Course: Biostatistics for Medical Product Regulation

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Primary Texts

Day S. Dictionary for Clinical Trials. John Wiley & Sons, 2007.

Senn S. Statistical Issues in Drug Development. John Wiley & Sons, 1997.

Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials, 3rd edition. Springer, 1998.

Meinert CL. Clinical Trials: Design, Conduct and Analysis. Oxford University Press, 1986.

Pocock SJ. Clinical Trials: A Practical Approach. John Wiley & sons, 1983.

ICH E8: General Considerations for Clinical Trials: .

ICH E9: Statistical Principles for Clinical Trials: .

Lecture 1: Biostatistics in Medical Product Regulation: Introduction

Green SB, Byar DP. Using observational data from registries to compare treatments: the fallacy of omnimetrics. Stats in Med. 1984;3:361-370.

Sibbald B, Roland M. Why are randomized controlled trials important? BMJ. 1998;316:201.

Couzin J. Advocating, the clinical way. Science. 2005;308:940-942.

CPMP Points to consider on application with (1) meta-analysis; (2) one pivotal study
Lecture 2: Study Designs, Objectives, Hypotheses

Tinmouth A, Hebert P. Interventional trials: an overview of design alternatives. Transfusion. 2007;47:565-567.

ISIS-3 Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41 299 cases of suspected acute myocardial infarction. Lancet. 1992;339:753-770.

ICH E10: Choice of Control Group

Ellenberg in Weinrich M, Rosen BG: Musculoskeletal Research Conference Summary Report. Am J Phys Med Rehabil. 2007;86(Suppl):S1-S18.
Lecture 3: Study Populations

Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting randomized controlled trials: the CONSORT statement. JAMA 1996;276:637-639.

Rothwell PM. External validity of randomized controlled trials - to whom do the results apply? Lancet. 2005;365:82-93.

Altman DG, Bland JM, Generalisation and extrapolation. BMJ. 1998;317:409-410.
Lecture 4: Study Designs

Day SJ, Altman DG. Blinding in clinical trials and other studies. BMJ. 2000;321:504.

Beller EM, Gebski V, Keech AC. Randomisation in clinical trials. Med J Aust. 2002;177:565-567.

Roberts C, Torgerson D. Randomisation methods in controlled trials. BMJ. 1998;317:1301.

Altman DG, Bland JM. Treatment allocation in controlled trials. Why randomize. BMJ. 1999;318:1209.

Mann H, London AJ, Mann J. Equipoise in the enhanced suppression of the platelet IIb/IIIa receptor with integrilin trial (ESPRIT): a critical appraisal. Clinical Trials. 2005;2:233-243.
Lecture 5: Comparison/Control Groups

Chalmers I. Assembling comparison groups to assess the effects of health care. JRSM. 1997;90:379-386.

Mann H, Djulbegovic B. Choosing a control intervention for a randomized clinical trial. BMC Med Res Meth. 2003;3:7.

ICH E10: Choice of Control Group

Spilker B. Guide to Clinical Trials. Raven Press, 1991.

Brody H. The lie that heals: the ethics of giving placebos. Ann Int Med. 1982 ;97:112-8, 27

World Medical Association. Declaration of Helsinki, 2004.

Temple R, Ellenberg SS. Placebo and active-controlled trials. Part I. Ann Int Med. 2000;133:456-463.

Ellenberg SS, Temple R. Placebo and active-controlled trials. Part II. Ann Int Med.2000;133:464-470.

21 CFR Sec. 314.126 Adequate and well-controlled studies.
Lecture 6: Outcomes, Surrogates, Composite Endpoints

Montori VM, Permanyer-Miraldi G, Ferreira-Gonzalez I, et al. Validity of composite endpoints in clinical trials. BMJ. 2005;330:594-596.

Hudgens MG, Gilbert PB, Self SG. Endpoints in vaccine trials. Stat Meth in Med Res. 2004;13:89-114.

Fleming TR. Surrogate endpoint and FDA's accelerated approval process. Health Affairs. 2005;24:67-78.

Spriet A, Simon P. Methodology of Clinical Drug Trials. Karger, 1985.

Schwartz D, Flamant R, Lellouch J. Clinical Trials. Academic Press, 1980.
Lecture 7: Analysis Issues, ITT, Post-Hoc, and Subgroups

Heritier SR. Inclusion of patients in clinical trial analysis. The ITT principle. Med J Aust. 2003;179:438-440.

Fergusson D, Aaron SD, Guyatt G and Hebert G. Post randomization exclusions. The ITT Principle. BMJ. 2002;325:652-654.

Roland M, Torgerson DJ. What are pragmatic trials? BMJ. 1998;316:285.

The Coronary Drug Project Research Group. Influence of adherence to treatment and response of cholesterol on mortality on the coronary drug project. N Eng J Med. 1980;303:1038-1041.

Grouin JM, Coste M, Lewis J. Subgroup analysis in randomized clinical trials. Statistical and regulatory issues. J Biopharm Stats. 2005;15:869-882.

Cook DI, Gebski VJ, Keech AC. Subgroup analysis in clinical trials. Med J Aust. 2004;180:289-291

Counsell CE, Clarke MC, Slattery J, Sandercock PAG. The miracle of DICE therapy for acute stroke. Subgroup analysis. BMJ. 1994;309:1677-1681.
Lecture 8: Multiplicity, Missing Data

ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;ii:349-360.

CPMP Points to consider on missing data.

Wiens B. Assessing the impact of endpoint shopping on the power in confirmatory clinical trials. J Biopharm Stats. 2003;13:229-240.

Rubin DB. Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons, 1987.

Lord SJ, Gebski VJ, Keech AC. Multiple analyses in clinical trials. Sound science or data dredging? Med J Aust. 2004;181:452-454.

CPMP Points to consider on multiplicity issues in clinical trials.

Huque MF, Sankoh AJ. A reviewer's perspective on multiple endpoint issues in clinical trials. J Biopharm Stats. 1997;7:545-564.

Westfall PH, Young SS. Resampling-Based Multiple Testing. John Wiley & Sons, 1993.
Lecture 9: Non-Inferiority Specification of Delta

CPMP Note for guidance on the evaluation of medicinal products for treatment of bacterial infections.

McAlister FA, Sackett DL. Active-control equivalence trials and antihypertensive agents. Am J Med. 2001;111:553-558.

CHMP Guideline on the choice of the non-inferiority margin.

CPMP Points to consider on switching between superiority and non-inferiority.

Kaul S, Diamond GA. Good enough: A primer on the analysis and interpretation of noninferiority trials. Ann Int Med. 2006;145:62-69.

Pater C. Equivalence and noninferiority trials - are they viable alternatives for registration of new drugs? (III).
Curr Control Trials Cardiovasc Med. 2004;5:8.
Lecture 10: Multi-Regional Studies and Bridging Studies ICH E5: Ethnic Factors in the acceptability of foreign clinical trial data
Lecture 11: Interim Monitoring

DAMOCLES. A proposed charter for clinical trial data monitoring committees. Lancet. 2005;365:711-722.

FDA. Guidance for clinical trial sponsors on the establishment and operation of clinical trial data monitoring committees. 2006

CHMP Guideline on data monitoring committees.

Siegel JP, O'Neill RT, Temple R , Campbell G and Foulkes MA. Independence of the statistician who analyses unblinded data. Stats in Med. 2004;23:1527-1529.

Wittes J, Holmgren E, Christ-Schmidt H, Bajamonde A. Making independence work. Monitoring the Bevacizumab colorectal trial. In:Data Monitoring in Clinical Trials. Springer, 2006.

Hemmings R, Day S. Regulatory perspectives on data safety monitoring boards - protecting the integrity of data. Drug Safety. 2004;27:1-6.

WHO. Operating guidelines for the establishment and functioning of data and safety monitoring boards, 2005.

21 CFR Sec. 50.24 Exception from informed consent requirements for emergency research.
Lecture 12: Course Summary and Review No Reading