Investigator Handbook Chapter 9: Unanticipated Problems, SAEs and Emergencies

Investigator Handbook
Chapter 9: UNANTICIPATED PROBLEMS, SAEs, AND EMERGENCIES

Unanticipated problems, serious adverse events, and emergencies involving human subjects protocols approved by the CPHS must be reported and reviewed by the CPHS (HRP PP IV.15 Review of Unanticipated Problems Involving Risks to Research Participants and Others http://www.uth.tmc.edu/orsc/policies/IV.15.htm). Requirements for reporting them are summarized below.

Unanticipated Problems

Unanticipated problems are not synonymous with “adverse events”. Unanticipated problems refer to untoward events involving any aspect of a research study, not just subjects, and can occur in clinical and non-clinical research. Some examples of unanticipated problems include:

An investigator loses a laptop that contains confidential information about participants.
A principal investigator is charged with a felony.
A lab reports that blood studies performed the previous week were in error.
A man physically abuses his wife because she agreed to take part in a research study without his permission.
Subjects in a group counseling session become unexpectedly violent.

All unanticipated problems must be promptly reported to CPHS via iRIS.

Serious Adverse Events (SAEs)

A serious adverse event (SAE) is any adverse experience occurring during the course of the study or during planned follow-up. Any adverse event that meets any of the following criteria MUST be reported to the CPHS:

results in death;
is life-threatening (places the patient at immediate risk of death from the experience as it occurred);
results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to carry out normal life functions)
results in medical or surgical intervention
results in OR prolongs an existing inpatient hospitalization (even if the hospitalization is a precautionary measure for observation);
is a congenital anomaly/birth defect in offspring of subjects taking the product regardless of time to diagnosis;
is a cancer;
is the result of an overdose, whether intentional or accidental, including a breach of protocol; or,
is medically unexpected, regardless of severity

An unexpected adverse event is any adverse event that is not consistent with the currently approved research protocol, investigator brochure, or informed consent form, or one that is not part of the normal disease progression.

An expected adverse event may qualify as “unexpected” and therefore be reportable IF the expected adverse event occurs more frequently than normal.

Adverse events that have occurred at other sites must be reported only if they are both serious and unexpected and probably related to the research.

Reporting SAEs to the CPHS

Serious adverse events (SAEs) must be reported promptly since some may require modification of study procedures, research protocols, and/or the informed consent forms. Before reporting a SAE to the CPHS, the investigator should assess the significance of the event in terms of risks and other human subject protection issues that will affect currently enrolled participants and future participants.

Any death occurring while a patient is on a study must be reported to the CPHS by phone (713 500-7942) or by email to the CPHS clinical research monitor within 24 hours and via iRIS within working five days.

SAEs or unanticipated adverse events involving investigational drugs or devices must be reported to the CPHS via iRIS within 5 working days.

SAEs that occur within 30 days after patient involvement in the protocol must also be reported to CPHS.
Other AEs do not need to be reported if the PI determines the AE is expected or due to the natural progression of the patient’s underlying disease.

In times of doubt (e.g. at the time of the event it cannot be determined whether the SAE is a consequence of the study procedure), the SAE must be reported to the CPHS. If there is a clarification/change to any of the information initially submitted, provide a follow-up report.

Adverse Event Evaluation/Reporting Guide

As defined by CPHS is the adverse event serious and unexpected?
Yes=> Use the Report of Serious Adverse Event, Injury, or Unexpected Problem Form found in the iRIS system.
No => Proceed to next question
As defined by CPHS is the adverse event serious but expected?
Yes => Use the Report of Serious Adverse Event, Injury, or Unexpected Problem Form found in the iRIS system.
No => Proceed to next question
As defined by CPHS is the adverse event expected and not serious?
Yes => You do not have to report an expected and/or non-serious adverse event to the CPHS.
No => If you are still not certain, please re-evaluate this adverse event to determine if it should fall into the categories of either
a) serious or non-serious and
b) expected or not expected.

Definitions

results in death;
is life-threatening (places the patient at immediate risk of death from the experience as it occurred);
results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to carry out normal life functions)
results in medical or surgical intervention
results in OR prolongs an existing inpatient hospitalization (even if the hospitalization is a precautionary measure for observation);
is a congenital anomaly/birth defect in offspring of subjects taking the product regardless of time to diagnosis;
is a cancer;
is the result of an overdose, whether intentional or accidental, including a breach of protocol; or,
is medically unexpected, regardless of severity

An expected adverse event may qualify as “unexpected” and therefore be reportable IF the expected adverse event occurs more frequently than normal.

Adverse events that have occurred at other sites must be reported only if they are both serious and unexpected and probably related to the research.

Data Safety Monitoring Boards

For research projects that have a DSMB, it is the responsibility of the PI to provide the CPHS with any correspondence regarding an adverse event from the DSMB within 5 working days of its receipt by the PI (HRP PP I.09 Data Safety Monitoring Boards and Plans - http://www.uth.tmc.edu/orsc/policies/I.9.htm).

Correspondence with Outside Agencies

All correspondence with outside agencies (FDA, NIH, etc.) regarding adverse event reports must be submitted to the CPHS via iRIS within 5 working days.

If the study sponsor requires submission of an adverse event report to the CPHS, please note that it is your responsibility as the investigator to review any and all reports and ONLY forward to the CPHS adverse events that are both serious and unexpected and are judged to be related or possibly related to the study drug. If this is the case, an IND report form must be submitted for each individual safety report within 5 working days of receipt.

Using an Investigational Drug or Unapproved Medical Device in an Emergency

The FDA regulations provide for the one-time emergency use of an investigational drug, agent, biologic or device. However, there is no provision in the DHHS regulations, 45 CFR 46, for any research activity to be started even in an emergency without prior CPHS review and approval. This is not intended to limit the authority of a physician to provide emergency medical care for patients in need. Therefore, when emergency medical care is initiated without prior CPHS review and approval, the patient may not be considered a research subject (HRP PP VIII.03 Emergency Use of Investigational Device, Biologic or Unapproved Medical Device http://www.uth.tmc.edu/orsc/policies/VIII.3.htm).

Emergency Use of an Investigational Drug

Emergency situations may arise in which there will be a need to use an investigational drug in a manner inconsistent with the approved investigational plan or by a physician who is not part of the clinical study. Criteria include:

The test article is used one time to treat a single patient;
Life-threatening or serious disease or condition;
No generally acceptable alternative is available; and
There is no time to use existing procedures to get FDA approval for the use. Approval should be sought from the CPHS Chairperson as described below.

When a physician wishes to use an investigational drug for treatment of an individual patient for a single use or a single course of treatment, and the use is not covered by an existing CPHS approved protocol, call the CPHS office (500-7942) with your request and justification. The Chairperson will advise if the justification for such use is sufficient for approval. A written memo outlining the situation must be received by the CPHS within 5 days of the telephone approval.

The manufacturer of the drug will usually add the physician as a clinical investigator on its IND. If the sponsor will not, or if there is no commercial sponsor, the physician can file an individual IND directly with the FDA (phone numbers: 301-827-0531/301-594-2000/after hours 202-857-8400).
An IND number will usually be given over the phone which permits the sponsor to ship the drug. An appropriate informed consent form must be constructed for use of the drug and informed consent obtained from the patient or responsible relative prior to giving the drug.

When the situation is life threatening and there is no time for CPHS approval, the physician may use the drug without such approval. A second non-involved physician should concur in the emergency use of the investigational article. The CPHS MUST be subsequently notified.

If the physician/clinical investigator anticipates that there will be more such use of the same drug, for the same patient or any additional patients, review and approval of a protocol at a convened CPHS meeting is necessary.

Emergency Use of an Unapproved Medical Device

Emergency situations may arise in which there will be a need to use an investigational device in a manner inconsistent with the approved investigational plan or by a physician who is not part of the clinical study. Emergency use of an unapproved device may occur before an IDE is approved. Criteria include:

Life-threatening or serious disease or condition;
No generally acceptable alternative is available; and
There is no time to use existing procedures to get FDA approval for the use. Approval should be sought from the CPHS Chairperson as described below for the emergency use of an unapproved device

When a physician wishes to use an investigational device for treatment of an individual patient for a single use or a single course of treatment, and the use is not covered by an existing CPHS approved protocol, call the CPHS office (713-500-7942) with your request and justification. The Chairperson will advise if the justification for such use is sufficient for approval. A written memo outlining the situation must be received by the CPHS within 5 days of the telephone approval.

The manufacturer of the device will usually add the physician as a clinical investigator on its IDE. If the sponsor will not, or if there is no commercial sponsor, the physician can file an individual IDE directly with the FDA (phone numbers: 301-827-0531/301-594-2000/after hours 202-857-8400). An IDE number will usually be given over the phone which permits the sponsor to ship the device. An appropriate informed consent form must be constructed for use of the device and informed consent obtained from the patient or responsible relative prior to using the device.

When the situation is life threatening and there is no time for CPHS approval, the physician may use the device without such approval. A second non-involved physician should concur in the use of the investigational article. The CPHS MUST be subsequently notified.

If the physician/clinical investigator anticipates that there will be more such use of the same device, for the same patient or any additional patients, review and approval of a protocol at a convened CPHS meeting is necessary.

The Center for Devices and Radiological Health (phone numbers: 301-594-1190 / after hours 202-857-8400) must be notified immediately after shipment of the device from the manufacturer is made. The physician must justify in writing to the FDA that an emergency actually existed.

Compassionate Use (or Single Patient Access) for an Unapproved Medical Device
The compassionate use provision allows access for patients who do not meet the requirements for inclusion in the clinical investigation but for whom the treating physician believes the device may provide a benefit in treating and/or diagnosing their disease or condition. This provision is typically approved for individual patients but may be approved to treat a small group. Criteria include:

Serious disease or condition
No alternative

FDA recognizes that there are circumstances in which an investigational device is the only option available for a patient faced with a serious, albeit not life-threatening, disease or condition. In these circumstances, FDA uses its regulatory discretion in determining whether such use of an investigational device should occur.

Prior FDA approval is needed before compassionate use occurs. In order to obtain Agency approval, the sponsor should submit an IDE supplement requesting approval for a protocol deviation under section §812.35(a) in order to treat the patient. The IDE supplement should include:

A description of the patient’s condition and the circumstances necessitating treatment;
A discussion of why alternative therapies are unsatisfactory and why the probable risk of using the investigational device is no greater than the probable risk from the disease or condition;
An identification of any deviations in the approved clinical protocol that may be needed in order to treat the patient; and,
The patient protection measures that will be followed. (Informed consent, concurrence of IRB chairperson, clearance from the institution, independent assessment from uninvolved physician, authorization from IDE sponsor).

The physician should not treat the patient identified in the supplement until FDA approves use of the device under the proposed circumstances. In reviewing this type of request, FDA will consider the above information as well as whether the preliminary evidence of safety and effectiveness justifies such use and whether such use would interfere with the conduct of a clinical trial to support marketing approval.

If the request is approved, the attending physician should devise an appropriate schedule for monitoring the patient, taking into consideration the investigational nature of the device and the specific needs of the patient. The patient should be monitored to detect any possible problems arising from the use of the device. Following the compassionate use of the device, a follow-up report should be submitted to FDA as an IDE supplement in which summary information regarding patient outcome is presented. If any problems occurred as a result of device use, these should be discussed in the supplement and reported to the CPHS as soon as possible.