Opening remarks from the Chair

A detailed analysis of the latest developments in the E14 clinical guidelines

• How the industry should read the ICH E14 paper
• The effect of these guidelines on the industry as a whole
• What are the subsequent requirements for drug development?

Nonclinical guidelines: What are the requirements from regulatory bodies?

• ICH S7A and ICH S7B Guideline
• Selection and Design of Studies
• Nonclinical Testing Strategy
• Which Relevant Nonclinical follow-up Studies are needed?
• The Role of Nonclinical Study Results

QT prolongation risk assessment and New ICHS7B guidelines: Impacts on Preclinical testing

• Re-assessing the effects of the international S7B guidelines on risk assessment and pre-clinical testing
• A critical look at how satisfactory non-clinical testing can diminish the need for extensive clinical testings
• Bringing into focus the impact of these new guidelines on the market and industry as a whole

Coffee and tea break

Review of the preclinical assays available to detect changes in QT

• A description of the inter-relationship of in vitro and in vivo assays with a particular emphasis on understanding concentration response relationships
• A comparison will be made of effects on the QT interval observed in pre-clinical and clinical studies
• Recommendations on how to integrate pre-clinical and clinical data will be made

Panel includes:

Rob Wallis
Executive Director
Head Global Safety Pharmacology
PFIZER

Klaus Olejniczak
Pre-clinical Pharmacology and Toxicology Division
BFARM
Member
ICH S7B WORKING GROUP

Panel Discussion:

Pros and cons of the E14 regulatory guidelines - debating the preclinical and clinical issues

• What the industry has to do to get drugs exempt
• Data collection: how to interpret results
• How are the FDA implementing the guidelines?

Understanding the primary points of ‘Thorough QT studies’

• What constitutes a thorough QT trial?
• How to optimise the studies
• The timing and planning of a thorough QT trial

Integrating cardiac safety assessments into a new product development strategy - knowing what to do and when

• How to meet safety assessment needs
• How to obtain enough information to do the most expensive work properly
• Meeting global regulatory cardiac safety assessments: which studies when?

QT/RR relationship in clinical data

• Strategies for heart rate correction of QT interval
• Design of individual-specific QTc correction formulae
• QT/RR dynamicity and achieving stable QT/RR data-points
• Handling of QT/RR hysteresis

Coffee and tea break

Data stability and implications for cost of thorough QT studies

• Implications of ECG measurement options on individual QTc variability
• Maximising data stability
• Design of time-points of thorough QT studies
• Sample size and cost implications

Manual vs. semi-automated analysis of ECG data

• What are the methods of data analysis?
• Major problems in terms of statistical analysis and clinical interpretations of data
• Defining manual data: measurements of QT intervals

End of Day one

Drinks Reception

Opening remarks from the Chair

Pro-arrhythmic Animal Models: From healthy animal to predisposed patient- implications for drug safety testing

• An overview on available in-vivo / ex-vivo animal models and biomarkers for proarrhythmicity
• Their relevance to human patients
• Their limitations and application in cardiac safety evaluation

Analysis of dynamic beat-to-beat QT interval through restitution

(QT-TQ interval relationship) to potentially predict arrhythmogenic risk

• Description and analysis of dynamic beat-to-beat data
• Theoretical use for assessment of increased risk of arrhythmia
• Methods for modeling restitution and hysteresis in dynamic beat-to-beat QT-TQ interval relations

Lability of Repolarisation: experimental and clinical studies

• A summary of preclinical studies
• Beat-to-beat variability of repolarisation determines the proarrhythmic outcome
• Advances in clinical assessment of repolarisation lability: Drug-induced TdP, Congenital long-QT syndrome and Sudden Cardiac Death
• QT prolongation can be pro- and anti-arrhythmic: Lability of repolarisation controls onset of TdP
• Antiarrhythmic screening - Lability stabilizers.

Best Practices for Cardiac Safety Analysis

• Impact of increased ECG data requirements on sponsor and provider (Implications from ICH E14 Step 4)
• Industry trends - Thorough QT study experience and best practices
• Strategies for planning, logistics, and operations of Thorough QT study
• Advantages and disadvantages of ECG analytical methodologies and business models

Case Study: Practical aspects of implementation of E14

• ECG capture
• Protocol Design
• Positive Control
• Logistical issues

The genetic background of abnormal QT prolongation and torsades de pointes: will it be possible to predict susceptibility of patients in the future?

• Rare genetic variants as human model disease
• Common genetic variants in candidate genes affect QT interval in the general population – increased risk for induceable LQT?
• From single SNPs to whole genome scans – a potential for risk stratification?
• Drug challenge to assess repolarization reserve – genetic aspects

Cellular mechanisms of repolarisation and arrhythmia disorders in humans

• Basic principles of repolarization
• Acquired or genetic condition with altered repolarization
• Target components (ion channels): structure-function relationships

Statistical analysis following from the new ICH E14 guideline

• A non technical view of the statistics
• Sample size implications
• Study design issues:
• How many time points?
• How many time points pre-baseline?
• How many replications?

Closing remarks from the chair

End of day two, Champagne prize draw & End of Conference