Presentation is loading. Please wait.

Presentation is loading. Please wait.

Introduction to Randomized Clinical Trials Deborah Grady Professor of Medicine University of California, San Francisco.

Similar presentations


Presentation on theme: "Introduction to Randomized Clinical Trials Deborah Grady Professor of Medicine University of California, San Francisco."— Presentation transcript:

1 Introduction to Randomized Clinical Trials Deborah Grady Professor of Medicine University of California, San Francisco

2 Randomized Trials –Rationale –Basic designs –Participants –Intervention –Blinding –Outcomes –Adherence –Follow-up

3 Rationale Why do a randomized blinded trialWhy do a randomized blinded trial –minimize confounding –minimize co-interventions –minimize biased outcome ascertainment Why not do a randomized trialWhy not do a randomized trial –major ethical issues –narrow research question –expensive –long time from idea to paper Generally reserved for mature questionsGenerally reserved for mature questions

4 Basic Trial Design Population Sample Intervention Randomization OutcomeOutcome ControlControl OutcomeOutcome + Blinding Placebo

5 Randomization Participants are assigned to treatment groups by chance with a known probabilityParticipants are assigned to treatment groups by chance with a known probability Random number table or computerRandom number table or computer Tamper-proof systemTamper-proof system –ordered, sealed envelopes –centralized system (phone, fax, web)

6 Value of Randomization Balances baseline characteristics of the treatment groupsBalances baseline characteristics of the treatment groups –eliminates confounding due to measured and unmeasured factors –provides an unbiased comparison between groups Does NOT maintain balance after randomizationDoes NOT maintain balance after randomization

7 Variations of Randomization Fixed Allocation - probability fixedFixed Allocation - probability fixed –Simple - flip a coin –Blocked - randomize consecutive small batches –Stratified - separate randomization in strata –Clustered - randomize groups Adaptive - probability changesAdaptive - probability changes –N in the groups (biased coin) –baseline characteristics –outcome (play the winner; two-armed bandit)

8 Cross-over Design Population Sample Intervention Randomization Placebo Washout Placebo Intervention Outcome

9 Factorial Design Population Sample Int A and Int B Int A and Pbo B Pbo A and Int B Pbo A and Pbo B Outcome

10 Vitamin D and Strength in the Elderly M uscle strength and renal function decline with agingM uscle strength and renal function decline with aging Vitamin D deficiency causes myopathy and rx with 1,25-D improves strengthVitamin D deficiency causes myopathy and rx with 1,25-D improves strength Declining renal function results in low levels of 1,25 DDeclining renal function results in low levels of 1,25 D RQ: Does treatment with vitamin D improve strength?

11 Participants Inclusion criteria to maximize:Inclusion criteria to maximize: –rate of outcomes (old, weak) –likely benefit from intervention (renal dz, institutionalized, vitamin D deficiency) –generalizability –ease of recruitment (none of the above)

12 Exclusion Criteria Intervention unsafeIntervention unsafe Intervention unlikely to be effectiveIntervention unlikely to be effective Unlikely to adhere to the interventionUnlikely to adhere to the intervention Unlikely to complete follow-upUnlikely to complete follow-up Practical problemsPractical problems Practice Parsimony Preserve Generalizability Practice Parsimony Preserve Generalizability

13 Choice of Intervention MaximizeMaximize –effectiveness (highest tolerable dose) –safety (lowest effective dose) –generalizability –trial design/conduct recruitmentrecruitment compliancecompliance blindingblinding

14 Vitamin D for Muscle Strength ConsiderConsider –Dose - in renal insufficiency 0.25 - 1.0 ug SQ 1,25 D daily normalizes calcium –Duration - few months usually restores strength in patients with rickets and myopathy –Route - SQ vs. PO? –Titration to normal 1, 25-D level or normal (safe) urine calcium?

15 Several Doses of Drug MORE Trial 7705 PM women with osteoporosis 7705 PM women with osteoporosis 60 mg raloxifene/day 120 mg raloxifene/day placebo identify “best” doseidentify “best” dose show dose-response effectshow dose-response effect larger sample sizelarger sample size more complex analysesmore complex analyses identify “best” doseidentify “best” dose show dose-response effectshow dose-response effect larger sample sizelarger sample size more complex analysesmore complex analyses

16 Multiple Interventions Combination interventionsCombination interventions –MRFIT –Ornish regimen –Multidrug HIV therapy AdvantagesAdvantages –maximize benefit –generalizable to clinical practice Disadvantage - which is effective?Disadvantage - which is effective?

17 Choice of Control Inert placebo usually best, but might not be possibleInert placebo usually best, but might not be possible Active therapy for control =Active therapy for control = equivalence trial: –Ho: not more than a stated difference between groups –Ha: one treatment better

18 Equivalence Trials AdvantageAdvantage –answers clinical question –may be more ethical DisadvantageDisadvantage –may require larger sample size –negative result may be due to low power –can’t tell if either better than placebo Only reasonable if potential advantage of new therapy

19 Trial of New Depression Drug Approved SSRIs effective for depression, but often cause loss of libidoApproved SSRIs effective for depression, but often cause loss of libido New drug thought to be as effective as old with no effect on libidoNew drug thought to be as effective as old with no effect on libido Untreated depression can result in suicideUntreated depression can result in suicide

20 Trial of Smiletraline for Depression Placebo controlled trial – –expected improvement 25% over placebo – –Ho: no difference Ha: 20% difference with a =.05, b =.90 – –sample size 100/group Compare smiletraline to sertraline – –expect no difference – –Ho: difference no greater than +/-10% – –sample size 125/group

21 Why Blind? Maintains balanced groups during follow-upMaintains balanced groups during follow-up EliminatesEliminates –cointervention –biased outcome ascertainment –biased measurement of outcome

22 Physicians’ 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 Many physicians had study drug tested for ASAMany physicians had study drug tested for ASA 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 Many physicians had study drug tested for ASAMany physicians had study drug tested for ASA

23 Cointerventions Unintended effective interventionsUnintended effective interventions –participants use other therapy or change behavior –study staff, medical providers, family or friends treat participants differently Nondifferential - decreases powerNondifferential - decreases power Differential - causes biasDifferential - causes bias

24 Oral Contraceptive Pills to Prevent Pregnancy 18,000 women age 21-35 years18,000 women age 21-35 years Randomly assigned to OCPs or usual birth control methodRandomly assigned to OCPs or usual 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 usual birth control methodRandomly assigned to OCPs or usual 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

25 Biased Outcome Ascertainment If group assignment is knownIf group assignment is known –participants may report symptoms or outcomes differently –physicians or investigators may elicit symptoms or outcomes differently If group assignment is knownIf group assignment is known –participants may report symptoms or outcomes differently –physicians or investigators may elicit symptoms or outcomes differently

26 Canadian Cooperative MS Trial 165 patients with multiple sclerosis165 patients with multiple sclerosis –plasma exchange + cyclo + pred –sham plasma exchange + placebo meds Outcome = structured neurologic exam by blinded and unblinded neurologistsOutcome = structured neurologic exam by blinded and unblinded neurologists More improvement with plasma exchange by unblinded, but not blinded assessmentMore improvement with plasma exchange by unblinded, but not blinded assessment 165 patients with multiple sclerosis165 patients with multiple sclerosis –plasma exchange + cyclo + pred –sham plasma exchange + placebo meds Outcome = structured neurologic exam by blinded and unblinded neurologistsOutcome = structured neurologic exam by blinded and unblinded neurologists More improvement with plasma exchange by unblinded, but not blinded assessmentMore improvement with plasma exchange by unblinded, but not blinded assessment Noseworthy, Neurology, 1994

27 Biased Outcome Adjudication Study staff who decide if a change or outcome has occurred mayStudy staff who decide if a change or outcome has occurred may –classify similar events differently in treatment groups Problematic with “soft” outcomesProblematic with “soft” outcomes –investigator judgement –participant reported symptoms, scales

28 What is Blinding? Single blind - participants are not aware of treatment groupSingle blind - participants are not aware of treatment group Double blind - both participants and investigators unawareDouble blind - both participants and investigators unaware Triple blind - various meaningsTriple blind - various meanings –persons who perform tests –outcome adjudicators –safety monitoring group Single blind - participants are not aware of treatment groupSingle blind - participants are not aware of treatment group Double blind - both participants and investigators unawareDouble blind - both participants and investigators unaware Triple blind - various meaningsTriple blind - various meanings –persons who perform tests –outcome adjudicators –safety monitoring group

29 Why Not Blind? ImpossibleImpossible –surgery –exercise –diet –education Possible, butPossible, but –dangerous –painful –cumbersome

30 Is It Really Blinded? Difficult even for drugsDifficult even for drugs –identical placebo difficult to prepare –drug may smell, taste, feel different –drug may cause side effects –test results may unblind –participants may test drug Difficult even for drugsDifficult even for drugs –identical placebo difficult to prepare –drug may smell, taste, feel different –drug may cause side effects –test results may unblind –participants may test drug

31 What if You “Can’t” Blind? Be courageousBe courageous Do the best you canDo the best you can –minimize differential cointervention –blind those measuring outcome –use “hard” outcomes Measure degree of unblindingMeasure degree of unblinding

32 Be Courageous Laparoscopic lysis of adhesions for pelvic painLaparoscopic lysis of adhesions for pelvic pain Internal mammary ligation for anginaInternal mammary ligation for angina Orthoscopic debridement for OAOrthoscopic debridement for OA Sham burr holes for fetal tissue implants for Parkinson’sSham burr holes for fetal tissue implants for Parkinson’s

33 Do the Best You Can Exercise to prevent coronary eventsExercise to prevent coronary events –exercise - supervised exercise to 80% maximum capacity 30 min 3/wk –control - supervised exercise to 40% maximum capacity 30 min 3/wk Psychotherapy for schizophreniaPsychotherapy for schizophrenia –therapy - psychotherapy weekly –control - advice about diet, exercise, and smoking weekly

34 Use a “Hard” Outcome DeathDeath MeasurementsMeasurements –test results MVO 2 vs.. self-reported exercise abilityMVO 2 vs.. self-reported exercise ability Doppler evaluation vs.. swollen leg for DVTDoppler evaluation vs.. swollen leg for DVT –scales 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”

35 Measure Degree of Unblinding In trials that are partially blindedIn trials that are partially blinded –ask participants to guess treatment –ask study staff to guess treatment If unblinding substantial - assess impact in discussion of paperIf unblinding substantial - assess impact in discussion of paper

36 Adherence Intervention cannot work if it isn’t usedIntervention cannot work if it isn’t used Adherence measuresAdherence measures –intervention pill count, diaries, biologic measure, measuring device in dispenserpill count, diaries, biologic measure, measuring device in dispenser –visits –study measurements

37 Women’s Health Initiative RQ: Does calcium plus vitamin D reduce risk of fractures in postmenopausal women? Design: Randomized trial Subjects: 36,282 PM women enrolled in WHI Intervention: 1 gm calcium + 400 IU vitamin D Outcome: clinical fractures Adherence at end of trial 60% and about 60% of placebo group was taking calcium

38 Follow-up RQ: Does diet and exercise reduce risk of developing type 2 diabetes in persons with glucose intolerance? Design: Randomized trial Subjects: 2500 with glucose intolerance Intervention: low fat weight loss diet and moderate intensity aerobic exercise Measurements: Predictor = treatment outcome = development of frank diabetes

39 Diet and Exercise to Prevent Diabetes in Persons with Glucose Intolerance DM No DM DM No DM D & E D & E No D& E 65 560 125 500 625 625 1060190 1250 RR =.5; p =.001

40 Maximizing Adherence and Follow-up Choose subjects likely to adhereChoose subjects likely to adhere –exclude if likely nonadherent –complete several visits before randomization –?complete a run-in Intervention easy and safeIntervention easy and safe Visits easy and enjoyableVisits easy and enjoyable –frequent enough to be engaging –night visits, travel and parking reimbursement –personal relationships with participants Measurements easy, safe and painlessMeasurements easy, safe and painless Never discontinue participantsNever discontinue participants

41 Outcomes in Clinical Trials Efficacy OutcomesEfficacy Outcomes –Primary –Secondary –Surrogate –Composite Adverse EffectsAdverse Effects –rare –common

42 Raloxifene Use for the Heart Potential OutcomesPotential Outcomes –Mortality –CHD events (death, MI, ACS) –Stroke –Breast cancer –Fracture –LDL-cholesterol –Quality of life

43 How to Proceed? Measure all outcomesMeasure all outcomes Pick one primary outcomePick one primary outcome –estimate sample size –FDA requirement Make all the rest secondaryMake all the rest secondary

44 Adverse Events and Side Effects AnticipatedAnticipated –use specific questions UnanticipatedUnanticipated –ask about general adverse experiences RareRare –sample size inadequate CommonCommon –multiple differences between groups

45 High Quality Randomized Trials Tamper-proof randomizationTamper-proof randomization Blinding of participants, study staff, lab staff, outcome ascertainment and adjudicationBlinding of participants, study staff, lab staff, outcome ascertainment and adjudication Adherence to study interventionAdherence to study intervention Complete follow-upComplete follow-up Adequate powerAdequate power


Download ppt "Introduction to Randomized Clinical Trials Deborah Grady Professor of Medicine University of California, San Francisco."

Similar presentations


Ads by Google