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UC San Francisco School of Medicine

Designing Clinical Research A course for pre-doctoral researchers January 4-March 8, 2007 Winter Quarter. UC San Francisco School of Medicine. Course overview. Thomas E. Novotny, MD, MPH January 4, 2007. Faculty and staff Dept. of Epid. and Biostat. Course Objectives.

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UC San Francisco School of Medicine

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  1. Designing Clinical ResearchA course for pre-doctoral researchersJanuary 4-March 8, 2007Winter Quarter UC San Francisco School of Medicine

  2. Course overview Thomas E. Novotny, MD, MPHJanuary 4, 2007

  3. Faculty and staff Dept. of Epid. and Biostat.

  4. Course Objectives • Acquire research skills • Produce a 5-page protocol for a real study • Help others in the course (peer review) • Provide feedback on the course • Have a multiplier effect

  5. Types of Study • Not the best choice for this course • Mice, molecules • Cost-effectiveness, meta-analysis • Secondary data analysis • Qualitative research • Ideal • A new observational study (or experiment) involving humans that you will do this year

  6. Structure of the course • 10 weeks in length, Thursdays 4-7 PM • Lecture 4-5:30 PM, break with sandwiches • Small group 5:30-7:00 PM • One excused absence permitted (attendance taken) • Assigned readings; writing sections to be completed by Monday at 5 PM, sent to group leader by email • Discuss the various sections of each other’s protocols in small groups each week • Full protocol Due Noon, March 2 to Olivia by email (olivia@epi.ucsf.edu) • Peer Review Thursday, March 8, 4-5:30 followed by evaluation and dinner meeting of John Snow Society at Kezar Pub

  7. Additional Course Essentials • On-line CHR Course prior to ethics lecture on January 25 https://www.researchonline.ucsf.edu/ • EndNote Classes in Library • Designing Clinical Research, 3rd Edition, Hulley et al.

  8. Lecture 1 Designing Clinical Research for Pre-doctoral researchers The research question Thomas E. Novotny, M.D., M.P.H.January 4, 2007

  9. Sections of the study protocol • Research question • Significance (background) • Study design • Study population and sampling • Variables and measurements • Statistical issues • Ethical issues • Quality control and data management

  10. The research question • All studies should start with a research question that addresses what the investigator would like to know • Goal is to find an important research question that can be developed into a feasible and valid study plan

  11. The research cycle Develop research question

  12. The research cycle Develop research question Design study

  13. The research cycle Develop research question Design study Implement study

  14. The research cycle Develop research question Design study Implement study Analyze results

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

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

  17. The research question • Format for descriptive study • “In a population of [study population], what is the prevalence (or mean, median, etc.) of [outcome variable]?” • Most studies will have more than one research question • The research protocol flows from the research question

  18. The research question • Usual format (analytic studies): “In a population of [study population], is [predictor variable] associated with [outcome variable]?”

  19. Examples of research questions • In a population of injection drug userswith HIV infection, is HAART use associated with fewer opportunistic infections? • In a population of HIV-infected Croatian patients on HAART, is a Mediterranean diet associated with lower risk of dyslipidemia? • In a population of Croatian merchant seaman, is unprotected sex with sex workers in African ports associated with HIV infection?

  20. What is the research question in this abstract? Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children. We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a randomized, double-blind study in Soweto, South Africa. At 6, 10 and 14 weeks of age, 19,922 children received the 9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin (CRM197), and 19,914 received placebo… Klugman KP, Madhi SA, Huebner RE, et al. A trial of 9-valent pneumococcal conjugate vaccine in children with and without HIV infection. N Engl J Med 2003; 349:1341-8.

  21. In a population of [study population] is [predictor variable] associated with [outcome variable]? In a population of South African infants is immunization with a 9-valent pneumococcal conjugate vaccine associated with invasive pneumococcal disease?

  22. Origins of a research question • Mastering the literature • Scholarship -- be a scholar and know the literature • Get a mentor • Be alert to new ideas and techniques • Importance of teaching • Be imaginative

  23. FINER characteristics • Feasible • Interesting to the investigator • Novel • Ethical • Relevant

  24. FINER characteristicsCriteria for feasibility • Adequate number of subjects • Adequate technical expertise • Affordable in time and money • Manageable in scope

  25. FINER characteristicsCriteria for novelty • Confirms or refutes previous findings • Extends previous findings • Provides new findings

  26. FINER characteristicsCriteria for relevance • To scientific knowledge • To clinic, public health or health policy • To future research directions

  27. Problems and solutions:Research plan is not FINER • Not feasible • Too broad • Not enough subjects available • Methods beyond skill of investigator • Too expensive • Not interesting, novel or relevant • Uncertain ethical suitability

  28. Problems and solutions:Research plan is not feasible • Too broad • Smaller set of variables • Narrow the question • Not enough subjects available • Expand inclusion criteria • Modify exclusion criteria • Add other sources of subjects • Lengthen the time frame for entry into study • Use strategies to decrease sample size

  29. Problems and solutions:Research plan is not feasible • Methods beyond skill of investigator • Collaborate with colleagues who have skills • Consult experts and review literature for alternative methods • Learn the needed skills yourself • Too expensive • Consider less costly study design • Fewer subjects and measurements • Less extensive measurement • Fewer follow-up visits

  30. Problems and solutions:Research plan is not FINER • Not interesting, novel or relevant • Consult with mentor • Modify the research question • Uncertain ethical suitability • Consult with institutional review board (ethics committee) • Modify the research question

  31. Problems and solutions • Study plan is vague • Write the research plan at an early stage • Get specific in the 1 to 2-page study plan • How the subjects will be sampled • How the variables will be measured

  32. Problems and solutions: examples • What is the relationship between depression and health? • Does eating red meat cause cancer? • Does lowering serum cholesterol prevent heart disease? • Do contraceptive vaginal sponges prevent HIV infection?

  33. Anatomy of Clinical Research

  34. Physiology of clinical research: How it works Using measurements in a sample to draw inferences about Phenomena (variables) in a population

  35. Confounding variables* Effect Modifiers* Types of variables Predictor* Outcome *Generally categorized as exposures

  36. The research question • In descriptive studies: “In a population of [study population], what is the prevalence of [outcome variable]?” • In analytic studies: “In a population of [study population], is [predictor variable] associated with [outcome variable]?”

  37. Types of clinical studies • Studies with no variables • Case studies, case series, editorials, opinions, reviews • Studies with single variables • Descriptive studies and surveys • Studies with ≥2 variables • Experiments • Observational studies • Meta-analyses and systematic reviews

  38. Hierarchy of clinical study types

  39. Variables Predictor variable (independent) Outcome variable (dependent)

  40. Hulley’s Research Question (1993) Should postmenopausal women receive hormones?

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

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

  43. FINER? Feasible Interesting Novel Ethical Relevant

  44. Need to specify design • Observational study • Cross-sectional • Case control • Cohort • Randomized clinical trial • Surrogate endpoints • Endpoints of primary interest

  45. Cohort design Subjects • 5000 women age 55+ living in the Bay Area Predictor: • Taking post-menopausal estrogen at baseline? Outcome: • Subsequent 5-year incidence of heart attacks

  46. Cross-sectional design Subjects • 2000 women age 55+ seen at SFGH Predictor: • Taking post-menopausal estrogen? Outcome: • History of heart attack?

  47. Case-control design Subjects • Cases: 100 women with heart attacks in the SFGH ED • Controls: 100 women with trauma in the SFGH ED Predictor: • Taking post-menopausal estrogen? Outcome: • Cases vs controls

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

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

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