A Framework for Device-Based Clinical Research in

Image-Guided Therapies

Keyvan Farahani, PhDGary Dorfman, MD

Image-Guided Interventions BranchCancer Imaging Program

NCI

Interventional Oncology (IO)

• IGI Defined: Device-based, minimally-, non-invasive cancer therapies* that use real-, or near real-time intra-procedural imaging for localization, targeting, monitoring, control, and endpoint determination.

* not just IR – also RT, endoscopy, surgery, etc.

Interventional Oncology

• Potential Clinical Utilities:

– Primary Palliation (Bone Mets, Celiac Axis Block)– Secondary Palliation (PCN, PBD, G-, J-tubes)– Adjunctive Therapy (PV Embolization, Access)– Bridge to Definitive Rx (HCC)– Cure (Early / Screen Detected CA, Pre-CA,

Indeterminate Lesions)– Intermediate Facilitator for Development of

Molecularly Targeted Therapies

Molecular Imaging (and Intervention?)

Molecular Signatureof Cancer

CellTargetedTherapy Imaging

Device(IGI Device?)

ImagingProbe

NCI Support for IO: Current Environment

• CTWG / TRWG / Multi-PI Initiative

• Existing PAs – R01 / SBIR / STTR

– Platform Development, Clinical Trials

– Now Two Quick Trials Mechanisms

• However, Current Payline is Dismal…

• NCI Unique in Offering Clinical Trials Support Outside of Investigator Initiated Mechanisms

• “I2” Imaging Initiatives, Including:– IO Clinical Trials Support

– Informatics (caBIG, NCIA, databases, analysis algorithms)

NCI IO Initiatives: Current

• CIP IGI Branch Initiatives– Largely Basic Science Through Investigator

Initiated Pathways

– Discovery, Development, Delivery

– Translational Research (inc. Early Trials)

– Clinical Trials Infrastructure• Targeted Towards Image-Guided, Device-Based Therapy

Similar to the Infrastructure Provided for Pharmaco-therapies

• Phase 0 – IV (Phase A – D)

• Goal: Bring Therapies with Disease-specific Indications to Market

Interventional Oncology

• Ideally Supported by Funded Research– Discovery / development – (Preclinical & ~ Phase 0)

– Optimization – (Preclinical and Phase 0 – early II)

– Validation for specific cancers / stages – (Phase II – IV)

– Regulatory approval – (Later Phase II and III)

– Supportive payor policies– (Later Phase II – IV)

– Widespread physician acceptance – (Later Phase II – IV)

– Patient recognition and “informed” demand

Clinical Trials Nomenclature:Phase 0 – IV vs. Pilot / Pivotal

• Pharma Phase 0 – IV– Works for many but not all drug trials

– Poor fit for IGI / IO trials based on standard definitions & procedures

• FDA/CDRH Pilot and Pivotal Designation– Regulatory purpose– No accepted linkage to “Phase 0 – IV”– Not sufficiently granular for scientific endpoints– Approval process different than CDER/CBER

Clinical Trials Construct:A Proposed Matrix for IO Trials

• Phase A – D

– A (0 / I, Pilot) – Single site: safety, QA, effect, optimize I & I – lesion, organ, patient

– B (I / II, Pilot) – Single / Multi-site: effect, standardize, translate, early data – lesion, organ, early patient level data

– C (II, Pilot / Pivotal) – Multi-site: organ/lesion outcome &/or more robust patient level data

– D (III / IV, Pivotal) – Multi-site: patient level data, comparative, randomized preferred

IO Clinical Trial Endpoints:Definitions of Success and Failure

• IO Therapies often repeatable

• Consider adoption of vascular definitions:– Primary Success – result post intent to treat– Primary Assisted Success – add’l Rx, different site– Secondary Success – re-treatment of residual / recurrent

disease at previously treated site– Failure – residual, recurrent, new disease

• Patient Refuses or Is Ineligible for Added Therapy; Death; etc.

• Worthy of Consideration:– Local control– Systemic control– Intent to treat and treatment plan– Purpose of treatment: cure, long-term control, control as

bridge therapy, palliation

Interventional OncologyImaging Issues – RECIST, etc.

• RECIST Criteria unless modified do not apply– Non-IGI RECIST issues already limiting– Immediate post-IGI lesion larger– Imaging lesion ≠ disease (viable tumor)– Recurrence / residual may not alter lesion dimensions

• Validation of imaging findings

• Imaging/sensing equivalent of the surgical tumor-free margin – Future interventional oncology; likely multi-parametric, co-registered data: anatomic, physiologic.

NCI IO Initiatives:IO Clinical Trials Infrastructure

• Targeted Towards Providing an Infrastructure for Image-Guided, Device-Based Therapy Similar to the Infrastructure Provided for Pharmacotherapies

• Phase 0 – IV (Phase A – D)

• Goal: Bring Therapies with Disease-specific Indications to Market

• Phase II and III Currently Implemented Through Existing Cooperative Groups

• Infrastructure is not All or Nothing– Variations in Collaborative Mechanisms

– Use of NCIA to Support non-NCI Trial under Specific Conditions

NCI IO Clinical Initiatives: Current

• Device Rx Strategy Meetings (2-3 / Year)– Exploratory “By Invitation” Meetings (Stage I and II Breast Cancer)

– “Open / Private” Device Rx Development Meetings (Renal Cell Cancer)

– Disease / Technology Focused

– Multi-purpose (Multilateral Education, Prioritization, Potential Solicitations)

• Support for Later Phase Clinical Trials– Collaboration among NCI, FDA, CMS

– Strong Ties with Industry (CTA, CSA, pre-IDE, etc.)

– Utilizes Cooperative Group Mechanism

– Two Protocols in Process NOW

NCI IO Clinical Initiatives: Current

• 7th Annual Forum on Biomedical Imaging in Oncology - Feb 1-2, 2007– Collaboration with NEMA, AdvaMed, MDMA

– Will Focus on Opportunities for Collaboration including Clinical Trials

– QC and Uncertainty Measurements

• SPORE and CC Initiatives– Tissue Acquisition in Early Phase Clinical Trials

– Standardized Imaging Protocols During IO Trials

– Trans-SPORE Activities

Phase II / III Infrastructure:Current “Implementation”

• PI / Industry Collaborator Work Through Cooperative Group to Submit Concept

– Considerations - ±IDE, ±CPT, etc.

– CSA / CTA between NCI and Industry

• Concept Approved– Pre-IDE Meeting with ODE/CDRH/FDA (include NCI, PI, etc.)

– Contract between Cooperative Group and Industry

– Protocol Developed

– IDE Application by NCI (if necessary)

– CMS Discussions Regarding Funding Clinical Care

• Protocol (and IDE) Approved by NCI and FDA

• Protocol Activated (Potential CTSU Listing)– Image Support through NCIA

Conclusion:

• IGI methods offer new challenges and possibilities in cancer care

• Opportunities for academia, industry, and federal agencies to work closely together to address issues and bring new therapies to the bedside