1. Overcoming Barriers to International Clinical Trials in Rare Cancers John Welch, M.D., Ph.D. Senior Investigator, Clinical Investigations Branch CTEP, NCI

2. Why are we here? To find ways to do international clinical trials in rare cancers. Alice laughed: "There's no use trying," she said; "one can't believe impossible things.“ "I daresay you haven't had much practice," said the Queen. "When I was younger, I always did it for half an hour a day. Why, sometimes I've believed as many as six impossible things before breakfast.”

3. Mission Impossible? Cost Time Site Concerns Regional Differences Administrative Overhead Lack of Tom Cruise

4. Why do definitive rare cancer trials? Numerical argument Cancer biology Economic resources economy of scale centralization So doctors and patients can make informed decisions about how to treat people with these diseases.

5. Why do definitive rare cancer trials? ^ international Because it is economical to do so. Added value: Faster accrual Sharing of cost Existing networks Also: Conformance with multiple domains Diversity of patient population

6. Focus of Today’s Meeting Rare Cancers Feasible International Clinical Trials Implementors GovernmentPublicIndustry

7. Who is and isn’t here today? Government: USG – NIH, FDA, ORDR, OHRP, DOS Public: Patient Advocacy Implementors: Clinical Trial Groups, Researchers National representation: Canada, France, Italy, Japan, Korea, UK, USA, European Union. Trial Networks: NCIC CTG (CA), NCRN (UK), EORTC (EU), JGOG (JP), NCC (KR), INCA (FR), Instituto Tumori (IT), CALGB, COG, GOG, NCCTG, NSABP, QARC, RTOG, SWOG (US)

8. Topics not on today’s meeting Trials aimed primarily at capacity building, technology transfer, global health development. Trials primarily about prevention, early detection/screening, diagnostics, supportive care or quality of life trials. Tom Cruise. To consider: The redefinition of common tumors as rare based on molecular diagnostics.

9. Structure of Today’s Meeting Multi-stakeholder background Lessons Learned: Examples Breakout: Process-related issues Breakout by specific diseases Integration and Follow-on Planning

10. Morning Rare Trials in International Setting Leveraging Patient Advocacy Alternate Approaches to IRB Regulatory view of rare/orphan CA CTSU as a model Lessons learned (positive / negative) EU/EORTC Perspective

11. Lunch Summary of December 9, 2010 ASCO Panel on Small Population Clinical Trials Mini-Workshop on EORTC Intergroup Operations

12. Afternoon Breakout Sessions Process-Related Expediting Protocols Patient Advocacy Building the Evidence International Partnerships Lead Disease Categories Pediatric Gynecological Sarcoma Cholangiocarcinoma Adult Brain Cancer

13. Output of Today’s Meeting Breakout session conclusions & discussion (90 min) Integration of entire day, plan for follow-on (30 min) Conference Deliverables: Manuscript on international studies of rare cancers: landscape, rationale, barriers, solutions, specific initiatives. Institutions: Operations meeting within 1 year. Advocacy: Networking plan, forum. Lead diseases: List of priorities, needed resources, three year plan, follow-up expert session.

14. Contact Information Email: jack.welch@nih.govjack.welch@nih.gov Phone: +1 301-496-6512 Fax: +1 301-402-0557 All materials for today’s meeting: bit.ly/rareca

15. Challenges intrinsic to study of rare cancers Absence of standard of care Absence of baseline data; no funding for prospective cohort studies Paucity of preclinical models, biomaterials Absence of forum to plan studies / share data Result: Scattered, uncoordinated phase II studies Difficulty obtaining reimbursement for treatments Regulatory burden versus pay off Competition with common tumors for resources Variable public support for academic trials Result: Pragmatic difficulty in launching trials

16. Challenges specific to international trials: I 1.Communications Logistics, Language, Time Zones Protocol Development 2.Agent Issues Country approval for distribution Country-specific regulatory documentation Country-specific shipping requirements Health authority approval to import Shipping limitations (dangerous goods, biologicals, dry ice) Qualified person to accept receipt of agent 3.Patient Protection Adherence to Declaration of Helsinki Principles IRB / Ethics approval (multiple levels) Privacy, identifying information, electronic data

17. Challenges specific to international trials: II 4.Data collection / management Demographic data (e.g., race / ethnicity) Lab standards Electronic data transfer standards (ICH) SAE data reporting: mechanism & timing 5.Auditing (and other QA) 6.Insurance Patient health insurance Indemnity for sites and investigators 7.Science Genetic difference in population Differences in disease etiology Access to technology, training Technical standards (certification, industry, radiation) Supplies, Logistics, Testing, Review Tissue banking

18. Challenges specific to international trials: III Specific regulatory issues related to US collaborations Federal Wide Assurance (FWA) Investigator 1572 forms US State Department Approval Industry: Clinical Trials Agreements

19. International Disease-Oriented Networks: International Intergroups Breast Cancer: BIG, IBCSG, NABCG, NSABP Gynecologic Cancer: Gynecological Cancer Intergroup Brain Cancer: Society of Neuro-Oncology Lung Cancer: IASLC, ETOP, IMIG Colorectal Cancer: PETACC, AGITC International Trial Organizations EORTC European Organisation for the Research and Treatment of Cancer INCTR International Network for Cancer Treatments and Research