Safety Workshop

1. Safety Workshop Ling Chin, MD, MPH Safety Pharmacovigilance Team, OPCRO, DAIDS, NIAID

2. 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

3. 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 (attribution)

4. Current FDAAA Environment 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 • New authorities to require postmarket studies and clinical trials, safety labeling changes, and Risk Evaluation and Mitigation Strategies (REMS) • Increased activities for active post market risk identification and analysis • New reporting of adverse events related to food and new regulations for pet food labeling, ingredients, and processing standards

5. Current FDAAA Environment FDAAA Implementation – Examples • Required postmarketing studies, or clinical trials to address safety issues (21 letters); postmarketing commitments now required (previously voluntary) and established timeframes are enforceable • Required safety label changes (4 times) • Can require REMS to ensure that the benefits of a drug outweigh its risks (13 REMS) • Sentinel Initiative (launched May 08): • Create and implement a nation-wide active, electronic surveillance system for monitoring medical product safety • Develop methods to obtain access to disparate data sources and to establish a postmarket risk identification and analysis system • Requires FDA to work closely with partners from public, academic, and private entities

6. Framing the context • Impact relevant to DAIDS: • When DAIDS holds the Investigational New Drug (IND): increased requirements for safety assessment, pharmacovigilance, risk evaluation • Clinical Trial Agreements (CTAs ) with pharmaceutical companies: • Increasing demands for safety data and safety reports, increasingly shortened timelines • Postmarketing requirements on Marketing Authorizing Holders (MAHs) irrespective of DAIDS obligations for IND studies vs. non-IND studies: expect final safety reports in 15 days or less

7. Framing the context • Impact relevant to pharmaceutical companies: • Increased requirements for safety assessment, pharmacovigilance, risk evaluation, and risk mitigation/ minimization • Parallel and additional requirements may be required by other authorities globally, including European Medicine Evaluation Agency(EMEA) • FDA can penalize pharmaceutical companies for a variety of noncompliance issues • Civil monetary penalties (CMPs): can be assessed for an assortment of violations such as violations of new REMS provisions, postmarket study requirements, or labeling violation • CMPs can reach substantial amounts, e.g. maximum of $10 million in a single proceeding

8. Framing the context • Increasing demands for safety data: • All Serious Adverse Events (SAEs) • Follow all AEs/SAEs till resolved or stable • Additional adverse events of interest: • Cancers • Myocardial Infarctions (MIs) • Hepatic events • Pregnancy outcomes • Global reporting to EMEA and regulatory agencies of European Union (EU) member states • Use of CIOMS form • Country of origin of AE

9. The times they are a changin’

10. Clinical Trial Continuum: From Drug Development to Optimal Regimensto Treatment Strategies

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

12. Purpose of Safety Monitoring

13. Purpose of Safety Monitoring

14. Clinical Role vs. Research RoleBalancing Both Roles Clinical Role: Subject OK Research Role: Study/Data OK 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/EAE Adhere to reporting requirements Adhere to toxicity management as specified Adhere to stopping rules as specified • 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

15. 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/EAE per protocol specifications • Follow protocol toxicity management section

16. 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/EAE • Research provisions vs. • Clinical care • Documentation • Follow until AE resolution or condition stabilizes

17. 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 • Therapeutic misconception • Subjects think they are receiving proven interventions, per their usual clinical care, despite being in a research study • Physicians think they can provide interventions, per usual practice

18. Roles and Responsibilities – Study Clinician/Physician • Action taken with Study product Subject 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?

19. Roles and Responsibilities – Study Team Safety: Ensure safety and well being of subjects at all times Data: Ensure data integrity to assess the risks/safety profile of the study intervention • Data capture; in particular, the collection of safety data • Overall monitoring of adverse events occurring in study • Take timely action regarding subject participation status in study • Be cognizant of expedited reporting requirements for safety data

20. Roles and Responsibilities – Study Team vs. Sponsor/RCC 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/RCC SAE/EAE sent to RCC RCC is not part of discussions that occur within study/safety monitoring teams regarding the event The RCC only has information about the event from the EAE Form; site should include relevant information from study team discussions RCC processes event and sends queries to site to obtain additional information All follow-up information should be provided to RCC

21. MentalBreak Land’s End at Cabo San LucasThe majestic stone arch at the southern tip of Baja, where the Sea of Cortez meets the Pacific Ocean

22. Safety Monitoring Environment 22

23. 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

24. Drug Development Model:Safety Data Flow in Clinical Trials

25. Safety Data from Clinical Trials Obligations to report data from DAIDS clinical trials irrespective of IND status. For both 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

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

27. 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/EAE Criteria Expedited time frames Form e.g. SAE, EAE form

28. Documentation Differences Between AE CRF and SAE/EAE Form

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

30. StrechBreak

31. 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)

32. 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

33. AE Term - Examples If “anaphylactic reaction” is reported with “rash, dyspnea, hypotension, and laryngospasm,” selecting “anaphylactic reaction” alone is considered appropriate. If “myocardial infarction” is reported with “chest pain, dyspnea, diaphoresis, ECG changes and jaundice,” it would be considered appropriate to select terms for both “myocardial infarction” and “jaundice.” EAE Form: List only one primary AE. Choose the one term that best describes the nature of the adverse event being reported.

34. 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, or • 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)

35. Adverse Event vs. Event Outcome Death • Death is an outcome and is not usually considered to be an AE. • Example: If “death due to myocardial infarction” is reported, “myocardial infarction” can be selected and death should be captured as the outcome. • If the only information reported is death, then the most specific death term available should be selected. • Example: If a reporter states only that “a study subject was found dead,” “found dead” can be selected.

36. Adverse Event vs. Event Outcome Hospitalization • Hospitalization is a consequence and is not usually considered an AE. • Example: If “hospitalization due to congestive heart failure” is reported, “congestive heart failure” can be selected and hospitalization should be captured as the consequence of the event. • If the only information reported is the outcome term, then the most specific term available should be selected. • Example: If a reporter states only that “a study subject was hospitalized,” “hospitalization” can be selected.

37. 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. • 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 existing condition persistent 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)

38. Severity • Describes the intensity of the event • Events are graded on a severity scale • Example: • Mild, Moderate, Severe • Numeric Scale e.g. 1 to 5

39. Severity vs. Serious Severity is not the same as Serious Severity = Intensity e.g., chest pain, moderate severity Serious (SAE) = Based on patient/event outcome or action criteria Used to define regulatory reporting obligations AE classification: must divorce usage of serious in a clinical sense from serious in a regulatory sense For clinical connotations, use severity descriptors

40. Action Taken with Drug • Action Taken with Drug: • Withdrawn • Dose reduced • Dose increased • Dose not changed • Unknown • Not applicable • Refer to protocol • Refer to DAIDS EAE Form > ICH E2B (R3)

41. 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 • Outcome of subject in study • Remains in Study • Withdrawn • Lost to follow-up • Death

42. 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)

43. 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/EAEs generally incomplete when first received • Follow-up information actively pursued • Judged by: • Reporting health professional • Sponsor

44. Determination of Relatedness • 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]?

45. Determination of Relatedness • ‘May be more art than science’ • 1st level of review: NR • 2nd level of review: any degree R • 3rd level of review: any evidence to compel moving in one direction or the other; i.e. from NR to any reasonable possibility of R, or from any R to NR • Clear-cut case; easy to make a determination • Not so clear-cut: use your best judgment based on available information; assure adequacy of information; obtain more whenever • Unless clear-cut case,there’s no absolute right or wrong; give your best judgment; substantiate and follow-up • Err on conservative side; contribute to knowledge base

46. 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 46

47. 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]. 47

48. 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]. 48

49. Review and Assessment of SAE/EAE 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/EAE]. If Outcome is not resolved at time of evaluation, follow until resolution or stability at each study visit Is it [Expected]? Is it [Related]? 49

50. 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 Clinical Case Evaluation