Clinical trials - facts and myths!

1. Clinical trials - facts and myths! Why do clinical trials How did it all start Do we really need to do trials in India SWOT Analysis reenanair@email.com

2. Why do Clinical trials? • Academic Investigators / Caregivers • ~Increased ability to publish results • ↑ professional stature, earlier promotion, ↑ salary • ~ Desire to offer more therapeutic options to patients • Government Sponsors • ~ Claims of success in advancing health care • ~ Leverage for ↑ in government funding • Industry Sponsors • ~ Company profits, ↑ value of stock options, promotion • ….Wide Spread & Significant Conflicts of Interest

3. Clinical Trial Gains! • Gains for mankind • National gains • Institutional gains Departmental gains • Personal gains

4. How did it all start 1639The surgeons Mate, by John WoodallThe cures of scurvy1753Two sailors (2X6) allocated to each of:a quart of cider daily25 gutts of elixir vitriol thrice daily2 spoonfuls of vinegar thrice dailyhalf a pint of sea water dailytwo oranges and a lemon dailythe bigness of a nutmeg thrice dailyDiet was constant1795Approved in all ships

5. The Flexner Report - the Standardizationof American Medical Education 1900s • If the sick are to reap the full benefit of recent progress in medicine, a more uniformly arduous and expensive medical education is demanded. • The AMA sought to eliminate schools that failed to adopt this rigorous brand of systematized, experiential medical education. • Editors of JAMA declared, “It is to be hoped that with higher standards universally applied their number will soon be adequately reduced, and that only the fittest will survive,”

6. American Medical Education –100 Years after the Flexner Report • Flexner envisioned a clinical phase of education in academically oriented hospitals, where thoughtful clinicians would pursue research stimulated by the questions that arose in the course of patient care and teach their students to do the same. • In academic hospitals, research quickly outstripped teaching in importance. • A “publish or perish” culture emerged in American universities and medical schools.

7. Current (Cancer) Drug Development Pathway Hypothesis Generation Clinical Candidate Development Commercialization TRWG/CTWG Chem-Biol Cons $1200 MM Discovery NEXT pipeline Cumulative Investment Risk Phase 0/PD Target/ Molecule Discovery & Biological Char- acteriz. $500-600 MM Target Validation Assay Development Lead Generation Pre-Clin. Development Phase I Phase II Phase III Regis- tration Global Launch Global Optimization Lead Optimization $200-300 MM $20-60 MM Risk Cumulative Investment Time: 6-8 Years Time: 12-15 Years

8. Therapeutic development - Oncology Phase I Phase II Phase III Phase I Aim Pharmacology Activity Efficacy Strategy (Cost Benefit) (post/ marketing) Sample 1-25 9-50 200 - 1000 (Adv) X 1000 - > 5000 (Adj) Patient refractory to refractory to 1st/2nd line treat (Adv) X all treatment* conventional 1st line treatment (Adj) Methods Fibonacci, Gehan, Randomized simple, X CRM*… Simon,… Stratified, Factorial, or cross-over…. * May be different with targeted therapy

10. Examples of (Cancer)Research Priorities

11. 1. Disease (Cancer) burden

12. Liver, Breast & Cervix Cancer burden

14. Health education improves survival 3-year survival improved from 26.6% to 44.0%

15. 2. Natural history varies

17. 3. Needs of our populations vary

18. Expansion of cancer care and control in countries of low and middle income: a call to action. Paul Farmer, MD, et al. Lancet August 2010

19. Can We Apply - What We Know? If breast cancer survival rates were uniformly as high as the best in the world, 100,000 fewer women would die of breast cancer each year in the developing world. Breast Cancer 5-yr Relative Survival “Do-Know Gap” }

21. 4. Co-morbidity varies

22. The percentage of women who are too thin is particularly high in Bihar (45%), Chhattisgarh, and Jharkhand (43% each). Malnutrition levels are lowest in Delhi, Punjab, and several of the small northeastern states.The percentage of women who are overweight or obese is highest in Punjab (30%), followed by Kerala (28%) and Delhi (26%) Variations in macro-nutrients

23. Variations in micro-nutrients

24. 5. Infections are very common and the bugs are different

26. 6. PK/PD can also vary. Toxicity and effectiveness varies

28. 7. Tumor response varies

29. Hypothesis generation observational data vs confirmation by clinical research • Mega doses of Vitamin C: • What is the effect on duration of survival in pre-terminal cancer patients? • Nobel Laureate Linus Pauling: Loch Lomanside, Scotland Cameron, Pauling. • Proc Natl Acad Sci 1976; 1978 • Median Survival: 50 vs. 210 days; • 38 vs. 293 days • Mayo Clinic sponsored randomized trial

30. Moertel, Fleming, Creagan et. al. NEJM 1985; 312: 137-141

31. An Illustration of Exploratory Analyses: Surgical Adjuvant Therapy of Colorectal Cancer 5-FU and Levamisole Levamisole Control R

32. 100 - 80 - 60 - 40 - 20 - 0 Surviving, % 0 1 2 3 4 5 6 Years from randomization Surgical Adjuvant Therapy: Colorectal Cancer NCCTG Trial Cancer Intergroup Trial 5-FU+LEV n=81 LEV n=85 Control n=81 5-FU+LEV n=304 LEV n=310 Control n=315 100 - 80 - 60 - 40 - 20 - 0 0 1 2 3 4 5 6 7 8 9 Years from randomization

33. 8. Genetic make up also varies- This is going to be important in the era of personalized medicine

34. NATURE| Vol 461|24 September 2009 Allele frequency differences between groups in India are larger than in Europe

35. Gefitinib by smoking history and ethnicity Gefitinib Placebo 16 16 16 16 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 Never smoked (n=375) p<0.0001 Ever smoked (n=1317)p=0.071 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 Proportion without treatment failure Asian ethnicity (n=342)p=0.008 Non-Asian ethnicity (n=1350)p=0.020 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 Time (months)

36. 9. Creating affordable treatments

37. Out of pocket expenditureresults of a pilot study 100 BPL patients interviewed Mean expenditure was 72000 rupees before any cancer treatment was started. Ranged 15000 to over 100000 Two thirds (Rs. 50000 /USD1000) were spent before reaching TMH. 70% spend on multiple diagnostic imaging Tmh 2010- survey

38. Outcome following adjuvant chemotherapy for pancreas cancer- recent trials 5FU costs 5% of Gemcitabine CONKO-001: Disease-Free Survival ESPAC-1: Survival 100% 75% 100% 75% 50% Cumulative Disease Free Survival 50% Survival (%) gemcitabine LV+ 5FU 25% 25% observation No chemotherapy 0% 0% 0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 Months Months Neoptolemos JP, et al. NEJM. 2004;350:1200-10. Oettle H, et al. J Am Med Assoc. Oettle H, et al. J Am Med Assoc.2007;297:267-77.

39. Adjuvant head to head Gem or 5FU in pancreas ESPAC-3 RCT JAMA 2010

41. Clinical Research in CancerA SWOT ANALYSISSpeaking for myself!!

42. CLINICAL TRIALS

43. STRENGTHS • Very large patient pool • Untreated patients • High volume services • World class facilities • Good record keeping • Operating costs are low • English speaking • Research culture is improving

47. Lancet August 2010

49. WEAKNESS • Lack of formal training in clinical research • We give up easily (like our cricket team) • We also need foreign coaches • Very large (migrant) patient pool • Lost to follow up • High volume (overburdened) services • Cheap (untrained and incompetent) labor • Regulatory affairs personnel lack experience • Illiterate or vernacular speaking • Drop out and lost to follow up rates are high

50. No. Clinical trials