PREDICTIVE SAFETY MODEL IN CLINICAL TRIALS – A SPOTFIRE CASE STUDY

Prem Narasimhan

Bristol Myers Squibb

Introduction • Current Environment

• Shifting through large volumes of data and glean knowledge from heterogeneous/multidimensional datasets, especially static and silo-ed.

• What are the Needs

• Need for interactive data visualization tools to improve the efficiency and effectiveness of their data review process.

• TIBCO Spotfire® value proposition for BMS

• Dynamic, interactive and capable of 360 degree data review. • Efficient identification of trends, patterns, and outliers and then seamlessly

engage in further exploration. • Spotfire has the ability to improve: the quality of data, the efficiency and

effectiveness of data review, the depth of understanding of the data and, most importantly, the safety of study patients.

Drug Development Process

Ph I: Healthy Volunteers to Determine Safety & Dose Ph II: Patient Volunteers to Efficacy & Side effects

Ph III: Used to Monitor Adverse Reactions to Long-Term use

Ph IV: Safety Surveillance

IND NDA

Drug Development Life Cycle

Objective

To characterize normal individuals safety parameter variability in Normal Healthy Volunteers (NHV) taking placebo in Phase-I clinical trials.

Current knowledge on NHV

1. Currently there are very few published studies of NHV receiving placebo from which to provide estimates of the variability of safety parameters.

2. Data to aid decision-making in early phase trials are limited. 3. Selected safety findings from early phase studies in NHV may

result in delay or termination. 4. Integrated 25 First-in-human (SAD/MAD) NHV placebo.

Questions addressed by the analysis?

What is the probability of selected safety events based on?

• Pre-determined criteria.

• Pre-treatment rates of selected safety events.

• Exposure-adjusted incidence rates.

What added to our knowledge?

• In an integrated analysis of NHV assigned to placebo, there were no safety concerns involving DILIs, ECGs, or SAEs/Deaths.

• Abnormalities in DBP were as noted

Future impact on clinical pharmacology and therapeutics? • Findings could help inform the evaluation of safety findings in future HNV

studies. • The inclusion and exclusion criteria for future studies in NHVs should be

carefully re-examined.

• Helps in analyzing safety parameters within a selected population of interest.

Home-Normal Health Volunteers

Demo NHV Spotfire Build

Studies included Normal Health Volunteers

Patient List of Normal Health Volunteers

Demographics of Normal Health Volunteers

Subject Characteristics of Normal Health Volunteers

AE Incidence in Normal Health Volunteers

AEs by Relatedness in Normal Health Volunteers

AEs by Severity/Intensity in Normal Health Volunteers

AEs by Relatedness (%) in in Normal Health Volunteers

Lab. Distribution in in Normal Health Volunteers

Labs. Over Time and Toxicity in Normal Health Volunteers

Labs. Over Time and Toxicity Box in Normal Health Volunteers

Labs. Over Time and Toxicity Waterfall in Normal Health Volunteers

eDISH Plot in Normal Health Volunteers (Evaluation of drug-induced serious hepatotoxicity)

EKG Waterfall in Normal Health Volunteers

EKG Box in Normal Health Volunteers

Filter Settings

adeg

- ECG Test or Examination: (QTC FRIDERICIA)

Vital Signs Waterfall in Normal Health Volunteers

Filter Settings

advs

- Vital Signs Test: (SYSTOLIC BLOOD PRESSURE)

adeg

- ECG Test or Examination: (QTC FRIDERICIA)

Vital Signs Box in Normal Health Volunteers

Benefits and Audience Takeaways

1. Safety parameters in Phase-I NHV studies can deviate from the normal range • possibly due to multiplicity of sampling and • fluctuations in normal physiology.

2. The safety parameter out-of-range findings in NHVs receiving placebo may

serve • as a reference to strengthen the basis for signal detection and • decision making during early drug development.

3. Inclusion and exclusion criteria for future studies should be re-examined with

these results in mind.

Key Points

1. First-in-human trials typically recruit normal healthy volunteers (NHVs) who are administered either placebo or investigational drug.

2. Safety parameters in clinical trials include pre-specified normal reference ranges for vital signs, physical examinations, electrocardiograms (ECGs) and laboratory tests.

3. Early phase studies can be terminated or interrupted due to select safety findings; however, deviation in safety parameters from normal reference ranges may not necessarily be pathologic or abnormal.

4. Careful interpretation of safety data is critical to decision making and future safety monitoring.

5. This tool could serve clinicians and PV&E group, as a fallback tool while planning.