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2003 FDA/Industry Statistics Workshop

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Presentation on theme: "2003 FDA/Industry Statistics Workshop"— Presentation transcript:

1 2003 FDA/Industry Statistics Workshop
Perspectives of Safety Issues in Drug Development Industry Statistical Perspective Timothy Costigan, Ph.D. Wei Shen, Ph.D. Eli Lilly and Company Indianapolis, Indiana 2003 FDA/Industry Statistics Workshop

2 Abstract We review the objectives and requirements of safety assessment through the phases of drug development. We summarize recent regulatory guidelines and initiatives. We discuss how to communicate results of safety analyses through efficient use of graphical displays and data reduction. We also discuss multiplicity issues relating to safety data.

3 Overview of Presentation
I. Background and General Considerations II. Recent Regulatory Guidances and Initiatives III. Presentation of Integrated Safety Data – Synthesis, Data Reduction, Graphical Displays IV. Multiplicity Issues in the Interpretation of Safety Data V. Appendix: Assessing safety during the Phases of Drug Development

4 I. Background and General Considerations
Risk Assessment and Management - Context Safety Data Collected in Clinical Trials Objectives of Safety Data Analysis Major Safety Issues in Drug Development Adequacy of Long Term Exposure and Breadth of Effects Studied Risk Benefit Interpretation of Safety and Efficacy – General Safety Effects

5 Risk Assessment and Management
Risk assessment is the process of identifying, estimating, and evaluating the nature and severity of risks associated with a product (draft FDA concept paper 2003). Occurs throughout a product’s lifecycle Comprehensive description of safety required by the Food, Drug and Cosmetic Act Emphasis on a Management Plan

6 Safety Data Collected in Clinical Trials
Standard Safety Data (Gait et al, 2000 DIA J, see appendix) Exposure and reasons for discontinuation Adverse events (SAE, DCAE, TEAE) Clinical laboratory measurements Vital signs ECGs Special Safety Data Based on indication, class of medication, findings

7 Objectives of Safety Data Analysis
Identify and understand safety issues as early as possible Identify risk factors related to increased toxicity and lack of efficacy Consequences Allow clinicians to assess the risk/benefit of therapies for classes of patients Patient safety maintained overall and within special populations

8 Responsibilities and Goals
Regulatory Agency and Sponsor(s) Joint Responsibility Drugs used in clinical trials are safe Marketed drugs are safe and efficacious Avoid product recalls and major label changes which could have been foreseen Goal: each patient receives the therapy relative to efficacy and dose with the best risk/benefit profile Adhere to the Declaration of Helsinki

9 Some Major Safety Issues in Drug Development
Hepatotoxicity QT interval prolongation – surrogate for a major safety issue Adverse events with etiology indicative of toxicity

10 Adequacy of Long Term Exposure and Breadth of Effects Studied
It is important to have adequate safety data in clinical studies of sufficient duration prior to approval Guidance – minimum required prior to submission Extension active treatment phases Continued long term safety assessment during regulatory review, post marketing clinical study commitments Breadth of effects studied overall and in special populations– Clinical pharmacology package is a major component (see Appendix)

11 Risk Benefit Interpretation of Safety and Efficacy
Safety and efficacy need to be considered jointly in a risk benefit analysis, particularly when comparing therapies Adherence for all communications to physicians Lack of efficacy after switching from an effective therapy is often a greater general safety concern than direct side effects, particularly when comparing therapies Risk Management may address Managing side effects Appropriately monitoring patients who switch therapies

12 II. Recent Regulatory Safety Guidance and Initiatives
Current - Final Assessment of hepatotoxicity Proposed - Draft Assessment of QT interval prolongation Risk management plan

13 Assessment of Hepatotoxicity
FDA PhRMA Sponsored Workshop Feb 12-13, 2001 Three White papers Pre and Non Clinical Clinical Post Marketing Considerations Model for standardization of analysis Clinical interpretation of liver enzymes discussed Special laboratory analysis (as opposed to standard) platelets, neutrophils, immunogenicity, immunotoxicity

14 Liver Signals Hy’s Law Individual Studies Cumulative Meta Analysis
Integration of Studies with > 2 weeks exposure By Study Design Placebo Controlled Active Control Open Label By Duration of Exposure By frequency of Evaluation

15 Assessment of QT Interval Prolongation
Assessed in clinical pharmacology and clinical studies New draft guidance: perform a large clinical pharmacology study to assess Qt prolongation very early in product development January 2003 workshop, “The Clinical Evaluation of QT Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs” which was sponsored by DIA, in collaboration with NASPE, FDA, and Health Canada.

16 Assessment of QT Interval Prolongation
Industry working group reviewing draft guidance Recent advisory committee for two products Midwestern Biompharm Workshop, May 2003 ‘Analysis of QT/QTc Interval Data’, Marilyn Agin chair Shah A and Hajian G (2003), ‘A maximum likelihood approach to estimating the QT correction factor using mixed effects model’, Statis Med,

17 Draft QT Guidance: Summary
Super-therapeutic doses in healthy volunteers, above highest possible attainable exposure Evaluation by clinical experts rather than computer readings Evaluation at times covering maximum concentration of agent and metabolites Inclusion of a positive control for assay sensitivity Clinical relevant changes described (< 5 ms increase not associated with Torsades de Pointes) Prominence given to outlier analysis and concentration effects Upper 90% confidence interval of change versus placebo < 10ms

18 Draft QT Guidance: Technical Issues
QT interval must be corrected for heart rate changes Standard corrections: Fridericia Bazzett (for historical purposes) Individual corrections Population based corrections Model based ANCOVA correction (Dmitrienko A, Smith B, “Repeated measures models analysis in the analysis of QT interval. Pharmaceutical Statistics, 2003, to appear) Averaging using at least 3 measurements recommended Issues: study timing, measurement methodology, positive control

19 Risk Management Plan Proactively identify safety issues as soon as possible Labeling (USPI and sometimes PPI) and monitoring spontaneous adverse events is usually adequate Key additional component: Physician and patient education Superiority over relying mainly on black box warnings Metrics to evaluate performance Sometimes establishes additional studies

20 Clinical Studies, Analyses and Components of Plan
Post marketing studies to investigate rare events Post marketing studies to assess safety in special populations not adequately studied in clinical studies Interaction studies to assess effects of administering contraindicated medications concurrently - clinical pharmacology studies with healthy volunteers Assessment of potential impact of off-label use Product naming, tamper proof packaging, counterfeit protection

21 III. Presentation of Integrated Safety Data
Context of Presentation Transparency, Consistency, Detail Data Reduction and Synthesis Graphical displays Descriptive versus inferential statistics

22 Context of Presentation of Safety Data
Degree of detail, sophistication of analysis and language used should be determined by target audience Regulatory Authorities for Approval Clinical Investigator Brochures Physician Education Patient Education Information Based Medicine Communication of risks is an important aspect of management

23 Data Reduction and Synthesis
Treatment Emergent Adverse Events Signal Detection (See Appendix: MedDRA) – large integrated database Incidence > 2% for treated patients and > 1% greater for treated patients than for placebo patients Simple and transparent Consistency with other TEAE signal detection criteria (relatedness, statistical significance) Adverse events within pre-specified clinically relevant clusters Incidence of selected serious events per patient year exposure across studies of various designs

24 Supportive Analyses of Selected Target
Further focus on selected target (for selected audiences) Related to study drug Severity - % patients with severe targeted event % targeted event classified as severe Incidence and prevalence by visit Concomitant medications taken for event

25 Presentation of Safety Data: Graphics
Typically, safety data are summarized in tabular forms by therapy groups Individual listing by subject One-page patient summary Graphical presentation of safety data can add value Kaplan-Meier curves commonly used to describe time to event data

26 Onset of Adverse Events
% of Occurrences Onset of AE by time of dose (hours) High dose is associated with an early onset of AE

27 Prevalence and Incidence of AE by Visit
AE decreases in frequency by visit, particularly for new occurrence.

28 Blood Pressure Change Over Time
Treatment decreases SBP, effect lasts 12 hours.

29 QTc Change vs Plasma Concentration
Lack of association between QTc change and serum concentration

30 Advantage of Graphical Analysis
Visual simplicity Describe the entire distribution of data, including outliers - Box plots Graphical summary of safety data is complimentary to tables and listings – use to illustrate most important features of data (observed patterns, lack of pattern)

31 Descriptive versus Inferential Statistics
Always present easily interpretable clinical summaries based on descriptive statistics (with basic statistical analyses such as Fisher’s exact test if appropriate) More sophisticated inferential statistical analyses are sometimes warranted (with appropriately large sample size - reduce type II error rate) Special safety studies Newly proposed QT pharmacology study Special laboratory analysis

32 IV. Multiplicity Issues Interpretation of Safety Data
Correction for multiplicity philosophy and strategy for efficacy and safety outcomes QTc Example, Hypothetical example Gate keeping strategy Assessment of safety in subgroups Multiplicity issues in meta analysis Multiplicity adjustments for tolerance and adverse events Identifying Optimal Treated Population References

33 Multiplicity adjustment philosophy
Dunnett C and Goldsmith C “When and how to do multiple comparisons”, in Statistics in the Pharmaceutical industry, Buncher and Tsai Eds, 1981, Marcel Decker Efficacy – often Safety – usually not Still need to ask the question Efficacy – always Safety – never Not correct When multiplicity adjustments are made for safety outcomes present both unadjusted and adjusted p-values – aids in synthesis (type II error still primary concern)

34 When? Usually not for standard safety data
More frequently for special safety data – pre-specified hypotheses in special safety studies – with adequate sample size to control type II error Determining factors Active versus placebo controlled Whether non-inferiority design Nature of outcome Phase of Study

35 Hypothetical example Special safety study undertaken due to non-clinical finding Regulatory agency and sponsor design a large study Primary endpoint main analysis (p>.5) Primary endpoint supportive analysis (p>.3) Secondary endpoints 2, 3 main analysis (p>.2) Secondary endpoint 2 supportive analysis (p>.3) Secondary endpoint 3 supportive analysis (p=.045)

36 Gate keeping strategy Dmintrinko A, Offen W and Westfall P (2003) ‘Gate keeping strategies for clinical trials that do not require all primary effects to be significant’, Statist Med, Specify a hierarchy of outcomes in the protocol and use a stage-wise testing strategy which controls the false error rate by the closed testing principle Main use is assessing secondary efficacy outcomes Is applicable in some special safety scenarios

37 QT example Many ways of analyzing one outcome; QTc
Multiplicity adjustments probably not appropriate, but multiple testing can result in false positives Synthesis is still needed Pre-specify a primary correction Present results based on all corrections in the same table Emphasize pre-specified primary correction and the method that fits the data best (Correlation with RR closest to 0) Give less emphasis to Bazzett (historical correction) – explain outliers due to large RR changes

38 Assessment of Safety in Subgroups
The correlation coefficients for test statistics for a single outcome in overlapping high (low) risk subgroups depends only on the sample sizes of the subgroups and the sample size of their intersection Moreover in these situations multivariate probabilities can be easily calculated Consequently model based multiplicity adjustments can be obtained to complement adjustments based on resampling

39 Multiplicity Considerations in Meta Analysis
Separate meta analyses should be performed based on study design and study duration Consistency of results across studies should be examined When meta analysis is performed in which not all studies contain all doses then a conservative test procedure based on direct comparisons is obtained when one includes study in the model and uses Dunnett’s test in SAS

40 Multiplicity adjustments for tolerance and adverse events
Novel Approaches for analyzing Clinical Safety/ Adverse event Data, Midwestern Biompharm Workshop, May 20, 2003 Devan Mehrotra organizer “Multiplicity considerations in evaluating safety in Clinical Trials”, Joe Heyse and Devan Mehrotra Active control setting 1. SAE 2. Pre-specified TEAE with expected high incidence 3. Remaining (multiplicity adjustment based on resampling and false discovery rate)

41 Identifying the optimal treated population
Therapy A and Therapy B are only treatments of a disease Populations A Therapy A superior B Therapy B superior E Both equally efficacious N Neither superior to placebo Goal: Subscribe therapy A to all population A patients and to no population B or N patients

42 Identifying the optimal treated population: strategies
Competitive non-inferiority for efficacy and superiority for selected TEAE Clinically relevant efficacy overall Clinically relevant efficacy in selected subgroups Diabetes, hypertension, hyperlipedemia Various indicators of less severe disease Competitive non-inferiority for efficacy and superiority for selected TEAE in selected subgroups

43 Conclusion Recent guidelines will help ensure patient safety, especially with respect to hepatotoxicity and QT interval prolongation Risk management occurs throughout a product’s life cycle and involves the effective communication of risks Special safety data should be analyzed and interpreted differently than standard safety data, including multiplicity considerations

44 Joint assessment of safety and efficacy: references
Bryant J and Day R (1995) ‘Incorporating toxicity considerations into the design of two-stage phase II trials, Biometrics, Jennison C and Turnbull B (1993), ‘Group sequential tests for bivariate response: interim analyses of clinical trials with both safety and efficacy endpoints, Biometrics, Letierce A, Tubert-Bitter P, Kramar A and Maccario J (2003) ‘Two treatment comparison based on joint toxicity and efficacy ordered alternatives in cancer trials’ Statist Med,

45 Identifying the optimal treated population: references
Bristol D, ‘p-value adjustments for subgroup analyses’, J Biopharm Stat, 1997, Byar D and Corle R,’Selecting optimal treatments in clinical trials using covariate information’, J Chron Dis, 1977, Gail M and Simon R, ‘Testing for quantitative interactions between treatment effects and patient subsets’ JASA, 1985, Koch GG, Stuart A and Gansky MS, “Statistical considerations for multiplicity in confirmatory protocols, DIA J, 1996, Pocock S, Assmann S, Enos L and Kasten L (2002) ‘Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems, Stat Med,

46 V. Appendix: Assessing Safety during the phases of development
Non-clinical and Toxicology Studies Clinical Pharmacology Studies Clinical Studies Post Approval Studies Interconnectedness of phases Predominance of Safety

47 Pre-clinical and Toxicology Studies
Animal and Laboratory Studies Target Organ Toxicity Liver is a major target organ Target reaction QT prolongation – HERG assay study Consequences of findings End development, clinical hold, design special safely study, implement special monitoring (additional laboratory measurements, post marketing study/surveillance)

48 Standard Clinical Pharmacology Studies
PK and PD Studies characterize exposure (Cmax, tmax, half life, accumulation) Food effect study Alcohol effect study PK in special populations – hepatic, renal, elderly Interaction of therapy with concomitant medications which inhibit or induce enzymes involved in metabolism Objective - characterize maximum exposure (increased toxicity) Objective - characterize minimum exposure (lack of efficacy)

49 Clinical Pharmacology Studies with Safety Outcomes
Effects on safety outcome (adverse event, laboratory analyte,vital sign) Aspirin interaction study– Bleeding time- Healthy volunteers Antihypertensive medication interaction study – Blood pressure outliers Exercise tolerance – Patients with stable angina

50 Clinical Pharmacology Studies under Extreme Conditions
Super-therapeutic dose –signal detection Healthy volunteers, no need to match target disease population Interpret in relation to phase 2/3 studies Additional clinical pharmacology studies under less extreme conditions may be useful

51 Clinical Studies Prior to Approval Reference
Gait JE, Smith S and Brown S, “Evaluation of safety data from controlled clinical trials: the clinical principles explained”, DIA Journal, Vol 34, , 2000. Disposition Exposure Adverse events: SAE, discontinuations due to AE, treatment emergent adverse events (TEAE) Laboratory safety data Safety profile for patients with targeted TEAE versus without

52 Adverse Events: MedDRA (new standard)
MedDRA ,a hierarchical dictionary which combines features of several dictionaries, is superior to COSTART which has inadequate specificity – actual term, LT, PT, HLT, HLGT, SOC Requires adequate site training for actual term recording Review of coding hierarchy relevant to each therapeutic area (TA) for subtleties in hierarchy Sometimes coding is too specific for required purpose and TA specific clustering required Regularly updated – logistical challenges (integration) A listing of all TEAE sorted by preferred term is helpful (in addition to sorted by patient)

53 Adverse Event Analysis References
1996 FDA/Industry Workshop, 1996 Biopharmaceutical Report, Vol 4, No 3 1996 Biopharmaceutical Report, Vol 4, No 2, B Northington, ‘A review of issues in the collection and reporting of adverse events’ and L Tremmel ‘Describing Risk in Long-Term Clinical Trials’ O'Neil R “Statistical analysis of adverse events from clinical trials, with emphasis to serious adverse events’ Drug Inf J, 1987, 9-20

54 Post Approval Data Types of Studies
Spontaneous Adverse Event Reporting Case Series Analysis, Registry for rare events Case Crossover Study -Within patient analysis based on exposure status while experiencing a targeted event relative to overall extent of exposure (Encyclopedia of Biostatistics, Wiley; Pharmacoepidemiology, Overview) Post marketing regulatory commitments dictated from results of earlier phases Other post-marketing studies - useful safety assessment in real world clinical practice (even when not primary objective)

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