Topics in Clinical Trials (1) - 2012

1. Topics in Clinical Trials (1) - 2012 J. Jack Lee, Ph.D. Department of Biostatistics University of Texas M. D. Anderson Cancer Center

2. 1: Introduction to Clinical Trials • Why do we need them? • What is a clinical trial? • History of clinical trials • Clinical trial phases • Major aspects of clinical trials • Ethics of clinical trials • Study protocol • Examples

3. Why do we need clinical trials? A researcher tried jalapenos on a stomach ulcer patient, and the ulcer went away. The researcher published an article: “Jalapenos Cure Stomach Ulcers.” The next patient subjected to the same treatment died. The researcher published a follow-up article: “More Detailed Study Reveals That Jalapenos Cures 50% of Stomach Ulcers.”

4. Is erlotinib (an EGFR inhibitors) effective in treating lung cancer? • Overall response rate: • Chemo – 30% Erlotinib – 25% • Response rate by EGFR mutation (a predictive marker)

5. Signal + Noise Data: Data Analysis: Extract the signal and filter out the noise Statistics: Find a needle in a haystack

6. Finding A Needle In A Haystack

7. Data Tsunami

8. Statistics and Medical Research • Premise: Advance in medical practice is based on research • Research validity is based on scientific credibility • Scientific Method: QuestionDesignStudyDataAnalysisConclusion New Question Good design + Good analysis  Valid Inference • Statistics is needed in every step • Sound statistics is the basis of evidence based medicine (EBM) • Statistician is a guardian of science

9. Triumph of Medical Research and Clinical TrialsDiscovery and Approval of STI571/Gleevec (Glivec) • 1960-1980s: • Identify chronic myelogenous leukemia (CML) is associated with chromosome translocation of the abl proto-oncogene, on chromosome 9 in non-CML patients and translocated to the chromosome 22 in patients with CML. • abl oncogene is activated by this translocation, which leads to the formation of an altered protein containing a piece of the Abl protein joined to a piece of a second protein, BCR. It is this fused protein product, called BCR-ABL, which is abnormally expressed in about 95 percent of CML patients. • 1990: • Several labs showed that bcr-abl alone causes leukemia in mice. • STI571 was formulated and shown to inhibit the growth of BCR-ABL-expressing cells. • The preliminary results of this early study showed that 31 out of 31 patients who received at least 300 milligrams daily had their blood counts return to normal. In nine of the 20 patients who were treated for five months or longer, no cells with the Philadelphia chromosome could be found. • 2001: • February: Novartis submitted the New Drug Application for STI571, now known as Gleevec, to FDA for the treatment of the late phases of CML. • April: Results of a larger study of STI571 in 83 patients were reported in New England Journal of Medicine. In the 54 chronic-phrase CML patients who were treated with doses of 300 milligrams or more, normal blood counts were restored in 53, and in 29 of the 54 patients, the Philadelphia chromosome disappeared. Most side effects were mild. • May: U.S. Food and Drug Administration approved the sale of STI571/Gleevec for CML.

10. Capdeville, Nature Review 2002

11. Vemurafenib for melanoma with BRAF V600E mutation FDA Approval August, 2011 Crizotinib for lung cancer with EML4-ALK translocation FDA Approval August, 2011

12. What is a clinical trial? • A clinical trial is a prospective study evaluating the effect and value of intervention(s) in human beings under pre-specified conditions. • A controlled clinical trial is a prospective study comparing the effect and value of intervention(s) against a control in human beings. • The clinical trial is the most definitive tool for evaluation of the applicability of clinical research. • It represents a key research activity with the potential to improve the quality of health care and control costs through careful comparison of alternative treatments. A properly planned and executed clinical trials is a powerful experimental technique for assessing the effectiveness of an intervention.

13. Type of Research • Case Report • Observational Study • Retrospective • Cross-sectional • Prospective • Clinical Trial • Single arm vs. multi-arm trials • Controlled clinical trials • Historical control • Concurrent control • Randomization • Blinding • Single center vs. multi-center trials

14. History of Clinical Trials • Daniel 1:12-16. A diet experiment (Royal food and wine versus vegetables and water) for 10 days • 17th century: Lancaster (captain of a ship of East Indian Shipping Co.) conducted an experiment to examine the effect of lemon juice on scurvy for sailors. Ships with lemons were free of scurvy compared to ships without lemons having scurvy. Lind (1753) – Study of 5 tx for scurvy in 10 pts (2/tx) plus 2 pts without tx (control). • First two pts given orange and lemons recovered quickly and was fit for duty after 6 days, compared favorably with all other patients. • Smallpox experiment (1721) at the Newgate prison in Great Britain. Voluntary inmates were inoculated and were free from smallpox.

16. Modern Clinical Trials (post WWII) • Medical Research Council (UK): treatment for common cold (1944), tuberculosis (1948) • National Institutes of Health (US): Cancer trials (1960’s), Coronary Drug Project (1965) • Observational studies lead to clinical trials • Cholesterol: • Framingham Heart Study (1951): high cholesterol, high blood pressure, smoking, and diabetes correlated with cardiovascular disease • Scandinavian Simvistatin Survival Study (1994): statin reduced mortality • Hormone Replacement Therapy (HRT) • Observation studies show that HRT reduced cardiovascular mortality and morbidity • HERS trial: HRT has no benefit but a risk for thrombosis (Grady, 1998) • WHI: HRT has no CV benefit but has a harmful effect due to blood clotting • Beta-carotene • Numerous epidemiology study showed benefit for protecting against cancers • ATBC trial and CARET trial showed a harmful effect among currentsmokers. Both trials stopped early. • PHS showed that beta-carotene has no effect on mostly non-smokers

17. Clinical Trial Phases • Phase I: clinical pharmacology and toxicity • Phase II: Initial Assessment of Efficacy • Phase III: Full-scale Evaluation of Treatment Efficacy • Phase IV: Postmarking Surveillance Ref: • Nottage M and Siu LL. Principles of clinical trial design. Journal of Clinical Oncology 20:42s-46s, 2002. • Lee JJ. Clinical trial design for anticancer therapies. In: The Cancer Handbook, 2nd Ed. Ed(s) Alison M. Wiley: London, UK, 1330-44, 2007.

18. Phase I: clinical pharmacology and toxicity • 1st experiment in human for new drug, schedule, or combination • Primary concern: Safety • Goal: define the maximum tolerated dose (MTD) in a dose-escalation study • Typically required 15-30 patients • Algorithm-based design: 3+3 • Model-based design: continual reassessment method (CRM)

19. Phase II: Initial Assessment of Efficacy • At MTD or recommended phase II dose, examine the efficacy and refine the toxicity profile of the agent • Goal: IIA – screen out ineffective drugs IIB – sending promising agents to Phase III • Typically, require 30-100 patients in a multi-stage design • Commonly used design: Gehan’s design, Simon’s two-stage design, randomized phase II design

20. Phase III: Full-scale Evaluation of Treatment Efficacy • Compare new treatment with standard treatment in a rigorous manner, e.g. a double-blind randomized placebo-controlled study • Goal: define the ‘best’ treatment, which has an implication of changing the current practice in treating patients. • Typically required hundreds or even tens of thousands patients in primary cancer prevention trials. • Long-term, expensive

21. Phase IV: Postmarking Surveillance • Goal: monitoring the adverse effects, long-term morbidity and mortality after the treatment being used in a large number of patients and patients being followed up for a long period of time

22. Examples • Pilot study (feasibility): N 18 • Phase I (toxicity): 20 N  40 • Phase II (efficacy): 30 N  100 • Phase III (confirmatory): N > 100 • Primary Prevention Trials: N > 10,000 • e.g. BCPT (Tamoxifen): N=16,000 (13,388) • PHS (aspirin, b-carotene): N=22,071

23. Drug Development Treatment of Choice Phase I Phase II Phase III Pt. Characteristics sicker healthier heavily pre-treated/ Untreated failed std. tx poor prognosis good prognosis heterogeneous homogeneous Treatment 2nd, 3rd, or 4th line front-line therapy therapy

24. Two Big Enemies Against Finding the Truth and Effective Weapons to Fight Against Them • Bias • Variation • To tackle bias • Randomization • Blinding • Intent to treat principle • To tackle variation • Control or reduce variation • Increase sample size

25. Randomized Control Trials • Advantages of randomization • Remove the potential bias in treatment assignment - conscious or subconscious • Randomization tends to produce comparable groups - known or unknown prognostic variables • Validity of statistical tests of significance is guaranteed

26. Randomization • 1st introduced by Fisher in 1926 in agriculture research • 1st clinical trial used randomization – Amberson et al. (1931) • Matching 24 pts with pulmonary tuberculosis into 2 comparable groups of 12 each • Flip a coin to decide which group received sanocrysin, a gold compound • Streptomycin trial by British Medical Research Council (1948) • 1st to use random numbers in allocation pt to experimental or control groups

27. 20 17 42 28 23 17 59 66 38 61 02 10 86 10 51 55 92 52 44 25 74 49 04 19 03 04 10 33 53 70 11 54 48 63 94 60 94 49 57 38 94 70 49 31 38 67 23 42 29 65 40 88 78 71 37 18 48 64 06 57 22 15 78 15 69 84 32 52 32 54 15 12 54 02 01 37 38 37 12 93 93 29 12 18 27 30 30 55 91 87 50 57 58 51 49 36 12 53 96 40 45 04 77 97 36 14 99 45 52 95 69 85 03 83 51 87 85 56 22 37 44 91 99 49 89 39 94 60 48 49 06 77 64 72 59 26 08 51 25 57 16 23 91 02 19 96 47 59 89 65 27 84 30 92 63 37 26 24 23 66 04 50 65 04 65 65 82 42 70 51 55 04 61 47 88 83 99 34 82 37 32 70 17 72 03 61 66 26 24 71 22 77 88 33 17 78 08 92 73 49 Random Number Table

28. Blindness • Amberson et al. (1931) • Pts were not aware of whether they received IV injection of sanocrysin or distilled water • Single-blinded study • Either pts or physicians are blinded to the tx allocation • Double-blinded study • Both pts and physicians are blinded to the tx allocation • Key: In general, it will be desirable that whosoever evaluates the outcome should be blinded to the treatment assignment

29. Controlled Trials • No treatment control • e.g.: standard practice is observation after surgery • Observation versus ‘adjuvant’ therapy • Different types of controls • Placebo • Active control • use standard therapy • use another new therapy • ‘sham’ treatment control • sham surgery or accupuncture • Reciprocal control • Tx A: smoking cessation counseling, no dietary intervention • Tx B: dietary intervention, no smoking cessation counseling • Two endpoints: Smoking cessation and weight loss

30. Primary Hypothesis and Endpoint • Each clinical trial must have a primary question. • The primary question, as well as any secondary or subsidiary questions, should be carefully selected, clearly defined, and stated in advance. • Hypothesis generation versus hypothesis testing • Definition of primary endpoint(s) • Definition of secondary endpoints

31. Primary Objective • Define one question the investigators are most interested in answering and is capable of being adequately answered. • Define the primary endpoint • Toxicity, efficacy (response/survival), QOL • Define the type of study: • Hypothesis testing or estimation, • Superiority or equivalence trials • The sample size is based on.

32. Secondary Objectives • Different endpoints • Subgroup hypotheses • Prospectively defined • Based on reasonable expectations • Limited in number • Hypothesis testing vs. hypothesis generating • Hunting expedition vs. fishing expedition • Multiplicity Issues

33. Examples of post-hoc subset analyses • In the International Study of Infarct Survival-2 (ISIS-2), the treatment effect seemed to differ by astrological sign: • More adverse effect of aspirin on mortality for patients born under Gemini (5/21-6/21) or Libra (9/23-10/23) than others (P < 0.00001). • Is the data convincing? • Do you believe it? • What is the one question you may ask to discern whether the claim is true or not?

34. Response Variables • Dose limiting toxicities (DLT), complications • Response, incidence of a disease, total mortality, death from a specific cause • Overall survival, time to progression, time to cancer • Blood pressure, biomarkers, PSA, CD4 count • Quality of life • Cost and ease of administrating the intervention • In general, a single response variable should be identified to answer the primary question.

35. General rules for response variable • Define the questions prospectively and specifically • Gleevec can increase the response rate from 50% to 80% in patients with chronic CML • The primary response variable can be assessed in all participants and as completely as possible • Informative drop-out or lost to f/u due to toxicity • Participation generally ends when the primary response variable occurs • Off-drug, off-study, extended f/u • Response variables should be unbiased assessed • Hard, objective endpoints vs. soft, subjective endpoints

36. Intent-to-treat (ITT) Principle • Unlike animal studies, investigator cannot dictate what a participant should do in a clinical trial. • A participant may forget to take the pills, receive dose reduction due to toxicity, drop out from the study at any point or lost to f/u. • Use only full compliers in the analysis? Use all subjects? • ITT compares ‘intervention strategies’ and not ‘interventions.’

37. Ethics of Clinical Trials • Do no harm. Clinical trials must be reasonably safe to participants and have a favorable risk-benefit ratio. • Proper informed consent is essential. • Rationale for randomization (clinical equipoise) must be sufficiently justified. • Finder fee for recruitment can result in bias. Unreasonable compensation to participants can also cause problems. • Equal opportunities to be recruited and treated, e.g.: race and gender. • Individual ethics and group ethics must be balanced.

38. Protect Human Subjects • Nuremburg Code (1947): In response to Nazi atrocities of using concentration camp prisoners for human experiments. • voluntary consent, avoid unnecessary suffering, subject/scientist free to end experiment • Declaration of Helsinki (1964, 1989) • informed consent • Belmont Report (1979) • risk/benefit assessment, fair selection of subjects • Human Subject Committee (HSC), Institutional Review Board (IRB), Ethics Committee, Surveillance Committee

39. STATISTICAL PRINCIPLES FOR CLINICAL TRIALS (ICH E9) • International Conference on Harmonisation encompassing three main ICH regions: Europe, Japan and the U.S.A. • An effort to establish clinical trial standards by integrating inputs from government (regulatory authority), industry, and academia. • A comprehensive guideline was developed in 1998 and published in Lewis, Statistics in Medicine 18:1903-1942,1999. • E10: Choice of Control Group in Clinical Trials • E9: Statistical Principles for Clinical Trials • E8: General Considerations for Clinical Trials • http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002928.pdf • http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/statistical-principles-for-clinical-trials.html

40. CONTENTS 1. Introduction . . 1.1 Background and Purpose 1.2 Scope and Direction 2. Considerations for overall clinical development 2.1 Trial Context 2.1.1 Development Plan 2.1.2 Confirmatory Trial 2.1.3 Exploratory Trial 2.2 Scope of Trials 2.2.1 Population 2.2.2 Primary and Secondary Variables 2.2.3 Composite Variables 2.2.4 Global Assessment Variables 2.2.5 Multiple Primary Variables 2.2.6 Surrogate Variables 2.2.7 Categorized Variables 2.3 Design Techniques to Avoid Bias 2.3.1 Blinding 2.3.2 Randomization 3. Trial design considerations 3.1 Design Configuration 3.1.1 Parallel Group Design 3.1.2 Cross-over Design 3.1.3 Factorial Designs 3.2 Multi-centre Trials 3.3 Type of Comparison 3.3.1 Trials to Show Superiority 3.3.2 Trials to Show Equivalence or Non-inferiority 3.3.3 Trials to Show Dose-response Relationship 3.4 Group Sequential Designs 3.5 Sample Size 3.6 Data Capture and Processing

41. CONTENTS (cont.) 4. Trial conduct considerations 4.1 Trial Monitoring and Interim Analysis 4.2 Changes in Inclusion and Exclusion Criteria 4.3 Accrual Rates 4.4 Sample Size Adjustment 4.5 Interim Analysis and Early Stopping 4.6 Role of Independent Data Monitoring Committee (IDMC) 5. Data analysis considerations 5.1 Prespecification of the Analysis 5.2 Analysis Sets 5.2.1 Full Analysis Set 5.2.2 Per Protocol Set 5.2.3 Roles of the Different Analysis Sets 5.3 Missing Values and Outliers 5.4 Data Transformation 5.5 Estimation, Confidence Intervals and Hypothesis Testing 5.6 Adjustment of Significance and Confidence Levels 5.7 Subgroups, Interactions and Covariates 5.8 Integrity of Data and Computer Software Validity 6. Evaluation of safety and tolerability 6.1 Scope of Evaluation 6.2 Choice of Variables and Data Collection 6.3 Set of Subjects to be Evaluated and Presentation of Data 6.4 Statistical Evaluation 6.5 Integrated Summary 7. Reporting . 7.1 Evaluation and Reporting 7.2 Summarizing the Clinical Database 7.2.1 Efficacy Data 7.2.2 Safety Data Glossary

42. Study Protocol • Every well-designed study required a protocol. • Protocol is a written agreement between investigators, participants, and the scientific community. • Protocol is a comprehensive operational manual. It specifies the standard operation procedure (SOP). • Examples

43. Intergroup Lung StudyStudy Objectives • To evaluate the efficacy of 13cRA in reducing the incidence of second primary tumors (SPTs) • To evaluate quantitative and qualitative toxicity of 13cRA 30 mg/day • To compare overall survival of patients treated with 13cRA vs. patients treated with placebo

45. Intergroup Lung StudyPatient Eligibility • Stage I non-small lung cancer, currently free of disease, between 6 wks and 36 mos from resection • No prior or concurrent therapy for lung cancer other than surgery • Normal hepatic, renal and bone marrow function • Fasting triglycerides < 320 mg/dL • Life expectancy > 12 mos & Zubrod 0-2 • No cancer history within last 5 years • No synchronous lesions • No history of high dose Vitamin A or beta-carotene

46. RANDOMIZATION REGISTRATION TREATMENT FOLLOWUP OFF STUDY 13cRA Placebo 3 Years Intergroup Lung Study 8 Week Run-in 4 Years

47. Study Design • Randomized, placebo controlled trial to compare the efficacy of 13cRA vs. placebo in reducing SPT • N=1,379 registered; 1,242 randomized • Annual SPT rate: 3% in the placebo group • SPT rate reduced by 50% in the 13cRA group • 3 years of accrual + 4 years of f/u or 4 years accrual + 3 years of f/u • Total study duration = 7 years from 1st patient randomized

48. Level of Significance 0.0005 0.014 0.045 Time since 1st pt randomized* 3 years 5 years 7 years 1st Analysis: 2nd Analysis: Final Analysis: * The 1st patient was randomized on 2/5/93. Planned Interim Analyses based on the O’Brien-Fleming Boundary • Primary endpoint: Time to SPT • Early stopping if Ho: No difference between arms is rejected • No early stopping based on futility

49. Trial History • 1,486 pts were enrolled from 12/8/92 to 4/9/97 • 1,304 were randomized from 2/5/93 to 6/23/97 • Among them, 1,265 were randomized and eligible • Major Analyses • 3/96: 1st interim analysis • 7/97: 2nd interim analysis • 7/98: 3rd interim analysis • 2/00: 4th and final analysis

50. Consort Diagram: Colin et al., JAMA 276: 637-639 1996. Lung Intergroup Trial: Lippman et al. JNCI 93:605-618, 2001.