3oumnal of Epidemiology and Community Health 1997;51:354-358

Putting trials on trial-the costs andconsequences of small trials in depression: asystematic review of methodology

Matthew Hotopf, Glyn Lewis, Charles Normand

AbstractStudy objective-To determine why, de-spite 122 randomised controlled trials,there is no consensus about whether theselective serotonin reuptake inhibitors ortricyclic and related antidepressantsshould be used as first line treatment ofdepression.Design-Systematic review of all RCTscomparing selective serotonin reuptakeinhibitors and tricyclic or heterocyclicantidepressants.Main results-The shortcomings iden-tified in the 122 trials were as follows:(1) there was inadequate description ofrandomisation, (2) the outcomes usedwere mainly observer rated measurementsof depression, and studies failed to usequality of life measures or perform eco-nomic evaluations, (3) doses of tricyclicantidepressants were inadequate, (4) gen-eralisability ofstudies was poor (includinga reliance on secondary care settings andinadequate follow up), and (5) there werestatistical shortcomings such as low stat-istical power, failure to use intention totreat analyses, and the tendency to makemultiple comparisons.Conclusions-Future RCTs should be de-signed to inform policy makers and ad-dress these methodological shortcomings.

(J Epidemiol Community Health 1997;51:354-358)

Department ofPsychologicalMedicine,Institute of Psychiatry,103 Denmark Hill,London SE5 8AZM Hotopf

Epidemiology Unit,London School ofHygieneand Tropical Medicineand Section ofEpidemiologyand General Practice,LondonG Lewis

Department of PublicHealth and Policy,London School ofHygieneand TropicalMedicine, LondonC Normand

Correspondence to:Dr M Hotopf.Accepted for publicationFebruary 1997

New treatments in medicine are often ex-

pensive. In the treatment of common chronicdiseases the licensing of a new treatment oftencreates difficult choices for policy makers andclinicians. How widely available should thenew treatment be? This question is especiallydifficult to answer when the new treatment hasonly modest advantages over placebo or theexisting treatment, or is extremely expensive.Recent examples of this dilemma include in-terferon beta-iB in multiple sclerosis,'2 andlipid lowering agents in primary prevention ofcoronary heart disease.' This systematic reviewexamines one new treatment in psychiatry-theselective serotonin reuptake inhibitors (SSRIs).It tries to discover why, despite intensive re-

search, doctors are uncertain whether these or

tricyclics should be used as first line treatmentin depression.The debate over the use of SSRIs as first line

treatment of depression remains unresolved,

despite at least six meta-analyses.9 SSRIs areconsiderably more expensive than tricyclics,10and it is estimated that the NHS bill for anti-depressants would rise from £88 m to £250 mif they were prescribed first line (1993 costs).3Those recommending wider prescribing ofSSRIs claim that the costs would be offset bythe advantages of these drugs. The debate inthe main has concentrated on differences inhow well the two classes of drug are toleratedrather than on efficacy per se. There is someevidence that the SSRIs are better toleratedand this is reflected by slightly lower attritionrates in clinical trials,6 and possibly better com-pliance in clinical practice. In addition SSRIsare safer in overdose. Policy makers need toknow the cost effectiveness ofSSRIs in primarycare before recommending a prescribing policyfor the primary care physicians who carry outmost treatment of depression. We aimed toreview the methodology of current research inthe light of recent recommendations,'2 and toidentify methodological weaknesses which mayhave contributed to current uncertainty.

MethodsLITERATURE SEARCHWe performed a literature search which wasvalidated against an independent search per-formed by another group (see acknowledge-ments). The target randomised controlled trials(RCTs) were those comparing four SSRIs(sertraline, fluoxetine, fluvoxamine, andparoxetine) with tricyclic and heterocyclic anti-depressants. Our search strategy was to use allRCTs cited in five previous meta-analyses,48 aliterature search on Medline using a searchstrategy which used the drug names as keywords, and a hand search in two journals-International Clinical Psychopharmacology andActa Psychiatrica Scandinavica. The in-dependent search concentrated on Medline andEmbase, using drug names as text words and,where available, using medical subject headings(Medline) or drug names for searches across allbasic index fields (Embase). Reference lists ofrelevant papers and previous systematic reviewswere scanned for published reports and ci-tations of unpublished research. The currentreview does not include any unpublished dataused for submission to licensing authorities.This review is part of an ongoing systematicreview and meta-analysis now submitted tothe Cochrane Collaboration. Studies were ex-cluded if (1) they duplicated results of pre-

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Table 1 Summary of main findings

Randomisation Only one trial (0.8%) had an adequate description of randomisation.

Outcomes All trials used unstructured assessments of depression.92% used the Hamilton depression rating scale.Two trials (1.6%) used quality of life measures.One study (0.8%) performed an economic analysis.

Tricyclic dosage 102 studies used tricyclic drugs as comparison treatment.In 22 (22%) the final dose attained was not given.In 26 (25%) the final dose attained was inadequate.

Generalisability of Setting:research Nine studies (7%) were performed exclusively in primary care.

39 studies (32%) usedhospital inpatients.Duration:78 trials (64%) compared treatment over six weeks.Four studies (3%) had a follow up of more than eight weeks.

Statistical problems Median sample size was 64 subjects (interquartile range 42-120).Only 11% of studies have "adequate" statistical power.69% of studies made multiple comparisons.

viously reported RCTs and (2) if the mainhypothesis under study was unrelated to de-pression (for example, some studies specificallyexamined outcomes such as electro-cardiographic changes,'3 sleep changes,415 cog-nitive status,'6 or psychomotor performance.'7

ASSESSMENT OF STUDIESIndividual RCTs were assessed on the followingcriteria:* Concealment of allocation;* The outcome measures used (specifically theuse of structured assessments, quality of lifemeasures, and economic analyses)* Dosage of tricyclic medication* Generalisability of the study, including itssetting and duration of follow up;* Statistical concerns, especially the power ofthe study and conclusions drawn, use of in-tention to treat analyses and uncorrected mul-tiple statistical testing (defined as testingmultiple outcomes, testing the same outcomeover several points in time or performing sub-group analyses).

ResultsTable 1 gives a summary of the main findingsof the study.

LITERATURE SEARCHAltogether 133 papers reporting 135 RCTswere identified. Eight of the 133 were excludedas they were duplicate publications and fivebecause their main aim was not the treatmentof depression. This left 122 RCTs. (A full listofpublications is available from authors.) Mostofthese studies were published in peer reviewedjournals. Thirty one (25%) of the studies ap-

peared in journal supplements often devotedto research on the new drug.

QUALITY OF STUDIESConcealment of allocationThere is evidence that the quality ofRCTs may

be judged on the adequacy of their descriptionofthe randomisation. We used Cochrane Col-laboration guidelines" to assess how adequatelythe randomisation had been described. Theseguidelines classify description ofrandomisation

as "adequate", "intermediate", or "inadequate".All but one,20 of the RCTs reviewed here fellinto the "intermediate" category since they gaveno information other than stating that the trialwas randomised. This is probably due to poordescriptions of the process rather than a seriousproblem in the conduct of the studies, but itdoes suggest that the overall quality of trialsmay not be especially high.

OutcomesThe measurement of depression. Most (115,

92%) of the RCTs we reviewed used the Ham-ilton rating scale for depression (HRSD)2122 as

their main outcome. The remainder used theMontgomery-Asberg scale.2' These are un-

structured assessments which rely on the as-

sessor (who should be a clinician) interviewingthe subject and rating symptoms of depressionaccording to specified criteria. The HRSD rep-resented an advance when it was first reported36 years ago, but there are now alternativessuch as semistructured 4 and structuredinterviews.'526

There are several reasons why such alter-natives are preferable. Firstly, observer basedassessments such as the HRSD depend heavilyon proper blinding of the assessors. All but oneof these studies were double blind, but themaintenance of blinding was not reported inany of them. Furthermore, only three RCTsused separate investigators to monitor sideeffects and assess severity. Since the side effectsbetween the two treatments differ, this in-creases the likelihood that the investigator rat-ing outcome will not be properly blinded. Theunstructured nature of the HRSD introducesthe possibility of observer bias especially whenthere is inadequate blinding, '8 since there isinevitably interest and optimism that the new

treatment will be beneficial. Secondly, many ofthe studies we reviewed were multi-centred.This makes the use of the HRSD problematicsince its inter-rater reliability has beenquestioned.'728 Thirdly, the HRSD requires a

clinician to assess the severity of depressionand relies on an interview lasting 30 minutes.Since most studies measured depression atweekly intervals this increases the cost of using

KEY POINTS* There is no consensus on whether selectiveserotonin reuptake inhibitors (SSRI) or tri-cyclic antidepressants should be used as thefirst line treatment of depression.* Review of all 122 randomised controlledtrials (RCTs) of these treatments showedseveral methodological shortcomings.* Shortcomings included an inadequate de-scription of randomisation; observer ratedmeasures of depression, no quality of lifemeasures or economic evaluation; in-adequate dosage of tricyclics; poor gen-eralisability; and statistical problems.* Future RCTs should address these prob-lems and aim to inform policy makers.

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the assessment with the consequence that largestudies using this design would be prohibitivelyexpensive. Many of these problems would beovercome if RCTs used structured interviews,especially those available in computerisedformat, such as the revised clinical inter-view schedule or the diagnostic interviewschedule.2930

Quality of life. Quality of life (QoL)3-33 isa measure of an illness's impact on functioningand measures of QoL have repeatedly beenrecommended in the setting of RCTs.123134Both depression and antidepressants impingeon many aspects ofan individual's life, affectingsocial or occupational roles.35 For example,antidepressants may stop the patient driving.Only two RCTs attempted to measure QoL.There are compelling reasons to measure

QoL. Firstly, since they are global measures offunctioning, they are capable of making usefulcomparisons between side effects of drugs. Forexample, tricyclic antidepressants are often sed-ating, whereas SSRIs may cause nausea. Unlessa global measure of functioning is used, it isimpossible to say which of these side effects ismore troublesome. Secondly, QoL measuresallow a useful assessment ofcost effectiveness tobe made. For example, direct costs oftreatmentmay be compared to improvements in QoL.Measuring QoL in depression is not without

its problems. Most QoL measures (such asthe widely used short form 36 (SF-36)37 andsickness impact profile (SIP)38 were designedto monitor QoL in physical illness. These scalesinclude some questions which assess the lim-itations the illness imposes on activities of dailyliving and occupational or social roles. Theyalso include many items related to general well-being such as fatigue and mood states. Clearly,the latter items will overlap with direct meas-ures of depression, and this makes the resultsof QoL measures harder to interpret in de-pression. Further, as discussed below, moststudies are of short duration and it may takelonger for these more distal measures of well-being to change. Despite these problems, thefailure of any RCT to measure QoL is strikingand some of these difficulties could be over-come by using some of the subscales fromgeneric scales such as the SIP. Using thesesubscales would allow some assessment of so-cial or occupational functioning, which mayeven be more useful outcomes than changes inscores on depression rating scales.Economic analysis. There will always be

budgetary constraints on any health service andit is necessary to determine the relative costeffectiveness of treatments.'239 In depression,the outcomes for an economic analysis mightinclude future health service use, occupationalstatus, impact ofthe illness on family members,and the use of resources such as social workand voluntary services.Only one of the RCTs performed an eco-

nomic analysis.20 This lack of direct costinghas not prevented the publication of economicmodels based on selected samples of the avail-able data.4"3 Unfortunately these analyses areflawed because they use non-random selectionsof clinical trials and tend to over estimate the

costs of treatment failure." There is no sub-stitute to performing an economic analysiswithin an RCT if valid conclusions about costeffectiveness are to be drawn.

TRICYCLIC DOSAGESThere is a consensus of opinion in the UK thattricyclics should be prescribed at doses of morethan 100 mg.45 Many studies only reported arange of dosages attained. In general, RCTsfrom North America used higher doses of tri-cyclics than those from Europe. It has pre-viously been noted that the doses of tricyclicsused were too low and this might have led toa spuriously low estimate of the drop out rateamong subjects taking tricyclics.5 We used thedose of 125 mg as the minimum satisfactorytricyclic dose. Twenty studies used non-tri-cyclic comparison treatments. Ofthe remaining102 RCTs, the final dosage was unclear in 22,and the average dose was less than 125 mg in26 (25%). Thus, in only 54 studies (53%)could one be sure that most subjects werereceiving adequate doses of the comparisondrug.

GENERALISABILITY OF RESEARCHSetting of researchIn the UK, 90% of depressed patients aretreated in primary care.4" This is not reflectedin these RCTs: only 9 (7%) studies were per-formed exclusively in primary care. The re-mainder were conducted in secondary care andmany came from teaching hospitals. Thirtynine studies included hospital inpatients withdepression. This is a rare group which formsonly 1/1000 cases of depression in UK.46Apart from the need for RCTs to reflect

clinical practice, there are specific reasons whythe setting of research is relevant. There areimportant differences between patients withdepression in primary and secondary care.47Compliance is notoriously poor in primarycare.48 If SSRIs are better tolerated, this ad-vantage should be most obvious in primarycare based studies. Tricyclic antidepressantsare more widely prescribed in primary care, soit is likely that many secondary care patientswill have failed to respond to tricyclics. Thiscould act as a systematic bias against tricyclics.Some trials make treatment resistance an ex-clusion criterion which may remove this bias.Even so, treatment resistance is usually definedas resistance to a full dose of antidepressantprescribed over a period of four to six weeks,a definition too restrictive to remove this po-tential bias with confidence. For example, inone trial49 65% ofthe patients entered had beentreated previously in the same episode.

Duration of researchDepression runs a chronic course" and theusual recommendation is that antidepressantsshould be prescribed for a minimum of sixmonths.45 This consensus is based on researchdemonstrating the superiority of tricyclics5" andSSRIs52 over placebo when prescribed for pro-

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longed periods. Only four of the trials (3%)had a follow up of more than 8 weeks and mostcompared treatments over 6 weeks (n= 78,64%).

Differences in costs and benefits of anti-depressant therapy may be particularly markedafter the acute illness. For example, patientsmay tolerate side effects during the acute phasesof the illness when they perceive a benefit intaking the medication. In contrast, most of theexpense of antidepressant prescribing is a resultof the longer maintenance period

STATISTICAL CONCERNSSample size and powerMost RCTs were small. The median samplesize was 64 subjects randomised to receiveactive treatment (interquartile range, 42-120).The sample size refers to the number ofpatientsentered into a study. The mean drop out inmost meta-analyses4 has approached one third,therefore the effective sample size in the studieswas much less. This glut of small RCTs ispartly a consequence of the range of possiblecomparisons between each of the four SSRIsand numerous tricyclic drugs, but this does nothelp the policy maker decide which class ofdrugs should be used as first line treatment.

Small studies lead to type 2 errors. If themedian sample size is 32 subjects per treatmentgroup, and one third of subjects drop out ofthe study, the completer analysis will only in-clude 21 subjects per group. These studiesdo not have the power to detect even quiteimportant differences between the two treat-ments. For example, it is widely accepted that60% of patients treated with a tricyclic anti-depressant will recover within six weeks oftreatment. A recovery rate of80% in the SSRIswould be a very important finding, with majorclinical significance. To detect such a differenceat 80% power and 95% confidence. 91 subjectswould be needed in each treatment group. Only13 (10.6%) of RCTs reviewed here would beable to detect such a difference.Many of the studies we reviewed did not

comment on their low power. One problem ofa study comparing two active treatments is theinterpretation of a "negative" finding, whereno statistically significant difference betweentreatments is detected. Many of the RCTs wehave reviewed reported the failure to find adifference between the two treatments as evi-dence that they had comparable clinical effic-acy, rather than comment on low power. Of86 studies with fewer than 100 randomisedsubjects, 51 interpreted a lack of difference inoutcome as evidence of comparable efficacy ofthe two treatments, without mentioning prob-lems of statistical power.

In principle, meta-analysis should overcomethe power problems of small trials. However,most trials did not produce elementary stat-istical information such as means and standarderrors of HRSD scores. Many expressed re-covery solely in terms of graphical rep-resentation and p values. Reporting the size ofthe observed effect together with confidenceintervals was rare. Only two meta-analyses48

have attempted to compare efficacy ratings onthe HRSD. In both, data from only a minorityof the identified RCTs were used due to thisproblem.

Statistical analysisIt was often difficult to determine the method ofstatistical analysis in these RCTs. In particularthere were frequently ambiguities over the useof intention to treat analysis, in which datafrom subjects who drop out is collected ormissing data is substituted with previous values.Forty four studies did not attempt any form ofintention to treat analysis and simply analyseddata from those who completed the study. Ina further 25 studies it was difficult to be sureexactly what form of analysis had been used.A commonly used method (38 studies) wasan analysis of data from the last visit, amongsubjects who had been evaluated since receivingsome randomised treatment. This is not a trueintention to treat analysis, since it excludesearly drop outs.The importance of an intention to treat ana-

lysis is that it maintains the original randomallocation upon which the validity of the RCTrelies. It is also more relevant to the healtheconomic evaluation of treatments as it takesaccount of treatments which are effective butpoorly tolerated and thereby provides a betterpicture of the overall effect of the treatmentunder study.Another common statistical fault with these

studies is their tendency to perform multiplecomparisons which lead to type I errors. Ac-cording to our definition (see above) 84 studies(69%) made some form of multiple com-parison, the most common being multiple end-points, such as comparing lists of side effectsor using various subscales of the HRSD.

DiscussionMost RCTs which compare SSRIs with tricyclicantidepressants are underpowered, use in-adequate outcome measures over inadequatefollow up periods, are based in settings whichlimit generalisability to primary care, and donot report an economic analysis. It is perhapsnot surprising, therefore, that they have sofar been unable to address the concerns ofclinicians and policy makers eager to knowwhich drugs should be used as first line treat-ment of depression.Why is it that so many studies failed to

answer these important questions? The sim-plest answer is that they were not designed todo so. The emphasis on most of these trials ismore to do with comparing efficacy and sideeffects than determining wider prescribing pol-icy. While this is clearly vital information, it isless easy to justify the number of inadequatelypowered studies. It is remarkable how un-informative many RCTs have been in de-termining the direction of future prescribing.These limitations of RCTs may be relevant

to other areas of clinical practice where a costlynew treatment is introduced for a chronic dis-ease. If the benefits of such a new treatment

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are modest there is a sound utilitarian argumentthat prescribing guidelines should not alter un-less there is clear evidence of cost effectiveness.The only sound way to measure cost effect-iveness is in the context of a well designedRCT.

This review is based upon a report" prepared for Lilly IndustriesLtd. Dr Hotopf is a Medical Research Council Clinical TrainingFellow. The authors would like to thank Mr Nick Freemantlefor providing access to his literature review.

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