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Slide 1: The Industry Sponsored IIT from the CRO perspective: Optimizing the interface between the industry and the sponsor-investigator Ran Frenkel, RPh CEO PFC Pharma Focus Israel www.pharmafocus.co.il European Investigator Initiated Trials October 30-31, 2008 Barcelona Spain
Slide 2: 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? 2
Slide 3: Investigator InitiatedTrial (IST) Industry Sponsored Trial (IIT) Initiator: Conductor: Regulations: Fund: MAH=Sponsor Investigator Investigator Sponsor Investigator FDCA, EMEA, ICH GCP, Local Regulations Act FDA, Federal Anti-Kickback Statute, False Claims MAH Industry  Government & Foundations  Philanthropy  Institutions/Cooperative Groups 
Slide 4: The CR&D Position 4
Slide 5: The IIT Position IIT IIT 5
Slide 6: CR&D • • • • • Well structured and organized SOPs and processes Experience Priority level Budget 6
Slide 7: IIT • • • • • Well structured and organized SOPs and processes Limited Experience Lower Priority level Low Budget 7
Slide 8: The “Leading Actors”
Slide 9: Industry Sponsored Trial
Slide 10: Industry-Sponsored IIT
Slide 11: The forces in IS-IIT
Slide 12: Marketing Authorization Holder (MAH)
Slide 13: Potential Risks for the MAH Legal Concerns: • Intellectual Property thefts Good tracking system to identify potential overlap
Slide 14: 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
Slide 15: Potential Risks for the MAH Financial Concerns: • Unexpected risks inherent in IITs Choose to support studies that maximize the benefits and minimize the risk Look at the trial proposal in the context of the organization’s strategy Making rationale decisions regarding support of IITs requires knowing the reason for conducting them in the first place
Slide 16: 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 16
Slide 17: 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 17
Slide 18: 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 18
Slide 19: 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 19
Slide 20: Avoid influence of Sales force • Extract the activities of marketing from the IIT process • Establish method to refer proposals • No impact on the decision 20
Slide 21: 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 21
Slide 22: Promote Transparency & Disclosure • Establish a “publication strategy” • Fully disclose any involvement in a publication 22
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Slide 24: 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
Slide 25: Contribution of the MAH • Provide study drug • Provide limited funding:       Non standard patient care costs RA fees Insurance Translation pharmacy costs CRO costs
Slide 26: Compliant IIT Program 26
Slide 27: Sponsor-Investigator
Slide 28: 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
Slide 29: 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 sponsorinvestigator include both those of a sponsor and those of an investigator” ICH Guideline for GCP 1.54
Slide 30: 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
Slide 31: 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
Slide 32: Industry Sponsored Trials Sponsor Project Director Medical Monitor/Advisor Pharmacovigilance IMP CRO Project Manager CRA Data Management & Biostatistics Central Laboratory Study Sites Principal Investigator & Study Team Patients 32 Investigator Initiated Trial Sponsor Investigator Project Director Medical Monitor/Advisor Project Manager Data Management & Biostatistics Laboratory Pharmacovigilance Study Team Patients
Slide 33: Juggling the patchwork
Slide 34: 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
Slide 35: Complexities 1. Limited study management: • • • • • Unclear objectives/ milestones No framework Flexible timelines Subjective site selection process Failure meeting recruitment targets
Slide 36: 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
Slide 37: Complexities 3. Lack of Quality Control • • • • • Limited Monitoring No SOPs or guidelines Safety issues unaddressed properly Monitoring reports deficiency Findings not followed up
Slide 38: 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
Slide 39: 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 39
Slide 40: Other facets of complexity
Slide 41: Contract Research Organization (CRO)
Slide 42: 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
Slide 43: The Discrepancy • Number of IITs is significantly higher than the number of conducted ISTs • CRO involvement in IITs is significantly lower than in ISTs 43
Slide 44: Considerations for CRO involvement • • • • • • Budget Study complexity MAH strategy Sponsor-Investigator’s strategy Study priority Resources/experience 44
Slide 45: Examples 1. Contract setup of multicenter IIT 2. Study budget prepared by an investigator 45
Slide 46: Contract setup of multicenter IIT Sponsor Investigator Site 1 Site 2 Site 3 Site 4 IMP Manufacturer CRO Vendor B 46 Vendor A Local CRO IMP Packaging & Labeling
Slide 47: Inv. Fees Legal, Insurance Inv. Meeting MON, MM, DM Site support IMP 47
Slide 48: The CRO Solution: Tailor made services • • • • Adjusted cost structure High flexibility Continuous training Intensive PM 48
Slide 49: Adjusted cost structure • • • • • • Minimalistic & modest Conservative Local FSPs Negotiate institutional overhead expense PM via web portal Lower operating margin 49
Slide 50: High Flexibility & Training • • • • Flexible study timelines and milestones Ability to handle day-to-day study issues Reaction time fluctuation Inexperienced teams 50
Slide 51: 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 51
Slide 52: Budget and figures • • • • Hourly rates for IITs are 15-20% lower Overall budget are 25% - 30% lower Change order is not an option Payment schedule is “flexible” 52
Slide 53: Considerations for CRO involvement • • • • • • Unmet service segment New clientele Extended networks of investigators and FSP Special niche for small CROs Establishing USP Vision 53
Slide 54: 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
Slide 55: Reaching the balance point 55
Slide 56: For additional info please contact: Ran Frenkel CEO PFC Pharma Focus Israel ran.frenkel@pfc-cro.com http://www.pharmafocus.co.il 56