Investigator Initated Trials (IIT)

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Information about Investigator Initated Trials (IIT)

Published on January 8, 2009

Author: frenkelr

Source: slideshare.net

Description

The Industry funded IIT from the CRO perspective: Optimizing the interface between the industry and the Sponsor- Investigator.
Presented by Ran Frenkel, CEO, Pharma Focus Israel at the First European Investigator Initiated Trials Conference in Barcelona, Spain.

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

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?

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?

Industry Sponsored Trial (IST) Initiator: Conductor: Regulations: Fund : MAH=Sponsor Investigator FDA, EMEA, ICH GCP, Local Regulations MAH Investigator Initiated Trial (IIT) Investigator Sponsor Investigator Industry Government & Foundations Philanthropy Institutions/Cooperative Groups FDCA, Federal Anti-Kickback Statute, False Claims Act

Initiator:

Conductor:

Regulations:

Fund :

MAH=Sponsor

Investigator

FDA, EMEA, ICH GCP, Local Regulations

MAH

Industry

Government & Foundations

Philanthropy

Institutions/Cooperative Groups

The CR&D Position

The IIT Position IIT IIT

CR&D Well structured and organized SOPs and processes Experience Priority level Budget

Well structured and organized

SOPs and processes

Experience

Priority level

Budget

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

Well structured and organized

SOPs and processes

Limited Experience

Lower Priority level

Low Budget

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

Legal Concerns :

Intellectual Property thefts

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

Ethical Concerns :

“ Supported”/Dictated trial conduct and conclusions

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

Financial Concerns :

Unexpected risks inherent in IITs

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

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

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

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

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

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

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

Periodically review IIT budgets

Make sure that all payments are consistent with FMV for the services made by the physician and any other support

Avoid influence of Sales force Extract the activities of marketing from the IIT process Establish method to refer proposals No impact on the decision

Extract the activities of marketing from the IIT process

Establish method to refer proposals

No impact on the decision

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

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

Promote Transparency & Disclosure Establish a “publication strategy” Fully disclose any involvement in a publication

Establish a “publication strategy”

Fully disclose any involvement in a publication



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

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

Provide study drug

Provide limited funding:

Non standard patient care costs

RA fees

Insurance

Translation

pharmacy costs

CRO costs

Compliant IIT Program

Compliant IIT Program

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

“ 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”

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

“ 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”

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

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

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 Patients

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

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 Limited study management: Unclear objectives/ milestones No framework Flexible timelines Subjective site selection process Failure meeting recruitment targets

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

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

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

“ … 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

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

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

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

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

CRO involvement in IITs is significantly lower than in ISTs

Considerations for CRO involvement Budget Study complexity MAH strategy Sponsor-Investigator’s strategy Study priority Resources/experience

Budget

Study complexity

MAH strategy

Sponsor-Investigator’s strategy

Study priority

Resources/experience

Examples Contract setup of multicenter IIT Study budget prepared by an investigator

Contract setup of multicenter IIT

Study budget prepared by an investigator

Contract setup of multicenter IIT Local CRO IMP Packaging & Labeling IMP Manufacturer Vendor A Vendor B CRO Site 3 Sponsor Investigator Site 1 Site 2 Site 4

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

Adjusted cost structure

High flexibility

Continuous training

Intensive PM

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

Minimalistic & modest

Conservative

Local FSPs

Negotiate institutional overhead expense

PM via web portal

Lower operating margin

High Flexibility & Training Flexible study timelines and milestones Ability to handle day-to-day study issues Reaction time fluctuation Inexperienced teams

Flexible study timelines and milestones

Ability to handle day-to-day study issues

Reaction time fluctuation

Inexperienced teams

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

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

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”

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

Unmet service segment

New clientele

Extended networks of investigators and FSP

Special niche for small CROs

Establishing USP

Vision

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

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

For additional info please contact: Ran Frenkel CEO PFC Pharma Focus Israel [email_address] http://www.pharmafocus.co.il

For additional info please contact:

Ran Frenkel

CEO

PFC Pharma Focus Israel

[email_address]

http://www.pharmafocus.co.il

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