| One of the most difficult responsibilities in carrying out clinical
trials on investigational drugs or devices is the assessment and reporting
of adverse events that might be related to the study drug. The clinical
investigator has the duty to carefully evaluate each adverse event for
severity and for the likelihood of its being caused by the drug.
If the investigator cannot rule out the possibility of the event having
been caused by the drug, he/she has an obligation to report any serious
adverse event to the IRB and to the study sponsor.
The Food and Drug
Administration criteria for reportable adverse events are that they
are "serious" and "unexpected". Whether an event is judged "serious"
depends largely on the clinical judgment of the investigator, often in
consultation with the Chair of the Scientific Committee (IRB). In
the following sections, a suggested framework is given for judging severity
of an event. The final weight assigned to an adverse event, however,
will stem from your close clinical knowledge of the patient and the context
of the event.
Whether an event is "unexpected" can be judged by referring to the information
compiled at the start of the study: is this an event that was noted in
the investigator's brochure supplied by the study sponsor? Is it an event
that was mentioned as a possible risk in the original consent form?
Remember that the emphasis placed on reporting adverse events grows
from the fact that assessing the risks and benefits of any program of human
research is a reiterative process. As our knowledge base about new agents
expands, we have an obligation to revisit the risk/benefit equation, and
to revise protocols, consent forms and patient information as necessary.
This has the advantage of not only maintaining an ethical relationship
between investigator and subject, it also has the effect of enlisting the
patient as an observer and reporter of what could be valuable information.
The following outline for evaluating and reporting potential adverse
events in drug trials is adapted from one devised by Roohollah Sharifi,
MD, University of Illinois Chicago.
I.
Triggers for Identifying Potential Adverse Drug Effects:
If one or more are present, the clinical investigator should undertake
a determination of causality and severity as outlined in the Sections II
and III.
A. Any new or worsening symptom or sign on follow-up
visit that was not present on baseline physical exam or medical history.
B. Any medical condition causing hospitalization or physician visit.
C. Any new medication started during the study.
II.
Determination of Causality:
Is the Investigational Drug Causing this Adverse Effect?
Signs in the chart indicate the suggested weight to be given to each factor
in determining the likelihood that the investigational drug is causing
the effect. Note that the strongest evidence comes from a rechallenge with
the drug after discontinuation. This strategy is often too risky with a
serious event, however, so investigators often must rely on combined information
from the other key characteristics.
| |
Likelihood: |
| Key Characteristic |
Definite |
Probable |
Possible |
Unknown |
Unrelated |
A. Temporal Relationship
|
+ |
+ |
+ |
+ |
- |
B. Rule out other drug/disease causes
|
+ |
+ |
+ |
+ |
- |
C. Dechallenge
|
+ |
+ |
+ |
+ |
- |
D. Rechallenge
|
+ |
- |
- |
- |
- |
Under FDA regulations, events deemed to be unrelated to the drug or
of unknown etiology do not require reporting. Some investigators, however,
err on the side of caution and report all serious adverse events, regardless
of judged relationship to the investigational agent. Certainly if you can't
rule out the investigational article as the cause of the event, it should
be reported.
III.
Determination of the Severity of Adverse Drug Effect
The table shows suggested weights to be given to determine the severity
an adverse event. Note that starting drug treatment, interruption
of routine activities, or patient seeking medical help might be deemed
either moderate or severe effects, but all other listed effects are considered
severe, and must be reported if the investigational agent cannot be ruled
out as a possible cause.
| |
Degree of Severity: |
Adverse Effect/Outcome
|
Severe |
Moderate |
Mild |
A. Drug treatment for adverse effect started
|
+ |
+ |
- |
B. Patient sought medical help
|
+
Visited
Emergency
Room |
+
Visited
Clinic |
- |
C. Adverse effect disrupts routine activities
|
+ |
+ |
- |
D. Patient required hospitalization
|
+ |
- |
- |
E. Adverse effect caused cancer
|
+ |
- |
- |
F. Adverse effect caused congenital anomaly
|
+ |
- |
- |
G. Adverse effect is permanently disabling
|
+ |
- |
- |
H. Adverse effect is life threatening
|
+ |
- |
- |
I. Adverse effect associated with death
|
+ |
- |
- |
IV.
Process for Documenting and Reporting Serious Adverse Drug Effects (ADE)
that Occur at the Local Site
(See also Adverse Event Report
Form)
A. All serious ADE need to be reported to the sponsor
(drug company) and the IRB if the investigator cannot rule
out the investigational agent as a possible cause of the event.
B. Information which should be provided
to the drug company and the IRB:
1. Full description of ADE:
-
Name of ADE
-
Onset of ADE
-
Clear description of symptoms and signs (from medical history and PE)
-
Lab tests or other tests performed to diagnose ADE (date and test results)
-
Medications or other treatments for ADE (start and stop dates)
-
Outcome of the ADE
-
If hospitalized, admission and discharge dates
-
If died, date of death, cause of death, copy of death certificate
2. Determination of causality (see above)
3. Assessment of severity (see above)
4. For the IRB, include recommendations for monitoring other patients
in the study so as to be able to perform an early diagnosis of the problem.
Revise consent form as necessary. Inform previously enrolled subjects as
necessary.
5. The drug company and the IRB should be contacted within 24
hours for a serious ADE that results in death, or within 3 days for other
serious ADE.
6. Advise as to the approach taken by the National Study Center
based on the ADE.
V.
Process for Handling ADE Reports from Other Investigational Drug Clinical
Trial Sites
Note: For NIH-sponsored
clinical trials the investigator may not receive individual ADE reports
from other sites, but rather a summary report from the study's Data Safety
Monitoring Board. Copies of these summary reports must be forwarded to
the IRB.
A. Send a copy of the report to the IRB with recommendations
for monitoring other patients in the study in the future. When a Data Safety
Monitoring Board (DSMB) exists, summaries of ADE reports, rather than individual
ADE reports, may be supplied periodically along with an analysis and recommendation
by the Board.
B. If necessary, revise the consent form to reflect
any new information about the ADE or any additional tests which may be
called for.
C. If necessary, inform already enrolled patients
about the new ADE; perform any additional tests which may be called for.
D. Advise as to the approach taken by the National Study
Center based on the ADE.
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