Safety Workshop: Part I Clinical Trial Safety and Safety Monitoring August 18, 2010 Albert Yoyin, M.D. DAIDS Regulatory Support Center (RSC)

Objectives At the conclusion of this workshop, participants will be able to demonstrate an understanding of: Current context regarding safety in clinical trials The concept of safety and safety monitoring and how it relates to clinical trials research Protocol requirements pertaining to areas relevant to safety Key roles and responsibilities related to safety Safety and adverse event terminology Expedited reporting of adverse events

Objectives At the conclusion of this workshop, participants will be able to demonstrate an understanding of: Ensuring safety in clinical trials The adverse event life cycle What makes a well-documented adverse event, including a comprehensive narrative How to assess an adverse event case, including causality assessment

Regulations: Federally Supported Research Involving Human Subjects 45 CFR 46: Protection of Human Research Subjects Applies to all research involving human subjects Institution 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 regulations Research reviewed and approved by IRB Subject to continuing review by IRB

Regulations: Non-Federally Supported Studies Involving Human Subjects 21 CFR 50: Protection of Human Subjects Clinical investigations regulated by FDA Requirements for informed consent Elements of informed consent Documentation of informed consent Form approved by IRB 21 CFR 56: Institutional Review Boards Requirements for IRB review Membership, functions, review procedures, etc Criteria for IRB approval

Current Safety Environment Increasing demands for safety data: All Serious Adverse Events (SAEs); Follow all AEs/SAEs till resolved or stable Additional adverse events of interest (e.g. cancers, MIs, hepatic events) Pregnancy outcomes Food and Drug Administration Amendments Act of 2007 (FDAAA): Provides FDA with additional requirements, authorities, and resources with regard to both pre- and postmarket drug safety Global reporting to EMEA and regulatory agencies of European Union (EU) member states Use of CIOMS form Country of origin of AE

Clinical Trial Continuum: From Drug Development to Optimal Regimens to Treatment Strategies SCHARP FSTRF U MN HVTN MTN HPTN IMPAACT ACTG INSIGHT PHASE I PHASE II PHASE III PHASE IV POST PHASE III/IV This 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 POSTMARKET CONTROLLED SETTING REAL-WORLD SETTING

Why is safety monitoring required in all clinical trials? To Ensure Subject Safety and Study Integrity

Roles and Responsibilities – Site Investigator Implementing the protocol “as written” Strict adherence to inclusion and exclusion criteria Investigator assures Subject Safety and Study Integrity by: Continued adherence throughout study duration Monitoring subject status, i.e. subject wellbeing, minimization of risk, toxicity management, etc. Monitoring safety data collection: Study database Safety database

Roles and Responsibilities – Research Staff Is immediate/emergency intervention needed? Yes No Follow site SOP for emergencies Follow site SOP to notify study clinician/physician Record the AE/SAE Record AE and/or SAE per protocol specifications Follow protocol toxicity management section The 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.

Roles and Responsibilities – Study Clinician/Physician Subject reports AE Emergency intervention vs. Non-emergency care Study clinician/physician will assess and manage the AE Decide if SAE Research provisions vs. Clinical care The 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. Documentation Follow until AE resolution or condition stabilizes

Assurance of Safety and Well-Being: Research vs. Medical Roles Emergency intervention vs. Non-emergency care Acute on-site management, as necessary, and per site SOP Referral to care when stable Research provisions vs. Clinical care Provide interventions permitted by the protocol Follow protocol specifications for toxicity management Beyond protocol specifications, refer out for clinical care

Clinical Role vs. Research Role Balancing Both Roles Balancing Both Roles Clinical Role: Subject OK Research Role: Study/Data OK Is subject in imminent jeopardy? Provide appropriate management commensurate with clinical situation, e.g. toxicity management Provide appropriate referral: emergent care or back to regular care Follow up with subject status Not Subject’s Primary Clinician Identification of adverse event Immediate notification necessary? To whom? [per protocol and safety monitoring plans] Complete documentation of adverse event. Follow until resolution/stability including updating records Determine if AE meets criteria for SAE Adhere to reporting requirements Adhere to toxicity management as specified Adhere to stopping rules as specified To assure safety for study participants REQUIRES a balance in the clinical role and the research role Reminder: However, the study site clinician in their research capacity is NOT the Subject’s Primary Clinician Work within the confines of the protocol If necessary to deviate from the protocol in subject’s interest, must withdraw subject from study Return to protocol is a clinical decision within protocol specifications “Stopping” rules in the last bullet on the right refers to “Pausing”

Therapeutic Misconception Subjects think they are receiving proven interventions, per their usual clinical care, despite participating in a research study Informed Consent Process must not be trivialized or relegated to administrative status Check for understanding Time for questions, making decision Physicians think they can provide interventions, per usual practice Strict adherence to protocol provisions for care, toxicity management Decide if subject can continue in study

Roles and Responsibilities – Study Clinician/Physician Action taken with Study product after AE Study Study Study product: Dose held, changed, or discontinued? Study participation: Continue, withdraw? Study product: Per site, per study? Study status: Safety pause, clinical hold, early termination?

Roles and Responsibilities – Study Team Safety: Ensure safety and well being of subjects at all times Monitor safety across all study sites Review all safety data at specified intervals Discuss need for change(s) driven by safety Data: Ensure data integrity to assess the risks/safety profile of the study intervention Data capture; especially safety data Be cognizant of expedited reporting requirements for safety data

Roles and Responsibilities – Study Team vs. Sponsor/RSC Safety monitoring by study team Acute on-site management and discussion with study team Periodic review by study team and monitoring committees Data generated by Data Management Centers (DMC) Expedited reporting to sponsor/RSC SAE sent to RSC RSC is not part of discussions that occur within study/safety monitoring teams regarding the event The RSC only has information about the event from the SAE Form; site should include relevant information from study team discussions RSC processes event and sends queries to site to obtain additional information All follow-up information should be provided to RSC

Mental Break Land’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

Safety Monitoring Environment IND Trials Pre-market Postmarket OHRP 45 CFR 46 FDA 21 CFR Part 312 - IND 21 CFR 312.32 (IND Safety Reports) 21 CFR 312.33 (Annual Reports) 21 CFR 812.150 (IDE Reports) 21 CFR Part 314 - NDA 21 CFR 314.80 (Postmarketing) 21 CFR 314.98 (Generics) 21 CFR 600.80 (Biologics) 21 CFR 803 (Medical Devices) ICH E2A (Oct 1994) ICH E2D (Nov 2003) NIH Policy Country/State Regulations IRBs/ECs Sponsor

ICH: E Documents on Safety Clinical Safety ICH E1 – The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening Conditions ICH E2A – Clinical Safety Data Management: Definitions and Standards for Expedited Reporting ICH E2B – Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports ICH E2C – Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs ICH E2D – Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting ICH E2E – Pharmacovigilance Planning ICH E2F – Development Safety Update Report Good Clinical Practice ICH E6 – Good Clinical Practice http://www.ich.org/cache/compo/276-254-1.html

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.

Adverse Event Flowchart Subject Enrolled AE Reported Record AE* Yes SAE? To Sponsor Record SAE** To IRB To FDA To other Follow until Resolution or Stability Outcome: Resolved/ Stable? Update SAE No To other Subject Enrolled To IRB AE Reported SAE? To Sponsor Yes Record SAE** Record AE* To FDA Outcome: Resolved/ Stable? Follow until Resolution or Stability AE Process When 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. No Update SAE

* Protocol specifications for AE Adverse Event * Protocol specifications for AE When to collect e.g., study visit Method of collection e.g., in person, telephone call What to collect e.g., all AEs, only certain AEs by body system, only certain AEs by severity What forms to use e.g. AE CRF, study CRFs ** Protocol specifications for SAE Criteria Expedited time frames Reporting form (e.g. SAE) Read

Documentation Differences Between AE CRF and SAE Form Record in source document Attach additional documentation Record on AE case report form Record on SAE Form (includes narrative) Does AE meet SAE criteria? Documentation differences between AE CRF and SAE/EAE form   When an AE occurs first record the AE in the source document Then 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

Documentation Differences Between AE CRF and SAE Form: Data Elements Start Date Stop Date / Continuing Is it SAE? Severity Relatedness Action taken with Study Agent Outcome (study participation) SAE Form Data Elements Participant Identifiers Study Agent details Narrative Past medical history Relevant labs, tests, procedures Concomitant meds Outcome of SAE Other supporting information SAE Form contains more information

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 database Data for expedited reporting: Recorded on AE CRF and linked to an SAE type form Goes to safety database IND timelines: 24o to sponsor, 7/15 days to FDA, EMEA Post-marketing timelines: depends on sponsor, 15 days to FDA, EMEA Annual/Periodic Reports : Need safety data from clinical and safety database Must be reconciled Clinical database: FSTRF for IMPAACT and ACTG SCHARP for HVTN, MTN and HPTN UMN for INSIGHT – See Slide #7 Safety database: RSC

Stretch Break

Adverse Event Any 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)

Adverse Event Term The AE should best describe what the subject says (i.e. verbatim description) Can be extracted from medical records Can 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

AE Term - Examples If “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.

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-threatening Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect In 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)   

Adverse Event vs. Event Outcome Hospitalization Hospitalization 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.

Hospitalization Hospitalization 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 condition Diagnostic 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)

Describes the intensity of the event Severity Describes the intensity of the event Events are graded on a severity scale Mild, Moderate, Severe Numeric Scale e.g. 1 to 5 Severity grading must match the clinical picture Presenting AE is Grade 1 AE progressed to SAE (hospitalization) The expedited report should have the grade of the SAE, not the AE

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 criteria Determined using the DAIDS grading table 35

Action Taken with Drug Action Taken with Drug: Withdrawn Dose reduced Dose increased Dose not changed Unknown Not applicable > ICH E2B (R3) Refer to protocol Refer to DAERS

Outcome Outcome of reaction/event at the time of last observation Recovered/resolved Recovering/resolving Not recovered/not resolved Recovered/resolved with sequelae Fatal Unknown > ICH E2B (R3) Outcome of subject in study Remains in Study Withdrawn Lost to follow-up Death

Expectedness Pertains 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)

Relatedness (Causality) No standard international nomenclature Conveys 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 relationship Information on SAEs generally incomplete when first received Follow-up information actively pursued Judged by: Reporting health professional Sponsor

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]?

Determination of Causality ‘May be more art than science’ NR: evidence for alternate etiology and/or low or no biologic plausibility R: reasonable possibility; facts or evidence to substantiate relationship, and biologic plausibility Is there evidence to compel change in previous conclusions? Clear-cut case; easy to make a determination Not so clear-cut: use your best judgment based on available information; assure adequacy of information Unless clear-cut case, there’s no absolute right or wrong; give your best judgment; substantiate and follow-up Err on conservative side

Comprehensive, stand-alone “medical story” Narrative Comprehensive, stand-alone “medical story” Written in logical time sequence Include key information from supplementary records Include relevant autopsy or post-mortem findings Summarize all relevant clinical and related information, including: Study subject characteristics Therapy details Medical history Clinical course of the event(s) Diagnosis (workup, relevant tests/procedures, lab results) Other information that supports or refutes an AE > ICH E2D

Narrative Template This 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].

Narrative Template Provide 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].

Review and Assessment of SAE Assemble all information available and use medical judgment Standard for each AE: Select [Seriousness Criteria] Grade [Severity] per DAIDS Toxicity Table Specify [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 visit Is it [Expected]? Is it [Related]?

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 care Clearly identified evaluations by the sponsor are considered appropriate and are required by some regulatory authorities Opportunity to render another opinion; may be in disagreement with; and/or provide another alternative to the diagnosis/assessment given by initial reporter Sponsor 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

Site vs. Sponsor Assessment Site Assessment Sponsor Assessment Balancing Both Roles Site advantage: has access to subject; may elicit further info, perform PE, obtain tests, labs, records Information from self-report (may lack validation) Know subject best Judgment stands Open to dialog with sponsor Information limited to what was submitted from site May initiate queries to site: incur time and delay Constraint: Must adhere to reporting timelines to FDA MO 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

Questions?