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

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)

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

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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