Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. 4th ed. New York, NY: Springer; 2010.

Instructor: Yu Shyr, Ph.D. Director, Vanderbilt Center for Quantitative Sciences Ingram Professor of Cancer Research Assoc. Director for Quantitative Sciences Integration, VICC Professor of Biostatistics, Biomedical Informatics, Cancer Biology, and Preventive Medicine 571 Preston Building Office phone: 615 936-2572; direct line: 615 343-4247 Cell: 615 423-4943 E-mail: [email protected] Assistant: Jill Shell ([email protected])

I. Design and Conduct The theoretical and practical challenges to be considered in designing and conducting a clinical trial will be presented. Topics to be discussed include the specification of a primary objective, adherence to accepted ethical guidelines, the role of randomization and the means of its implementation, the type and assessment of blinding, the choice of design strategy and designstrengthening features, and the considerations involved in sample size determination and patient recruitment.

II. Analysis of Clinical Trials Methods of analysis appropriate to various designs, such as up-and-down design, titration design, Bayesian design, randomized controlled studies, crossover designs, factorial designs, group allocation designs, hybrid designs, and designs for non-inferiority study, will be presented.

The statistical

approach will be based on empirical use of methodologies rather than formal algebraic knowledge, the emphasis on understanding what the procedures do and applications to data analysis. Methods of data collection, monitoring response variables, and data quality control will be discussed.

All classes meet 8:30 – 11:30. Classes meet in Light Hall 431 unless noted.

Week 1 11/5 -11/9 Monday November 5 Tuesday November 6 Wednesday November 7 Thursday November 8 Friday November 9 LH 419CD

Week 2 11/12 -11/16 Monday November 12 LH 419CD Tuesday November 13 LH 419CD Wednesday November 14

Chapter FDA case study Overview of clinical trials


Experiment design I


Guest speaker: Wayne Ray Experiment design II


Randomization and blinding


Chapter Sample size determination Homework 1 due


Monitoring trial progress

13, 15

Baseline assessment, subgroup analysis, subject recruitment, multicenter trials


Thursday Statistical approaches for various November 15 endpoints (statistical analysis I)

4, 12

Friday Statistical approaches for various November 16 endpoints (statistical analysis II) LH 419CD Homework 2 due

14, 16, 18

Week 3 11/19-11/20


Monday November 19 Tuesday November 20

Non-inferiority, data collection, trial closeout, intent-to-treat Homework 3 due Presentations: Students will critique recently published clinical trials. Report due Dec. 3

10-11, 16

Week 1 Lecture 1 Monday November 5

Lecture 2 Tuesday November 6

Lecture 3 Wednesday November 7 Lecture 4 Thursday November 8

Lecture 5 Friday November 9 LH 419CD

GOALS FDA case study Overview of clinical trials  What is a clinical trial?  Issues in modern clinical trials  Formulating research questions  Study population Phase I trials:  Up-and-down design  Single patient per cohort design  Titration design Phase II trials:  Randomized dose ranging design  Randomized titration design  Two-stage phase II designs  Multistage design  Bayesian design  Randomized phase II design  Multiple outcomes design Guest Lecture: Wayne Ray Phase III trials:  Randomized controlled clinical trials  Uncontrolled trials  Historical controls  Crossover designs  Withdrawal studies  Factorial designs  Group allocation designs  Studies of equivalency Ethical issues Randomization methods:  Simple randomization  Replacement randomization  Random permuted blocks  Biased coin Other randomization methods Blinded studies

Week 2 Lecture 6 Monday November 12 LH 419CD Lecture 7 Tuesday November 13 LH 419CD


Sample size determination:  Dichotomous response variables (independent, paired)  Continuous response variables (independent, paired)  Time to failure Monitoring trial progress:  Reasons for interim monitoring  Repeated testing for significance  Decision for early termination  Decision for extending a trial  Techniques for repeated testing Lecture 8 Baseline assessment, subgroup analysis, recruitment, Wednesday multicenter trials: November 14  Use of baseline data  Analysis of baseline comparability  Balance and imbalance  Difficulties of subgroup analysis  Recruitment of study subjects  Multicenter trials Lecture 9 Statistical analysis I: Thursday  Statistical approach for various experimental designs November 15  Key concepts for statistical analysis  Statistical approaches for various endpoints: t-test, chisquare test, Fisher’s exact test, analysis of variance, regression analysis, longitudinal analysis, nonparametric statistics  Logistic regression model Lecture 10 Statistical analysis II: Friday  Statistical approaches for crossover and factorial designs November 16  Estimation and comparison of survival curves LH 419CD  Cox proportional hazards model  Analysis of covariance (ANCOVA)  Multivariate analysis  Multiple comparisons  Missing data analysis

Week 3 GOALS Lecture 11 Non-inferiority, data collection, trial closeout, intent-to-treat Monday  Non-inferiority trials November 19  Statistical methods for non-inferiority analysis  Data collection and quality control  Trial closeout procedures  Intent-to-treat Tuesday Student presentations November 20 Final report due Dec. 3

Other References Chow SC, Liu JP. Design and Analysis of Clinical Trials: Concepts and Methodologies. New York, NY: Wiley; 1998. Geller N, Chow SC. Advances in Clinical Trial Biostatistics. New York, NY: Marcel Dekker; 2004. Green S, Benedetti J, Crowley J. Clinical Trials in Oncology. Interdisciplinary Statistics. New York, NY: Chapman & Hall; 1997. Jennison C, Turnbull BW. Group Sequential Methods with Applications to Clinical Trials. New York, NY: Chapman & Hall; 2000. Machin D, Day S, Green S, Everitt B, George S. Textbook of Clinical Trials. New York, NY: Wiley; 2004. Meinert CL. Clinical Trials: Design, Conduct, and Analysis. New York, NY: Oxford University Press; 1986. Piantadosi S. Clinical Trials: A Methodologic Perspective. New York, NY: Wiley; 1997. Pocock SJ. Clinical Trials: A Practical Approach. New York NY: Wiley; 1991. Shapiro SH, Louis TA. Clinical Trials: Issues and Approaches. New York, NY: Marcel Dekker; 1983. Spilker B. Guide to Clinical Trials. New York, NY: Raven Press; 1991. Wooding W. Wiley; 1994.

Planning Pharmaceutical Clinical Trials.

New York, NY:

Software PS Sample Size and Power Calculations (developed by William Dupont, free download) PASS 11: Power Analysis and Sample Size Program. EaST 5.4: Software for Design and Interim Monitoring of Group Sequential Clinical Trials. nQuery Advisor 7.0: Sample Size and Power Determination. Microsoft Access

Grade Homework




Final report



Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357(18): 1799-1809. 2010 papers


Yu AL, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324-1334. 2011 papers


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Stiell IG, et al. Early versus later rhythm analysis in patients with out-of-hospital cardiac arrest. N Engl J Med. 2011;365(9):787-797. 2012 papers


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Fergusson DA, et al. Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial. JAMA 2012;308(14):1443-1451.


Scher HI, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197.


SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367(9):817-825.