investigator initated trials (iit)
TRANSCRIPT
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
Patients32
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 [email protected]://www.pharmafocus.co.il
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