Vanderbilt Human Research Protections Program Adverse Events Shannon Simmons Vanderbilt Human Research Protections Program July 11, 2014

Outline Review key terms and federal definitions used in the context of adverse event reporting Review federal and local information on adverse event reporting requirements Summarize information and identify main points Present list of Resources Present example scenarios for evaluation

Everyone Wants Something Different Protocol IRB Sponsor FDA OHRP

Disclaimer Regarding the Differences You are responsible to keep track of each involved agencies reporting policy and report accordingly. Often different requirements imposed by: FDA OHRP IRB Funding agencies Collaborating Institutions

Accurate AE Reporting and Documentation is Important It is the law per Federal Regulations and applies to all research involving human subjects, conducted, supported or otherwise subject to regulation by any federal department or agency For FDA regulated studies, it is a contractual obligation of all physicians who sign the FDA 1572 investigator registration form Ensures human subject safety Facilitates accurate analysis of effects from investigational interventions

DEFINITIONS

OHRP

OHRP Reporting Regulations 45 CFR 46.103(a) and (b)(5) require that institutions have written procedures to ensure the following incidents related to research conducted under an OHRP approved assurance is promptly reported to OHRP. These incidences include: Any unanticipated problems involving risks to subjects or others Any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB

Unanticipated Problems Involving Risk to Participants or Others Any incident, experience, or outcome that meets ALL of the following criteria: 1. Unexpected (nature, severity and frequency AND 2. Related or Possibly related -reasonable possibility that the adverse event may have been caused by the procedures involved in the research AND 3. Suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized. OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events

Unanticipated Problems Involving Risk to Participants or Others Have all three criterion answered yes. Incidents, experiences, or outcome that meets the three criteria generally will warrant consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions in order to protect the safety, welfare, or rights of subjects or others such as: Modification of the inclusion/exclusion criteria Implementation of additional monitoring procedures Suspension of enrollment of new subjects or research procedures in enrolled subjects Providing additional information about newly recognized risks to enrolled subjects

OHRP and Adverse Events 45 CFR part 46 does not define or use the term adverse event, nor is there a common definition of this term across government and non-government entities.  Adverse event according to the regulations, in general is used very broadly and includes any event meeting the following definition:  “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 (modified from the definition of adverse events in the 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical Practice).” Adverse events encompass both physical and psychological harms. 

FDA

No Wonder We Are Confused FDA regulations use different terms when referring to an adverse event. adverse effect is used in 21 CFR 312.64; adverse experience is used in 21 CFR 312.32; adverse reactions /adverse event (used interchangeably) in 21 CFR 312.32 ; unanticipated problems is used in 21 CFR 312.66. with qualifiers/descriptors to specifically identify: life- threatening, suspected and/or unexpected. All have their own definition and very closely related

Adverse Event (adverse experience) Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. 21CFR 312.32

Unexpected Adverse Event FDA defines this as any event where: the specificity or severity of which is not consistent with the current Investigator Brochure (IB); or if an IB is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application.

Serious Adverse Events Any event resulting in the following outcome should be reported to FDA : Death Life-threatening adverse event; Inpatient hospitalization or prolongation of existing hospitalization; A persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions; A congenital anomaly/birth defect; or May jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Reporting Requirements

IRB Policy III.L Reporting of Adverse Events, Serious Adverse Events and Unanticipated Problems Involving Risk to Participants or Others

When VU is the IRB of Record VU PI Responsible for Research Report with in 10 days Any serious adverse event that in the Investigator’s opinion: Was unanticipated (not foreseeable at the time of the occurrence) or unexpected (not previously seen), AND Involved risk to participants or others AND Was possibly related to the research procedures; AND/OR Any noncompliance with the IRB approved protocol that increased the risk or affected the patients rights, safety or welfare. Any unanticipated problem that falls within the guidelines listed above require reporting to the IRB even after the participant has completed the study or after the participant has withdrawn from the study including after study closure Occurrences also happen at VU or other locations that the PI is responsible for

When VU Is not the IRB of Record and the Study Related Event does not occur at VU or a Location that a VU PI is Responsible for Research. Does not need to be reported to the IRB unless, the event is : Related, Unanticipated, And Places subjects at greater risk then previously known In these cases the PI will: Submit the event to the VU IRB as an amendment Request The Amendment Form should include: Sponsor and/or DSMB’s assessment of the event and the VU PI’s assessment of the event; and the amendment request form should outline the necessary revisions to the VU IRB approved protocol and associated documents needed to address the potential risk.

Flowchart for Reporting Unanticipated Problems involving risk to Others and Serious Adverse Events

Reporting Requirements for Unanticipated Problems and Adverse Events Involving Risk to Participants and Others Include: The Investigator’s assessment of causality and A description of the actual event; An evaluation of whether the event meets the following criteria: Unanticipated; AND Related; AND Serious-An event that suggests that the research places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized.

Other Safety Reporting Requirements Independent safety monitoring reports, Interim analysis reports or Data and Safety Monitoring Board reports. Report When received by PI

VU IND Safety Reporting Requirements Outside Safety Reports are no longer reported to the VU IRB Unless it caused increased safety risk to subjects which necessitated revising study documents such as the protocol, IB and/or consent documents. Submit as an amendment

FDA Reporting Requirements An investigator must immediately report to the sponsor any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event. 21CFR312.64

FDA Reporting Program-MedWatch The FDA Safety Information and Adverse Event Reporting Program Voluntary and Mandatory reporting Used to report a serious adverse event, product quality problem, product use error, or therapeutic inequivalence/failure that is suspected to be associated with the use of an FDA-regulated drug, biologic, medical device, dietary supplement or cosmetic. FDA uses the reporting of events to maintain safety surveillance on FDA regulated products which may prompt action needed to increase patient safety.

FDA Reporting Requirements FDA has 3 reporting forms: Form FDA 3500A - Mandatory Reporting For use by IND reporters, manufacturers, distributors, importers, user facilities (Sponsors/Sponsor-Investigator), Submitted as specified in the investigational new drug/biologic regulations or investigational device exemptions. For sponsored studies, may be required per the study protocol and sent to the address and contact person listed in the study protocol. Form FDA 3500 [voluntary] For use by healthcare professionals, consumers, and patients. Voluntary reporting of adverse events noted spontaneously in the course of clinical care, not events that occur during clinical trials under an IND application. You can report even if: You are not certain the product caused the event You don’t have all the details Form FDA 3500 B [Consumer voluntary] Completed by non-health Professionals or consumers New and easier version (4/2013)

MedWatch 3500A Form

Unanticipated Adverse Device Effect Definition: any serious adverse effect on the health or safety of subjects, or any life-threatening problem or death caused by, or associated with, a device, if that problem or death was not previously identified in nature, severity or degree of incidence in the investigational plan. The sponsor and the VU IRB must be informed of any unanticipated adverse device effect during a study within 10 days of the investigator first learns of the effect. A sponsor (the holder of the IDE) must immediately conduct an evaluation of a unanticipated effect and report to the FDA and to all investigators and the IRB within 10 days of the sponsors receiving notice of the effect. Investigators must send these reports to the IRB. FDA: 21 CFR 812.150 IRB Policy: XI.C

How Will I Ever Get it Right?

Relationship Between Adverse Events and Unanticipated Problems The diagram illustrates not all adverse events are unanticipated problems: The vast majority of adverse events are not unanticipated problems (area A). A small proportion of adverse events are unanticipated problems (area B). Unanticipated problems include other incidents, experiences, and outcomes that are not adverse events (area C). Adverse events are things that happen during the process of the study that are stated may happen Adverse evnts turn into unanticipated problems when they appear more often than expected this may be the B-group The C group is related to those reactions that occur that were truly not known and are not stated adverse events but related to study participation So you want to report the events that are happening more frequently, related and could pose risk and those events that occur that are unexpected, related, and pose risk. http://www.hhs.gov/ohrp/policy/advevntguid.html

Stay or Become Organized Print out and use adverse event flow charts available to you. Check the VU IRB flow chart prior to any submission. Create tip sheet of who to report to and when. Discuss requirements with Sponsor Understand the reporting requirements described in the Protocol and Data Safety Plan Call (IRB or FDA) if you have questions regarding whether to submit or not submit. Document who reports were submitted to (FDA, IRB, Sponsor etc.) and when. Stay current with regulations and Institution policies.

Summary Although the regulations place the burden of responsibility on the PI, the protection of human research subjects is a shared responsibility among all research professionals involved in the conduct of the study. We all have a common goal to keep participants safe and have strict regulations to ensure drugs are safe prior to FDA approval for use.

Resources Office for Human Research Protections (OHRP) --45 CFR 46.103(b)(5) http://www.hhs.gov/ohrp/ OHRP Guidance Document, “Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events,” January 15, 2007 Food and Drug Administration (FDA)--45 CFR 46.103(b)(5) http://www.fda.gov/ http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126572.pdf Instructions for completing Medwatch Form 3500A http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/ucm149238.htm#send Institutional Review Board (IRB) IRB Policy III.L Reporting of Adverse Events, Serious Adverse Events and Unanticipated Problems Involving Risk to Participants or Others IRB Policy XI.C Investigational Devices Good Clinical Practice http://www.fda.gov/oc/gcp/guidance.html

Scenarios

Should this be Reported? Event: A 52 year old female went to the oncologic clinic to received Cycle 2 of A/C. The participant was seen and reported fever, pain, redness and hardness of right breast. She was treated with Cipro and a drainage catheter was inserted. 120 ml of fluid was sent for culture. Other labs were normal and cultures are pending. The plan for the participant is to receive Cycle 2 on 10/22/03. The PI determined that the event was related to the study and risk is currently contained in the informed consent document. No, this example is not an unanticipated problem because the occurrence is currently listed in the consent document– was expected.  What could make this an unanticipated problem that could be reportable? A/C means

Should this be Reported? A participant takes a new investigational anti-inflammatory agent for management of osteoarthritis develops severe abdominal pain and nausea one month after randomization. Medical evaluation reveals gastric ulcers. The protocol and ICD state there is a 10% chance of developing mild to moderate gastritis and a 2% chance of developing gastric ulcers if assigned to the active agent. No, because the event is expected.

Should this be Reported? Due to a processing error by a pharmacy technician, a participant receives a dose of an experimental agent that is 10-times higher than the dose stated in the IRB approved protocol. While the dosing error increased the risk of toxicity, the participant experienced no detectable harm or adverse effects. Yes, This is an unanticipated problem that needs to be reported because the incident was: Unexpected Related to study participation Placed the subject at a greater risk of physical harm

Should this be Reported? An investigator is conducting a psychology study evaluating the factors that affect reaction times in response to auditory stimuli.  In order to perform the reaction time measurements, subjects are placed in a small, windowless soundproof booth and asked to wear headphones.  The IRB-approved protocol and informed consent document describe claustrophobic reactions as one of the risks of the research.  The twentieth subject enrolled in the research experiences significant claustrophobia, resulting in the subject withdrawing from the research.   No, this example is not an unanticipated problem because the occurrence of the claustrophobic reactions in terms of nature, severity, and frequency – was expected.

Should this be Reported? An investigator conducting behavioral research collects individually identifiable sensitive information about illicit drug use and other illegal behaviors by surveying college students.  The data are stored on a laptop computer without encryption, and the laptop computer is stolen from the investigator’s car on the way home from work.  Yes, this is an unanticipated problem that must be reported because the incident was (a) unexpected (i.e., the investigators did not anticipate the theft); (b) related to participation in the research; and (c) placed the subjects at a greater risk of psychological and social harm from the breach in confidentiality of the study data than was previously known or recognized. 

Should This be Reported? A study nurse realizes the consent form signed by the participant is not the most recent version, however, the consent form has not expired. There were no changes to the consent document other than new expiration date. No, This example is not an unanticipated problem because it is not serious and does not place the subject at greater risk than was previously known.

Questions Shannon Simmons Regulatory Compliance Analyst Phone: 322-2918 Email: shannon.d.simmons@vanderbilt.edu