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Designing Clinical Research
A course for pre-doctoral and Resident researchers
August 4-29, 2008
UC San Francisco School of Medicine
Training in Clinical Research Program
August 4, 2008
Course overview
Faculty and staff Dept. of Epidemiology and
Biostatistics
Name Role
Douglas Bauer Co-Director/group leader
Kirsten Bibbins-Domingo Co-Director/group leader
Thomas E. Novotny Co-Director/group leader
Olivia de Leon Course Support
Allison Deneen Website Management and Communications
Small Group Leaders
• Residents: Doug Bauer, Emily Von Scheven and Jeff Kohlwes
• Students: Tom Novotny, Kirsten Bibbins-Domingo, Jean Tang, Andy Choi
• Alternate: Kala Mehta
Course Schedule
Date Lecture Title Instructor Chapters8/4 The Research Question T. Novotny 1, 2, 198/6 Subjects and variables D.Bauer 3, 48/11 Study designs K. Bibbins-Domingo 7, 8, 14 8/13 Causality/clinical trials D.Grady 9, 108/18 Sampling/sample size S. Hulley 5, 68/20 Statistical issues C. McCulloch 11, 12 (consult session) B. Grimes CL1138/25 Data Management M. Kohn 13, 16
(Small group optional)8/26 Protocols due [email protected] 8 AM8/27 Pre-testing, questionnaires,
quality control C.Kaplan 15, 178/29 Peer review session Faculty
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
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
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)
• Three Assigments, Due by noon on Aug 8, 5, and 22• Discuss the various sections of each other’s protocols
in small groups each week• Full protocol Due 8 AM, Aug 26 (Tues) to Olivia by
email ([email protected])• Peer Review Friday August 29, 9-11:OO (or by
arrangement).
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.
• Assignments (3 only)
The Research Question
Thomas E. Novotny, M.D., M.P.H.August 4, 2008
Lecture 1
Designing Clinical Research for Pre-doctoral and Resident researchers
Schematic of Clinical Research: Anatomy and Physiology
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
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
The research cycle
Develop research question
The research cycle
Develop research question
Design study
The research cycle
Develop research question
Design study
Implement study
The research cycle
Develop research question
Design study
Implement studyAnalyze results
The research cycle
Develop research question
Design study
Implement studyAnalyze results
Infer conclusions
The Study Plan
Develop research question
Design study
Implement studyAnalyze results
Infer conclusions
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
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
Examples of research questions
• In a population of injection drug users with 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?
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.
In a population of South African infants is immunization with a 9-valent pneumococcal conjugate vaccine associated with reduced incidence of invasive pneumococcal disease?
In a population of [study population] is [predictor variable] associated with [outcome variable]?
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
Characteristics of the Research Question: FINER
• Feasible
• Interesting to the investigator
• Novel
• Ethical
• Relevant
FINER characteristicsCriteria for feasibility
• Adequate number of subjects
• Adequate technical expertise
• Affordable in time and money
• Manageable in scope
FINER characteristicsCriteria for interesting
• Something to be passionate about
• Something to be an expert in
• Something that makes a difference in the world
FINER characteristicsCriteria for novelty
• Confirms or refutes previous findings
• Extends previous findings
• Provides new findings
FINER characteristicsCriteria for ethical
• Respect for human rights
• Respect for confidentiality
• Respect for informed consent
• Respect for beneficence, non-maleficence, social justice
FINER characteristicsCriteria for relevance
• To scientific knowledge
• To clinic, public health or health policy
• To future research directions
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
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
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
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
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
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?
Schematic of Clinical Research: Anatomy and Physiology
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)
Predictor* Outcome
Confounding variables*
Effect Modifiers*
Types of variables
*Generally categorized as exposures
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
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]?”
Hierarchy of clinical study types
Descriptive studies
Experimental studies
Cohort Case-control Cross-sectional
Observational studies
Analytic studies
Example Dr. Hulley’s Research Question (1993)
Should postmenopausal women receive hormones?
Should postmenopausal women receive hormones?
Subjects: postmenopausal women
Predictor: “hormones”
Outcome: ?
Improved Research Question
Does estrogen treatment prevent heart attacks in postmenopausal women?
Subjects: postmenopausal women Predictor: estrogen treatment vs none Outcome: heart attacks
FINER?
Feasible
Interesting
Novel
Ethical
Relevant
Need to specify design
• Observational study Cross-sectional Case control Cohort
• Randomized clinical trial Surrogate endpoints Endpoints of primary interest
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
Cross-sectional design
Subjects 2000 women age 55+ seen at SFGH
Predictor: Taking post-menopausal estrogen?
Outcome: History of heart attack?
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
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
Relevant?
• Premarin/Prempro: #1 in sales• Decision faced by half the population
Anatomy: Study Outline
• Research question• Significance (background)• Study design• Subjects and sampling
• Variables and measurements
• Statistical issues
• Ethical issues• Quality control and data
management
• What is the focus of the study?• Why is it important?• How will you study it?
• Who are the research subjects and how are you going to select them?
• What measures will be done?• What will the size of the study
be and how will you analyze it?• Are there ethical issues?• How will the study be managed
to assure high quality results?
First Assignment: Developing background and significance section
• Same role as introduction in a paper• Puts the research question in context• Describes the rationale for the study• What is known about the topic to be studied• Why is the research question important?• What type of answer will be the study
supply?
Background and significance
• Cites previous research that is relevant (including the investigator’s own work)
• Indicates the strengths and weakness (or problems) of previous studies and what questions remain unanswered
• Be clear how the results of the proposed studies will help lead to resolution of uncertainty and influence public health policy or clinical practice (the SOCO)
Finding pertinent literature
• Use End Note or a similar program• Check format of references from journal’s
instructions to authors and include them as you write protocol
• Keep copies of all references handy• Search PubMed• Personal communications (who and when)• Unpublished data (best to avoid)
Course End Product: The Study Plan
• Develop the research question
• Background and Significance
• Outline the study (second assignment)
• Expand to the 5-page protocol
• Develop the operations manual for management and implementation
• Analysis and reporting
Examples from students
