William Norman Birkett

1. 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

2. April 14, 2009 Sponsor-CRO Relationships: Managing Risk Bradley Merrill Thompson

3. Topics • ABCs of CROs • Planning • RFP and Due Diligence • Contracting • Execution of Work • Evaluation • 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

5. SMOs Defined • What is a Site Management Organization (SMO)? • 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. • A CRO may perform SMO functions • Definition based on agency relationships

6. CROs v SMOs Sponsor Sponsor’s Agent (CRO) Researcher’sAgent (SMO) Research Site/ Investigator

7. Topics • ABCs of CROs • Planning • RFP and Due Diligence • Contracting • Execution of Work • Evaluation • Take Aways I've often wondered how some people in positions of this kind . . . manage without having had any acting experience. Ronald Reagan

8. Potential Risks of Outsourcing to CROs • Risks generally associated with reduced control of the clinical trial process by the Sponsor • Risks include: • Delays in completion of studies • Lost or poor data • Regulatory infractions produce indirect consequences • FDA regulations/GCPs • HIPAA • Fraud and Abuse • Private litigation exposure

9. Weighing risk can be tricky www.txrollergirls.com

10. 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

11. 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 • Sponsor retains responsibility to report to investigators and FDA, and the regulatory liability for failure to do so • 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

12. Traditional Pattern of Outsourcing Integration Strategic Alliance • Shares common goal/objectives • Engages in joint strategic planning • Forms relationship-based structure • Makes open-ended agreements • New business forms Partnership • Incorporates client into strategic planning • Assigns dedicated relationship management • Makes directed investments • Builds collaborative mechanisms Preferred Supplier Transactional • Establish core team • Builds collaborative mechanisms • Develops understanding of client’s customers • Responsiveness to requests Source: August 2004, Goldman Sachs Research

13. Checks and Balances

14. Topics • ABCs of CROs • Planning • RFP and Due Diligence • Contracting • Execution of Work • Evaluation • 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

15. 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: • Expertise: Does the CRO have the expertise to undertake duties Sponsor desires? • Compatibility: Can the CRO fulfill its duties in manner that is compatible with the Sponsor (i.e., is there a good fit)? • Capacity: Does the CRO have the ability to commit the manpower and resources needed in the Sponsor’s timeframe? • Price: Does the CRO provide services at same price as competitors? If not, what added value is being offered?

16. CRO Selection • Sponsor usually conducts an RFP process tailored to the specific trial at hand • Sponsor’s due diligence should include: • Web research • Public directories • Careful analysis of Responses to RFP • Interviews with operational leaders • 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

17. 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

18. Quality is important www.spelrite.com

19. Topics • ABC of CROs • Planning • RFP and Due Diligence • Contracting • Risks to manage • Metrics • 3rd Party Agreement • Change Orders • Staffing Issues • Execution of Work • Evaluation • Take Aways

20. A lot of this is obvious

21. 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

22. Factors Most Often Causing Study Delays in the U.S. Source: Thomson CenterWatch 2007 Survey of 522 Investigative Sites in the U.S.

23. Expect the Unexpected

24. Topics • ABCs of CROs • Planning • RFP and Due Diligence • Contracting • Risks to manage • Metrics • 3rd Party Agreement • Change Orders • Staffing Issues • Execution of Work • Evaluation • Takeaways My mother never saw the irony in calling me a son-of-a-bitch.Jack Nicholson

25. CRO and Sponsor Relationships • Transparency of performance builds trust • Assures alignment on study quality • Provides tools for proactive and focused management of issues early so they don’t become bigger problems • Allows for shared consensus on steps for resolution

26. Metric Creation Metric Use Feedback Critical Success Factors Key Performance Indicators Specific Performance Indicators Senior Committee Discussion Feedback & Adjustment Junior Committee Discussion CRO Engagement Measurement Analysis Planning RFP and Due Diligence Execution of work Contracting Evaluation Metrics in a CRO Relationship

27. Make metric development collaborative www.bp3.blogger.com

28. 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

29. Example Metric Definition Table Cuddigan & King *All days specified are elapsed time

30. Example Metric Definition Table, contd. *All days specified are elapsed time Cuddigan & King

31. Example Metric Definition Table, contd. Cuddigan & King

32. Example Metric Definition Table, contd. Cuddigan & King

33. Metric Creation Metric Use Feedback Critical Success Factors Key Performance Indicators Specific Performance Indicators Senior Committee Discussion Feedback & Adjustment Junior Committee Discussion CRO Engagement Measurement Analysis Planning RFP and Due Diligence Execution of work Contracting Evaluation Metrics in a CRO Relationship

34. 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

35. How Do We Use Metrics? • Just as you would internally, for performance management • Dispute Resolution (later) • Contractually in a few cases • Contractual management process and dispute resolution • Contractual rewards • Contractual penalties

36. Topics • ABC of CROs • Planning • RFP and Due Diligence • Contracting • Risks to manage • Metrics • 3rd Party Agreement • Change Orders • Staffing Issues • Execution of Work • Evaluation • 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

37. DSMB, MRC, etc SPONSOR Services Agreements CTA CTA CTAs CRO* INSTITUTION/ CLINICAL SITE *Contracts on behalf of sponsor (donated by dotted line) INVESTIGATOR Blue = CTA Orange = Service Agreement Green = Regulatory “agreement” Informed Consent 1572 **May or may not be a written agreement - depends on whether IRB is commercial, local, centralized, etc FDA SUBJECT IRB** Third party vendors (e.g., labs)

38. Ability to Bind Sponsor to CTAs • Sponsor may want CRO to handle CTAs because of: • Speed • Cost • Strength of CRO’s relationships with research sites/investigators • However, sponsors may have problems with CROs protecting sponsors’ interests • CRO sometimes want to get contract in place quickly and not expend resources in lengthy negotiations • CRO may not have adequate legal expertise

39. Ability to Bind Sponsor to CTAs • Contractual controls: Range of Possibilities • CTA template • 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 • Notification of changes and amendments

40. Topics • ABC of CROs • Planning • RFP and Due Diligence • Contracting • Risks to manage • Metrics • 3rd Party Agreement • Change Orders • Staffing Issues • Execution of Work • Evaluation • Takeaways 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

41. Change Orders • Statement of Work sets forth services to be provided by CRO • Services beyond or different from SoW are generally subject to a “change order” • Points to consider • 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 • CRO must prepare the change order and describe in detail changes to scope, timing, costs, personnel, etc • 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

42. Topics • ABC of CROs • Planning • RFP and Due Diligence • Contracting • Risks to manage • Metrics • 3rd Party Agreement • Change Orders • Staffing Issues • Execution of Work • Evaluation • Takeaways Democracy used to be a good thing, but now it has gotten into the wrong hands.-Senator Jesse Helms

43. Personnel • Experience & qualification of CRO personnel varies widely • Educational background • Therapeutic area experience • Monitoring experience • Training • Accreditation (e.g. ACRP, SoCRA) • Study personnel change frequently • Advancement • Turnover • Re-assignment

44. 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 personnel • Cost of study-specific training typically included in the budget • Training of replacement personnel may generally be allocated to the CRO • Reduce impact. Institutionalize communication, documents and systems to reduce dependence on outstanding people

45. Topics • ABC of CROs • Planning • RFP and Due Diligence • Contracting • Execution of Work • Communications • Monitoring performance • Red Flags • Dispute resolution • Evaluation • Takeaways I have always wanted to be somebody. I guess I should have been more specific.-Lily Tomlin

46. Sometimes the obvious stuff escapes us Farm1.static.flicker.com

47. Managing Communications • Poor communication is often cited as a prime reason for frosty relations between CRO and Sponsors • You need a comprehensive plan: • 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 • Structure • Provide for basic joint committee structure • Frequency • Form (e.g. meetings, conference calls, written and other content issues)

48. Topics • ABC of CROs • Planning • RFP and Due Diligence • Contracting • Execution of Work • Communications • Monitoring performance • Red Flags • Dispute resolution • Evaluation • Takeaways

49. Monitoring Performance • Monitoring reports should be • Submitted by CRO timely • Reviewed by sponsor timely • Resolved timely, including evaluation and escalation, if necessary, of reported protocol violations and other non-compliance • Contract language should address this • Commitments • Metrics

50. CRO Progress Reports • In the agreement, require written progress reports at regular intervals • Budget for frequent status calls between sponsor and CRO • Topics • Contract status • IRB approval status • Site initiation/monitoring/close-out visits • Enrollment • 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)