Did that just happen?And What do I do now?

Identifying and Reporting Adverse Events and Protocol

Deviations

Elizabeth Mathis, CCRP18 February 2014

Overview and Objectives

http://www.hhs.gov/ohrp/policy/advevntguid.html

Adverse EventsSerious Adverse Events

Protocol Deviations

Recognize Review Report

Unanticipated Problem Definition

http://www.hhs.gov/ohrp/policy/advevntguid.html

Incident, Experience, or Outcome

Unexpected

Nature

Frequency

Severity

Possibly related to participation in

Research

Places subjects or others at greater

risk of harm

Physical

Psychological

Social

Economic

Unanticipated Problem or Not?Behavioral Study

Collects identifiable info

Illicit drug use and illegal behaviors of college students

Data stored on unencrypted laptop

Laptop stolen from car

Checklist:

⃝� Incident, experience, or outcome?

⃝� Unexpected?

⃝� Related to participation?

⃝� Greater risk of harm?

Unanticipated Problem or Not?Device Intervention Study

Vascular stent placement vs surgery for severe carotid artery stenosisPatient assigned to stent placement study group  After procedure, the patient suffers a severe stroke resulting in left-sided paralysis Protocol and ICF indicated a 5-10% chance of stroke for both study groups. The DSMB concludes the occurrence of stroke was expected as well as frequency. 

Checklist:

⃝� Incident, experience, or outcome?

⃝� Unexpected?

⃝� Related to participation?

⃝� Greater risk of harm?

Unanticipated Problem or Not?Drug Intervention Study

For essential hypertension testing new anti-hypertensive drug. 

Three of the first ten subjects have severe GERD symptoms that began within one week of starting the investigational drug and resolve after drug discontinued.

At beginning of trial, no documented evidence of GERD in protocol and ICF do not describe GERD as risk.   

Investigator determines that GERD symptoms were caused by the study drug and warrant modification of the ICF to include GERD as a risk of the research. 

Checklist:

⃝� Incident, experience, or outcome?

⃝� Unexpected?

⃝� Related to participation?

⃝� Greater risk of harm?

Adverse EventsDefinition

Unintended or Unfavorable

Temporally Associated Related or Not

Abnormal SignsPhysical Exam Lab Results Symptom Disease

http://www.hhs.gov/ohrp/policy/advevntguid.html

Unanticipated Problem vs.

Adverse Events

http://www.hhs.gov/ohrp/policy/advevntguid.html

A= Adverse Events that are not Unanticipated Problems

C= Unanticipated problems that

are not Adverse Events

B= Adverse Events

that are Unanticipated

Problems

Unanticipated problems

Adverse Events

AE or Not?

Subject # 1On quadruple therapy study for Hepatitis C

ICF states: Decreases in laboratory tests measuring white blood cells, platelets, red blood cells.

AE or Not?Subject # 1

AE or Not?

Subject # 2On triple therapy study for Hepatitis C

Package insert states:

AE or Not?

Subject # 2Progress note for Follow up week 24 visit:

AE or Not?

Subject # 3Device study to detect mucosal oxygenation during

AAA repairFrom ICF:

Physical Risks: Rare

Pain or discomfort upon insertion of the rectal sensor due to an anal fissure (tear), Abscess, Fistula or inflamed hemorrhoid.

Rectal perforation (puncture).

AE or Not?

Subject # 4On triple therapy study for Hepatitis C

http://sv-galena.com/Trip6/201012Bahamas/Part01.html

Serious Adverse EventsDefinition

http://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm

Any adverse event that:

Results in death

Is life-threatening

Results in hospitalization

Results in disability

Results in birth defect

Results in intervention to prevent one of

these

SAE or Not?Subject # 5

On quadruple therapy study for Hepatitis C

SAE or Not?Subject #6

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/ucm244336.htm

(1) Subject #389204 had Week 8 laboratory tests collected on February 18, 2008, and the corresponding laboratory report that was faxed to your site on February 20, 2008, showed that the subject’s creatinine (CR) level measured 3.2 mg/dL.*

* Normal range is 0.5 -1.2 mg/dL.

Serious Adverse EventsImportant Distinction

Severe Serious

Not Severe

Minor Stroke

Headache Not Serious

Protocol Deviations

Recognize Review Report

Protocol DeviationsDefinition

IRB Approved Protocol

Actual Research Activities

Performed

Protocol DeviationsDefinition

http://research/f/f#Forms-IRBAdmin

Harmed subjects or others

Indicates subjects or others might be at increased risk of

harm

Significantly affects conduct of clinical

trial

Non-compliance with federal

regulations or requirements of IRB

Failure to follow protocol through action or inaction

Change to protocol to eliminate

immediate hazard

Deviation or Not?

Exclusion Criteria #4:Prohibited 6 months prior to Day 0 and throughout the trial (i.e., to last dose to last dose and/or EOT): azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; fenofibrate orother fibrates; budesonide and other systemic corticosteroids;

Subject # 7On treatment for PBC-related liver enzyme

elevation

Deviation or Not?

Subject # 8On triple therapy for

Hep-C

Deviation or Not?Subject # [Redacted]

• Records of each subject's case history are not all accurate and complete. Specifically, individual subject case history files including source documentation and CRFs contain missing or discrepant information, including, but not limited to the following:

• for subject [redacted] missing documentation of required physical examinations, incomplete or missing documentation regarding the placement of [redacted] and Complications Report or Intercurrent Event Report not completed;

• missing information regarding surgical complications, the number of devices implanted, and device accountability for subject [redacted] and,

• source worksheets and CRFs do not record any information or measurements regarding required evaluations for subjects [redacted]

http://www.fda.gov/ICECI/EnforcementActions/WarningLetter

Overview and Objectives

Adverse Events, Serious Adverse Events, and Protocol Deviations

Recognize Review Report

AE Review

AE Review

SAE Review

Deviation Review

http://www.nia.nih.gov/sites/default/files/protocoldeviationscoreformfillable.pdf

Overview and Objectives

Adverse Event, Serious Adverse Event, and Protocol Deviations

Recognize Review Report

Adverse EventsReporting to IRB

http://research/f/f#Forms-IRBAdmin

Internal Serious Adverse EventsReporting to Sponsor

CTSC Research Guidebook, pg 79

Internal Serious Adverse EventsReporting to IRB

http://research/f/f#Forms-IRBAdmin

Internal Serious Adverse EventsReporting to IRB

http://research/f/f#Forms-IRBAdmin

External Serious Adverse Events

External Serious Adverse EventsReporting to IRB

External Serious Adverse EventsReporting to IRB

Protocol DeviationsReporting to Sponsor

Protocol DeviationsReporting to IRB

http://research/f/f#Forms-IRBAdmin

Protocol DeviationsReporting to IRB

http://research/f/f#Forms-IRBAdmin

RecapAdverse EventsSerious Adverse EventsProtocol Deviations

Recognize Review Report

Resources1. IRB Forms http://research/f/f#Forms-IRBAdmin2.OHRP guidance:

http://www.hhs.gov/ohrp/policy/advevntguid.html3.FDA Warning Letter

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/ucm244336.htm

4.SACHRP recommendations on Protocol Deviations: http://www.hhs.gov/ohrp/sachrp/mtgings/2012%20Feb%20Mtg/protocoldeviations.pdf

5. IRB SOPs: http://research.ucdavis.edu/gt/irb-sop