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REVIEW ARTICLES |
Lyme Brook Centre, Stoke on Trent
Eli Lilly, Lilly House, Basingstoke
University Department of Psychological Medicine, Gartnavel Royal Hospital, Glasgow, UK
Correspondence: Dr Richard Hodgson, Lyme Brook Centre, Bradwell Hospital, Talke Road, Stoke-on-Trent, Staffordshire ST5 7TL, UK. Email: richarde.hodgson{at}northstaffs.nhs.uk
Declaration of interest R.H. and R.H. have received funding from several pharmaceutical companies. C.B. is an employee of Eli Lilly UK. Funding detailed in Acknowledgements.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONEVOLUTION OF CLINICAL TRIALSRANDOMISED CONTROLLED TRIALSOBSERVATIONAL STUDIESCOMMON METHODOLOGICAL ISSUESTHE WAY FORWARDCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Aims To review how traditional RCTs may be triangulated with other methodologies such as observational studies and pragmatic trials by highlighting recently reported studies, outcomes used and their respective merits.
Method Literature review focusing on drug treatment.
Results Recently reported observational and some pragmatic studies show a degree of consistency in reported results and use outcomes that have face validity for clinicians.
Conclusions No single experimental paradigm or outcome provides the necessary data to optimise treatment of mental illness in the clinical setting.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONEVOLUTION OF CLINICAL TRIALSRANDOMISED CONTROLLED TRIALSOBSERVATIONAL STUDIESCOMMON METHODOLOGICAL ISSUESTHE WAY FORWARDCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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It is assumed that psychiatrists will base their treatment on the best available evidence but what is the best available evidence for a given clinician? Many factors are relevant and include personal experience, the literature, anecdote, opinion leaders, the pharmaceutical industry, guidelines and cost. However, little is known about actual prescribing and other treatment decisions (Hoblyn et al, 2006). Clinicians, purchasers and user advocates are also demanding more pragmatic end-points, and longer trials have shown the utility of relapse rates, hospitalisation and discharge rates as outcome measures (Csernansky et al, 2002).
Thus in 2007 `best available evidence' is generally accepted as the RCT, but the available RCT evidence is at best incomplete, and at worst, flawed (Black, 1996). The aim of this paper is to show practising clinicians the spectrum of quantitative evidence and pragmatic outcomes.
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EVOLUTION OF CLINICAL TRIALS |
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TOPABSTRACTINTRODUCTIONEVOLUTION OF CLINICAL TRIALSRANDOMISED CONTROLLED TRIALSOBSERVATIONAL STUDIESCOMMON METHODOLOGICAL ISSUESTHE WAY FORWARDCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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RANDOMISED CONTROLLED TRIALS |
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TOPABSTRACTINTRODUCTIONEVOLUTION OF CLINICAL TRIALSRANDOMISED CONTROLLED TRIALSOBSERVATIONAL STUDIESCOMMON METHODOLOGICAL ISSUESTHE WAY FORWARDCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Patient recruitment and selection bias
Whether clinically significant selection bias occurs during recruitment to
clinical trials is contentious. Although Burns
(2006) reported that the basic
demography of patients in a large naturalistic study was similar to that of a
widely reported RCT, other authors have noted that the more chaotic patient
who is difficult to manage will not be entered into a clinical trial as, even
if they consent, they will undoubtedly drop out of follow-up
(Lester & Wilson, 1999;
Harrison-Read et al,
2002). Trials rarely report the number of patients considered or
screened for a trial who are never included. Although this is a CONSORT
requirement, clinicians will make prescreening decisions regarding eligibility
that are never reported. This is a potential source of bias and might limit
extrapolation of results. It is likely that these difficulties are a serious
unreported bias in published RCTs for psychological treatments. For example,
reviews of the impact of day hospital treatment have failed to take entry
criteria into account, leading to potentially erroneous conclusions
(Thornicroft & Strathdee,
1994). The need for informed consent might inadvertently affect
the generalisability of data from RCTs. All trials of intramuscular olanzapine
(Meehan et al, 2001;
Wright et al, 2001)
were conducted in patients who gave informed consent and, although positive,
the results cannot be interpreted as indicating that the drug will be as
effective in patients who are highly disturbed.
Although biases are reduced in RCTs they are not eliminated, and indeed specific biases may even be created. Aside from the increased practical difficulties of including older adults in clinical trials, only 4.2% of older patients with major depression meet the increasingly rigorous inclusion and exclusion criteria of phase 3 studies (Yastrubetskaya et al, 1997). Women have sometimes been underrepresented in RCTs primarily because of concerns regarding conception while on trial medication, although this may be changing.
Patients with comorbid disorders are usually excluded from RCTs and this does not allow trials to reflect the rate of substance misuse and physical ill health in people with mental illness (Phelan et al, 2001). Previous exposure to trial medication is often unreported, but McQuade et al (2004) reported that 25% of patients in this randomised trial had prior exposure to one of the evaluated drugs. Generally, RCTs do not control for previous number of admissions or other markers of `difficult to treat' patients (Hodgson et al, 2005). This might lead to newer treatments being tried in patients who are more difficult to treat, which may lead to suboptimal results for newer treatments (Davis et al, 2003).
Rating scale outcomes
The outcome measures used in RCTs affect the generalisability of the
results. Although these outcome measures have been refined over decades to
improve reliability, in studies their use may affect the face validity of the
results. Clinicians would have difficulties in understanding what a fall of
20% in score on the Positive and Negative Syndromes Scale (PANSS;
von Knorring & Lindstrom,
1995) means in clinical practice. Indeed Kane et al
(1988) suggested this as an
outcome only for treatment-resistant patients and a recent analysis
(Leucht et al, 2005)
has shown that a drop of 50% in PANSS score may better equate to a Clinical
Global Impression Scale (CGI; Haro et
al, 2003) rating of `much improved'.
Pragmatic outcomes
Rating scales might not reflect clinical reality and there may be
dissonance between rating scale response and a pragmatic clinical end-point
such as discharge from hospital (McCue
et al, 2006). Pragmatic research and outcomes focus on
whether an intervention works under real-life conditions and whether it works
in terms that matter to the patient. However, if broader concepts are used,
such as remission, relapse or rehospitalisation, then other problems emerge.
Rehospitalisation is easily measured, but in an individual trial may be
mediated by other variables such as admission criteria. Remission or response
rates might have more clinical utility but have been criticised on the grounds
of variability of results if an arbitrary cut-off is used, although
sensitivity analysis can be used to assess the effect of changing parameters
(Linden et al, 2006;
van Os et al,
2006).
Rates of discontinuation of treatment may be a proxy for treatment effectiveness (Hodgson, 2005; Lieberman et al, 2005; Kinon et al, 2006). Kinon et al (2006) undertook a meta-analysis of RCTs of atypical antipsychotics using reported discontinuation as an outcome and found far more variability between drugs than might have been anticipated from the head-line results, which usually (marginally) favour the sponsor's product (Heres et al, 2006). Further exploration of these pragmatic end-points in long-term studies facilitate a better understanding of the face and predictive validity of rating scales. Any dissonance between comparator drugs using varied end-points might be cause for concern. A recent non-inferiority RCT comparing two atypical antipsychotics at 1 year showed consistency of superiority for one in parameters ranging from PANSS score to discontinuation and hospitalisation rates (www.clinicalstudyresults.org/drugdetails/?drug_name_id=187&sort-c.company_name&page=1&drug_id=509). However, use of outcomes such as hospitalisation might preclude cross-service comparisons. Quality of life has also been used as an outcome but although such measures are laudable, in practice the outcomes are difficult to measure and may not be amenable to change (Boardman et al, 1999).
Tolerability
Published RCTs have been criticised for inadequate reporting of
side-effects and adverse events (Ioannidis
& Lau, 2001; Papanikolaou
et al, 2004). The incidence is usually reported but
duration and severity are not. These are important variables and may make the
difference between persevering with medication or abandoning a therapeutic
trial. For data such as prolactin levels RCTs often report mean cohort values
rather than pragmatically useful categorical rates
(Bushe & Shaw, 2007).
Study length and drop out
Typically patients in secondary services receive treatment for periods of
time that far exceed those of RCTs, which are often as short as 4 weeks. The
Schizophrenia Outpatient Health Outcomes (SOHO) study
(Haro et al, 2006)
demonstrated continued improvement over 3 years. Short RCTs will not assess
all tolerability issues and whether improvement is maintained. However, RCTs
are getting longer (Lieberman et
al, 2003; McQuade et
al, 2004). The corollary of longer study periods is lower
follow-up rates and, paradoxically, high follow-up rates might be an indicator
of a biased study population. Drop-out rates over 6 weeks are on average 35%
and at 6 months can be around 72% (Leucht
et al, 2003; McQuade
et al, 2004), making interpretation of data complex.
Randomised controlled trials are designed to minimise bias and in creating this artificial environment treatment effects may be obviated. Although the true masking of many trials has been debated (Moncrieff, 1997), clinicians cannot intervene in trials in a timely or appropriate manner. Doses and visits are predetermined, as is the ability to respond to potential side-effects. These issues are relevant to the placebo arm, as often placebo group patients are receiving a psychoactive drug such as lorazepam (Meehan et al, 2001; Wright et al, 2001). Randomised controlled trials are often designed to fulfil regulatory requirements to obtain marketing authorisations for a new drug. There will be significant delays between study conception, recruitment, follow-up and publication of results. Clinicians often anticipate this with off-label prescribing (Hodgson & Belgamwar, 2006). The reality is that few RCTs are ever undertaken by pharmaceutical companies after launch. This is for many reasons, including the relatively short patent life. Thus, when such RCTs are performed there is often a perceived need for the data to be available quickly. Rarely are these trials long term.
Evolution of the RCT paradigm is seen in the CATIE trial (Lieberman et al, 2005; Table 2). In addition to traditional outcome measures, continuation on an antipsychotic was used as an outcome. Such an outcome should resonate with clinicians as medication is most commonly discontinued owing to lack of effectiveness or side-effects (Hodgson, 2005). Meta-analysis shows that lack of effectiveness is the major reason for discontinuation and differentiates between atypical antipsychotics in RCTs. In contrast, discontinuation for side-effects is relatively uniform (Kinon et al, 2006).
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For the reasons above, RCTs fail to provide the clinician with all the necessary information to prescribe confidently. In order to prescribe a new product the clinician uses previous experience, critical review of early results and the experience of others. In other words the clinician is in effect, albeit informally, undertaking a naturalistic/observational study. The definition of an observational study can be problematic, but in the context of this paper we have identified the key element as a research design where the allocation of treatment is not fully under the control of the researcher (Table 1).
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OBSERVATIONAL STUDIES |
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TOPABSTRACTINTRODUCTIONEVOLUTION OF CLINICAL TRIALSRANDOMISED CONTROLLED TRIALSOBSERVATIONAL STUDIESCOMMON METHODOLOGICAL ISSUESTHE WAY FORWARDCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Observational studies have been criticised because they are believed to overestimate treatment effects. However, recent comparison between RCTs and observational studies does not support this view (Benson & Hartz, 2000; Concato et al, 2000; Kasper et al, 2001). Concato et al (2000) challenge the accepted hierarchy of clinical designs by reviewing outcomes from various methodologies in a variety of study areas and conclude that observational studies neither over- nor underestimate treatment effects to any significant degree. They opine that observational studies are more likely to produce homogeneous results as they include a broad spectrum of the population at risk. In addition, there is less chance of systematic treatment biases because of the broad treatment population.
Recent observational studies
The CATIE study (Lieberman et
al, 2005), an RCT sponsored by the National Institute of
Mental Health, compared the outcome of atypical antipsychotics with the
typical antipsychotic perphenazine and also incorporated a switching strategy
to evaluate clozapine. The results mirror those of Tiihonen et al
(2006) in that clozapine and
olanzapine were the only oral atypical antipsychotics to demonstrate lower
discontinuation rates when compared with oral first-generation and other
second-generation antipsychotics. The study reported by Tiihonen et
al (2006) is particularly
noteworthy as it follows a nationwide cohort of over 2000 people with
first-episode schizophrenia for up to 7 years. In addition to showing
differences in rehospitalisation and relapse rates between commonly available
antipsychotics in Finland, it also shows the effectiveness of medication in
reducing suicide and physical morbidity (adjusted relative risk 37.4, 95% CI
5.1–276 and 12.3, 95% CI 6.0–24.1 respectively). The relative
therapeutic effects of the drugs studied did not vary whether discontinuation
or rehospitalisation was considered, and this is echoed in the SOHO study
(Haro et al, 2006).
Another long-term study of over 500 patients in England
(Hodgson et al, 2005)
demonstrated the same rank order of effectiveness of oral atypicals using
medication discontinuation as an outcome. In this study it was apparent that
clozapine was being used for a treatment-resistant cohort. Taylor et
al (2006) studied
duration of treatment as a proxy in a Scottish population over 3 years and
reported similar results to Tiihonen et al
(2006) and Hodgson et
al (2005).
McCue et al (2006) in a randomised open-label study of atypical antipsychotics and haloperidol in in-patients using the Brief Psychiatric Rating Scale (BPRS; Overall & Gorham, 1962) and time to discharge as outcome measures found similar effectiveness between haloperidol, olanzapine and risperidone and that these drugs were significantly better than aripiprazole and quetiapine. However, there was a dissonance between time to discharge and the BPRS outcomes, which might suggest that rating instruments are not sensitive to important changes that influence management, at least in the short term. Although haloperidol was equal to risperidone and olanzapine it was associated with more extrapyramidal side-effects. Jones et al (2006) failed to detect any differences in effectiveness between first- and second-generation antipsychotics and reported no difference in extrapyramidal-type side-effects, in stark contrast to many other RCTs. A recent RCT of 400 first-episode patients (McEvoy et al, 2006) compared olanzapine, quetiapine and risperidone over 1 year and failed to detect a difference in discontinuation rates between these drugs although olanzapine had a significantly greater effect on positive symptoms. Discontinuation was associated with poor response (P<0.001) and poor medication adherence (P=0.02).
In general, RCTs are powered for one primary outcome which does not always reflect primary clinical concern (McQuade et al, 2004). As observational studies are larger, there is more scope for legitimate subgroup analysis, such as treatment effect on those with comorbid disorder. The 3-year results of the SOHO study provide insights into social function and factors associated with relapse and remission. These are consonant with other independent studies and increase the face validity of this study. Although the SOHO study demonstrates relatively high switching rates for some medications, 65% of patients achieved remission, which resonates with the results of other long-term studies (Ciompi, 1980; Harding, 1988).
Observational studies and safety
Although often not acknowledged as such, post-marketing surveillance is
essentially an observational study, albeit often poorly conducted
(Vray et al, 2005).
However, post-marketing surveillance often reports important safety
information that was not apparent from RCTs. The association between blood
dyscrasias, clozapine and remoxipride are prime examples. In general, RCTs
provide useful information on common adverse events, but identifying the
relative risk of uncommon adverse events is realistically possible only in
observational trials. In this regard, adverse event reporting in observational
trials has been shown to enhance safety during the trial and facilitate the
role of data monitoring committees and institutional review boards confronted
with multiple reports of adverse events
(Califf & Lee, 2001).
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COMMON METHODOLOGICAL ISSUES |
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TOPABSTRACTINTRODUCTIONEVOLUTION OF CLINICAL TRIALSRANDOMISED CONTROLLED TRIALSOBSERVATIONAL STUDIESCOMMON METHODOLOGICAL ISSUESTHE WAY FORWARDCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Randomised controlled trials have highlighted relatively high switching rates between therapies and potentially confounding baseline variation, with lower rates measured in observational studies. Baseline variation can be accommodated in analysis but, as with drop out from RCTs, it cannot be assumed that this variation is random and may reflect clinical practice. For example, in the study reported by Hodgson et al, (2005) and the SOHO study (Haro et al, 2006) young men with multiple illness episodes were more likely to receive clozapine.
Switching treatments within an observational study can be studied using marginal structural models (MSM), a new class of causal models that allow for improved adjustment of confounding in longitudinal data analysis in naturalistic settings by consistently estimating the parameters of the inverse-probability-of-treatment weighted estimators (Mortimer et al, 2005); MSM are an extension of propensity scoring to longitudinal data. Whereas propensity scoring controls for selection bias by reweighting observations to produce `balance' between groups, MSM do the same but in a longitudinal fashion; MSM allow estimation of the causal effect of treatments in longitudinal naturalistic data when patients switch or stop treatment, even in the presence of missing (at random) data and time-varying confounding variables.
Patient concordance and sample size
In estimating treatment effects both RCTs and observational studies are
challenged by patient concordance. Drug levels, which are highly variable for
many psychotropics, are not routinely used, with pill counting being a common
concordance measure in RCTs. However, poor adherence may underestimate
treatment effects. Patient and clinician choice is important in determining
outcome (Black, 1996) and
controlling for these variables in RCTs limits the exploration of these
factors. Zelen (1979) has
advocated a methodology that has the advantage that, before providing consent,
a patient will know whether an experimental treatment is to be used. Further
development of patient and clinician preference trials has been described
(Korn & Baumrind, 1991;
Wennberg et al,
1993). McCue et al
(2006) demonstrate that
physician knowledge of a treatment might enhance optimum treatment dosing.
The nature of observational studies allows large sample sizes that add to the power of the study, facilitate subgroup analysis and provide data for robust sample size estimates for RCTs. Although in general appropriate sample sizes are important in RCTs, the superiority of those with large sample sizes over those with smaller samples has been challenged with regard to overestimating treatment effects (Contopoulos-Ioannidis et al, 2005).
Publication bias and sponsorship
Publication bias might also affect the two methodologies. Given the
hierarchy of evidence, journals may be less willing to accept observational
studies (Barton, 2000).
Journals are less likely to publish negative studies and both methodologies
are potentially biased by the study sponsor, with positive results often being
associated with the vested interest of the sponsor
(Als-Nielsen et al,
2003). However, a review of atypical antipsychotic trials and
funding sources indicates that this is not invariably so
(Heres et al, 2006).
Moreover, government-funded trials cannot be assumed to be unbiased
(Coyne, 2006)
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THE WAY FORWARD |
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TOPABSTRACTINTRODUCTIONEVOLUTION OF CLINICAL TRIALSRANDOMISED CONTROLLED TRIALSOBSERVATIONAL STUDIESCOMMON METHODOLOGICAL ISSUESTHE WAY FORWARDCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Randomised controlled trials and observational studies are not mutually exclusive, and there are examples from other areas of medicine of two designs running in parallel. For example, several studies quoted in Benson & Hartz (2000) in coronary artery disease illustrate the merits of enhancing an RCT by the addition of observational data from a concurrent registry of all non-randomised patients in the same centres. This approach improves the quality of observational research, since the same rigorous attention to detail in defining eligible patients, maintaining follow-up and recording outcomes is applied in both the randomised and the observational cohorts. The observational cohort may still suffer from selection bias, but there is a greater likelihood that its causes can be identified. The corollary also applies in that the observational cohort inform on the typicality of the experimental group.
Rapid changes in methodologies without bridging links with older methodologies may preclude legitimate comparison and subsequent meta-analysis. However, advances in the understanding of the biological and psychological mechanisms of mental illness will also dictate the evolution of relevant end-points. This is typified by the increasing interest in cognitive outcomes (Stroup et al, 2003) for which NICE recommends audits and provides standardised templates. This is another potential for supplementing treatment information and should facilitate the collection of data pools that inform treatment practice. The introduction of new treatment presents the possibility of mirror image studies (Hodgson et al, 2002) that allow some measure of utility, although regression towards the mean precludes overinterpretation of the results.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONEVOLUTION OF CLINICAL TRIALSRANDOMISED CONTROLLED TRIALSOBSERVATIONAL STUDIESCOMMON METHODOLOGICAL ISSUESTHE WAY FORWARDCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONEVOLUTION OF CLINICAL TRIALSRANDOMISED CONTROLLED TRIALSOBSERVATIONAL STUDIESCOMMON METHODOLOGICAL ISSUESTHE WAY FORWARDCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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REFERENCES |
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