Blinding, Intervention and ControlsBlinding, Intervention and Controls

Deborah Grady, MD, MPHDeborah Grady, MD, MPH

Professor of Epidemiology Professor of Epidemiology and of Medicineand of Medicine

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

Physicians’ Health StudyPhysicians’ Health StudyPhysicians’ Health StudyPhysicians’ Health Study

• 22,071 male physicians22,071 male physicians

• Aspirin 325 mg qod or placeboAspirin 325 mg qod or placebo

• Follow-up 5 yearsFollow-up 5 years

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

• 22,071 male physicians22,071 male physicians

• Aspirin 325 mg qod or placeboAspirin 325 mg qod or placebo

• Follow-up 5 yearsFollow-up 5 years

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

CointerventionsCointerventions

• Unintended effective interventionsUnintended effective interventions–participantsparticipants use other therapy or change use other therapy or change

behaviorbehavior–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

• 18,000 women age 21-35 years18,000 women age 21-35 years

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

• Followed Q6 months for 2 yearsFollowed Q6 months for 2 years

• Pregnancy risk decreased 75%Pregnancy risk decreased 75%

• VTE risk increased 5-foldVTE risk increased 5-fold

• 18,000 women age 21-35 years18,000 women age 21-35 years

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

• Followed Q6 months for 2 yearsFollowed Q6 months for 2 years

• Pregnancy risk decreased 75%Pregnancy risk decreased 75%

• VTE risk increased 5-foldVTE risk increased 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 differentlyoutcomes differently– physicians or investigatorsphysicians or investigators may elicit may elicit

symptoms or outcomes differently symptoms or outcomes differently

• Problematic with “soft outcomes”Problematic with “soft 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 differentlyoutcomes differently– physicians or investigatorsphysicians or investigators may elicit may elicit

symptoms or outcomes differently symptoms or outcomes differently

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

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 by Outcome = structured neurologic exam by blinded and unblinded neurologistsblinded and unblinded neurologists

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

• Correct guess about treatment group by Correct guess about treatment group by patients did not affect outcomepatients did not affect outcome

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

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

• Correct guess about treatment group by Correct guess about treatment group by patients did not affect outcomepatients did not affect outcome

Noseworthy, Neurology, 1994Noseworthy, Neurology, 1994

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 “soft” outcomesProblematic with “soft” outcomes

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) Can’t Blind?Can’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 “hard” outcomesuse “hard” 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

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

• Laparoscopic treatment of pelvic painLaparoscopic treatment of pelvic pain– laparoscopy with lysis of adhesionslaparoscopy with lysis of adhesions– laparoscopy without lysis of adhesionslaparoscopy without lysis of adhesions

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 burr holes for fetal tissue Sham burr holes for fetal tissue implants for Parkinson’simplants for Parkinson’s

Do the Best You CanDo the Best You Can

• Exercise to prevent coronary eventsExercise to prevent coronary events–exercise - supervised exercise to 80% exercise - supervised exercise to 80%

maximum capacity 30 min 3/wkmaximum capacity 30 min 3/wk–control - ?control - ?

• Psychotherapy for schizophreniaPsychotherapy for schizophrenia– therapy - psychotherapy weeklytherapy - psychotherapy weekly–control - ?control - ?

• Paced respiration for hot flashesPaced respiration for hot flashes– training 10’ per day using biofeedbacktraining 10’ per day using biofeedback–control ?control ?

Do the Best You CanDo the Best You CanDo the Best You CanDo the Best You Can

• Hormone therapy to prevent CHDHormone therapy to prevent CHD– separate gyn staff to manage bleeding separate gyn staff to manage bleeding

and breast tendernessand breast tenderness– lipoproteins revealed only if dangerouslipoproteins revealed only if dangerous

• Bisphosphonate to prevent fractureBisphosphonate to prevent fracture– densitometer output maskeddensitometer output masked– change in BMD reported if dangerous change in BMD reported if dangerous

• Hormone therapy to prevent CHDHormone therapy to prevent CHD– separate gyn staff to manage bleeding separate gyn staff to manage bleeding

and breast tendernessand breast tenderness– lipoproteins revealed only if dangerouslipoproteins revealed only if dangerous

• Bisphosphonate to prevent fractureBisphosphonate to prevent fracture– densitometer output maskeddensitometer output masked– change in BMD reported if dangerous change in BMD reported if dangerous

Use a “Hard” OutcomeUse a “Hard” Outcome

• DeathDeath

• MeasurementsMeasurements– lab valueslab values

• HgA1C vs. diabetes severity scaleHgA1C vs. diabetes severity scale• UA vs. dysuria and frequencyUA vs. dysuria and frequency

– test resultstest results• 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. “improved”Geriatric Depression Scale vs. “improved”• 7-day urinary diary vs. “dry”7-day urinary diary vs. “dry”

Measure Degree of UnblindingMeasure Degree of Unblinding

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

• 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 calcium0.25 - 1.0 mg SQ QD normalizes calcium

• 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 – teaching session 2/wk for 90 minutesteaching session 2/wk for 90 minutes

• Duration Duration –12 weeks12 weeks

Dose TitrationDose Titration

• 300 women with urge incontinence300 women with urge incontinence

• randomized to Detrol 1 mg BIDrandomized to Detrol 1 mg BID

• if inadequate effect titrate dose to if inadequate effect titrate dose to TID, then to ii pills BIDTID, then to ii pills BID

• outcomes - frequency of incontinent outcomes - frequency of incontinent episodes and side effectsepisodes and side effects

• issues - blinding, analyses, issues - blinding, analyses, interpretationinterpretation

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

Multiple InterventionsMultiple Interventions

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

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

• Disadvantage - which is effective?Disadvantage - which is effective?

Background TreatmentsBackground Treatments

• Test effect of adding to current standard of Test effect of adding to current standard of carecare– add to diuretic, ACEI, bb, aldosterone blocker add to diuretic, ACEI, bb, aldosterone blocker – MRFITMRFIT– Ornish regimenOrnish regimen– Multidrug HIV therapyMultidrug HIV therapy

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

• Disadvantage - which is effective?Disadvantage - which is effective?

Choice of ControlChoice of Control

• Inert placebo usually best choiceInert placebo usually best choice–Ho: no difference between groups in Ho: no difference between groups in

outcomeoutcome–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–ethicalethical

• DisadvantageDisadvantage–maymay require larger sample size require larger sample size–negative result may be due to low powernegative result may be due to low power–can’t tell if either better than placebocan’t tell if either better than placebo

• Only reasonable if potential advantage Only reasonable if potential advantage of new therapyof new therapy

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 Ha: different with a =.05, b =.90–sample size 100/group

• Compare smiletraline to sertraline–Ho: difference no greater than +/-10%–Ha: difference greater than +/-10%–sample size 125/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 trial if Consider equivalence trial if clear standard of careclear standard of care