1. Drug - Device Combination Issues : Oncology Perspective Ramzi Dagher, M.D. DODP/CDER/FDA

2. Drug - Device Goals –optimize efficacy –limit toxicity Approaches in Oncology –hyperthermia –light activation –electroporation –novel delivery formulations

3. Multidisciplinary Challenges Multidisciplinary considerations when a drug is involved –regardless of ‘regulatory jurisdiction’ Disciplines –chemistry –pharm/tox –clinical pharmacology –clinical

4. Chemistry Manufacturing and Controls Drug Substance Subject of an approved NDA or ANDA Approved Source – Right of reference to NDA/ANDA New Molecular Entity (no NDA exists) Unapproved Source – DMF reference or Active IND exists – Reference to IND No active IND exists – Complete CMC information in DMF Drug Product Approved NDA or ANDA Active IND exists for the proposed formulation – Reference to IND No active IND exists – Complete CMC information should be provided

5. Critical CMC Issues Drug Substance Manufacturing Controls Specifications Stability Drug Product Components/Composition Manufacturing Controls Specifications Stability Sterility (parenteral products)

6. Toxicology isolation of drug versus device effects systemic versus local toxicity –requirements for systemic evaluation may be waived if already addressed

7. Clinical Pharmacology device effect on drug –PK, metabolism, elimination device itself –metabolized or eliminated systemic exposure to the drug

8. Clinical Patient populations Trial design –single arm, randomized Appropriate comparators –challenging when there are multiple interventions available but no clear standard –need to isolate contribution of the device to the treatment effect

9. Clinical Efficacy endpoints –depend on disease, stage –survival, time to progression, response, symptoms –should be evidence of clinical benefit Safety endpoints –NCI CTC grading system –deaths within a defined period of administration –length of followup important

10. Drug Combinations In oncology, many disease settings rely on –drug combinations –multiple modalities (surgery+chemo+radiation) –aggressive supportive care methods which include drugs, growth factors, transfusions

11. Drug Combinations Oncology drug labels usually refer to general supportive care measures and not specific products –exception for safety considerations Drug combinations approached differently

12. Example : Cisplatin Labels which include indications for use in combination with cisplatin for NSCLC –gemcitabine –paclitaxel –vinorelbine –docetaxel Cisplatin label does not refer to these combination uses

13. Cisplatin (continued) Safety concerns addressed by –individual labels provide information regarding safety profile, appropriate monitoring, and dose modification for both drugs in the combination –labels for cytotoxic drugs identify need for chemotherapy-experienced practitioners

14. Summary Multidisciplinary considerations when a drug is involved –regardless of ‘regulatory jurisdiction’ Focus of challenges depends on nature of device-drug approach and its effect on drug characteristics