BST 665 Advanced Clinical Trials

Wednesdays1-3:30

Instructors:

Dr. Shari Messinger

CRB 1051

Course Description:

This course will introduce some basic statistical concepts and methods usedin Epidemiology and will focus on the statistical principles and methodsused in clinical trials, including phase I to IV clinical trials. Although theclass will have emphasis on phase III trials, we will also discuss the featuresand statistical issues in phase I and II clinical trials. For phase III trials, wewill discuss ways of treatment allocation that will ensure valid inference ontreatment 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

Tentative Schedule of Topics

Date / Topics / Reading Material and Assignments
September 2 /
  • Course Objectives
  • Review of Epidemiology principles
  • History and Introduction to Clinical Trials
/ Tsiatis and Zheng Ch 1
FCT chapters 1-2
September 9 /
  • Phase I
  • pharmacology, toxicity, safety, MTD; early phase
  • Phase II Clinical Trials
  • common designs, Gehan, Simon
/ Tsiatis and Zheng Ch 2
FCT Ch 1-2
PiantatosiCh 4,12
September 16 /
  • Phase III
  • Rationale
  • Issues to consider before designing trial
  • Ethical consideratons
  • The RCT
  • Common designs
  • Review of conditional Expectation and variance
/ Tsiatis and Zheng Ch 3
PiantatosiCh 6
FCT Ch 1,5
September 23 /
  • Fixed Allocation Randomization
  • Simple Randomization
  • Permuted block randomization
  • Stratified Randomization
  • Additional Issues in Phase III
  • Blinding and Placebo
  • Ethics
  • Protocol document
  • Sample size considerations
  • Hypothesis testing
  • Deriving sample size to achieve desired power
  • Comparing two response rates
/ Tsiatis and Zheng Chapter 4,5,6
FCT Ch6,7,8
Piantadosi Ch. 5, 7,9
HW set 1 due.
September 30 /
  • Comparing More Than Two Treatments
  • Testing equality using independent normally distributed estimators
  • Testing equality of dichotomous response rates
  • Multiple comparisons
  • K-sample tests for continuous
  • Equivalency Trials
/ Tsiatis and Zheng Ch 7
FCT Ch 5,8
October 7 / No Class (Fall Break)
October 14 /
  • Survival analysis in Clinical trials
  • Describing the Distribution of Time to Event
  • Censoring and Life-Table Methods
  • Kaplan-Meier or Product-Limit Estimator
  • Two-sample Log-rank
  • Power and Sample Size Based on the Log-rank Test
  • K-Sample tests
  • Sample-size Considerations
/ 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 /
  • Factorial Designs and Cross-Over Designs
/ PiantadosiCh 15,16
October 28 /
  • Early Stopping of Clincal Trials
  • Design and Monitoring
  • Type I error spending
  • Choice of boundaries
  • Pocock
  • O’Brien-Fleming
  • Power and Sample Size
  • Inflation factor
  • Information
based monitoring
  • Average Information
  • Group sequential tests
/ Tsiatis and Zheng Ch 10
FCT Ch 16
Piantatosi Ch. 10
Mid-term exam due
Homework set 2 due
November 4 /
  • Causality
  • Counterfactual random variables
  • Noncompliance and intent-to-treat
/ Tsiatis and Zheng Ch 8
November 11 / No Class
November 17 /
  • Overview Bayes. Adaptive Designs
  • Adaptive advantages
  • Bayes. advantages
  • Trial Simulation
  • Phase I/Dose Finding
  • Model based approaches
  • Efficacy vs. toxicity
/ Berry Ch 1 and 3.2-3.3
November 24 / No Class (Thanksgiving break)
December 1 /
  • Phase II/III
  • Predictive probabilities
  • Sequential stopping
  • Adaptive randomization
  • Arm dropping
  • Seamless designs
/ Berry Ch 4.2-4.4 and 5.2-5.3, 5.7
Tsiatis and ZhengCh 4
Final exam assigned
December 8 / Reading days
December 15 / Final exam due