Transcript Slide 1

SAFETY PHARMACOLOGY:
Opportunities and Expectations
8th Annual
Safety Pharmacology Society Meeting
Madison, Wisconsin
September 24, 2008
Peter K.S. Siegl, Ph.D.
Siegl Pharma Consulting LLC
[email protected]
Safety Pharmacology 1979
“The adverse drug reactions which the standard toxicological test
procedures do not aspire to recognize include most of the functional
side-effects. Clinical experience indicates, however, that these are
much more frequent than the toxic reactions due to morphological
and biochemical lesions…”
Gerhard Zbinden, 1979 Pharmacol Methods in Toxicology
Opportunities/Expectations
• Nonclinical studies to identify pharmacological activities of drug
candidate that increase risk of adverse drug reactions in patients.
• Complement toxicology studies.
• Improve clinical safety and reduce attrition of drug candidates.
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ICH Guideline M3, 1997
“Safety pharmacology includes the assessment of effects on vital
functions, such as cardiovascular, central nervous system and
respiratory systems, and these should be evaluated prior to human
exposure.”
ICH M3: Nonclinical safety studies for the conduct of human
clinical trials for pharmaceuticals. (July 1997)
Opportunities/Expectations
Value of safety pharmacology acknowledged by regulators and
sponsors.
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ICH Guideline S6, 1997
“[Safety pharmacology studies] .. investigate the potential for
undesirable pharmacological activity in appropriate animal models
and, where necessary, to incorporate particular monitoring for these
activities in the toxicity studies and/or clinical studies.”
“.. these studies may allow for a mechanistically-based explanation
of specific organ toxicities, which should be considered carefully
with respect to human use and indication(s).”
ICH S6 “Preclinical Safety Evaluation of Biotechnology-Derived
Pharmaceuticals” (July 1997)
Opportunities/Expectations
Pharmacological activity in animals should be considered in
toxicology and clinical studies.
Mechanism-based understanding of toxicities (or pharmacological
activities) should be carefully considered in the risk assessment.
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ICH Guideline S7A, 2001
“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 S7A “Safety Pharmacology Studies for Human
Pharmaceuticals” (July 2001)
Opportunity/Expectation
Safety pharmacology studies have the potential to reduce use of
animals and other resources.
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ICH Guideline S7B, 2005
“The study results can be used to elucidate the mechanism of action
and, when considered with other information, estimate risk for
delayed ventricular repolarization and QT interval prolongation in
humans.”
ICH S7B: Nonclinical Evaluation of the Potential for Delayed Ventricular
Repolarization (QT Interval Prolongation) by Human Pharmaceuticals
(October 2005)
Opportunities/Expectations
Mechanism of action can be a goal of studies.
Use data with other data to estimate risk for QT prolongation in
humans.
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Safety Pharmacology: Roadmap from ICH Guidelines
Improve clinical safety and reduce attrition of drug candidates
• Identify pharmacological activities of drug candidates that could increase
risk of adverse drug reactions in patients.
• Characterize safety pharmacological activity
• Relative potency
• Mechanism of action
• Compare to reference drugs with clinical experience.
• Include all data (safety pharmacology, toxicology, metabolism and
clinical) in risk assessment.
• Estimate risk for AE in humans.
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Scientific approach encouraged in guidelines
Animal safety studies and human clinical trials should be planned
and designed to represent an approach that is scientifically and
ethically appropriate for the pharmaceutical under development. (M3 )
It is important to adopt a rational approach when selecting and
conducting safety pharmacology studies. The specific studies that
should be conducted and their design will vary based on the
individual properties and intended uses of the pharmaceuticals. (S7A)
The investigational approach and evidence of risk should be
individualized for the test substance, depending on its
pharmacodynamic, pharmacokinetic, and safety profiles. (S7B)
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Lessons from ICH S7B and Assessing
Risk for QT Interval Prolongation.
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Opportunity: Risk factor = molecular mechanism
Continuous
ECG tracing
Long QT syndromes (1)
Two components of cardiac delayed rectifier K+ current (2)
Genetic linkage analysis and long QT syndrome (3)
Drug-induced prolongation of the QT interval (4)
1. Schwartz et al. Am Heart J 1975;89:378-390
2. Sanguinetti & Jurkiewicz, 1990;J. Gen. Physiol. 96:195 -215.
3. Keating M. Circulation 1992; 85:1973-1986.
4. Roden D, NEJM 2004; 350: 1013-1022.
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Drugs Removed From Market
Associated with Cardiac Arrhythmia: Torsade de Pointes
Prenylamine (Anti-anginal)
Terodiline (Urinary incontinence)
Sparfloxacin (Antibiotic)
Sertindole (Antipsychotic)
Terfenadine (Antihistamine)
Astemizole (Antihistamine)
Grepafloxacin (Antibiotic)
Cisapride (Gastro-esophageal reflux)
Droperidol (Schizophrenia)
Levacetylmethadol (Opiate addiction)
1989 (UK)
1991 (UK, US)
1996 (US)
1998 (UK)
1998 (US)
1999 (US)
1999 (UK, US)
2000 (UK, US)
2001 (UK, US)
2003 (UK)
Turner JR and Durham TA, Integrated Cardiac Safety: Assessment methodologies for noncardiac drugs
in discovery, development, and postmarketing surveillance.
Copyright © 2009 by John Wiley & Sons, Inc., All Rights Reserved
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DRUGS WITH RISK FOR WITH TORSADE DE POINTES
IKr Inhibition
Delayed
Ventricular
Repolarization
QT/QTc Prolongation
ADDITIONAL RISK FACTORS
Arrhythmia
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QT is unique
QT is first case where we have:
• A molecular mechanism for a pharmacologicallymediated risk factor.
• Positive and negative reference drugs with clinical
outcomes.
• A regulatory-guided clinical assay (ICH E14) to validate
nonclinical risk assessment (for QT/QTc interval
prolongation).
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Evolution of QT/ TdP Testing
Eliminate risk of Torsade de Pointes (TdP) by screening for compounds
that inhibit IKr (hERG).
Many compounds interact with hERG protein – margins and importance
of PK/PD relationships
Improved methodology for data capture and analysis
QT interval is imperfect index of ventricular repolarization
HR correction can be source of error
Autonomic nervous system influences
Multi-channel activity
E14 TQT assay – false positives
Not all QT prolonging drugs have the same risk for TdP
TRIaD (Hondeghen)
Instability (Vos, Fossa)
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DRUGS WITH RISK FOR WITH TORSADE DE POINTES
IKr Inhibition
Delayed
Ventricular
Repolarization
QT/QTc Prolongation
ADDITIONAL RISK FACTORS
Arrhythmia
• Do all IKr blockers have equal risk for arrhythmia?
• Does QT Interval prolongation always reflect delayed repolarization?
• Does QT Interval prolongation always have similar proarrhythmic risk?
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DRUGS WITH RISK FOR WITH TORSADE DE POINTES
IKr Inhibition
Delayed
Ventricular
Repolarization
QT/QTc Prolongation
ADDITIONAL RISK FACTORS
Arrhythmia
IKr inhibitory potency:
can help predict risk of QT/QTc prolongation.
is not a biomarker for Torsade de Pointes.
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What Does the Future Look Like?
Safety Pharmacology
Characterizing potent toxicity of drug candidate is
usually straight forward.
The real challenge is to determine and document if a
drug candidate with potentially adverse activity is
safe in broad patient populations.
Often Safety Pharmacology findings by themselves do
not represent a risk but may be clinically important
in a small subset of patients when combined with
multiple additional risk factors.
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ILLUMINATE Data, redrawn from Figure 1, N Eng J Med 356:1304 – 16, 2007
Hypothetical distributions of blood pressure patients
Relative Frequency
Atorvastatin: N(1, 8); Both: N(5, 9)
Atorvastatin
only
Torcetrapib &
Atorvastatin
-20
-15
-10
-5
0
5
10
15
20
Change in Systolic Blood Pressure (mm Hg)
(Credit: John Szumiloski)
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Case study: Torcetrapib blood pressure effects
Summary of Nonclinical Studies
• Increase in blood pressure is observed in nonclinical
and clinical assays.
• Mechanism:
• The blood pressure effect is not due to primary
mechanism of action (CETP inhibition).
• Adrenalectomy in animals prevents the blood
pressure response.
• Competitor drug candidates without blood pressure
effects.
Forrest et al., British J Pharmacol. 2008
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Risk or No Risk?
FDA updates boxed warning for GlaxoSmithKline's
Avandia (November 14, 2007)
•
“A meta-analysis of 42 clinical studies … showed Avandia to be associated
with an increased risk of myocardial ischemic events such as angina or
myocardial infarction."
•
The updated labeling also indicates that other studies of the product have
"not confirmed or excluded this risk" and "in their entirety, the available data
on the risk of myocardial ischemia are inconclusive."
•
The FDA stated it has concluded that there is not enough evidence to
"indicate that the risks of heart attacks or death are different between
Avandia and some other oral type 2 diabetes treatments."
•
The regulatory agency has requested that GlaxoSmithKline conduct a new
long-term study in an effort to evaluate the potential cardiovascular risk of
Avandia compared with an active control agent.
Results expected in 2014.
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Opportunity?
July 02, 2008
US panel recommends cardiovascular studies for diabetes drugs
An FDA advisory panel voted 14-2 in favor of recommending that
drugmakers be required to conduct long-term studies examining the
cardiovascular risks for all new diabetes drugs.
“The FDA already has to decide whether the safety database of a
drug in the approval application is sufficient to rule out harm. But the
committee is now recommending we should have more data to do
this and an unacceptably high risk needs to be ruled out before
approval. This approach could also well be applied to drugs in other
classes such as the NSAIDs.”
FDA official Dr. John Jenkins
Reference: Heartwire (http://www.theheart.org/article/879839.do)
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FDA Critical Path = Opportunity
“The first Critical Path paper, published in March 2004, was intended
as a wake-up call to all stakeholders: that without significant
investment in development science, our ability to evaluate and
predict product performance would continue to be quite limited, and
the path to market and beyond, fraught with problems”
“The public and private sectors have made massive investments in
basic biomedical research over the past three decades. At the same
time, investment in development science, or what we call “regulatory
science,” needed to predict and evaluate product performance, has
lagged significantly.”
Janet Woodcock Aug 17, 2007.
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Opportunities for Safety Pharmacology
Public Watch Dogs: Flushing out potential safety issues
with new and marketed drugs.
Critical Path:
Advancing “development science”.
FDA (and public):
Asking for more information in safety
data base before approvals.
Guidelines:
Encouraging scientific approach.
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Leverage Science with Technology
“Unfortunately, much of current drug invention is driven
by an obsession with technology such that techniques
have taken the place of looking for drug ideas rather
than the reverse.”
Sir James Black,
Safety Pharmacology Society:
7th Annual Meeting
19 – 20 September 2007, Edinburgh, UK
Ref: Icilio Cavero, Expert Opin. Drug Saf. (2008) 7(1):91-100
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Safety Pharmacology: Roadmap from ICH Guidelines
Improve clinical safety and reduce attrition of drug candidates
• Identify pharmacological activities of drug candidates that could increase
risk of adverse drug reactions in patients.
• Characterize safety pharmacological activity
• Relative potency
• Mechanism of action
• Compare to reference drugs with clinical experience.
• Include all data in risk assessment (safety pharmacology, toxicology,
metabolism and clinical).
• Estimate risk for AE in humans.
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Parting Editorial Comments
Most commonly asked questions:
• How can we move more drug candidates through
development faster and use fewer resources?
• What do we have to do to get into man?
• Will these results be good enough to satisfy the FDA?
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Parting Editorial Comments
Most commonly asked questions:
• How can we move more drug candidates through
development faster and use fewer resources?
• What do we have to do to get into man?
• Will these results be good enough to satisfy the FDA?
Drug development should not be an obstacle course
of hurtles set by regulatory expectations.
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Parting Editorial Comments
Most commonly asked questions:
• How can we move more drug candidates through
development faster and use fewer resources?
• What do we have to do to get into man?
• Will these results be good enough to satisfy the FDA?
Drug development should not be an obstacle course
of hurtles set by regulatory expectations.
When approached as a rational-based endeavor
supported by sound scientific principles, drug
development will have the greatest probability of
providing maximum benefit to patients.
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THANK YOU FOR YOUR KIND ATTENTION,
VALUDED FELLOWSHIP
AND MANY COLLABORATIONS!
Safety Pharmacology Society
ROCKS!
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SAFETY PHARMACOLOGY:
Opportunities and Expectations
8th Annual
Safety Pharmacology Society Meeting
Madison, Wisconsin
September 24, 2008
Peter K.S. Siegl, Ph.D.
Siegl Pharma Consulting LLC
[email protected]