Presentation on theme: "Adverse Events and Serious Adverse Events"— Presentation transcript:
1Adverse Events and Serious Adverse Events Office of Research Education and Regulatory Management
2Objectives Recognize Adverse Events and serious adverse events Review FDA inspection findings related to adverse eventsReview regulations related to adverse eventsDiscuss recording and reporting of adverse eventsDiscuss auditing of adverse eventsDemonstrate audit of adverse events
3FDA Inspection“Failure to prepare and submit complete and accurate and timely reports of unanticipated adverse device effects”
4RecognizingFirst we will cover recognizing Adverse Events and Serious Adverse Events
5Adverse EventsAny adverse event associated with the use of a drug in humans, whether or not considered related.21CFRAny untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatmentICH E6Although the definitions in the regulations address drugs, we expand the definition for those trials that do not involve drugs.
6Adverse EventNCIAn unexpected medical problem that occurs during treatment with a drug or other therapy.Adverse events do not have to be a caused by the drug or therapy
7Serious Adverse Event Fred Doesn’t Have Any Money Left Fatal DisabilityHospitalizationAnomalyMedically SignificantLife ThreateningThis slide lists the event outcomes that are considered serious.Fun way to remember which events are classified as seriousFred Doesn’t Have Any Money Left (Wilma went shopping at the Bedrock Mall!)Serious Adverse Events are those associated with the patient’s participation in research that:Results in fatality– “Fred”Results in persistent or significant disability/incapacity – “Doesn’t”Results in patient hospitalization or prolongation of existing hospitalization – “Have”Results in a congenital anomaly or birth defect – “Any”A Medically significant event- “Money”What is considered medically significant?...Patient has baseline creatinine of 1.8 due to a renal condition which is Grade 1, not too high but now creatinine jumped to 8. A creatinine of 8 is clinically significant.Lastly, event is life threatening– “Left” Life threatening events include:Any adverse pharmaceutical product that places the patient, in the view of the PI, at immediate risk of death from the reaction as it occurred OR if it is suspected that continued use of the product under investigation would result in pt’s death Examples: allergic bronchospasm requiring intensive treatment, gastrointestinal hemorrhage, pacemaker failure
8Expected Vs. Unexpected 4/5/2017Expected Vs. UnexpectedUnexpectedNot listed in Investigational Brochure, Informed Consent, or General Investigational PlanAlso not listed in a drug package insertExpectedKnown to Occur and is Listed in the Investigational Brochure, Informed Consent, or General Investigational PlanTo determine if an event is expected or unexpectedCheck Investigational Brochure, Informed Consent or General Investigational PlanTo see if the event is listedIf the event is listed, then it is expectedIf not, the event is unexpected
9RecordingNext, talk about recording adverse events.
10RecordingKnow which adverse events the protocol requires to be capturedSometimes we forget how unique our different protocols are and we go along doing the same thing for every protocol.Need to be familiar with what adverse events your protocol requires to be captured.This will vary with your sponsor and with your PIFor example, for a particular protocol, sponsor may only require that you capture Grade 3 or Grade 4 adverse eventsCould cut down on your work if that is the casePI may want to capture every adverse eventThis is certainly something you want to discuss with both sponsor and PI before begin protocol
11Source DocumentationSource Documentation of adverse events include documentation in the medical records of:EventDate it occurredGrade as determined by CTCAEExpected or UnexpectedAttribution as assigned by PIDate resolvedTreatment patient received specifically related to eventIn order to adequately capture the information to document an adverse event, you need to include:EventDate it beganGrade as determined by the appropriate Common Terminology Criteria for Adverse EventsWhether or not it was expected or unexpectedMust have relationship of event to study agent assigned by PIDate event endedDocument any treatment patient received as a result of the event (took Neurontin for neuropathy, specify dose)
12Sample Adverse Event Recording Form See template behind this presentation
13Here is an example of a template that contains all the required elements and place for physician who is assigning attribution to sign.You decide what form of documentation works best for your protocol to prompt you to include all of the necessary information including the physician’s signature to confirm the PI is in agreement with the assignment of the attribution of the study product to the event.
14Attribution (Causality) The attribution (relationship or causality or drug related assessment) must be determinedA determination made by a clinical investigator that describes the relationship or association of the study product with an adverse experienceThis determination must be recorded both in the medical record as well as in the case report form.Very important part of documentation of adverse events is documentation as to if the event was related to or caused by the pharmaceutical product.The relationship between the study product and the event must be decided by the clinical investigator and this attribution must be documented indicating the attribution was assigned by the investigator.BECAUSE, assigning attribution is a medical judgment. And, all AEs are to be communicated to the PIPlan the best way to document the attribution in the medical record as well as providing a source that the investigator assigned that relationship.Audits reveal that attribution is found in the CRF but not in source documents.
15AttributionWhat should the investigator consider prior to assigning attribution?Individual medical historyKnown effects of concomitant medications
16Attribution Definite – Clearly related to study agent Probable – Likely related to study agentPossible – May be related to study agentUnlikely – Doubtfully related to study agentUnrelated – Clearly not related to study agentOnce again, the determination of attribution is a medical judgment because patients on study trials come with other medical conditions .The physician must take into consideration the patient’s co-morbidities in order to make an adequate assessment of the relationship between the study agent and the adverse event.
17How to Capture Adverse Events? Split or LumpedFever, Diarrhea, and Vomiting (Viral Gastroenteritis)Cough, Sniffles, Sore throat (Flu)Some sponsors want the symptoms lumped and others want it separated.Regardless of how these are captured, we must try to stay consistent.Reference: When a Cough is Just a Cough: The Trouble with AesHerschel R. Lessin, MD
18How to Capture Adverse Events? Problems with similar termsRash or DermatitisWheezing, reactive airway disease, congestion, cold, , asthmaSometimes documenting adverse events can be a challenge.Patients and healthcare workers interchangeably will use terms for symptoms described by subjects.
19Documenting Resolution Dates ChallengeDoes the patient remember when their adverse event resolved?Do you call the patient? Or wait till the next visit?
20Patient Toxicity Diary Diaries where patients capture toxicities between their follow up appointments
21Patient Toxicity Diaries Patient writes down constipation because he did not have a bowel movement one dayResearch nurse captures constipation without assessing furtherPhysician copies the research nurse’s note and also dictates constipationDid anyone ask about the constipation?According to CTC V3, constipation is grade 1 only if there is occasional or intermittent symptoms; occasional use of stool softeners, laxatives, dietary modification, or enema
22Patient Adverse Event Diaries AdvantagesDisadvantagesAllows capturing information on a daily basis while patient is away from clinicA communication tool for patient returns to clinicUseful in capturing onset and resolution dates of adverse eventsTime consumingPatient non-compliancePatient self diagnosis or interpretationComplicated Instructions
23Question to askWhen should site staff begin collecting adverse event information?This is protocol specific. Most of the time, study staff collect information from the time informed consent is obtained.Generally, reporting of serious events are not required until administration of the investigational product or protocol intervention.P. 262
24Question to askHow long should one collect adverse events after the subject completes study treatment?There are no requirements or regulations that specify the length of time that Adverse events that should be collected after a subject completes the study treatment period. The protocol should clearly define this. A 30 day follow up period is common. Investigators should consider half lives of investigational products, prior experience with the product, and any delayed adverse event concerns prior to establishing a cut off date or time point.
25ReportingWe have talked about recognizing and recording adverse events, now let’s talk about reporting adverse events!
26Reporting 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.21CFR312.64Investigators assigning attribution is addressed here as well. If the investigator is not aware of adverse events and assign attribution, how can he or she follow this regulation?
27Reporting Criteria Routine Reporting Expedited Reporting Know which events can be reported at interim analysis or annual reviewsExpedited ReportingKnow which events require immediate reportingNeed to be familiar with the reporting requirements for your protocolOnce again, be familiar with your protocolIn some protocols, you will be responsible for providing data for the interim analysis (point where evaluate data) or for the annual reviewNeed to know which events require immediate reporting
28Reporting CriteriaKnow which type of expedited reports each regulatory body requiresFDASponsorCo-SponsorMD AndersonNCICollaborative GroupsAlthough MD Anderson IRB requires only prompt reporting :of deathsand serious, related and unexpected eventsOther sponsors might have additional requirements.Some sponsors require you to report all serious adverse events regardless of the relationship.
29Issues in reporting Primary events Example Patient admitted with Congestive Heart FailureSubsequently develops: Pulmonary Edema and Cardiogenic ShockOften 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 listing CHF as the primary event for example here.
30Consequences of Improper Reporting Protocol ViolationsIRB will close protocolFDA HoldSponsor HoldResearch Privileges RevokedPatient Safety
31AuditingNow we are going to talk about what we are here for today….auditing!
32Auditing Check PointsHow are AEs being recorded in the medical record?Does documentation include grade, onset, resolution, and attribution?Be sure that all adverse events are documented appropriately to include the:EventDates for beginning and endGradeWas the event resolvedWas it expected or unexpectedDocumentation of the attribution assigned by the PIDocumentation of any treatment patient received as a result of the event
33Auditing Check Points Were all toxicities included? Was the proper CTCAE version used for the protocol?Were the toxicities graded appropriately?Were all toxicities included?In addition to adverse events described by the patient, are there any abnormal lab values or hassomething shown up on any scans or x-rays?Even though newer protocols require Version 3 of the CTCAE, is that the case for this particular protocol?Were the toxicities actually graded according to the descriptions provided in the Common Terminology Criteria for Adverse Events?
34Auditing Check Points Was the event a dose limiting toxicity? Should the dose have been reduced?If so, did the research team realize it as such and identify it correctly?Documentation of a dose limiting toxicity is tremendously important!That is not only for source documentation purposes, but also for patient safety issues.Your patient shows up in the ER and there is a good chance the only documentation of a dose reduction would be your notes.
35AuditingAre adverse events appropriately reported within the time periods required by regulations, sponsor, and IRB policies?
36We have reviewed……….Recognizing adverse events and serious adverse eventsInspections and findings related to adverse eventsRegulations related to adverse eventsRecording and reporting of adverse eventsAuditing of adverse events