Causality Assessment Training ACTG Network Meeting June 20, 2011

1. Causality Assessment TrainingACTG Network MeetingJune 20, 2011 Ling Chin, MD, MPH Safety Pharmacovigilance Team Leader, DAIDS Olu Ogunyankin, MD DAIDS RSC Safety & Pharmacovigilance Specialist Deborah McMahon, MD University of Pittsburgh ACTG - PEC

2. Training Agenda • Learning Objectives • Methods for Assessment of Causality • Shift in Relationship Categories • FDA’s New Final Rule on IND Reporting • DAIDS clinical trials: What all this means for you • Case Discussions: Focus on Causality Assessment

3. Learning Objectives At the conclusion of this session, participants will be able to demonstrate an understanding of: Methods used for assessing causality Implications for causality assessment based on the New Final Rule for IND Reporting to FDA Assessment of adverse event cases for causality

4. Causality Assessment Causality assessment is the evaluation of the likelihood that a particular treatment is the cause of an observed adverse event • is an essential part of evaluating adverse events for reporting to sponsors, regulatory agencies, and safety monitoring committees • an important component of the evaluation of the benefit/harm profiles of drugs

5. Methods used for Causality Assessment

6. Adverse Drug Reactions:Methods for Evaluation of Causality Global Introspection:causality inference obtained via clinical judgment, such as with an expert panel Algorithms: sets of specific questions with associated scores for calculating the likelihood of a cause-effect relationship Bayesian approaches: • need a probability for causality calculated from available knowledge (prior estimate) • need the specific findings in a case, which combined with the background information, determines the probability of drug causation for the case (posterior estimate)

7. Global Introspection Is the most common approachfor individual causality assessment of adverse drug reports However the process of global introspection is known to be subjective Despite its usefulness, the global introspection method has been subject to criticisms of subjectivity, imprecision, and poor reproducibility because it is mainly based on expert clinical judgements

8. Algorithms/Scales/Systems Lots of algorithms have been developed (>30) Some examples of algorithms/scales used for causality assessment: WHO assessment scale Karch and Lasagna’s scale Naranjo’s scale  Kramer scale Yale logarithm European ABO system Spanish imputation system

9. Algorithms The use of a standardized instrument was intended to lead to a reliable and reproducible measurement of causality, in a structured way There are several decision support algorithms available to make an explicit and reproducible assessment of causality Causality assessment algorithms differ in many respects but share certain common features. • Questions are used to capture details of the ADR • Different procedures are thereafter adopted to convert answers from these questions to estimates of probability Disadvantages: No one universal algorithm, scoring can be arbitrary, responses to questions can be subjective

10. Causality Assessment: Commonality The 3 methods of causality assessments while different share common factors for consideration: Temporal relationship Dose relationship De-challenge/Re-challenge Recognized association with the product/class Pharmacological Plausibility Underlying illness/concurrent conditions Other medications Note: Regardless of number of factors present, the quality of the information is critical to the assessment

11. Shift in reducing Relationship Term choices from many to two

12. Causality Determinations

13. Decreasing Relationship Term Choices • Difficulties in establishing a causality assessment: differentiate between scales with four or more levels • CIOMS* working group VIrecommends that the investigator be asked to use a binary decision for the drug causality (related/not related) for serious adverse events • EMA (Oct 2010): Reasonable possibility for causality assessment (based on CIOMS Working Group VI report) • FDA (Sep 2010): Reasonable possibility for causality assessment (is there evidence to suggest drug caused the event) * Council for International Organizations of Medical Sciences

14. FDA’s ‘New’ Final Rule for IND Reporting 21 CFR 312.32

15. Problem: Uninformative Safety Reports • Sponsors often report serious adverse events as individual cases that: • Are likely to have been manifestations of the underlying disease • Commonly occur in the study population independent of drug exposure • Are study endpoints • Reducing the number of uninformative reports will enhance the ability of sponsors, FDA, investigators, and IRBs to focus on safety issues that affect human subjects. • Making a judgment about causality (“reasonable possibility”) is generally not always possible for single cases

16. Causality: Reasonable Possibility • A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure • One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug • An analysis of specific events observed in a clinical trial indicates those events occur more frequently in the drug treatment group than in a control group

17. Examples of Reasonable Possibility Individual occurrence • a single occurrence of an event that is uncommon and known to be strongly associated with drug exposure

18. Examples of Reasonable Possibility One or more occurrences • a single occurrence, or a small number of occurrences, of an event: • not commonly associated with drug exposure, • uncommon in the population exposed to the drug • occurs in association with other factors strongly suggesting causation (e.g. temporal association, re-challenge)

19. Examples of Reasonable Possibility Aggregate analysis of specific events • an analysis of events observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a control group, e.g. • known consequences of underlying disease • events common in study pop independent of drug therapy

20. Reasonable Possibility: Implications for Sponsor Assessment • Obvious individual occurrence: do not expect sponsor and investigator causality assessments to differ • One or more occurrences and aggregate analyses: sponsor has leeway to perform safety review to arrive at causality, via all available safety information: • Across clinical trials with same product • Animal studies • Epidemiologic experience • Global post-marketing experience • Scientific literature

21. IND Reporting Responsibilities • Investigator: • Must immediatelyreport to the sponsor any SAE, whether or not considered drug related • Must include an assessment of whether there is a reasonable possibility drug caused the event • Sponsor: • Must report any Suspected Adverse Reaction*that is both: • Serious • Unexpected *Only if there is evidence to suggest a causal relationship between the drug and the adverse event

22. Definition: Adverse Event ICH E2A: 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.

23. Definition: Serious Adverse Event

24. Definition: Suspected Adverse Reaction and Adverse Reaction Suspected adverse reaction implies a lesser degree of certainty about causality than Adverse reaction

25. Reasonable Possibility: Shift to Evidence • ICH E2A p.2: "responses to a medicinal products" means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationshipcannot be ruled out. • ICH E2A p.5: "reasonable causal relationship" is meant to convey in general that there are facts (evidence) or argumentsto suggest a causal relationship.

26. The Universe of Adverse Events Suspected Adverse Reactions Adverse Events Adverse Reactions

27. What This Means For YOU Manual for Expedited Reporting of Adverse Events to DAIDS v2.0

28. Use of Manual 2.0 • New protocols are required to use Manual 2.0 • Ongoing protocols with last participant f/u date beyond May 31, 2011 are required to switch to Manual 2.0 • For specific status on your protocol for switch to Manual 2.0, contact your study team/network ops • Successful completion of protocol registration through the DAIDS Protocol Registration System (DPRS) will trigger a switch to Manual 2.0

29. Definitions: Manual 2.0 • AE: Any untoward medical occurrence in a patient or clinical investigation subject administered a study agent and which does not necessarily have a causal relationship with this treatment • SAE: A serious adverse event (SAE) is defined as 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 • Is an important medical event that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent on of the other outcomes listed in the definition above

30. Definitions: Manual 2.0 • SUSAR:an adverse event that is a Suspected Unexpected Serious Adverse Reaction • For the SUSAR reporting category, an SAE will be reported if it fulfills the following criteria: • Related and • Unexpected

31. Relationship Assessment: Manual 2.0 • Relationship assessment changed from a five term to a two term classification • The terms used to assess the relationship of an event to study agent(s) are: • Related – There is a reasonable possibility that the AE may be related to the study agent(s). • Not Related – There is not a reasonable possibility that the AE is related to the study agent(s). • Alternative etiology, diagnosis, or explanation for the SAE should be provided

32. Reasonable Possibility • DAIDS considerations: • Move to “facts (evidence) or arguments to suggest a causal relationship” [ICH E2A p. 5] • Move away from the category in Manual 1.0: “Probably Not Related” (i.e. the possibility cannot be excluded) • Facts (evidence) or arguments that may support “a reasonable relationship" may include: • a temporal relationship, • a pharmacologically or biologically plausible event, or • positive dechallenge or rechallenge. Presence of confounding factors, such as concomitant medication, concurrent illness, or relevant medical history, should also be considered

33. What You Have to Provide:Critical to Causality Assessment • Provide accurate, adequate details on the case to allow for a reasoned assessment, on the basis of evidence, to suggest a causal relationship of the drug to the adverse event • Include a relevant comprehensive narrative • Include continued follow-up: • For additional details that were initially unavailable, from all potential sources • For final resolution of the event

34. Quality of Information: 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) (hospitalization) • Diagnosis (workup, relevant tests/procedures, lab results) • Other information that supports or refutes an AE

35. Case Discussions

36. Causality Assessment By default, Global Introspection is the common method used to assess causality, performed by a clinician/investigator The use of the following set of questions allows for a more structured way to perform global introspection Based solely on the information provided: • Is there [Drug Exposure] and [Temporal Association]? • Is there [Dechallenge/Rechallenge] or [Dose Adjustments]? • Is there known association per [Investigator’s Brochure/Package Insert]? • Is there [Biological Plausibility]? • Is there any other possible [Etiology]?

37. Dose ExposureTemporal Association Is there Temporal Association? Did the AE occur after Dose Exposure? • Establish that AE occurred after receiving intervention • Time to onset: from exposure to AE: • Duration of AE: • Pharmacologic parameters • Biologic parameters • Short latency: hypersensitivity reactions • Long latency: autoimmune processes, cancer

38. Dose RelationshipsChallenge/Dechallenge/Rechallenge Is there any change in dosage? Is there Dechallenge/Rechallenge? • If dose adjustments made, any impact on the AE, such as a dose-relationship? • If intervention discontinued, any impact on the AE, such as improvement or resolution? • If intervention re-started, any impact on the AE, such as re-emergence of AE? Nature of re-emergence?

39. What’s Known and Plausibility Is there pharmacologic plausibility? Is there biologic plausibility? • Based on pharmacologic properties, AE likely • Consistent with knowledge of drug: PK, PD, mechanism of action, etc • Based on understanding of biological properties, AE likely • Consistent with knowledge of disease, drug, multiple interactions between disease, drug, host, etc • Based on knowledge of the drug: • IB/PI, literature references, global experience • Drug class effects • Clinical experience

40. Alternate Etiology Is there another likely cause for the AE? • Concomitant Drugs, Other substances? • Medical History: current and past • Consequence of underlying disease • Family, social history • Other factors • Inherent to the population • Other exposures, e.g. environmental factors

41. Case Discussions Group Activity Based on the information available: • Assess for causality: Related or Not Related • Use structured set of questions • Make your determination • Provide your rationale: Argue for R or Argue for NR • Any issues raised regarding assurance of subject well-being?

42. Case Discussion Death

43. Case Review • 35 year-old, HIV-infected, African female • July 30, 2008: Enrolled • CD4 count : 92 cells/mm3, HIV viral load: 192,879 copies/mL • Started study agent, LPV/RTV • October 22, 2008: • Study clinic visit: BP: 140/100 mm Hg, started on hydrochlorothiazide • September 25, 2009: • Subject seen at the study clinic, complains of general body pains, dry cough of 2 days duration • Treated for malaria and upper respiratory tract infection

44. Case Review • November 05, 2009: • Subject seen at private clinic complaining of vomiting, headache, lower extremities weakness; 1 week duration • PE: Grade 2 hypertension discovered • Subject hospitalized and treated for malaria (lumefantrin/artemether) and hypertension (nifedipine, hydrochlorothiazide) • November 06, 2009: • Blood work: Hgb: 9.7 g/L, WBC: 3,900 cells/mm3, no malaria parasites on peripheral blood smear • November 09, 2009: • Chloramphenicol, benzyl penicillin added. LP requested but not performed

45. Case Review • November 11, 2009: • Subject died from unknown cause; no autopsy or death certificate • PMH: appendicitis (2003), and tuberculosis lymphadenitis (2004). • Past Ob & GynHx: • Para 3 (no abortions). • Pre-eclamptic during first pregnancy in 1997. Treated with hydrochlorothiazide • Subsequent pregnancies by normal vaginal delivery with no complications

46. Assessment Is there [Drug Exposure]: Yes Is there [Temporal Association]: Yes Is there [Dechallenge/Rechallenge]or [Dose Adjustments]: No Is there known association per [Package Insert]: No, death is not viewed as expected event Is there [Biological Plausibility]: Possible (unlikely), on antibiotics and other drugs for hypertension, malaria. CYP3A inhibitor Is there any other possible [Etiology]: No information, infectious disease etiology not convincing Is there evidence to support causality:No Under ‘can’t rule out’: Probably Not Related Under ‘evidence’: Not Related Action to be taken: Pursue cause of death

47. Case Discussion BrainHerniation

48. Case Review • 37 year-old, HIV infected, White female • May 1, 2009: Screening visit • HIV viral load: 44,566 copies/mL • CD4: 393 cells/mm3 • May 8, 2009: • Administered a single dose of the study agent Quadrivalent Human Papillomavirus Vaccine • CD4: 432 cells/mm3 • June 22, 2009: Went to ED • Migraine-like headache, left hand numbness, dysarthria, anomia, altered mental status • CT scan was normal and subject was discharged

49. Case Review • June 23, 2009: Second ED visit • Complained of persistent headache with anomia • Admitted to neurology service • Empirical treatment: vancomycin, cefapime, acyclovir, and ampicillin for bacterial meningitis and herpes simplex virus encephalitis • CSF: cellular containing mixed reactive monocytes and lymphocytes • Brain MRI: showed diffused supratentorialleptomeningeal enhancement consistent with leptomeningitis • All antibiotics other than acyclovir were discontinued • June 28, 2009: discharged from hospital • Plans for close follow-up

50. Case Review • July 2, 2009: Return to ED • Worsening headache, worsening confusion, and progressive acute mental status changes • CT scan (with contrast): diffuse cerebral edema and brainstem herniation • Chest X-ray: mild left-sided hilar congestion • At 0600 hours: subject found unresponsive with fixed, dilated pupils bilaterally; intubation ordered • At 1000 hours: intervention discontinued • At 1529 hours: pronounced dead • Cause of death: brain herniation from extensive CNS vasculitis, unlikely due to infection