1. FDA’s Public Workshop: Innovative Systems for Delivery of Drugs and Biologics: Scientific, Clinical, and Regulatory Challenges Paul Goldfarb, MD, FACS Oncology Associates San Diego, CA July 8, 2003

2. Surgeon’s Perspective  There is a pressing clinical need to develop new techniques to control localized disease, which will be less invasive and more protective of normal tissues than standard surgical approaches.  The rapid adoption of thermal ablation, targeted radionuclides, hyperthermia, embolic agents and cryosurgery reflects the interest of both patients and clinicians in achieving these goals.  Drug-device combinations as novel drug delivery systems provide the potential to enhance effectiveness, and reduce adverse events with intra-tumoral delivery.

3.  Targeted Sites: – Brain – Lung – Liver – Kidney – Pancreas – Limb – Bladder – GI Tract – Head & Neck – Breast – Prostate Focused Tumor Ablation Utilizing Combination Drug/Delivery Systems  High local drug concentrations  Low systemic exposure  Equivalent to ablative therapies in preserving normal tissues

4. Innovative Drug/Device Combination Products Under Investigation  FeRx Incorporated –Intra-tumoral drug delivery of doxorubicin using Magnetic Targeted Carriers  Genetronics –Intra-tumoral drug delivery of bleomycin using electroporation  Site-Specific Drug Delivery in Both Systems: –Utilize well characterized drugs with known safety profiles –Deliver drug to a localized area with minimal systemic exposure –Utilize novel devices to deliver the drug –Have an ablative effect that is confined to the area of drug delivery and affects malignant tissues independent of histology demonstrating a clinical benefit analogous to thermal ablation.

5. The Issues –  The regulatory pathway and standards are inappropriate for the perceived clinical benefit.  CDER is the lead review agency for both of these combination products.  No other product that has a localized ablation effect at the disease site has been required to do such extensive testing.  The drug components of these combination products: –have been approved and used clinically for decades –have safety profiles that are well characterized –have extensive scientific and medical literature supporting multiple therapeutic applications –are being developed for reduced therapeutic doses of drug –have minimal systemic exposure  Both of these products which have a local effect are currently held to the same evidentiary standards and regulatory burdens of new drugs having a systemic effect.

6. FeRx Incorporated  FeRx is conducting a Phase III study of 240 patients with hepatocellular carcinoma (HCC) comparing their local therapy (MTC-DOX) to systemic chemotherapy (IV DOX) in patients with end-stage disease with a survival endpoint.  Phase I/II studies demonstrated efficient tumor targeting using MTC-DOX resulting in: –Durable local disease control –New dosing paradigm Shift from traditional drug dosing (body weight or surface area) to dose based upon cross sectional area of tumor – analogous to other local therapiesShift from traditional drug dosing (body weight or surface area) to dose based upon cross sectional area of tumor – analogous to other local therapies  New Treatment Paradigms –Role of ablation is a bridge to liver transplant –Stabilization of disease is a clinically relevant end point

7. MTC-DOX Targeting Efficiency in HCC Patients Post Tx Angiogram Vessels patent Post Tx MRI MTC-DOX well localized

8. Local Tx for Liver Metastases Using MTC-DOX Pre TxPost Tx Breast Cancer 67% Reduction of Metabolic Activity Bladder Cancer 58% Reduction of Metabolic Activity

9. Genetronics  GENETRONICS was in a study of advanced head and neck cancer trying to demonstrate that the use of their local system would improve the survival of patients receiving systemic chemotherapy. With the assistance of the combination products office and in negotiation with CDER, the study was changed to one in which patients with early recurrence will have either ablation or surgery and the endpoint will be improved function with local control, which is no worse than surgery.

10. Electroporation Technology

11. Summary  Both of these products are subject to review standards typically applied to novel drugs that act systemically (e.g., large numbers of patients and survival endpoint).  Device products that have been approved for local ablation type effects have not been subjected to such extensive clinical data requirements. Given that the safety profiles of both drugs are well characterized and there is minimal systemic exposure, requirements for approval should be comparable to devices that have an ablation effect.  Both products are innovative device/drug combinations that utilize a new route of administration for old drugs (drugs formerly administered intravenously) and should have reduced time in clinical development, and reduced evidentiary requirements.

12. Recommendations  New therapies need to be compared to other therapies that have a similar effect on the patient.  Therapies which are local, regional, or systemic in their effects should be compared to therapies with a like effect, regardless of which division is assigned the lead review; Device, Drug or Biologic.  To expedite the review and approval of innovative devices for the delivery of known drugs, the evidentiary standards must be appropriate to the potential risk/benefit to the cancer patient.  We need to implement new regulatory pathways and least burdensome principles for innovative technologies that allows for rapid market entry for patient benefit.