Dominic Chiarelli, JD

by Dominic Chiarelli

Minimizing Risks: An Explanation of Safety Reporting in Human Subjects Research

Safety is Imperative to Human Subjects Protection

The assurance of the rights and welfare of research participants is central to the ethical conduct of research. This responsibility is widely shared across the clinical research enterprise between PIs, IRBs, Sponsors, and regulatory authorities. The result is a web of overlapping obligations, which can make knowing who should report or when, an often confusing determination.

The stakes are high. A lapse in a safety reporting can lead to an unrecognized safety signal that compromises the health of individual participants and the trust of the greater community. Such lapses may also result in the imposition of non-compliance findings, suspensions or clinical holds, or even the termination of all research activities. In recognition of this importance, many within clinical research revert to non-discriminately reporting all safety related information they become aware of – no matter the implication. The result is huge volumes of unusable information that cascades through the clinical research enterprise and which serves to inhibit rather than enhance human subjects protection.[1]

What can be done? The most important thing is to appreciate that there is an existing integrated framework in place and to learn how to identify and distinguish between the various safety obligations so that the right information is provided to the right party.

The following is a simplified depiction of the various roles and responsibilities for participant safety within clinical research. This is intended to give a broad view of the overall regulatory scheme and highlight the role that each member plays. The discussion will then turn to the often-vexing safety event known as an unanticipated problem (“UP”) and several considerations for how best to discharge this critical safety reporting responsibility.

Safety Related Roles and Responsibilities within Clinical Research

Role: An investigator conducts the research and must ensure the safety of his/her participants.

Responsibilities: An investigator is responsible for performing the investigation according to the signed investigator statement, the investigational plan, and applicable regulations; protecting the rights, safety, and welfare of subjects under the investigator’s care; and controlling the test article under investigation.[2],[3]

An investigator must immediately report to the sponsor any serious adverse event (“SAE”), whether or not considered related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the research caused the event. In addition, an investigator must record non-serious adverse events (“AE”) and report them to the sponsor according to the timetable for reporting specified in the protocol.[4]

An investigator must also promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.[5]

Investigator reporting obligations:

  • Sponsors: All AEs (per protocol) and SAEs (immediately)
  • IRBs: Unanticipated Problems

Role: An IRB oversees the investigator’s conduct of the research and must ensure the risks to participants are minimized and reasonable.

Responsibilities: An IRB, which must be qualified through experience and expertise to promote respect for its advice and counsel, is responsible for the initial and continuing review of a study to assure the protection of the rights and welfare of the human subjects.[6],[7] An IRB must continually assess and re-assess its approval in light of information learned throughout the course of the study.[8] Critical to this obligation, an IRB must be provided information from either PIs or Sponsors concerning possible unanticipated problems involving risk to human subjects, including reports of deviations and serious adverse events.[9] Typically, whenever such information is received, the IRB may label the event as an unanticipated problem and, if appropriate, require changes to the research to ensure the criteria for IRB approval are still met.

IRB reporting obligations:

  • Institutional Officials: Unanticipated Problems
  • Agencies: Unanticipated Problems

Role: A sponsor initiates a clinical investigation and must ensure the investigation can meet its objectives.[10]

Responsibilities: A sponsor is responsible for selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s), ensuring the investigation(s) is conducted in accordance with the protocols, and ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the test article.[11]

The sponsor must review and evaluate the evidence relating to the safety and effectiveness of the research as it is obtained from the investigator and keep each participating investigator informed of new observations discovered by or reported to the sponsor, particularly with respect to adverse effects and safe use.[12] Such information may be distributed to investigators by means of periodically revised investigator brochures, reprints or published studies, reports or letters to clinical investigators, or other appropriate means. A sponsor who determines there is an unreasonable and significant risk to subjects must discontinue those investigations that present the risk, notify FDA, all institutional review boards, and all investigators who have at any time participated in the investigation of the discontinuance.[13]

Sponsor reporting obligations:

  • FDA: AEs and SAEs (annual reports), Serious and Unexpected AEs (IND Safety Reports)
  • PI: Serious and Unexpected AEs (IND Safety Reports)

Departments/Agencies (i.e., FDA)
Role: Departments/Agencies advance public health by assuring adequate standards for the safety, efficacy, and ethical conduct of human subjects research.

Responsibilities: Departments/Agencies promulgate rules for human subjects research and the clinical investigation of test articles.

Agency reporting obligations:

  • Sponsor: Clinical holds

Determining Whether a Safety Event is an Unanticipated Problem

The most challenging safety responsibility to dutifully meet is the investigator’s obligation to report unanticipated problems to the IRB.[14] This difficulty has come about due to the continued increases in the size and complexity of research and the corresponding decrease in the influence of individual investigators.[15] The regulations have been slow to adapt to this trend and thereby still require an investigator to report all unanticipated problems they become aware of even if they lack the context necessary to understand the event and/or the ability to make changes to the protocol.[16]

An unanticipated problem, which is not defined by regulation, is any adverse event, or other event, observed during the conduct of a study that is unexpected, serious, and may have broader implications for the conduct of the study.[17]

An event is unexpected if it is related or possibly related to participation and the nature, severity, or frequency is inconsistent with the known risks described in the study materials (i.e., IB and informed consent) or the expected natural progression of the participant’s underlying condition.[18]

An event is serious if it is life-threatening or if it results in death, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. [19]

An event has implications for the conduct of the study if it may require a significant change in the protocol. This may include revising inclusion/exclusion criteria, adding a new monitoring requirement, or revising the informed consent document or investigator’s brochure. An individual event ordinarily would not meet this requirement because its implication cannot be fully understood. The major exception to this general rule is an event that is uncommon, clearly not related to the participant’s condition, and strongly associated with the test article, such as Stevens-Johnson syndrome.[20]

Determining Who Should Report the Information

In a multicenter research study, Sponsors are typically in the best position to analyze the significance of safety information and determine whether an event represents an unanticipated problem.[21] Sponsors receive AE information from all study sites and have more experience and expertise with the study drug. Accordingly, the FDA has stated that it will exercise enforcement discretion for any investigator who chooses to rely on a sponsor’s assessment of whether an AE is an unanticipated problem.[22] The FDA will also allow for a sponsor to report an unanticipated problem on behalf of the investigator if the investigator, sponsor, and IRB all have explicitly agreed to this arrangement.

This type of flexibility is especially important for IND Safety Reports. An IND safety report, which is any serious and unexpected event that has occurred under the IND, would typically trigger an investigator’s obligation to report an unanticipated problem to the IRB.[23] This is true even if the event occurred in a foreign country under a completely different protocol. However, if all involved have agreed that the sponsor will assume the duty of reporting unanticipated problems to the IRB, an investigator can be absolved of this responsibility. In this scenario, an IRB should receive a single report of the event and the Sponsor’s analysis of its significance when viewed against all the available information.

Despite this flexibility, most IRBs still require prompt reporting by the investigator of any serious safety event that occurs at the investigator’s own site. In this instance, the investigator should have a complete understanding of the circumstances and an opinion regarding whether changes to the research may be warranted. If this occurs, the IRB and Sponsor will generally be reviewing the information concurrently and the IRB may request changes to the conduct of the study, i.e., modify the consent or add extra monitoring procedures. Sponsors may appeal such requests if they provide sufficient supporting rationale, usually from access to a more complete data set.

Report Safety Information with Confidence

Reporting useful safety information is the obligation of all within the clinical research enterprise. Gone should be the days of non-discriminate and redundant safety reporting that overwhelmed the system as opposed to protecting participants. In order to achieve this ideal, it is important that each member of the clinical research enterprise understand their role and responsibilities and, in particular, any policies or other special arrangements (i.e., use of central IRB and direct reporting of Sponsor) that may be in place to facilitate meaningful safety reporting.

For more information on Quorum’s practices, please see Quorum’s Safety Information and Unanticipated Problems Guidelines.

For more information on reporting obligations in general, please see Quorum’s Webinar – Understanding Reporting Obligations to the IRB.


[1] FDA Guidance, Adverse Event Reporting to IRBs-Improving Human Subjects Protection,

[2] 21 CFR §312.60; see also 21 CFR §812.100.

[3] Note all information herein is based on the IND regulations and guidance, which is consistent with investigator safety obligations under the IDE regulations.

[4] 21 CFR §312.64.

[5] 21 CFR §312.66, See also 21 CFR §56.108(a)(2) & 45 CFR §46.403(b)(4).

[6] 21 CFR §56.102(g)

[7] 21 CFR §56.107(a); 45 CFR §46.107(a).

[8] 21 CFR §56.109(f); 45 CFR §46.109(e).

[9] 21 CFR §56.108(a)(3),(4),(b); 45 CFR §46.103(b)(4),(5).

[10] 21 CFR §312.3(b)

[11] 21 CFR §312.50.

[12] 21 CFR §312.56; 21 CFR §312.55.

[13] 21 CR §312.56.

[14] FDA Guidance, Adverse Event Reporting to IRBs-Improving Human Subjects Protection,; see also OHRP, Unanticipated Problems Involving Risks & Adverse Events Guidance,

[15] Id.

[16] Id.

[17] Id.

[18] Id.

[19] Id.

[20] Id.

[21] Id.

[22] Id.

[23] FDA Guidance, Safety Reporting Requirements for INDs and BA/BE Studies,…/Guidances/UCM227351.pdf