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Designing Clinical Research A course for pre-doctoral and Resident researchers February 1-27, 2008

Designing Clinical Research A course for pre-doctoral and Resident researchers February 1-27, 2008. UC San Francisco School of Medicine Training in Clinical Research Program. Course overview. February 1, 2008. Faculty and staff Dept. of Epidemiology and Biostatistics. Course Schedule.

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Designing Clinical Research A course for pre-doctoral and Resident researchers February 1-27, 2008

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  1. Designing Clinical ResearchA course for pre-doctoral and Resident researchersFebruary 1-27, 2008 UC San Francisco School of Medicine Training in Clinical Research Program

  2. Course overview February 1, 2008

  3. Faculty and staff Dept. of Epidemiology and Biostatistics

  4. Course Schedule Date     Lecture Title            Instructor  Chapters 2/1         The Research Question  T. Novotny                1, 2, 19 2/4          Subjects and variables    D.Bauer                    3, 4 2/6          Study designs                  K. Bibbins-Domingo 7, 8, 14  2/11        Causality/clinical trials    J.Tice             9, 10 2/13        Sampling/sample size    S. Hulley                   5, 6 2/18 Holiday 2/20        Statistical issues C. McCulloch 11, 12               (consult session)              B. Grimes          2/22        Protocols due                13, 16 2/25        Pre-testing, questionnaires, quality control           J. Paul                  15, 17, 18 2/27        Peer review session         Faculty             

  5. 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

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

  7. Structure of the course • 4 weeks in length, 9 AM-12 noon • Breakfast 8:30 AM • Lecture 9-10:15AM, break • Small group 10:30-noon • One excused absence permitted (attendance taken) • Assigned readings; writing sections to be completed by day of lecture 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, February 20 to Olivia by email (olivia@epi.ucsf.edu) • Peer Review Wednesday February 27, 9-11:OO followed by evaluation feedback session, 11-noon.

  8. Additional Course Essentials • On-line CHR Course https://www.citiprogram.org/default.asp • EndNote Classes in Library • Designing Clinical Research, 3rd Edition, Hulley et al.

  9. Lecture 1 Designing Clinical Research for Pre-doctoral and Resident researchers The Research Question Thomas E. Novotny, M.D., M.P.H.February 1, 2008

  10. Schematic of Clinical Research: Anatomy and Physiology

  11. Anatomy of Clinical Research: the Study Protocol (Table 1.1) • Research question • Background and Significance • Study design • Subjects and sampling • Variables and measurements • Statistical issues • Ethical issues • Quality control and data management

  12. 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

  13. The research cycle Develop research question

  14. The research cycle Develop research question Design study

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

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

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

  18. The Study Plan Develop research question Infer conclusions Design study Analyze results Implement study

  19. The research question (1) • Format for a descriptive study “In a population of [study population], what is the prevalence (or mean, median, etc.) of [outcome variable]?” • This is the format for much of public health research

  20. The research question (2) • Format for analytic studies: “In a population of [study population], is [predictor variable] associated with [outcome variable]?” • This is the usual format for much of clinical research

  21. 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?

  22. 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.

  23. 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 reduced incidence ofinvasive pneumococcal disease?

  24. 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

  25. Characteristics of the Research Question: FINER • Feasible • Interesting to the investigator • Novel • Ethical • Relevant

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

  27. FINER characteristicsCriteria for interesting • Something to be passionate about • Something to be an expert in • Something that makes a difference in the world

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

  29. FINER characteristicsCriteria for ethical • Respect for human rights • Respect for confidentiality • Respect for informed consent • Respect for beneficence, non-maleficence, social justice

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

  31. Problems and solutions:Research question 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

  32. Problems and solutions:Research question 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

  33. Problems and solutions:Research question 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

  34. Problems and solutions:Research question 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

  35. Problems and solutions • Research question is vague • Write the research plan outline at an early stage • Get specific in the study protocol • How the subjects will be sampled • How the variables will be measured

  36. Study question challenges: 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?

  37. Schematic of Clinical Research: Anatomy and Physiology

  38. Physiology of clinical research: How it works • Using measurements in a sample to draw inferences about phenomena (variables) in a population • Accounting for Random Error (chance) • And Systematic Error (Bias)

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

  40. Types of clinical studies (physiology) • 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

  41. The research question: study types • 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]?”

  42. Hierarchy of clinical study types

  43. Example Dr. Hulley’s Research Question (1993) Should postmenopausal women receive hormones?

  44. Should postmenopausal women receive hormones? Subjects: postmenopausal women Predictor: “hormones” Outcome: ?

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

  46. FINER? Feasible Interesting Novel Ethical Relevant

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

  48. 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

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

  50. 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

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