gms | German Medical Science

Introduction: Rare diseases, also referred to as orphan diseases, are illnesses that affect a predefined small proportion of the population. No single cut-off number has been agreed upon for which a disease is considered rare and, not surprisingly, various definitions for rare diseases do exist. For example, the European Commission defines the prevalence for a rare disease as affecting no more than 5 per 10 000 persons in the European Union (EU) [1]. It is estimated that at present in the EU, 5000-8000 distinct rare diseases affect 6-8% of the population, that is, between 27 and 36 million people [2]. Hence, rare diseases create an enormous health and economic burden and research on these deserves considerable attention.

About 80% of rare diseases have a genetic basis and onset is often in childhood and adolescence. Many rare conditions have neurological manifestations [3], of which two prominent examples are paediatric multiple sclerosis (MS) and Creutzfeldt-Jakob disease (CJD). The estimated prevalence of CJD is 1-9 cases per 1,000,000 people [4]. Multiple sclerosis has an estimated prevalence of 1 individual in 170 to 4000 persons and is therefore not rare [5]. Its onset is usually in adult life but in 3-5% of cases MS manifests before the age of 18 years [6]. This paediatric form qualifies as a rare disease.

The purpose of the present paper is to review evaluations of therapeutic interventions in paediatric MS and CJD as two prominent examples of rare conditions. Instead of summarizing the evidence in a narrative fashion, we provide a systematic review that is the result of applying an explicit, rigorous and reproducible logic. The focus has been on obtaining a qualitative synthesis of the evidence from a methodological perspective. In particular, in view of the paucity of a large number of patients that are available for conducting clinical trials for paediatric MS and CJD, we aim to shed light on the implemented study designs for investigating the endpoints of interest, the statistical methodologies applied to analyse the patient collectives and the obtained outcomes of the interventions.

Methods: Literature searches using the database PubMed were carried out to identify relevant primary studies for the illnesses under investigation. Reference lists in all publications that were found to be of relevance were examined for further suitable studies. Studies with less than twenty patients in the intervention group were discarded. The following items were extracted from the studies: reference, study design, objectives, endpoints, patient characteristics, randomization and masking, type of intervention, control, withdrawals, statistical methodology and outcomes. The quality of the selected primary studies has been classified according to the scheme of the American Academy of Neurology for assigning levels of evidence [7]. In addition, randomized controlled trials have been assessed by means of the Oxford quality scoring system [8]. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement [9] guided the writing up of the systematic reviews.

Results: Twelve (seven) primary studies on paediatric MS (CJD) were included in the qualitative synthesis. The relapse-remitting course is the overwhelming manifestation in early-onset MS. Disease-modifying therapies that were successfully tested for adults such as interferon-beta therapy are used off-label in patients who are younger than 18 years. No double-blind, randomized placebo-controlled trial for evaluating interventions in paediatric MS has been published yet. Evidence from one randomized controlled trial (RCT) with a total sample size of sixteen patients is available but the RCT lacks appropriate blindness and the patients in the control group receive no treatment of any kind. Five of the eleven observational studies are controlled trials including natural history controls or patients serving as their own controls, whereas six studies do not contain a control group. The typical endpoints under investigation are changes in the annualized relapse rate (ARR) and in the expanded disability status scale (EDSS) score. Studies also verify whether the offered treatment is safe and well tolerated in children and adolescent patients. Comparisons between pre- and post-treatment status were mostly done with parametric or nonparametric two-sample tests. Some studies only use descriptive measures, e.g. comparing frequencies, to evaluate intervention effects. Most studies found that treatment reduced the relapse rate and disease progression.

Creutzfeldt-Jakob disease, of which a number of subtypes do exist, is a fatal, untreatable prion encephalopathy. Treatment is aimed at alleviating symptoms and making the patient as comfortable as possible. Three of the seven selected studies are RCTs, of which two received the maximum mark on the Oxford quality scale. Four trials are controlled observational studies. All studies investigate time-to-event endpoints such as time from randomization to death. Kaplan-Meier estimates and log-rank tests were used to compare the survivor functions of patients in the two treatment groups. Cox models were applied to analyse the effect of covariates on the survival experience. One RCT shows that doxycyline does not prolong survival in patients with CJD, contradicting previously published evidence arising from some observational studies.

Discussion: In light of the lack of any class I level evidence on the effects of therapeutic interventions that is available in the paediatric MS population, it would be desirable to design and conduct an RCT for this subgroup of patients. However, there is lack of clarity on how to design and conduct an RCT in the paediatric MS population, given the small numbers of patients in childhood and adolescence as well as general ethical and practical challenges of paediatric studies. In such situations methods that incorporate data from other sources onto the estimation of the treatment effects may be beneficial. Information external to the study that can be used on the experimental and control arms could stem, for example, from related patient populations such as adults or from expert knowledge elicitation.

Acknowledgement: This research has received funding from the EU‘s 7th Framework Programme for research, technological development and demonstration under grant agreement number FP HEALTH 2013 – 602144 with project title (acronym) „Innovative methodology for small populations research“ (InSPiRe).