PREP Course #10: Adverse Event Assessing, Recording, and Reporting

Presented by: Sharon Hochman

• The North Shore LIJ Health System adheres to the ACCME’s new Standards for Commercial Support. Any individuals in a position to control the content of a CME activity, including faculty, planners, and managers, are required to disclose all financial relationships with commercial interests. All identified potential conflicts of interest are thoroughly vetted by the North Shore-LIJ for fair balance and scientific objectivity and to ensure appropriateness of patient care recommendations.

• Course Director and Course Planner, Kevin Tracey, MD and Tina Chuck, MPH have nothing to disclose.

• Sharon Hochman has nothing to disclose

CME Disclosure Statement

Objectives

• Definitions and terminologies • How to identify and access the safety

events • How to record the safety events • How to report the safety events • Case study

FDA Safety Reporting: AE & SAE Definitions

• An adverse event is any undesirable experience associated with the use of a medical product in a patient

• Reported on the source documents, CRFs.

Adverse Event

• Defined as death; or a life threatening experience; • hospitalization (for a person not already hospitalized);

prolongation of hospitalization (for a patient already hospitalized);

• persistent or significant disability or incapacity; congenital anomaly and/or birth defects;

• or an event that jeopardizes the subject and may require medical or surgical treatment to prevent one of the preceding outcomes.

• Reported on the source documents, SAE report

Serious Adverse

Event

What is an adverse event • Any change in the subject health, a new symptom,

an accident or new diagnosis after the subject has received a drug or device or during a medical procedure

• These are documented for all device or drug trials while subjects on study

• They are classified by grade 1-5, or mild, moderate or severe and death. Relationship to the experimental drug or device must be included

FDA definitions

• FDA regulations use different terms when referring to an adverse event. For example, adverse effect is used in 21 CFR 312.64; adverse experience is used in § 312.32; and unanticipated problems is used in § 312.66. For the purposes of this guidance, the term adverse event is used, except when quoting specific regulations. For device studies, part 812 uses the term unanticipated adverse device effect, which is defined in 21 CFR 812.3(s).

FDA Inspection

• “Failure to prepare and submit complete and accurate and timely reports of unanticipated adverse device effects”

Expected Vs. Unexpected

• Expected – Known to Occur and

is Listed in the Investigational Brochure, Informed Consent, or General Investigational Plan

• Unexpected – Not listed in

Investigational Brochure, Informed Consent, or General Investigational Plan

– Also not listed in a drug package insert

Unanticipated problems

• Report as an unexpected problem • Related to participation in research • Placed subject at a greater risk of physical harm than was previously

known

Examples would be: • A single occurrence of a serious, unexpected event that

is uncommon and strongly associated with drug exposure

• A single occurrence, or a small number of occurrences, of a serious, unexpected event that is not commonly associated with drug exposure, but uncommon in the study population

• An AE that is described or addressed in the investigator’s brochure, protocol, or informed consent documents, but occurs at a specificity or severity that is inconsistent with prior observations.

Identifying and assessing safety events • AEs can be directly observed by research staff or

reported by research subjects. • If a subject experiences a change in condition

during the course of participation, the change may constitute an AE. Changes can take two forms:

1) The appearance of a new symptom or sign or

2) The increased severity or frequency of an existing symptom or sign

Examples :

Examples of observed AEs include • A rash noted during a physical examination • An abnormal laboratory result • A headache that the subject mentions during a study visit

Examples of Adverse Events which are not related to [or caused by] the study drug but if they occur while the subject is on study, would have to be collected, reviewed by PI and tracked: • Transfusion reactions • Accidental injuries • Surgery

Attribution

• What should the investigator consider prior to assigning attribution? – Individual medical history – Known effects of concomitant medications – Trends in adverse events for their study.

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

• Classifying AE’s

•On the Common Terminology Criteria for Adverse Events (CTCAE ) scale, AE’s are assigned a grade based on their severity. •Grade 1- Mild •Grade 2-Moderate •Grade 3-Severe •Grade 4-life threatening or disabling

Monitoring studies

• Monitoring is done to ensure safety of the subjects in the clinical studies. Separate safety and clinical study conduct monitoring is done.

Data Safety Monitoring board (DSMB)

• A DSMB is an independent group of people that reviews on a regular basis accumulating data from a clinical study.

• They must have no involvement with the conduct of the study

DSMB • The DSMB should review each protocol for any

major concern prior to implementation. During the trial, the DSMB should review cumulative study data to evaluate safety, study conduct, and scientific validity and integrity of the trial.

• There are 3-7 members and one must be a biostatistician. None of them should have direct involvement with the conduct of the study.

Most common monitoring findings • not recording ALL AEs regardless of causality or severity to look for

trends over time • ignoring reports of minor seemingly unrelated events like stomach

aches or dizziness • not having appropriate CRFs to document AE assessments - we

always try to suggest using the Common Terminology Criteria for Adverse Events (CTCAE):

• not having delegation or appropriate clinician to assess AEs - AE CRFs signed off by coordinators lacking source documentation for assessment of severity or significance

• Lab results outside of normal range are often not assessed by clinician

• inadequate documentation in the protocol to define AE severity and SAE reporting criteria

When do you start communicating about the AE?

• AE’s should be captured starting at the baseline visit • PI should always be notified as soon as an AE is identified

regardless of the casuality or type. • Discussions should occur with the sponsor and study team . • PI determines need to Update informed consent, or protocol

if multiple similar events happen • Patients can be educated to be aware of symptoms that may

be associated with an adverse reaction.

Subject diary

Monitoring tips

• Reviewing AEs is a priority for monitors • All AEs must have source documentation (e.g. clinic note, medical record) • It is essential to have the patient’s medical record available for review by the

monitor (to make sure none are missed) • The monitor can provide advice on completing the AE case report form properly • When in doubt, ask your monitor or the sponsor about how to complete the AE

Case Report Form • The monitor can also connect you with the sponsor’s medical director if requested.

Serious & Life-Threat

Case Report Forms Completion Participating Sites

• Case Report Forms will be completed by the local PI and/or his/her designee at each subject visit. For Multi center studies, Case Report forms will be sent to the Coordinating Center, where they will perform data integrity monitoring through cross-checking and source documentation.

GCP CRF Tips • The investigator should ensure the accuracy, completeness,

legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports (GCP E6 4.9.1).

• Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained (GCP E6 4.9.2).

• Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry; this applies to both written and electronic changes or corrections. The investigator should retain records of the changes and corrections (GCP E6 4.9.3).

• Ink should be used when completing paper CRFs. Pencil and correction fluid should not be used.

Source Documentation • Source Documentation of adverse events include

documentation in the medical records of: – Event – Date it occurred – Grade as determined by CTCAE – Expected or Unexpected – Attribution as assigned by PI – Date resolved – Treatment patient received specifically related to

event

Source Documents

27

Medical records

Clinical & office charts

Labs Rx

X-rays, ECGs, scans

Progress notes Notes to file

The foundation of study data: • Where information was first recorded - Original documents, data, and

records to supports subject eligibility, enrollment, and protocol required data

• Monitors will need to view Source and compare to completed CRFS and Eligibility determinations

• Attributable – Does the documentation clearly demonstrate who created the record and when,, what happened, and when it occurred? A

• Legible – Can the information be easily read and understood? L

• Contemporaneous - Was the information documented with timeliness?

• Complete – Does the documentation include all of the necessary information?

C • Original – Did you maintain the “source” of the

information (see GCP Glossary, Sections 1.51 and 1.52)? O • Accurate – Does the information

represent what actually happened? A Adapted from - FDA - GUIDANCE FOR INDUSTRY - COMPUTERIZED SYSTEMS USED IN CLINICAL TRIALS - ALCOA http//www.fda.gov/downloads/ICECI/EnforcementActions/BioresearchMonitoring/UCM133749.pdf

Fundamental Elements of Data Quality

Sample Adverse Event Recording Form The following are required when completing an AE

form • Date of onset • Description • Grading • Relatedness • Expected/unexpected • Treatment • Resolution date/outcome

Reporting

Reporting Serious Events

• An investigator must promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by or probably caused by the drug. If the adverse effect is alarming, the investigator shall report the adverse effect immediately. – 21CFR312.64

Reporting Criteria

• Routine Reporting – Know which events can be reported at interim analysis or

annual reviews • Expedited Reporting

– Know which events require immediate reporting

Safety Reporting Requirements

• Investigator must immediately report all unanticipated problems and deviations involving risk to subjects or others, serious adverse events related to participation in the study and subject deaths related to participation in the study

• Major protocol/consent modifications related to change of safety information

This is the responsibility of the sponsor not each

investigator

.

Reporting timelines example What Event is Reported When is Event Reported

Fatal or life-threatening unexpected, suspected serious adverse reactions

Within 7 calendar days of initial receipt of information

Non-fatal, non-life-threatening unexpected, suspected serious adverse reactions

Within 15 calendar days of initial receipt of information

Unanticipated adverse device effects Within 10 working days of investigator first learning of effect

Unanticipated Problem that is not an SAE

Within 14 days of the investigator becoming aware of the problem

All Unanticipated Problems2 Within 30 days of the IRB’s receipt of the report of the UP from the investigator.

Reporting Criteria

• Know which type of expedited reports each regulatory body requires – FDA – Sponsor – Co-Sponsor – IRB

FDA IND Safety Report Criteria

Three Criteria: 1. Suspected adverse reaction 2. Serious 3. Unexpected

Issues in reporting

• Often times, patients are admitted with one diagnosis such as this one. Following admission, secondary events are found.

• All of these can be reported using one form

Consequences of Improper Reporting

• Protocol Violations • IRB may suspend protocol • FDA Hold • Sponsor Hold • Research Privileges Revoked • Patient Safety

Multi center trial rules • Sponsors are specifically required to notify all

participating investigators (and FDA) in a written IND safety report of “any adverse experience associated with the use of the drug or device that is both serious and unexpected” and “any finding from tests in laboratory animals that suggests a significant risk for human subjects” (§ 312.32(c)(1)(i)(A),(B)). And, more generally, sponsors are required to “keep each participating investigator informed of new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects and safe use” (§ 312.55(b)).

Possible Adverse event???

• Phase 2 study of an antihypertensive agent •3/10 subjects develop GERD within a week of starting the drug

Take home points… • Record all AEs and report as appropriate and

according to guidelines • Report to FDA annual safety reports when

applicable • Protocol should include appropriate safety

language and reporting criteria and timeframes and safety monitoring process