Are OMERACT recommendations followed in clinical trials on fibromyalgia? A systematic review of patient-reported outcomes and their measures

Fibromyalgia is a chronic pain condition characterized by pain in various areas of the body and other symptoms such as fatigue or concentration problems. There are no established laboratory values or examination techniques for detecting or monitoring the disease, which is why patient-reported outcomes (PROs) are particularly important. A PRO is a health outcome, such as the severity of depression or pain, self-reported by the patient who experienced it. The Outcome Measures in Rheumatology (OMERACT) initiative recommended assessing PROs in clinical studies on fibromyalgia to determine whether a treatment was successful. The Patient-Reported Outcome Measurement Information System® (PROMIS®) initiative provides “generic” measures of PROs (PRO measures, PROMs) that can be used in many conditions including the rheumatologic ones. The aim of this study was to investigate which PROs were assessed in clinical trials on fibromyalgia and which PROMs were used to assess each PRO. In addition, we aimed to find out how current practice of PRO assessment corresponds to the recommendations by OMERACT and PROMIS.

To achieve this goal, we looked at 107 different publications from 105 different studies on fibromyalgia patients. We found that the majority of PROs recommended by OMERACT were captured in these studies, but only few studies met the recommendations in full. Most of the studies included PROs that reflect the general PROMIS health domains. Noteworthy, many different PROMs were used for assessing the same PROs. These results suggest that while there is consensus on the use of PROs, there is still a long way to go towards standardizing the instruments used.

Fibromyalgia (FM) is a chronic health condition that severely affects various areas of health-related quality of life (HRQoL) including physical, social, and emotional well-being. Due to the wide variety of clinical phenotypes and due to the unavailability of biomedical markers, treatment monitoring poses a significant challenge. Therefore, recommendations emphasize assessing patient-reported outcomes (PROs) as the most informative and efficient way of determining, whether a patient's health has deteriorated, remained the same, or improved over time during treatment. Unlike for many other chronic health conditions[1] there is to date no consensus on a specific set of PRO measures (PROMs) for fibromyalgia that should be used in research or clinical settings, which complicates the comparability across clinical settings and studies[2]. Limited comparability of outcome measures, for example, renders pooling of data in meta-analyses inconvenient and increases the risk of bias [3, 4]. To capture the current practice of outcome assessment in clinical trials, in the present study we aim to collect information on domains and instruments that have been used in previous studies.

In an effort of standardization, the Outcome Measures in Rheumatology (OMERACT) initiative has suggested various core sets of outcome measures that allow for better comparison across clinical trial results in Rheumatology. The outcome set for FM was introduced in 2009 [5] and includes groups of domains that should be assessed with graded priority: pain, tenderness, fatigue, patient global health, multidimensional function, and sleep disturbance were regarded as mandatory for all clinical trials, whereas depression and cognitive dysfunction may be assessed in some FM trials. Stiffness and anxiety, as well as the non-PRO markers cerebrospinal fluid biomarkers and functional imaging were regarded as optional for research purposes [6]. In accordance with the general OMERACT approach, the core set does not include recommendations for one specific instrument per domain. Instead, the OMERACT working group suggested a variety of instruments per domain that meet predefined quality criteria [6]. Many instruments have been designed for disease-specific application. That is, the questions are specific for FM and these instruments cannot be used in other (rheumatological) conditions.

The most widely used disease-specific instrument for FM is the Fibromyalgia Impact Questionnaire (FIQ), which covers many of the domains that are relevant for FM patients. The first version was introduced in 1991 and several revised versions have been developed since then [7]. This version covers a broad range of domains including physical functioning, work status, depression, anxiety, sleep, pain, stiffness, fatigue, and well-being as described by the author [7]. In 1997 and 2002, modifications regarding the scoring were implemented [8]. The revised FIQ (FIQ-R), published in 2009, additionally covers the domains memory, tenderness, balance, and environmental sensitivity [9]. The FIQ and its revised versions have been translated into several languages and it has been used in trials around the globe.

In recent years, a more generic approach to PRO measurement has been increasingly favoured, where disease-independent instruments are preferred over disease-specific ones. The U.S. National Institutes of Health funded Patient-Reported Outcome Measurement Information System® (PROMIS®), for example, has introduced a framework of health domains with the aim of standardizing health outcomes [10]. PROMIS core domains include physical, emotional, and social health aspects, which are relevant for almost every health condition including rheumatologic diseases such as FM. PROMIS has invested great efforts in developing psychometrically sound and efficient PROMs for each domain which is why it has been increasingly used in many clinical and research settings in recent years. A great advantage of the PROMIS approach is that conventional “legacy” instruments can be linked to the PROMIS metric, which facilitates comparability across different measurement systems [11, 12]. The metric used by PROMIS is the T-Score metric where 50 reflects the population average with a standard deviation of 10 [13].

In the present review, we investigate which PROs were selected as treatment outcomes and which PROMs were used to assess these outcomes in clinical trials of FM patients since 2015. We compare the selection of domains and instruments in these studies to the OMERACT recommendations [5]. Furthermore, we investigate whether the assessed domains were covered by a generic health assessment (i.e. PROMIS Profile). The PROMIS 29 profile covers eight health domains: anxiety, depression, pain intensity, pain interference, physical function, ability to participate in social roles and activities, sleep disturbance, and fatigue [10, 14]. These primary objectives were augmented by some more specific questions that were deemed relevant for PRO assessment and reporting of FM studies. Guidelines of the American Psychological Associations recommend including key psychometric information for each instrument in publications [15, 16]. Thus, we examined whether validity and reliability data on instruments provided in the articles are included in this systematic review. Moreover, motivated by the frequent use of the FIQ in FM trials, we investigate the use and interpretation of different versions of the FIQ in detail. Finally, we evaluate whether the studies included instruments that would allow determining the health state utilities (HSU) of the intervention under investigation. Data from clinical trials are increasingly used for evaluating the health utility of new treatments in secondary analyses. Thus, assessment of instruments that can be used for these analyses is deemed important. Preference-based PROs, such as the EQ-5D and the SF-6D, can not only be used to describe HRQoL but also to measure HSU for quality-adjusted life years (QALY) in the economic evaluations of treatments[17].

The overarching goal of this systematic review is to provide a substantial overview on the current practice of PRO assessment in clinical trials in FM patients in order to indicate a potential need for further standardization of outcome assessment in this population. Advancing standardization is essential to ensure better comparability of treatment outcomes across studies and settings.

We report our results in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines as well as with the Cochrane Recommendation for Systematic Reviews [18]. Graphics were created using Microsoft Word 2019 and Microsoft Power Point 2019.

In this systematic review we examined the selection of PROs and PROMs in (randomized) controlled trials that were published since 2015. We found that most of the studies assessed the majority of the domains that have been recommended by OMERACT. Only a minority of studies, however, followed these recommendations in full. In addition, the results show great heterogeneity in the use of PROMs across studies which reduces comparability of outcomes between these studies.

The most frequently covered domains were pain and depression. The heterogeneity and number of domains and instruments collected in FM trials were somewhat surprising. Across all included studies, 50 different PRO domains were measured by as much as 126 different instruments. Only 12 of these 50 domains were recommended by OMERACT, whereas 38 were not [5]. Whereas 18 of 50 domains were only measured once, most domains were assessed in several studies. This pronounced heterogeneity in the assessment of PROs in FM might have several reasons. First, there is still disagreement among researchers on how FM is best defined and classified [132]. Researchers who chose to use the ACR 1990 criteria, for example, might have felt that the existence of trigger points is important in FM, whereas researchers who preferred using the ACR 2010 criteria might have intended to emphasize that FM is accompanied by psychological and social problems [132]. Second, many researchers may not be aware of recommendations such as the OMERACT recommendations or do not agree with those. Third, researchers tend to use instruments that they are familiar with and that are available in their language. Fourth, the selection of the instruments and domains also clearly depends on the specific aims of the studies.

Across the investigated studies, the OMERACT recommendations were followed to varying degrees. For example, the prioritization of different layers of core domains as suggested by OMERACT does not translate to the use of domains in the studies. Most studies failed to include all mandatory domains, because tenderness was only assessed in about 17% of the studies. Remarkably, several studies preferred assessing domains that were deemed less important. In addition, a wide variety of standalone domains that were not recommended at all by OMERACT were collected.

The FIQ was by far the most frequently administered disease-specific instrument. This is not surprising because the FIQ is probably the most widely used FM instrument, it has demonstrated good psychometric properties, and it is available in several languages [8, 9, 133‐136]. In addition, in its revised version, it covers many aspects of the most recent classifications. Disease-specific instruments have the advantage of focussing on aspects of a disease that are most relevant to a particular condition. Given the trend towards standardization of health outcomes, however, there are also reasons against using disease-specific instruments because the resulting scores are not easily comparable to other similar HRQOL instruments. This renders comparisons across different (similar) diseases—such as across pain conditions—inconvenient [137]. In addition, using generic health assessments may help clinicians integrate the effects of multiple conditions [138]. Maybe the most prominent example are the instruments provided by the PROMIS initiative, which allow flexible and precise assessment. The results of the present review demonstrate that the majority of domains that were assessed in the included studies were covered by the domains of the PROMIS Profile, an increasingly widely used generic health instrument.

One of the questions that motivated this study was whether instruments were used that would allow secondary cost-effectiveness analyses. These analyses are required if healthcare systems are re-modelled towards value-based healthcare [139]. We found that while about 45% of our studies used the SF-36, an instrument that can be used to calculate the preference-based HSU score of the SF-6D, only 7.6% used the EQ-5D, which is most widely used for cost-effectiveness analyses [17]. The EQ-5D measures coarsely, particularly in individuals, which is probably why it is not preferred in a clinical context [140]. The PROMIS Preference Score (PROPr), which is based on the PROMIS framework, may be an alternative for HSU measurement. In contrast to the EQ-5D and SF-6D, it covers FM-relevant domains such as fatigue and cognition [140]. Another direction could be mapping of available FM instruments to the EQ-5D or other preference-based measures. A recent paper from a spanish working group, for example, suggested that the FIQ-R might be used for calculating QALYs in FM [141]. If the mapping algorithm developed in this paper proofs reliable in future studies this would greatly increase the number of FM studies that could be used for cost-effectiveness analyses.

A wide variety of PROs and PROMs were used in FM trials. A continuing attempt to standardize outcome measurement in FM is highly desirable.