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May 17, 2022


6 months


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6 months

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6 months


Provides a broad understanding of the application of biostatistics in a regulatory context. Reviews the relevant regulations and guidance documents. Includes topics such as basic study design, target population, comparison groups, and endpoints. Addresses analysis issues with an emphasis on the regulatory aspects, including issues of missing data and informative censoring. Discusses safety monitoring, interim analysis and early termination of trials with a focus on regulatory implications.


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Course Objectives

Understanding the relevance and application of statistics and of statistical thinking to the regulatory process; an understanding of the basic principles of clinical studies and clinical trials, and their importance to the regulatory evaluation of new drugs, biologics and devices; and an awareness of sources of regulatory guidance, requirements, and evaluation information.


The intended audience is graduate students in clinical medicine and public health interested in regulatory applications, or medical product development professionals, e.g., the biologics, medical device or pharmaceutical industry. Prerequisite courses in basic biostatistics or epidemiology such as:
  • Principles of Epidemiology
  • Statistical Reasoning I or II
  • Fundamentals of Epidemiology


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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: http://www.ich.org/LOB/media/MEDIA484.pdf . ICH E9: Statistical Principles for Clinical Trials: http://www.ich.org/LOB/media/MEDIA485.pdf .
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. The 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 integrin 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 the 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 the 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 the 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 Stat. 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 Stat. 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 Stat. 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 the 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

Course Curriculum

    • Biostatistics in Medical Product Regulation: Introduction ( Day ) 00:02:00
    • Study Designs, Objectives, Hypotheses (Foulkes) 02:00:00
    • Study Populations (Day) 02:00:00
    • Study Designs (Day) 02:00:00
    • Comparison/Control Groups (Foulkes) 02:00:00
    • Outcomes, Surrogates, Composite Endpoints (Day) 02:00:00
    • Analysis Issues, ITT, Post-Hoc, and Subgroups (Day) 02:00:00
    • Multiplicity, Missing Data (Foulkes) 02:00:00
    • Non-Inferiority Specification of Delta (Foulkes) 02:00:00
    • Multi-Regional Studies and Bridging Studies (Day) 02:00:00
    • Interim Monitoring (Foulkes) 02:00:00
    • Course Summary and Review (Foulkes) 02:00:00

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