Unresolved Issues in the Globalization of Clinical Trials

1. Unresolved Issues in the Globalization of Clinical Trials Robert M Califf MD Vice Chancellor for Clinical Research

2. Globalization of Clinical Trials • Current State • Money • Ethics • Cultural environment • Genetic variation • Envisioning a positive future

3. Since 2002, the number of FDA investigators outside the US has grown by 15% annually, while the number inside the US has declined by 5.5%. • One-third of phase 3 trials of the 20 largest US pharmaceutical companies are being conducted solely outside the US. • For those same firms and studies, a majority of study sites (13,521 of 24,206) are outside the US. Source: Glickman, SW et al. NEJM 2009

4. The Globalization of Clinical Investigators Percent of Total 1572s Filed Sources: Tufts CSDD

5. Growth in Numbers of ActiveFDA-Regulated Investigators Sources: Tufts CSDD

6. The test of a first-rate intelligence is the ability to hold two opposed ideas in the mind at the same time, and still retain the ability to function.F. Scott Fitzgerald, "The Crack-Up" (1936)US novelist (1896 - 1940)

7. Creative Tension • Globalization of clinical research is a very good thing for the US and for all of us in a flat world • We need more evidence to guide effective practice in the US • So does every other country in the world • Driving globalization because of poor efficiency in the conduct of research in the US is a bad thing for the US • By the way, the same thinking could be applied to any economically advantaged country that begins to think it is “above it all”

8. Dollars and Sense: Factors Pushing Clinical Research Out of the U.S. Kevin Schulman, MD Director, Health Sector Management Program The Fuqua School of Business Director, Center for Clinical and Genetic Economics Duke University Medical Center American Federation for Medical Research (AFMR) April 14, 2009

9. Globalization of Clinical Trials—The Good • Larger sample sizes are needed • Modest treatment effects predominate • Subgroups must be validated • Will become even more important in “personalized” or “stratified” medicine • Competition spurs improvement • More research will be done • Collaboration leads to shared learning • Practice patterns • Ethics • Will ensure transparency on results reporting • Adequate sample sizes/study designs to understand genetic heterogeneity

10. Globalization: A Necessity • Proof of concept trials—there are pharmacogenomic differences • Efficacy trials—the context of clinical practice matters • Effectiveness trials—the relative costs and balance of risk and benefits are context dependent The question is not whether we globalize, it is why we do it, how we handle cultural differences and how we lump or split findings

11. Economic Proposition to Industry From Globalization $ duration* $1 – $10 billion* Pre-Launch Potential local market opportunity No requirement to match study populations to target markets Return speed* fall-off* ROI maximize area* $800 – $880 mil (2001) 0 Patent Expiration Patent Launch Decrease costs or time

12. The Good– the US Needs to Wake Up! • Rapid movement to moving clinical trials away from US • US is inferior in: • Study cost index • Population indicators (tx naïve patients) • Business environment • US is better, but losing ground quickly in: • Clinical research personnel qualification • Study site organization • Thought leader quantity

13. Image Source: http://www.pandora.ca/pictures21/900666.jpg

14. The Demise of Empires • Dominance at a point in time • Arrogance about superiority • Failure to pay attention to quality of work • Leaders content to “ride the wave” • Entrenched interests can buy stability through controlling laws and regulations • Inability to create or respond to innovation • Cost of transactions exceeds cost of actually doing the work!

15. Data gathered by the Tufts Center for the Study of Drug Development (Tufts CSDD) • >90% of all clinical trials delayed due to over-ambitious timelines and difficulty with patient enrollment • Top reasons for delays in trials: • Protracted budget negotiations • Slow IRB review and approval • Poor patient recruitment and retention • Estimated 20% of PIs fail to enroll a single patient and 30% under-enroll in a given trial • Between 2000 and 2005 38% of PIs who participated in clinical trials in a given year did not return in a subsequent year through 2008 • Up from 26% in previous 5 years

16. Patient Recruitment and Retention • Performance data on 57 phase II and III (across TAs) protocols provided by five pharmaceutical companies Source: Tufts CSDD

17. Protocol Designs More Complex and Burdensome (2000-2006) Annual Growth Rate Compensation per Procedure Represents 10,038 industry protocols; provided by Fast Track Systems Work effort values based on Medicare’s RVU methodology Sources: Tufts CSDD; Getz et al. Assessing the Impact of Protocol Design Change on Clinical Trial Performance. American Journal of Therapeutics. 2008 15(5); 450 - 457

18. Performance ‘Impact’ of protocol complexity Compared US-based pivotal trial protocols executed 1999-2002 (lower complexity) and 2003-2006 (higher complexity): Number of CRF pages rose to an average of 180 pages vs. 55 Controlling for treatment duration, cycle times increased substantially across all measures Enrollment rates worsened Source: Tufts CSDD

19. Cycle Time Metrics 69% - 75% Increase 12% – 20% Increase Median Days Elapsed Source: Tufts CSDD

22. Clinical Trial Cost Estimates $ In US 2007 Millions Full Cost Industry Streamlined Industry More Streamlined

23. Pharmacogenomics Source: Roses AD. Nature 2000;405:857-865.

24. Randomized Trial of Genotype-Guided Dosing of Warfarin Therapy: Influence of Genotype on Warfarin Dose? Herman et al, The Pharmacogenomics J 4:1-10. 2005 (From L. Lesko) McClain et al, ACMG Presentation, October 30, 2006 (In Press)

25. Randomized Trial of Genotype-Guided Dosing of Warfarin Therapy Boxplots of distribution of warfarin dose by CYP2C9 and VKORC1 genotype Sconce et al. Blood 2005; 106:2329

26. -NEJM 360; 2009

27. Cytochrome P-450 Polymorphisms and Clopidogrel Response -NEJM 360; 2009

28. Cytochrome P-450 Polymorphisms and Clopidogrel Response -NEJM 360; 2009

29. GENEVA, SWITZERLAND—World Health Organization officials expressed disappointment Monday at the group's finding that, despite the enormous efforts of doctors, rescue workers and other medical professionals worldwide, the global death rate remains constant at 100 percent. Death, a metabolic affliction causing total shutdown of all life functions, has long been considered humanity's number one health concern. Responsible for 100 percent of all recorded fatalities worldwide, the condition has no cure. "I was really hoping, what with all those new radiology treatments, rescue helicopters, aerobics TV shows and what have you, that we might at least make a dent in it this year," WHO Director General Dr. Gernst Bladt said. "Unfortunately, it would appear that the death rate remains constant and total, as it has inviolably since the dawn of time."

30. The Good--More Research will be Done • Broader sources of funding • Many governments now giving tax breaks for industry funded research • Do the research where costs are less • Do the research where barriers to trial initiation are less

31. ACC/AHA Clinical Practice Guidelines

32. ACC/AHA Guidelines: Level of Evidence of Recommendations LoE A LoE B LoE C

33. A B C A B C A B C A B C A B C A B C Atrial Fibrillation (2001-2006) Heart Failure (2001-2006) Stable Angina (1999-2002) Unstable Angina (2000-2007) PCI (2001-2005) Pacemaker (1998-2002) ACC/AHA Guidelines: More GuidelinesNo Improvement in Proportion with High Quality!

34. The Bad • Differences in practices can be found as a function of geography • Differences in outcomes can be found as a function of geography • Differences in treatment effect can be found as a function of geography

35. Current Practices in ACS Care USA vs Rest of GRACE Andrzej Budaj for the GRACE Investigators Postgraduate Medical School, Grochowski Hospital, Warsaw Poland

36. In-hospital ManagementAll ACS USA Rest of GRACE AA (%)9595  B-blockers (%)8882  B-blockers iv (%)27 9  ACE-I (%)6166  ARB (%) 7 5 Statins (%)6566  Other lipid lowering (%)83

37. Temporal trendsUSA vs Rest of GRACE Death in hospital All ACS %

38. Death and/or MI at 30 Days Placebo Eptifibatide Total n 16.88 13.89 6103 13.68 14.88 3357 EptifibatideBetter PlaceboBetter PT-E2-7

39. Death and/or MI Placebo Eptifibatide Total n 16.16 12.35 2499 12.89 10.57 1328 16.03 13.03 2542 12.10 15.52 1154 20.35 20.43 814 19.05 21.78 727 21.43 16.39 248 5.63 15.58 148 NA WE EE LA EptifibatideBetter PlaceboBetter PT-E2-8

40. Timing of Angiography Overall North America Western Europe Eastern Europe Latin America PT-C-17

41. Study Undertaken by FDA statisticians to evaluate possibility of systematic regional differences • Major cardiovascular outcome studies evaluated over the last 10 years • Overall study result statistically positive, ie. demonstrated overall effect • Region never pre-specified as a factor to be evaluated statistically • 16 independent studies

42. Estimates and confidence intervals for difference between US and Non-US treatment effects for each study In 13 of 16 , US log hazard above 0 J. Lawrence

44. A figure From the label

45. Goal External Validity X Internal Validity

46. Article cites numerous examples of trials, which produce parameter estimates of questionable value to Western European decision makers and highlights differences between emerging regions and Western Europeans, which suggest the two are mutually incomparable. • Proposed that these differences may confound study outcomes, decision-making parameter estimates and data pertaining to the incidence of adverse drug interactions • Further research should be undertaken in order to explore the relationship between geographical variance and external validity, particularly where safety data derived from relatively drug naïve regions are assumed to pertain to a maximally treated populations elsewhere in the world Source: Wathal. Outsourcing Clinical Trials www.samedanltd.com

47. Extrinsic factors such as medical practice, disease definition and study population may influence applicability of foreign data to an EU setting • Global drug development doesn’t necessarily support approval of unrestricted indications in an EU population • Consider and discuss possible influence of extrinsic factors on interpretation of results and wording of indications • In depth, prospective analysis of potential ethnic factors when conducting a clinical trial in a certain region. • Depending on the outcome of analyses can be decided whether certain clinical trials conducted in a specific area of the world would be relevant to EU setting or if there are reasons to perform additional clinical trials within the EU Source: European Medicines Agency, Pre-Authorization Evaluation of Medicines for Human Use. Feb. 19, 2009

48. Verification at time of evaluation of marketing authorization application that trials have been conducted in accordance with GCP and ethical standards • Greater transparency of this process and its outcome should be described in the European Public Assessment Report (EPAR) • Increased GCP inspection including further extension of GCP policy on increasing numbers of routine inspections as part of the need for greater supervision of the conduct and ethical standards of clinical trials performed outside the EEA Source: European Medicines Agency, EMEA strategy paper: acceptance of clinical trials conducted in the third countries, for evaluation in Marketing Authorization Applications. Feb. 5, 2008

49. Source: Reed SD, Drug Information Journal, 2007

50. Source: Reed SD, Drug Information Journal, 2007