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ADVERSE EVENTS

Investigators involved in behavioral intervention research also need to be aware of guidelines and policies regarding AEs and put into place specific procedures that are to be followed to identify, track, and resolve such events. This aspect of behavioral intervention research can be confusing as the definition of AEs varies across government and nongovernment agencies and DSMBs (described later), as well as institutions and types of studies. The guidelines provided by the U.S. Department of Health and Human Services (2007) defines AEs as

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 . . .

Importantly, these guidelines note that AEs encompass both physical and psychological harm. They also distinguish AEs from “unanticipated problems,” which refers to incidents that meet the following criteria:

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 participation in the research (in this guidance document, possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
  • 3. suggests that the research places study participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized. (U.S. Department of Health and Human Services, 2007)

The NIH further distinguishes between serious AEs (SAEs) and other AEs. Using the Food and Drug Administration (FDA) definition, SAEs include AEs that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity, or result in a congenital anomaly/birth defect. Other important medical events, based upon appropriate medical judgment, may also be considered SAEs if a trial participant’s health is at risk. “Other AEs” are defined using the HHS guidelines (provided earlier).

An issue for those involved in behavioral intervention research is how to define AEs for a given intervention trial. As noted by Horigan and colleagues (Horigian, Robbins, Dominguez, Ucha, & Rosa, 2011), the process of defining, identifying, reporting, and monitoring AEs has received limited attention in behavioral intervention research. There is a lack of clear guidelines to aid investigators. In the Resources for Enhancing Alzheimer’s Caregivers Health II (REACH II) multisite caregiver intervention trial (Belle et al., 2006), based on the consensus of the investigators, two categories of events were defined for both caregivers and patients: AEs and safety alerts. The definition of “AE” was consistent with the FDA and NIH definition of AEs and included events such as death, hospitalization, and emergency room visits. “Safety alerts” were events that were relevant to the study population and posed safety risks to study participants. Examples of safety alerts included caregivers having symptoms of depression or the care recipient driving (Table 13.2). Given that the intervention was based on a risk appraisal approach and the baseline assessment, which included measures of depression, quality of care, and care recipient problem behaviors, was administered prior to randomization, AEs and potential risks to the participants could be detected prior to the start of the intervention. Thus, a distinction was also made between events that were detected at baseline (baseline AEs and baseline safety alerts) versus those that occurred following randomization and the 6-month follow-up assessment (AEs and safety alerts) (Czaja et al., 2006).

Behavioral intervention researchers also need to be aware of the reporting processes for AEs. Reporting processes are somewhat confusing as existing policies vary across government and nongovernment agencies. Investigators who are engaged in an efficacy or effectiveness intervention trial generally need to develop an AE reporting form that includes information about the nature of the event, time

TABLE 13.2 Examples of the Adverse Events Protocol for the REACH II Trial

Baseline

Adverse

Adverse Events

Resolution

Event

Resolution

Caregiver emergency room visit

Not

applicable

Caregiver emergency room visit

The PI or designee (e.g., clinical supervisor, project coordinator) contacted the caregiver to determine the reason for the emergency room visit and how the problem was handled (e.g., received treatment, is currently under treatment, and/or is being monitored by health care provider)

Care recipient institutionalization

Not

applicable

Care recipient institutionalization

The PI or designee (e.g., clinical supervisor, project coordinator) contacted the caregiver to determine the reason and planned duration of the institutionalization

Care recipient death

Not

applicable

Care

recipient

death

The PI or designee (e.g., clinical supervisor, project coordinator) obtained information regarding the circumstances of the event

Baseline Safety Alerts

Resolution

Safety

Alerts

Resolution

Caregiver CESD score > 15

The PI or designee (e.g., clinical supervisor, project coordinator) contacted the caregiver to discuss the seriousness of the situation and referred the caregiver to his or her primary care physician (or other health care or mental health professional) to discuss the symptoms

Caregiver CESD score > 15

The PI or designee (e.g., clinical supervisor, project coordinator) contacted the caregiver to discuss the seriousness of the situation and referred the caregiver to his or her primary care physician (or other health care or mental health professional) to discuss the symptoms

Care

recipient

driving

The PI or designee (e.g., clinical supervisor, project coordinator) contacted the caregiver to discuss the safety implication of the care recipient driving and devise a plan of action to stop the care recipient from driving. Caregivers who were randomized to the control condition were sent the material on driving and dementia. Caregivers who were randomized to the intervention condition were encouraged to read the materials in the Caregiver Notebook related to driving

Care

recipient

driving

The PI or designee (e.g., clinical supervisor, project coordinator) contacted the caregiver to discuss the safety implication of the care recipient driving and devise a plan of action to stop the care recipient from driving. Caregivers who were randomized to the control condition were sent the material on driving and dementia. Caregivers who were randomized to the intervention condition were encouraged to read the materials in the Caregiver Notebook related to driving

TABLE 13.2 Examples of the Adverse Events Protocol for the REACH II Trial (Continued)

Baseline Safety Alerts

Resolution

Safety

Alerts

Resolution

Care

recipient has

access to a gun

The PI or designee (e.g., clinical supervisor, project coordinator) contacted the caregiver to discuss the safety implications and devise a plan of action to block the care recipient's access to the gun. If the caregiver refused or was unable to block the care recipient's access, Adult Protective Services may have been contacted.

If it appears that an assessor or interventionist was in danger, the caregiver's/care recipient's participation in the study was terminated

Care

recipient

has

access to a gun

The PI or designee (e.g., clinical supervisor, project coordinator) contacted the caregiver to discuss the safety implications and devise a plan of action to block the care recipient's access to the gun. If the caregiver refused or was unable to block the care recipient's access, Adult Protective Services may have been contacted.

If it appears that an assessor or interventionist was in danger, the caregiver's/care recipient's participation in the study was terminated

PI, principal investigator; CESD, Center for Epidemiologic Studies Depression Scale.

frame, action take, relationship to study treatment, and the severity of the event. An example of an AE form is provided in Figure 13.1.

A form for reporting SAEs typically requires additional information such as a brief description of the participant who experienced the event (Figure 13.2). It may be possible to combine these two forms for a study depending on the requirements of the IRB and the study monitoring committee if one exists (e.g., Data and Safety Monitoring Committee). These forms must be standardized for multisite trials. Protocols for resolution of the event must also be established and approved by the IRB and study-monitoring entities.

When reporting AEs, the PI of an intervention study is also responsible for determining the likely relationship between the AE and the intervention. The National Institute on Aging (NIA) has provided some guidance on this issue and provides the following scale:

Definitely Related: The adverse event is clearly related to the investigational agent/ procedure—i.e. an event that follows a reasonable temporal sequence from administration of the study intervention, follows a known or expected response pattern to the suspected intervention, that is confirmed by improvement on stopping and reappearance of the event on repeated exposure and that could not be reasonably explained by the known characteristics of the subject’s clinical state.

Possibly Related: An adverse event that follows a reasonable temporal sequence from administration of the study intervention, follows a known or expected response pattern to the suspected intervention, but that could readily have been produced by a number of other factors.

An example of an adverse event reporting form

Figure 13.1 An example of an adverse event reporting form.

Source: The National Institute on Aging (2013).

Not Related: The adverse event is clearly not related to the investigational agent/ procedure—i.e. another cause of the event is most plausible; and/or a clinically plausible temporal sequence is inconsistent with the onset of the event and the study intervention and/or a causal relationship is considered biologically implausible. (NIA, 2013, p. 5)

An example of serious adverse event reporting form. (Continued)

Figure 13.2 An example of serious adverse event reporting form. (Continued)

(Continued) An example of serious adverse event reporting form. Source

Figure 13.2 (Continued) An example of serious adverse event reporting form. Source: National Institute on Aging 2013.

While these guidelines are helpful, consideration also needs to be given to the characteristics of the study population and the contextual factors surrounding the intervention. For example, in a multisite trial that evaluated a psychosocial intervention for caregivers of persons with spinal cord injury (Schulz et al., 2009), a DSMB for the trial was established along with a protocol for tracking and reporting AEs. One of the AEs established for the study by the DSMB in collaboration with the PIs was the development of pressure ulcer sores in the patients. However, given that the onset of pressure ulcer sores is common among people with spinal cord injury, it was highly unlikely that the occurrence of this AE was related to the intervention. In contrast, if there were a significant number of caregivers who experienced symptoms of clinical depression since the trial onset (this in fact was not the case), this could potentially be linked to the intervention. However, depression is common among caregivers; so, if this in fact occurred, the causality would need careful examination by the PI, the research team, and the DSMB.

As noted, there are also requirements/guidelines for reporting AEs to the IRB, the monitoring entities established for the trial, and, in some cases, the funding agency. In general, the PI is responsible for reporting AEs to the IRB and the study monitoring entity within time windows agreed upon by the IRB and the monitoring entity. For example, in a current caregiver intervention trial, the DSMB agreed that quarterly reports would be sufficient unless significant issues arose within the trial—for example, a significant increase in the frequency of an AE or its high probability of occurrence due to the intervention. Unless otherwise specified in the protocol and approved by the IRB and monitoring entity, all SAEs require expedited reporting to the IRB and the monitoring entity as detailed in the approved Data and Safety Monitoring Plan (DSMP) (NIA, 2013).

Importantly, the PI must also establish an internal study-reporting protocol that encompasses the reporting structure and time windows for reporting and resolving the event. For example, in the intervention study targeted for caregivers and spinal cord injury patients (Schulz et al., 2009), for any AE identified by a member of the research team, the event needed to be reported to the PI or the designee of the PI within 24 hours and recorded on the AE form. In addition, the event needed to be resolved using the protocols established for the study within 3 days of learning of the event. A weekly review of SAEs and AEs should be conducted to ensure that they have been recorded properly, sufficiently resolved, and submitted to reporting bodies as required.

Finally, protocols must be established for resolution of AEs and SAEs, and these protocols must be approved by the IRB or the monitoring entity. Examples of the protocols used in the REACH II intervention trial (Belle et al., 2006) are provided in Table 13.2. The establishment of protocols for resolution of AEs can also be confusing for behavioral intervention trials. For example, in the REACH II trial, nursing home placement of persons with dementia was considered an AE. However, in question was determining its resolution. That is, should resolution be defined as the return of the person with dementia to the home setting or knowledge that placement occurred and the reason for the placement decision. Obviously, placement of patients who were permanently placed would never be “resolved” if the definition of resolution of this event was the person with dementia returning to home. Instead, it was agreed that the definition of “resolution” would be that the

PI or designee contact the caregiver to determine the reason for, and planned duration of, the placement of the person with dementia. This protocol was approved by the DSMB, which underscores the importance of educating the DSMB or any other monitoring entity about the nature of the intervention and the characteristics of the target population. It is also critical to ensure that all members of the research team are trained in the protocols for handling AEs and SAEs and that these protocols are included in the manual of operations developed for the study (see Chapter 6).

 
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