Unanticipated Problems Involving Risks to Subjects or Other (UPIRTSO)

I. PURPOSE / BACKGROUND

This policy establishes the reporting requirements and the types of local unanticipated problems or unanticipated problems reported by the sponsor that a University of Louisville (U of L) principal investigator or designee must report to the U of L Institutional Review Board (IRB) to ensure prompt reporting of unanticipated problems involving risks to subjects or others. Regulatory requirements for reporting unanticipated problems involving risks to subjects and others may be found in 45 CFR 46.103(b)(5)(i) and 21 CFR 56.108(b)(1).

The following Venn diagram summarizes the general relationship between adverse events and unanticipated problems: 

Unanticipated Problems Involving Risks to Subjects or Other

The diagram illustrates three key points:

The vast majority of adverse events occurring in human subjects are not unanticipated problems (area A).  A small proportion of adverse events are unanticipated problems (area B).  Unanticipated problems include other incidents, experiences, and outcomes that are not adverse events (area C).

II. DEFINITIONS

Adverse event:  Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research.

External adverse event:  From the perspective of one particular institution engaged in a multi-center clinical trial, external adverse events are those adverse events experienced by subjects enrolled by investigators at other institutions engaged in the clinical trial. 

Internal adverse event:  From the perspective of one particular institution engaged in a multi-center clinical trial, internal adverse events are those adverse events experienced by subjects enrolled by the investigator(s) at that institution.  In the context of a single-center clinical trial, all adverse events would be considered internal adverse events.  

Possibly related to the research:  There is a reasonable possibility that the adverse event, incident, experience or outcome may have been caused by the procedures involved in the research (modified from the definition of associated with use of the drug in FDA regulations at 21 CFR 312.32(a)).

Serious adverse event:  Any adverse event temporally associated with the subject’s participation in research that meets any of the following criteria:

  1. results in death;
  2. is life-threatening (places the subject at immediate risk of death from the event as it occurred);
  3. requires inpatient hospitalization or prolongation of existing hospitalization;
  4. results in a persistent or significant disability/incapacity;
  5. results in a congenital anomaly/birth defect; or
  6. any other adverse event that, based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition (examples of such events include allergic bronchospasm requiring intensive treatment in the emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse (Modified from the definition of serious adverse drug experience in FDA regulations at 21 CFR 312.32(a).)

Unanticipated problem involving risks to subjects or others:  Any incident, experience, or outcome that meets all of the following criteria:

Is unexpected, serious, and would have implications for the conduct of the study, or is

  1. unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
  2. related or possibly related to a subject’s participation in the research; and
  3. suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) related to the research than was previously known or recognized.

If the answer to all three questions is yes, then the adverse event is an unanticipated problem and must be reported to appropriate entities under the HHS regulations at 45 CFR 46.103(a) and 46.103(b)(5).

Unexpected adverse event:  Any adverse event occurring in one or more subjects in a research protocol, the nature, severity, or frequency of which is not consistent with either:

  1. the known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in (a) the protocol–related documents, such as the IRB-approved research protocol, any applicable investigator brochure, and the current IRB-approved informed consent document, and (b) other relevant sources of information, such as product labeling and package inserts; or
  2. the expected natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for the adverse event. (Modified from the definition of unexpected adverse drug experience in FDA regulations at 21 CFR 312.32(a).

III. POLICY

A University of Louisville principal investigator or designee must promptly report any of the following problems:

  1. Unanticipated problems, including serious adverse events related to a drug or device (whether occurring on-site or reported to the investigator by a sponsor or other site), which in the opinion of the principal investigator are:

    unexpected, serious, and would have implications for the conduct of the study, or is
    1. unexpected, 
    2. related or possibly related to participation in the research, and
    3. the research places subjects or others at a greater risk of harm than was previously known or recognized.
  2. Problems that required prompt reporting to the sponsor or funding agency,
  3. Accidental or unintentional change to the IRB approved protocol that involved risks to subject or others, or that has the potential to recur,
  4. Changes to the protocol taken without prior IRB review to an eliminate apparent immediate hazard to a research subject,
  5. Information (publication in the literature, safety monitoring report, interim result, or other finding) that indicates a change to the risks or potential benefits of the research,
  6. DSMB summary reports that indicate a change to the risks or potential benefits of the research,
  7. Breach of confidentiality of research data,
  8. Incorrect labeling of study medication/test article,
  9. Incorrect dosing of study medication/test article,
  10. Study medication/test article accountability discrepancies that trigger a study subject to be withdrawn from a study,
  11. Breach of privacy/confidentiality/data security/loss of study data/destruction of study data due to noncompliance,
  12. Unauthorized use or disclosure of protected health information (PHI),
  13. Subject complaints that indicate an unanticipated risk, or that cannot be resolved by the research staff,
  14. Incarceration of a subject while participating in research,
  15. Suicide attempt related to participation in a research study,
  16. Death of a healthy volunteer while participating in research or within 30 days of participation,
  17. Injury (needle stick, drug ingestion, chemical exposure, etc.) of study personnel related to preparation or administration of study drug,
  18. Unanticipated adverse device effect, or
  19. Any other problem which in the opinion of the principal investigator was:
    1. unexpected, 
    2. related or possibly related to participation in the research, and
    3. the research places subjects or others at a greater risk of harm than was previously known or recognized.

IV. PROCEDURE FOR POLICY

The principal investigator will report to the IRB using the reporting process in BRAAN2 or the UPIRTSO or Local SAE Report Form found at the forms link on the Human Subjects Protection Program Office (HSPPO) website. Principal investigators may also report events by email or letter by providing the same information as requested in the UPIRTSO or Local SAE Report Form.

If, in response to the report, the IRB chair/vice-chair/member/alternate, conducting the initial review, believes that immediate action is needed to ensure research subject safety; the reviewer may request that the investigator suspend research procedures or take action to suspend research procedures pending discussion of the event at the next convened meeting of the IRB. Suspensions suggested by the reviewer, and in concurrence with the IRB chair/vice-chair, will follow IRB policies and procedures regarding suspensions.

Each report will have initial review by a primary reviewer (usually an IRB chair or vice-chair) from the Unanticipated Problems Subcommittee (UPS) to determine if the report may be an unanticipated problem involving risks to subjects or others.  Members of the UPS will be members/alternates of the IRB.

HSPPO staff will provide the following documents to the UPS primary reviewer:

  1. A copy of the problem report and all attachments provided by the investigator,
  2. A copy of the protocol,
  3. A copy of the current informed consent, and
  4. Any other material that the IRB staff believes relevant to the event.

HSPPO staff will retain these documents and the primary reviewer’s notes if the UPS recommendation is to report the event.

If the recommendation is to report the event, the HSPPO staff will schedule IRB review at the next convened meeting whose agenda has not been finalized.

The HSPPO staff will bring the UPS primary reviewer’s, documents to the IRB meeting where the primary reviewer will discuss the report.  Should the UPS primary reviewer be unavailable, the IRB chair for the meeting will lead the discussion.

HSPPO staff will provide the following documents to all other IRB members:

  1. A copy of the problem report and all attachments provided by the investigator, and
  2. A copy of the current informed consent.

HSPPO staff will bring the protocol file to the meeting.

The UPS primary reviewer will present a summary of the problem and make a recommendation to the IRB about whether the event represents an unanticipated problem involving risks to subjects or others. The IRB will deliberate and vote to determine whether the event represented an unanticipated problem involving risks to subjects or others. The determination of whether an event represents an unanticipated problem is based on whether the event represents all of the following:

  1. unexpected, 
  2. related or possibly related to participation in the research, and
  3. the research places subjects or others at a greater risk of harm than was previously known or recognized.

If the UPS primary reviewer determines that the problem (see III. Policy) was unanticipated, was related to the research and affects the safety and welfare of current or future subjects or others involved with the research, the reviewer will make a recommendation to the IRB about proposed actions. The IRB will deliberate and vote to approve these or any other appropriate actions.  Actions the UPS primary review and IRB should consider include, but are not limited to:

  1. Requiring no action,
  2. Requiring changes in informed consent documents,
  3. Requiring changes in the protocol or other study documents,
  4. Requiring re-consenting or informing current or previously enrolled research subjects (to occur whenever the information may relate to subjects willingness to continue participation in the research,
  5. Requiring steps to reduce any immediate risks to subjects or others,
  6. Modifying the continuing review schedule,
  7. Suspending or terminating the research study (according to the IRB policy and procedure regarding suspensions and terminations),
  8. Requesting more information pending a final decision,
  9. Referring to other organizational entities (e.g., legal counsel, risk management, institutional official), or
  10. Taking other actions appropriate for the local context.

V. ORGANIZATIONAL RESPONSIBILITIES

Any principal investigator who conducts research under the auspices of the University of Louisville IRBs.  The University’s IRBs must follow this policy.

VI. VIOLATIONS OF THIS POLICY

Failure of investigators to report problems as required by this policy could result in a range of penalties. These penalties are outlined in the University’s Administrative Sanctions for Violations of University of Louisville Research Policies. This policy may be found on the Research Integrity Program home page (http://research.louisville.edu/researchintegrity) under research policies and procedures.

VII. REPORT OF FINDINGS

Follow the University of Louisville IRB Report of Findings policy for reporting unanticipated problems involving risks to subjects or others.  This policy is located on the HSPPO website under Research Related Policies. 

VIII. ADDITIONAL INFORMATION AND REFERENCES

  1. Appendix A is an algorithm for determining whether an adverse event is an unanticipated problem.  
  2. Appendix B provides examples of unanticipated problems that do not involve adverse events and need to be reported under the HHS regulations at 45 CFR Part 46.  
  3. Appendix C provides examples of adverse events that do not represent unanticipated problems and do not need to be reported under the HHS regulations at 45 CFR Part 46.  
  4. Appendix D provides examples of adverse events that represent unanticipated problems and need to be reported under the HHS regulations at 45 CFR Part 46.
  5. Appendix E provides examples of adverse events that represent unanticipated problems and need to be reported under the FDA regulations.
  6. Office for Human Research Protections Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events
  7. FDA Guidance on Adverse Event Reporting to IRBs Improving Human Subject Protection

Appendix A

The flow chart above provides an algorithm for determining whether an adverse event represents an unanticipated problem that needs to be reported under HHS regulations. 

Appendix B

Examples of Unanticipated Problems that Do Not Involve Adverse Events and Need to be Reported Under the HHS Regulations at 45 CFR Part 46

  1. An investigator conducting behavioral research collects individually identifiable sensitive information about illicit drug use and other illegal behaviors by surveying college students.  The data are stored on a laptop computer without encryption, and the laptop computer is stolen from the investigator’s car on the way home from work.  This is an unanticipated problem that must be reported because the incident was (a) unexpected (i.e., the investigators did not anticipate the theft); (b) related to participation in the research; and (c) placed the subjects at a greater risk of psychological and social harm from the breach in confidentiality of the study data than was previously known or recognized.  
  2. As a result of a processing error by a pharmacy technician, a subject enrolled in a multicenter clinical trial receives a dose of an experimental agent that is 10-times higher than the dose dictated by the IRB-approved protocol.  While the dosing error increased the risk of toxic manifestations of the experimental agent, the subject experienced no detectable harm or adverse effect after an appropriate period of careful observation.  Nevertheless, this constitutes an unanticipated problem for the institution where the dosing error occurred that must be reported to the IRB, appropriate institutional officials, and OHRP because the incident was (a) unexpected; (b) related to participation in the research; and (c) placed subject at a greater risk of physical harm than was previously known or recognized.
  3. Subjects with cancer are enrolled in a phase 2 clinical trial evaluating an investigational biologic product derived from human sera.  After several subjects are enrolled and receive the investigational product, a study audit reveals that the investigational product administered to subjects was obtained from donors who were not appropriately screened and tested for several potential viral contaminants, including the human immunodeficiency virus and the hepatitis B virus.  This constitutes an unanticipated problem that must be reported because the incident was (a) unexpected; (b) related to participation in the research; and (c) placed subjects and others at a greater risk of physical harm than was previously known or recognized.

The events described in the above examples were unexpected in nature, related to participation in the research, and resulted in new circumstances that increased the risk of harm to subjects.  In all of these examples, the unanticipated problems warranted consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions in order to protect the safety, welfare, or rights of subjects.  In addition, the third example may have presented unanticipated risks to others (e.g., the sexual partners of the subjects) in addition to the subjects.  In each of these examples, while these events may not have caused any detectable harm or adverse effect to subjects or others, they nevertheless represent unanticipated problems and should be promptly reported to the IRB, appropriate institutional officials, the supporting agency head and OHRP in accordance with HHS regulations at 45 CFR 46.103(a) and 46.103(b)(5).

Appendix C

Examples of Adverse Events that Do Not Represent Unanticipated Problems and Do Not Need to be Reported under the HHS Regulations at 45 CFR Part 46

  1. A subject participating in a phase 3, randomized, double-blind, controlled clinical trial comparing the relative safety and efficacy of a new chemotherapy agent combined with the current standard chemotherapy regimen, versus placebo combined with the current standard chemotherapy regimen, for the management of multiple myeloma develops neutropenia and sepsis.  The subject subsequently develops multi-organ failure and dies.  Prolonged bone marrow suppression resulting in neutropenia and risk of life-threatening infections is a known complication of the chemotherapy regimens being tested in this clinical trial and these risks are described in the IRB-approved protocol and informed consent document.  The investigators conclude that the subject’s infection and death are directly related to the research interventions.  A review of data on all subjects enrolled so far reveals that the incidence of severe neutropenia, infection, and death are within the expected frequency.  This example is not an unanticipated problem because the occurrence of severe infections and death – in terms of nature, severity, and frequency – was expected. 
  2. A subject enrolled in a phase 3, randomized, double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of a new investigational anti-inflammatory agent for management of osteoarthritis develops severe abdominal pain and nausea one month after randomization.  Subsequent medical evaluation reveals gastric ulcers.  The IRB-approved protocol and informed consent document for the study indicated that the there was a 10% chance of developing mild to moderate gastritis and a 2% chance of developing gastric ulcers for subjects assigned to the active investigational agent.  The investigator concludes that the subject’s gastric ulcers resulted from the research intervention and withdraws the subject from the study.  A review of data on all subjects enrolled so far reveals that the incidence of gastritis and gastric ulcer are within the expected frequency.  This example is not an unanticipated problem because the occurrence of gastric ulcers – in terms of nature, severity, and frequency – was expected.  
  3. A subject is enrolled in a phase 3, randomized clinical trial evaluating the relative safety and efficacy of vascular stent placement versus carotid endarterectomy for the treatment of patients with severe carotid artery stenosis and recent transient ischemic attacks.  The patient is assigned to the stent placement study group and undergoes stent placement in the right carotid artery.  Immediately following the procedure, the patient suffers a severe ischemic stroke resulting in complete left-sided paralysis.  The IRB-approved protocol and informed consent document for the study indicated that there was a 5-10% chance of stroke for both study groups.  To date, 25 subjects have been enrolled in the clinical trial, and 2 have suffered a stroke shortly after undergoing the study intervention, including the current subject.  The DSMB responsible for monitoring the study concludes that the subject’s stroke resulted from the research intervention.  This example is not an unanticipated problem because the occurrence of stroke was expected and the frequency at which strokes were occurring in subjects enrolled so far was at the expected level. 
  4. An investigator is conducting a psychology study evaluating the factors that affect reaction times in response to auditory stimuli.  In order to perform the reaction time measurements, subjects are placed in a small, windowless soundproof booth and asked to wear headphones.  The IRB-approved protocol and informed consent document describe claustrophobic reactions as one of the risks of the research.  The twentieth subject enrolled in the research experiences significant claustrophobia, resulting in the subject withdrawing from the research.  This example is not an unanticipated problem because the occurrence of the claustrophobic reactions – in terms of nature, severity, and frequency – was expected.  
  5. A subject with advanced renal cell carcinoma is enrolled in a study evaluating the effects of hypnosis for the management of chronic pain in cancer patients.  During the subject’s initial hypnosis session in the pain clinic, the subject suddenly develops acute chest pain and shortness of breath, followed by loss of consciousness.  The subject suffers a cardiac arrest and dies.  An autopsy reveals that the patient died from a massive pulmonary embolus, presumed related to the underlying renal cell carcinoma.  The investigator concludes that the subject’s death is unrelated to participation in the research.  This example is not an unanticipated problem because the subject’s pulmonary embolus and death were attributed to causes other than the research interventions.
  6. An investigator performs prospective medical chart reviews to collect medical data on premature infants in a neonatal intensive care unit (NICU) for a research registry.  An infant, about whom the investigator is collecting medical data for the registry, dies as the result of an infection that commonly occurs in the NICU setting.  This example is not an unanticipated problem because the death of the subject is not related to participation in the research, but is most likely related to the infant’s underlying medical condition.

NOTE:  For purposes of illustration, the case examples provided above represent generally unambiguous examples of adverse events that are not unanticipated problems.  OHRP recognizes that it may be difficult to determine whether a particular adverse event is unexpected and whether it is related or possibly related to participation in the research.  In addition, the assessment of the relationship between the expected and actual frequency of a particular adverse event must take into account a number of factors including the uncertainty of the expected frequency estimates, the number and type of individuals enrolled in the study, and the number of subjects who have experienced the adverse event. 

Appendix D

Examples of Adverse Events that Represent Unanticipated Problems and Need to be Reported Under the HHS Regulations at 45 CFR Part 46

  1. A subject with chronic gastroesophageal reflux disease enrolls in a randomized, placebo- controlled, double-blind, phase 3 clinical trial evaluating a new investigational agent that blocks acid release in the stomach.  Two weeks after being randomized and started on the study intervention the subject develops acute kidney failure as evidenced by an increase in serum creatinine from 1.0 mg/dl pre-randomization to 5.0 mg/dl.  The known risk profile of the investigational agent does not include renal toxicity, and the IRB-approved protocol and informed consent document for the study does not identify kidney damage as a risk of the research.  Evaluation of the subject reveals no other obvious cause for acute renal failure.  The investigator concludes that the episode of acute renal failure probably was due to the investigational agent.  This is an example of an unanticipated problem that must be reported because the subject’s acute renal failure was (a) unexpected in nature, (b) related to participation in the research, and (c) serious.   
  2. A subject with seizures enrolls in a randomized, phase 3 clinical trial comparing a new investigational anti-seizure agent to a standard, FDA-approved anti-seizure medication.  The subject is randomized to the group receiving the investigational agent. One month after enrollment, the subject is hospitalized with severe fatigue and on further evaluation is noted to have severe anemia (hematocrit decreased from 45% pre-randomization to 20%).  Further hematologic evaluation suggests an immune-mediated hemolytic anemia.  The known risk profile of the investigational agent does not include anemia, and the IRB-approved protocol and informed consent document for the study do not identify anemia as a risk of the research.  The investigators determine that the hemolytic anemia is possibly due to the investigational agent.  This is an example of an unanticipated problem that must be reported because the hematologic toxicity was (a) unexpected in nature; (b) possibly related to participation in the research; and (c) serious. 
  3. The fifth subject enrolled in a phase 2, open-label, uncontrolled clinical study evaluating the safety and efficacy of a new oral agent administered daily for treatment of severe psoriasis unresponsive to FDA-approved treatments, develops severe hepatic failure complicated by encephalopathy one month after starting the oral agent.  The known risk profile of the new oral agent prior to this event included mild elevation of serum liver enzymes in 10% of subjects receiving the agent during previous clinical studies, but there was no other history of subjects developing clinically significant liver disease.  The IRB-approved protocol and informed consent document for the study identifies mild liver injury as a risk of the research.  The investigators identify no other etiology for the liver failure in this subject and attribute it to the study agent.  This is an example of an unanticipated problem that must be reported because although the risk of mild liver injury was foreseen, severe liver injury resulting in hepatic failure was (a) unexpected in severity; (b) possibly related to participation in the research; and (c) serious.     
  4. Subjects with coronary artery disease presenting with unstable angina are enrolled in a multicenter clinical trial evaluating the safety and efficacy of an investigational vascular stent.  Based on prior studies in animals and humans, the investigators anticipate that up to 5% of subjects receiving the investigational stent will require emergency coronary artery bypass graft (CABG) surgery because of acute blockage of the stent that is unresponsive to non-surgical interventions.  The risk of needing emergency CABG surgery is described in the IRB-approved protocol and informed consent document.  After the first 20 subjects are enrolled in the study, a DSMB conducts an interim analysis, as required by the IRB-approved protocol, and notes that 10 subjects have needed to undergo emergency CABG surgery soon after placement of the investigational stent.  The DSMB monitoring the clinical trial concludes that the rate at which subjects have needed to undergo CABG greatly exceeds the expected rate and communicates this information to the investigators.  This is an example of an unanticipated problem that must be reported because (a) the frequency at which subjects have needed to undergo emergency CABG surgery was significantly higher than the expected frequency; (b) these events were related to participation in the research; and (c) these events were serious.
  5. Subjects with essential hypertension are enrolled in a phase 2, non-randomized clinical trial testing a new investigational antihypertensive drug.  At the time the clinical trial is initiated, there is no documented evidence of gastroesophageal reflux disease (GERD) associated with the investigational drug, and the IRB-approved protocol and informed consent document do not describe GERD as a risk of the research.  Three of the first ten subjects are noted by the investigator to have severe GERD symptoms that began within one week of starting the investigational drug and resolved a few days after the drug was discontinued.  The investigator determines that the GERD symptoms were most likely caused by the investigational drug and warrant modification of the informed consent document to include a description of GERD as a risk of the research.  This is an example of an adverse event that, although not serious, represents an unanticipated problem that must be reported because it was (a) unexpected in nature; (b) possibly related to participation in the research; and (c) suggested that the research placed subjects at a greater risk of physical harm than was previously known or recognized.
  6. A behavioral researcher conducts a study in college students that involves completion of a detailed survey asking questions about early childhood experiences.  The research was judged to involve no more than minimal risk and was approved by the IRB chairperson under an expedited review procedure.  During the completion of the survey, one student subject has a transient psychological reaction manifested by intense sadness and depressed mood that resolved without intervention after a few hours.  The protocol and informed consent document for the research did not describe any risk of such negative psychological reactions.  Upon further evaluation, the investigator determines that the subject’s negative psychological reaction resulted from certain survey questions that triggered repressed memories of physical abuse as a child.  The investigator had not expected that such reactions would be triggered by the survey questions.  This is an example of an unanticipated problem that must be reported in the context of social and behavioral research because, although not serious, the adverse event was (a) unexpected; (b) related to participation in the research; and (c) suggested that the research places subjects at a greater risk of psychological harm than was previously known or recognized.  

Appendix E

Reporting AEs To IRBs In Clinical Trials Of Drug And Biological Products Conducted Under IND Regulations

FDA recommends that there be careful consideration of whether an AE is an unanticipated problem that must be reported to IRBs. In summary, FDA believes that only the following AEs should be considered as unanticipated problems that must be reported to the IRB.

  1. A single occurrence of a serious, unexpected event that is uncommon and strongly associated with drug exposure (such as angiodema, agranulocytosis, hepatic injury, or Stevens-Johnson syndrome).
  2. A single occurrence, or more often a small number of occurrences, of a serious, unexpected event that is not commonly associated with drug exposure, but uncommon in the study population (e.g., tendon rupture, progressive multifocal leukoencephalopathy).
  3. Multiple occurrences of an AE that, based on an aggregate analysis, is determined to be an unanticipated problem. There should be a determination that the series of AEs represents a signal that the AEs were not just isolated occurrences and involve risk to human subjects (e.g., a comparison of rates across treatment groups reveals higher rate in the drug treatment arm versus a control). We recommend that a summary and analyses supporting the determination accompany the report.
  4. An AE that is described or addressed in the investigator’s brochure, protocol, or informed consent documents, but occurs at a specificity or severity that is inconsistent with prior observations. For example, if transaminase elevation is listed in the investigator’s brochure and hepatic necrosis is observed in study subjects, hepatic necrosis would be considered an unanticipated problem involving risk to human subjects. We recommend that a discussion of the divergence from the expected specificity or severity accompany the report.
  5. A serious AE that is described or addressed in the investigator’s brochure, protocol, or informed consent documents, but for which the rate of occurrence in the study represents a clinically significant increase in the expected rate of occurrence (ordinarily, reporting would only be triggered if there were a credible baseline rate for comparison). We recommend that a discussion of the divergence from the expected rate accompany the report.
  6. Any other AE or safety finding (e.g., based on animal or epidemiologic data) that would cause the sponsor to modify the investigator’s brochure, study protocol, or informed consent documents, or would prompt other action by the IRB to ensure the protection of human subjects. We recommend that an explanation of the conclusion accompany the report.

Reporting AEs To IRBs In Clinical Trials Of Devices Under The IDE Regulations

The investigational device exemption (IDE) regulations define an unanticipated adverse device effect (UADE) as “any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects” (21 CFR 812.3(s)). UADEs must be reported by the clinical investigator to the sponsor and the reviewing IRB, as described below:

  1. For device studies, investigators are required to submit a report of a UADE to the sponsor and the reviewing IRB as soon as possible, but in no event later than 10 working days after the investigator first learns of the event (§ 812.150(a)(1)).
  2. Sponsors must immediately conduct an evaluation of a UADE and must report the results of the evaluation to FDA, all reviewing IRBs, and participating investigators within 10 working days after the sponsor first receives notice of the effect (§§ 812.46(b), 812.150(b)(1)).

Subject: Reporting of Unanticipated Problems Involving Risks to Subjects or Others|  Policy and Procedure | Author: Institutional Review Board  |   Original Effective Date: 1-1-2005  |   Last Revised Date: 2-2-09