bios 6648: design and conduct of clinical...

Course AdministationObjectives, syllabus, andschedule

Content and objectives

0. Motivation andcontext0.1 Examples

Case Study 1: Neural tubedefects

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Bios 6648: Design and Conduct ofClinical Research

Fall Semester 2013

John M. KittelsonDepartment of Biostatistics & Informatics

Colorado School of Public HealthUniversity of Colorado Denver

c©2013 John M. Kittelson, PhD





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Bios 6648:Design and Conduct of Clinical Research

Course Objectives and Administration

I SyllabusI Course objectives and lecture topicsI Textbooks

I Required: Piantadosi S. Clinical Trials: A MethodologicPerspective. 2nd edition (2005) John Wiley & Sons, Inc.Hoboken, NJ.

I Recommended: Meinert CL, Clinial Trials: Design, Conduct,and Analysis. 2nd edition (2012) Oxford University Press,NY.

I Additional materials: www.RCTdesign.org





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The course is organized around the 5 main objectives:0. Motivation, context, and objectives for clinical trials (and

clinical research)1. Specifying the study setting and objectives2. Formulating the scientific and statistical design3. Essential principles of trial conduct: assuring unbiased

and reproducible results.4. Documenting the study5. Software to support study design and monitoring





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Section 0: Course motivation, context, and objectives

I Purpose: describe the overall clinical, scientific, andethical context for clinical studies

I Approach0.1 Examples:

I Historic approach to coronary artery diseaseI Neural tube defectsI Selenium supplementation

0.2 Public health objective for clinical researchI Reading : Piantadosi chapters 1-4

I Notice in particular:I Scientific, clinical, and ethical context for clinical researchI Breadth of possibilitiesI Science/design follows from context





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Section 0: Course motivation, context, and objectives

0.1 Examples

I A very early approach to surgery for coronary arterydisease

I Other useful examplesI Two case studies:

(a) Folic acid and neural tube defects(b) Selenium supplementation for cancer prevention





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0.1 Examples

Surgery for coronary artery disease

“Medicine at the Crossroads: Part 6 Random Cuts"(PBS / BBC video, 1993)





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0.1 Examples

Notes: Surgical treatment for coronary artery disease

I “Experience has shown"I Testimonials are not sufficientI There are (too) many examples of treatments that seemed

logical but which turned out to be harmful:I Retrolentil fibroplasia (Scientific American 236:100-107;

1977).I Cardiac arrhythmias (NEJM, 321:406-412; 1989).I Coronary bypass surgery (NEJM, 297:621-627; 1977).I Chest physiotherapy (J. Pediatrics 132:400-444; 1998).I Cholesterol lowering treatments and suicide (e.g., JAMA

226:652-657; 1973)I Beta carotene for prevention of lung cancer (e.g., NEJM,

330:1029-35; 1994).





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0.1 Examples

Notes (con’t):

I There are (too) many examples of treatments that seemedlogical but turned out to be harmful:

I Hormone replacement therapy for postmenopausal women;Womens Health Initiative:

I Effect on coronary heart disease and cancer (JAMA288:321-333; 2002).

I Effect on quality of life (NEJM 348:1839-1854; 2003).I Effect on mental health (JAMA 289:2651-2672; 2002).

I VioxxI Thiazolidinediones (rosiglitazone)I Alendronate (fosamax)I All-metal hip replacements?

Question:

So when do we have enough information to use a new therapy?





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0.1 Examples

Notes (con’t):

I There are (too) many examples of treatments that seemedlogical but turned out to be harmful:

I Hormone replacement therapy for postmenopausal women;Womens Health Initiative:

I Effect on coronary heart disease and cancer (JAMA288:321-333; 2002).

I Effect on quality of life (NEJM 348:1839-1854; 2003).I Effect on mental health (JAMA 289:2651-2672; 2002).

I VioxxI Thiazolidinediones (rosiglitazone)I Alendronate (fosamax)I All-metal hip replacements?

Question:

So when do we have enough information to use a new therapy?





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0.1 Examples

Case study 1: folic acid for prevention of neural tube defects

I Neural tube defects (NTD):I Incomplete formation of the neural tube (spine and head)

during fetal development (risk of about 1 per 1000 births).I Common outcomes:

I Spontaneous abortion or still-birthI Spina bifida.

I Causes for NTD have been extensively studied from1950’s through 1990’s

I Hypothesized causes (circa 1960-80):I Environmental exposures during pregnancyI Maternal illness (and drug exposure) during pregnancyI Maternal occupational exposuresI DietI Genetic causes

I Extensive epidemiology from 1950 through 1990’s(Elwood 1993) included:

I Descriptive epidemiologyI Case-control studiesI Cohort studies





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The dietary hypothesis

I Evidence in support of dietary hypothesis:I Geographical and seasonal variation in NTD risk consistent

with folic acid deficiencyI Specific dietary hypotheses:

I Malnutrition or poor diet in motherI Low hemoglobinI Blighted potatoesI Tea or coffee drinking (caffeine)I Exposure to nitrates/nitritesI Excess of: vitamin D or vitamin AI Deficiencies: Calcium/magnesium; folate; nicotinic acid,

riboflavin, thiamin, vitamin B12, vitamin C, zinc.





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Early studies related to the dietary hypothesis:I A“Natural experiment" (non-randomized trial; 1964-66):

I (New South Wales) Women with previous NTD birth werecounseled to improve their diet and stop smoking at the timethey stopped contraceptive measures.

I Women in a neighboring area were not counseled.I Collected data that showed diets changed as a result of

counselingI Results:

I Among counseled women 2.8% (2/128) pregnancies had NTDI Among non-counseled women 6.5% (5/77) had NTDI Difference is not significant (p > 0.10)I Secondary evaluation supported dietary role in NTD





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Early studies related to the dietary hypothesis:I Case-control study (Western Australia, 1989):

I Cases (n = 77) identified from Western AustraliaMalformations Registry

I Normal controls (n = 154) (matched on date of lastmenstrual period) selected from population birth registry.

I Detailed dietary survey administered and used to estimatepericonceptional nutrient intake.

I Results:Odds ratios for estimated periconceptional nutrient intake

Free TotalQuartile folate folate Fibre Calcium Riboflavin Vit C Carotene

Low 1(ref) 1(ref) 1(ref) 1(ref) 1(ref) 1(ref) 1(ref)2 0.44 0.94 0.41 0.73 0.31 0.65 1.203 0.34 0.61 0.37 0.49 0.33 0.51 0.47Hi 0.16 0.38 0.29 0.27 0.48 0.18 0.31

p-val < 0.001 0.03 0.005 0.006 0.22 < 0.001 0.002





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Early studies related to the dietary hypothesis:I Cohort study (Milunsky, 1989):

I Prospective prenatal screening (both blood tests and dietrecall) on 23491 women

I Results show protective effect of folic acid:





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Early studies related to the dietary hypothesis:I UK multicenter non-randomized trial (Smithells, 1980):

I Periconceptional vitamins to prevent recurrent NTD.I Women with previous NTD-affected child who wanted more

childrenI Fully supplemented group: 454 women who became

pregnant and took a multivitamin prior to pregnancyI Comparison group: 519 women who were already pregnant

when seen or who refused to take a vitamin.





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I Randomized trials for recurrence of NTD (MRC vitamintrial; Lancet 1991):

I Intense debate over the ethics of a randomized trial.I Randomized 1817 women at high risk of having a

pregnancy with NTD (because of previous NTD birth)* 2 × 2 factorial design (depicted on pg 132).

I Results show 72% reduction in risk of NTD.I Other highlights of this example:

* Required new methods for monitoring a trial (allowing earlytermination)

* Questions remain regarding utility of primary prevention ofNTD.





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I Randomized trials for primary prevention of NTD(Hungarian Family Planning Program; NEJM 1992):

I Evaluated primary prevention as opposed to prevention ofrecurrence

I Randomized 4753 women who were planning a pregnancy* 2420 to receive vitamin supplement; 2333 to receive

trace-element supplement.I Results show 0 cases of NTD with vitamin and 6 cases with

control treatment.





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I Has the question been answered?I Debate continues over risks of supplementation for

individuals who are not planning to get pregnant.





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I Has the question been answered?I Debate continues over risks of supplementation for

individuals who are not planning to get pregnant.

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