Composite endpoints, including patient reported outcomes, in rare diseases

Abstract

Background: When assessing the efficacy of a treatment in any clinical trial, it is recommended by the International Conference on Harmonisation to select a single meaningful endpoint. However, a single endpoint is often not sufficient to reflect the full clinical benefit of a treatment in multifaceted diseases, which is often the case in rare diseases. Therefore, the use of a combination of several clinically meaningful outcomes is preferred. Many methodologies that allow for combining outcomes in a so-called composite endpoint are however limited in a number of ways, not in the least in the number and type of outcomes that can be combined and in the poor small-sample properties. Moreover, patient reported outcomes, such as quality of life, often cannot be integrated in a composite analysis, in spite of their intrinsic value.

Results: Recently, a class of non-parametric generalized pairwise comparisons tests have been proposed, which members do allow for any number and type of outcomes, including patient reported outcomes. The class enjoys good small-sample properties. Moreover, this very flexible class of methods allows for prioritizing the outcomes by clinical severity, allows for matched designs and for adding a threshold of clinical relevance. Our aim is to introduce the generalized pairwise comparison ideas and concepts for rare disease clinical trial analysis, and demonstrate their benefit in a post-hoc analysis of a small-sample trial in epidermolysis bullosa. More precisely, we will include a patient relevant outcome (Quality of life), in a composite endpoint. This publication is part of the European Joint Programme on Rare Diseases (EJP RD) series on innovative methodologies for rare diseases clinical trials, which is based on the webinars presented within the educational activity of EJP RD. This publication covers the webinar topic on composite endpoints in rare diseases and includes participants' response to a questionnaire on this topic.

Conclusions: Generalized pairwise comparisons is a promising statistical methodology for evaluating any type of composite endpoints in rare disease trials and may allow a better evaluation of therapy efficacy including patients reported outcomes in addition to outcomes related to the diseases signs and symptoms.

Keywords: Composite endpoints; EJP-RD; Epidermolysis bullosa; Generalized pairwise comparisons; Patient reported outcomes; Quality of life; Rare disease.

Fig. 1

QoL difference between start and end of the treatment in the EBS trial over both treatment periods (left) and by each treatment period (right)

Fig. 2

Responses of the participants to the EJP RD webinar (n = 65) to the question: What is your experience to define a single meaningful endpoint for the study of a disease?

Fig. 3

Responses of the participants to the EJP RD webinar (n = 65) to the question: What is your preferred method to handle multiple endpoints?

Fig. 4

Responses of the participants to the EJP RD webinar (n = 65) to the question: What are the limitations you encounter with multiple endpoint analyses?

Fig. 5

Three examples of pairwise comparisons of a composite prioritized GPC, with 40% reduction in blister prioritized over the difference in QoL. The pairwise comparison is initiated on the blister outcome. If a subject with a better outcome is assigned (example 1) the QoL outcome is not evaluated. Only when the better outcome cannot be decided on the blister outcome (example 2 and 3) the QoL outcome is compared. If both subjects have equal values in each outcome, the pair is considered a tie (example 3). T= Experimental treatment and C= Control treatment

Fig. 6

Responses of the participants to the EJP RD webinar (n = 65) to the question: How often is, in your experience, a patient relevant outcome, such as quality of life, important for the evaluation of a treatment effect?