requirement for single IRB for cooperative research.

While NIH was previously able to grant exceptions from its own single IRB policy, it is unable to grant exceptions to the revised Common Rule requirement.  HHS interprets the regulatory text (see excerpt below) to mean that exceptions not based in law may only be granted at the Department or Agency Head level.

45 CFR 46.114(b)(2) The following research is not subject to this provision:

(i) Cooperative research for which more than single IRB review is required by law (including tribal law passed by the official governing body of an American Indian or Alaska Native tribe); or

(ii)
Research for which any Federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular context.

Requests for exceptions for HHS agencies and offices are managed by OHRP while the decisions are made at the Department Head level (i.e., the Office of the Secretary).  A listing of HHS agencies and offices is available here: https://www.hhs.gov/about/agencies/hhs-agencies-and-offices/index.html.  At this time, requests for HHS exceptions may be emailed to OHRP at OHRP@HHS.gov.  OHRP anticipates that few exceptions will be granted.  It is unclear whether SACHRP’s 2018 recommendations on the topic will be taken into consideration.

Decisions regarding single IRB exceptions for other Common Rule Departments or Agencies (see list below) must also be made at the department or agency head level.  Organizations seeking such exceptions should reach out to the department or agency supporting the research for guidance on the process.

    • Department of Homeland Security
    • Department of Agriculture
    • Department of Energy
    • NASA
    • Department of Commerce
    • Social Security Administration
    • Agency for International Development
    • Department of Housing and Urban Development
    • Department of Labor
    • Department of Defense
    • Department of Education
    • Department of Veterans Affairs
    • Environmental Protection Agency
    • National Science Foundation
    • Department of Transportation
    • Office of the Director of National Intelligence
    • Central Intelligence Agency
    • Consumer Product Safety Commission