Download Safety of the Subject - The University of Iowa

Cena Jones-Bitterman, MPP, CIP, CCRP
Holden Comprehensive Cancer Center
Protocol Development and Monitoring
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Key definitions
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Identifying, documenting and reporting Adverse Events
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Investigator Responsibilities
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How are research participants protected?
◦ Safety related roles in clinical research
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Adverse Event (AE)
◦ any untoward medical occurrence associated
with the use of a drug in humans, whether or not
considered drug related. (FDA)
◦ 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(ICH GCP and OHRP)
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Serious Adverse Event (SAE)
◦ An adverse event is considered "serious" if, in the view of either the
investigator or sponsor, it results in any of the following outcomes:
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Death
A life-threatening adverse event
Inpatient hospitalization or prolongation of existing hospitalization
A persistent or significant incapacity or substantial disruption of the
ability to conduct normal life functions, or a congenital anomaly/birth
defect
 Important medical events that may not result in death, be lifethreatening, or require hospitalization may be considered serious when,
based upon appropriate medical judgment, they may jeopardize the
patient or subject and may require medical or surgical intervention to
prevent one of the outcomes listed in this definition
21 CFR 312.32(a)
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Unanticipated problems
◦ Includes any incident, experience, or outcome that
meets all of the following criteria:
1. Unexpected in nature, severity, or frequency given:
 research procedures
 the characteristics of the subject population being studied
2. Related or possibly related to participation in the research
3. Suggests that the research places subjects or others at a greater
risk of harm
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Not all adverse events (AEs) are reportable
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Adverse events do not have to be caused by the drug or
therapy
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Not all adverse events are serious
◦ When they are serious, typically require expedited
reporting
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The PI is responsible for assessing whether or not the AE
meets reporting criteria (to the IRB, sponsor, etc.)
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Know the protocol
◦ What events need to be captured?
◦ When do events need to be captured?
◦ Following initiation of study medication, collect all AEs, regardless of
cause or relationship, until 30-days after last administration of study
drug
◦ All AEs will be recorded by the investigator from the time the subject
signs informed consent until 28 days after the last dose of Drug A, 90
days after the last dose of Drug B
◦ For non-serious Adverse Events (AEs ≥ grade 3), documentation must
begin from the first day of study treatment and continue through the 30
day follow-up period after treatment is discontinued
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The purpose of AE monitoring:
◦ To identify events that may have immediate effect on the
safety of the subject
◦ Inform regulators, investigators, and others of new and
important information about events that occur on a clinical
trial
◦ Provide a summary of adverse experiences in order to develop
the drug or regimen toxicity profile
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Assessing adverse events is done by the PI or designee
(qualified sub-investigator) and includes determining
the following:
◦ Severity of event
◦ Attribution of the event
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This assessment + expectedness of the event helps in
determining the timeliness for reporting the event to
the IRB, sponsor, or other regulatory/oversight groups
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Expected
o Known to occur and
is listed in the
Investigational
Brochure, Informed
Consent, or protocol
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Unexpected
◦ Not listed in
Investigational
Brochure, Informed
Consent, or General
Investigational Plan
◦ Also not listed in a
drug package insert
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Once the severity of the event is established, find the
cause, or attribution, of the event
◦ Is the event related to the study agents, the subject’s
underlying illness or preexisting condition?
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It is important to identify what the AE is related to,
NOT merely what it is not related to
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Information assists regulatory/oversight groups to
assess safety and protect human subjects
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The PI should determine attribution by considering the
following:
◦ What do we already know about the drug/therapy, or classification
of drug?
◦ What is the temporal relationship of the AE to the study therapy?
◦ Does the AE improve or disappear when drug/therapy is stopped?
◦ If the drug/therapy, is re-administered, does the AE reappear? At
the same severity? At the same time point?
◦ Is the AE a result of existing disease and symptoms?
◦ Is the AE a worsening of baseline symptom(s)?
◦ Is the AE a result of an underlying concurrent medical condition(s)
or concurrent medication(s)?
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Definite—clearly related to study agent
Probable—likely related to study agent
Possible—may be related to study agent
Unlikely—doubtfully related to study agent
Unrelated—clearly not related to study agent
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Clinical trial protocols are often complex, involving
multiple drugs in sick patients
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A subject’s prior therapies can affect the occurrence or
severity of an AE
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Concurrent medical conditions and/or medications can
affect the occurrence and/or severity of an AE
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Conflicting and/or incomplete information
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Conflicting opinions between the PI, treating
physicians, medical monitors, sponsor, etc.
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Confusing reporting requirements
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Applicable regulatory bodies:
◦ FDA
◦ IRB
◦ Sponsor
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Two types of mechanisms used when reporting AEs to
regulatory bodies:
◦ Routine
◦ Expedited
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Routine reporting
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Expedited reporting
◦ FDA will be informed by the Sponsor in a summary fashion of AEs in the
annual report required for all Investigational New Drugs (INDs)
◦ Sponsor is to notify FDA and all participating investigators of potential
serious risks, from clinical trials or any other source, as soon as
possible, but in no case later than 15 calendar days
◦ Sponsor must notify FDA of any unexpected fatal or life-threatening SAR
as soon as possible but in no case later than 7 calendar days after the
sponsor's initial receipt of the information
◦ An IND Safety report may result in a safety-related change in the
protocol, informed consent, investigator’s brochure, or other aspects of
the overall conduct of the clinical investigation
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IRB reporting
◦ Routine:
 Continuing Review
◦ Expedited:
 Reportable Events (REF)
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Other committee reporting
◦ Data and safety monitoring boards/committees (DSMB/DSMC)
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Sponsor reporting
◦ Routine:
 Electronic/Case Report Forms, logs, database submissions, etc.
◦ Expedited
 Database submission, email
 Clinical trials are sponsored by various organizations or individuals,
including physicians, foundations, medical institutions, voluntary groups,
and pharmaceutical companies, as well as federal agencies
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ClinicalTrials.gov
◦ Applicable clinical trials
◦ Registration requirements
◦ Results reporting
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Obtain IRB approval prior to enrollment
Obtain and document informed consent
Follow the study protocol
Obtain IRB approval prior to initiating changes to the
protocol
Control the investigational product
Ensure AEs are appropriately documented and
reported
Maintain adequate records and reports
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Principal Investigator
IRB
Sponsor
Departments/agencies
◦ HHS
◦ FDA
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Obtain IRB approval
Follow the protocol
Obtain and document informed consent
Record keeping
Reporting
Monitoring
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Guide for Human Subjects Research at the University of
Iowa
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Office for Human Research Protections (OHRP)
◦ Guidance on Reviewing and Reporting Unanticipated Problems
Involving Risks to Subjects or Others and Adverse Events
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HHS Regulations
◦ 45 CFR 46.103(b)(5)
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FDA Regulations
◦ 21 CFR 50; 21 CFR 312