Or…why aren’t we making more progress?

1. Challenges In Translating Success From The Lab To The Clinic A Perspective On Our Current Infrastructure And Suggestions On Ways To Improve It Or…why aren’t we making more progress? Lee M. Ellis, M.D. Departments of Cancer Biology and Surgical Oncology Metastasis Research Center UT MD Anderson Cancer Center Houston, Texas, USA

2. “Progress” For Patients With Advanced Stage Disease (Solid Tumors) * < 1yr improvement in PFS, more commonly < 6 mos My own views: Although we may be achieving significant “p values” in studies, are we really make a difference in the lives of our patients?

3. Barriers to Progress(And Potential Solutions) • The Obvious • Mice are not humans • We need to learn how to use our murine models correctly • Integrity • The “System” and The Lack of a Sense of Urgency

4. Nature Medicine 2010

5. The Growth Rates of Tumors in Mice is Much Faster than Growth Rates in Humans • Rapidly proliferating cells are more sensitive to nearly all therapies • Duration of therapy is also shortened in mice • The Fix: Utilize models with smaller inoculums, allowing for slower tumor growth, slower endothelial cell proliferation and increased stroma formation. Or use transgenics. • Allows for longer duration of therapy, which is more relevant to humans Ellis, Fidler, Nat Med 2010

6. We Often Times Study Complex Regimens Into Patients Without Testing Them First In Mice

7. Most Patients With Metastatic CRC Will Receive FOLFOX • Only 5 studies combined oxaliplatinand 5FU in CRC murine models • Only one study used an orthotopic model

8. No Preclinical Studies Evaluated the Combination of 5-FU, Oxaliplatin, VEGF inhibition (standard of care) AND inhibition of either EGFR, Hedgehog, or Cox-2 2 failed (or even harmful) Phase III trials 1 failed Phase II trial Phase III trial in the adjuvant setting ongoing

9. Why Is It Important To Study Combination Therapy In Mice Even Though Experiments With 1-2 Agents Seems Promising? • Chemotherapies and targeted therapies lead to cytokine responses • Are these compensatory survival pathways? • Shouldn’t we know about this biology prior to subjecting our patients to this therapy? • More is not better (and may even be worse) • Chemo + Bev + EGFR MoAB in mCRC • PACCE • CAIRO-2

10. We Often Times Study Complex Regimens In Patients Without Testing Them First In Mice My personal view: We should never subject humans to any regimen that has not been studied in mice! • The Fix: We must study complex regimens in mice BEFORE moving these regimens into clinical trials • Should this be mandated by the FDA or CTEP?

11. There Are Times When We Are Not Sure What We Are Studying In The Lab Cell line contamination/misidentification has been thought to occur in up to 60% of cell lines commonly used • 3 commonly used esophageal cancer cell lines were cell lines from other tumor types • data from these cell lines formed the foundation for • several ongoing clinical trials • 100 publications • 11 patents • Many journals require or request validation of cell line within 6 months of use • - This should be mandatory for all publications • Institutes should also mandate (and offset costs) of cell line genomic fingerprinting

12. Viewing The Entire Spectrum From Mice To Humans The 50% Rule for Drug DevelopmentYou Need to Make a Big Difference in a Mouse for It To Translate Into a Meaningful Difference in a Human • For every step along the way, the delta (D) in improvement in efficacy over the control arm decreases by ~50% • Mice  better mice models • SQ orthotopic or genetically engineered murine model • Preclinical  Phase Ib/II • Phase II Phase III • Maitland et al CCR 2010

13. Chemo +/- Targeted Agents in Phase II/III Trials Examples of Trials Where PFS is Shorter in the Phase III Study Caveat: Most regimens advance to a Phase III study without having been studied in a RANDOMIZED Phase II trial Chan at al. JCO 2008 EI-Maraghi, Eisenhauer, JCO 2008 Tang…Sargent. JCO 2010

14. The Disappointment of Progressing from Phase II to Phase III Trials Mark Ratain “Estimating from these data, the likelihood that a published phase II combination chemotherapy trial will result in a subsequent trial showing an improvement in standard of care within five years was 0.038% (CI 0.016-0.064)”

15. Barriers to Progress(And Potential Solutions) • The Obvious • Mice are not humans • Integrity • Selective Reporting • “Massaging” Data to Stay Alive/Advance in Academia • The “System” and The Lack of a Sense of Urgency

16. Selective Reporting of Laboratory Studies • Journals prioritize “positive” results • If a drug works in 2 cell lines, and does not in 8, we only see the results on the 2 cell lines • Students, post-docs and faculty need publications for advancement • “Publish or perish” • In many labs, 2 trainees work on the same project competing with each other…guess who wins? • Therefore, we tend to report only the “positive” data and ignore the negative data

17. But….There is Value In Reporting Negative Data (Targeted Therapies) • Identification of biomarkers for resistance or sensitivity • Reporting of negative outcomes in the lab, may lead to new insights into why the outcomes were negative • Understand a detrimental effect of combination therapies • Saving costs and time invested by others in the field • It is the right thing to do (integrity) • Unfortunately, that is not how the system currently works

18. The Fixfor Selective Reporting of “Positive” Data • Journals must provide a forum for publication (accessible in PubMed) of negative data • This can be: • an independent on-line publication to save costs for the publishers and authors • included within the manuscript, where both positive and negative data are reported • Companies must allow reporting of negative data when writing contracts and MTAs • Universities/Cancer Centers must insist on this • Authors must sign a statement confirming that all relevant data, both negative and positive, have been included in this publication

19. The Tougher Issue Lapses in Integrity and the “Massaging” of Data

21. Combating Human Nature:The Need to Succeed at Any Cost

22. The “Perfect Story” • High impact journals, and their reviewers, only accept the “perfect story” • Unfortunately, biology is not linear and never presents a perfect story • Seeking to tell the perfect story leads to • The temptation to “massage data” • Delays in submission for publication • One investigator told me that it took him 9 yrs of work to publish an article in a high impact journal • In the 9 yrs it took to publish this work, ~3,000,000 US patients died of cancer

23. The “Archeological Dig” of High Impact Publications • The two layers of most high impact publications • The original manuscript has a well defined hypothesis • and experiments • But…the final manuscript reports on a number of studies that just don’t seem to fit…..these are done to appease the reviewer (who make investigators jump through hoops) • The outcome of the experiments done for the revision must be perfect, as we are “oh so close” • Trainees are sent to do these studies • Unspoken request: “come back with the data we need”

24. One Example of Our Focus on the Process Rather Than The Product • Reviewers should estimate costs of extra experiments • Academic editors should play a larger role and determine if studies will add to scientific value • “Yes or No”..is this work of value? Nature April, 2011

25. Can Our Academic Work Be Reliably Reproduced? • Industry has to reproduce academic data before launching a program • My colleagues in Industry tell me that preclinical studies from academia cannot be reproduced >50% of the time

26. The Fix for “Lapses” in Integrity • Trainee’s careers should depend more on the mentor’s recommendation and less on high impact publications • Journals must allow publication of “imperfect stories” as cancer rarely presents as a perfect story • More credit should be given to teaching and mentoring • It is not just about grants and publications • We must succeed at multiple levels in academia • Educate basic scientists on the reality of cancer • Have them attend tumor boards and clinics! • Or at least have lunch in the lobby of the cancer center…… • There must be more transparent opportunities for reporting unethical behavior • Whistle-blowers (trainees) must be protected

27. Barriers to Progress(And Potential Solutions) • The Obvious • Integrity • The “System” and The Lack of a Sense of Urgency

28. Our System....(with a few exceptions) • Is cumbersome and slow • A recent shift towards overemphasizing compliance regulations that go beyond the issues of patient safety and confidentiality • Does not encourage taking risks with innovative translational research and clinical trials • More on this later • Is too focused on process and not focused enough on productivity(real advances)

29. To Administrators, Compliance Officers and Lawyers • Make the effort to facilitateresearch rather than search for trivial issues that delay or obstruct the process • If our patients are safe, and our animal studies are ethical, limit the “hoops” we have to jump through to do our work • Accelerate approval of contracts, MTAs, IP issues • “the enemy is cancer, not each other” • Can Universities and Cancer Centers develop a common template? • Let us do what we are here to do, rather than spend our time on paperwork and trivial items

30. Grants Write a grant due for Feb deadline 4 months Study section meets 4 months later Council meets 2-3 months later and pink sheets sent Repeat Process • Reviews Take Too Long/Funding Takes Too Long • By the time the grant is approved and funding is available for the work, 18-24 months have passed • Reviewers are told to evaluate grants, but not to tell grantees how to do it better • Why not? • Writing grants takes too long and keeps us from doing the actual research • The ideas in the grant are what counts, not the accessory paperwork (layman’s abstract, protocol approvals, etc) • Delay the submission of all accessory information until the funding decision is made (expand the “Just in Time” program)

31. The Fix for Our Grants System • The Fix • Speed up reviews…...money talks • Cancer Prevention and Research Institute of Texas (CPRIT) pays reviewers $2,000/day for a 2 day study section…and they attract outstanding reviewers • Use a “Line Item Veto” and immediately fund the best aims/sections of grants, and don’t fund the less exciting aims • Quicker funding in exchange for lesser amounts of funding • But MORE grants can be funded • We must provide good pay for the highly qualified grants administrators who are comfortable and qualified to take on this increased work load • Take the best projects from rejected P-01 and SPOREs and fund them independently and immediately

32. The “System” Does Not Reward Innovation or Boldness • We lack the ability/courage to fund high risk/high impact laboratory and clinical studies • This is risky for young academic investigators, but these are exactly the people who should be doing these studies and trials • Too many “me too” drugs and “me too” trials with limited or marginal expectations • It is not just about p values! • We need to train more Physician-Scientists and we must provide the infrastructure for them to succeed Science May 27, 2011

33. Lastly…..Our Loss of a Sense of UrgencyIt takes too long to do….. everything!! • Write grants and protocols • Peer review of grants and protocols • Company approval of protocols • MTAs • IP issues (and fights) • IRB approvals • Initiation of clinical trials • Acquisition of tissues for translational studies

34. In the US, 900 people die each day of cancer In the time it takes to… We must do everything possible to accelerate all processes!!

35. The Overall Fix • All of these fixes require financial support and a change in the “system”…we must renew our sense of urgency • Increase payment to Scientific Review Officers as they will need to be more autonomous, and we must attract the best people for these important jobs • Yes, this is tough……But, if we are to make advances in cancer therapy, EVERYONE needs to step up to the plate • NIH/NCI/DOD, etc • Journals and editors • Investigators and Universities • Congress and taxpayers • After all, we are battling cancer, this is not a “game” • Let’s get serious about this

36. If We Are Not Satisfied With Current Outcomes, We Must Provide Suggestions on Moving Forward “If you are not part of the solution, you are part of the problem” Eldridge Cleaver

37. Credit Should be Given To: • NIH/CSR for shortening grants and grant reviews • NCI response to Institute of Medicine Recommendations (ASCO Post, May 15, 2011) • Those who fund true innovation in the lab and the clinic • CTEP/Cooperative groups for shortening deadlines • The DOD (and other agencies) for providing suggestions on how to improve studies in funded grants • Institutes/Universities who recognize a scientist’s value that goes beyond a high impact publication

38. Thank you for your attention! Now…let’s get moving! Thanks to Chuck Blanke for reviewing these slides and for leading the ASCO Education Committee, 2011

40. Preclinical Findings Can Be MisleadingInterpretation of Results • Basic Scientist interpretation • Inhibition of tumor Growth (success) • Medical Oncologist interpretation • Progressive disease (failure) Control Arm Experimental Arm