Causality Assessment Training ACTG Network Meeting June 20, 2011 Ling Chin, MD, MPH Safety...

Causality Assessment TrainingACTG Network Meeting

June 20, 2011

Causality Assessment TrainingACTG Network Meeting

June 20, 2011

Ling Chin, MD, MPHSafety Pharmacovigilance

Team Leader, DAIDS

Ling Chin, MD, MPHSafety Pharmacovigilance

Team Leader, DAIDS

Deborah McMahon, MDUniversity of Pittsburgh

ACTG - PEC

Deborah McMahon, MDUniversity of Pittsburgh

ACTG - PEC

Olu Ogunyankin, MDDAIDS RSC Safety &

Pharmacovigilance Specialist

Olu Ogunyankin, MDDAIDS RSC Safety &

Pharmacovigilance Specialist

Training AgendaTraining 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

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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

Learning ObjectivesLearning Objectives

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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

Causality AssessmentCausality Assessment

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Methods used for

Causality Assessment

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1. Global Introspection: causality inference obtained via clinical judgment, such as with an expert panel

2. Algorithms: sets of specific questions with associated scores for calculating the likelihood of a cause-effect relationship

3. 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)

Adverse Drug Reactions:Methods for Evaluation of CausalityAdverse Drug Reactions:Methods for Evaluation of Causality

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Is the most common approach for 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

Global IntrospectionGlobal Introspection

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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

Algorithms/Scales/SystemsAlgorithms/Scales/Systems

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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

AlgorithmsAlgorithms

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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

Causality Assessment: CommonalityCausality Assessment: Commonality

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Shift in reducing Relationship Term choices

from many to two

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Causality DeterminationsCausality Determinations

Difficulties in establishing a causality assessment: differentiate between scales with four or more levels

CIOMS* working group VI recommends 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)

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Decreasing Relationship Term ChoicesDecreasing Relationship Term Choices

* Council for International Organizations of Medical Sciences

FDA’s ‘New’ Final Rule for IND Reporting

21 CFR 312.32

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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

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Problem: Uninformative Safety ReportsProblem: Uninformative Safety Reports

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

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Causality: Reasonable PossibilityCausality: Reasonable Possibility

Individual occurrence a single occurrence of an event that is uncommon and

known to be strongly associated with drug exposure

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Examples of Reasonable PossibilityExamples of Reasonable Possibility

One or more occurrences a single occurrence, or a small number of occurrences, of

an event:

i. not commonly associated with drug exposure,

ii. uncommon in the population exposed to the drug

iii.occurs in association with other factors strongly suggesting causation (e.g. temporal association, re-challenge)

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Tendon Rupture

Heart Valve Lesions in young adults

Intussusception in healthy infants


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.

i. known consequences of underlying disease

ii. events common in study pop independent of drug therapy

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i. non-acute death in a cancer trial

ii. acute MI in a long-duration trial with an elderly population with cancer


Reasonable Possibility: Implications for Sponsor AssessmentReasonable 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

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IND Reporting ResponsibilitiesIND Reporting Responsibilities

Investigator:• Must immediately report 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

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Definition: Adverse EventDefinition: Adverse Event

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New 21 CFR 312.32:

“Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related”

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.

Definition: Serious Adverse EventDefinition: Serious Adverse Event

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An adverse event is considered “serious” if it results in any of the following outcomes:• Death • A life-threatening AE• Inpatient hospitalization or prolongation of existing hospitalization• A persistent or significant incapacity or substantial disruption of the

ability to conduct normal life functions• A congenital anomaly/birth defect• Important medical events that may not result in death, be life-

threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition

Definition: Suspected Adverse Reaction and Adverse ReactionDefinition: Suspected Adverse Reaction and Adverse Reaction

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Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that the drug caused the adverse event

Adverse Reaction: Any adverse event caused by a drug

Suspected adverse reaction implies a lesser degree of certainty about causality than Adverse reaction

Reasonable Possibility: Shift to EvidenceReasonable Possibility: Shift to Evidence

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For the purpose of IND reporting: reasonable possibility means “there is evidence to suggest a causal relationship between the drug and the adverse event”

• 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 relationship cannot be ruled out.

• ICH E2A p.5: "reasonable causal relationship" is meant to convey in general that there are facts (evidence) or arguments to suggest a causal relationship.

The Universe of Adverse EventsThe Universe of Adverse Events

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Adverse Events

Suspected Adverse Reactions

Adverse Reactions

What This Means For YOU

Manual for Expedited Reporting of Adverse Events to DAIDS v2.0

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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

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Use of Manual 2.0Use of Manual 2.0

Definitions: Manual 2.0Definitions: 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

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Definitions: Manual 2.0Definitions: 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

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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

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Relationship Assessment: Manual 2.0Relationship Assessment: Manual 2.0

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

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Reasonable PossibilityReasonable Possibility

What You Have to Provide:Critical to Causality AssessmentWhat 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

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Quality of Information: NarrativeQuality 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

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Case Discussions

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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]?

Causality AssessmentCausality Assessment

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Dose ExposureTemporal AssociationDose 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

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Dose RelationshipsChallenge/Dechallenge/RechallengeDose 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?

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What’s Known and PlausibilityWhat’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

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Alternate EtiologyAlternate 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

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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?

Case Discussions Group ActivityCase Discussions Group Activity

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Death

Case DiscussionCase Discussion

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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

Case ReviewCase Review

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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


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November 11, 2009:• Subject died from unknown cause; no autopsy or death certificate

PMH: appendicitis (2003), and tuberculosis lymphadenitis (2004).

Past Ob & Gyn Hx: • Para 3 (no abortions).

• Pre-eclamptic during first pregnancy in 1997. Treated with hydrochlorothiazide

• Subsequent pregnancies by normal vaginal delivery with no complications


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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

AssessmentAssessment

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Brain Herniation


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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


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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 supratentorial leptomeningeal enhancement consistent with leptomeningitis

• All antibiotics other than acyclovir were discontinued

June 28, 2009: discharged from hospital• Plans for close follow-up


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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


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PMH: Metamphetamine abuse (20 years), Bells palsy (Jan 2009), HIV infection (Mar 2009), Chlamydia (Apr 2009), and migraine-like headaches (~ 7 mos)

Social History:• Non-consensual unprotected sex by a HIV + male

• Started drug detoxification for metamphetamine abuse: doing well till 06/09; resides in a local rehabilitation center

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Is there [Drug Exposure]: Yes Is there [Temporal Association]: Yes, occurred 6 wks. post vaccine

administration Is there [Dechallenge/Rechallenge] or [Dose Adjustments]: N/A, one

dose only Is there known association per [Package Insert]: No Is there [Biological Plausibility]: Possible (immune system phenomena?) Is there any other possible [Etiology]: Possible, Leptomeningitis??

Vasculitis?? Is there evidence: Not enough Reasonable possibility: No New FR: Pursue etiology, Look for similar cases, Re-assess What about subject well-being? Repeat MRI?


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Chest Pain


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49 year-old, HIV infected, male

April 15, 2004: Started on RTV prior to enrollment

December 20, 2004: Enrolled• Started on the study agent vicriviroc

• Baseline CD4: 148 cells/mm3

• HIV viral load: 9,382 copies/mL

February 23, 2010:• CD4: 522 cells/mm3

• HIV viral load: <50 copies/mL


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April 29, 2010: Hospitalized for chest pain• Coronary angiogram showed 99% stenosis in LAD artery distal to a

previous stent (placed in 2002)

• Percutaneous transluminal balloon angioplasty was performed with placing of two bare stent distal to previous stent

• Subject complained of chest pain after the procedure

• No MI or myocardial damage was noted

• All ARVs were held due to non-availability at this hospital

• Clopidogrel was started


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April 30, 2010: Discharged from hospital• Subject restarted on all medications and continued with clopidogrel

PMH:• Subject had a previous stent placed in Jan 2002; continued to

smoke and developed recurrent chest discomfort on exertion

• CAD, HTN, dyslipidemia with low HDL, COPD, nicotine addiction, depression, upper gastrointestinal bleeding


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Is there [Drug Exposure]: Yes Is there [Temporal Association]: Yes Is there [Dechallenge/Rechallenge] or [Dose Adjustments]: Yes, study

agents withheld at hospital (no info on its impact) Is there known association per [Package Insert]:

Vicriviroc Raltegravir

Is there [Biological Plausibility]: Possible (MIs are events of interest) Is there any other possible [Etiology]: Pre-existing severe CAD requiring

stent placement, continued tobacco use Alternate Etiology: Strongly established Reasonable possibility: Not Related New FR: Track cases, Consider aggregate analysis to explore further


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Ventricular Septal Defect


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27 year-old, HIV infected, White female• Baseline CD4 count: 10 cells/mm3

May 8, 2006: Enrolled• Randomized and started of EFV and FTC/TDF or placebo

August 30, 2006:• HIV viral load undetectable

March 1, 2008:• DSMB recommendation led to unblinding: study agents were

changed to active FTC/TDF and EFV continued

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November 17, 2008: Positive pregnancy test• Study agents held• Primary care physician prescribed ATV, RTV, and FTC/TDF• [Conception estimated at October 2008]

May 17, 2009:• CD4 count: 498 cells/mm3

July 11, 2009:• Presented to hospital at 38 weeks gestation; blood stain (10 by 10 cm

on bed sheet)• Had pressure-like pain every 5 mins in the pelvis (felt like

contractions)• PE: vital signs normal, appeared to be in moderate pain• Evaluation via monitor showed uterine irritability• Cervix revealed sac with possible fetal parts

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July 11, 2009 (cont.):• Diagnosis: “term pregnancy and labor with breech presentation”• Emergency caesarian; viable female infant, 5 lbs 15 oz, Apgar score

was 7 at 1 min, 9 at 5 mins• Right 3 cm paratubal pedunculated cyst was removed due to risk of

torsion and pain; all other findings at delivery were normal

July 14, 2009: Discharged

August 4, 2009: First post-delivery study visit• Subject reports infant was diagnosed with VSD by a pediatric

cardiologist• Subject’s mother was born with a heart defect, childhood heart

murmur• Smoked marijuana and tobacco (1/2 pk/day) throughout pregnancy

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Is there [Drug Exposure]: Yes Is there [Temporal Association]: Yes, + pregnancy test on study agents Is there [Dechallenge/Rechallenge] or [Dose Adjustments]: Yes, switched to

ATV, RTV, and FTC/TDF Is there known association per [Package Insert]: No• EFV: Category D, may cause fetal harm during 1st trimester• FTC/TDF: Category B• ATV: Category B, some use in pregnant women, must be used with RTV• RTV: Category B

Is there [Biological Plausibility]: Possible (low), no specific association /w VSD

Is there any other possible [Etiology]: Marijuana, Tobacco use throughout pregnancy, no specific association with VSD

Evidence for causality: not much, no known association with VSD: Not Related is reasonable conclusion

New FR: Look for similar cases, Pharmacovigilance, Re-assess


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Final PointsFinal Points

Challenge to determination of causality is having adequate information that could provide the evidence for reasonable possibility the drug caused the event

All relevant information is useful to the assessment. If not initially available, site should continue to obtain the information. Your efforts in this endeavor is recognized and much appreciated

Making the causality determination requires the judgment of a medically qualified person based on best available information at the time. This determination can be modified/influenced by any new information

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Questions?

CitationsCitations

Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacol Ther. 1977 Mar;21(3):247-54.

C. A. Naranjo, M.D. et al. Clin. Pharmacol. Ther. Aug 1981, Vol 30, No 2, p 239-245. Naranjo Probability Scale

Taofikat B. Agbabiaka, J. Savovi´c and Edzard, E. Methods for Causality Assessment of Adverse Drug Reactions: A Systematic Review. Drug Safety 2008; 31 (1): 21-37

Arimone Y, Bégaud B, Miremont-Salamé G, et al. Agreement of expert judgment in causality assessment of adverse drug reactions. Eur J Clin Pharmacol. 2005 May;61(3):169-73.

Théophile H, Arimone Y, Miremont-Salamé G, Moore N, et. al. Comparison of three methods (consensual expert judgement, algorithmic and probabilistic approaches) of causality assessment of adverse drug reactions: an assessment using reports made to a French pharmacovigilance centre. Drug Safety. 2010 Nov 1;33(11):1045-54.

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