Bios 6648: Design and Conduct of Clinical Research

Transcription

1 Bios 6648: Design and Conduct of Clinical Research Fall Semester 2013 John M. Kittelson Department of Biostatistics & Informatics Colorado School of Public Health University of Colorado Denver c 2013 John M. Kittelson, PhD Bios pg 1

2 Bios 6648: Design and Conduct of Clinical Research Course Objectives and Administration Syllabus Course objectives and lecture topics Textbooks Required: Piantadosi S. Clinical Trials: A Methodologic Perspective. 2nd edition (2005) John Wiley & Sons, Inc. Hoboken, NJ. Recommended: Meinert CL, Clinial Trials: Design, Conduct, and Analysis. 2nd edition (2012) Oxford University Press, NY. Additional materials: Bios pg 2

3 Bios 6648: Design and Conduct of Clinical Research The course is organized around the 5 main objectives: 0. Motivation,, and objectives for clinical trials (and clinical research) 1. Specifying the study setting and objectives 2. Formulating the scientific and statistical design 3. Essential principles of trial conduct: assuring unbiased and reproducible results. 4. Documenting the study 5. Software to support study design and monitoring Bios pg 3

4 Bios 6648: Design and Conduct of Clinical Research Section 0: Course motivation,, and objectives Purpose: describe the overall clinical, scientific, and ethical for clinical studies Approach : Historic approach to coronary artery disease Neural tube Selenium supplementation 0.2 Public health objective for clinical research Reading : Piantadosi chapters 1-4 Notice in particular: Scientific, clinical, and ethical for clinical research Breadth of possibilities Science/design follows from Bios pg 4

5 Section 0: Course motivation,, and objectives A very early approach to surgery for coronary artery disease Other useful examples Two case studies: (a) Folic acid and neural tube (b) Selenium supplementation for cancer prevention Bios pg 5

6 Surgery for coronary artery disease Medicine at the Crossroads: Part 6 Random Cuts" (PBS / BBC video, 1993) Bios pg 6

7 Notes: Surgical treatment for coronary artery disease Experience has shown" Testimonials are not sufficient There are (too) many examples of treatments that seemed logical but which turned out to be harmful: Retrolentil fibroplasia (Scientific American 236: ; 1977). Cardiac arrhythmias (NEJM, 321: ; 1989). Coronary bypass surgery (NEJM, 297: ; 1977). Chest physiotherapy (J. Pediatrics 132: ; 1998). Cholesterol lowering treatments and suicide (e.g., JAMA 226: ; 1973) Beta carotene for prevention of lung cancer (e.g., NEJM, 330: ; 1994). Bios pg 7

8 Notes (con t): There are (too) many examples of treatments that seemed logical but turned out to be harmful: Hormone replacement therapy for postmenopausal women; Womens Health Initiative: Effect on coronary heart disease and cancer (JAMA 288: ; 2002). Effect on quality of life (NEJM 348: ; 2003). Effect on mental health (JAMA 289: ; 2002). Vioxx Thiazolidinediones (rosiglitazone) Alendronate (fosamax) All-metal hip replacements? Question: So when do we have enough information to use a new therapy? Bios pg 8

9 Notes (con t): There are (too) many examples of treatments that seemed logical but turned out to be harmful: Hormone replacement therapy for postmenopausal women; Womens Health Initiative: Effect on coronary heart disease and cancer (JAMA 288: ; 2002). Effect on quality of life (NEJM 348: ; 2003). Effect on mental health (JAMA 289: ; 2002). Vioxx Thiazolidinediones (rosiglitazone) Alendronate (fosamax) All-metal hip replacements? Question: So when do we have enough information to use a new therapy? Bios pg 9

10 Case study 1: folic acid for prevention of neural tube Neural tube (NTD): Incomplete formation of the neural tube (spine and head) during fetal development (risk of about 1 per 1000 births). Common outcomes: Spontaneous abortion or still-birth Spina bifida. Causes for NTD have been extensively studied from 1950 s through 1990 s Hypothesized causes (circa ): Environmental exposures during pregnancy Maternal illness (and drug exposure) during pregnancy Maternal occupational exposures Diet Genetic causes Extensive epidemiology from 1950 through 1990 s (Elwood 1993) included: Descriptive epidemiology Case-control studies Cohort studies Bios pg 10

11 Case study 1: folic acid for prevention of neural tube Bios pg 11

12 Case study 1: folic acid for prevention of neural tube Bios pg 12

13 Case study 1: folic acid for prevention of neural tube Bios pg 13

14 Case study 1: folic acid for prevention of neural tube The dietary hypothesis Evidence in support of dietary hypothesis: Geographical and seasonal variation in NTD risk consistent with folic acid deficiency Specific dietary hypotheses: Malnutrition or poor diet in mother Low hemoglobin Blighted potatoes Tea or coffee drinking (caffeine) Exposure to nitrates/nitrites Excess of: vitamin D or vitamin A Deficiencies: Calcium/magnesium; folate; nicotinic acid, riboflavin, thiamin, vitamin B 12, vitamin C, zinc. Bios pg 14

15 Case study 1: folic acid for prevention of neural tube The dietary hypothesis Early studies related to the dietary hypothesis: A Natural experiment" (non-randomized trial; ): (New South Wales) Women with previous NTD birth were counseled to improve their diet and stop smoking at the time they stopped contraceptive measures. Women in a neighboring area were not counseled. Collected data that showed diets changed as a result of counseling Results: Among counseled women 2.8% (2/128) pregnancies had NTD Among non-counseled women 6.5% (5/77) had NTD Difference is not significant (p > 0.10) Secondary evaluation supported dietary role in NTD Bios pg 15

16 Case study 1: folic acid for prevention of neural tube The dietary hypothesis Early studies related to the dietary hypothesis: Case-control study (Western Australia, 1989): Cases (n = 77) identified from Western Australia Malformations Registry Normal controls (n = 154) (matched on date of last menstrual period) selected from population birth registry. Detailed dietary survey administered and used to estimate periconceptional nutrient intake. Results: Odds ratios for estimated periconceptional nutrient intake Free Total Quartile folate folate Fibre Calcium Riboflavin Vit C Carotene Low 1(ref) 1(ref) 1(ref) 1(ref) 1(ref) 1(ref) 1(ref) Hi p-val < < Bios pg 16

17 Case study 1: folic acid for prevention of neural tube The dietary hypothesis Early studies related to the dietary hypothesis: Cohort study (Milunsky, 1989): Prospective prenatal screening (both blood tests and diet recall) on women Results show protective effect of folic acid: Bios pg 17

18 Case study 1: folic acid for prevention of neural tube The dietary hypothesis Early studies related to the dietary hypothesis: UK multicenter non-randomized trial (Smithells, 1980): Periconceptional vitamins to prevent recurrent NTD. Women with previous NTD-affected child who wanted more children Fully supplemented group: 454 women who became pregnant and took a multivitamin prior to pregnancy Comparison group: 519 women who were already pregnant when seen or who refused to take a vitamin. Bios pg 18

19 Case study 1: folic acid for prevention of neural tube The dietary hypothesis Randomized trials for recurrence of NTD (MRC vitamin trial; Lancet 1991): Intense debate over the ethics of a randomized trial. 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). Results show 72% reduction in risk of NTD. Other highlights of this example: * Required new methods for monitoring a trial (allowing early termination) * Questions remain regarding utility of primary prevention of NTD. Bios pg 19

20 Case study 1: folic acid for prevention of neural tube The dietary hypothesis Randomized trials for primary prevention of NTD (Hungarian Family Planning Program; NEJM 1992): Evaluated primary prevention as opposed to prevention of recurrence Randomized 4753 women who were planning a pregnancy * 2420 to receive vitamin supplement; 2333 to receive trace-element supplement. Results show 0 cases of NTD with vitamin and 6 cases with control treatment. Bios pg 20

21 Case study 1: folic acid for prevention of neural tube The dietary hypothesis I I Has the question been answered? Debate continues over risks of supplementation for individuals who are not planning to get pregnant. Bios pg 21

22 Case study 1: folic acid for prevention of neural tube The dietary hypothesis I I Has the question been answered? Debate continues over risks of supplementation for individuals who are not planning to get pregnant. Bios pg 22