BackgroundClinical trials in rare diseases are more challenging than trials in frequent diseases. Small numbers of eligible trial participants, often complicated by heterogeneity among rare disease patients, hamper the design and conduct of a ‘classical’ Randomized Controlled Trial. Therefore, novel designs are developed by statisticians. However, it is important to be aware of possible design aspects that may jeopardize the feasibility of trial conduct. If the burden of participation is considered out of proportion by patients or parents, recruitment may fail or participants may drop out before trial completion. In order to maximize the chance of success of trials in small populations, it is important to know which aspects of trial design are considered important by patients.ResultsWe have interviewed all ten members of the Patient Think Tank (PTT) of the ASTERIX project, a European research consortium on methodology for clinical trials in small populations. The PTT members are rare disease patient representatives who have completed extensive training in clinical trial methodology. We have analyzed the interviews qualitatively according to Grounded Theory using a thematic analysis, and we structured the topics in four chronologically ordered themes: 1. Involvement in trial design; 2. Opinions on trial design; 3. Trial participation; 4. Phase after the trial. Our main findings are that the PTT-members recommend that patients are involved in trial design from an early stage on, and have influence on the outcomes and measurement instruments that are chosen in the trial, the length of the study, the choice of participants, and the information that is sent to potential participants. Also, according to the PTT-members, patient groups should consider setting up disease registries, placebo groups should be minimized, and more education on clinical trials is advised.ConclusionsRare disease patient representatives who have been educated about clinical trial methodology think it is important to involve patient representatives in research at an early stage. They can be of advice in trial design in such a way that the ratio of potential benefit and burden of trial participation as well as the chosen outcome measures and in- and exclusion criteria are optimized.Electronic supplementary materialThe online version of this article (10.1186/s13023-019-1002-z) contains supplementary material, which is available to authorized users.

BackgroundGoal Attainment Scaling (GAS) is an instrument that is intended to evaluate the effect of an intervention by assessing change in daily life activities on an individual basis. However, GAS has not been validated adequately in an RCT setting. In this paper we propose a conceptual validation plan of GAS in the setting of rare disease drug trials, and describe a hypothetical trial where GAS could be validated.MethodsWe have used the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) taxonomy to deduce which measurement properties of GAS can be evaluated, and how. As individual GAS scores cannot be interpreted outside the context of a RCT, the validation of GAS needs to be done on trial as well as on individual level.ResultsThe procedure of GAS consists of three steps. For the step of goal selection (step 1) and definition of levels of attainment (step 2), face validity may be assessed by clinical experts. For the evaluation of the goal attainment (step 3), the inter and intra rater reliability can be evaluated on an individual level. Construct validity may be evaluated by comparison with change scores on other instruments measuring in the same domain as particular goals, if available, and by testing hypotheses about differences between groups. A difference in mean GAS scores between a group who received an efficacious intervention and a control group is an indication of well-chosen goals, and corroborates construct validity of GAS on trial level. Responsiveness of GAS cannot be evaluated due to the nature of the construct being assessed.ConclusionGAS may be useful as an instrument to assess functional change as an outcome measure in heterogeneous chronic rare diseases, but it can only be interpreted and validated when used in RCTs with blinded outcome assessment. This proposed theoretical validation plan can be used as a starting point to validate GAS in specific conditions.

BackgroundLow prevalence, lack of knowledge about the disease course, and phenotype heterogeneity hamper the development of drugs for rare diseases. Rare disease registries (RDRs) can be helpful by playing a role in understanding the course of the disease, and providing information necessary for clinical trial design, if designed and maintained properly. We describe the potential applications of a RDR and what type of information should be incorporated to support the design of clinical trials in the process of drug development, based on a broad inventory of registry experience. We evaluated two existing RDRs in more detail to check the completeness of these RDRs for trial design.ResultsBefore and during the application for regulatory approval a RDR can improve the efficiency and quality in clinical trial design by informing the sample size calculation and expected disease course. In exceptional circumstances information from RDRs has been used as historical controls for a one-armed clinical trial, and high quality RDRs may be used for registry-based randomized controlled trials. In the post marketing phase of (conditional) drug approval a disease-specific RDR is likely to provide more relevant information than a product-specific registry.ConclusionsA RDR can be very helpful to improve the efficiency and quality of clinical trial design in several ways. To enable the applicability and optimal use of a RDR longitudinal data collection is indispensable, and specific data collection, prepared for repeated measurement, is needed. The developed checklist can help to define the appropriate variables to include. Attention should be paid to the inclusion of patient-relevant outcome measures in the RDR from the start. More research and experience is needed on the possibilities and limitations of combining RDR information with clinical trial data to maximize the availability of relevant evidence for regulatory decisions in rare diseases.

BackgroundOne of the main challenges for drug evaluation in rare diseases is the often heterogeneous course of these diseases. Traditional outcome measures may not be applicable for all patients, when they are in different stages of their disease. For instance, in Duchenne Muscular Dystrophy, the Six Minute Walk Test is often used to evaluate potential new treatments, whereas this outcome is irrelevant for patients who are already in a wheelchair. A measurement instrument such as Goal Attainment Scaling (GAS) can evaluate the effect of an intervention on an individual basis, and may be able to include patients even when they are in different stages of their disease. It allows patients to set individual goals, together with their treating professional. However, the validity of GAS as a measurement instrument in drug studies has never been systematically reviewed. Therefore, we have performed a systematic review to answer two questions: 1. Has GAS been used as a measurement instrument in drug studies? 2: What is known of the validity, responsiveness and inter- and intra-rater reliability of GAS, particularly in drug trials?MethodsWe set up a sensitive search that yielded 3818 abstracts. After careful screening, data-extraction was executed for 58 selected articles.ResultsOf the 58 selected articles, 38 articles described drug studies where GAS was used as an outcome measure, and 20 articles described measurement properties of GAS in other settings. The results show that validity, responsiveness and reliability of GAS in drug studies have hardly been investigated. The quality of the reporting of validity in studies in which GAS was used to evaluate a non-drug intervention also leaves much room for improvement.ConclusionsWe conclude that there is insufficient information to assess the validity of GAS, due to the poor quality of the validity studies. Therefore, we think that GAS needs further validation in drug studies, especially since GAS can be a potential solution when a small heterogeneous patient group is all there is to test a promising new drug.Trial registrationThe protocol has been registered in the PROSPERO international prospective register for systematic reviews, with registration number CRD42014010619. http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014010619.Electronic supplementary materialThe online version of this article (doi:10.1186/s12874-016-0205-4) contains supplementary material, which is available to authorized users.

Goal Attainment Scaling is an assessment instrument to evaluate interventions on the basis of individual, patient-specific goals. The attainment of these goals is mapped in a pre-specified way to attainment levels on an ordinal scale, which is common to all goals. This approach is patient-centred and allows one to integrate the outcomes of patients with very heterogeneous symptoms. The latter is of particular importance in clinical trials in rare diseases because it enables larger sample sizes by including a broader patient population. In this paper, we focus on the statistical analysis of Goal Attainment Scaling outcomes for the comparison of two treatments in randomised clinical trials. Building on a general statistical model, we investigate the properties of different hypothesis testing approaches. Additionally, we propose a latent variable approach to generate Goal Attainment Scaling data in a simulation study, to assess the impact of model parameters such as the number of goals per patient and their correlation, the choice of discretisation thresholds and the type of design (parallel group or cross-over). Based on our findings, we give recommendations for the design of clinical trials with a Goal Attainment Scaling endpoint. Furthermore, we discuss an application of Goal Attainment Scaling in a clinical trial in mastocytosis.

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