Department of Epidemiology and Biostatistics DESIGNING CLINICAL RESEARCH Session #1

1. Department of Epidemiology and BiostatisticsDESIGNING CLINICAL RESEARCHSession #1 • About this course • Chapters 1 & 2 • Examples

2. Course Objectives 1. Acquire research skills 2. Produce a protocol for a study 3. Help others in the workshop 4. Provide feedback on the workshop 5. Have a multiplier effect

3. Course Ingredients July 29- Lectures (9:00 - 9:50) Sept 9 Selected issues from DCR 3 text Sections (10:00 - 11:50) Protocol components More issues from the text Sept 16 5-page protocols due Oct 7, 14 Protocol review sessions In pairs, new faculty

4. Types of Study • Not the best choice for this course • Mice, molecules without humans • Cost-effectiveness, meta-analysis • Secondary data analysis • Qualitative research • Ideal • A new observational study or clinical trial involving humans (+ molecules) that you will do this year

5. Computer skills • You need to know how to • Word process, use Pubmed • Use a reference program such as Endnote • You can learn by • Getting a mentor or friend to show you • Taking a course in the UCSF Library

6. Certificate • For satisfactory performance in all 3 TICR Summer Workshop courses, including: • Turning in your 5-page protocol on time • Turning in your ethics project on time • Turning in your career plan on time

7. Faculty for sections Christian Apfel MD, PhD Anaesthesia Heidi Bauer MD, MPH Public Health Valerie Flaherman MD, MPH Pediatrics Ari Green MD, MAS-CR Neurology John Inadomi MD, MPH Gastroenterology Steve Hulley MD, MPH Cardiovascular Epidemiology Michael Kohn MD, MPP Emergency Medicine Kathleen Liu MD, PhD, MAS-CR Nephrology/Pulm Crit Care Chris Madsen MD, MPH Pediatrics Mark Pletcher MD, MPH General Internal Medicine Travis Porco PhD Mathematical Modeling Joel Simon MD, MPH General Internal Medicine

8. Faculty for sections Christian Apfel MD, PhD Clinical Research Methods Heidi Bauer MD, MPH Clinical Research Methods Valerie Flaherman MD, MPH Clinical Research Methods Ari Green MD, MAS-CR Clinical Research Methods John Inadomi MD, MPH Clinical Research Methods Steve Hulley MD, MPH Clinical Research Methods Michael Kohn MD, MPP Clinical Research Methods Kathleen Liu MD, PhD, MAS-CR Clinical Research Methods Chris Madsen MD, MPH Clinical Research Methods Mark Pletcher MD, MPH Clinical Research Methods Travis Porco PhD Clinical Research Methods Joel Simon MD, MPH Clinical Research Methods

9. Course Coordinator Olivia DeLeon Olivia@epi.ucsf.edu 514-8231 (tel) 514-8150 (fax) (Please let her know if your email address has changed by sending her an email)

10. Anatomy of research: What it’s made of • Research question • Significance • Design • Subjects • Population • Sample • Variables • Predictor • Outcome

11. Physiology of research: How it works Using measurements in a sample to draw inferences about phenomena in a population

13. Hulley’s Research Question (1993) Should postmenopausal women receive hormones? Subjects: postmenopausal women Predictor: “hormones” Outcome: ?

14. Improved Research Question Does estrogen treatment prevent heart attacks in postmenopausal women? Subjects: postmenopausal women Predictor: estrogen treatment vs none Outcome: heart attacks

15. Is RQ FINER? Feasible Interesting Novel Ethical Relevant

16. Is RQ FINER? Need to specify the design of the study

17. Designs • Observational study • Cohort • Cross-sectional • Case control • Randomized clinical trial • Surrogate endpoints • Endpoints of primary interest

18. Cohort design Subjects • 5000 post-menopausal women living in the Bay Area Predictor: • Taking estrogen? Outcome: • Subsequent 5-year incidence of MI

19. Cross-sectional design Subjects • 2000 PM women seen at SFGH Predictor: • Taking/took estrogen? Outcome: • History of MI?

20. Case-control design Subjects • Cases: 50 PM women with MI in the SFGH ED • Controls: 50 PM women with trauma in the SFGH ED Predictor: • Taking/took post-menopausal estrogen? Outcome: • Cases vs controls

21. Observational Studies of Estrogen and CHD Author (year)Relative risk Lafferty (1985) 0.2* Sullivan (1990) 0.2* Hammond (1979) 0.3* Nachtigall (1979) 0.3* Stampfer (1991) 0.3* Bush (1987) 0.4* Pettiti (1987) 0.5* Grodstein (1996) 0.6* Henderson (1991) 0.7* Psaty (1994) 0.7 Wolf (1991) 0.7* Falkeborn (1992) 0.7* Criqui (1988) 1.0 Wilson (1985) 1.9 Combined 0.7* Barrett-Connor, Public Health Reviews, 1997 * p < .05

22. NB, when choosing a research question and design Importance of thorough literature review and scholarship

23. Randomized blinded trial design: Surrogate outcomes Subjects • 60 Post-menopausal women Predictor: • Randomized to estrogen vs placebo Outcome 4 weeks later: • LDL-C decreased by 10%, p<.01 • HDL-C increased by 10%, p<.01

24. Randomized blinded trial design:Disease event outcomes Subjects • Post-menopausal women Predictor: • Randomized to estrogen vs placebo Outcome: • Subsequent incidence of MI

25. Feasible? Clinical trial of estrogen vs placebo to prevent MI/CHD death in 10,000 women with prior hysterectomy

26. More feasible Secondary prevention trial of estrogen + progestin vs placebo to prevent MI/CHD death in 2500 women with a uterus and prior CHD • Participants willing, available in 20 centers • Wyeth-Ayerst willing to fund, with UCSF controlling the science

27. HERS trial(Heart and Estrogen/progestin Replacement Study) • Subjects • 2763 women; age < 80 (mean age = 67) • postmenopausal, with a uterus • documented coronary disease • Predictor • .625 mg Premarin + 2.5 mg MPA (E+P) vs blinded placebo, randomly assigned • Outcome • 4-year rate of non-fatal MI and CHD death

28. Interesting?

30. Novel? First randomized blinded trial with disease endpoints of whether estrogen treatment prevents CHD

31. Ethical? • Equipoise (uncertain whether benefits or harms predominate) • Benefits of hormone Rx • Reduce menopausal symptoms • ? Prevent CHD • ? Prevent fractures • ? Prevent Alzheimer’s Disease • ? Improve quality of life • Harms • ?Venous thrombo-embolism • ? Breast cancer

32. Relevant? • Premarin/Prempro: #1 in sales • Decision faced by half the population

33. Please notice the changes in research question Observational RQ: Is estrogen associated with heart attacks in postmenopausal women? Intended clinical trial RQ: Does estrogen prevent CHD events in postmenopausal women? HERS RQ: Does estrogen + progestin prevent new CHD events in postmenopausal women with coronary disease?

34. HERS findings All primary CHD events 290 293 .99 .99 Hulley et al JAMA 1998;280:605-13 Treatment Group E + P Placebo RH p

35. Why the null CHD result?Three possibilities 1. HERS got the wrong answer 2. The observational and other studies got the wrong answer 3. They answered different questions

36. 1. HERS got the wrong answer • Random error? • Systematic error?

37. Random error? All primary CHD events 290 293 .99 .84-1.17 Hulley et al JAMA 1998;280:605-13 Treatment Group E + P Placebo RH 95% CI

38. HERS got the wrong answer: Systematic error? • Randomization • Blinding • Co-intervention • Biased outcome ascertainment • Adherence to treatment • Loss to follow-up

39. 2. The observational studies got the wrong answer • Random error? • Systematic error? • Confounding?

40. Confounding • Big problem in observational studies of drugs for preventive medicine • Women who take hormones are inherently healthier • Statistical adjustment is only a partial solution • Only a randomized trial can solve the problem

41. 3. HERS answered a different question • Other populations more responsive? • Primary prevention earlier in menopause • Other interventions better benefit/harm ratio? • Estrogen only • Different E, different P • Lower doses

42. Three possibilities Physiology: 1. HERS got the wrong answer 2. The observational studies got the wrong answer Anatomy: 3. They answered different questions

43. How to decide?

44. Replication:The primary prevention Women’s Health Initiative WHI E+P Trial • Subjects:16,608 women with a uterus, mean age 63 • Predictor: E+P vs placebo (as in HERS) • Outcome: MI + CHD death (as in HERS) WHI Estrogen-only Trial • Subjects:10,739 women with no uterus, mean age 64 • Predictor: E vs placebo • Outcome: MI + CHD death

45. Disease outcomes in HERS and WHI RH (95% CI) OutcomeHERS E+PWHI E+P WHI E-alone MI+CHD death 1.0 (0.8-1.2) 1.3 (1.0-1.6) 0.9 (0.8-1.1) Stroke 1.2 (0.9-1.7) 1.4 (1.1-1.8) 1.4 (1.1-1.8) Pulm Embolism 2.1 (1.3-3.4) 2.1 (1.6-2.8) 1.3 (0.9-2.1) Breast cancer 1.3 (0.8-1.9) 1.3 (1.0-1.6) 0.8 (0.6-1.0) Hip fracture 1.1 (0.5-2.5) 0.7 (0.5-1.0) 0.6 (0.4-0.9) Dementia* 2.0 (1.2-3.5) 1.5 (0.8-2.7) Hulley, JAMA 2004;291:1769 (editorial) *Schumaker, JAMA 2004;291:2947

46. Ethical? • Equipoise (uncertain whether benefits or harms predominate) • Benefits of hormone Rx • Reduce menopausal symptoms • ? Prevent CHD • ? Prevent fractures • ? Prevent Alzheimer’s Disease • ? Improve quality of life • Harms • ?Venous thrombo-embolism • ? Breast cancer

47. Bottom lines • HERS did get the right answer • If properly designed and carried out, experiments trump observational studies • Observational studies of drugs are often confounded • Practice guidelines on hormones after menopause • Do not use forprevention of CHD, dementia • This applies to any regimen, pending further trials • Can use for treating menopausal symptoms • Low dose, short duration

48. Annual Number of US Prescriptions for Hormone Therapy WHI HERS Hersh, JAMA 2004;291:47 Source: IMS Health NPA Plus

49. NB HERS and WHI were very large studies. How about something bite-sized?

50. The research cycle Develop research question Infer conclusions Design study Analyze results Implement study