Past, present, and future - MBSW Online

Past, present, and future34 th Annual Midwest BiopharmaceuticalStatistics WorkshopMuncie, IN May 25, 2011

• Cristiana Gassmann-Mayer is an employee ofJohnson & Johnson• The views and comments presented here a solelythose of the presenter and not necessarilyrepresentative of those ofJohnson & Johnson or PhRMA organization• Several slides are adapted from the presentationto the FDA of April 4, 2011 (courtesy of MaryNilsson, Eli Lilly)Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson 2

• Research question in clinical trials• Terminology• General background• Role of statisticians• Data collection: from retrospective toprospective scales• Statistical concepts and remaining areasfor debate• ConclusionsMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson 3

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Is suicidalitythe right term ?Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson5

• Avoid the term suicidality• In favor of more clinically meaningful andspecific terms such as :• “suicidal ideation”• “suicidal behavior”• “completed suicides” etc.Meyer et al. (2010)SuicidalityMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson6

Where we wereWhere we areWhere we are goingWho we areMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson 7

• Last 2 decades• Early 1990’s : SSRI’s in adults with depression• 2002-2008 SSRIs in pediatric populationand anti-epileptics, treatments of psychiatrydisorders, smoking cessation therapy, obesity,anti-allergy, etc.• Retrospective assessment of adverse eventsdata resulted in multiple label changes and black box warning• 2007• Dr. Kelly Posner and U of Columbia : Columbia- ClassificationAlgorithm of Suicide Assessment (C-CASA)Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson8

• 2008- 2009• PhRMA* Working group: consensuson the assessment, analysis andreporting of suicide-related data• 2009• PhRMA white paper tothe FDA in January 2009• 2009-2010• Statistical sub-team continuedworking independently of PhRMA* Pharmaceutical Research and Manufacturers of AmericaMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson9

Current Sub-Team of the original PhRMA WG:• Cristiana Gassmann-Mayer (J&J) – leader• Mary Nilsson (Eli Lilly) – co-lead analysis guideline• Shailaja Suryawanshi (Merck) - co-lead analysis guideline• Kaihong Jiang (Sanofi-Aventis)• Paul McSorley (GSK)• Ramin Arani (previously BMS, now Astellas Inc.)• Sarah DuBrava (Pfizer)• David Webb (previously Eli Lilly, now Dow AgroSciences)Previous participants in the first year:• Suna Barlas (Wyeth)• John Polzer (Eli Lilly)Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson 10

• September 2010• FDA Draft Clinical and Medical Guidance on “Suicidality:Prospective Assessment of Occurrence in Clinical Trials”http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225130.pdfMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson11

• FDA draft guidance includes:• Emphasis on using prospective suicide scales that map to theC-CASA system• Support to the C-SSRS instrumentMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson12

C-CASA=classification system1. Completed Suicide Completed Suicide2. Suicide Attempt Actual Attempt3. Preparatory Actions Toward Imminent SuicidalBehaviorC-SSRS=prospective questionnaire-Interrupted Attempt-Aborted Attempt-Preparatory Acts or Behavior4. Suicidal Ideation 1. Wish to Die2. Active Suicidal Thought3. Active Suicidal Thought with Method4. Active Suicidal Thought with Intent5. Active Suicidal Thought with Plan and Intent7. Non-suicidal Self-injurious Behavior Non-suicidal Self-injurious BehaviorOther Categories Become Obsolete with Prospective Data Collection5. Self-injurious Behavior, Intent Unknown aN/A- Unknowns are eliminated with prospective data6. Not Enough Information: Death acollection a9. Not Enough Information: Non-Death a8. Other (Accident; Psychiatric; Medical) N/A: No indication of suicidal ideation or behavioraThe C-CASA codes #5,6,9 were created only to make sense of limitations of retrospective adverse events.Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson13

• FDA draft guidance• Includes note that the analytical issues will beaddressed in separate guidancehttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225130.pdfMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson14

• Since 2009The statistical sub team worked on:• A manuscript on “Clinical and Statistical Assessment ofSuicidal Ideation & Behavior in Pharmaceutical Trials”(accepted May 2011)• An industry Scoring & Analysis Guide for data collected withthe C-SSRS scalewill be posted on Columbia University’s C-SSRS websitehttp://www.cssrs.columbia.edu/scales_cssrs.htmlMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson15

• 4 th April 2011• F2F meeting of our group with the FDA to shareindustry guidelines on the proposed analyses anddefinitions on suicide-related data from C-SSRS• Future• More F2F scientific dialogues with the FDA (nextin September 2011)• Prospective collection of suicide data with a scaleas standard practice in clinical trials• FDA draft guidance on the statistical analysis ofsuicide-related dataMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson16

• Contribute the scientific dialogue and promotecollaboration across industry, with the FDA, andacademia on key safety domains and urgent researchquestions• Interact with the FDA as the guidance for industryfor suicidal events statistical analyses is beingdeveloped• Develop and contribute to scientific clinical/statistical documents [eg. White paper, clinical/statisticalpublications, C-SSRS Scoring & Analysis Guide]• Outline the remaining areas for debate and shapethe environmentMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson17

• BE ACTIVE AND PROACTIVE• Collaborate with colleagues from other functions• Understand clinical concepts, regulatory requirements, backgroundof the research question, and implications in using differentstatistical methodologies• Communicate clearly and use strong analytical skills• Network with colleagues across industry and regulatoryagencies• Stay up-to-date with the specific research field of interest• Both for the statistical and clinical aspects• Present and participate in workshops and symposia to illustrateideas and learn about new proposalsMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson18

Collection of suicide-related dataIn the pastNowRetrospectiveSearch of AE terms and partialverbatim stringsProspectiveSuicide scales and instrumentsMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson 19

• C-SSRS: Columbia-Suicidality Severity RatingScale• STS: Sheehan Suicidality Tracking Scale• HASS: Harkavy-Asnis Suicide Survey• SBQ-R: Suicidal Behaviors Questionnaire-Revised (SBQ-R)• ISST: InterSePT Scale for Suicidal Thinking• SSI: Scale for Suicide Ideation• BSI: Beck Suicide Ideation scale• Single item on Hamilton Depression RatingScale or the Beck Depression InventoryMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson20

www.cssrs.columbia.edu/scales_cssrs.htmlColumbia-Suicide Severity Rating Scale:• Prospective counterpart of the C-CASA classificationscheme• Instrument designed to collect the:▪ Occurrence▪ Severity▪ Frequencyof both suicidal thoughts and behaviors• Outcomes for clinical management of safety▪ Suicidal behavior lethality rating (actual lethality/medicaldamage; potential lethality)▪ Suicidal ideation intensity rating (frequency, duration,controllability, deterrents, reason)Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson21

Current Industry Proposal andRemaining Areas of DebateMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson 22

• Suicide-related endpoints• Treatment emergence• History/Baseline• Assume suicidal ideation with all behaviors?• Suicidal behaviors as a hierarchy• Statistical analyses:• single trial• aggregated databasesMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson 23

Suicidal IdeationSuicidal BehaviorSuicidal ideationor behaviora “yes” answer at any time duringtreatment to any one of the suicidalideation questionsa “yes” answer at any time duringtreatment to any one of the suicidalbehavior questionsa “yes” answer at any time duringtreatment to any one of the suicidalideation and behavior questionsNOTE:These definitions are based on C-SSRS; can be modified if usingother suicide scalesMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson24

• Definition of treatment-emergence• TE definition varies across companies for theanalysis of adverse events in general• Recommend comparing max ideation duringtreatment with max during the pre-specified pretreatmentperiodSuicidal ideation present before treatment, notexperienced for some time, comes back during treatment It is not TE unless the category is higher/worseMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson25

Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson26

Recent HistoryAll prior History =LifetimeTime prior to treatment with studymedication closer to the start of the study.How close?All past history during the lifetime and priorto the subject’s study enrollmentLife timeX monthsprior tostudyBetweenScreeningand BaselineStudyTreatmentScreening VisitBaseline VisitRecent historyAll prior history27Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson

• Assume suicidal ideation with suicidal behavior?For example:Data Entry Suicidal ideation Suicidal behaviorSubject 12345NO XYESVisit 3• Impacts treatment emergence as wellYES?▪ If someone has a suicidal behavior during the pre-treatmentperiod, and has suicidal ideation during the treatment period,is that really TE suicidal ideation?• Area for debate !Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson28

• Suicidal behaviors have no “natural” ordering• No implied hierarchyCompletedSuicide>Attempt>Interrupted>Aborted>PreparatoryBehavior?• Still contentious and questionable to analyzeinterpret the behaviors as possessing ordinalnatureMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson29

• Be consistent with Sponsor standards; usesame statistical approach as for other safetyassessments• No adjustments for multiplicity typically in asingle trial• No inferential statistics except where indicated,otherwise exact tests; 95%CIs are recommended• Metrics: at least one analysis using odds ratio andone using risk differencePeto ORMantel-Haenszel risk differenceArcsine differenceMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson30

• Time-to-event analyses• Time-to-event analyses may not be appropriatefor trials of short duration, when there are longtime intervals between scale collections, or due to“informative censoring” situations• Interpret with caution – Need to understandassumptions• Exposure-adjusted analyses• Consider Exposure Adjusted Incidence Rates, fortaking into account variable duration of exposureMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson31

• Follow the approach recommended in the SPERTCrowe et al (2009)• Use multiple approaches (eg, fixed effects vs randomeffects)• Bayesian methods• Multi-item Gamma Poisson Shrinker• Three level hierarchicalmixture modelSPERT: Safety Planning Evaluationand Reporting TeamMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson32

• Establish criteria for studies to include• Placebo-controlled studies only• Across indications and by indication• Consider separate meta-analysesfor considerable differences in duration• Routinely use Forest PlotsMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson33

Include: Stratification by study Sensitivity analyses (eg. mixed effects vs fixed effects) Also studies with no events DerSimonian-Laird test (random effects) Exact meta-analytic approach that combines confidencedistributions to estimate the risk difference CI withoutcontinuity correction Pay attention to continuity correctionsStandard 0.5 correction is NOT recommendedOther corrections are preferredMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson34

• No uniformly “best” method• Need for pre-specified safetyanalysis plans• Need for sensitivityanalyses• Need for cautionMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson35

• Role of industry statisticians is key in SAFETY for:• developing new ideas to improve the statistical analyses andreporting of clinical safety data• analyzing data in the most appropriate way to ensureadequate and accurate estimate of the drug benefit/risk ratio• shaping and influencing the definition of “best practices” bycontributing to industry guidelines, white papers,publications and regulatory guidance• promoting and contributing to urgent scientific debates onkey statistical and clinical inter-related issues• collaborating with different groups (FDA, academia,pharmaceutical industry)Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson36

Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson37

Statistics may be defined as"a body of methods for makingwise decisions in the face ofuncertainty."~W.A. WallisMuncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson 38

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• Meyer, R.E. et al.(2010) Suicidality and risk of suicide--definition, drug safetyconcerns, and a necessary target for drug development: A brief report. J ClinPsychiatry 71, 1040-6.• Oquendo, M.A., Halberstam, B. & Mann, J.J.(2008) Columbia Suicide HistoryForm. In: Handbook of Psychiatric Measures, Vol. 2nd (eds. Rush, J., First, M.B.and Black, D.) 241-2 (American Psychiatric Publishing, Inc;, Washington, D.C.• Osman, A., Bagge, C.L., Gutierrez, P.M., Konick, L.C., Kopper, B.A. & Barrios,F.X. (2001) The Suicidal Behaviors Questionnaire-Revised (SBQ-R): Validationwith clinical and nonclinical samples. Assessment 8, 443-54.• PhRMA White Paper, December 2008, on the Assessment of Suicidality ,December 19, 2008. On file upon request.• Posner, K., Oquendo, M., Gould, M., Stanley, B. & Davies (2007), M. ColumbiaClassification Algorithm of Suicide Assessment (C-CASA): Classification ofsuicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. AmJ Psychiatry 164, 1035-43.• Posner, K., Melvin, G.A., Stanley, B., Oquendo, M.A. & Gould, M.(2007)Factors in the assessment of suicidality in youth. CNS Spectr 12, 156-62.• Stone, M. et al. (2009) Risk of suicidality in clinical trials of antidepressants inadults: analysis of proprietary data submitted to US Food and DrugAdministration. BMJ 339, b2880.Muncie, IN May 25, 2011 C. Gassmann-Mayer Johnson & Johnson40

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