department of epidemiology and biostatistics designing clinical research session #1 about this...
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Department of Epidemiology and Biostatistics
DESIGNING CLINICAL RESEARCH
Session #1
• About this course
• Chapters 1 & 2
• Examples
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
Course Ingredients
July 29- Lectures (9:00 - 9:50)Sept 9 Selected issues from DCR 3 text
Sections (10:00 - 11:50)Protocol componentsMore issues from the text
Sept 16 5-page protocols due
Oct 7, 14 Protocol review sessions In pairs, new faculty
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
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
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
Faculty for sections
Christian Apfel MD, PhD AnaesthesiaHeidi Bauer MD, MPH Public HealthValerie Flaherman MD, MPH PediatricsAri Green MD, MAS-CR NeurologyJohn Inadomi MD, MPH GastroenterologySteve Hulley MD, MPH Cardiovascular
EpidemiologyMichael Kohn MD, MPP Emergency MedicineKathleen Liu MD, PhD, MAS-CR Nephrology/Pulm Crit CareChris Madsen MD, MPH PediatricsMark Pletcher MD, MPH General Internal MedicineTravis Porco PhD Mathematical ModelingJoel Simon MD, MPH General Internal Medicine
Faculty for sections
Christian Apfel MD, PhD Clinical Research MethodsHeidi Bauer MD, MPH Clinical Research MethodsValerie Flaherman MD, MPH Clinical Research MethodsAri Green MD, MAS-CR Clinical Research MethodsJohn Inadomi MD, MPH Clinical Research MethodsSteve Hulley MD, MPH Clinical Research MethodsMichael Kohn MD, MPP Clinical Research MethodsKathleen Liu MD, PhD, MAS-CR Clinical Research MethodsChris Madsen MD, MPH Clinical Research MethodsMark Pletcher MD, MPH Clinical Research MethodsTravis Porco PhD Clinical Research MethodsJoel Simon MD, MPH Clinical Research Methods
Course Coordinator
Olivia DeLeon
514-8231 (tel)
514-8150 (fax)
(Please let her know if your email address has changed by sending her an email)
Anatomy of research: What it’s made of
• Research question– Significance
• Design• Subjects
– Population– Sample
• Variables– Predictor– Outcome
Physiology of research: How it works
Using measurements in a sample
to draw inferences about
phenomena in a population
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
Hulley’s Research Question (1993)
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
Is RQ FINER?
Feasible
Interesting
Novel
Ethical
Relevant
Is RQ FINER?
Need to specify the design
of the study
Designs
• Observational study– Cohort – Cross-sectional– Case control
• Randomized clinical trial– Surrogate endpoints– Endpoints of primary interest
Cohort design
Subjects– 5000 post-menopausal women living in the
Bay Area
Predictor:– Taking estrogen?
Outcome:– Subsequent 5-year incidence of MI
Cross-sectional design
Subjects– 2000 PM women seen at SFGH
Predictor:– Taking/took estrogen?
Outcome:– History of MI?
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
Author (year) Relative riskLafferty (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) 0.7Wolf (1991) 0.7*Falkeborn (1992) 0.7*Criqui (1988) 1.0Wilson (1985) 1.9
Combined 0.7*
Observational Studies of Estrogen and CHD
Barrett-Connor, Public Health Reviews, 1997 * p < .05
NB, when choosing a research question and design
Importance of thorough literature review and scholarship
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
Randomized blinded trial design:Disease event outcomes
Subjects– Post-menopausal women
Predictor:– Randomized to estrogen vs placebo
Outcome:– Subsequent incidence of MI
Feasible?
Clinical trial of estrogen vs placebo to prevent MI/CHD death in 10,000 women with prior hysterectomy
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
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
Interesting?
QuickTime™ and aTIFF decompressor
are needed to see this picture.
Novel?
First randomized blinded trial with disease endpoints of whether estrogen treatment prevents CHD
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
Relevant?
• Premarin/Prempro: #1 in sales• Decision faced by half the population
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?
HERS findings
All primary CHD events 290 293 .99 .99
Hulley et al JAMA 1998;280:605-13
Treatment GroupTreatment Group
E + PE + P PlaceboPlacebo RHRH p p
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
1. HERS got the wrong answer
• Random error?
• Systematic error?
Random error?
All primary CHD events 290 293 .99 .84-1.17
Hulley et al JAMA 1998;280:605-13
Treatment GroupTreatment Group
E + PE + P PlaceboPlacebo 95% CI95% CIRHRH
HERS got the wrong answer: Systematic error?
• Randomization
• Blinding– Co-intervention– Biased outcome ascertainment
• Adherence to treatment
• Loss to follow-up
2. The observational studies got the wrong answer
• Random error?
• Systematic error?
• Confounding?
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
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
Three possibilities
Physiology:
1. HERS got the wrong answer
2. The observational studies got the wrong answer
Anatomy:
3. They answered different questions
How to decide?
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
Disease outcomes in HERS and WHI
Outcome HERS E+P WHI 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
RH (95% CI)
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
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 for prevention of CHD, dementia
• This applies to any regimen, pending further trials
– Can use for treating menopausal symptoms
• Low dose, short duration
Source: IMS Health NPA Plus
0
10
20
30
40
50
60
1995 1996 1997 1998 1999 2000 2001 2002 2003Year
An
nu
al
Pre
sc
rip
tio
ns
by
Fo
rmu
lati
on
(m
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Oral E Oral E/P Trnd/Vag
Annual Number of US Prescriptions for Hormone Therapy
HERSWHI
Hersh, JAMA 2004;291:47
NB
HERS and WHI were very large studies.
How about something bite-sized?
The research cycle
Develop research question
Design study
Implement studyAnalyze results
Infer conclusions
Next …
One sentence describing anatomy of your study
• Research question• Design• Subjects• Variables
– Predictor– Outcome
FINER?
Feasible
Interesting
Novel
Ethical
Relevant