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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

To determine the generalizability of randomized controlled trials (RCTs) in the treatment of systemic sclerosis (SSc) using the Canadian Scleroderma Research Group (CSRG) database.

Methods

We identified articles related to SSc published from 1958 to 2006. Key points on trial design were recorded. The inclusion/exclusion criteria were used in conjunction with the CSRG database to determine the proportion of patients with SSc who would theoretically be eligible for these trials. Articles were classified into subcategories according to the target system. The CSRG database contains 438 patients with SSc from 14 Canadian centers. Results were in median (%) and mean (%) with 95% confidence intervals (95% CIs).

Results

In total, 210 articles were evaluated and 73 were selected for inclusion in this study. The mean percentage of eligible patients with SSc associated with other conditions was 35% (95% CI 17–53) for Raynaud's phenomenon, 24% (95% CI 1–47) for digital ulcers, 48% (95% CI 27–68) for gastrointestinal (GI) involvement, 32% (95% CI 20–43) for overall disease modification, 6% (95% CI 4–8) for pulmonary arterial hypertension, 2% (95% CI 0–4) for interstitial lung disease, and 38% (95% CI 12–64) for other categories.

Conclusion

Except for GI trials, <38% of the identified patients with SSc would have been suitable to enter the RCTs. Although some patients would be ineligible because they lack certain organ involvement, RCTs designed to include appropriate patients with SSc are needed; there are few proven treatments and trials typically do not include the majority of those who could potentially benefit from the intervention.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Time, energy, and millions of dollars are expended during the long process from early development of a new drug to approval. Therefore, it is justifiable that many people in the target population should benefit from efficacy studies, especially when a disease has very few treatment options. Randomized controlled trials (RCTs) are the gold standard in evaluating the usefulness of potential treatments. For all studies, specific eligibility criteria are relevant to define the enrolled population, but highly selected populations are usually unrepresentative of clinical practice. Thus, external validity (i.e., generalizability or applicability) may be limited.

Previous publications have examined the relationship between recruitment criteria and generalizability of results (1–3). Generalizability depends largely on the characteristics of the enrollees, the trial setting, and the treatment regimens (4). Restrictive eligibility criteria have been a limiting factor for recruitment and applicability of results. A recent study showed that only 2% of a large psychiatric population was eligible for a psychopharmacologic study (1).

In spite of its rare incidence (∼1–2 per 10,000) (5), the disease burden of systemic sclerosis (SSc; scleroderma) is significant. For many aspects of SSc (e.g., pulmonary arterial hypertension [PAH] and renal crisis), treatments exist, but there is a large unmet need in terms of modifying the overall disease and treating some of its aspects, such as interstitial lung disease. Although an increasing number of RCTs within the past decade have investigated promising new treatments, ranging from endothelin receptor antagonists to antioxidants, the armamentarium for halting the progression of SSc remains limited. As new RCTs expand their list of exclusion criteria and tighten inclusion criteria compared with their predecessors, the number of patients that can benefit early from the use of new drugs may be decreasing. Such a design strategy selects for an ideal study patient, but not necessarily for one that will reflect the typical clinic patient with SSc. There are tradeoffs between trial validity and generalizability when the majority of patients have no proven treatment options.

The aims of this study were to determine the generalizability of RCTs in the treatment of SSc using the Canadian Scleroderma Research Group (CSRG) database, and to determine the statistical relationship between trial quality and generalizability. The specific hypotheses to be tested were that a very low percentage of patients with SSc are eligible for most RCTs, that generalizability of study results is lacking, and that there would be tradeoffs between trial quality and generalizability (i.e., less restrictive inclusion/exclusion criteria may allow for increased generalizability but may lessen trial quality).

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

The CSRG is a group of Canadian rheumatologists that has been enrolling patients with SSc from 14 centers since 2004. After consent, prospective data are collected. The CSRG database contains >1,850 variables, including sociodemographic questionnaires, disease activity, laboratory parameters, echocardiograms, pulmonary function tests, and damage measures. Our study used 438 patients with SSc; 82% were female, the mean ± SEM age was 55.4 ± 0.6 years, 40% had diffuse SSc, 50% had limited SSc (10% uncharacterized) with a mean ± SEM disease duration of 10.6 ± 0.4 years, and 43 (9.8%) had early diffuse SSc (<3 years duration). Thus, this is an all-inclusive database with mostly prevalent disease, which is compatible with the majority of people with longstanding SSc. This Canadian database seems to have more patients with limited and mild disease compared with some large US databases.

Articles related to SSc published from 1958 to 2006 (inclusive) were identified using the PubMed database (online at www.ncbi.nlm.nih.gov/entrez). Terms used in the PubMed searches (in various combinations) were: “scleroderma,” “systemic sclerosis,” “randomized controlled trial,” “arthritis,” “bosentan,” “calcinosis,” “chlorambucil,” “domperidone,” “D-penicillamine,” “erectile dysfunction,” “metoclopramide,” “methotrexate,” “myopathy,” “proton pump inhibitor,” “renal crisis,” “renal involvement,” “sildenafil,” “sitaxsentan,” “somatomedin,” “somatostatin,” and “Zelnorm.” Also, unpublished RCTs were sought to obtain protocols for inclusion/exclusion criteria. Only blinded (observer-blinded, single-blinded, or double-blinded) RCTs were selected from these searches. Articles were eliminated on the basis of the following exclusion criteria: not a primary research article, not an RCT, mixed population (not enough of the population having SSc), and/or not available in English. Due to the vast amount of literature available, especially in SSc associated with Raynaud's phenomenon (RP), some smaller trials were not included.

Two authors (RV and JEP) reviewed each trial independently in order to develop the final selection of articles. Trial quality was scored, and key points on trial design, including inclusion and exclusion criteria, were recorded.

The inclusion and exclusion criteria were used in conjunction with the CSRG database to determine the number of patients with SSc who would theoretically be eligible for these trials. In addition, articles were classified into subcategories according to the target system. In our study, criteria with >50% missing data from the CSRG database were censored, with 2 exceptions to this rule. We used echocardiography and right heart catheterization for PAH (49.1% of the CSRG database had echocardiogram results). Likewise, chest computed tomography (CT) scan is a standard diagnostic test for interstitial lung disease (ILD). We assumed that if a chest CT scan had not been performed, then significant ILD was not present because these tests were ordered when deemed clinically relevant.

If a trial stated that other drugs had to be withdrawn, then we assumed that patients would do this to increase recruitment (e.g., withdrawal of current vasodilatator for RP trials).

For each randomized trial, 4 items were used to evaluate quality of trial: double-blinded trial, sample size calculation, intention-to-treat analysis, and assessment by independent observer (4). Each variable was recorded as a 0 or a 1, where 0 = no and 1 = yes. Studies were scored from 0 to 4, and we categorized trials into 3 subsets: 0–1 = poor, 2 = passable, and 3–4 = good.

We obtained the percentage of patients eligible for each trial from the CSRG database by running all inclusion/exclusion criteria of each study through the database. Then, we calculated the mean percentage with 95% confidence intervals (95% CIs) of CSRG patients eligible for each organ system category. Given that each category had only a small number of observations, results in mean percentage of eligible patients with SSc provide only an approximation. Thus, we also calculated the median percentage with interquartile range (IQR). We completed analyses (percentage of eligible patients with SSc) for each subgroup of trial quality (good, passable, and poor), combining all trials, and for the largest trial subcategory (overall disease modification), which usually dealt with improvement in skin as the primary outcome measurement. Temporal trends in trial quality of SSc RCTs were also assessed. Nonparametric statistical tests were used to compare trial quality and the percentage of eligible patients.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

In total, 210 articles were evaluated and 73 were ultimately selected for inclusion in this study (refs.6–77, and Seibold JR et al: unpublished observations). Studies were divided into 7 subcategories: SSc associated with: RP (13 trials), digital ulcers (6 trials), gastrointestinal (GI) involvement (6 trials), overall disease modification (25 trials), PAH (13 trials), ILD (4 trials), and other categories (6 trials: 1 heart disease, 1 drug safety, 2 antioxidant, and 2 vascular reactivity). Table 1 describes the characteristics of the patients with SSc in the CSRG database and the median percentage of patients eligible for RCTs with respect to organ involvement.

Table 1. Characteristics of patients with SSc from the CSRG database (n = 438) compared with the median (%) of patients eligible for RCTs from our study analysis, classified by organ involvement*
CharacteristicsCSRG patientsEligible for RCTs, median (%)
  • *

    Values are the number (percentage) unless otherwise indicated. SSc = systemic sclerosis; CSRG = Canadian Scleroderma Research Group; RCT = randomized controlled trial; ACR = American College of Rheumatology; NYHA = New York Heart Association; PAP = pulmonary arterial pressure; CT = computed tomography.

  • PAP by echocardiogram >26 mm Hg; n = 192 (43.8%).

  • The majority of patients enrolled were in class III; some trials also included class II.

  • §

    Physician's definition; n = 78 (17.8%).

Female357 (81.5) 
Age, mean ± SEM years55.4 ± 0.6 
White363 (82.9) 
French Canadian80 (18.3) 
ACR criteria for scleroderma319 (72.8) 
Limited disease219 (50.0) 
Diffuse disease175 (40.0) 
Disease duration, mean ± SEM years10.6 ± 0.4 
NYHA  
 Class I194 (44.3) 
 Class II175 (40.0) 
 Class III38 (8.7) 
 Class IV6 (1.4) 
Raynaud's phenomenon407 (92.9)18.7
Digital ulcers  
 Current41 (9.4)12.1
 Ever273 (62.3) 
Gastrointestinal196 (44.7)35.4
Elevated PAP  
 NYHA I74 (16.9) 
 NYHA II89 (20.3) 
 NYHA III23 (5.3)5.7
 NYHA IV6 (1.4) 
Pulmonary arterial hypertension§  
 NYHA I16 (3.7) 
 NYHA II39 (8.9) 
 NYHA III16 (3.7)5.7
 NYHA IV6 (1.4) 
Interstitial lung disease  
 Abnormalities on CT scan52 (11.9)2.1
 Abnormalities on chest radiograph81 (18.5) 

The percentage of patients eligible for each category of trials is presented in Figure 1. Because data were occasionally non-normally distributed, medians were more representative than means for a few organ systems. Both results and trends were similar in mean and in median except for digital ulcers (24% [95% CI 1–47] using mean percentage versus 12% [IQR 41] using median), RP (35% [95% CI 17–53] using mean percentage versus 19% [IQR 37] using median), and GI (48% [95% CI 27–68] using mean percentage versus 35% [IQR 38] using median). SSc lung disease trials had the lowest generalizability (6% for PAH, 2% for ILD).

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Figure 1. Median % of patients eligible by categories of trials. Eligibility = % (with interquartile range) of patients with systemic sclerosis eligible from the Canadian Scleroderma Research Group database. ILD = interstitial lung disease; PAH = pulmonary arterial hypertension; DU = digital ulcers; RP = Raynaud's phenomenon; ODM = overall disease modification; OC = other categories; GI = gastrointestinal. Lines outside the boxes represent the highest and lowest non-outlier values.

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Seventy studies were assessed for quality of trial; 3 unpublished trials (for which we obtained the protocols) were excluded from this analysis (refs.61, 77, and Seibold JR et al: unpublished observation). Results demonstrated that good trial quality is related to a smaller percentage of eligible patients with SSc. Conversely, poor trial quality had better generalizability (Figure 2). Similar results were obtained from the analysis of the largest subgroup (overall disease modification, 24 published trials) (Figure 3). The difference between good and poor quality was statistically significant in both analyses (P = 0.002 for all trials; P = 0.04 for the overall disease modification subgroup). We also noticed that trial quality has improved over time (P < 0.001) (Figure 4).

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Figure 2. Median % of patients eligible by quality of trial for all results. Eligibility = % (with interquartile range) of patients with systemic sclerosis eligible from the Canadian Scleroderma Research Group database. Lines outside the boxes represent the highest and lowest non-outlier values.

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thumbnail image

Figure 3. Median % of patients eligible by quality of trial for overall disease modification subgroup. Eligibility = % (with interquartile range) of patients with systemic sclerosis eligible from the Canadian Scleroderma Research Group database. Lines outside the boxes represent the highest and lowest non-outlier values.

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thumbnail image

Figure 4. Quality of trial by publication date. Dark bars = good quality, shaded bars = passable quality, and light bars = poor quality.

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Reasons for exclusion varied. In order to not bias against maximal trial recruitment in the published studies, we assumed that patients would cease taking conflicting medications, that patients would practice contraception, and that laboratory abnormalities would not be used as excluding factors to create a “best-case” scenario. Thus, the major reasons for exclusion were lack of significant target organ involvement (e.g., class III PAH) or disease duration (e.g., ILD) and subset (e.g., some disease modification trials allowed only early diffuse SSc or a minimum skin score). For RP, the frequency of attacks or disease severity limited potential eligibility, and the GI RCTs were primarily in a disease subset (diffuse SSc).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

In this study, we provide evidence that the generalizability of most SSc RCTs is very low, as demonstrated by a low percentage of patients being eligible for most studies despite common involvement of many systems. For instance, >90% of patients with SSc have RP, nearly all have gastroesophageal reflux or other bowel dysmotility, as many as one-quarter may have abnormal pulmonary arterial pressure as estimated by echocardiography (78), and one-third may have pulmonary fibrosis. Our results indicate that the past and current design of RCTs for the evaluation of SSc treatments is failing to provide the majority of patients with clinically significant options for improvement in their disease state. Eligibility for RCTs ranges from 2–48%. Our finding is not an isolated case in the literature. Khan et al (1) reported that only 2% of a target population of 36,000 was eligible in a psychiatric drug trial. Similar results have been reported in oncology (79, 80). Also, we noticed that more recent RCTs (in ILD and PAH) have a larger exclusion list, and therefore the generalizability is decreased for studies in these serious complications of SSc (Figure 1). The same phenomenon has been observed in cancer trials (81).

Given that SSc is a relatively rare disease (5, 82), recruitment for research might be difficult. A complex screening process with restrictive eligibility criteria affects the applicability of results in clinical practice. Furthermore, in the current study we found that depending on the category of the trial, investigators must screen up to 50 people to identify 1 potential enrollee if serial patients are used. Gross et al (2) have found that the number needed to screen for each potential participant varied widely across studies, ranging from 1 to 68 for various RCTs. In fact, stringent eligibility criteria are often used to prevent adverse events and to minimize the number of nonresponders. Some authors state that for effectiveness trials, eligibility criteria must allow heterogeneity reflecting the real external population (83). Most studies, however, are not effectiveness trials but efficacy trials conducted under strict conditions. Also, results under real-world conditions may be different (e.g., less effect, more risks).

Our study shows an obvious inverse relationship between trial quality and ability to include more patients with SSc (Figure 2). In general, studies that were eligible to more patients with SSc had less trial quality, confirming the tradeoffs between unmet need (generalizability) and highly-selected inclusion/exclusion criteria (P = 0.002). We defined 4 quality criteria based on several existing publications (4, 84, 85). We did not use dropout because many small studies had short periods of observation; therefore, their dropout rates were relatively low.

Some data from the CSRG database were missing and some inclusion/exclusion criteria were not available in the database. For instance, many patients have not had a right heart catheterization or a 6-minute walk test. We decided to include criteria with ≥50% available data in order to minimize this potential bias, except for trials in PAH and ILD because invasive tests like right heart catheterization are done when PAH is suspected and lung CT scans are not done routinely on all patients. However, only high-resolution CT scan and PAH investigations had >50% missing data. Thus, our data were a best-case scenario of generalizability. We assumed patients' comorbidity, other medications, and laboratory outlying values would not exclude them, so the percentage of patients eligible is an overestimate. Also, in general, some eligible patients do not enter RCTs due to lack of consent, long distances to travel, and other reasons.

As discussed previously, recruitment information and eligibility criteria are important tools with which to evaluate the internal validity of a study's design and its applicability in clinical practice (external validity or generalizability). Previous studies reported that investigators frequently provided incomplete eligibility criteria (2, 86). Given that our analyses were based on inclusion/exclusion criteria reported from each trial, our results might be further overestimated.

A possible explanation for low generalizability of SSc RCTs is that SSc is heterogeneous, with a wide spectrum of manifestations. For instance, most patients with SSc have RP or GI involvement, but most do not have severe ILD and only a small minority have ever had scleroderma renal crisis. In addition, our Canadian population may have milder SSc, possibly due to under-representation of certain ethnicities and use of both SSc referral centers and general rheumatologists' practices.

In summary, except for GI trials, <38% of patients with SSc from the CSRG would be allowed into RCTs. SSc lung disease studies had the least generalizability. We need RCTs designed to include many patients with SSc without compromising good trial quality because there is a large burden of disease, and trials do not usually include the majority of patients. This goal could be achieved by including patients with less severe organ involvement. For instance, some PAH trials included patients with SSc who were in the World Health Organization criteria class II, allowing for presence of an affected organ that does not have as much involvement and has potential for reversibility, thus possibly improving outcome and producing results applicable to more patients with SSc.

To our knowledge, this is the first study to illustrate the large unmet need in SSc through systematic analysis of multiple RCTs and comparison of inclusion/exclusion criteria to real patients with SSc in a large database. It also demonstrates the tradeoffs between trial quality and patient eligibility in SSc trials to date. We recommend that those developing RCTs in SSc remove unnecessary inclusion/exclusion criteria and consider the unmet need, especially for patients with clinically relevant organ manifestations who are not currently eligible for trials. The first priority should still be internal validity and enrollment of patients who may have the ability to be treatment-responsive. However, a research population should be reflective of the patients anticipated to be prescribed the intervention in clinical practice.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Dr. Pope had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Villela, Yuen, Pope.

Acquisition of data. Villela, Yuen, Baron.

Analysis and interpretation of data. Yuen, Pope.

Manuscript preparation. Villela, Yuen, Pope.

Statistical analysis. Yuen.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
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