Blinding, Intervention and ControlsBlinding, Intervention and Controls

Deborah Grady, MD, MPHDeborah Grady, MD, MPH

Professor of MedicineProfessor of Medicine

Director, Clinical and Director, Clinical and Translational Research TrainingTranslational Research Training

UCSFUCSF

The Importance of The Importance of BLINDINGBLINDING

• Why blind?Why blind?

• What is blinding? What is blinding?

• What to do when blinding What to do when blinding is difficult or impossibleis difficult or impossible

Why Randomize?Why Randomize?

• Assures that groups are balancedAssures that groups are balanced

• Balances both measured and Balances both measured and unmeasured variablesunmeasured variables

• Balances groups Balances groups only at baselineonly at baseline

Why Blind?Why Blind?

• Maintains balanced groups Maintains balanced groups during follow-upduring follow-up

• Eliminates Eliminates –cointerventioncointervention–biased outcome ascertainmentbiased outcome ascertainment–biased measurement of outcomebiased measurement of outcome

WomenWomen’’s Health Studys Health StudyWomenWomen’’s Health Studys Health Study

• 39,876 female health care providers39,876 female health care providers

• Aspirin 100 mg every other day or Aspirin 100 mg every other day or placeboplacebo

• Follow-up 10 yearsFollow-up 10 years

• Outcomes - CVD events and deathOutcomes - CVD events and death

• 39,876 female health care providers39,876 female health care providers

• Aspirin 100 mg every other day or Aspirin 100 mg every other day or placeboplacebo

• Follow-up 10 yearsFollow-up 10 years

• Outcomes - CVD events and deathOutcomes - CVD events and death

CointerventionsCointerventions

• Unintended effective interventionsUnintended effective interventions–participantsparticipants use other therapy (statins) use other therapy (statins)

or change behavior (diet, exercise)or change behavior (diet, exercise)–study staff, medical providers, family or study staff, medical providers, family or

friendsfriends treat participants differently treat participants differently

• Nondifferential decreases powerNondifferential decreases power

• Differential causes biasDifferential causes bias

Oral Contraceptive Pills Oral Contraceptive Pills to Prevent Pregnancy to Prevent Pregnancy

Oral Contraceptive Pills Oral Contraceptive Pills to Prevent Pregnancy to Prevent Pregnancy

• 18,021 women age 21-35 years18,021 women age 21-35 years

• Randomly assigned to OCPs or Randomly assigned to OCPs or usual birth control methodusual birth control method

• Followed every 6 months for 2 yearsFollowed every 6 months for 2 years

• Pregnancy risk decreased 75%Pregnancy risk decreased 75%

• Risk of venous thromboembolism Risk of venous thromboembolism increased 5-foldincreased 5-fold

• 18,021 women age 21-35 years18,021 women age 21-35 years

• Randomly assigned to OCPs or Randomly assigned to OCPs or usual birth control methodusual birth control method

• Followed every 6 months for 2 yearsFollowed every 6 months for 2 years

• Pregnancy risk decreased 75%Pregnancy risk decreased 75%

• Risk of venous thromboembolism Risk of venous thromboembolism increased 5-foldincreased 5-fold

Biased Outcome AscertainmentBiased Outcome AscertainmentBiased Outcome AscertainmentBiased Outcome Ascertainment

• If group assignment is known If group assignment is known – participantsparticipants may report symptoms or may report symptoms or

outcomes differently (leg pain, swelling)outcomes differently (leg pain, swelling)– physicians or investigatorsphysicians or investigators may elicit may elicit

symptoms or outcomes differently symptoms or outcomes differently

• Problematic with Problematic with ““soft outcomessoft outcomes””– chest painchest pain– disabilitydisability– satisfactionsatisfaction

• If group assignment is known If group assignment is known – participantsparticipants may report symptoms or may report symptoms or

outcomes differently (leg pain, swelling)outcomes differently (leg pain, swelling)– physicians or investigatorsphysicians or investigators may elicit may elicit

symptoms or outcomes differently symptoms or outcomes differently

• Problematic with Problematic with ““soft outcomessoft outcomes””– chest painchest pain– disabilitydisability– satisfactionsatisfaction

Biased Outcome AdjudicationBiased Outcome Adjudication

• Study staff who decide if a change Study staff who decide if a change or outcome has occurred mayor outcome has occurred may–classify similar events differently in classify similar events differently in

treatment groupstreatment groups

• Problematic with Problematic with ““softsoft”” outcomes outcomes

Canadian Cooperative MS TrialCanadian Cooperative MS TrialCanadian Cooperative MS TrialCanadian Cooperative MS Trial

• 165 patients with multiple sclerosis165 patients with multiple sclerosis–plasma exchange + cyclo + predplasma exchange + cyclo + pred–sham plasma exchange + placebo medssham plasma exchange + placebo meds

• Outcome = structured neurologic exam Outcome = structured neurologic exam by blinded and unblinded neurologistsby blinded and unblinded neurologists

• More improvement with plasma More improvement with plasma exchange by unblinded, but not exchange by unblinded, but not blinded neurologistsblinded neurologists

• 165 patients with multiple sclerosis165 patients with multiple sclerosis–plasma exchange + cyclo + predplasma exchange + cyclo + pred–sham plasma exchange + placebo medssham plasma exchange + placebo meds

• Outcome = structured neurologic exam Outcome = structured neurologic exam by blinded and unblinded neurologistsby blinded and unblinded neurologists

• More improvement with plasma More improvement with plasma exchange by unblinded, but not exchange by unblinded, but not blinded neurologistsblinded neurologists

Noseworthy, Neurology, 1994Noseworthy, Neurology, 1994

What is Blinding?What is Blinding?What is Blinding?What is Blinding?

• Single blind - participants are not Single blind - participants are not aware of treatment groupaware of treatment group

• Double blind - both participants Double blind - both participants and investigators unawareand investigators unaware

• Triple blind - various meaningsTriple blind - various meanings– persons who perform testspersons who perform tests– outcome adjudicatorsoutcome adjudicators– safety monitoring groupsafety monitoring group

• Single blind - participants are not Single blind - participants are not aware of treatment groupaware of treatment group

• Double blind - both participants Double blind - both participants and investigators unawareand investigators unaware

• Triple blind - various meaningsTriple blind - various meanings– persons who perform testspersons who perform tests– outcome adjudicatorsoutcome adjudicators– safety monitoring groupsafety monitoring group

Why Not Blind?Why Not Blind?

• ImpossibleImpossible– surgerysurgery– exerciseexercise– dietdiet– educationeducation

• Possible, butPossible, but– dangerousdangerous– painfulpainful– cumbersomecumbersome

Is It Really Blinded? Is It Really Blinded? Is It Really Blinded? Is It Really Blinded?

• Difficult even for drugsDifficult even for drugs– identical placebo difficult to prepareidentical placebo difficult to prepare– drug may smell, taste, feel differentdrug may smell, taste, feel different– drug may cause side effectsdrug may cause side effects– test results may unblindtest results may unblind– participants may test drugparticipants may test drug

• Difficult even for drugsDifficult even for drugs– identical placebo difficult to prepareidentical placebo difficult to prepare– drug may smell, taste, feel differentdrug may smell, taste, feel different– drug may cause side effectsdrug may cause side effects– test results may unblindtest results may unblind– participants may test drugparticipants may test drug

What if You (Think You) What if You (Think You) CanCan’’t Blind?t Blind?

• Be clever and/or courageousBe clever and/or courageous

• Do the best you canDo the best you can–minimize differential cointerventionminimize differential cointervention–blind those ascertaining and blind those ascertaining and

adjudicating outcomesadjudicating outcomes–use use ““hardhard”” outcomes outcomes

• Measure degree of unblindingMeasure degree of unblinding

Be CleverBe Clever

• Garlic for cholesterol loweringGarlic for cholesterol lowering–odorless, tasteless garlic preparationodorless, tasteless garlic preparation– identical placeboidentical placebo

• Dietary soy protein for hot flushesDietary soy protein for hot flushes–soy protein meal soy protein meal –animal protein meal with same caloriesanimal protein meal with same calories

Be CourageousBe Courageous

• Laparoscopic lysis of adhesions for Laparoscopic lysis of adhesions for pelvic painpelvic pain

• Internal mammary ligation for anginaInternal mammary ligation for angina

• Orthoscopic debridement for OAOrthoscopic debridement for OA

• Sham fetal nigral tissue implants for Sham fetal nigral tissue implants for ParkinsonParkinson’’ss

Use a Use a ““HardHard”” Outcome Outcome

• DeathDeath

• MeasurementsMeasurements– Lab/imaging/test resultsLab/imaging/test results

• UA findings vs. dysuria or frequencyUA findings vs. dysuria or frequency• MRI of knee vs. knee pain questionnaireMRI of knee vs. knee pain questionnaire• MVOMVO2 2 vs. self-reported exercise abilityvs. self-reported exercise ability• doppler evaluation vs. swollen leg for DVT doppler evaluation vs. swollen leg for DVT

– scales and diaries vs. investigator judgmentscales and diaries vs. investigator judgment• Geriatric Depression Scale vs. Geriatric Depression Scale vs. ““improvedimproved””• 7-day urinary diary vs. 7-day urinary diary vs. ““drydry””

Measure Degree of UnblindingMeasure Degree of Unblinding

• In trials that are partially blindedIn trials that are partially blinded–ask participants and study staff to guess ask participants and study staff to guess

treatmenttreatment–should be correct about 50% of the timeshould be correct about 50% of the time

• If unblinding substantial - assess If unblinding substantial - assess impact in discussion of paperimpact in discussion of paper

Choice of InterventionChoice of Intervention

• Type (drug, education, surgery)Type (drug, education, surgery)

• Intensity, dose, routeIntensity, dose, route

• FrequencyFrequency

• DurationDuration

• TitrationTitration

PrinciplesPrinciples

• Maximize benefitMaximize benefit

• Minimize riskMinimize risk

• Generalizable to clinical practiceGeneralizable to clinical practice

• Strengthen trial design/conductStrengthen trial design/conduct– recruitmentrecruitment–compliancecompliance– follow-upfollow-up–blindingblinding

Vitamin D for Muscle StrengthVitamin D for Muscle Strength

• Presumed mechanismPresumed mechanism– normalize 1,25--OHDnormalize 1,25--OHD

• RisksRisks–hypercalcuria, hypercalcemiahypercalcuria, hypercalcemia

• Dose Dose –0.25 - 1.0 mg SQ QD normalizes calcium in 0.25 - 1.0 mg SQ QD normalizes calcium in

patients with vitamin D deficiencypatients with vitamin D deficiency

• Duration Duration –6 months (long enough to restore strength)6 months (long enough to restore strength)

Yoga for Control of DiabetesYoga for Control of Diabetes

• Presumed mechanismPresumed mechanism– reduces sympathetic tonereduces sympathetic tone

• RisksRisks–muscle aches and injuriesmuscle aches and injuries

• Dose Dose – twice per week for 90 minutestwice per week for 90 minutes

• Duration Duration –12 weeks12 weeks

Dose TitrationDose Titration

• 300 women with urge urinary incontinence300 women with urge urinary incontinence

• Randomized to Detrol 1 mg BID or placeboRandomized to Detrol 1 mg BID or placebo

• If inadequate effect, titrate dose (of active If inadequate effect, titrate dose (of active drug or placebo) to TID, then to ii pills BIDdrug or placebo) to TID, then to ii pills BID

• Outcomes - frequency of incontinence Outcomes - frequency of incontinence episodes and side effectsepisodes and side effects

Several Doses of DrugSeveral Doses of Drug

• MORE TrialMORE Trial–7704 women with osteoporosis7704 women with osteoporosis–60 or 120mg raloxifene or placebo60 or 120mg raloxifene or placebo– followed for 3 years for fracturefollowed for 3 years for fracture

• identify identify ““bestbest”” dose dose• show dose-response effectshow dose-response effect• larger sample sizelarger sample size• more complex analysesmore complex analyses

Multiple InterventionsMultiple Interventions

• Combination interventionsCombination interventions–MRFITMRFIT–Ornish regimenOrnish regimen–Multidrug HIV therapyMultidrug HIV therapy

• AdvantagesAdvantages–maximize benefitmaximize benefit–mimic clinical practicemimic clinical practice

• Disadvantages - not sure which Disadvantages - not sure which element of the element of the ““smorgasbordsmorgasbord”” works works

Background TreatmentsBackground Treatments

• Add intervention to standard careAdd intervention to standard care–new CHF med or placebo new CHF med or placebo in addition toin addition to: :

• diuretic, ACEI, bb, aldosterone blocker diuretic, ACEI, bb, aldosterone blocker

• AdvantagesAdvantages–mimic clinical practicemimic clinical practice–ethicalethical

• DisadvantagesDisadvantages - reduces power - reduces power

Choice of ControlChoice of Control

• Inert placebo usually best choiceInert placebo usually best choice–Ho: no difference between groupsHo: no difference between groups–Ha: there is a differenceHa: there is a difference

• Active therapy for control = Active therapy for control =

equivalence (noninferiority) trial:equivalence (noninferiority) trial:–Ho: not more than a stated difference Ho: not more than a stated difference

between groupsbetween groups–Ha: more than a stated difference Ha: more than a stated difference

Equivalence TrialsEquivalence Trials

• AdvantageAdvantage–better answer to clinical questionbetter answer to clinical question–might be more ethicalmight be more ethical

• DisadvantageDisadvantage– requires larger sample sizerequires larger sample size–negative result may be due to low power negative result may be due to low power

or to poorly conducted trialor to poorly conducted trial–cancan’’t tell if either better than placebot tell if either better than placebo

• Only reasonable if good standard of Only reasonable if good standard of care care andand potential advantage of new potential advantage of new therapytherapy

Trial of New Depression DrugTrial of New Depression Drug

• Approved SSRIs effective for Approved SSRIs effective for depression, but often cause loss of depression, but often cause loss of libidolibido

• New drug thought to be as effective as New drug thought to be as effective as old with no effect on libidoold with no effect on libido

• Untreated depression can result in Untreated depression can result in suicidesuicide

Trial of Smiletraline for DepressionTrial of Smiletraline for Depression

• Placebo controlled trial–expected improvement 25% over placebo–Ho: no difference smiletraline vs. placebo Ha: different with a =.05, b =.90–sample size 100/group

• Non-inferiority trial–Ho: smiletraline >10% worse than sertraline –Ha: smiletraline < 10% worse than sertraline–sample size 622/group

BLINDINGBLINDING

• As important as randomization to As important as randomization to prevent potential bias due to:prevent potential bias due to:– co-interventionco-intervention– outcome ascertainmentoutcome ascertainment– outcome measurementoutcome measurement

• Difficult to accomplishDifficult to accomplish

• If not possible, do your bestIf not possible, do your best– minimize co-interventionminimize co-intervention– blind those ascertaining and blind those ascertaining and

adjudicating outcomeadjudicating outcome– use hard outcomesuse hard outcomes

Choice of InterventionChoice of Intervention

• Maximize benefit vs. riskMaximize benefit vs. risk

• Generalizable to clinical practiceGeneralizable to clinical practice

• Strengthen trial designStrengthen trial design

• EthicalEthical

Choice of ControlChoice of Control

• Placebo generally bestPlacebo generally best

• Consider equivalence or non-Consider equivalence or non-inferiority trial if clear standard inferiority trial if clear standard of careof care