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

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

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)

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 312.32(a)

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

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.)

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

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

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

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

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

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)?

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

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

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

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

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

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

Other Reporting Requirements 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 ClinicalTrials.gov Applicable clinical trials Registration requirements Results reporting

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

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

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

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 46.103(b)(5) FDA Regulations 21 CFR 50; 21 CFR 312