i do not object to people looking at their watches when i'm speaking. but i strongly object...
TRANSCRIPT
I do not object to people looking at their watches when I'm speaking.
But I strongly object when they start shaking them to make sure they are still going.
William Norman Birkett
April 14, 2009
Bradley Merrill Thompson
Sponsor-CRO Relationships: Managing Risk
3
Topics
1. ABCs of CROs2. Planning3. RFP and Due
Diligence4. Contracting5. Execution of Work6. Evaluation7. Take Aways
I feel like Zsa Zsa Gabor’s fifth husband. I know what I'm supposed to do
but I don't know if I can make it interesting. Al Gore
4
It’s good to know the basics
politicalhumor.about.com
6
SMOs Defined
– What is a Site Management Organization (SMO)?
o A person that is retained as an independent contractor of the principal investigator or research site to provide administrative support of the conduct of the study, such as recruitment of the subjects, collection and preparation of the study data and reports for submission to the sponsor.
o A CRO may perform SMO functions
o Definition based on agency relationships
7
CROs v SMOs
Sponsor
Sponsor’s Agent (CRO)
Researcher’sAgent (SMO)
Research Site/
Investigator
9
Topics
1. ABCs of CROs2. Planning3. RFP and Due
Diligence4. Contracting5. Execution of Work6. Evaluation7. Take Aways
I've often wondered how some people in positions of this kind . . .
manage without having had any acting experience.Ronald Reagan
12
Potential Risks of Outsourcing to CROs
– Risks generally associated with reduced control of the clinical trial process by the Sponsor
– Risks include:
o Delays in completion of studies
o Lost or poor data
o Regulatory infractions produce indirect consequences
FDA regulations/GCPs
HIPAA
Fraud and Abuse
o Private litigation exposure
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Weighing risk can be tricky
www.txrollergirls.com
14
Delegation of Authority to CRO
– Sponsors may delegate responsibility for regulatory obligations to a CRO
– However, device sponsor remains liable – This is different from the drug world, where
the drug regulations contemplate that sponsors may transfer regulatory obligations to CROs such that they assume regulatory liability
– FDA may be coming out with guidance in this area
15
Delegation of Authority to CRO
– CRO may have important role in meeting regulatory responsibilities, even though obligation is not “transferred” to CRO
– Example: Adverse Event Reporting o Sponsor retains responsibility to report to
investigators and FDA, and the regulatory liability for failure to do so
o CRO may still be responsible for: Reporting AEs to Sponsor Drafting AE descriptions Providing summary reports of AEs Following up with sites to ensure complete AE
information is obtained Safety database maintenance and/or
reconciliation- These responsibilities should be described in
the Work Order
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Shares common goal/objectives
Engages in joint strategic planning
Forms relationship-based structure
Makes open-ended agreements
New business forms
Strategic Alliance
Preferred Supplier
Establish core team Builds collaborative
mechanisms Develops
understanding of client’s customers
Incorporates client into strategic planning
Assigns dedicated relationship management
Makes directed investments
Builds collaborative mechanisms
Partnership
Source: August 2004, Goldman Sachs Research
Traditional Pattern of Outsourcing Integration
Responsiveness to requests
Transactional
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Checks and Balances
Primary Vendor Secondary Vendors– Clinical research
operations Protocol Development Site/Investigator
Recruitment and Selection Personnel Training Clinical Trial Management Data Analysis Medical Writing Processing and Preparing of
Regulatory Filings and liaison with Regulatory bodies
– QA and QC
– Monitoring– Systems auditing– Trial auditing– Contract
negotiations
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Topics
1. ABCs of CROs2. Planning3. RFP and Due
Diligence4. Contracting5. Execution of Work6. Evaluation7. Take Aways.Politics gives guys so much power that
they tend to behave badly around women. And I hope I never get into that.
Bill Clinton
19
CRO Selection
– Business and legal risks will be minimized when the Sponsor-CRO relationship is based on open communication and trust
– Imperative that Sponsor adopt a CRO selection process that assesses:
o Expertise: Does the CRO have the expertise to undertake duties Sponsor desires?
o Compatibility: Can the CRO fulfill its duties in manner that is compatible with the Sponsor (i.e., is there a good fit)?
o Capacity: Does the CRO have the ability to commit the manpower and resources needed in the Sponsor’s timeframe?
o Price: Does the CRO provide services at same price as competitors? If not, what added value is being offered?
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CRO Selection
– Sponsor usually conducts an RFP process tailored to the specific trial at hand
– Sponsor’s due diligence should include: o Web research o Public directorieso Careful analysis of Responses to RFP o Interviews with operational leaders o Site visits
– Information gleaned by Sponsor during the CRO selection process should be communicated to counsel to ensure that CRO’s verbal claims are reflected in the CRO contract
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QA Questions to Ask
– How does the CRO measure quality?– What CRO processes are in place to
continually monitor quality?– What is the size of the CRO quality
assurance (QA) department? – What internal QA procedures are in
place? For example, does QA audit studies independent of sponsor-CRO contract, as part of internal CRO quality control?
Winther
22
Quality is important
www.spelrite.com
23
Topics
1. ABC of CROs2. Planning3. RFP and Due Diligence4. Contracting
a. Risks to manageb. Metricsc. 3rd Party Agreementd. Change Orderse. Staffing Issues
5. Execution of Work6. Evaluation7. Take Aways
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A lot of this is obvious
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Common Project Risks
– Inefficiency and quality issues from staff changeover or inexperience
– Delays in site initiation– Delays in patient recruitment– Difficulties with management of clinical
trial supplies– Issues with vendors– Delays with the processing of CRFs– Utilization of resources at a level that
exceeds the budget– Delays in obtaining regulatory and IRB
approvals
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Factors Most Often Causing Study Delays in the U.S.
38%
31%26% 24% 24%
0%
25%
50%
75%
Contract/budgetnegotiation &
approval
Patient recruitment& enrollment
Protocolamendment &
refinement
Legal review &approval
Review & approvalof consent form
Source: Thomson CenterWatch 2007 Survey of 522 Investigative Sites in the U.S.
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Expect the Unexpected
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Topics
1. ABCs of CROs2. Planning3. RFP and Due Diligence4. Contracting
a. Risks to manageb. Metricsc. 3rd Party Agreementd. Change Orderse. Staffing Issues
5. Execution of Work6. Evaluation7. Takeaways
My mother never saw the
irony in calling me a son-of-
a-bitch.
Jack Nicholson
29
CRO and Sponsor Relationships
– Transparency of performance builds trusto Assures alignment on study qualityo Provides tools for proactive and
focused management of issues early so they don’t become bigger problems
o Allows for shared consensus on steps for resolution
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CRO EngagementCRO Engagement
RFP and Due Diligence
Contracting Execution of work
Evaluation
Metric Creation
Key Performance Indicators
Critical Success Factors
Specific Performance Indicators Discussion
Senior Committee
Junior Committee Discussion
AnalysisMeasurement
Feedback & Adjustment
Feedback
Planning
Metric UseMetric Use
Metrics in a CRO Relationship
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Make metric development collaborative
www.bp3.blogger.com
32
Key Metrics for Early Identification of Project Risk
Clinical Operations
• Start-up metrics
• Enrollment metrics
• CRF backlog
Data Management
• Data entry
• Data review
• Data quality
Varawalla
33
Example Metric Definition Table
KPIRelated Metrics Definition
Data Source
Target*
Achievement of key project timelines
Final protocol to first patient recruited
Number of days from final protocol approval by sponsor to first patient enrolled at first site
Clinical trial management system (CTMS)
60 days (mean); 90 days
(oncology)
Visit data to lab data available in database
Average number of days from patient visit to lab data available in CDMS
Clinical data management system (CDMS)
5 days
*All days specified are elapsed timeCuddigan & King
34
Example Metric Definition Table, contd.
KPIRelated Metrics
DefinitionData
SourceTarget*
Last patient last visit (LPLV) to database lock
Number of days from LPLV at site to database locked
CDMS 5 days
Database lock to final study report
Number of days between database lock and final approval study report
CTMS 21 days
*All days specified are elapsed time Cuddigan & King
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Example Metric Definition Table, contd.
KPIRelated Metrics Definition
Data Source
Achievement of target quality standards
Database error rate
Number of database errors found on database audit/total number of data fields audited
Data manager
Percent of non-performing centers
Percent of sites enrolled that recruits 1 subject within one month of initiation visit
CTMS
Cuddigan & King
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Example Metric Definition Table, contd.
KPIRelated Metrics
DefinitionData
Source
Compliance with agreed contract value
Final actual contract cost as percent of initial contract value
Total project fees after final invoice paid, compared with initial contract value (includes pass-through costs)
Finance
Number of change orders
Number of change orders approved after initial contract sign-off
Finance
Cuddigan & King
37
CRO EngagementCRO Engagement
RFP and Due Diligence
Contracting Execution of work
Evaluation
Metric CreationMetric Creation
Key Performance Indicators
Critical Success Factors
Specific Performance Indicators Discussion
Senior Committee
Junior Committee Discussion
AnalysisMeasurement
Feedback & Adjustment
Feedback
Planning
Metric UseMetric Use
Metrics in a CRO Relationship
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Utility in Managing Sites
Compare sites on the basis of:– Subjects (overall enrollment, enrollment
per month, screen fail rate, dropout rate)– Start up (contract completion time,
document completion time)– Data (query rate, query completion time)– Money (overall cost per patient,
advertising cost per patient)
Winter related injuries occur more often in the winter.-newswoman for WHIZ-TV, Zanesville, Ohio
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How Do We Use Metrics?
– Just as you would internally, for performance management
– Dispute Resolution (later)– Contractually in a few cases
o Contractual management process and dispute resolution
o Contractual rewardso Contractual penalties
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Topics
1. ABC of CROs2. Planning3. RFP and Due Diligence4. Contracting
a. Risks to manageb. Metricsc. 3rd Party Agreementd. Change Orderse. Staffing Issues
5. Execution of Work6. Evaluation7. Takeaways
Attorney: Now doctor, isn’t it true that when a
person dies in his sleep, he doesn’t know about
it until the next morning?
-testimony from court records
SPONSOR
SUBJECTFDAIRB**
DSMB, MRC, etc
CRO*
INVESTIGATOR
INSTITUTION/ CLINICAL SITE
CTA
Informed Consent1572
CTA
CTAs
*Contracts on behalf of sponsor (donated by dotted line)
**May or may not be a written agreement - depends on whether IRB is commercial, local, centralized, etc
Services Agreements
Blue = CTA
Orange = Service Agreement
Green = Regulatory “agreement”
Third party vendors (e.g., labs)
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Ability to Bind Sponsor to CTAs
– Sponsor may want CRO to handle CTAs because of:o Speed
o Cost
o Strength of CRO’s relationships with research sites/investigators
– However, sponsors may have problems with CROs protecting sponsors’ interests o CRO sometimes want to get contract in place
quickly and not expend resources in lengthy negotiations
o CRO may not have adequate legal expertise
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Ability to Bind Sponsor to CTAs
– Contractual controls: Range of Possibilitieso CTA templateo CRO authority to negotiate
Only extends to certain provisions Sponsor provides approved fall back
language and negotiation guidance/instruction
CRO must submit all changes to Sponsor for review and approval
o Notification of changes and amendments
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Topics
Attorney: You say the stairs went down to the basement?
Witness: Yes.Attorney: And these stairs, did they
go up also?-testimony from court records
1. ABC of CROs2. Planning3. RFP and Due Diligence4. Contracting
a. Risks to manageb. Metricsc. 3rd Party Agreementd. Change Orderse. Staffing Issues
5. Execution of Work6. Evaluation7. Takeaways
45
Change Orders
– Statement of Work sets forth services to be provided by CRO o Services beyond or different from SoW are
generally subject to a “change order” – Points to consider
o Require signed change orders before implementation that might affect the budget– Require CRO to notify you if your instructions would
have the effect of changing scope Absent such notification, preclude cost recovery
o CRO must prepare the change order and describe in detail changes to scope, timing, costs, personnel, etc
o CRO agrees to not unreasonably refuse change order Remember, you’ll always get a better price if you
address issues upfront, before need for change order
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Topics
1. ABC of CROs2. Planning3. RFP and Due Diligence4. Contracting
a. Risks to manageb. Metricsc. 3rd Party Agreementd. Change Orderse. Staffing Issues
5. Execution of Work6. Evaluation7. Takeaways
Democracy used to be a good thing,
but now it has gotten into the wrong hands.
-Senator Jesse Helms
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Personnel
– Experience & qualification of CRO personnel varies widelyo Educational backgroundo Therapeutic area experienceo Monitoring experienceo Trainingo Accreditation (e.g. ACRP, SoCRA)
– Study personnel change frequentlyo Advancemento Turnovero Re-assignment
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Managing Personnel
―Specify minimum qualifications.―Change control. Retain the right to
approve at least key personnel, including additional or replacement personnel
―Costs of change. Consider specifying training requirements for the study team, including any replacement personnelo Cost of study-specific training typically
included in the budget o Training of replacement personnel may
generally be allocated to the CRO
– Reduce impact. Institutionalize communication, documents and systems to reduce dependence on outstanding people
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Topics
1. ABC of CROs2. Planning3. RFP and Due Diligence
4. Contracting5. Execution of Work
a. Communications b. Monitoring performancec. Red Flagsd. Dispute resolution
6. Evaluation7. Takeaways
I have always wanted to be somebody. I guess I should have been more specific.
-Lily Tomlin
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Sometimes the obvious stuff escapes us
Farm1.static.flicker.com
51
Managing Communications
– Poor communication is often cited as a prime reason for frosty relations between CRO and Sponsors
– You need a comprehensive plan:o People
CRO contract should contain an express liaison provision establishing a point of contact for each party
List of all key operations, billing and legal personnel
o Structure Provide for basic joint committee structure
o Frequencyo Form (e.g. meetings, conference calls,
written and other content issues)
52
Topics
1. ABC of CROs2. Planning3. RFP and Due Diligence4. Contracting
5. Execution of Worka. Communications b. Monitoring performancec. Red Flagsd. Dispute resolution
6. Evaluation7. Takeaways
53
Monitoring Performance
– Monitoring reports should beo Submitted by CRO timelyo Reviewed by sponsor timelyo Resolved timely, including evaluation and
escalation, if necessary, of reported protocol violations and other non-compliance
– Contract language should address thiso Commitmentso Metrics
54
CRO Progress Reports
– In the agreement, require written progress reports at regular intervals
– Budget for frequent status calls between sponsor and CRO
– Topicso Contract statuso IRB approval statuso Site initiation/monitoring/close-out visitso Enrollmento Issues/concerns of sponsor or CRO (e.g. CFR
completion or protocol noncompliance concerns that may require clarification to study team and/or sites, AE trends, other problems with sites)
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Topics
1. ABC of CROs2. Planning3. RFP and Due Diligence 4. Contracting5. Execution of Work
a. Communications b. Monitoring performancec. Red Flagsd. Dispute resolution
6. Evaluation7. Takeaways
56
Watch for Red Flags
– Selection of inexperienced investigators by the CRO
– Questions from study site directed to sponsor– Inadequate or untimely monitoring reports– Enrollment of patients who don’t fit criteria– Higher screening-to-enrollment ratio at one
site than others– Frequent rescheduling of meetings and reports
by CRO– Delays in cleaning up CRFs– Delays in adverse event reporting– Changes in CRO personnel– Unscheduled request for payment by the CRO
Vogel
57
Compliance isn’t always easy
www.mustreadblogs.blogspot.com
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Scope creep
– If you have fee for service or unitized costs--o Limit. Use limits on unitized costs (e.g.
not to exceed without approval)o Monitor. Be proactive in monitoring
“scope creep” Be cognizant of
– Your instructions as the sponsor– CRO activities; example: Repeated monitoring
visits» Site uncooperative? If so, WHY?» CRO personnel inexperienced, untrained?» If/when will you bear the costs?
o Communicate. If unsure, ASK – better than being surprised later
– Ties back to change control
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Topics
1. ABC of CROs2. Planning3. RFP and Due Diligence
4. Contracting5. Execution of Work
a. Communications b. Monitoring performancec. Red Flagsd. Dispute resolution
6. Evaluation7. Takeaways
60
Make sure materials are clear
– Make sure materials are clear (contract, statement of work, budget, payment schedule, etc)
– Good dispute resolution process that allows o Discussion among
joint committees and
o Business escalationwww.robertstevensonfiles.com
61
Payment Terms
– CRO should remain cash neutral: not a bank
– Negotiate payment for performance, including milestones and deliverables
o Clearly define “delivery” and “completion”
o Remember, “milestones” link back to work order – what is the plan for arriving at the milestone?
– Make delivery of data independent of payment
o Sponsor timeframes can move forward even with a payment dispute
o CRO will want limitations on liability, such as limiting damages to contract price, not actual damages due to delay
o If CRO does withhold data to secure payment, the CRO opens itself up to actual damages—the limitation is lost
62
Make lemonade out of lemons
Mchenrycountyblog.com
63
Topics
1. ABC of CROs2. Planning3. RFP and Due Diligence
4. Contracting5. Execution of Work6. Evaluation7. Takeaways
Lawyer: "You don't know what it was, and you didn't know what it looked like,
but can you describe it?"
64
Post Study Learning
– Review the performance of:o The CROo Other third partieso The sponsor
– What unexpected problems were there, and how can they be better managed in the future?
– How can operations be improved, including communication?
– Channel that learning back to the contracting and operations units
Capitalinsight.com
65
Topics
1. ABC of CROs2. Planning3. RFP and Due Diligence
4. Contracting5. Execution of Work6. Evaluation7. Takeaways
Counsel: Are you qualified to give a urine sample?
Witness: Yes, I have been since early childhood.
66
Takeaways
– Establish realistic objectives and expectationso Understand your internal capabilities and advise
the other party accordingly
– Budget early, and well– Deliberately --
o Establish clear lines of communications between parties and
o Identify liaisons
– Use contract templates with cautiono Do templates contain party’s wish list or
minimum requirements? o Review/update templates periodically, particularly
MSAs
67
Different Cultures, Different Rules
www.break.com
Questions?
Two lawyers were out hunting when they came upon a pair of tracks. They stopped and examined the tracks closely.
The first lawyer announced, "Those are deer tracks. It's deer season, so we should follow the tracks and find our
prey."
The second lawyer responded, "Those are clearly elk tracks, and elk are out of season. If we follow your advice, we'll
waste the day."
Each attorney believed himself to be the superior woodsman, and they both bitterly stuck to their guns.
They were still arguing when the train hit them.