Safety Pharmacology for Oncology Pharmaceuticals at CDER

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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 BiologicsICH 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 S9Draft 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 StatusSafety 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?