The Common Rule requires reporting of certain unanticipated problems that occur in the course
of conducting research.
This tutorial explains what these requirements are for reporting to the Office for Human
Research Protections (or OHRP).
To report incidents to other Common Rule agencies, investigators and IRBs should seek advice
from the respective funding agency directly.
For HHS-funded nonexempt human subjects research, the Common Rule requires that each IRB must
establish and follow written procedures to ensure prompt reporting of any unanticipated
problems involving risks to subjects or others to the IRB, OHRP, and other relevant officials.
Reporting unanticipated problems is a responsibility that both investigators and IRBs share.
Typically, investigators are the first to become aware of a potential unanticipated
problem that might need reporting.
This commonly happens in the course of conducting the research or as a result of information
they receive from co-investigators, sponsors, or data-monitoring boards.
Investigators report these unanticipated problems to their institution for review according
to established procedures.
The responsibility for review usually falls on the IRBs although not always.
After reviewing the reported problems, it is the IRB chairperson, an administrator,
or another institutional official identified under the institution’s written procedures
who reports to OHRP.
When investigators become aware of a potential unanticipated problem, they should follow
their institutional policies for prompt reporting to the IRB.
If the unanticipated problem indicates apparent immediate hazards to research subjects, the
Common Rule allows investigators to make changes to the approved research to eliminate those
hazards and ensure subjects’ safety.
They must then report these changes to the IRB.
Additionally, investigators may have other reporting responsibilities.
These may come from institutional requirements, or requirements imposed by research sponsors,
data and safety monitoring boards, the FDA, and others.
Investigators should work with their institution’s human research protection program (HRPP) or
IRB office to learn more about these responsibilities.
After an investigator reports an unanticipated problem to the IRB, a review of the information
follows to determine if the event meets the criteria for the type of unanticipated problem
that needs to be reported to OHRP.
If it does, then the IRB—or the designated official—must report the unanticipated problem
to OHRP promptly and in accordance with the institution’s written procedures.
If it does not meet those criteria, the IRB is not required to report the problem to OHRP.
For unanticipated problems that must be reported to OHRP, the IRB will review the appropriateness
of any actions the investigator might have taken to eliminate risks to subjects.
In addition, the IRB may need to consider, in light of the unanticipated problem, whether
the risks to subjects or others in the research are still minimized and reasonable in relation
to anticipated benefits.
The IRB should also consider whether protocol changes, informed consent document updates,
or other corrective actions are necessary to adequately protect the safety, rights,
and welfare of research subjects.
The regulations require prompt reporting to OHRP but do not define what “prompt” means.
OHRP addressed this issue in its 2011 Guidance on Reporting Incidents to OHRP.
In general, for a serious incident that poses a significant risk to research subjects or
others, prompt reporting to OHRP should occur within a few days.
For a less serious incident, however, reporting within a few weeks may be sufficient.
Sometimes institutions may want to investigate an incident further.
In this case, the institution may send an initial report to OHRP and indicate that a
follow-up or final report will follow when its investigation has been completed or a
corrective action plan has been implemented.
Institutions should have written policies that indicate which official should send reports
to OHRP.
This includes initial, interim, and final reports.
Please visit OHRP’s Compliance & Reporting website on Reporting Incidents for detailed
information.
Things can go wrong and investigators may encounter unexpected challenges throughout
the course of a research study.
For unanticipated problems in HHS-funded nonexempt human subjects research, the Common Rule only
requires prompt reporting of those involving risks to subjects or others.
The regulations do not define what constitutes “unanticipated problems involving risks
to subjects or others.”
However, OHRP has interpreted this to include any incident, experience, or outcome that
is: • Unexpected in nature, severity, or frequency;
• Related or possibly related to participating in the research; and
• Suggesting that the research has placed subjects or others at a greater risk of harm
than was previously recognized.
Let’s take a closer look at these three criteria.
To determine if an incident, experience, or outcome is unexpected, IRBs should take into
account factors such as the nature, severity, or frequency of the incident in light of the
research procedures as described in the protocol, consent form, and other protocol-related documents,
as well as characteristics of the subject populations.
For example, in a study that involved interviewing victims of assault about the attack, some
of the questions were expected to cause minor emotional distress to some subjects.
The protocol and consent form clearly stated this, and the investigator has implemented
measures to minimize this risk.
In this protocol, therefore, subjects becoming distressed during or immediately following
the interview would not be considered unexpected.
However, if subjects suffered severe panic attacks following the interviews, for example,
then this could be an event of an unexpected severity that may warrant reporting.
The term “related or possibly related” suggests that there is a reasonable possibility
that the incident, experience, or outcome may have been caused by the procedures involved
in the research.
In the example we just described, it is a reasonable possibility that the severe panic
attacks following interviews about assault may have been caused by the research procedures—in
this case, the interview questions.
Finally, not all unanticipated events related to the research increase risks to subjects
or others.
The only unanticipated events that need to be reported are those that also suggest that
the research has placed subjects or others at a higher risk of harm than originally recognized,
including physical, psychological, economic, or social harm.
For example, the severe panic attacks in the last example could suggest that the research
placed subjects at a greater risk of harm than just “emotional distress,” as it
was originally recognized.
Let’s take a look at an example about how to decide if an event constitutes a reportable
unanticipated problem Elderly people were recruited to test if wearing
pads on their hips would protect against hip fractures after a fall.
Investigators asked participants to wear a hip pad over one hip.
Investigators expected that participants would be equally likely to fall on either hip.
They hoped that the research would show fewer fractures on the side where the hip pad was
worn.
Several months into the study, however, interim data analysis showed that participants were
falling more frequently and experiencing a higher rate of fractures on the side with
the hip pad.
Does this finding qualify as an unanticipated problem that is reportable to OHRP?
Here’s how to decide: • Are the frequent falls and fractures on
the side where the hip pad was worn an unexpected problem?
Yes.
The more frequent falls and fractures on the side with the hip pad were unexpected because
investigators expected that participants were equally likely to fall on either hip, and
that the hip pad would help prevent fractures.
• Is this unexpected problem related or possibly related to participating in the research?
Yes.
There is a reasonable possibility that the greater likelihood of falling to one side
was caused by the placement of the hip pads, so this change was possibly related to the
research.
• Does this unexpected problem related to the research suggest that subjects have been
placed at higher risk than previously recognized?
Yes.
The study found a higher chance of falls resulting in fractures on the side with the hip pad.
This suggests that the research placed subjects at a higher risk of falling and fracturing
their hips on that particular side than was originally recognized.
Based on this analysis, this series of events meets the three criteria for the type of unanticipated
problems that must be reported promptly to OHRP.
This analysis shows a systematic method that investigators and IRBs can use to make a determination
about whether an incident might qualify as an unanticipated problem that is reportable
to OHRP.
Now let’s consider a related but distinct concept: adverse events.
Many confuse reportable unanticipated problems with the term “adverse events” commonly
used in clinical trials.
The term “adverse events” generally refers to unfavorable medical occurrences, including
abnormal signs, symptoms, or diseases that occur during a subject’s participation in
research, regardless of whether the occurrences are related to the research.
Adverse events can include both physical and psychological harms.
Although adverse events most commonly occur in biomedical research, they can also occur
in social and behavioral research.
The Common Rule does not refer to “adverse events” and there is no specific requirement
to report adverse events to OHRP.
However, there is a requirement to report “unanticipated problems involving risks
to subjects or others.”
Adverse events that also meet the criteria for “unanticipated problems involving risks
to subjects or others” need to be reported to OHRP.
An adverse event is reportable when it is: • Unexpected in nature, severity, or frequency;
• Related or possibly related to participating in research; and
• Suggesting that the research has placed subjects or others at a greater risk of harm
than previously recognized.
Adverse events that do not meet these criteria do not need to be reported to OHRP.
Many adverse events are incidents that investigators can expect and describe in the research-related
documents, so they would not be unanticipated problems.
Occasionally, however, there are adverse events that investigators did not expect.
One way to assess whether an adverse event is unexpected is to consider whether it is
consistent with: (1) Risks related to the research procedures
that are described in the research related documents such as the research protocol, OR
(2) Expected effects or progression of the subject’s underling disease, disorder, or
health condition.
If it is not consistent with the above, then it is an unexpected adverse event.
Consider these scenarios.
The research protocol and associated documents submitted to the IRB for a drug trial with
healthy volunteers did not identify a risk of liver damage.
In the course of the study, investigators noticed moderate and persistent abnormalities
in the liver function of a number of subjects.
The abnormal liver functions were adverse events not previously identified in the research-related
documents and were inconsistent with the subjects’ health condition.
Therefore, these are potentially unanticipated problems reportable to OHRP.
Contrast that example with another research study involving an experimental treatment
for diabetes.
The treatment had a known risk of damaging kidney functions.
This risk was addressed in both the protocol and the consent form that participants signed.
When a few of the research subjects who received the experimental treatment showed mild deteriorations
in kidney function, it would not be considered an unanticipated problem because it is consistent
with research-related documents.
Therefore, these events would not be reportable to OHRP.
Adverse events that are solely caused by a subject’s underlying disease, disorder,
or condition are not unanticipated problems related to the research and, do not need to
be reported to OHRP.
However, adverse events that are at least partially caused by the procedures involved
in the research are considered related or possibly related to participation in research.
These are reportable to OHRP if they also meet the other two criteria for unanticipated
problems.
Consider these scenarios.
Cancer patients were recruited to participate in a clinical trial that studied the use of
a new surgical procedure to remove cancerous growths.
A few of the participants died during the surgery.
It can be reasonably concluded that their deaths were at least partially related to
the surgery.
Therefore, these are potentially unanticipated problems reportable to OHRP.
Contrast this with another research study in which patients who received palliative
care for liver cancer were recruited to participate in an observational study.
Some participants inevitably succumbed to the liver cancer.
These deaths were adverse events by definition, but they were not caused by the observational
procedures of the research.
Rather they were solely caused by the natural progression of their underlying disease.
These deaths need not be reported to OHRP.
Assessing whether an adverse event suggests that subjects or others have been placed at
a greater risk of harm than was previously known or recognized
Any adverse event that suggests that subjects or others have been placed at a greater risk
of harm than previously known or recognized is potentially reportable to OHRP.
If they also meet the other two criteria for unanticipated problems, then they should be
reported to OHRP.
OHRP considers that all serious adverse events meet the criterion of placing subjects or
others at greater risk of harm.
Serious adverse events include those that are life-threatening or result in death, hospitalization,
significant disability, or birth defect among others.
For example, a research subject had an unusually severe allergic bronchospasm after receiving
the research intervention and had to be intubated.
The fact that the subject had to be intubated indicates that this was a serious adverse
event, so it is considered to have placed subjects at a greater risk of harm.
If this also meets the other two criteria, then it would constitute an unanticipated
problem that should be reported to OHRP.
Contrast this example with a different research study that examined the effectiveness of cognitive
behavioral therapy to overcome symptoms of PTSD.
A few participants experienced unexpected transient chest pain after the therapy sessions.
The chest pain did not lead to serious consequences.
These adverse events, while not ‘serious’, nonetheless suggest that the research placed
subjects at a greater risk of harm than was initially recognized.
If these also meet the other two criteria, then they would constitute an unanticipated
problem that should be reported to OHRP.
Investigators who become aware of an adverse event should follow their institution’s
policies for reporting to the IRB.
Investigators may also have reporting duties to others, such as the sponsor or a data and
safety monitoring board, according to the IRB-approved protocol and institutional policies,
and should comply with those as well.
IRBs assess whether the adverse event also constitutes a reportable unanticipated problem
using the criteria described above.
If the adverse event meets those criteria, the IRB should follow institutional policies
for prompt reporting to OHRP.
This concludes our discussion on reporting unanticipated problems to OHRP.
We hope you found it useful.