BST 665 Advanced Clinical Trials
Wednesdays 1-3:30
Instructors:
Dr. Shari Messinger smessinger@biostat.med.miami.edu
CRB 1051
Course Description:
This course will introduce some basic statistical concepts and methods used in Epidemiology and will focus on the statistical principles and methods used in clinical trials, including phase I to IV clinical trials. Although the class will have emphasis on phase III trials, we will also discuss the features and statistical issues in phase I and II clinical trials. For phase III trials, we will discuss ways of treatment allocation that will ensure valid inference on treatment comparison.
Other topics include sample size calculation, survival analysis and early stopping of a clinical trial and noncompliance. The second half of the semester will cover advanced topics in clinical trials including factorial and crossover designs as well as Bayesian approaches to designing adaptive clinical trials, predicting trials and synthesizing multiple trials through meta-analysis.
Recommended texts:
You will be given lecture notes in class, and will periodically be given supplemental articles and example protocols to review. Additional recommended reading includes:
Fundamentals of Clinical Trials
L.M. Friedman, C.D. Furberg and D.L. DeMets
Statistical Principles of Clinical Trials (Course Materials composed by Dr. Anastasios Tsiatis and Dr. Daowen Zhang, Department of Statistics, NCSU)
Clinical Trials A Methodologic Perspective
Steven Piantatosi
Bayesian Adaptive Methods for Clinical Trials
S.M. Berry, B.P. Carlin, J.J. Lee and P.M. Muller
Assignments and Grading:
There will be periodic homework assignments, a midterm exam and a final project/exam.
Grading will be as follows:
HW assignments > 40% of final grade
Midterm Exam -> 30% of final grade
Final Exam -> 30% of final grade

Date
Tentative Schedule of Topics
September 2
September 9
September 16
Topics

Course Objectives

Review of Epidemiology principles

History and Introduction to Clinical Trials

Phase I o pharmacology, toxicity, safety,
MTD; early phase

Phase II Clinical Trials o common designs, Gehan, Simon

Phase III o Rationale o Issues to consider before designing trial o Ethical consideratons o The RCT o Common designs o Review of conditional Expectation
September 23
September 30
October 7 and variance

Fixed Allocation Randomization o Simple Randomization o Permuted block randomization o Stratified Randomization

Additional Issues in Phase III o Blinding and Placebo o Ethics o Protocol document

Sample size considerations o Hypothesis testing o Deriving sample size to achieve desired power o Comparing two response rates

Comparing More Than Two Treatments o Testing equality using independent normally distributed estimators o Testing equality of dichotomous response rates o Multiple comparisons o K-sample tests for continuous

Equivalency Trials
No Class (Fall Break)
October 14

Survival analysis in Clinical trials o Describing the Distribution of
Time to Event o Censoring and Life-Table
Methods o Kaplan-Meier or Product-Limit
Estimator o Two-sample Log-rank o Power and Sample Size Based on the Log-rank Test o K-Sample tests
Reading Material and Assignments
Tsiatis and Zheng Ch 1
FCT chapters 1-2
Tsiatis and Zheng Ch 2
FCT Ch 1-2
Piantatosi Ch 4,12
Tsiatis and Zheng Ch 3
Piantatosi Ch 6
FCT Ch 1,5
Tsiatis and Zheng Chapter 4,5,6
FCT Ch6,7,8
Piantadosi Ch. 5, 7,9
HW set 1 due.
Tsiatis and Zheng Ch 7
FCT Ch 5,8
FCT Ch 15
Tsiatis and Zheng Ch 9
Piantadosi Ch. 12
Mid-term exam distributed
(Due October 28)
Note: you will get a homework set and your exam after this class.

October 21
October 28 o Sample-size Considerations

Factorial Designs and Cross-Over
Designs

Early Stopping of Clincal Trials o Design and Monitoring o Type I error spending o Choice of boundaries
 Pocock
 O’Brien-Fleming o Power and Sample Size
 Inflation factor
 Information
November 4 based monitoring
 Average Information

Group sequential tests

Causality o Counterfactual random variables o Noncompliance and intent-to-treat

November 11 No Class
November 17
December 1

Overview Bayes. Adaptive Designs o Adaptive advantages o Bayes. advantages o Trial Simulation

Phase I/Dose Finding o Model based approaches o Efficacy vs. toxicity
November 24 No Class (Thanksgiving break)

Phase II/III o Predictive probabilities o Sequential stopping o Adaptive randomization o Arm dropping o Seamless designs
December 8 Reading days
December 15
Piantadosi Ch 15,16
Tsiatis and Zheng Ch 10
FCT Ch 16
Piantatosi Ch. 10
Mid-term exam due
Homework set 2 due
Tsiatis and Zheng Ch 8
Berry Ch 1 and 3.2-3.3
Berry Ch 4.2-4.4 and 5.2-5.3, 5.7
Tsiatis and Zheng Ch 4
Final exam assigned
Final exam due