Presentation on theme: "Safety Workshop: Part I Clinical Trial Safety and Safety Monitoring"— Presentation transcript:
1 Safety Workshop: Part I Clinical Trial Safety and Safety Monitoring August 18, 2010Albert Yoyin, M.D.DAIDS Regulatory Support Center (RSC)
2 ObjectivesAt the conclusion of this workshop, participants will be able to demonstrate an understanding of:Current context regarding safety in clinical trialsThe concept of safety and safety monitoring and how it relates to clinical trials researchProtocol requirements pertaining to areas relevant to safetyKey roles and responsibilities related to safetySafety and adverse event terminologyExpedited reporting of adverse events
3 ObjectivesAt the conclusion of this workshop, participants will be able to demonstrate an understanding of:Ensuring safety in clinical trialsThe adverse event life cycleWhat makes a well-documented adverse event, including a comprehensive narrativeHow to assess an adverse event case, including causality assessment
4 Regulations: Federally Supported Research Involving Human Subjects 45 CFR 46: Protection of Human Research SubjectsApplies to all research involving human subjectsInstitution must provide assurance of compliance, such as a Federal Wide Assurance (FWA) on file with the Office for Human Research Protection (OHRP)FWA provides assurance that research is conducted in accordance with the regulationsResearch reviewed and approved by IRBSubject to continuing review by IRB
5 Regulations: Non-Federally Supported Studies Involving Human Subjects 21 CFR 50: Protection of Human SubjectsClinical investigations regulated by FDARequirements for informed consentElements of informed consentDocumentation of informed consentForm approved by IRB21 CFR 56: Institutional Review BoardsRequirements for IRB reviewMembership, functions, review procedures, etcCriteria for IRB approval
6 Current Safety Environment Increasing demands for safety data:All Serious Adverse Events (SAEs); Follow all AEs/SAEs till resolved or stableAdditional adverse events of interest (e.g. cancers, MIs, hepatic events)Pregnancy outcomesFood and Drug Administration Amendments Act of 2007 (FDAAA): Provides FDA with additional requirements, authorities, and resources with regard to both pre- and postmarket drug safetyGlobal reporting to EMEA and regulatory agencies of European Union (EU) member statesUse of CIOMS formCountry of origin of AE
7 Clinical Trial Continuum: From Drug Development to Optimal Regimens to Treatment Strategies SCHARPFSTRFU MNHVTNMTNHPTNIMPAACTACTGINSIGHTPHASE I PHASE II PHASE III PHASE IV POST PHASE III/IVThis slide illustrates that DAIDS sponsors clinical trials that span a clinical trial continuum, such as the type of clinical trial, marketing status, and experimental setting.Usually, the arrow points in one direction along a developmental path, from Phase I to Phase II to Phase III trials etc, such as for the development of a new agent. However, for DAIDS trials, the arrow is bi-directional, because we have trials that are on new products (e.g. new vaccines) or approved products (e.g. ART), and we can take an approved ART back to Phase I trials for expansion of the indication or the patient population.We are dealing with trials that are testing either in the pre-market environment or the post-market environment, and this has implications for expedited adverse event reporting obligations to regulatory authorities. Finally, our trials can be conducted under tightly controlled settings (e.g. new vaccine development) or real world settings (e.g. treatment strategy trials).PRE-MARKET POSTMARKETCONTROLLED SETTING REAL-WORLD SETTING
8 Why is safety monitoring required in all clinical trials? To Ensure Subject Safety and Study Integrity
9 Roles and Responsibilities – Site Investigator Implementing the protocol “as written”Strict adherence to inclusionand exclusion criteriaInvestigator assures Subject Safety and Study Integrity by:Continued adherencethroughout study durationMonitoring subject status, i.e. subject wellbeing, minimization of risk, toxicity management, etc.Monitoring safety data collection:Study databaseSafety database
10 Roles and Responsibilities – Research Staff Is immediate/emergency intervention needed?YesNoFollow site SOP for emergenciesFollow site SOP to notify study clinician/physicianRecord the AE/SAERecord AE and/or SAE per protocol specificationsFollow protocol toxicity management sectionThe most important responsibility for research staff is to assure subject safety and well-being. Research staff must determine if immediate/emergency intervention is needed for an AE. If yes, one must (1) follow the site SOP for emergencies, (2) follow site SOP to notify study clinician/physician, and (3) record the AE/SAE. If immediate/emergency intervention is not needed, research staff must record the AE and/or SAE per protogol specifications and follow the protocol toxicity management section.
11 Roles and Responsibilities – Study Clinician/Physician Subject reports AEEmergency intervention vs.Non-emergency careStudy clinician/physicianwill assess and managethe AE Decide if SAEResearch provisionsvs.Clinical careThe roles and responsibilities of a study clinician/physician are as follows:When a subject reports an adverse event, the study clinician/physician will assess and manage the adverse event. The study clinician/physician needs to decide whether the subject needs emergency intervention or non-emergency care to manage the AE. They will also determine if the AE meets SAE/EAE reporting criteria. So the role of the study clinician/physician is dual- responsibility for the clinical care of the subject as well as to fulfill the research provisions. We will discuss this a bit more in detail in our next slide.The study clinician/physician then needs to document the AE reported by the subject. The AE has to be followed until it has resolved or the subject’s condition has stabilized.DocumentationFollow until AE resolutionor condition stabilizes
12 Assurance of Safety and Well-Being: Research vs. Medical Roles Emergency intervention vs. Non-emergency careAcute on-site management, as necessary, and per site SOPReferral to care when stableResearch provisions vs. Clinical careProvide interventions permitted by the protocolFollow protocol specifications for toxicity managementBeyond protocol specifications, refer out for clinical care
13 Clinical Role vs. Research Role Balancing Both RolesBalancing Both RolesClinical Role: Subject OKResearch Role: Study/Data OKIs subject in imminent jeopardy?Provide appropriate management commensurate with clinical situation, e.g. toxicity managementProvide appropriate referral: emergent care or back to regular careFollow up with subject statusNot Subject’s Primary ClinicianIdentification of adverse eventImmediate notification necessary? To whom? [per protocol and safety monitoring plans]Complete documentation of adverse event. Follow until resolution/stability including updating recordsDetermine if AE meets criteria for SAEAdhere to reporting requirementsAdhere to toxicity management as specifiedAdhere to stopping rules as specifiedTo assure safety for study participants REQUIRES a balance in the clinical role and the research roleReminder: However, the study site clinician in their research capacity is NOT the Subject’s Primary ClinicianWork within the confines of the protocolIf necessary to deviate from the protocol in subject’s interest, must withdraw subject from studyReturn to protocol is a clinical decision within protocol specifications“Stopping” rules in the last bullet on the right refers to “Pausing”
14 Therapeutic Misconception Subjects think they are receiving proven interventions, per their usual clinical care, despite participating in a research studyInformed Consent Process must not be trivialized or relegated to administrative statusCheck for understandingTime for questions, making decisionPhysicians think they can provide interventions, per usual practiceStrict adherence to protocol provisions for care, toxicity managementDecide if subject can continue in study
15 Roles and Responsibilities – Study Clinician/Physician Action taken with Study productafter AEStudyStudyStudy product:Dose held, changed,or discontinued?Study participation:Continue, withdraw?Study product: Per site, per study?Study status: Safety pause, clinical hold, early termination?
16 Roles and Responsibilities – Study Team Safety: Ensure safety and well being of subjects at all timesMonitor safety across all study sitesReview all safety data at specified intervalsDiscuss need for change(s) driven by safetyData: Ensure data integrity to assess the risks/safety profile of the study interventionData capture; especially safety dataBe cognizant of expedited reporting requirements for safety data
17 Roles and Responsibilities – Study Team vs. Sponsor/RSC Safety monitoring by study teamAcute on-site management and discussion with study teamPeriodic review by study team and monitoring committeesData generated by Data Management Centers (DMC)Expedited reporting to sponsor/RSCSAE sent to RSCRSC is not part of discussions that occur within study/safety monitoring teams regarding the eventThe RSC only has information about the event from the SAE Form; site should include relevant information from study team discussionsRSC processes event and sends queries to site to obtain additional informationAll follow-up information should be provided to RSC
18 MentalBreakLand’s End at Cabo San Lucas The majestic stone arch at the southern tip of Baja,where the Sea of Cortez meets the Pacific Ocean
20 ICH: E Documents on Safety Clinical SafetyICH E1 – The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening ConditionsICH E2A – Clinical Safety Data Management: Definitions and Standards for Expedited ReportingICH E2B – Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety ReportsICH E2C – Clinical Safety Data Management: Periodic Safety Update Reports for Marketed DrugsICH E2D – Post-Approval Safety Data Management: Definitions and Standards for Expedited ReportingICH E2E – Pharmacovigilance PlanningICH E2F – Development Safety Update ReportGood Clinical PracticeICH E6 – Good Clinical Practice
21 Drug Development Model: Safety Data Flow in Clinical Trials When an AE occurs, a multistep process begins. The site records the AE in the Case Review File and submits it to the Data Management Center where it is stored in the Study Database. Additionally, the site assesses if the AE is a Serious Adverse Event (SAE) per DAIDS (according to the study protocol and the Manual for Expedited Reporting).If the AE is found to be a SAE, an SAE form is completed and submitted in an expedited timeframe to the DAIDS RCC. All reports received by the DAIDS RCC are stored in the RCC Safety Database. DAIDS RCC then determines if the AE meets the regulatory safety reporting requirements needed for the report to be sent to the Food and Drug Administration (FDA). If so, the report is sent to the FDA.
22 Adverse Event Flowchart Subject EnrolledAE ReportedRecord AE*YesSAE?To SponsorRecord SAE**To IRBTo FDATo otherFollow until Resolutionor StabilityOutcome:Resolved/Stable?Update SAENoTo otherSubject EnrolledTo IRBAE ReportedSAE?To SponsorYesRecord SAE**Record AE*To FDAOutcome:Resolved/Stable?Follow until Resolutionor StabilityAE ProcessWhen a subject is participating in a DAIDS study, an AE is reported, and the AE is recorded in the CRF. An assessment is made regarding whether the AE is an SAE / EAE. If so, it is recorded in the SAE/EAE form as an SAE / EAE and reported to the IRB, other entities as required, and sponsor who then reports it to the FDA if needed. The site follows the AE until resolution or stability at which point the SAE/EAE is updated and reported again to the IRB, other entities as required, and sponsor.NoUpdate SAE
23 * Protocol specifications for AE Adverse Event* Protocol specifications for AEWhen to collect e.g., study visitMethod of collection e.g., in person, telephone callWhat to collect e.g., all AEs, only certain AEs by body system, only certain AEs by severityWhat forms to use e.g. AE CRF, study CRFs** Protocol specifications for SAECriteriaExpedited time framesReporting form (e.g. SAE)Read
24 Documentation Differences Between AE CRF and SAE Form Record in source documentAttach additional documentationRecord on AE case report formRecord on SAE Form (includes narrative)Does AE meet SAE criteria?Documentation differences between AE CRF and SAE/EAE formWhen an AE occurs first record the AE in the source documentThen record the AE in the case report form (CRF)Determine if the AE meets SAE/EAE criteria?If yes, record the event on the SAE/EAE form (this form includes narrative the section)Attach any additional documentation to this form such as relevant hospital progress notes, discharge summary, laboratory test results, diagnostic test reports, death certificate etc.Yes
25 Documentation Differences Between AE CRF and SAE Form: Data Elements Start DateStop Date / ContinuingIs it SAE?SeverityRelatednessAction taken with Study AgentOutcome (study participation)SAE FormData ElementsParticipant IdentifiersStudy Agent detailsNarrativePast medical historyRelevant labs, tests, proceduresConcomitant medsOutcome of SAEOther supporting informationSAE Form contains more information
26 Safety Data from Clinical Trials Obligations to report safety data (IND or Non-IND studies):Data for non-expedited reporting:Recorded on AE CRF, goes to clinical trial databaseData for expedited reporting:Recorded on AE CRF and linked to an SAE type formGoes to safety databaseIND timelines: 24o to sponsor, 7/15 days to FDA, EMEAPost-marketing timelines: depends on sponsor, 15 days to FDA, EMEAAnnual/Periodic Reports :Need safety data from clinical and safety databaseMust be reconciledClinical database: FSTRF for IMPAACT and ACTGSCHARP for HVTN, MTN and HPTNUMN for INSIGHT – See Slide #7Safety database: RSC
28 Adverse EventAny untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. (ICH E2A)
29 Adverse Event TermThe AE should best describe what the subject says (i.e. verbatim description)Can be extracted from medical recordsCan incorporate medical assessment (including a diagnosis if available)The more accurate the AE term, the more accurate the safety database. The AE terms will be coded using a standard dictionary, e.g. Medical Dictionary for Regulatory Activities (MedDRA); this is NOT site responsibility
30 AE Term - ExamplesIf “anaphylactic reaction” is associated with “rash, dyspnea, hypotension, and laryngospasm,” report primary AE as “anaphylactic reaction.”If “myocardial infarction” is associated with “chest pain, dyspnea, diaphoresis, ECG changes and jaundice,” report “myocardial infarction” and “jaundice” as separate primary AEs.
31 Serious Adverse Event (SAE) A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose:Results in death,Is life-threateningRequires inpatient hospitalization or prolongation of existing hospitalizationResults in persistent or significant disability/incapacityIs a congenital anomaly/birth defectIn addition, “…important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above…should also usually be considered serious.”(ICH E2A)
32 Adverse Event vs. Event Outcome HospitalizationHospitalization is a consequence and is not usually considered an AE.Example: If the subject was hospitalized due to congestive heart failure, “congestive heart failure” is the primary AE and hospitalization is the outcome.If the only information available is that the study subject was hospitalized, “hospitalization” can be reported.
33 HospitalizationHospitalization in the absence of a medical AE is not in itself an AE and does not need to be reported in an expedited time frame, such as:Admission for treatment of a pre-existing condition (can include target disease) not associated with the development of a new AE or with a worsening of the pre-existing conditionDiagnostic admission (e.g. for work-up of persistent existing condition such as pre-treatment lab abnormality)Protocol-specified admission (e.g. procedure required by study protocol)Administrative admission (e.g. for yearly physical exam)Social admission (e.g. study subject has no place to sleep)Elective admission (e.g. elective surgery)
34 Describes the intensity of the event SeverityDescribes the intensity of the eventEvents are graded on a severity scaleMild, Moderate, SevereNumeric Scale e.g. 1 to 5Severity grading must match the clinical picturePresenting AE is Grade 1AE progressed to SAE (hospitalization)The expedited report should have the grade of the SAE, not the AE
35 Seriousness is NOT the same as Severity Based on outcome of the AE and is a factor in determining reportability (regulatory definition)Based on the intensity of the AE and is not a factor in determining reportability (clinical descriptor)Determined using the SAE criteriaDetermined using the DAIDS grading table35
36 Action Taken with Drug Action Taken with Drug: Withdrawn Dose reduced Dose increasedDose not changedUnknownNot applicable > ICH E2B (R3)Refer to protocolRefer to DAERS
37 Outcome Outcome of reaction/event at the time of last observation Recovered/resolvedRecovering/resolvingNot recovered/not resolvedRecovered/resolved with sequelaeFatalUnknown > ICH E2B (R3)Outcome of subject in studyRemains in StudyWithdrawnLost to follow-upDeath
38 ExpectednessPertains to whether an event is expected or unexpected (on the basis of previous observation, not what might be anticipated from the pharmacological properties of the product)Unexpected: the nature or severity of the adverse event is not consistent with the applicable product information (e.g. Investigator’s Brochure for unapproved product, Package Insert for approved product)
39 Relatedness (Causality) No standard international nomenclatureConveys that a “causal relationship” between the study product and the adverse event is “at least a reasonable possibility” [ICH E2A]Facts (evidence) exist to suggest the relationshipInformation on SAEs generally incomplete when first receivedFollow-up information actively pursuedJudged by:Reporting health professionalSponsor
40 Determination of Causality Standard determinations include:Is there [Drug Exposure] and [Temporal Association]?Is there [Dechallenge/Rechallenge] or [Dose Adjustments]?Any known association per [Investigator’s Brochure] or [Package Insert]?Is there [Biological Plausibility]?Any other possible [Etiology]?
41 Determination of Causality ‘May be more art than science’NR: evidence for alternate etiology and/or low or no biologic plausibilityR: reasonable possibility; facts or evidence to substantiate relationship, and biologic plausibilityIs there evidence to compel change in previous conclusions?Clear-cut case; easy to make a determinationNot so clear-cut: use your best judgment based on available information; assure adequacy of informationUnless clear-cut case, there’s no absolute right or wrong; give your best judgment; substantiate and follow-upErr on conservative side
42 Comprehensive, stand-alone “medical story” NarrativeComprehensive, stand-alone “medical story”Written in logical time sequenceInclude key information from supplementary recordsInclude relevant autopsy or post-mortem findingsSummarize all relevant clinical and related information, including:Study subject characteristicsTherapy detailsMedical historyClinical course of the event(s)Diagnosis (workup, relevant tests/procedures, lab results)Other information that supports or refutes an AE> ICH E2D
43 Narrative TemplateThis is a [Age] year old [Race] [Male/Female] in [Study] who reported [Primary AE] on [Date of AE]. Enrolled into study on [Date Enrolled], Study medication was started on [Date], which is [Study Day _/Week _], taken for [Duration]. The event occurred during the [Treatment/Follow-up Phase].If fetus: provide [Gestational Age], (or mother’s LMP), at time of event. Also, [Gestational Age/Trimester] at first drug exposure and duration of exposure. If birth, provide details of [Infant Status] at birth. If hospital stay is complicated, provide details of hospital stay.Provide details of the [AE] in chronological order, along with other [Signs/Symptoms]. Provide details of [Physical Exam], along with all relevant [Procedures] and [Lab Results].
44 Narrative TemplateProvide details of [Treatment] and [Treatment Rationale] on basis of [Findings/Test Result(s)]. Describe [Treatment Response].If hospitalization, provide [Dates Hospitalization], describe relevant [Hospital Course], [Diagnostic Work-up], [Procedures/Tests and Results], [Treatment], [Treatment Response].Provide [Discharge Diagnosis], and any [Follow-up Information]. List [Discharge Meds].Provide pertinent [Past Medical Hx], [Family Hx], [Concomitant Meds], [Alcohol/Tobacco/Substance Use] and any previous similar [AEs].
45 Review and Assessment of SAE Assemble all information available and use medical judgmentStandard for each AE:Select [Seriousness Criteria]Grade [Severity] per DAIDS Toxicity TableSpecify [Actions Taken on Study Product]Specify [Outcome of SAE]. If Outcome is not resolved at time of evaluation, follow until resolution or stability at each study visitIs it [Expected]?Is it [Related]?
46 Clinical Case Evaluation Sponsor role: (ICH E2D)Information about the case should be collected from the healthcare professionals who are directly involved in the study subject’s careClearly identified evaluations by the sponsor are considered appropriate and are required by some regulatory authoritiesOpportunity to render another opinion; may be in disagreement with; and/or provide another alternative to the diagnosis/assessment given by initial reporterSponsor makes an assessment of causality (attribution) just as the PI makes an assessment of causality (attribution)If causality (attribution) is different between the sponsor and the investigator, both assessments are reported
47 Site vs. Sponsor Assessment Site AssessmentSponsor AssessmentBalancing Both RolesSite advantage: has access to subject; may elicit further info, perform PE, obtain tests, labs, recordsInformation from self-report (may lack validation)Know subject bestJudgment standsOpen to dialog with sponsorInformation limited to what was submitted from siteMay initiate queries to site: incur time and delayConstraint: Must adhere to reporting timelines to FDAMO level: Serious? Unexpected? Related?SPT level: sign-off, agree with Site PI, agree with DAIDS MO. Any critical flaw in reasoning?Open to dialog with Site PI, DAIDS MO