Transcript Why Combine Sph and Tox Studies

Safety Pharmacology Endpoints: Integration into Toxicology Studies
Combining Large Animal IND Enabling
Toxicology and CV Sph Studies- PRO
Marc Bailie DVM, PhD
Director In Vivo Facility Michigan State University,
Chief Development Officer Integrated Nonclinical Development
Solutions (INDS) Inc.
Preface to the Discussion
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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.
Why Combine Sph and Tox Studies
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 preclinicalclinical 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 decisionmaking by better understanding of the
translation of the preclinical signals to
humans.
Why Combine Sph and Tox Studies
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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)
How to Effectively Combine Sph and Tox Studies
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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)
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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
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Address known histologic changes
Address possible confounding effects on the CV endpoints
“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