# Presentation: 479477

## Use of New Tools for Safety Analysis

- Chuck Cooper, M.D.
- Clinical Reviewer
- Division of Biometrics VI
- Office of Biostatistics
- CDER, FDA

## Disclaimer	

- The views and opinions presented here are those of the presenter and must not be taken to represent guidance or policy on behalf of the Food and Drug Administration.

## Outline

- Introduction
- New Standards
- Standards vs. tools
- Challenges to successful completion of safety reviews
- Current Process for Safety Review
- Example: liver toxicity
- New Review Tools
- Summary

## Introduction

- New standards for Safety Review have been established
- Clinical Review Template – Safety Section
- annotated
- Good Review Practices
- Review Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, February 2005
- 84 pages

## New Standards for Safety Review (1)

- Deaths
- Overall mortality
- Cause specific
- Expected vs unexpected
- Dose response
- Time to death analysis
- Subgroup analysis
- Interaction analysis
- SAEs
- Overall rates
- Rates by event
- Dose response
- By duration of exposure
- By person-time exposure as denominator
- Assessment according to alternative explanation
- Assessment of interaction by subgroup
- Dropouts and other SAEs
- Overall rates
- Profile of dropouts (by reason)
- AEs associated with Dropouts
- Exposure response
- Time dependency
- Other significant AEs as defined by ICH
- Marked lab abnormalities
- Any AE leading to dropout or intervention
- Potentially important abnormalities not meeting above definition
- Construct of algorithms of combo’s of clinical findings
- Identify possible combinations of clinical findings that may be a marker for a particular toxicity

- Identify possible consequences of a safety signal from any source
- Common AEs
- Incidence for subsets -controlled studies
- LLT’s should be compared to mapped PT’s
- Assess for causality
- Comparison of severity between treatment arms
- Dose dependency for AEs
- Titration studies
- Time to onset for AEs
- Particularly for events that occur commonly
- AE incidence by interaction
- demographic
- race, gender, age
- Drug-drug interaction
- Underlying medical problems such as DM or renal disease
- Dose response
- body weight-adjustted dose
- cumulative dose
- Body surface area-adjusted dose
- dosing schedule
- Exposure adjusted event rates “person-time approach”
- When hazard rate is constant over time
- Break observation period into intervals

## New Standards for Safety Review (2)

- AE incidence by interaction (cont.)
- Relative risks and attributable risks for subgroup differences
- Life table/ time-to-event analyses/ cumulative incidence anlayses
- Hazard rates – risk over time estimation
- Less common AEs
- Identify and group by body system for rates
- Laboratories
- Overview of testing methodology
- Analysis of measures of central tendency
- Analysis of outliers or shifts to abnormal
- Marked outliters and dropouts due to lab abn
- Dose dependency
- Time dependency
- Demographic interactions
- Drug-drug interactions
- Underlying medical condition interactions
- Special section on Liver laboratory abn
- Shift tables
- Scatter plots
- Box plots
- Cumulative distribution displays
- Tables of deviation in >1 parameter
- Vital signs
- Overview of testing
- Analysis of measures of central tendency
- Analysis of outliers or shifts to abnormal
- Marked outliters and dropouts due to lab abn
- ECG’s
- Describe baseline and number of on-study ECGs
- Analysis of measures of central tendency
- Analysis of outliers or shifts to abnormal
- Marked outliters and dropouts due to lab abn

- Immunogenicity
- Summarize and assess available data
- Carcinogenicity
- Summarize and assess
- Special Safety Studies
- Summarize any such studies
- Similar to other drugs in pharmacological class?
- Studies on cumulative irritancy, sensitizing potential
- Photosensitivity, photoallergenicity
- Special Thorough QT study
- To be done on all NMEs
- Studies to demonstrate a safety advantage over existing therapeutics
- Withdrawal phenomenon or Abuse potential
- Reivew/summary of relevant studies
- Scheduling recommendations
- Human Repro and Pregnancy data
- Assessment of Effect on Growth
- Overdose Experience
- Post-marketing experience
- Causality determination
- Adequacy of patient exposure and Safety assessments
- Refer to ICH
- Adequate numbers of various demogrpahic subsets
- Doses and durations of exposrue were adequate to assess safety for intended use
- Were study designs adequate to answer critical questions
- Were potential class effects evaluated
- Did patient exclusions from studies limit relevance of satey assessments
- Review of secondary clinical data sources
- IND data
- Post-marketing data
- Literature reports

## New Standards for Safety Review (3)

- Additional Clinical Issues
- Level of confidence for dose/regimen
- Dose-toxicity and dose response relationships
- Dose modification for special populations
- General assessment of adequacy of Special Animal and/or In Vitro testing
- Pre-clinical animal models
- QT studies
- Adequacy of routine clinical testing
- Labs, vital signs, ECGs, assessment of certain events
- Adequacy of metabolic, clearance, and interaction workup
- P450 and p-glycoprotien pathways
- Other drug-drug interaction studies
- Specify potential safety consequences
- Adequacy of evaluation for potentially problematic AEs that might be expected for a new drug
- Assess adequacy and note pertinant negative findings (absences of findings)
- Assessment of Quality and completeness of data
- Generall overall assessment of the quality an dcompleteness of data with a description of the basis for this assessment
- Additional submissions, including safety update
- Particularly those submission whose data were not incorporated into the rest of the review

- Summary assessment of important identified adverse events
- Not important limitations of data and make conclusions
- General Methodology
- Discussion of general methodological issues
- Pooled data vs. individual study data
- Causality determination
- Exploration of predictive factors
- Plasma levels, duration of treatment, concom meds, concom illnesses, age, sex, race
- Special populations
- Pediatrics
- AC meeting
- Literature review
- Post-marketing Risk management plan
- Other relevant materials
- Result of consultations with DDMAC, ODS reviews, actual use and labeling comprehension studies, marketing studies
- Overall assessment
- Conclusions
- Recommendation (regulatory)
- Recommendations on post-marketing actions
- Risk management activity
- Include all such recommended activity with rationale
- Required phase 4 commitments
- Include the agreed upon studies, the timeline for submission, and basis for each phase 4 commitment
- Labeling review

## Standards Versus Tools	

- 21st Century Standards
- Represents the first big step
- But we are still using tools with limited capabilities
- JMP
- Excel
- The completion of such a review presents a significant challenge given the limitations of the available tools, time constraints and other responsibilities?
- Risk of missing a safety signal is increased

## Challenges to Successful Completion of A Safety Review	

- Non-standard formats
- Reviewers have to learn new variable names, data location, and data format for each submission
- Time intensive database management
- Dependant on user skill/ability
- Limitations of tools such as JMP or Excel
- Lack of audit trail when using JMP
- Doesn’t allow for continuity with intermittent use
- Difficulty understanding chronologic relationship of data
- Difficulty generating sub-group analyses
- Age, BMI, gender, concom. meds, SAE’s, severity, renal function, etc.
- Number of analyses limited by time constraints

## Other Challenges 

- Difficulty identifying potential safety signals
- Inability to quickly and easily review data from multiple sources at the same time
- Statistical resources
- Majority of review time spent analyzing data instead of interpreting and understanding results of data analyses

## Example: Liver Toxicity

- What are some of the methods that are currently used to assess this?

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## Unanswered Questions	

- Which patients are included?
- What concomitant medications were used?
- Did anyone experience a serious adverse event (SAE)?
- What additional laboratory measures were obtained, eg.,serologies, liver biopsy?
- Did this adverse event (AE) lead to discontinuation from study treatment and/or the study?
- Were there pre-disposing baseline factors that might impact the patient’s outcomes?
- What is final status of the patient when last observed: resolved (return to baseline) or unresolved?

## How Do Medical Officers Currently Attempt to Answer these Questions?

- Explore data from datasets:
- Identify and understand patients with possible liver toxicity events
- Review their LFT’s
- Review their concomitant medications
- Review their past medical history
- Review Social History items such as ETOH use history
- Review recorded Adverse Events for possible related AEs
- Review demographic factors which could contribute
- How does a medical officer gather this information together for review?
- Medical Officers are clinicians
- No programming skills
- limited database management skills

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## End Result of Liver Toxicity Analysis

- Great deal of effort and time spent to assess only one SINGLE potential toxicity
- Sometimes it is still difficult to understand the chronologic relationship of all data
- Multivariable relationships are often difficult to explain
- Lack of documentation as to the analysis methods (no audit trail)
- High probability of making mistakes
- Tiring, tedious, and traumatic process
- Clearly, this process is inefficient

## Is there a Better Way?

- Standardized data helps to organize the review process
- FDA adopted data standards (July, 2004) as proposed by the Clinical Data Interchange Standards Consortium (CDISC)
- Standardized Data allow for development of Review Tools which, together, can generate expected analyses across applications
- Allows for more efficient and accurate data analysis and exploration
- Reviewers don’t have to recreate the same standard analyses for each new NDA since analyses are reusable
- Reviewers don’t have to relearn data formats and data location

## New Tools	

- FDA is evaluating several different tools for purposes of improving safety review
- Unlikely that a single tool will meet all needs
- Envision a review environment in which reviewers will have access to multiple different tools
- Two examples:
-  IReview (Integrated Clinical Systems, Inc.)
- WebSDM (Phase Forward, Inc.)

## IReview

- Intuitive, simple to use
- Allows for rapid data analysis and exploration
- Can create many of the standard safety analyses in a matter of minutes
- Analysis designs can be saved and re-used when using CDISC data
- Can run on CDISC data or non-CDISC data
- Re-use of analysis designs with CDISC data

## Examples of IReview-generated Analyses

- 3,542 CPK measurements were recorded during the study. In this table, each patient is counted only once per row (or per range category). For example, if a patient had more than one lab result in the 0 to 50 range, they were counted only once in that row.

## Examples of IReview-generated Analyses

- Rates of AEs by Body System and Treatment arm, age range

## Data Exploration

## Data Exploration

## Data Exploration

## Other Functions

## Many Other Functions

- Analyses can be shared easily between reviewers
- Multiple graphing capabilities
- Other data exploration browsers
- Statistical Analysis
- SAS Programs

## WebSDM

- Unique safety signal detection capabilities
- Sector Map Analysis
- Allows reviewers to focus their reviews
- Particularly helpful in settings where there is a lot of background noise
- Difficult to separate disease related events from drug-related events
- Also incorporates ability to explore potential safety signals quickly and efficiently
- Runs on CDISC data

## Sector Map Analysisof Adverse Events

- A Sector Map analysis is a graphical method for detecting differences  in adverse events rates between treatment groups
- The “map” is display of adverse events broken down into different sectors (rectangles)

## Sector Map Configuration

- The colors in the sector maps provide a “big picture” overview of differences in the rates of adverse events between the study drug and control
- Red signifies an increased rate of a particular AE in study drug
- Green signifies an increased rate in the control drug
- The intensity of the colors corresponds to the strength of the difference in rates (based on a Chi-square computation)

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## Patient Narrative can be inserted here.

## Conclusion	

- Current Methods are not efficient
- Use of Standardized data (CDISC) and new review tools (such as I-Review and WebSDM) provide the opportunity for more efficient, thorough, and complete safety reviews

## Acknowledgements

- George Rochester, PhD, Lead Statistician for Safety, Office of Biostatistics, FDA
- Ana Szarfman, MD, PhD, Medical Officer, Office of Biostatistics, FDA