Drug - Device Combination Issues : Oncology Perspective

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. 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 Chemistry Manufacturing and Controls

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

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