Transcript Safety Pharmacology for Oncology Pharmaceuticals at CDER

Safety Pharmacology for
Oncology Pharmaceuticals at
CDER
John K. Leighton
Associate Director for Pharmacology
CDER/OND/OODP
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Disclaimer
The views expressed in this presentation do
not necessarily reflect the views of the
Food and Drug Administration
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Definitions
• Pharmaceutical – for the purpose of ICH S9, refers to
both oncology drug and biological products
– Pharmaceuticals for the treatment of active disease
• ICH S9 does not include
– Supportive care therapeutics
– Chemoprevention
– Risk reduction therapeutics
• IRT – Interdisciplinary Review Team
– In CDER consulted as needed for QT protocols and studies
• See MaPP 6020.14
• “cytotoxic” – pharmaceutical that targets rapidly dividing
cells of the bone marrow and GI as determined in
general toxicology studies
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Oncology Drugs
• Safety Pharmacology for “cytotoxics”
– Discussed in ICH S7A; published FR July,
2001
– “Safety pharmacology studies prior to the first
administration in humans may not be needed
for cytotoxic agents for treatment of end-stage
cancer patients. However, for cytotoxic agents
with novel mechanisms of action, there may
be value in conducting safety pharmacology
studies.”
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Oncology Drugs
• More recently: extended recommendations for safety
pharmacology studies to non cytotoxic drugs and
cytotoxic drugs with novel mechanism.
– Rationale:
• Major liabilities should be seen in screening assays and in general
toxicology observations
• Per ICH E14, a comprehensive QT assessment should be done in
patients
– A thorough QT study should be done if possible (rarely conducted in
practice)
• Considering the patient population, nonclinical findings will not
necessarily stop approval or development
• Mechanism of action usually plays little to no role in determining
need for safety pharmacology studies.
– Effects not usually related to mode of action
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Oncology Biologics
ICH S6
“It is important to 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. Safety pharmacology
studies measure functional indices of potential toxicity. These
functional indices may be investigated in separate studies or
incorporated in the design of toxicity studies. The aim of the safety
pharmacology studies should be to reveal any functional effects on
the major physiological systems (e.g., cardiovascular, respiratory,
renal, and central nervous systems). Investigations may also include
the use of isolated organs or other test systems not involving intact
animals. All of 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).”
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ICH S9
Draft Proposal
“An assessment of vital organ function, including
cardiovascular, respiratory and central nervous systems,
should be available before the initiation of clinical
studies; such parameters could be included in general
toxicology studies. Detailed clinical observations
following dosing and appropriate electrocardiographic
measurements in nonrodents are generally considered
sufficient. Conducting stand-alone safety pharmacology
studies to support studies in patients with advanced
cancer is not called for. In case of concern, appropriate
safety pharmacology studies described in ICH S7A
should be considered.”
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Current Status
Safety Pharmacology CDER OODP
• No need for hERG for Biologicals
• Safety pharmacology part of general toxicology
evaluation
– Primary concern is with nonclinical CV assessment
• Toxicities can be immediately life threatening
– Respiratory, CNS toxicities should also be noted
• Safety pharmacology studies may be useful to
understand risk identified in clinical studies.
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Case Studies
• Case 1:
– Unexplained sudden deaths seen in clinical trial
– Nonclinical safety pharmacology studies may be useful in assessing
drug toxicity (e.g., cardiac liability)
• Case 2:
– Drug identified through clinical monitoring as having QT liability
– Nonclinical safety pharmacology studies, including studies of
metabolites, will not likely contribute to the overall safety assessment
• Case 3:
– Potential signal identified in 1 of 5 animals in nonclinical study at dose
exceeding MTD – may or may not be drug related (e.g., related to
instrument or to condition of the animal)
• Consider half life of the drug relative to finding
– Adequate clinical monitoring is proposed
– Additional nonclinical study considered unnecessary
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Questions?
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Questions
• For the Safety Pharmacologists
– Will ICH S9 change the safety pharmacology
package you currently conduct?
– How do you decide what the package should
contain?
– What future trends do you see which could
positively or negatively impact the studies you
do for these oncolytics? As an example:
jackets for ECG abd BP in toxicology studies
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Questions
• For Clinicians and Regulators
– Overall, how do you see these changes to the
safety pharmacology packages impacting
you?
– Are you getting the safety pharmacology
information you need?
– What additional thing could the safety
pharmacology community provide which
would help you?
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