Navigating the Clinical Trials System and Clinical Trials in the Cooperative Groups

1. Navigating the Clinical Trials System and Clinical Trials in the Cooperative Groups Neal J. Meropol Ireland Cancer Center, University Hospitals Case Medical Center Case Comprehensive Cancer Center Cleveland, OH

2. Ireland Cancer Center 2011UH Case Medical Center

3. Philly vs. The Cleve

4. Philly vs. The Cleve

5. Philly vs. The Cleve

6. So you have an idea��..

7. Question 1

8. Put it on paper: Letter of Intent 3-5 pages Key ingredients Rationale/Background � why is this important? Objectives � what do you hope to prove? Study population � who are the patients? Procedures � what is the intervention? Endpoints � what will you measure? Statistics � how will this study answer the question? Accrual � can you do what you claim?

9. What will make your LOI stand out?(everyone wants the same hot drug) Track record of you, your mentor, your institution Evidence that you can get the work done � quickly (time = $) Importance of the question � how will your study ultimately contribute to curing more patients with cancer? Novelty of the question Preliminary data; preclinical rationale � especially if from your lab, your institution Cost vs. potential payoff Complements other ongoing studies � elucidates mechanism Well-written, no typos!

10. Resource needs will guide where you shop the concept Patients (single- vs. multi-institution) Drugs Diagnostics Support for clinical trial staff, treatment, correlative studies IRB/regulatory staff Your time Urgency to activate

11. Often, support for a clinical trial will come from more than 1 source NCI: CTEP, R03, R21, SPORE, R01, K�s, cooperative group, etc ACS, AACR, ASCO �young investigator awards Foundations Philanthropy Institutional support Industry

12. Working with Industry: The Medical Science Liaison Your link with the main office Can provide insight into the current portfolio of investigator-initiated studies Can provide insight into company needs Handle LOIs and assist in post-approval logistics They seek to build good will Your success is their success They are not making decisions It doesn�t hurt if your mentor has a relationship higher up in the organization to have them make contact

13. NCI Clinical Trials System NCI Program Descriptions http://www.cancer.gov/aboutnci/organization/ Org Charts http://www1.od.nih.gov/oma/manualchapters/management/1123/nci.pdf�

17. The CTEP LOIhttp://ctep.cancer.gov/protocolDevelopment/letter_of_intent.htm Patient characteristics Phase Treatment plan Rationale/Hypothesis Lab correlates Endpoints/Stats Monthly accrual

18. CTEP Evaluation Criteria Strong scientific hypothesis Supporting preliminary data and/or a strong rationale Adequate patient accrual Innovative and well-justified correlative studies Ability to meet regulatory requirements Not duplicative Agent availability Industry sponsor concurrence

19. Question 2

20. What is a Cooperative Group? Clinical Trials Cooperative Groups established in 1955 NIH U10 cooperative agreement (�assistance� rather than �acquisition� mechanism); compete every 6 years Major emphases definitive studies or preparatory efforts for these studies combined modality approaches translational research, correlating biologic insights gained from the laboratory with disease behavior and treatment outcome Goals: Improve therapy, Adjunct studies, Cancer Control, Clinical trials methodology 20,000 patients enrolled annually; ~$100M annual budget

21. Cooperative Group Structure Three required components: headquarters, statistical/data management center, investigators/institutions Four main type: disease (e.g. GOG), modality (e.g. RTOG), expertise (e.g. COG), multiumodality (e.g. ECOG) Examples: ACOSOG, ACRIN, SWOG, RTOG, GOG, NCCTG, CALGB, ECOG, COG, NSABP

22. Disease vs. Modality Committees Disease Committees the driver of phase III trials Included as components of the U10 grant Not all types of cancer are represented in every group Modality Committees Vary by group May stand alone or be embedded in operations portion of U10 grant May play supportive role or conduct studies Examples: surgery, radiation, developmental therapeutics, pathology/laboratory science Cross individual disease barriers

23. �Developmental Therapeutics� Committees May spearhead studies or conduct correlatives embedded in other trials Pharmacogenetics Population pharmacology New drug development Disease-independent correlatives Orphan diseases Special populations Organ dysfunction, elderly

24. Question 3

25. How to break �in� Note: Cooperative Group leadership is dependent upon young investigators, and notices talent Write a letter to introduce yourself to the group and committee chair Have your mentor do the same; your local mentor can help by continuing to bring your name forward Make an appointment to meet with the committee chair at the next group meeting Contribute to discussion at meetings; be visible Volunteer to write up old data Pitch concepts; don�t forget about archival tissue and data Written and oral presentations should be more complete and polished than those of established investigators

26. The Players at Macro Level

27. The Relationship with Industry The public system is dependent upon industry support Pharma not only supplies drug; it is a major support mechanism for correlative science and increasingly for administrative costs ($ = accrual) CRADAs (cooperative research development agreements) mandate dual sign-off Find shared goals Recognize your value and that of your industry partner Remember: you are more than a source of patients

28. Levels of cooperative group review Disease committee chair Disease committee core members Your cooperative group�s executive committee and lab science committee NCI disease Task Force NCI disease Steering Committee Cancer Therapy Evaluation Program (CTEP) Then, write a protocol���.

29. NCI Steering Committees and Task Forces Implemented in response to NCI Clinical Trials Working Group report regarding conduct of phase III clinical trials Effort to ensure involvement of all constituencies, including those not participating in cooperative groups (e.g. RO1 investigators, SPORE investigators) Effort to improve coordination, reduce redundancy Effort to streamline ultimate NCI review, by beginning CTEP involvement earlier in the development process

30. GI Steering Committee Charge Phase III concept development, evaluation, prioritization Monitoring phase III trials Large, multigroup randomized phase II trials Organize State of the Science Meetings Create Task Forces as appropriate

31. Example: Gastrointestinal Cancer

32. Protocol Development Process in the Public system

33. Question 4

34. Timelines

35. Process Flow Map: CALGB(Dilts, Sandler, Baker et al. JCO, 2006)

36. Calendar Day per Step: CALGB(Dilts, Sandler, Baker et al. JCO, 2006)

37. What can you do to keep the process moving? Get to know the protocol development team Respond rapidly to requests Keep an eye on the process Ask how you can help � be proactive Stay in touch with the contract team

38. Barriers to Success of Cooperative Phase III Trials Note: 50% of accrual comes from community oncologists; the ivory tower does not represent reality Cooperative Group studies are not adequately reimbursed and cost the investigator money Correlative study participation may not receive appropriate credit/reimbursement Competition from industry trials The system is heavily dependent on volunteerism

39. Key Criteria for a Successful Study Keep it simple Ask an important clinical question Ask one clinical question Use a treatment that can�t be obtained outside of a trial Involve patient advocates in design and beyond Design a marketing strategy early, and implement early and often

40. Why conduct cooperative group research? Personal You get to visit cool places and stay in nice hotels �...not National platform with thought leaders Access to infrastructure and patient resources; tissue and data, not merely patients

41. What defines a successful investigator-initiated study? You got it paid for and done You presented the results and interacted with other experts with relevant interests You published the results You addressed an hypothesis You contributed knowledge that leads to further exploration You obtained results that will advance cancer treatment You enjoyed the experience