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The Investigator,
Site selection,
Budget Negotiation
OBJECTIVES
 Describe the Process for Selecting an Investigator and Site
 Define the Qualification Process
 Identify Components of a Study Budget
 Recognize Negotiating Styles
Introduction
 Sponsors are required to select Investigators qualified by training and
experience
 Typically reviewing an Investigator’s CV or credentials is not
adequate
 Sponsor personnel research prospective candidates to evaluate
many other aspects of the site, prior to final selection
 Sponsors will evaluate the site
 Site should anticipate and prepare for evaluation activities ahead
 To show enthusiasm and commitment to working with sponsor to
help the site in the evaluation process
Criteria for Investigator /Site Selection
 Sponsor team will first assess the study General considerations:
 What is the therapeutic area under study?
 Can Investigators from various disciplines be selected ? (e.g., for a
leukemia study: oncologists, internal medicine, and/or general
practitioners)
 How complicated is the study? (e.g., duration, phase, types of
screening exams. length of visits)
 What type of facility is needed? (e.g., inpatient, outpatient, public
health clinics, outpatient facility, etc.)
 What phase of study or level of device trial is being conducted?
 Sponsor team will then begin considering specific site qualifications in
the following categories: (these are “ideal”)
Criteria for Investigator /Site Selection
 Specific site qualifications categories:
 Training
 Ability and experience
 Honesty and integrity
 Cooperation
 Reputation
 Accessibility
 Staff
 Study conduct
 Facilities and equipment
Criteria for Investigator /Site Selection
 Specific site qualifications categories:
 Training
 The Investigator must have the appropriate licensure
 Specialty training (review CV for credentials), and
 Research training
 Ability and experience
 The investigator is currently involved in or has
conducted clinical research studies in the past. (may
not be required if an experienced CRC is working on
study. But will require extra training from the
sponsor.)
 The Investigator has adequate time to meet all study
commitments (conducting a minimal number of
competing studies).
Criteria for Investigator /Site Selection (Cont.)
 Specific site qualifications categories:
 Honesty and integrity
 The following are “triggers” and warning signals that a CRA might
observe that would indicate a poor choice of an Investigator:
 A tendency on the part of the Investigator to make unrealistic
promises
 An unwilling to hire a study coordinator
 Tardiness in completing pre-study paperwork
 Requests excessively high fees; a tendency to direct all
conversation to financial issues
 Demands a very high up-front payment
 Inordinate emphases or focuses on the publication potential
of the study
 lack of questioning or lack of concern by the
Investigator/study staff regarding the protocol
 Lack of initiative shown by the Investigator (he/she did not
read the protocol prior to being contacted by the CRA).
Criteria for Investigator /Site Selection (Cont.)
 Specific site qualifications categories:
 Cooperation
 An investigator should:
 Have systematic, efficient record keeping
 Have internal quality assurance/auditing practices
 Have a simplified contract negotiation process (e.g., minimal
layers of committee and legal review)
 Request reasonable grant requests
 Honor confidentiality agreements
 Be willing to make staff and procedural changes to facilitate
the study
Criteria for Investigator /Site Selection (Cont.)
 Specific site qualifications categories:
 Reputation
 An Investigator should have/be:
 A proven track record with the sponsor specifically, and clinical
research in general
 A solid reputation and good recommendations from colleagues
 An understanding of good research conduct and design; A
sound relationship with staff, patients, and referring physicians
 A good working relationship with the IRB for quicker protocol
approval turnaround time, and
 A thought leader in the industry
Criteria for Investigator /Site Selection (Cont.)
 Specific site qualifications categories:
 Accessibility
 The CRC and Principal Investigator should dedicate time for the CRA
during each monitoring visit (i.e., the Investigator and staff should be
available)
 The Investigator should be responsive to requests and follow through
promptly on requests; and
 Access to subjects. The Investigator should have:
 Appropriate and compliant subjects
 None or minimal studies competing for the same patient
populations; if they do have competing studies there should be a
large pool of potential patients
 A strong referral network
 An up-to-date database of patients (by diagnosis codes) for easy
searching
Criteria for Investigator /Site Selection (Cont.)
 Specific site qualifications categories:
 Staff
 The site should have:
 A dedicated and experienced study coordinator
 A dedicated subject recruitment specialist (CRC usually)
 Trained, interested, and actively involved sub-Investigators
 Knowledgeable, professional administrative support staff
 Experienced pharmacy and ancillary services staff
 Limited staff turnover and realistic workloads for each staff member
 Flexible staff hours to accommodate subjects’ schedules
 Staff who pays attention to detail and who follow efficient
procedures
 Staff with good interpersonal skills; and
 Good communication/follow through (i.e., site staff promptly return
calls and/or they are easily accessible by phone)
Criteria for Investigator /Site Selection (Cont.)
 Specific site qualifications categories:
 Study conduct
 A site must demonstrate:
 Adequate source documentation practices
 Adherence to protocols (e.g., history of prior FDA audits
with positive outcomes)
 Timely CRF submission; with errors minimal
 Prompt and accurate resolution to data queries
 Well-planned recruitment strategy
Criteria for Investigator /Site Selection (Cont.)
 Specific site qualifications categories:
 Facilities and equipment
 The site should when possible:
 Be easily accessible and have “patient-friendly” facilities
 Parking close to facility
 Ample waiting room
 Day care facilities or activities provided for caretakers/children
 Comfortable setting for patients should ling houses be required
 Have adequate drug/device storage facilities (controlled access,
environmentally controlled)
 Have adequate document storage and archiving facilities
 The site should also have limited access to protect the
confidentiality of the sponsor, and to assure that unqualified staff do
not enter/change data
 Have good access to medical records, and
 The site should have adequate space for the CRA to review records
and have access to specialized laboratory/testing facilities reports
Criteria for Investigator /Site Selection
 Additional elements considered by the sponsor when selecting a
site:
 Geographic concerns
 Availability and convenience for subjects, to assure
attendance and compliance at office visit, and
 Monitoring visit convenience (e.g., proximity to airport)
 Time and cost factors
 Affordability
 Additional time commitments
 Institutional Review Board meeting schedule and
turnaround time
 Anticipated rate of enrollment
Site Selection Process
 Many times begins with a telephone or email contact to the site’s key
contact for clinical research.
 Commonly the Principal Investigator or the CRC
 The contact purpose is to introduce the study and explore
preliminary interest
 The CRC should become familiar with the information and
assist in preparing to respond
Site Selection Process
 Potential site Selection Questions
 Investigator, Site Personnel Information
 In what field is the PI Board Certified? (Year?)
 How many years experience does the site have in
conducting clinical trials? What type of trials? How many
years experience does the site have in conducting
[indication] trials?
 Has the site ever been involved with a clinical trial that was
terminated prematurely? If so, for what reason?
 Who would be the other site study staff members
participating in this clinical trial?
 Would the site need to hire any staff prior to beginning this
study? If yes, when would the site be ready to begin?
 Who would be responsible for dispensing the study material?
Site Selection Process (Cont.)
 Potential site Selection Questions
 Recruitment/Handling Subjects
 What are the site’s methods for recruiting patients? How
many patients did the site enroll in past [indication] trials?
What was the target enrollment?
 What is the sites’ method for handling subjects lost to followup?
 What is the number of patient with [indication] that the site
treats in one month?
 Is the site conducting other studies that would conflict with the
[sponsor] clinical trial?
 How many studies is the study Coordinator currently
managing?
Site Selection Process (Cont.)
 Potential site Selection Questions
 Site Performance & Institutional Review Board(IRB)/Institutional
Ethics Committee(IEC)
 Has the site been inspected by the FDA? Is yes, when and
what were the findings? If applicable, can the sponsor
receive a copy?
 Does the site’s study facility have an IRB/IEC to review and
approve a protocol?
 How long does it take for the IRB/IEC to review and approve
a protocol?
 Must the site have a final budget agreement prior to IRB/IEC
submission?
 Would the site be able to use central IRB/IEC?
 Are there any other review committees that the protocol must
be approved by?
Assignment 3
Assignment 3--key
Selecting an Investigator /site
Letter of Agreement/Contract
Purpose and Content:
 Outlines the roles of the Investigator set forth by the sponsor/Contract
Research Organization (CRO) for the conduct of the clinical investigation.
 Not the same as “1572” or device Investigator Agreement.
 May contain indemnification and study budget
 Describes the PI’s obligations, i.e., must follow the protocol.
 Investigator/Institution is agreeing to:
 Conduct the study in accordance with the protocol
 Ensure an IRB approves any changes to the study
 Follow all state, federal and local laws, rules and regulations,
applicable to the conduct of the study
Letter of Agreement/Contract
 Letter of Indemnification:
 Because clinical trials are not risk-free,
 Investigators/sites seek indemnification from sponsors to
secure against potential damage or harm caused by
investigational drug/device
 Potentially all of the following are covered by the indemnification:
 Principal Investigator
 Sub-investigators
 Investigator's staff
 Corporation or partnership and its shareholders, and
 Site’s IRBs
Letter of Agreement/Contract
 What is covered under the indemnification (compensation of loss or
damage):
 Typical clause states the sponsor will cover “the harm that may be
caused by the administration of the investigational drug/device”.
 Common Implications:
 Wash-out periods, placebo controls, active treatment controls
 Investigators should insist on indemnification from any claims that
arise due to the administration of or subject exposure to the test article
 Modification or the withdrawal of any test article, control, placebo or
other study medications for the patients participating in the trial.
Letter of Agreement/Contract
What invalidates the indemnification
 Reasonable:
 Investigator must promptly report the filing of a lawsuit against the
investigator, and
 Investigator must cooperate in the defense of the lawsuit.
 Questionable
 Investigator is indemnified, as long as he/she:
 “Normal and usual compliance to the protocol, is being
understood that minor protocol violations do not void the
indemnification.”
Negotiating a Study budget
 What is a study budget?
 Agreement between the sponsor and investigator /institution that
specifies:
 Financial obligations of parties in supporting the clinical study.
 Note: financial arrangements between the investigator and the
sponsor are typically not part of the documentation that the FDA
requests in an audit.
Negotiating a Study budget
 Budget Development Approaches
 Sponsor/CRO may ask sites to create and submit a draft budget
from scratch (sites have template on hand!)
 Sponsor/CRO may provide a blank budget template and ask
sites to “fill in the blanks” with their costs; and/or
 Sponsor/CRO may provide a draft budget based on their
estimates of fees per subject (this usually reflects industry and
geographic region averages.
 NOTE: important for the site to accurately project time investment
and current cost for study activities, a low budget is risky for both
sponsor and site.
Items Covered in a Study Budget
Essentially ALL items are negotiable!
 Direct Costs
 Study staff related
 Subject related activities
 Data related activities
 Regulatory related activities
 Investigational product related activities
 Technical procedure related activities
 Study management activities
 Subject related
 i.e. stipend or record archiving fee
 Other Direct expenses: i.e. postage or IRB application fees
 Indirect Costs
 Site Overhead
Handout 3
Items Covered in a Study Budget
 Discussion Timing:
 Many times take place at the site Qualification (or Pre-study) visit.
 If the investigator is selected, the negotiations continue with the
goal of completion by the time the site is ready for the initiation visit.
 What is negotiation?
 We all negotiate nearly everyday! Examples may be:
 At Work when you agree with your manager that you can have
next week off if you work twice as hard this week.
 At home when you agree with your partner that you will cook
this evening if they cook the rest of the week
 Or in your free time when you decide to buy a new car if the
dealer includes a free 3 year warranty.
 Definition: process of two parties, or individuals reaching an
agreement and actively participating in making decisions.
The Negotiation Process
 Preparation
 Exchange positions
 Bargaining: consider options, Give & Take
 Reach Agreement: action plan and commitment
The Negotiation Process
Goals of negotiation
 For both sides to work together to reach a decision that you are
both happy with and which you will both carry out
 Not to beat the other side, but to maintain your relationship with
them
 You have to know where you are willing to bend and still feel as
if you have gotten what you needed
General Negotiation Principles
 Set goals or expected outcomes
for negotiations up front—Plan
and Prepare
 Separate the people from the
problem
 Clearly state issues/positions
 Follow through on commitments
 Negotiate as an equal
 Identify all negotiable items upfront
 Separate the must-haves, want-tohaves, and nice-to-haves
 Look for alternative arrangements
that meet all must-haves
 Plan and prepare
 Listen closely to the other party
 Focus on interests rather than
positions
 Summarize agreements
 Obtain feedback
Handout 4 and 5
Qualification Visits
 Preparing for Potential Investigator contract:
 Relationship may start with a qualification telephone
questionnaire
 Might be prior executing a confidentiality agreement between
the sponsor and the site.
 Be sure to find out what you are allowed to disclose prior
to the contract
Site Qualification Questionnaire
May capture many things
Refer to handout 6
Qualification Visit CRA Preparation
 Preparing for the call:
 Clinical Research Associate (CRA) should think about the
following prior to initially contacting the site:
 Be sure to have a clear understanding of what information
can be disclosed to the site personnel at this time
 A strategy for getting past the secretary to talk with the
investigator
 Define time frames for the study qualification and initiation
visits, subject accrual, and study completion
 Become familiar with the telephone questionnaire before
calling the investigator
Qualification Visit CRA Follow-up
 After the call the CRA should:
 Develop an understanding of IRB/IEC turnaround time and
preliminary expectations for the site‘s enrollment
projections
 Pending site interest and availability, send a confidentiality
agreement $ protocol synopsis to investigator
 Establish a specific follow-up date, time, and mode of
contact (e.g., phone, fax, in-person meeting)
 Set the attendance expectations for an upcoming
investigator meeting 9if already planned)
Qualification of Study Sites
 Visit Terminology
 Terms Pre-study, Pre-investigation, Potential Site
Visit, evaluation Visit and Qualification visits are used
synonymously.
 Objective of the Qualification Visit/Assessments
 To assess site’s qualifications, interest in, and
capability of conducting the study.
Preparing for Site Qualification Visits
 Some sites may NOT require a sponsor evaluation visit if recently
used the site in the past.
 Sponsor’s SOPs should outline theses criteria.
 If site requires a qualification visit CRA should write or obtain and
review the following:
 Pre-qualification telephone script information
 Confidentiality agreement
 A site visit confirmation letter
 Make travel arrangements
 Some CRA/Clinical Research Coordinator (CRC) prepare a
qualification visit notebook/folder to consolidate site/study
information for easy reference
Qualification Visit
 Note:
 Remain flexible and appreciate patient care concerns which take
precedence over research studies,
 e.g., patient emergencies, etc.
 Sample site questionnaire/script Handout 7
 Sample confirmation letter. Handout 8
Conducting the Qualification Visit
 CRA should address the following during the qualification
visit and the CRC should prepare for the following:
 Introductions:
 CRA should identify briefly introduce him/herself and
exchange business cards/contact information with the
site staff
 CRA should determine roles of the investigative staff
members and discuss the CRA’s role of monitoring the
study at the site
Conducting the Qualification Visit
 Topics to discuss during the meeting: refer to the confirmation
letter
 The obligations of the investigator
 An overview of the test article (both clinical and clinical data, if
available)
 A brief of the protocol, including dosing requirements, key efficacy
and safety parameters, visit and procedure schedules, etc.
 Source document requirements
 A brief review of the Case Report Forms (if available)
 Required document retrieval requirements
 Maintenance of the site regulatory file
 Test article accountability
 Facilities tour
Conducting the Qualification Visit
Specifically:
 CRA should question/review
 Refer to the handout 9
CRC/Site Feasibility Assessment
 Investigator and staff must determine if can successfully conduct the
trial per regulations, current policies, and per sponsor agreement.
 To do this the CRC may conduct a feasibility assessment of the protocol.
 What does it take to implement a successful study?
 Access to correct patient information
 Efficient IRB approval process
 Recruiting and screening patients
 Securing interest and willingness of patients to participate and stay in
study
 Proper training and experience of site personnel to comply with protocol
 Adequate site resources (personnel, time and equipment)
 Adequate source document and prompt/efficient data collection
 Others specific to the project
CRC Feasibility Assessment
 For each of the Key Activities required for a successful study answer
the following:
 Who will perform the following activities? (sponsor. CRO, Site
Personnel, others?)
 How ling will it take to do this?
 Who should absorb the costs for performing the activity?
 Will the information gained be worth the investment?
 Refer to the Feasibility Assessment Tool example—handout 10
Documenting the Qualification Visit
 CRA writes a monitoring report following completion of
Qualification visit.
 Report should include:
 Factual statements describing dates and location of the visit
and a list of attendees
 CRA’s objective assessment of the Investigator’s ability to
conduct the study, and the rationale (evidence) for his/her
decision
 Objective impressions (opinion based on objective facts)
 Assessment of facilities documenting any areas of concern
 Completed report is routed to and reviewed by key personnel involved
in final site selection decision
 Any assessment not done at site should be documented according to
the sponsor monitoring procedures and/or study plan.
Qualification Visit Follow-up Correspondence
 For all sponsor visits, follow-up documentation of what was accomplished
and outstanding issues should be sent to the site.
 This is most commonly sent in the form of a visit follow-up letter.
 Qualification f/u visit letter should contain the following:
 CRA should extend appreciation to the site staff for their time during
the visit
 Define a timeframe for the final selection decision
 Document what was accomplished
 Address any outstanding questions/items tht were raised during the
meeting
Qualification Visit Follow-up
Handout
Example qualification visit report template Handout 11
Sample qualification visit follow-up letter Handout 12
Assignment: FDA Financial Disclosure Form—Handout 13