Marc Bailie DVM, PhD Director In Vivo Facility Michigan State University,

Chief Development Officer Integrated Nonclinical Development Solutions (INDS) Inc.

Safety Pharmacology Endpoints: Integration into Toxicology Studies

Combining Large Animal IND Enabling Toxicology and CV Sph Studies- PRO

Preface to the Discussion Primary intent of GLP IND-enabling Sph study is to

characterize potential adverse CV pharmacology prior to human use

The study is also designed to fulfill regulatory requirements prior to FIH

This study should not be informing drug development decisions routinely. Too late in the process

ICH S7 Guidance provides for this type of study design

A. Objectives of S7A the Guidance (1.1) This guidance was developed to help protect

clinical trial participants and patients receiving marketed products from potential adverse effects of pharmaceuticals, while avoiding unnecessary use of animals and other resources.

ICH S7 Guidance provides for this type of study design

A. Objectives of Studies S7A (2.1) The objectives of safety pharmacology studies are

(1) to identify undesirable pharmacodynamic properties of a substance that may have relevance to its human safety, (2) to evaluate adverse pharmacodynamic and/or pathophysiological effects of a substance observed in toxicology and/or clinical studies, and (3) to investigate the mechanism of the adverse pharmacodynamic effects observed and/or suspected.

ICH S7 Guidance provides for this type of study design

A. Objectives of S7B Studies (2.1) The objectives of studies are to: (1) identify the

potential of a test substance and its metabolites to delay ventricular repolarization, and (2) relate the extent of delayed ventricular repolarization to the concentrations of a test substance and its metabolites.

Shortcoming Impact Solution?1. Lack of early detection of safety signals

‘Doomed’ compounds enter in vivo tox phase

Improve frontloaded screening: in silico and in vitro

2. Lack of detection of safety hazards preclinically

‘Doomed’ compounds enter clinical development

Improve quality and increase information content of safety pharmacology and toxicology studies

3. Lack of confidence/knowledge/ precision in preclinical-clinical translation

Defective risk assessment: ‘Doomed’ compounds may be let through, anticipating a large safety margin; ‘safe’ compounds may be stopped, anticipating an inadequate safety margin.

Improve risk assessment and decision-making by better understanding of the translation of the preclinical signals to humans.

Why Combine Sph and Tox Studies

Addresses three Rs When appropriately designed and controlled provide robust data in

compliance with ICH S7 Due to animal numbers sensitivity may be increased Allows for easy monitoring of multi-dose and metabolite effects Allows for definition of delayed/steady state effects on CV function Provides for a thorough characterization of “adaptive” (diminished or

enhanced effects over time) May allow for definition of physiologic correlates with histologic findings Financial savings??? (Up to the providers)

Why Combine Sph and Tox Studies

Overcome preconceived notion of what a quality Sph study is Use for IND enabling GLP Sph. where we are addressing a

regulatory/subject safety issue NOT “drug development” decision making!! That needs to be done earlier.

Give up Day 1 CV data. What do we actually lose??? Build the study so it is robust (appropriate conditions, environment,

sensitivity)– Complex so training and logistics need to be appropriately addressed– Thoroughly educate/train personnel in the conduct of the study

Educate Pathologists and Safety Pharmacologists about how to appropriately deal with/interpret combined data

– Address known histologic changes– Address possible confounding effects on the CV endpoints

How to Effectively Combine Sph and Tox Studies

“The most rewarding things you do in life are often the ones that look like they cannot be done." Arnold Palmer

“We cannot solve our problems with the same thinking we used when we created them.” Albert Einstein