The Industry Sponsored IIT from the CRO perspective: 

Optimizing the interface between the industry and the sponsor-investigator

Ran Frenkel, RPhCEOPFC Pharma Focus Israelwww.pharmafocus.co.il

European Investigator Initiated TrialsOctober 30-31, 2008 Barcelona Spain

Main Discussion Points

• What is the difference between IST and IIT?• What are the forces in IIT?• What are the incentives of each party?• Are the rules of the game any different?• What are the expectations of each player?

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Industry Sponsored Trial (IST)

Initiator:Conductor:Regulations:Fund:

MAH=SponsorInvestigatorFDA, EMEA, ICH GCP, Local Regulations

MAH

Investigator Initiated Trial (IIT)

InvestigatorSponsor Investigator

Industry Government & Foundations Philanthropy Institutions/Cooperative Groups

FDCA, Federal Anti-Kickback Statute, False Claims Act

The CR&D Position

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The IIT Position

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IIT

IIT

CR&D

• Well structured and organized• SOPs and processes• Experience• Priority level• Budget

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IIT

• Well structured and organized • SOPs and processes• Limited Experience • Lower Priority level• Low Budget

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The “Leading Actors”

Industry Sponsored Trial

Industry-Sponsored IIT

The forces in IS-IIT

Marketing Authorization Holder(MAH)

Potential Risks for the MAH

Legal Concerns:• Intellectual Property thefts

Good tracking system to identify potential overlap

Potential Risks for the MAH

Ethical Concerns:• “Supported”/Dictated trial conduct and conclusions

Balancing the commitment to high ethical standards against the desire to maximize the investment value

Potential Risks for the MAH

Financial Concerns:• Unexpected risks inherent in IITs

Choose to support studies that maximize the benefits and minimize the riskLook at the trial proposal in the context of the organization’s strategyMaking rationale decisions regarding support of IITs requires knowing the reason for conducting them in the first place

Protective Measures

• Establish Proper Intent• Establish the Clinical Investigator and Trial

sponsor• Establish Fair Market Value (FMV)• Avoid influence of Sales Force in IIT process• Limit involvement in IIT studies after study

approval• Promote transparency and Disclosure

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Establish proper intent

• Result in a clinical trial and publication• Should not be driven by the marketing

department (OIG compliance program guidance for pharmaceutical manufacturers)

• Move the authority for grant funding from marketing operations to medical affaires or R&D department

• Establish grant committees and a structured IIT grant process

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Establish the clinical investigator and Trial sponsor

• Ensure that the clinical investigator is the “sponsor” of the study and in control of the study

• Study concepts are generated by the physician• Little involvement in the study

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Establish Fair Market Value

• Periodically review IIT budgets• Make sure that all payments are consistent

with FMV for the services made by the physician and any other support

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Avoid influence of Sales force

• Extract the activities of marketing from the IIT process

• Establish method to refer proposals • No impact on the decision

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Limit involvement in IIT

• Limit involvement in drafting trial documents (e.g. protocol, ICF)

• Limit assistance during the trial• Limit communication with investigators• Limit input on the conduct of the trial

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Promote Transparency & Disclosure

• Establish a “publication strategy”• Fully disclose any involvement in a publication

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The MAH should avoid:

• Drafting or designing protocol or other study docs.

• Monitoring the study• Perform data management or data analysis• Provide indemnification• Perform selection of study personnel• Being involved in safety reporting issues

Contribution of the MAH

• Provide study drug• Provide limited funding:

Non standard patient care costs RA fees Insurance Translation pharmacy costs CRO costs

Compliant IIT Program

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Sponsor-Investigator

Sponsor Investigator

“An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to dispensed to, or used by a subject. The term does not include any person other than an individual. The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator”

ICH Guideline for GCP 1.54

Sponsor Investigator

“An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to dispensed to, or used by a subject. The term does not include any person other than an individual. The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator”

ICH Guideline for GCP 1.54

Key Responsibilities of Sponsor

• Selection of qualified investigators• Provide the relevant information regarding the

investigation and safety • Quality assurance and Quality control• Record keeping and retention• Financial arrangements• IMP control

Key Responsibilities of Investigator

• Ensure that the investigation is conducted according to the protocol and applicable regulations

• Obtaining informed consent forms from the subjects• Control of the investigational drug• Record Keeping and retention• Reports: Progress, safety, final, financial disclosure

Industry Sponsored Trials Investigator Initiated Trial

Sponsor Sponsor Investigator

Project Director Project Director

Medical Monitor/Advisor Medical Monitor/Advisor

Pharmacovigilance Project Manager

IMP Data Management & Biostatistics

CRO Laboratory

Project Manager Pharmacovigilance

CRA Study Team

Data Management & Biostatistics Patients

Central Laboratory

Study Sites

Principal Investigator & Study Team

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Juggling the patchwork

Discrepancy in perception

• Lack of knowledge and experience in the complex and evolving area of clinical trial processes and regulatory aspects

• Lack of infrastructure (staff, equipment, premises etc.)

• Lack of experts support (i.e. medical writing, biostatistics, data management)

• Time and resources constraints

Complexities

1. Limited study management:

• Unclear objectives/ milestones• No framework• Flexible timelines• Subjective site selection process• Failure meeting recruitment targets

Complexities

2. Poor Documentation

• Inadequate protocol & Informed Consent Form• Lacking Submission Package• Revealed patient information• Incorrect patient information• Incomplete source data• Lack of essential documents

Complexities

3. Lack of Quality Control

• Limited Monitoring• No SOPs or guidelines • Safety issues unaddressed properly• Monitoring reports deficiency• Findings not followed up

A field report

“ …performing an IIT according to the new requirements is nearly impossible for clinicians and academic researchers without cooperating with expensive specialized experts such as project managers, statisticians, data managers, pharmacists and monitors.”

Welzing et al. Eur J Pediatr (2007) 166

Main Challenges

• Protocol• Funding• ICF• CRF and data handling• Insurance• IMP• IB• EC• Request for authorization to the

CA• TMF and ISF

• Contracts• Randomization• Monitoring• Documentation of AE• SAE-/ SUSAR documentation

and reporting• DSMB• Statistics• Final report • Archiving

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Other facets of complexity

Contract Research Organization(CRO)

The CRO Solution

• Experts in all facets of clinical trial processes• Management of clinical studies is the sole core

business • Independent organization without conflict of interests• Independent QA/QC

The Discrepancy

• Number of IITs is significantly higher than the number of conducted ISTs

• CRO involvement in IITs is significantly lower than in ISTs

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Considerations for CRO involvement

• Budget• Study complexity• MAH strategy• Sponsor-Investigator’s strategy• Study priority • Resources/experience

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Examples

1. Contract setup of multicenter IIT 2. Study budget prepared by an investigator

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Local CRO IMP Packaging &

Labeling

IMP Manufacturer

Vendor AVendor B

CRO

Site 3

Sponsor Investigator

Site 1

Site 2

Site 4

Contract setup of multicenter IIT

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Inv. Fees

Legal, Insurance

Inv. Meeting

MON, MM, DM

Site support

IMP

The CRO Solution: Tailor made services

• Adjusted cost structure• High flexibility• Continuous training • Intensive PM

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Adjusted cost structure

• Minimalistic & modest• Conservative• Local FSPs• Negotiate institutional overhead expense• PM via web portal• Lower operating margin

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High Flexibility & Training

• Flexible study timelines and milestones• Ability to handle day-to-day study issues• Reaction time fluctuation• Inexperienced teams

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Intensive Project Management

• Assure ethical and legal compliance• Control study timelines and milestones• Assist the sponsor- investigator• Reduce the risk for the MAH• Increase efficiency• Liaise between all parties involved

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Budget and figures

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• Hourly rates for IITs are 15-20% lower• Overall budget are 25% - 30% lower• Change order is not an option• Payment schedule is “flexible”

Considerations for CRO involvement

• Unmet service segment• New clientele• Extended networks of investigators and FSP• Special niche for small CROs• Establishing USP• Vision

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Conclusions

• IITs are becoming more complex and difficult to manage

• MAH should guarantee a compliant IIT process

• The sponsor investigator cannot comply with his role without professional support

• CRO should be an integral part of the IIT

Reaching the balance point

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For additional info please contact:

Ran FrenkelCEOPFC Pharma Focus Israelran.frenkel@pfc-cro.comhttp://www.pharmafocus.co.il

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