Randomized Trials 9 Sessions9 Sessions Grady (course director), Black (lecturer), Cummings...

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Randomized Trials Randomized Trials 9 Sessions 9 Sessions Grady (course director), Black (lecturer), Grady (course director), Black (lecturer), Cummings (lecturer) Cummings (lecturer) Mechanics Mechanics Turn in homework to Olivia Romero prior Turn in homework to Olivia Romero prior to each session to each session NEW NEW
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Transcript of Randomized Trials 9 Sessions9 Sessions Grady (course director), Black (lecturer), Cummings...

Randomized TrialsRandomized Trials

• 9 Sessions9 Sessions

• Grady (course director), Black (lecturer), Cummings Grady (course director), Black (lecturer), Cummings (lecturer)(lecturer)

• MechanicsMechanics

– Turn in homework to Olivia Romero prior to each Turn in homework to Olivia Romero prior to each sessionsession

NEWNEW

Randomized Trials: the Randomized Trials: the EvidenceEvidence in in “Evidence-Based”“Evidence-Based”

• TodayToday

– Randomized trials: why bother?Randomized trials: why bother?

– RandomizationRandomization

– Selection of participants (Inclusion/exclusion)Selection of participants (Inclusion/exclusion)

– Design options for trialsDesign options for trials

• Dennis Black, PhDDennis Black, PhD

[email protected]@psg.ucsf.edu

– 597-9112597-9112

Feedback from last year (observed)….Feedback from last year (observed)….

• Great course but…..Great course but…..

HERSHERSHERSHERS

NEWNEW

Feedback from this year (predicted)….Feedback from this year (predicted)….

• Great course but…..Great course but…..

WHIWHIWHIWHI

NEWNEW

Randomized Trials: the Randomized Trials: the EvidenceEvidence in in “Evidence-Based”“Evidence-Based”

• TodayToday

– Randomized trials: why bother?Randomized trials: why bother?

– RandomizationRandomization

– Selection of participants (Inclusion/exclusion)Selection of participants (Inclusion/exclusion)

– Design options for trialsDesign options for trials

• Dennis Black, PhDDennis Black, PhD

[email protected]@psg.ucsf.edu

– 597-9112597-9112

Randomized Controlled Trial (RCT)Randomized Controlled Trial (RCT)

A study design in which subjects are A study design in which subjects are randomizedrandomized to to intervention or control and followed for occurrence of diseaseintervention or control and followed for occurrence of disease

• • Experimental (as opposed to observational)Experimental (as opposed to observational)

Definitive test of interventionDefinitive test of intervention

Confounders are equally distributed across intervention groupsConfounders are equally distributed across intervention groups• • Treated not younger, richer, healthier, Treated not younger, richer, healthier, better dieters better dieters

Examples of interventionsExamples of interventions

• Drug vs. placeboDrug vs. placebo

• Low fat diet vs. regular dietLow fat diet vs. regular diet

• Exercise vs. CPPExercise vs. CPP

Number of randomized trials published*Number of randomized trials published*

20002000

30003000

40004000

50005000

60006000

70007000

80008000

19861986 19881988 19901990 19921992 19941994 19961996 19981998

* Based on Medline search for “Randomized”* Based on Medline search for “Randomized”

Disadvantages of RCTsDisadvantages of RCTs

• ExpensiveExpensive

• Time ConsumingTime Consuming

• Can only answer a single questionCan only answer a single question

So, why bother?So, why bother?

Alternatives to RCTsAlternatives to RCTs(30 second Epi. Course)(30 second Epi. Course)

• Case-control studiesCase-control studies

– Compare those with and without diseaseCompare those with and without disease

• Cohort studies (prospective)Cohort studies (prospective)

– Identify those with and without risk factorIdentify those with and without risk factor

– Follow forward in time to seeFollow forward in time to see who gets disease who gets disease

• Cohort and case-control are Cohort and case-control are observationalobservational (not (not experimental)experimental)

Reasons for doing RCTsReasons for doing RCTs

• Only study design that can prove causationOnly study design that can prove causation

• Required by FDA (and others) for new drugs and some Required by FDA (and others) for new drugs and some devicesdevices

• Most influential to clinical practiceMost influential to clinical practice

Example: Estrogen Replacement TherapyExample: Estrogen Replacement Therapyin post-menopausal womenin post-menopausal women

• Important therapeutic questionImportant therapeutic question

• Applies to 30 (?) million women in USApplies to 30 (?) million women in US

• Prempro Prempro (estrogen/progestin combo)(estrogen/progestin combo)may be most prescribed drug in USmay be most prescribed drug in US

• Potentially huge impact on public healthPotentially huge impact on public health

• Complex, ERT effects multiple diseases Complex, ERT effects multiple diseases

Estrogen Replacement Therapy (ERT)Estrogen Replacement Therapy (ERT)

DiseaseDisease Effect on Risk*Effect on Risk*

Coronary heart diseaseCoronary heart disease Decrease by 40 - 80%Decrease by 40 - 80%Osteoporosis (hip fx)Osteoporosis (hip fx) Decrease by 30 - 60%Decrease by 30 - 60%Breast cancerBreast cancer Increase by 10 - 20%Increase by 10 - 20%Endometrial cancerEndometrial cancer Increase by 700%Increase by 700%

Alzheimer’sAlzheimer’s Decrease by ?Decrease by ?

Pulmonary embolism &Pulmonary embolism & Increase by 200 - 300%Increase by 200 - 300%deep vein thrombosisdeep vein thrombosis

* From observational (case-control and cohort) studies* From observational (case-control and cohort) studies

Nurses Health Study (NEJM, 9/12/91)Nurses Health Study (NEJM, 9/12/91)

• Prospective cohort study, n = 48,470Prospective cohort study, n = 48,470

• 337,000 person years of follow-up337,000 person years of follow-up

Risk of MajorRisk of MajorEstrogen UseEstrogen Use Coronary Disease*Coronary Disease* Relative Risk**Relative Risk**

Never UsedNever Used 1.41.4 1.01.0

Current userCurrent user 0.60.6 0.56 (0.40-0.80)0.56 (0.40-0.80)

Former userFormer user 1.31.3 0.83 (0.65-1.05)0.83 (0.65-1.05)

* Events per 1000 women-years of follow-up* Events per 1000 women-years of follow-up** Relative Risk (95% CI) compared to never users** Relative Risk (95% CI) compared to never users

Meta-analysis of ERT, Published ~4/10/97Meta-analysis of ERT, Published ~4/10/97

““Benefits (for CHD, osteoporosis) outweigh risks Benefits (for CHD, osteoporosis) outweigh risks (breast cancer) and side effects…(breast cancer) and side effects…

All post-menopausal women should be All post-menopausal women should be taking ERT”*taking ERT”*

* CNN, 4/10/97* CNN, 4/10/97

Virtually all estrogen results areVirtually all estrogen results arebased on observational databased on observational data

• Women chose to take ERTWomen chose to take ERT

• Are ERT users different from non-users?Are ERT users different from non-users?– AgeAge– Health statusHealth status– More exerciseMore exercise– Health behaviors (see Dr.)Health behaviors (see Dr.)– SESSES

• Try to adjust in analysis, but may not be possibleTry to adjust in analysis, but may not be possible

• Randomized trials alleviate these problemsRandomized trials alleviate these problems

Heart and Estrogen-Progestin Replacement Heart and Estrogen-Progestin Replacement Study (HERS)Study (HERS)

• Secondary prevention of heart diseaseSecondary prevention of heart disease

• HRT (Prempro) vs. placebo (4-5 years)HRT (Prempro) vs. placebo (4-5 years)

• ~ 2763 women with established heart disease~ 2763 women with established heart disease

– Postmenopausal, < 80 years, mean age 67Postmenopausal, < 80 years, mean age 67

• 20 clinical centers in U.S./UCSF Coordinating center20 clinical centers in U.S./UCSF Coordinating center

• Funding by Wyeth-Ayerst (post-NIH refusal)Funding by Wyeth-Ayerst (post-NIH refusal)

• Expected results????Expected results????

– Real results: JAMA: 8/98Real results: JAMA: 8/98

HERS: Summary of resultsHERS: Summary of results

EndpointEndpoint PlaceboPlacebo HRTHRT RRRR PP

New CHDNew CHD 176176 172172 0.990.99 0.910.91

Any fractureAny fracture 138138 130130 0.950.95 0.700.70

Conclusion: RandomizedConclusion: Randomized trials can lead to big surprises! trials can lead to big surprises!

Women’s Health Initiative Women’s Health Initiative HRT study* (7/10/02)HRT study* (7/10/02)

• Randomized trial (2)Randomized trial (2)

– 16,608 women with uterus (ERT + progestin vs. placebo)16,608 women with uterus (ERT + progestin vs. placebo)

– ~11,000 women without uterus (ERT alone vs. placebo)~11,000 women without uterus (ERT alone vs. placebo)

• Ages 50-79, mean age 64Ages 50-79, mean age 64

• Represent broad range of U.S. womenRepresent broad range of U.S. women

• 40 clinical centers40 clinical centers

• Follow-up planned for 8.5 years, to end in 2005Follow-up planned for 8.5 years, to end in 2005

* * only one component of WHI..more lateronly one component of WHI..more later* * only one component of WHI..more lateronly one component of WHI..more later

WHI HRT study: 7/10/02WHI HRT study: 7/10/02

• Combination therapy arm stopped early (3 years)Combination therapy arm stopped early (3 years)

– Mean 5.2 years of follow-upMean 5.2 years of follow-up

• Overall, health risks outweigh benefitsOverall, health risks outweigh benefits

• Significant increased risk for invasive breast cancer HRT usersSignificant increased risk for invasive breast cancer HRT users

WHI: Invasive Breast CancerWHI: Invasive Breast Cancer

years 1 2 3 4 5 6 7

1%

2%

3%

WHI: Coronary Heart DiseaseWHI: Coronary Heart Disease

years 1 2 3 4 5 6

Other surprises:Other surprises:Beta Carotene and cancerBeta Carotene and cancer

• Strong suggestions that beta carotene would prevent Strong suggestions that beta carotene would prevent cancercancer

1. Observational epi. (diets high in 1. Observational epi. (diets high in fruits and vegetables withfruits and vegetables withbeta carotene lower cancer risk)beta carotene lower cancer risk)

2. Pathophysiology2. Pathophysiology

• Clinical trials needed to establish cause and effectClinical trials needed to establish cause and effect

Beta carotene: Clinical trial #1Beta carotene: Clinical trial #1

The Alpha-Tocopherol, Beta CaroteneThe Alpha-Tocopherol, Beta CaroteneCancer Prevention StudyCancer Prevention Study

RQ:RQ: Do vitamin E and Do vitamin E and beta-carotenebeta-caroteneprevent lung cancer in smokers?prevent lung cancer in smokers?

Design:Design: RCT, factorial, 6.1 yearsRCT, factorial, 6.1 years

Subjects:Subjects: 29,133 smokers, Finnish men aged 50-6929,133 smokers, Finnish men aged 50-69

Intervention:Intervention: 1. Alpha-tocopherol, 50 mg/day vs. placebo1. Alpha-tocopherol, 50 mg/day vs. placebo(factorial)(factorial) 2. Beta-carotene, 20 mg/day vs. placebo2. Beta-carotene, 20 mg/day vs. placebo

Outcome:Outcome: Lung cancer incidenceLung cancer incidence

Beta-carotene: Clinical Trial #1Beta-carotene: Clinical Trial #1Results Results

Beta-CaroteneBeta-Carotene ControlControl RR*RR*

Lung Cancer CasesLung Cancer Cases 56.356.3 47.547.5 1.191.19

Lung Cancer DeathsLung Cancer Deaths 35.635.6 30.830.8 1.161.16

* Relative risk: Beta carotene vs. control* Relative risk: Beta carotene vs. control

Incidence per 10,000 person yearsIncidence per 10,000 person years

Beta carotene: Clinical trial #2Beta carotene: Clinical trial #2

The Beta-Carotene and Retinol Efficacy Trial (CARET)The Beta-Carotene and Retinol Efficacy Trial (CARET)

RQ:RQ: Do vitamin A and Do vitamin A and beta-carotene prevent lungbeta-carotene prevent lungcancer in smokers?cancer in smokers?

Design:Design: RCT, 4.0 yearsRCT, 4.0 years

Subjects:Subjects: 18,314 men, smokers or asbestos workers18,314 men, smokers or asbestos workers

Intervention:Intervention: Retinol (25,000 IU) and beta carotene (15 mg)Retinol (25,000 IU) and beta carotene (15 mg)vs. placebovs. placebo

Outcome:Outcome: Lung cancer incidenceLung cancer incidence

Lung Cancer*Lung Cancer* Death (all Death (all causes)*causes)*

All SubjectsAll Subjects 1.28 (1.04-1.57)1.28 (1.04-1.57) 1.17 (1.03-1.33)1.17 (1.03-1.33)

Asbestos-exposedAsbestos-exposed 1.40 (0.95-2.07)1.40 (0.95-2.07) 1.25 (1.01-1.56)1.25 (1.01-1.56)

SmokersSmokers 1.23 (0.96-1.56)1.23 (0.96-1.56) 1.13 (0.96-1.32)1.13 (0.96-1.32)

Beta-carotene: Clinical Trial #2Beta-carotene: Clinical Trial #2Results Results

* Relative Risk (95% CI), treatment vs. placebo* Relative Risk (95% CI), treatment vs. placebo

Beta Carotene RCTsBeta Carotene RCTs

• Beta carotene not recommended for Beta carotene not recommended for cancer preventioncancer prevention

• Similar story for beta carotenes and heart Similar story for beta carotenes and heart diseasedisease

• RCT’s very usefulRCT’s very useful

Examples of major Examples of major breakthroughs from RCTsbreakthroughs from RCTs

• Protease inhibitors and AIDSProtease inhibitors and AIDS

• Aspirin and heart diseaseAspirin and heart disease

• Lipid lowering (statins) and heart diseaseLipid lowering (statins) and heart disease

Steps in a “Classical”Steps in a “Classical” Randomized, Controlled Trail (RCT) Randomized, Controlled Trail (RCT)

11.. Select participants Select participants

2. Measure baseline variables2. Measure baseline variables

3. Randomize (to 1 or more treatments)3. Randomize (to 1 or more treatments)

4. Apply intervention4. Apply intervention

5/6. Follow-up--measure outcomes5/6. Follow-up--measure outcomes

Most commonly: one treatment vs. controlMost commonly: one treatment vs. control

Can be used for various types of outcomes Can be used for various types of outcomes (binary, continuous)(binary, continuous)

RandomizationRandomization

• Key element of RCT’sKey element of RCT’s

• Assure equal distribution of both...Assure equal distribution of both...

– measured/known confoundersmeasured/known confounders

– unmeasured/unknown confoundersunmeasured/unknown confounders

• Important to do wellImportant to do well

– True random allocationTrue random allocation

– Tamper-proof (no peaking, altering order of Tamper-proof (no peaking, altering order of participants, etc)participants, etc)

• Simple randomizationSimple randomization

– Low techLow tech

– High techHigh tech

Other types of randomizationOther types of randomization

• Blocking*: equal after each n assignmentsBlocking*: equal after each n assignments

– e.g., block size of 4, treatments a and be.g., block size of 4, treatments a and b

abab aabb bbaa baab abab aabb bbaa baab

– Assure relatively equal number of ppts. to each Assure relatively equal number of ppts. to each treatment treatment

– Disadvantages of blockingDisadvantages of blocking

– Size of block: 2 treatments--4 or 6Size of block: 2 treatments--4 or 6

– Very commonly usedVery commonly used

*Formally: random, permuted blocks*Formally: random, permuted blocks

Randomization to balance prognostic Randomization to balance prognostic variablesvariables

• Stratified permuted blocksStratified permuted blocks

– Blocks within strata of prognostic variableBlocks within strata of prognostic variable

– e.g., HRT study of prevention of MI. High LDL at much e.g., HRT study of prevention of MI. High LDL at much higher risk--want to avoid more higher LDL in placebo.higher risk--want to avoid more higher LDL in placebo.

– StratumStratum

High LDL: aabb baba …High LDL: aabb baba …

Normal LDL: baab abab ….Normal LDL: baab abab ….

– Limited number of risk factors Limited number of risk factors

– Very commonly used in multicenter studies to balance Very commonly used in multicenter studies to balance within clinical centerwithin clinical center

• Fancier techniques for assuring balanceFancier techniques for assuring balance

– Adaptive randomization (not much used)Adaptive randomization (not much used)

Implementation of randomizationImplementation of randomization

• Less challenging for blinded studiesLess challenging for blinded studies

• Sealed envelopes in fixed order at clinical sitesSealed envelopes in fixed order at clinical sites

• Alternatively: list of drug numbersAlternatively: list of drug numbers

– a b a b b b a aa b a b b b a a

– 1 2 3 4 5 6 7 81 2 3 4 5 6 7 8

– Clinic receives bottles labeled only by Clinic receives bottles labeled only by numbers--assign in ordernumbers--assign in order

• Unblinded studies: important to keep next Unblinded studies: important to keep next assignment secret assignment secret

– Problem with blocks within strataProblem with blocks within strata

Who to Study: Who to Study: Principles for Inclusion/exclusionPrinciples for Inclusion/exclusion

• Widest possible generalizabilityWidest possible generalizability

• Sufficiently high event rate (for power to be Sufficiently high event rate (for power to be adequate)adequate)

• Population in whom intervention likely to be Population in whom intervention likely to be effectiveeffective

• Ease of recruitmentEase of recruitment

• Likelihood of compliance with treatment and Likelihood of compliance with treatment and FUFU

Explicit criteria for inclusion in a trialExplicit criteria for inclusion in a trial

• Typically written as “inclusion/exclusion” criteria in protocolTypically written as “inclusion/exclusion” criteria in protocol

• The more explicit the betterThe more explicit the better

• Want centers or investigators to be consistentWant centers or investigators to be consistent

• Examples of exclusion decisionsExamples of exclusion decisions

– 1. Women with heart disease vs. 1. Women with heart disease vs.

Women with CABG surgery or documented MI byWomen with CABG surgery or documented MI by ecg (criteria) or enzymes (criteria) ecg (criteria) or enzymes (criteria)

– 2. Users of estrogen vs2. Users of estrogen vs

Use of ERT for more than 3 months over last 24 mos.Use of ERT for more than 3 months over last 24 mos.

Valid reasons to exclude participantsValid reasons to exclude participants (Table 10.1) (Table 10.1)

• Treatment would be unsafeTreatment would be unsafe

– Adverse experience from active treatmentAdverse experience from active treatment

– ““Risk” of placebo (SOC)Risk” of placebo (SOC)

• Active treatment cannot/unlikely to be effectiveActive treatment cannot/unlikely to be effective

– No risk of outcomeNo risk of outcome

– Disease type unlikely to respondDisease type unlikely to respond

– Competing/interfering treatment (history of?)Competing/interfering treatment (history of?)

• Unlikely to adhere or follow-upUnlikely to adhere or follow-up

• Practical problemsPractical problems

Design-a-trial: Design-a-trial: Inclusion criteria options for HRTInclusion criteria options for HRT

• Study HRT and prevention of heart disease, 4 years (HERS-like)Study HRT and prevention of heart disease, 4 years (HERS-like)

– Women over age 50 yearsWomen over age 50 years

– Women over 60 yearsWomen over 60 years

– Women over 75 yearsWomen over 75 years

– Women with existing heart diseaseWomen with existing heart disease

• Generalizability?Generalizability?

• Feasible sample size?Feasible sample size?

• Population amenable to intervention?Population amenable to intervention?

• Logistic difficulties (recruitment? cost? adherence)Logistic difficulties (recruitment? cost? adherence)

HERS inclusion optionsHERS inclusion options

• HERS trial options (event rate)HERS trial options (event rate)

– Women over age 50 years (0.1%/year)Women over age 50 years (0.1%/year)

– Women over 60 years (0.5%/year)Women over 60 years (0.5%/year)

– Women over 75 years (1%/year)Women over 75 years (1%/year)

– Women with existing heart disease (4%/year)Women with existing heart disease (4%/year)

HERS inclusion optionsHERS inclusion options

• HERS trial options (event rate) [n required]HERS trial options (event rate) [n required]

– Women over age 50 years (0.1%/year) [55,000]Women over age 50 years (0.1%/year) [55,000]

– Women over 60 years (0.5%/year) [45,000]Women over 60 years (0.5%/year) [45,000]

– Women over 75 years (1%/year) [34,000]Women over 75 years (1%/year) [34,000]

– Women with existing heart disease (4%/year) Women with existing heart disease (4%/year)

[3,000][3,000]

(Choose last option as most practical: common (Choose last option as most practical: common to generalize from secondary to primary to generalize from secondary to primary prevention)prevention)

Exclusions/inclusions examplesExclusions/inclusions examples

• Important impact on generalizability of both Important impact on generalizability of both efficacy and safetyefficacy and safety

• Example: Fracture Intervention Trial (FIT)Example: Fracture Intervention Trial (FIT)

– Study of alendronate (amino-bisphosphonate) Study of alendronate (amino-bisphosphonate) vs. placebo in women with low bone massvs. placebo in women with low bone mass

– 6459 women randomized to alendronate or 6459 women randomized to alendronate or placeboplacebo

– Fracture endpointFracture endpoint

– Upper GI and esophagitis concerns with Upper GI and esophagitis concerns with bisphosphonates, esp. aminosbisphosphonates, esp. aminos

– Who to exclude?Who to exclude?

FIT inclusion/exclusion exampleFIT inclusion/exclusion example

• Alendronate studies (pre-FIT) excluded:Alendronate studies (pre-FIT) excluded:

– Any history of upper GI eventsAny history of upper GI events

– Any (remote) history of ulcerAny (remote) history of ulcer

– Esophagial problems, etc.Esophagial problems, etc.

• Reports of upper GI problems in clinical practice: 5% to Reports of upper GI problems in clinical practice: 5% to 20% of patients stop alendronate. Due to:20% of patients stop alendronate. Due to:

– Use by “real world” patients?Use by “real world” patients?

– Use in real world?Use in real world?

– Psychological--due to warnings about potential Psychological--due to warnings about potential problemsproblems

Inclusion may impact effect of treatmentInclusion may impact effect of treatment

• FIT: Included women with baseline BMD T-score FIT: Included women with baseline BMD T-score below -1.6 (only those below -2.5 officially below -1.6 (only those below -2.5 officially osteoporotic)osteoporotic)

• Reduction in hip fractures only among those with Reduction in hip fractures only among those with more severe osteoporosismore severe osteoporosis

• Similar findings in statin trials: higher lipids, Similar findings in statin trials: higher lipids, more benefit more benefit

Effect of alendronate Effect of alendronate on hip fxon hip fx depends on baseline depends on baseline hip BMDhip BMD

Baseline BMD T-scoreBaseline BMD T-score

OverallOverall

< - 2.5< - 2.5

-1.6 – -2.5-1.6 – -2.5

0.10.1 11 1010Relative Hazard (± 95% CI)Relative Hazard (± 95% CI)

0.79 (0.43, 1.44)0.79 (0.43, 1.44)

0.44 (0.18, 0.97)0.44 (0.18, 0.97)

1.84 (0.7, 5.4)1.84 (0.7, 5.4)

NEWNEW

Effect of alendronate Effect of alendronate on non-spine fxon non-spine fx depends on depends on baseline hip BMDbaseline hip BMD

Baseline BMD T-scoreBaseline BMD T-score

OverallOverall

< - 2.5< - 2.5

-2.0 – -2.5-2.0 – -2.5

-1.6 – -2.0-1.6 – -2.0

0.10.1 11 1010Relative Hazard (± 95% CI)Relative Hazard (± 95% CI)

0.86 (0.73, 1.01)0.86 (0.73, 1.01)

0.64 (0.50, 0.82)0.64 (0.50, 0.82)

1.03 (0.77, 1.391.03 (0.77, 1.39))

1.14 (0.82, 1.60)1.14 (0.82, 1.60)

NEWNEW

Inclusion, exclusion, ConclusionInclusion, exclusion, Conclusion

• Many factors to balance in deciding who to Many factors to balance in deciding who to includeinclude

• Generally not a clear cut or single correct Generally not a clear cut or single correct decisiondecision

– Many academics have simplistic Many academics have simplistic understanding of issuesunderstanding of issues

NEWNEW

Alternative RCT designs: Alternative RCT designs: Factorial designFactorial design

• Test of more than one treatment (vs. placebo)Test of more than one treatment (vs. placebo)

• Each drug alone and in combinationEach drug alone and in combination

• Allows multiple hypotheses in single trialAllows multiple hypotheses in single trial

• Efficient (sort of)Efficient (sort of)

• e.g., Physician’s Health Studye.g., Physician’s Health Study

– Test aspirin ==> MI Test aspirin ==> MI

– beta caratene ==> cancerbeta caratene ==> cancer

Factorial design: Physician’s Heath StudyFactorial design: Physician’s Heath Study

PlaceboPlaceboPlaceboPlacebo

AspirinAspirinAspirinAspirin

Beta-Beta-carotenecarotene

Beta-Beta-carotenecarotene

Aspirin plusAspirin plus

Beta-Beta-carotenecarotene

Aspirin plusAspirin plus

Beta-Beta-carotenecarotene

Aspirin vs. no Aspirin vs. no aspirin (MI)aspirin (MI)

Aspirin vs. no Aspirin vs. no aspirin (MI)aspirin (MI)

Beta carotene vs. Beta carotene vs. no beta carotene no beta carotene (cancer)(cancer)

Beta carotene vs. Beta carotene vs. no beta carotene no beta carotene (cancer)(cancer)

Factorial design assumptions/limitationsFactorial design assumptions/limitations

• Treatments do not interactTreatments do not interact

– Effect of aspirin on MI is same with and without Effect of aspirin on MI is same with and without beta-carotenebeta-carotene

– Must test for interaction of treatmentsMust test for interaction of treatments

– Difficult to prove, requires large sampleDifficult to prove, requires large sample

Factorial design assumptions/limitationsFactorial design assumptions/limitations

• Women’s Health Initiative (MOAS, $600M +)Women’s Health Initiative (MOAS, $600M +)

– Estrogen vs. placebo (all outcomes)Estrogen vs. placebo (all outcomes)

– Calcium/Vit D vs. placebo (fractures)Calcium/Vit D vs. placebo (fractures)

– Low fat vs. regular diet (breast cancer)Low fat vs. regular diet (breast cancer)

– Effect of calcium on fractures is the Effect of calcium on fractures is the same/additive with and without estrogen..same/additive with and without estrogen..

•very shaky

NEWNEW

3-way factorial design of WHI3-way factorial design of WHI

HRT vs. no HRT vs. no HRTHRT

HRT vs. no HRT vs. no HRTHRT

Low fat vs. regular Low fat vs. regular dietdiet

Low fat vs. regular Low fat vs. regular dietdiet

Calcium vs. no

Calcium vs. no

calcium

calcium

Calcium vs. no

Calcium vs. no

calcium

calciumNEWNEW

Factorial design assumptions/limitationsFactorial design assumptions/limitations

• Factorial designs are seductive but problematicFactorial designs are seductive but problematic

• Best used for unrelated RQ’s (both treatments Best used for unrelated RQ’s (both treatments and outcomes)and outcomes)

NEWNEW

Cross-over designsCross-over designs

• Both treatments are administered sequentially to Both treatments are administered sequentially to all subjectsall subjects

• Subject serves as own control, random orderSubject serves as own control, random order

• Compare treatment period vs. control periodCompare treatment period vs. control period

• Diuretic vs. beta blocker for blood pressureDiuretic vs. beta blocker for blood pressure

– 1/2 get d followed by bb1/2 get d followed by bb

– 1/2 get bb followed by d1/2 get bb followed by d

Cross-over assumptions/limitationsCross-over assumptions/limitations

• Continuous variables onlyContinuous variables only

• No order effectsNo order effects

• No carry-over effectsNo carry-over effects

• Need quick response and quick resolutionNeed quick response and quick resolution

• ““Wash out” period helpfulWash out” period helpful

• More commonly used in phase I/IIMore commonly used in phase I/II

Other special designsOther special designs

• Matched pairs randomizedMatched pairs randomized

–One of each pair to each treatmentOne of each pair to each treatment

–e.g., two eyes within an individual (one e.g., two eyes within an individual (one to each treatment)to each treatment)

–Diabetic Retinopathy studyDiabetic Retinopathy study

Other special designsOther special designs

• Cluster or grouped randomizationCluster or grouped randomization

–Randomize groups to treatmentsRandomize groups to treatments

–Often useful especially for public health-Often useful especially for public health-type interventionstype interventions

Other special designs (clusters)Other special designs (clusters)

• Cluster or grouped randomization examplesCluster or grouped randomization examples

–Medical practices to stop-smoking interventionsMedical practices to stop-smoking interventions

–Cities to public health risk factor reduction (5 Cities to public health risk factor reduction (5 Cities Project)Cities Project)

–Baseball teams to chewing-tobacco interventionBaseball teams to chewing-tobacco intervention

• Analysis complexAnalysis complex

• Sample size complex: true n is between n clusters Sample size complex: true n is between n clusters and n individuals (closer to clusters)and n individuals (closer to clusters)

Previews of coming attractionsPreviews of coming attractions

• Blinding, interventions, controls (placebo vs. active) Blinding, interventions, controls (placebo vs. active) (1/16)(1/16)

• Follow-up, compliance, etc. (1/23)Follow-up, compliance, etc. (1/23)

• Outcomes (efficacy and adverse effects)Outcomes (efficacy and adverse effects)

• Ethical issues (many!!)Ethical issues (many!!)

• Nuts and boltsNuts and bolts

• Interim monitoringInterim monitoring

• Multi-center trials and working with the evil empire (drug Multi-center trials and working with the evil empire (drug cos)cos)