Slide 1

Clinical trials

Andrea Cipriani

ECNP School of Old Age Neuropsychopharmacology 2015

Conflict of interest: None Randomized controlled trials (RCTs) are:

quantitative, comparative studies

designed to determine whether an association exists between treatment and outcome

in clinical research RCTs are recognised as the most rigorous way of assessing the efficacy of interventions.

Which is the key feature of a RCT?

RecruitmentVALIDITYAllocation concealment?comparable groups? IGCG+-+-DCBA

ParticipantsIntervention Group (IG) & Comparison Group (CG)Outcome

Measurementsblind? ORobjective?Maintenance

- treated equally?- compliant?9Appraisal checklist - RAMMboRecruitment-Who did the subjects represent?Allocation Was the assignment to treatments randomised? Were the groups similar at the trials start?MaintenanceWere the groups treated equally?Were outcomes ascertained & analysed for most patients?MeasurementsWere patients and clinicians blinded to treatment? ORWere measurements objective & standardised?

Study statistics (p-values & confidence intervals)Guyatt. JAMA, 1993

10

3 7??LikelyUnlikelyImpossible100

30 70??1000

300 700??Appraisal checklist - RAMMboRecruitment-Who did the subjects represent?Allocation Was the assignment to treatments randomised? Were the groups similar at the trials start?MaintenanceWere the groups treated equally?Were outcomes ascertained & analysed for most patients?MeasurementsWere patients and clinicians blinded to treatment? ORWere measurements objective & standardised?

Study statistics (p-values & confidence intervals)Guyatt. JAMA, 1993

By random allocation we mean that each patient has a known chance, usually an equal chance, of being given each treatment, but the treatment to be given cannot be predicted

Random allocationAltman & Bland. BMJ, 1999

BEST most valid technique Central computer randomization

DOUBTFUL Envelopes, etcEnsuring Allocation Concealment?RANDOMISATION & ALLOCATION CONCEALMENTABABAAABBBABABABBAABABABBRANDOMISATIONALLOCATION CONCEALMENT+=ABABAAABBBABABABBAABABABBPassengers were randomly allocated to one of two groups: one group wore class-I below-knee graduated elastic compression stockings, the other group did not.

Random allocation was conducted according to a computer-generated randomization list.

The randomization was done, without imposing a randomization constraint, by use of computer-generated random numbers (in SPSS) by the research team in Amsterdam.

During the baseline measurements every participant was given a consecutive number [...] depending on whether their number was an even or odd one, participants were respectively assigned to an intervention group or to a control group.

Appraisal checklist - RAMMboRecruitment-Who did the subjects represent?Allocation Was the assignment to treatments randomised? Were the groups similar at the trials start?MaintenanceWere the groups treated equally?Were outcomes ascertained & analysed for most patients?MeasurementsWere patients and clinicians blinded to treatment? ORWere measurements objective & standardised?

Study statistics (p-values & confidence intervals)Guyatt. JAMA, 1993Losses-to-follow-up How many is too many?5-and-20 rule of thumb5% probably leads to little bias>20% poses serious threats to validity

Depends on outcome event rate and comparative loss rates in the groupsLoss to follow-up rate should not exceed outcome event rate and should not be differential

Intention-to-Treat PrincipleOnce a patient is randomized, s/he should be analyzed in the group randomized to - even if they discontinue, never receive treatment, or crossover.542-10-#22Intention To Treat (ITT) PrincipleAnalyze all subjects randomized & all eventsBeware of look alikesModified ITT: Analyze subjects who get some interventionPer Protocol: Analyze subjects who comply according to the protocol Key PointsDeviation from intent-to-treat can result in bias from not comparing like with like.

This method of analysis needs to be firmly in mind when designing the study, e.g., realistic estimates of treatment effect that account for non-adherence.

There are practical difficulties in carrying out a strict intention to treat analysis and a strict per protocol analysis.Arguments for Intention to TreatConsistent with randomization get the right significance probability for hypothesis testing.

Addresses the question of practical interest a comparison of treatment policies.

If the objective is to understand the implication of using a specific intervention in practice, this is the right analysis (e.g., non-adherence is a consequence of using a strategy in practice).

Arguments for Per Protocol AnalysisBetter estimate of pure pharmaceutical effect of treatment (i.e., including non-compliers dilutes the treatment difference).

The relevant question is whether the treatment can work when used as intended, e.g., is it effective among patients who can tolerate it?

In a non-inferiority study, this may be a more conservative analysis (less dilution toward no difference)

Key Point: Make sure you discuss the questionbefore you start the study. Intention-to-TreatAdvantage:Comparability of treatment groups; no bias resulting from exclusions.

Disadvantage:Possible dilution of treatment effect; loss of power unless sample size was increased to account for it.Per protocolAdvantage:Undiluted treatment effect

Disadvantage:Comparison of groups may be biased and it is not predictable in which direction.Summary / RecommendationsPrimary analysis should usually be intent-to-treat (need to continue collecting data to do this right) it addresses a pragmatic policy/management question.It is appropriate to carry out secondary per protocol analyses but these have to be interpreted with caution.For analyses which are not intent-to-treat it is often difficult/impossible to quantify bias resulting from not comparing like with likeIf exclusions after randomization are to be made as part of secondary per protocol analyses, they should be specified in the protocol.Discontinuation of treatment and adherence should be outcomes and reported.Appraisal checklist - RAMMboRecruitment-Who did the subjects represent?Allocation Was the assignment to treatments randomised? Were the groups similar at the trials start?MaintenanceWere the groups treated equally?Were outcomes ascertained & analysed for most patients?MeasurementsWere patients and clinicians blinded to treatment? ORWere measurements objective & standardised?

Study statistics (p-values & confidence intervals)Guyatt. JAMA, 1993Measurement BiasBlinding Who?Participants?Investigators?Outcome assessors?Analysts?

Most important to use "blinded" outcome assessors when outcome is not objective!

Papers should report WHO was blinded and HOW it was done

31 Allocation concealment vs. blindingtimerandomisationConcealment of allocationBlindingSelection biasPerformance bias31Were measurements objective and standardised?

Surrogate End Points in RCTFleming T, et al.Ann Intern Med 1996DiseaseSurrogateTrue Clinical OutcomeInterventionEnd Point

ARR = 10%

RRR = 25%

ARR = 2.5%

RRR = 25%

Type 1 and type 2 errorReal world+-RCT+Type 1 error-Type 2 errornew agent bettercontrol better0TREATMENT DIFFERENCE+-new agent bettercontrol better0TREATMENT DIFFERENCE+-Type 1 and type 2 errorReal world+-RCT+Type 1 error-Type 2 errorBeware multiple comparisons over time

***we found antidepressant B had a quicker onset of action than ABeware multiple endpointsOutcomeTreatment ATreatment BP valueHamilton score13.112.8NSBDI score13.612.9NSCGI (severity)2.662.78NSCGI (change)2.092.17NSSocial Adaptation (SASS)35400.04We have demonstrated that treatment B is associated with improved social functioning than the reference antidepressant.Beware subgroups

Although we found no overall difference in outcomes between antidepressant A and antidepressant BBeware subgroups

we were able to show that among patients with non-melancholic symptoms treatment B was more effective than the reference.

Cohen D, McCubbin M, Collin J, Perodeau G.Medication as a social phenomena. Health 2001, 5, 461-489consumptionobservational studiesconceptionbasic studiesregulatory approvalmarketing and promotionprescriptionover the counterwithdrawalclinical trials (III)phase I and II studies

pragmatic trials (IV)

systematic reviews

RCT 2Treatment APlaceboversusRCT 1Treatment APlaceboversusRCT 3Treatment APlaceboversusRCT 1Treatment ATreatment BRCT 2Treatment ATreatment BRCT 3Treatment ATreatment B= standard meta-analysis= standard meta-analysisGroup 1 of RCTsGroup 2 of RCTsPlaceboTreatment BDIRECT COMPARISONDIRECT COMPARISONTreatment ATreatment ARCT 1RCT 2PlaceboTreatment BDIRECT COMPARISONDIRECT COMPARISONin commonTreatment ATreatment ARCT 1RCT 2PlaceboTreatment BDIRECT COMPARISONDIRECT COMPARISONin commonINDIRECT COMPARISONTreatment ATreatment A

Network of experimental comparisons

Network of experimental comparisons

Network of experimental comparisons

Network of experimental comparisonsComprehensive use of all available data (direct evidence + indirect evidence)

Comparison of interventions which havent been directly compared in any trial

Ranking of many treatments for the same condition

Improved precision for each comparison

Advantages of MTM

Thanks!

andrea.cipriani@psych.ox.ac.uk