FDA’s Public Workshop: Innovative Systems FDA’s Public Workshop: Innovative Systems for Delivery of Drugs and Biologics: for Delivery of Drugs and Biologics: Scientific, Clinical, and Regulatory Scientific, Clinical, and Regulatory

ChallengesChallenges

Paul Goldfarb, MD, FACSPaul Goldfarb, MD, FACSOncology AssociatesOncology Associates

San Diego, CASan Diego, CAJuly 8, 2003July 8, 2003

Surgeon’s PerspectiveSurgeon’s Perspective

There is a pressing clinical need to develop new techniques There is a pressing clinical need to develop new techniques to control localized disease, which will be less invasive and to control localized disease, which will be less invasive and more protective of normal tissues than standard surgical more protective of normal tissues than standard surgical approaches. approaches.

The rapid adoption of thermal ablation, targeted The rapid adoption of thermal ablation, targeted radionuclides, hyperthermia, embolic agents and radionuclides, hyperthermia, embolic agents and cryosurgery reflects the interest of both patients and cryosurgery reflects the interest of both patients and clinicians in achieving these goals.clinicians in achieving these goals.

Drug-device combinations as novel drug delivery systems Drug-device combinations as novel drug delivery systems provide the potential to enhance effectiveness, and reduce provide the potential to enhance effectiveness, and reduce adverse events with intra-tumoral delivery.adverse events with intra-tumoral delivery.

Targeted Sites:Targeted Sites:– BrainBrain– LungLung– LiverLiver– KidneyKidney– PancreasPancreas– LimbLimb– BladderBladder– GI TractGI Tract– Head & NeckHead & Neck– BreastBreast– ProstateProstate

Focused Tumor Ablation Utilizing Focused Tumor Ablation Utilizing Combination Drug/Delivery SystemsCombination Drug/Delivery Systems

High local drug High local drug concentrationsconcentrations

Low systemic Low systemic exposureexposure

Equivalent to ablative Equivalent to ablative therapies in preserving therapies in preserving normal tissuesnormal tissues

Innovative Drug/Device Combination Innovative Drug/Device Combination Products Under InvestigationProducts Under Investigation

FeRx IncorporatedFeRx Incorporated– Intra-tumoral drug delivery of doxorubicin using Magnetic Targeted Intra-tumoral drug delivery of doxorubicin using Magnetic Targeted

Carriers Carriers

Genetronics Genetronics – Intra-tumoral drug delivery of bleomycin using electroporation Intra-tumoral drug delivery of bleomycin using electroporation

Site-Specific Drug Delivery in Both Systems:Site-Specific Drug Delivery in Both Systems:– Utilize well characterized drugs with known safety profilesUtilize well characterized drugs with known safety profiles– Deliver drug to a localized area with minimal systemic exposureDeliver drug to a localized area with minimal systemic exposure– Utilize novel devices to deliver the drugUtilize novel devices to deliver the drug– Have an ablative effect that is confined to the area of drug delivery and Have an ablative effect that is confined to the area of drug delivery and

affects malignant tissues affects malignant tissues independent of histologyindependent of histology demonstrating a demonstrating a clinical benefit analogous to thermal ablation.clinical benefit analogous to thermal ablation.

The Issues – The Issues –

The regulatory pathway and standards are inappropriate for the perceived The regulatory pathway and standards are inappropriate for the perceived clinical benefit.clinical benefit.

CDER is the lead review agency for both of these combination products.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 No other product that has a localized ablation effect at the disease site has been required to do such extensive testing. has been required to do such extensive testing.

The drug components of these combination products:The drug components of these combination products:– have been approved and used clinically for decadeshave been approved and used clinically for decades– have safety profiles that are well characterizedhave safety profiles that are well characterized– have extensive scientific and medical literature supporting multiple have extensive scientific and medical literature supporting multiple

therapeutic applicationstherapeutic applications– are being developed for reduced therapeutic doses of drugare being developed for reduced therapeutic doses of drug– have minimal systemic exposurehave minimal systemic exposure

Both of these products which have a Both of these products which have a locallocal effect are currently held to the effect are currently held to the same evidentiary standards and regulatory burdens of new drugs having same evidentiary standards and regulatory burdens of new drugs having a systemic effect.a systemic effect.

FeRx IncorporatedFeRx Incorporated

FeRx is conducting a Phase III study of 240 patients with FeRx is conducting a Phase III study of 240 patients with hepatocellular carcinoma (HCC) comparing their local therapy hepatocellular carcinoma (HCC) comparing their local therapy (MTC-DOX) to systemic chemotherapy (IV DOX) in patients with (MTC-DOX) to systemic chemotherapy (IV DOX) in patients with end-stage disease with a survival endpoint. end-stage disease with a survival endpoint.

Phase I/II studies demonstrated efficient tumor targeting using Phase I/II studies demonstrated efficient tumor targeting using MTC-DOX resulting in:MTC-DOX resulting in:– Durable local disease control Durable local disease control – New dosing paradigmNew dosing paradigm

• Shift from traditional drug dosing (body weight or surface area) to dose Shift from traditional drug dosing (body weight or surface area) to dose based upon cross sectional area of tumor – analogous to other local based upon cross sectional area of tumor – analogous to other local therapiestherapies

New Treatment ParadigmsNew Treatment Paradigms– Role of ablation is a bridge to liver transplantRole of ablation is a bridge to liver transplant– Stabilization of disease is a clinically relevant end pointStabilization of disease is a clinically relevant end point

MTC-DOX Targeting Efficiency in HCC PatientsMTC-DOX Targeting Efficiency in HCC Patients

Post Tx AngiogramPost Tx Angiogram

Vessels patentVessels patent

Post Tx MRIPost Tx MRI

MTC-DOX well localizedMTC-DOX well localized

Local Tx for Liver Metastases Using MTC-DOXLocal Tx for Liver Metastases Using MTC-DOX

Pre Tx Post Tx

Breast Cancer

67% Reduction

of Metabolic Activity

Bladder Cancer

58% Reduction

of Metabolic Activity

GenetronicsGenetronics

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

Electroporation TechnologyElectroporation Technology

SummarySummary

Both of these products are subject to review standards typically Both of these products are subject to review standards typically applied to novel drugs that act systemically (e.g., large numbers applied to novel drugs that act systemically (e.g., large numbers of patients and survival endpoint).of patients and survival endpoint).

Device products that have been approved for local ablation type Device products that have been approved for local ablation type effects have not been subjected to such extensive clinical data effects have not been subjected to such extensive clinical data requirements. Given that the safety profiles of both drugs are well requirements. Given that the safety profiles of both drugs are well characterized and there is minimal systemic exposure, characterized and there is minimal systemic exposure, requirements for approval should be comparable to devices that requirements for approval should be comparable to devices that have an ablation effect.have an ablation effect.

Both products are innovative device/drug combinations that Both products are innovative device/drug combinations that utilize a new route of administration for old drugs (drugs formerly utilize a new route of administration for old drugs (drugs formerly administered intravenously) and should have reduced time in administered intravenously) and should have reduced time in clinical development, and reduced evidentiary requirements.clinical development, and reduced evidentiary requirements.

RecommendationsRecommendations

New therapies need to be compared to other therapies that have a New therapies need to be compared to other therapies that have a similar effect on the patient.similar effect on the patient.

Therapies which are local, regional, or systemic in their effects Therapies which are local, regional, or systemic in their effects should be compared to therapies with a like effect, regardless of should be compared to therapies with a like effect, regardless of which division is assigned the lead review; Device, Drug or which division is assigned the lead review; Device, Drug or Biologic.Biologic.

To expedite the review and approval of innovative devices for the To expedite the review and approval of innovative devices for the delivery of known drugs, the evidentiary standards must be delivery of known drugs, the evidentiary standards must be appropriate to the potential risk/benefit to the cancer patient.appropriate to the potential risk/benefit to the cancer patient.

We need to implement new regulatory pathways and least We need to implement new regulatory pathways and least burdensome principles for innovative technologies that allows for burdensome principles for innovative technologies that allows for rapid market entry for patient benefit.rapid market entry for patient benefit.