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Rheumatology Advance Access originally published online on June 24, 2008
Rheumatology 2008 47(9):1367-1372; doi:10.1093/rheumatology/ken230
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Learning from past mistakes: assessing trial quality, power and eligibility in non-renal systemic lupus erythematosus randomized controlled trials

S. Y. Yuen and J. E. Pope

The University of Western Ontario, London, Ontario, Canada.

Correspondence to: J. E. Pope, St Joseph's Health Care London, 268 Grosvenor Street, Box 5777, London, ON N6A 4V2, Canada. E-mail: janet.pope{at}sjhc.london.on.ca


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives. To evaluate the post hoc study power of randomized controlled trials (RCTs) in the treatment of non-renal SLE and to determine the generalizability of these RCTs using an SLE database.

Methods. RCTs in non-renal SLE were identified using PubMed (1975–2007). Inclusion/exclusion criteria, trial quality (5-point scale) and results of each study were recorded. The inclusion/exclusion criteria were compared with an SLE database to determine the proportion of patients from the database who would theoretically be eligible for these trials. For each negative study, we calculated the post hoc study power. We also looked for temporal improvements of trials in the literature and examined if pharmaceutical involvement influenced trial quality.

Results. Sixty-four articles were included; the mean power of 30 negative studies was 24.6 ± S.E.M. 3.9% (range 2.5–81.1%). Only one study had a power > 80%. Overall, potential eligibility of SLE patients in the database was 45.1 ± S.E.M. 3.6%. Only 14 studies (21.9%) were of good quality. Fortunately, RCT quality is improving over time (trials <1995, compared with 1996–2002 and >2003; P < 0.001). Trials with pharmaceutical involvement had a significantly higher number of enrollees and better study quality.

Conclusions. Negative RCTs in SLE were mostly underpowered but the generalizability of these trials was high. Determination of study power and the impact of eligibility criteria on generalizability of study results are crucial in the design of clinical trials to ensure applicability to clinical practice.

KEY WORDS: Systemic lupus erythematosus, Randomized controlled trial, Study power, Generalizability, Trial quality


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Designing a randomized controlled trial (RCT) in SLE can be challenging, as SLE is a relatively rare autoimmune disease with a prevalence of 0.5–1/1000 and with multiple manifestations. In addition, stringent inclusion/exclusion criteria diminish the number of eligible patients and, therefore, recruitment of subjects for a sufficient sample size can be difficult. In lupus trials focused specifically on renal involvement, the outcomes are established such as 24-h creatinine clearance, need for dialysis, urinary protein/creatinine ratios, urinary sediment and cumulative steroid dose, although these outcomes may be difficult to collect. However, in trials of lupus patients with no renal involvement the heterogeneity of other organ system involvement can potentially create difficulty with respect to choice of primary outcome measurements. We are searching for proven treatment in SLE and do not want to consider a drug ineffective if the study is underpowered. Publication bias would predict that some negative trials in SLE have not been published, so publication of RCTs in SLE may represent the ‘best’ studies.

When a study is underpowered a type II or β error can occur. Type II or β error is the probability to conclude that no difference exists between the experimental group and the control group when there is a true difference. In general, a β error of <20% or a study power (1 – β) of >80% are considered an acceptable risk for false-positive results. To avoid or minimize this error, the investigator should include a larger sample size, which will increase the power of the study thereby decreasing the β error. Most authors agree that sample size and power calculations are important in the planning of clinical trials to ensure an adequate cohort size to detect a difference if it actually exists [1–8]. Unfortunately, calculations are not always reported in the methods [2, 3, 7, 9, 10], so the null hypothesis cannot be rejected due to insufficient power.

Restrictive eligibility criteria could be an additional problem in enrolling patients in SLE trials. In fact, specific inclusion/exclusion criteria are necessary to characterize the study population, but highly selected eligibility criteria do not adequately represent the clinical practice, so generalizability of the results could be limited.

Many authors have previously commented on poor quality in lupus studies [10–13], and these reports were mostly on lupus renal trials. Indeed, some differences may exist between these two groups of RCTs (renal and non-renal) in terms of design or quality [10]. In this present study, we wanted to describe mainly the non-renal group, as very few publications have assessed these RCTs in the past. Trends over time in trial quality, influence of pharmaceutical involvement and generalizability have not been statistically quantified. The objectives of this study were to: (i) evaluate the post hoc study power of RCTs in the treatment of non-renal SLE; (ii) determine trial quality; (iii) determine if pharmaceutical involvement was related to trial quality; (iv) determine temporal trends with respect to trial quality; and (v) determine the generalizability of these RCTs (percent eligibility) using a database from a Canadian lupus clinic.

Our hypotheses were that many negative RCTs in the treatment of SLE are generally underpowered (could be type II error) and the generalizability of non-renal SLE RCTs is modest at best.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Publications related to the treatment of SLE were identified using the PubMed database, available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=pubmed, for the years 1975–2007. We also searched in all languages using MEDLINE and OVID. Terms used were (in various combinations): ‘systemic lupus erythematosus’, ‘randomized controlled trial’, ‘clinical trial’, ‘flares’, ‘treatment’. RCTs published in English and French on treatment of non-renal SLE were selected. Articles were eliminated according to the following exclusion criteria: not an RCT, not a primary research publication and articles related to the treatment of lupus nephritis or other renal diseases.

Inclusion and exclusion criteria, quality of the trial and results of each study were recorded. The inclusion/exclusion criteria were compared with the lupus database to determine the proportion of SLE patients in the database who would theoretically be eligible for these trials. In addition, articles were classified into subgroups according to the type of treatment investigated or the outcome measure.

Since 2005, we have prospectively collected information including socio-demographics, health-related habits, cultural background, medications, clinical manifestations, comorbidities, ACR criteria [14], SF-36 version 1 [15], SLAM [16], SLICC [17], SLEDAI [18], Systemic Lupus Activity Questionnaire (SLAQ) [19] measurements and laboratory parameters in our lupus patients, trying to obtain consent from all lupus patients that we follow. Thus, all patients followed by our SLE clinic were invited to participate. Data have been collected annually. In total, data from 148 patients were available for analysis. Table 1 summarizes the characteristics of these patients. Eligibility criteria of the selected trials were compared with those of this database for the purpose of determining generalizability. Criteria were censored if they were not available from the lupus database or >50% of data were missing. If a trial stated that other drugs had to be withdrawn, we assumed patients would do this to increase recruitment (e.g. withdrawal of current vasodilator for RP trials).,


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  		TABLE 1. Characteristics of 148 lupus patients

 
For each study that reported a non-significant difference in primary outcome we calculated the post hoc study power using standardized formulae [20]. If the primary outcome was not explicitly reported then the most clinically relevant outcome measure was considered. Only RCTs with two treatment arms and sufficient outcome data were included in this analysis. We used sample size calculations for dichotomous and continuous response variables [20]. For continuous variables, if S.D.s were not reported, they were calculated according to the reference methods [21].

In addition, we evaluated trial quality with a 5-point scale, selected from the revised CONSORT statement for reporting randomized trials, which included the presence or absence of: sample size calculation, double-blinding, description of randomization allocation and description of statistical methods and intention-to-treat analysis [22]. Each variable was recorded as 0 = no or 1 = yes. Studies were scored from 0 to 5 and we combined trials into three subsets (0–1 = poor, 2–3 = passable, 4–5 = good). A temporal trend in trial quality in the literature was assessed dividing the trials roughly equally into three time periods. We also determined if pharmaceutical involvement influenced trial quality.

Descriptive statistics were computed using SPSS (Statistical Package for the Social Sciences, Chicago, USA) version 15. Results were presented as mean ± S.E.M. or median and ranges as appropriate.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
In total, 64 publications [23–86] were reviewed and included in this present study. Twenty-five studies were positive and 39 were negative (total of 39% positive studies). The study power of nine negative RCTs was not calculated as information provided by four trials was insufficient to perform calculations and five RCTs had three or four parallel-group designs. The mean power of the 30 remaining studies was 24.6 ± 3.9% (range 2.5–81.1%). Only one RCT had a study power >80% which is considered the minimum for determining sample sizes. Twenty studies (31.3%) (7 positive, 13 negative) reported the sample size calculation.

Studies were classified as positive/negative trial or divided into three subgroups: adjuvant therapy (diet, n = 5; exercise, n = 4; immunization, n = 2; psychotherapy, n = 6; quality of life, n = 3); disease activity (pregnancy, n = 1; disease activity, n = 27); and organ target therapy (arthropathy, n = 1; osteoporosis related, n = 5; neurology in SLE, n = 1; RP, n = 4; skin disease, n = 2; pulmonary arterial hypertension, n = 3). Table 2 shows the results for each subcategory of trials including number of negative studies and study power. In addition, Table 3 presents the mean percentage ± S.E.M. and median (range) of sample size per trial and the mean percentage ± S.E.M. of eligibility in 64 non-renal SLE trials when the lupus database was used as a reference population. RCTs related to prevention of flares were included in the category of disease activity. As mentioned previously, RCTs designed to evaluate renal function as the primary outcome were excluded. Potentially eligible patients ranged from 0% to 92.6% with a mean of 45.1 ± 3.1%. Mean eligibility was 54.5 ± 7.8% for the adjuvant therapy subgroup (n = 20 trials), 49.4 ± 4.4% for the disease activity subgroup (n = 28 trials) and 25.9 ± 5.7% for the organ target therapy group, respectively.


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  		TABLE 2. Study power by subcategory of trials

 

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  		TABLE 3. Patients’ eligibility and sample size/trial by category of trials

 
All RCTs were assessed for quality. The mean score was 2.4/5. Only 14 studies (21.9%) had good quality (score 4–5), 34 were passable (score 2–3) and 16 had poor quality (score 0–1). Trial quality did not differ between positive (score 2.6/5, n = 25) and negative studies (score 2.4/5 n = 39). We noticed an improvement in trial quality over time dividing the studies into roughly equal numbers over three time periods (P < 0.001) (Fig. 1). In addition, we redivided trials into three subgroups according to the total number of participants/study (subgroups: ≤29, 30–69, ≥ 70 participants/study). It was found that studies that had ≤29 subjects had a statistically significantly lower quality than the two other groups (P = 0.001) (Table 4). Table 5 shows the mean and median score of trial quality classified by the involvement of pharmaceutical companies in research funding. Trials that were fully financed by pharmaceutical companies had a statistically higher number of enrollees (P < 0.001) and a trend of better study quality (Table 5).


Figure 1
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  		FIG. 1. Quality of trial by publication date.

 

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  		TABLE 4. Quality of trial by sample size subgroups

 

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  		TABLE 5. Quality of trial by source of funding

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In this study, we provided evidence that RCTs in the treatment of non-renal SLE are generally underpowered. Only 39% of non-renal lupus trials were positive. Indeed, we obtained a mean power of 24.6% from the analysis of 30 negative studies, suggesting that many may have a type II error. Also, only 31.3% of trials reported a sample size calculation. Our findings are not unique in the medical literature. In 1978, Freiman et al. [87] published a survey of 71 negative trials. This report showed that for a power of 90%, only 5.6 and 29.6% of the trials were large enough to detect a therapeutic improvement of 25 and 50%, respectively. Over time, authors of several medical and surgical specialties have documented this problem, even in articles published in high-impact journals [2–7, 9, 10, 88]. More recently, a study of orthopaedics analysing 117 randomized trials reported a mean overall study power of 24.7% (range 2–99%) and a type II error rate of 90.5% [88]. Karassa et al. [10] systematically analysed 94 RCTs on SLE treatment, of which only 7.5% of trials had a study power of >80%. Also, sample size or power calculations are infrequently reported (range from 6% to 32%) [2, 3, 7, 9, 10].

Fortunately, the situation has improved over time. Moher et al. [9] compared 102 negative studies published in 1975, 1980, 1985 and 1990. They found that a sample size calculation was not reported in any study in 1975, but increased to 32% in 1980, 48% in 1985 and 43% in 1990. The objective of an RCT is to determine the efficacy of an intervention. Lack of determination of sample size and power in RCTs may be unethical as the research is conducted on human subjects, so if no conclusions can be drawn, then therapies that may be useful can be discarded and resources are wasted.

In this study, we included non-renal RCTs of all types of interventions. Some trials were reported more than once (35 and 37; 47 and 56; 52 and 85), but the publications added further analysable data. We did not exclude them from our analysis because their therapeutic interventions, analyses methods or outcome measurements were different. In addition, we did not subclassify RCTs in terms of trial phase. Indeed, we wanted to describe the overall quality of current and past RCTs in this field. Most RCTs were Phase III and, except for two trials (72, 82), all were testing drugs in SLE that are already on the market. However, analyses on outcome measurement, trial quality and statistical power were done as reported. If a study was designed for a certain number of participants or study power and this trial obtained the expected result, it was categorized as a positive study and was not included in the post hoc power calculation.

Our results indicate that the generalizability of non-renal RCTs in SLE is low. Indeed, about 46–74% of our cohort of patients would not be eligible to enter most RCTs and eligibility was overestimated. Similar data in psychiatry and oncology literature have been reported [89–92]. The number of exclusion criteria has increased over time [89]; therefore, more patients might be deprived of possible benefits of the trial treatment. Researchers have questioned if increasingly restrictive criteria are necessary to ensure the internal validity of the study. Fuks et al. [89] analysed eligibility criteria of two groups of cancer trials. They concluded that many of the eligibility criteria were not necessary for study quality and these criteria should be explicitly justified [89]. In fact, clinical researchers carefully assess the suitability of each patient for trial entry and an extensive list of exclusion criteria might not be justified and may be unnecessary to the protection of research patients.

SLE is an uncommon disease, so enrolment for an RCT might be problematic. Ferland and Fortin [93] documented the recruitment challenge of a pan-Canadian SLE trial of MTX vs placebo: 15% refused to participate in their study, 45% did not meet the eligibility criteria and only 40% of the approached patients were randomized [93]. An extensive list of exclusion criteria might reduce adverse effects or reduce the number of non-responders, but it also limits recruitment and restricts applicability of the results. There are trade-offs between a well-characterized RCT population and generalizability, but either way power must be adequate to avoid ruling out potentially helpful treatment in SLE where new therapies are needed.

Our results of generalizability are certainly an overestimate. In fact, some data were not available from the lupus database and we did not exclude patients with certain comorbidities, other medications and laboratory outlying values. The assumptions that patients would stop current treatment if appropriate to enrol and that all who were eligible would agree to participate were further overestimates, as we wanted to use the best case scenario for study inclusion. Eligible patients might also not be enrolled in an RCT due to lack of consent, large distances to travel and other reasons (working, language barrier, etc.).

This study numerically illustrates the lack of quality and study power in RCTs in the treatment of non-renal SLE. Fortunately, trial quality is improving over time (Fig. 1). Interestingly, studies that were fully supported by pharmaceutical companies obtained a better quality score and a significantly higher number of participants (P < 0.001) (Table 5). Differences in trial quality did not reach significance due to the small number of trials in certain groups. As mentioned by Karassa et al. [10] in a systematic analysis of 94 nephritis and non-nephritis RCTs in SLE quality variables in reporting such as description of blinding (masking), sample size specification, randomization mode, allocation concealment, withdrawals, intention-to-treat analysis, power calculations and outcome measurement have been neglected in most studies. Rather than evaluating the quality of each trial with an individual score, as we did in our analysis, they extracted variables from each selected trial and reported the mean frequency (presence or absence) of each quality variable for 94 publications overall. They found correlations between some quality characteristics and study size. Similarly, from our analysis, larger studies obtained a significantly higher quality score (P = 0.001) (Table 4). They also assessed changes over time; outcome specification was the only variable that has improved significantly.

In summary, this study evaluated two important concepts in the design of non-renal RCTs in SLE: the internal validity, which is the trial quality including β error, and the external validity (generalizability). We found that the study power of current and previous negative RCTs was generally low; therefore, the risk of β-error was increased. There may have been different achievable effect sizes desired, however, which could affect power, such as in proof of concept studies where the sample size and effect size may be smaller than a Phase III RCT. We also demonstrated that the generalizability of SLE trials was modest at best. We believe that study power and sample size calculations are important steps in the planning of all RCTs, including SLE trials. Researchers should assess the impact of restrictive eligibility criteria on the applicability of results in clinical practice.

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 12 September 2007; revised version accepted 20 May 2008.
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