Are There Better Alternatives to Phase III Clinical Trials: Con

1. Are There Better Alternatives to Phase III Clinical Trials: Con Nevin Murray

2. A Short History of Clinical Trials • Theoretical rationale sufficient. • Case Reports. • James Lind: A Treatise of the Scurvy, 1753. • Claude Bernard 1813-1878: observations in groups rather than case reports. • Oslerian Era: Results of treatment of a series of patients by Professor A versus Professor B.

3. Van Helmont’s Wager: 1662Theory versus Experience “Let us take out of the hospitals, out of the camps, or from elsewhere, 200, or 500 poor people that have fevers and pleurisies. Let us divide them into half, let us cast lots, that one half of them may fall to my share, and the other to yours…We shall see how many funerals both of us shall have. But let the reward of the wager be 300 florens, deposited on both sides.”

4. Middle Ages Purging the System of Toxins. Bloodletting: leeches, phlebotomy etc. 2003 Purging the System of Toxins Boosting the Immune System Theory Based Treatments

5. A Short History of Clinical Trials • Theoretical rationale sufficient. • Case Reports. • James Lind: A Treatise of the Scurvy, 1753. • Claude Bernard 1813-1878: observations in groups rather than case reports. • Oslerian Era: Results of treatment of a series of patients by Professor A versus Professor B.

6. Fibiger’s Trial of Serum Treatment for Diphtheria • Johannes A G Fibiger 1867-1928 • Nobel Laureate 1927: Spiroptera carcinoma and gastric cancer. • Diphtheria trial 1896-7, Blegdamhospitalet • Roux, Paris: benefit versus serum sickness • “To compensate for the large seasonal variation in mortality, the study should last one year”

8. Fibiger’s Trial of Serum Treatment for Diphtheria • Random allocation central methodological principle. • May 1896-May 1897: 484 pts “randomized” • Serum versus No Serum by admission day. • Planning, conduct, reporting high quality. • No statistics (statistical analysis later) • Efficacy of serum Rx for diphtheria shown • First properly conducted clinical trial.

9. Controlled Trials: The 1948 Watershed • Concurrent versus historical. • Alternate patients method: selection bias. • Two Groups then coin flip gambit: groups not comparable. • Austin Bradford Hill recommended randomization of individual patients 1946 • Provided an estimate of random error and eliminated bias of selection of pts in trial. • MRC Streptomycin in TB: 1948

14. A Comparative Study of Two Regimens of Combination Chemotherapy in Acute Leukemia Frei E III, Holland JF, Schneiderman MA, et al: Blood 13:1126-1147, 1958

15. Classification of Evidence I. Adequately powered, high quality randomized trial, or meta-analysis of randomized trials showing statistically consistent results. II. Randomized trials inadequately powered, possibly biased, or showing statistically inconsistent results. III. Non-randomized trials with concurrent controls. IV. Non-randomized studies with historical controls (ie typical single arm phase II studies). V. Expert committee review, case reports, retrospective studies.

16. Quality of Medical Evidence in Oncology • Between 1966-1996 783 controlled trials pertaining to 24% common decisions or interventions (level 1) • Additional 21% of decisions/interventions supported by (level 2) • 55% supported by level III, IV, V Djulbegovic et al. Am J Med 1999,106:198-205.

17. Quality of Medical Evidence in Oncology • Investigation of evidence-based oncology project examined the level I evidence in solid tumors by an in-depth review of the papers published since 1975. • 1967 randomized clinical trials. • 1238 clinical endpoints. • 130 (11%) ranked as contributing to level I. Brooks et al. Evidence-based Oncology Project. Surg Oncol 2002.

18. Do we always need randomised controlled trials?

19. Res ipsa loquitur 1. Childhood Leukemia 2. Hodgkin’s Lymphoma 3. Testicular Cancer 4. Gastrointestinal Stromal Tumors

20. How large should the trials be? As of today, there has not been a single systematic review of randomised trials in solid tumors that has shown an absolute long-term survival improvement of >10%. Many trials have targeted > 15%. Controversy until meta-analysis.

22. British Medical Journal 1995;311:899-909

23. R A N O M I Z E • No chemotherapy • Eligibility: • pStage I-III NSCLC • Age: 18-75 yr • No prior malignancy • Informed consent • Chemotherapy* IALT Trial DesignOpen Design Phase III * PE: 56%; PVin: 27%; PVlb: 11%; PVnd: 6%

24. Summary 4.1% absolute benefit from 40.4% to 44.5% at 5 years for overall survival p<0.03 • 5.1 % absolute benefit from 34.3% to 39.4% • at 5 years for disease-free survival (p< 0.003) • No treatment interaction identified • Lethal toxicity 0.8%

25. 775 181 932 450 308 624 At risk 935 602 432 286 164 774 Overall Survival Chemotherapy Control Years

26. Adjuvant Chemotherapy of Resected NSCLC: the Difference 1. Relative Risk Reduction: 14% 2. Absolute difference: 4% 3. Number Needed to Treat: 25 patients

27. “A difference is not a difference unless it makes a difference.” Gertrude Stein

31. Corynebacterium parvum “Shake and Bake”

32. CODE Regimen Week Chemotherapy 1 2 3 4 5 6 7 8 9 Cisplatin 25 mg/m2 IV x x x x x x x x x Vincristine 1 mg/m2 IV x x x x x Doxorubicin 40 mg/m2 IV x x x x x Etoposide Day 1 - 80 mg/m2 IV x x x x x x Day 2 - 80 mg/m2 PO x x x x x Day 3 - 80 mg/m2 PO x x x x x

34. High Dose Chemotherapy in Breast Cancer • 1990’s Phase II trials of high dose chemotherapy with bone marrow transplantation made public. • Compared to historical controls, high dose chemotherapy suggested a 40% improvement compared to historical controls at 3 years. • 41,000 women treated before phase III trials reported in 1999.

35. High-Dose Standard NCIC CTG MA.16 Overall Survival 100 80 60 Percentage 40 20 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 High-Dose Standard 112 99 76 56 35 23 11 0 111 101 76 54 40 17 5 1 Time from Randomization (years) Log-Rank test for equality of groups: p=0.9558

36. Breast cancer Endometrial cancer VTE cholelithiasis Menopausal Sx Lipid lowering Ischemic cardiac disease Alzheimer’s Osteoporosis Colorectal cancer “ALLEGED”Harms and Benefits H B Where does the balance rest? HRT

37. Sources of Information • Observational Studies • Case-control Cohorts • Consensus Reports • Randomized trials HRT

38. Breast cancer Endometrial cancer VTE Cholelithiasis Menopausal Sx Lipid lowering Ischemic cardiac disease Alzheimers Osteoporosis Colorectal cancer “ALLEGED”Harms and Benefits ? B H HRT: JAMA, 2002

40. Concurrent Chemoradiation of Locally Advanced Epithelial Ca • Stage III Non-small Cell Lung Cancer • Limited Stage Small Cell Lung Cancer • Head and Neck Cancer • Esophageal Cancer • Anal Cancer • Cervical Cancer

42. Phase III Randomised Clinical Trials • Hallmark is to expose trial participants to exposures based on the play of chance. • Reduces likelihood of biases (known and unknown) in determination of outcome. • Amenable to statistical analysis • Especially useful for the examination of small and moderate treatment effects.

44. Opposition to Phase III Randomized Clinical Trials Rebuttal from the 1940’s

45. T. Lewis: Clinical Science Illustrated by Personal Experience. London: Shaw and Sons 1934:178-83 “It is to be recognised that the statistical method of testing treatment is never more than a temporary expedient, and that but little progress can come of it directly: for in investigating cases collectively, it does not discriminate between cases that benefit and those that do not, and so fails to determine criteria by which we may know beforehand in any given case that treatment will be successful.”

46. Bradford Hill’s Reply: 1946 “Tell me the criteria to distinguish patients who will respond from those who don’t and we will build this into the trial.”