1. 1 Safety Pharmacology for Oncology Pharmaceuticals at CDER John K. Leighton Associate Director for Pharmacology CDER/OND/OODP

2. 2 Disclaimer The views expressed in this presentation do not necessarily reflect the views of the Food and Drug Administration

3. 3 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

4. 4 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.”

5. 5 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

6. 6 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).”

7. 7 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.”

8. 8 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.

9. 9 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

10. 10 Questions?

11. 11 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

12. 12 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?