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Agreement between the results of meta-analyses from case reports and from clinical studies regarding the efficacy of laronidase therapy in patients with mucopolysaccharidosis type I who initiated enzyme replacement therapy in adult age: An example of case reports meta-analyses as an useful tool for evidence-based medicine in rare diseases

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Highlights

  • Case reports and clinical studies meta-analyses obtained equivalent results when evaluating laronidase therapy efficacy.

  • Case reports showed a greater agreement with clinical studies meta-analysis when only well-defined outcomes were considered. The results from aggregating case reports were more valid when only well-defined outcomes were considered.

  • Case reports have a prominent role in the rare diseases field and increasingly, in other areas of personalized medicine.

Abstract

Background

Case reports might have a prominent role in the rare diseases field, due to the small number of patients affected by one such disease. A previous systematic review regarding the efficacy of laronidase therapy in patients with mucopolysaccharidosis type I (MPS-I) who initiated enzyme replacement therapy (ERT) in adult age has been published. The review included a meta-analysis of 19 clinical studies and the description of eleven case reports. It was of interest to perform a meta-analysis of those case reports to explore the role of such meta-analyses as a tool for evidence-based medicine in rare diseases.

Methods

The study included all case reports with standard treatment regimen. Primary analysis was the percentage of case reports showing an improvement in a specific outcome. Only when that percentage was statistically higher than 5%, the improvement was confirmed as such. The outcomes that accomplished this criterion were ranked and compared to the GRADE criteria obtained by those same outcomes in the previous meta-analysis of clinical studies.

Results

There were three outcomes that had a significant improvement: Urine glycosaminoglycans, liver volume and 6-minute walking test. Positive and negative predictive values, sensitivity and specificity for the results of the meta-analysis of case reports as compared to that of clinical studies were 100%, 88.9%, 75% and 100%, respectively. Accordingly, absolute (Rho = 0.82, 95%CI: 0.47 to 0.95) and relative agreement (Kappa = 0.79, 95%CI: 0.593 to 0.99) between the number of case reports with improvement in a specific outcome and the GRADE evidence score for that outcome were good. Sensitivity analysis showed that agreement between the meta-analysis of case reports and that of the clinical studies were good only when using a strong confirmatory strategy for outcome improvement in case reports.

Conclusions

We found an agreement between the results of meta-analyses from case reports and from clinical studies in the efficacy of laronidase therapy in patients with MPS-I who initiated ERT in adult age. This agreement suggests that combining case reports quantitatively, rather than analyzing them separately or qualitatively, may improve conclusions in the field of rare diseases.

Introduction

Evidence-based medicine considers that randomized clinical trials (RCTs) provide the strongest evidence regarding the efficacy of new treatments in patients with a specific disease. On the other hand, case reports are considered as hypothesis generators with lower level grade of evidence [1].

However, RCTs can be more difficult to run for rare diseases due to lack of patients to be enrolled. In this case, the search for clinical knowledge regarding efficacy of pharmacological treatments and other kind of interventions may be based on observational studies and case reports.

In fact, there are situations in which non-controlled studies provide evidence of the same high quality as that provided by RCTs [2]. As an example, a study conducted with 189 phase 3 trials testing systemic cancer therapy, which cited phase 2 trials supporting the experimental arm, concluded that randomized controlled trials were not superior to single-arm trials predicting phase 3 study success [3].

Some publications consider case report research in rare diseases the lesser evil option, justified by the lack of patients and by case reports often being the first evidence of the effectiveness of a new therapy or new indication [4]. Due to their prominent role in rare diseases and their richness in details, there is an increasing interest in case reports analysis and in aggregating their results in systematic reviews [5], [6].

Although journals and publishers are beginning to develop case reports databases and there are recent initiatives to homogenize and upgrade quality of the information published in case reports (CARE guidelines) [7], questions related to how to aggregate them in ways that are meaningful remain unclear [6].

The efficacy of starting enzyme replacement therapy (ERT) in adults with Mucopolysaccharidosis type I (MPS-I) is controversial. A previous systematic review in MPS-I patients with ERT initiated in adult age (≥ 18 years) has been published [8]. The study combined results from 19 clinical studies selected to determine which endpoints improved after ERT was initiated in adult age. Twelve case reports were also described, but only the results of clinical studies were combined and graded in a meta-analysis. The aim of the present study is to assess the agreement between the results of the meta-analysis of those case reports and that of the clinical studies. As a secondary objective, we explored the role of meta-analyses of case reports as a tool for evidence-based medicine in rare diseases.

Section snippets

Data sources and study selection

A comprehensive search of journal articles and congress communications containing information on effectiveness of ERT for adult patients (≥ 18 years) with MPS-I (Hurler-Scheie syndrome and Scheie's syndrome) up to July 2016 was previously published [8], in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [9]. The original papers were reviewed to select those meeting the following inclusion criteria: a) Studies conducted in patients with

Results

As previously mentioned there was a total of 11 case reports. Nine case reports described ERT administration at standard dose (100 UI/kg body weight administered once every week) and standard administration via (intravenous), one analyzed the effect of ERT on a pregnant woman [14], and the last one, the effects of treatment discontinuation (due to pregnancy) [14], [15]. The other two clinical reports analyzed the effect of ERT using different doses or administration via than the usual ones: One

Discussion

The diseases that meet the criterion of being rare are not limited to certain groups of genetic diseases traditionally known as such. The personalized medicine based on the developments of molecular diagnosis and genomic analysis has fragmented complex diseases into multiple molecular subtypes or strata [28]. In this regard, subtypes of different cancers would individually represent a rare disease [29]. Therefore, research methods derived from rare diseases, will become increasingly important

Conclusions

We found an agreement between the results from case reports- and clinical studies-meta-analyses in the efficacy of laronidase therapy in patients with MPS-I who initiated enzyme replacement therapy in adult age. We suggest that combining quantitatively results from case reports (confirmed with a strong confirmatory method), rather than analyzing them separately or qualitatively, can improve conclusions extracted regarding the effect of treatment. Therefore, case reports meta-analyses might help

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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