1. Safety of the Subject Cena Jones-Bitterman, MPP, CIP, CCRP
Holden Comprehensive Cancer Center
Protocol Development and Monitoring

2. Objectives Key definitions
Identifying, documenting and reporting Adverse Events
Investigator Responsibilities
How are research participants protected?
Safety related roles in clinical research

3. Definitions 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)

4. Definitions 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:
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 life- threatening, 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 (a)

5. Definitions Unanticipated problems
Includes any incident, experience, or outcome that meets all of the following criteria:
Unexpected in nature, severity, or frequency given:
research procedures
the characteristics of the subject population being studied
Related or possibly related to participation in the research
Suggests that the research places subjects or others at a greater risk of harm

6. Considerations Not all adverse events (AEs) are reportable
Adverse events do not have to be caused by the drug or therapy
Not all adverse events are serious
When they are serious, typically require expedited reporting
The PI is responsible for assessing whether or not the AE meets reporting criteria (to the IRB, sponsor, etc.)

7. Recording Adverse Events
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

8. Adverse Event Monitoring
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

9. Assessment
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
This assessment + expectedness of the event helps in determining the timeliness for reporting the event to the IRB, sponsor, or other regulatory/oversight groups

10. Expected vs. Unexpected
Known to occur and is listed in the Investigational Brochure, Informed Consent, or protocol
Unexpected
Not listed in Investigational Brochure, Informed Consent, or General Investigational Plan
Also not listed in a drug package insert

11. Attribution or Relatedness
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?
It is important to identify what the AE is related to, NOT merely what it is not related to
Information assists regulatory/oversight groups to assess safety and protect human subjects

12. Determining Attribution
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)?

13. Determining Attribution
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

14. Challenges
Clinical trial protocols are often complex, involving multiple drugs in sick patients
A subject’s prior therapies can affect the occurrence or severity of an AE
Concurrent medical conditions and/or medications can affect the occurrence and/or severity of an AE

15. More Challenges Conflicting and/or incomplete information
Conflicting opinions between the PI, treating physicians, medical monitors, sponsor, etc.
Confusing reporting requirements

16. Reporting Adverse Events
Applicable regulatory bodies:
FDA
IRB
Sponsor
Two types of mechanisms used when reporting AEs to regulatory bodies:
Routine
Expedited

17. FDA Reporting Requirements
Routine 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)
Expedited reporting
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

18. Institutional Reporting Requirements
IRB reporting
Routine:
Continuing Review
Expedited:
Reportable Events (REF)
Other committee reporting
Data and safety monitoring boards/committees (DSMB/DSMC)

19. Other Reporting Requirements
Sponsor reporting
Routine:
Electronic/Case Report Forms, logs, database submissions, etc.
Expedited
Database submission,
Clinical trials are sponsored by various organizations or individuals, including physicians, foundations, medical institutions, voluntary groups, and pharmaceutical companies, as well as federal agencies
ClinicalTrials.gov
Applicable clinical trials
Registration requirements
Results reporting

20. Investigator Responsibilities
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

21. Safety Related Roles in Clinical Research
Principal Investigator
IRB
Sponsor
Departments/agencies
HHS
FDA

22. Safety of research participants
Obtain IRB approval
Follow the protocol
Obtain and document informed consent
Record keeping
Reporting
Monitoring

23. References Guide for Human Subjects Research at the University of Iowa
Office for Human Research Protections (OHRP)
Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events
HHS Regulations
45 CFR (b)(5)
FDA Regulations
21 CFR 50; 21 CFR 312