Project initiation

·     Contracting

·     On-site quality audit of ARUP (2 days and up to 3 auditors)

·     Project charter

·     Project planning process

·     Establishment of design team and weekly team meetings

·     Commencement of design control activities, including initial design risk assessment activities

·     Establishment of design requirements including, but not limited to: product description, assay functional requirements, assay performance specifications, hardware/software requirements, manufacturing/QC specifications, regulatory requirements, draft Verification Master Plan, draft Validation Master Plan

·     Initiation of purchasing controls for critical components

·     In-sourcing of materials

Preparation of HUD request

·     Collection of literature to support rare disease (<8,000 in US/year)

·     Preparation of HUD request and submission to FDA

Investigational Device Exemption activities

Assumption: FGFR2 FISH assay will be significant risk (SR)

·     Preparation of request for pre-IDE meeting to discuss IDE development and validation plan

·     Submission of pre-IDE meeting request to FDA

·     Briefing book preparation

·    FDA pre-IDE meeting and slide preparation

·     Preparation of slide deck, dialog with FDA

·     Fulfillment of IDE requirements including labeling, investigational plan, subject selection criteria, informed consent

·     Review and revision of IDE application

·     Submission of IDE application

·     Preparation of IRB application

·     Payment of IRB fees

ARUP IUO Development and Validation

·     Feasibility studies of conducting assay using ARUP standard FISH method

·     Establishment of assay reference range, sensitivity, specificity

·     Verification of ARUP IUO performance (concordance, reproducibility/precision)

·     Transfer of assay to clinical lab including training of operators

·     Preparation of quality plan

·     Preparation of experimental coversheets

·     Preparation of results, summaries

·     Preparation of protocol history table with itemization of protocol changes

·     Quality audits

·     Medical director approvals

·     Executive approvals

Implementation of Design Control (Phase 1-3)

·     Design control documentation including, but not limited to, project plan, project schedule, component list, design history file, checklists, summaries

·     Supplier assessment and drafting of component specifications under purchasing controls

·     Preliminary hazard analysis and failure mode and effects analysis (FMEA); multiple and iterative

·     Finalization and approval of assay SOP and forms

·     Development of process documents (batch records)

·     End of phase design reviews

·     Preparation of MasterControl organizer

·     Development of Device Master Record

·     Design History File development and audit

·     Laboratory notebook, correspondence, memo and meeting minutes maintenance

HDE application preparation

·    Modular submission: quality/manufacturing, analytical, clinical, software

·    Required forms and sections including coversheet, indications for use, summary, description of disease and assay, results, summary of safety and probable benefit, product description

·    Development and iterative revision of labeling documents (test request form, physician instructions, product datasheet, website)

·    Literature review and reference collection

·    Development of FDA interaction history

·    Collection of all referenced documents (current versions; estimated 100-150)

·    Electronic and paper copies of modules

·    Document archiving

HDE approval and post-approval activities

·     IRB application and approval

·     Build of test in ARUP’s laboratory information system (LIS)

·     Validation of test build

·     Addition of test to ARUP’s laboratory test directory

·     Development of test-specific website

·     Registration of test with FDA

·     Physician IRB enrollment instructions

·     Training of Client Services

o     Test ordering information for ARUP non-clients

o     Other test-specific topics included but not limited to IRB enrollment requirements for ordering physicians (HDE requirement), intended use, specimen requirements

·     Maintenance of test under QSR (21 CFR Part 820) and all FDA conditions of approval

·     Complaint handling

·     Medical device reporting

Estimate of two (2) amendments

*Note – this does not include additional experimentation if required by FDA.

Additional assay development & validation activities required for CDx to include but not limited (final determined in conjunction with Sponsor and FDA):

·    To conduct any required bridging studies

·    Sensitivity

·    Specificity

·    Interference

·    Reproducibility (including Intra-Run, Inter-Run)

·    Guard-banding

·    Specimen stability

·    Reagent stability

·    Accuracy

Design Control (Phase 3-5)

Implementation of design control under ARUP's PDP Program portion of the Quality Management System including:

·     Phase 3 – Design Verification (2nd part)

·     Phase 4 – Design Transfer

·     Phase 5 – Design Validation

Regulatory oversight throughout the assay lifecycle with regards to quality audits, document controls, design controls, design reviews, purchasing controls, software validation, risk management, change controls, process controls and CAPA to maintain compliance with QSR (21 CFR §820.30).

Project Initiation*

Evidence of milestone achievement – Execution of Master Services Agreement including SOW #1

Humanitarian Use Device Exemption (HUD)*

Evidence of milestone achievement – Notification from FDA of receipt of HUD request

Investigational Device Exemption (IDE)*

Evidence of milestone achievement – Submission of request for pre-IDE meeting to CDRH and acknowledgement of delivery

IDE application

Evidence of milestone achievement – Notification from CDRH of successful IDE application

ARUP IUO Analytical Development and Validation*

First 50% of activity

Evidence of milestone achievement – ArQule’s review and acceptance of development and validation plan.

ARUP IUO Analytical Development and Validation*

Second 50% of activity

Evidence of milestone achievement – ArQule’s review and acceptance of ARUP IUO validation report.

Design Control for ARUP IUO(Phases 1-3)*

First 50% of activity

Evidence of milestone achievement – ArQule’s review and acceptance of design control plans and Project Charter

Design Control for ARUP IUO (Phases 1-3)*

Second 50% of activity

Evidence of milestone achievement – completion of ARUP IUO validation

HDE Application Preparation*

First 50% of activity

Payable upon commencement of application preparation.

HDE Application Preparation*

Second 50% of activity

Evidence of milestone achievement – evidence of receipt by CDRH

HDE Application Amendments*

(if required)

Each amendment is $*** with a **% project management fee (estimated that two (2) amendments may be needed)

Evidence of milestone achievement – Acknowledgement of receipt by CDRH

Companion Diagnostic (CDx) Development and Validation*

First 50% of activity

Evidence of milestone achievement – ArQule’s review and acceptance of validation plan

Companion Diagnostic (CDx) Development and Validation*

Second 50% of activity

Evidence of milestone achievement – ArQule’s review and acceptance of validation report

Design Control (Phases 3-5)*

First 50% of activity

Evidence of milestone achievement – ArQule’s review and acceptance of validation plan

Design Control (Phases 3-5)*

Second 50% of activity

Evidence of milestone achievement – completion of Phase 5 Design Validation summary

Registration of the test with FDA*

Evidence of milestone achievement – Acknowledgement of registration receipt by the FDA

Preparation of IRB (post-approval)*

Evidence of milestone achievement – Acknowledgement of submission by the University of Utah IRB

Development and Maintenance of Website for Test*

Evidence of milestone achievement – Release of Test on ARUP’s Test Directory

Travel to meetings including

·     Pre-submission meetings

·     Travel to ArQule up to *** yearly

·     Travel must be in accordance with ArQule’s Travel Policy

Evidence of achievement – Receipts attached to invoice 

License agreement

(if required)

Third-party license agreement if required to practice the FGFR2 FISH assay

·     Upfront license fee

·     Royalties

·     Other fees 

Assay Annual Maintenance Fee

Annual assay maintenance

·     Training of personnel

·     Troubleshooting

·     Instrument service contract

·     Instrument preventive maintenance

·     Proficiency testing (CAP requirement)

·     Annual device report to FDA

·     Reagent procurement, qualification and performance monitoring of critical component suppliers

Evidence of achievement – Acknowledgement of annual device report submission to FDA