Measuring the effect of therapy in rheumatoid arthritis clinical trials from the patient's perspective.

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Measuring the effect of therapy in rheumatoid arthritis clinical trials from the patient’s perspective a

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Regina Rendas-Baum , Martha Bayliss , Mark Kosinski , Aditya Raju , Samuel H. Zwillich , b

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Gene V. Wallenstein & Tamas Koncz a

QualityMetric Inc. Lincoln, RIUSA

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Pfizer Medicines Development Group Groton, CTUSA

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Pfizer Medicines Development Group New York, NYUSA Published online: 26 May 2015.

Click for updates To cite this article: Regina Rendas-Baum, Martha Bayliss, Mark Kosinski, Aditya Raju, Samuel H. Zwillich, Gene V. Wallenstein & Tamas Koncz (2014) Measuring the effect of therapy in rheumatoid arthritis clinical trials from the patient’s perspective, Current Medical Research and Opinion, 30:7, 1391-1403 To link to this article: http://dx.doi.org/10.1185/03007995.2014.896328

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Vol. 30, No. 7, 2014, 1391–1403

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Downloaded by [Emory University] at 22:25 10 August 2015

Review article Measuring the effect of therapy in rheumatoid arthritis clinical trials from the patient’s perspective

Regina Rendas-Baum Martha Bayliss Mark Kosinski Aditya Raju QualityMetric Inc., Lincoln, RI, USA

Samuel H. Zwillich Gene V. Wallenstein

Abstract Objective: Health measurements used to evaluate the effectiveness of rheumatoid arthritis (RA) therapies often fail to reflect patients’ priorities, despite recommendations towards more patient-centered assessments. The goals of the current review are: (1) to present guidelines, tools, and required steps for successful implementation of patient-reported outcome (PRO) measurement in RA clinical trials; and (2) to identify gaps between recommendations and current practices.

Pfizer Medicines Development Group, Groton, CT, USA

Tamas Koncz Pfizer Medicines Development Group, New York, NY, USA Address for correspondence: Dr. Gene Wallenstein, Specialty Care Medicines Development Group, Pfizer Inc., MS 8260-2515, 445 Eastern Point Road, Groton, CT 06340, USA. Tel.: +1 860 441 5251; Fax: +1 860 686 7528; [email protected] Keywords: Disease-modifying antirheumatic drugs – Healthrelated quality of life – Patient-reported outcomes – Rheumatoid arthritis – Treatment response Accepted: 13 February 2014; published online: 8 April 2014 Citation: Curr Med Res Opin 2014; 30:1391–403

Methods: The first objective was addressed by reviewing existing frameworks for assessment of health-related quality of life among patients with RA and guidelines on the evaluation of PRO instruments, with a focus on evidence required to demonstrate the adequacy of PRO-based labeling claims. The second goal was addressed by conducting an empirical investigation of the overlap between patients’ perspectives and current practices regarding PROs in RA studies, elaborated from systematic literature searches. The first search identified qualitative studies that reported direct input from patients with RA, while the second identified the main health outcomes measured in RA trials, with a focus on biologic therapy. Results: Our review revealed a set of outcomes that have thus far not been widely used to assess treatment benefit in RA, despite evidence of their importance to patients. The psychometric properties of PRO instruments used to evaluate commonly assessed domains are presented, as are recommendations for PRO tools that assess domains less often measured in RA studies. Conclusions: Although the validity of some PRO tools among patients with RA is well established, further work needs to be done in several health domains which have traditionally received insufficient attention.

Introduction The introduction of new therapies for rheumatoid arthritis (RA) over the past few decades has dramatically improved treatment outcomes. Clinical strategies have shifted from treatment of symptoms after appearance of joint damage to preventative treatment for control of inflammation and slowing of joint damage. The aggressive use of disease-modifying antirheumatic drugs (DMARDs) in the treatment of RA patients1–4 has led to marked improvements in outcomes, including decreased mortality in patients treated with intramuscular gold5 and, more recently, in those treated with methotrexate6,7. New biological therapies have further widened treatment options for RA, particularly for patients ! 2014 Informa UK Ltd www.cmrojournal.com

RA clinical trials from the patient’s perspective Rendas-Baum et al.

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who have not responded to conventional DMARDs. A recent long-term study8 has identified a trend of progressively decreasing physical disability and psychological distress after the first years of treatment among RA patients, across the last two decades. Although no causal link can be established from this observational study, improvements in treatment over the decades are likely to explain, at least partially, such longitudinal trends. While some outcomes, such as those related to disease activity and joint damage, can be measured with limited representation of patient self-evaluation, other outcomes, such as those related to health-related quality of life (HRQoL), entail individuals’ evaluation of their own health status by self-reported survey instruments9. These survey instruments, which are referred to as patient-reported outcome (PRO) measures, are important tools to assess whether improvement in clinical factors translates into recognizable benefits to patients. Early efforts10,11 to develop and introduce PRO tools to RA treatment evaluation were subsequently followed by the creation of the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) network of researchers. These initiatives, now in place for nearly two decades, sought to promote a broader, more patientcentered approach to assessment of RA treatment benefits. Although the importance of the patient’s perspective has gained increasing recognition over the last two decades, a review12 on the use of PRO measures in RA clinical studies published between 2005 and 2007 indicated that, while function, patient global assessment, and pain were reported in more than 50% of studies, other health domains were seldom measured or reported. Several reasons may account for the apparent gap between expert recommendations towards a more patient-centered view of RA assessment and limited actual measurement of health domains that reflect patients’ priorities. First, the interpretation of clinically based measures, such as disease activity scores and joint radiographs, is well documented and understood by clinicians, much more so than that of many PROs. Second, it can be difficult to identify wellvalidated PRO tools that capture the domains most relevant to patients. Finally, the links between multiple PROs and clinically based composite measures may not be well understood, so it is unclear how to integrate the data generated when multiple PROs are measured alongside clinically based endpoints. The objectives of the current review are to: (1) present the elements of successful implementation of patient-centered assessment in RA clinical studies through the use of PROs, including guidelines, required steps, and tools; and (2) identify gaps between recommendations and current practices. The paper is organized into two main parts. In the first part, we review current recommendations for assessment of treatment effect in RA randomized clinical trials (RCTs), and guidelines on 1392


the identification and evaluation of PRO instruments for use in RA studies. The second part is based on an empirical investigation of the degree of overlap between patients’ perspectives and current practices regarding PROs in RA studies, elaborated from two systematic reviews. The first review identified health outcomes of importance to patients with RA, as documented in qualitative studies providing direct input from patients, while the second review identified the health outcomes measured in RA RCTs, using trials of biologic treatments for RA as a case study. Gaps between the patient’s perspective and actual outcome assessment in RA trials are presented along with a general framework linking these to the other key elements of RA clinical trials. The psychometric properties of PRO instruments used to evaluate commonly assessed domains are also presented, as are recommendations for PRO tools that assess domains less frequently measured in RA clinical trials.

PROs as endpoints in RA clinical trials The core set of endpoints currently recommended for use in clinical studies of RA13,14 include tender joint count, swollen joint count, patient’s assessment of pain, patient’s and physician’s global assessment, patient’s assessment of physical function, and evaluation of acute-phase reactants. The American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) have recently recommended15 that the core set of endpoints be expanded to include fatigue, and have further identified sleep as an additional outcome of interest. Since some of these endpoints are indeed patient-reported, the PRO measures of RA are, to some extent, embedded in wellestablished core criteria for assessing the impact of treatment. In practical terms, when outcomes of importance to patients with RA are included as endpoints in clinical studies, they must be operationalized within the context of the specific study objectives, the study population, and the expected effects of the intervention. The selection of appropriate PRO endpoints entails the development of an endpoint model that clearly states the role of the PRO(s) with respect to treatment and its relationship to other endpoints in the study. Once this step has been accomplished, the operationalization of a PRO endpoint implies the choice of an existing PRO instrument or the development of a new PRO instrument when no appropriate measure exists. Guidelines for the selection and evaluation of PROs are in place and are invaluable tools for the successful incorporation of PROs into RA trials. The growing number of clinical research applications incorporating PROs has stimulated governmental agencies www.cmrojournal.com ! 2014 Informa UK Ltd



to develop recommendations on the role of PROs in the regulatory process, particularly when such endpoints are used to support label claims for medical products. The United States Food and Drug Administration (FDA) has outlined the evaluation of PROs as a threestep process: (1) assessment of a valid conceptual framework; (2) evaluation of content validity; (3) quantitative assessment of measurement properties9. The objective of the first step is to ascertain that the PRO is based on a solid conceptual framework that explains the relationship between the items, how they relate to the concept being measured, and the potential relationships between the primary concept and its subconcepts (domains). The validity of the conceptual framework must be established by providing empirical evidence that outcomes that are meaningful to the specific group of patients are represented. Most often, this evidence is provided in the form of documentation of patient input obtained during focus groups. The second step of establishing content validity implies showing that the instrument measures what it is intended to measure. Various aspects of the assessment of the content validity of a PRO are outlined by the FDA: namely, evidence that items, including response options, were generated by and are appropriate for the intended patient population, evidence that the recall period is commensurate with the frequency and variability of the concept being measured, and evidence that the instrument’s scoring algorithm is valid. The third step is the quantitative evaluation of measurement properties, which involves assessment of the instrument’s reliability, construct and criterion validity, and ability to detect change, all of which are fundamental aspects of the psychometric validity of a PRO instrument. Similar to the FDA guidance on the use of PROs to support medical claims, the European Medicines Agency has published a reflection paper that shares some of the same principles outlined in the FDA guidance16. Guidelines proposed by regulatory agencies have been accompanied by recommendations of independent health researchers17,18 on the process of evaluating PROs used in medical claims. In 2010, a formal collaboration between regulatory agencies, industry, and academia had its first annual workshop with the aim of creating standards for the development, evaluation, and use of PRO instruments for medical claims19. Despite the development of guidelines and efforts towards standardizing the process of PRO evaluation, the selection of a PRO can remain a challenge, particularly for endpoints infrequently measured. Further, many of the established PRO tools have been developed prior to the most recent regulatory guidelines9 and may thus lack the desired level of documentation regarding their validity. ! 2014 Informa UK Ltd www.cmrojournal.com

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PROs in RA: patients’ perspectives and use in clinical trials In this section of the review we present empirical evidence obtained from two systematic literature searches regarding the gap between patient-generated outcomes and health outcomes traditionally measured in RA studies. The first search was carried out with the objective of identifying qualitative studies that reported direct input from patients with RA regarding health outcomes that were of importance to them. Relevant publications were identified through PubMed based on the following search criteria: ‘arthritis, rheumatoid’ (Medical Subject Headings [MeSH] terms) or ‘arthritis’ and ‘rheumatoid’ (all fields) or ‘rheumatoid arthritis’ (all fields), in conjunction with ‘focus groups’ (MeSH terms) or ‘focus’ and ‘groups’ (all fields) or ‘focus groups’ (all fields). Publications were included if they reported findings from focus groups based on domain elicitation among patients with RA in semistructured interviews. Publications were excluded if any of the following applied: the patient population was not specific to RA or the input of patients with RA was focused on a specific domain, such as work-related impact. The search identified 137 articles, of which 13 were preliminarily selected based on their title. After abstract review, seven were kept according to the inclusion/exclusion criteria described above. The reference lists of the selected publications were inspected to identify any publications that might have been missed by the search. Four additional publications were identified through reference lists, making up a total of 11 published studies. The second search sought to identify the main PROs measured in recent RCTs of licensed biologic DMARDs. This search, also conducted through PubMed, used the following parameters: RCT (type of article), humans (species), all adult: 18þ years, English language, ‘rheumatoid arthritis’ (MeSH term), published in the past 5 years (dates), and ‘infliximab’ or ‘etanercept’ or ‘adalimumab’ or ‘golimumab’ or ‘certolizumab pegol’ or ‘abatacept’ or ‘anakinra’ or ‘rituximab’ or ‘tocilizumab’ (all fields). This search resulted in 138 articles, of which seven were excluded because no PRO results were reported. Both searches were conducted on July 28, 2010.

Agreement between use of PROs in RA RCTs and patients’ priorities Our findings indicated that publications on qualitative research among patients with RA contained consistent reports about limitations to physical functioning, daily activities, and social life, as well as fatigue and impaired emotional health (Table 1). Despite differences among studies, possibly due to cultural or demographic characteristics, several common concepts emerged. Conceptual RA clinical trials from the patient’s perspective Rendas-Baum et al.

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DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis; SD, standard deviation; TNF, tumor necrosis factor.

Sanderson et al., 201025 – Twenty-three patients with RA participated: 13 patients receiving anti-TNF therapy, 4 who had discontinued anti-TNF therapy, and 6 receiving other types of DMARDs. Sanderson et al., 201021 – Five nominal groups of 26 patients with RA were conducted to prioritize the 63 outcomes previously generated in Sanderson et al., 201025. A subset of the 63 outcomes was then ranked by a total of 254 patients with RA recruited from 4 sites.

Schneider et al., 200867 – Sixty women living with RA in South Africa. The mean age was 53 years and the average number of completed years of schooling was 9. Eight women lived alone and 13 lived in households without children. Gossec et al., 200920 – Ten patients identified 17 domains or areas of health relevant for inclusion in the score, then 96 patients (across 10 European countries) ranked these domains in order of decreasing importance. The seven most important domains were selected.

Goodacre et al., 200743 – Interviews with 30 patients recruited from outpatient departments across 3 hospitals in the UK were conducted within 3 weeks after initiation of DMARD therapy.

Lutze and Archenholtz, 200724 – Twenty-three patients with RA (12 male), aged between 27 and 67 years and with a disease duration ranging from 1 to 5 years, were included.

Hewlett et al., 200522 – Three hundred and twenty-three patients with RA (235 female) with a mean age of 60.8 years (SD 13.2 years) and disease duration of 13.7 years (SD 11.1 years) were included.

Ahlmen et al., 200523 – Twenty-five patients with RA (16 females) with a median age of 55 years and median disease duration of 14 years were recruited from 4 distinct centers in Sweden. Stamm et al., 200530 – Twenty-one patients (3 males; 15 retired, with a median age of 61 and median disease duration of 6 years) were included.

Carr et al., 200342 – Focus groups were held in 5 clinical centers in different geographical locations in the UK. Each group contained 6 to 9 patients (N ¼ 39) with RA who were purposively sampled to include men and women with an appropriate age range (33–81 years), disease duration (3–24 years), functional disability, work disability, and current disease activity.

Bath et al., 199966 – Fifteen patients (9 females) with RA were recruited for this study, either at outpatient clinics or as inpatients in the UK. Mean age was 59 years and mean disease duration was 5.4 years.

Whalley et al., 199726 – Potential interviewees were identified from RA self-help groups, a consultant rheumatologist, and a university hospital, in the United Kingdom (UK) and the Netherlands. The ages and disease duration of the 50 participants (41 females) ranged between 33 and 75 years, and 7 months and 35 years, respectively. The interviews were informal and conducted in patients’ homes.

Sample description

Table 1. Patient-centered domains obtained from qualitative studies of RA.

– – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –

Domains/themes Mobility Dexterity Pain Fatigue Difficulty sleeping Medication Pain Wellbeing Social support Pain Fatigue Functional activities Work Social activities Normal life Physical capacity Mental function Movement and mobility Domestic life Support and relationships General wellbeing Day-to-day functioning Emotional and physical wellbeing Depression Dependence Anger Personal care Mobility/transportation Household activities and maintenance Social activities Pain Mobility and transportation Self-care Pain Functional disability Fatigue Emotional wellbeing Pain Activities of daily living Joint damage Mobility


– – – –

– – – – – – – – – – – – – – – – – – – – – –

– – – –

Life enjoyment Independence Fatigue Valued activities

Independence Wellbeing Coping Psychological wellbeing Keeping/losing job Fatigue Social role and confidence Physical symptoms Medication issues Fear Insecurity Hope Relaxation/hobbies Paid/voluntary work Caring for others Sexual relationships Unpredictability of RA Social roles and activities Employment Sleep Coping Physical wellbeing

Treatment efficacy Symptom reduction Sleep General wellbeing

– Mobility – Information – Work

– Difficulty concentrating – Depression/anger – Social contact/isolation

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proximity and information from three of the reviewed studies20–22 that specifically asked patients to rank concepts were used to further aggregate the outcomes. Specifically, aggregation was based on the following considerations: (1) ‘disability’ and ‘mobility’ were thought to be captured in the concept of physical functioning; (2) ‘medication issues’, ‘sexual relationships’, and ‘coping’ were either not highly ranked or sufficiently frequent, or not considered direct outcomes of treatment efficacy, but rather possible treatment-effect modifiers. As a result, seven concepts were identified as potential PRO endpoints in trials of RA treatment: (1) pain; (2) fatigue; (3) physical health (functioning); (4) mental health (emotional wellbeing); (5) social functioning; (6) sleep; (7) work. The findings from the second search revealed that several of the domains that emerged from our review of qualitative studies were often absent from RCT publications (Table 2). In addition to physical functioning and pain, only fatigue was represented in RCT publications, being reported in 17% (n ¼ 24) of publications. A comparison of Tables 1 and 2 suggests gaps between patients’ priorities and reporting of treatment effects in RA. Although the Short Form-36 Health Survey (SF-36), a generic multidimensional PRO instrument, captures several of the domains identified through the qualitative literature, not all domains (sleep and work, for example) are specifically captured in that measure. The findings from qualitative studies and published reports of RA biologic treatment effect are discussed below with respect to specific HRQoL domains thought to be important to patients but not currently frequently reported in RCTs. Because they are part of the core set of endpoints for RA, pain and physical functioning are not included in the discussion presented below.

Psychological status Several of the studies presented in Table 1 reported that patients with RA frequently discussed feelings of anger, frustration, fear, anxiety, and depression in connection with RA20,23–26. In the study of Whalley et al.26, patients linked feelings of anger and frustration to the inability to perform even simple tasks, while feelings of irritability were considered by patients to be a consequence of being tired or in pain. Mood and depressive symptoms were also linked to anxiety about the future, particularly in the earlier stages of the disease24. Regardless of patients’ ability to connect them to other RA symptoms or outcomes, depressive symptoms ranked high among patients with RA20, lending support for their assessment in trials of RA treatment. Despite findings from qualitative studies, our search indicated that psychological status has been traditionally absent from the list of endpoints assessed in RA RCTs. ! 2014 Informa UK Ltd www.cmrojournal.com

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From among the 131 manuscripts reviewed for the current study, there were only two that included measures specific to anxiety and depression as treatment outcomes. These results are similar to those of a previous review on the use of PROs in RA clinical studies12. Although measures specific to psychological status were rare in RCTs, the SF-3627 was frequently used to capture information on psychological aspects of HRQoL (Table 2). SF-36 Mental Component Summary (MCS) scores were reported in 34 of the 131 manuscripts reviewed, while Mental Health subscale scores were reported in 32. Although SF-36 MCS scores have been used to report significant gains in mental-health functioning that resulted from treatment in recent-onset RA28, a meta-analysis29 of seven RA RCTs found the scale to have a low effect size (0.21). Despite the high ranking which patients with RA give to psychological status and emotional health, there may be challenges associated with its assessment in RA RCTs. An important consideration regarding the assessment of psychological status is that changes in anxiety and/or depressive symptoms may be moderated by the patient’s degree of coping with the disease. For example, patients with more established (or longer duration of) disease may have adapted their lifestyle to the limitations imposed by RA. Indeed, mood and depressive symptoms in patients with RA are linked to anxiety about the future, but the strength of this effect varies with age and is strongest in earlier stages of the disease30. Thus, the degree of association between treatment and psychological status may be dependent on specific aspects of the study.

Fatigue Our review of qualitative studies provided overwhelming evidence that patients regard fatigue as a symptom of paramount importance. In a ranking of 23 concepts made by patients with RA, fatigue was more frequently included in patients’ top three important outcomes than stiffness and joint swelling22, and in other studies fatigue replaced pain as the top patient priority31. Fatigue from RA was described by patients as being ‘overwhelming’ and different from normal tiredness, interfering with every aspect of life, from common daily activities to expected social roles. Patients have linked the overwhelming aspect of fatigue to feeling ‘frustrated’, ‘limited’, and ‘restricted’ in what they could do32, but also to disturbed sleep33. Fatigue has been shown to be responsive to different biologic DMARDs for RA in multiple clinical studies34–36. It has also been shown to independently explain variation in scores derived from the core set of RA endpoints37 and it has been linked to RA remission, which in turn is a therapeutic goal of treatment38. In our review, we identified 24 RCT publications which reported treatment-related changes in fatigue. RA clinical trials from the patient’s perspective Rendas-Baum et al.

1395

1396 N 103

45

37

PRO measure

*Health Assessment Questionnaire (HAQ) Generic tool assessing daily functioning and pain in the past week. Although a larger form exists, in clinical trials the shorter version is generally used. The HAQDisability Index (DI) covers 8 areas: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and outdoor activities. The HAQ-DI ranges between 0 (not disabled) and 3 (completely disabled). The Modified HAQ (MHAQ)11 is a shorter version of the HAQ-DI using only one item for each of its 8 areas. The HAQ-DI was reported in 98 (95%) of the 103 instances, while the MHAQ was reported 5 times.

*VAS – Pain Single item measuring pain, consisting of a 10 cm scale anchored at ‘0’ (‘No pain at all’) and ‘10’ (‘Pain as bad as it could be’).

Short Form-36 Health Survey (SF-36) Generic PRO with 35 items measuring 8 domains: Physical Functioning (10 items); Role Physical (4 items); Bodily Pain (2 items); General Health (5 items); Vitality (4 items); Social Functioning (2 items); Role Emotional (3 items); Mental Health (5 items). One additional item asks respondents to rate their present health compared with that of 1 year ago. The 8 subscales are further aggregated into two measures assessing mental health (Mental Component Summary [MCS]) and physical health (Physical Component Summary [PCS]). The majority (32 or 86%) of publications reported scores for the 8 scales, PCS and MCS; two publications reported only PCS and MCS; the following combinations, PCS only, PCS and Physical Functioning, and Role Emotional, Social Functioning and Role Physical, were each reported once.

Reliability Test–retest reliability: the ICCs were high, ranging from 0.89– 0.9768 Internal consistency: Cronbach’s alpha ¼ 0.9568

Test–retest reliability: ICC ¼ 0.87 (95% CI: 0.80–0.92%)73

Test–retest reliability: the ICCs were moderate to high, ranging from 0.5–0.9277 Internal consistency: Cronbach’s alpha ¼ 0.75–0.91 for all 8 scales (median ¼ 0.84)78

Construct validity Convergent validity with pain (r ¼ 0.71), fatigue (r ¼ 0.62), overall health (r ¼ 0.41)68 HAQ discriminated between patients with RA with differing disease activity level68

Convergent validity with fatigue (r ¼ 0.71), physical functioning (r ¼ 0.65), and bodily pain (r ¼ 0.82)68 Discriminated between patients with RA with differing disease activity level68 Convergent validity with pain (r ¼ 0.35 to 0.74), fatigue (r ¼ 0.26 to 0.68), physical functioning (r ¼ 0.32 to 0.69)76 SF-36 discriminated between patients with RA with differing disease activity level76

Content validity Literature/instrument review Interviews with patients and healthcare professionals, with a main focus in RA10

A variety of VAS scales with different line orientation and anchor wording have been tested in RA, with preference being given to the current form70–72

Literature and instrument review75 Items in each SF-36 scale were based on longer extant tools and were selected using the corresponding fulllength MOS scale as the criterion27

Table 2. Patient-reported outcome measures frequently used in randomized clinical trials of RA biologic treatments (2005–2010)y.



SRM for SF-36 scales and summaries range from 0.28–0.68 with most SRMs being around 0.535 Overall the scales and summary measure assessing physical health had higher SRMs than those measuring mental health35 In RA, changes of 5 points in domain scale scores and 2.5 points in PCS and MCS have been used to represent MID79

SRM was 0.95 for improvement, 0.06 for ‘no change’, and 0.60 for deterioration68 MID estimates for improvement and worsening of pain ranged from 0.5 to 1.1 units74

SRM for HAQ ¼ 0.63 (95% CI: 0.42– 0.85%)35 MID estimates for HAQ improvement range from 0.22 to 0.2469

Responsiveness

Abatacept, Adalimumab, Anakinra, Certolizumab pegol, Etanercept, Golimumab, Infliximab, Leflunomide, Rituximab, Tocilizumab (12 included improvements in HRQoL)

Abatacept, Adalimumab, Anakinra, Certolizumab pegol, Etanercept, Golimumab, Infliximab, Leflunomide, Rituximab, Tocilizumab

Abatacept, Adalimumab, Anakinra, Certolizumab pegol, Etanercept, Golimumab, Infliximab, Leflunomide, Rituximab, Tocilizumab

FDA/EMA RA label claims



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No evidence of content validity in RA

Discriminated between patients with RA with low vs moderate DAS28, and across 3 levels (low/moderate/ high) of arthritis activity68 Correlated more strongly with HAQ (r ¼ 0.78) than with ESR (r ¼ 0.39)83


SRM for improvement, no change, and deterioration were 0.65, 0.06, and 0.36, respectively82

None

Based on 138 publications. *Part of the core set of endpoints used in clinical trials and used to derive ACR response criteria. Instruments used in 5 or fewer publications: Arthritis Measurement Scale (AIMS); Beck Depression Inventory (BDI); General Heath VAS; General Well Being VAS; Medical Outcomes Study – Sleep (MOS Sleep); Hospital Anxiety and Depression Scale (HADS); Morning Stiffness VAS; Rheumatoid Arthritis Quality of Life (RAQol); Work Productivity and Activity Impairment Scale (WPAI); Work Limitation Questionnaire (WLQ); Work Instability Scale (WLQ); Profile of Fatigue and Discomfort (PROFAD) Questionnaire; Ritchie Articular Index (RAI). ACR, American College of Rheumatology; CI, confidence interval; DAS, disease activity score; EQ-5D, EuroQOL five dimensions questionnaire; EMA, European Medicines Agency; ESR, erythrocyte sedimentation rate; FDA, Food and Drug Administration; HRQoL, health-related quality of life; ICC, intraclass correlation coefficient; MID, minimum important difference; MOS, Medical Outcome Study; PRO, patient-reported outcome; RA, rheumatoid arthritis; SRM, standardized response mean; VAS, visual analog scale.

y

7

Abatacept, Adalimumab, Golimumab, Rituximab (two claims included improvement in fatigue)

SRMs were 0.77, 1.21, and 1.45, for ACR20, ACR50, and ACR70, respectively82 MID estimates in RA indicated 3–4 point change is clinically significant82

Internal consistency: Cronbach’s alpha ¼ 0.81–0.8682

Correlations with other fatigue scales ranged from 0.68 to 0.8882 Discriminated between ACR-based clinical response groups

Interviews with patients and healthcare professionals, with a main focus on cancer patients with anemia, were used to elicit items Patient ratings and expert review used in final item selection

10

Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) Single-page 13-item questionnaire assessing self-reported fatigue and its impact upon daily activities and function over the past 7 days. Each question is answered using a 5 point Likert-type scale.

EQ-5D/EuroQOL Generic preference-based instrument assessing 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each divided into 3 levels of severity. The 243 possible health states are weighted yielding an index score anchored at 0 (death) and 1 (perfect health). This index is used to derive quality-adjusted life-years used in healthcare economic evaluations.

None

SRM ¼ 0.59 (95% CI: 0.38–0.81%) MID estimates ranged from 0.82 to 1.12 for improvement and 1.13 to 1.26 for worsening of fatigue81


Convergent validity with pain (r ¼ 0.31–0.8), poor sleep (r ¼ 0.6), disability (r ¼ 0.33– 0.41), low mood (r ¼ 0.41–0.47)40 Discriminated between patients with RA and healthy controls, and patients with RA with and without pain40

Face validity was good, although additional information is needed40

14

Abatacept, Adalimumab, Anakinra, Etanercept, Golimumab, Infliximab, Leflunomide, Rituximab, Tocilizumab

VAS – Fatigue Multiple versions of VAS fatigue scales are used in RA40, with differences in the numerical scale (0–10 or 0–100, most often) and descriptors used for the anchors of the scale.

SRM ¼ 0.55 (95% CI: 0.53–0.57%)73


Correlated with the DAS28 (r ¼ 0.39) and physician global assessment (r ¼ 0.41)80

No evidence of content validity in RA. However, no difference in validity was found between the VAS–PGA and a modified rating scale that included marker states and more clearly defined anchors80

24

*VAS – Patient Global Assessment (PGA) Self-reported rating of global arthritis status with endpoints of ‘very poor’ and ‘very well’.




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When compared to a similar review conducted several years prior to the current study12, our results indicate a marked increase in the use of fatigue as an endpoint in RA RCTs since 2007. In that review, only two of the 50 RCT publications reported changes in fatigue, both of which used the fatigue Visual Analog Scale (VAS). For the 24 publications identified in the current study, two fatigue measures were nearly equally represented; the VAS–Fatigue and the Functional Assessment of Chronic Illness Therapy–Fatigue. Multiple PRO measures are currently available for the assessment of fatigue, with recent studies indicating ongoing efforts to evaluate existing scales and develop new, well validated scales specific to RA39. Hewlett et al.40 conducted a systematic review of the various scales used to measure fatigue in patients with RA. Despite some problems in standardization which limited the comparability of the VAS fatigue scales across studies, where the scales were described, face and content validity were found to be good. Construct validity was acceptable, with evidence of convergent validity with pain, poor sleep, and disability. Although the VAS–Fatigue is simple to administer and has good psychometric properties, it does not provide a multidimensional assessment of fatigue, which is in contrast with current understanding of fatigue as a concept with physiological, cognitive, and emotional dimensions40. Although some multi-item scales go beyond assessment of fatigue severity and may have shown good psychometric properties in RA, evidence of content validity specifically in RA is lacking40. Recent work39,41 on the measurement of fatigue in patients with RA has led to the development of the multidimensional Bristol RA Fatigue Multi-Dimensional Questionnaire (BRAF-MDQ) and the short BRAF numerical rating scales and VAS for severity, effect, and ability to cope with fatigue. These scales, though not yet extensively used, hold promise as tools for a more comprehensive and accurate assessment of fatigue.

Social functioning Our review of several studies of RA focus groups22,23,25,42 revealed that participants frequently described how RA negatively impacted their relationships, and their ability to participate in social activities and to perform expected roles. In the study of Lutze and Archenholtz24, focus-group participants described the struggle that resulted from not being able to enjoy leisure time, either because they were no longer able to perform the activity or because it was too strenuous for them24. In other studies26, patients reported that simple activities such as shaking hands or hugging were difficult for them, making social contact difficult. Patients with RA who were self-reporting improvement 1398


in disease status associated it with being able to engage in a wider range of social activities43. Consistent with findings from a previous study12, our review revealed that social functioning is most often reported in the context of multi-dimensional HRQoL instruments, such as the SF-36 or the Arthritis Impact Measurement Scale–expanded version (AIMS2). The SF-36 was reported in RCT publications more frequently than the AIMS2 (Table 2). Despite being ‘disease-specific’, one study44 found the AIMS2 social interaction scale was less responsive to change due to treatment than the social functioning scale of the SF-36. In that study, after 12 months of anti-tumor necrosis factor treatment, the standardized response mean (SRM) for the AIMS2 was 0.20 while for the SF-36 it was 0.49. As in the case of psychological status, the use of broader instruments which assess treatment-related changes in social functioning is recommended by the FDA as they provide an overall assessment of health from the patient’s perspective45.

Work limitations Two related aspects of work limitations attributed to RA were identified from documented patient input uncovered by our review: the economic consequences caused by the reduction or loss of work hours30, and the emotional toll caused by not being able to fulfill work-related roles22. Overall, we found that the impact of RA on patients’ ability to work was a common theme across qualitative studies, although the relative importance of these outcomes sometimes depended on patient characteristics, such as age and gender. For example, in the qualitative study of Hewlett et al.22, men selected ‘Be able to fulfill my usual role at work’ as a top priority more frequently than women (19.5% of men vs 10.3% of women). Nevertheless, work limitations are one of the top concerns of patients with RA, a finding that has been well documented in the RA literature46–48. Despite the well-documented impact of RA-related work limitations, work-related outcomes associated with treatment were not frequently reported in RA RCTs. Our review found two RCT publications reporting the effect of therapy on work-related outcomes. In one publication49 work impairment was measured by weekly work diaries and the Rheumatoid Arthritis Work Instability Scale, while in the other publication50 work-related outcomes were measured by a self-reported questionnaire that included work status at baseline and absenteeism during the trial period. Self-reported measures of worker productivity display large variability over a number of key factors – operational definition (absenteeism, presenteeism, or both; degree of impairment and so on), conceptual framework, generic vs www.cmrojournal.com ! 2014 Informa UK Ltd



disease specific, and different combinations of scales and subscales51. Extensive literature reviews and discussions involving patients with RA and clinical experts52,53 have identified the following scales as the most promising for use in RA: Work Instability Scale for Rheumatoid Arthritis (WIS-RA), Rheumatoid Arthritis Specific Work Productivity Survey (WPS-RA), and Workplace Activity Limitations Scale. Both the WIS-RA and the WPS-RA have been used in trials of RA to demonstrate the effect of biologic treatment on work productivity49,54,55. The vast content variation of work-related measures implies that the selection of an appropriate questionnaire must be based on the specific clinical research question, the study sample characteristics, and psychometric properties of the measure. The high level of disability and the known impact of RA on work productivity, lost income due to absence from work, and eventual job loss46 indicate the need to measure any potential gains in work productivity that may occur as a result of treatment. Effective RA therapies significantly alleviate work-related disability54,56.

Sleep disturbance Our review of 11 RA focus-group studies identified four studies in which sleep was a key outcome for patients (Table 1). In the study of Gossec et al.20, sleep was ranked fifth by an international group of approximately 100 patients with RA from a total of 17 key domains previously identified through focus groups. Sleep function is an element of the RA International Classification of Functioning, Disability and Health (ICF) core set and was further supported as a key PRO through interviews with patients in the study of Stamm et al.30. Difficulty sleeping at night caused by pain was a recurrent theme in the study of Whalley et al.26, and in the study of Sanderson et al.25 patients linked ‘sleeping better’ to having ‘RA under control’. Changes in sleep disturbances due to treatment are rarely reported in RA clinical studies. A previous review of RA clinical studies published between 2005 and 2007 revealed that only two out of 109 studies reported outcomes related to sleep17. Likewise, our review identified two published reports of RA RCTs in which the Medical Outcomes Study (MOS) Sleep questionnaire was used to report the effect of treatment. Despite scant reporting, the results of one study57 using polysomnographic recordings of 41 patients with RA and 19 matched controls indicated that some key parameters of sleep structure are associated with RA clinical parameters, such as pain and morning stiffness. This suggests that therapeutic interventions for RA may improve patient-reported disturbances in sleep domains. Although more carefully designed studies are needed to understand the sleep structure of patients with ! 2014 Informa UK Ltd www.cmrojournal.com

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RA, it is clear that sleep is an area of concern to both patients and clinical researchers58. There are encouraging results indicating that significant reductions in sleep problems observed at 6 months were maintained after 2 years of treatment59. In an extensive review60, 45 sleep-quality instruments were evaluated based upon their feasibility, reliability, validity, as well as their psychometric and responsiveness properties for patients with RA. In addition, the review identified 14 domains of sleep, of which the following four were top ranked: (1) sleep adequacy, defined as getting sufficient quality and quantity of sleep so as to feel rested on awakening; (2) sleep maintenance, defined as ability to stay asleep all through the night or to get back to sleep if awakened; (3) sleep initiation or the ability to fall asleep; and (4) daytime functioning, defined as being able to carry out work, leisure, household activities, and social relationships. The top-ranked instruments in terms of their feasibility were: Athens Insomnia Scale, MOS Sleep, Insomnia Severity Index, and Women’s Health Insomnia Rating Scale. The instruments which scored highest on psychometric properties were: Athens Insomnia Scale, Sleep Assessment Questionnaire, Pittsburgh Sleep Diary, and MOS Sleep, all of which were recommended for use in planned clinical trials of patients with RA to further assess their applicability. The Athens Insomnia Scale was, however, the only scale assessing the four domains considered in the study, while the remaining scales considered three of the four domains.

A general framework for endpoint models involving PROs In order to clearly define the role of a PRO in measuring the value of a particular intervention, a framework that explains the links between treatment, clinically assessed markers of disease, and patient-reported experiences of physical and psychosocial disability must be in place. Careful consideration of such a framework is an essential first step in ensuring the validity of PRO-based treatment benefits. Figure 1 presents a schematic representation of the connections that exist between key elements of RA clinical trials: treatment, RA signs and symptoms, and other outcomes impacted by the disease. This general framework is in agreement with recommendations that the assessment of the effectiveness of RA therapies be undertaken as a multidimensional process encompassing the physical, psychological, and social wellbeing of patients61. RA therapies are conceptualized as directly affecting the specific signs and symptoms of RA, such as pain or C-reactive protein. Therapies impact HRQoL across domains thought to be most important to patients with RA – including fatigue, RA clinical trials from the patient’s perspective Rendas-Baum et al.

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Rheumatoid arthritis

Treatments

Signs

Symptoms

• Joint swellingΔ‡ • C-reactive proteinΔ • Erythrocyte sedimentation rateΔ • X-ray • Rheumatoid subcutaneous nodules • Rheumatoid factors

• NSAIDs • Corticosteroids • Traditional DMARDs • Biologic DMARDs

• PainΔ‡ • Morning stiffnessΔ‡ • FatigueΔ‡ • Joint tendernessΔ‡


Impacts

Physical functioningΔ‡

Psychological status‡

Social functioning‡

Work limitations‡

Sleep‡

Health-related quality of life

Figure 1. PRO framework for RA clinical trials. Included in the ACR/EULAR core set of endpoints. zIncluded in the Comprehensive ICF Core Set for RA. œKey outcome from the perspective of patients with RA. ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; EULAR, European League Against Rheumatism; ICF, International Classification of Functioning, Disability and Health; NSAID, non-steroidal anti-inflammatory drug; PRO, patient-reported outcome; RA, rheumatoid arthritis.

physical functioning, psychological status, social functioning, work limitations, and sleep disturbances – both indirectly, through their effect on signs and symptoms, but also directly both positively and, due to possible medication side effects, negatively. We note that, although Figure 1 presents fatigue as a symptom of RA, fatigue may be both a symptom and a consequence of RA. Indeed, a recent study62 testing possible causal pathways between fatigue and other key RA variables indicated that mood disturbance, poor sleep quality, and patient-reported disease activity all played major roles in explaining fatigue. Figure 1 also reveals where overlap exists across key sets of endpoints addressed in this study: the ACR/EULAR core set of endpoints, the ICF for RA63, and the patients’ set of domains uncovered by the current review. The outcomes that are recommended by ACR/EULAR clearly focus on signs and symptoms and physical functioning, several of which were also endorsed by patients, but fail to measure psychological outcomes as well as sleep disturbance, work limitations, and social functioning. The comprehensive ICF core set for RA covers all the key domains of relevance to patients. Despite recent efforts to develop an ICF-based framework that may be more suitable for clinical trial applications, in its current form the ICF 1400


core set for RA may present a challenge in terms of mapping its items directly to clinical trial endpoints and candidate PRO measures.

Discussion Our review revealed that several patient-centered concepts captured in studies of RA focus groups were largely absent in publications reporting treatment benefit in RA. Although physical functioning, pain and, to a lesser extent, fatigue appear to be reported in treatment-related publications, psychological status, social functioning, work limitations, and sleep disturbance were generally absent from the set of PRO-based endpoints used to describe treatment efficacy. Inclusion of these PRO-based endpoints in RA treatment studies is essential to obtain additional empirical evidence of the value they provide from patients’ perspectives. The importance of capturing patients’ views is illustrated by results indicating that patients with RA and clinicians differ in how they evaluate and prioritize the same health and symptom status outcomes64. In the study of Kwoh and Ibrahim65, four rheumatologists and www.cmrojournal.com ! 2014 Informa UK Ltd



79 of their patients were asked to select the ‘most important’ outcomes from a list of 19 health and symptom status outcomes organized along four dimensions – physical functioning (7 outcomes), mental functioning (5 outcomes), social functioning (4 outcomes), and a three-outcome symptom status dimension. For each of the four dimensions, the physicians’ ability to identify patients’ choices for ‘important’ (‘most important’ and ‘next most important’ combined) was evaluated as the ratio of the total number of instances in which they correctly identified patients’ choices for most important outcomes to the total number of possible correct cases (sensitivity). Similar calculations were done to evaluate rheumatologists’ ability to identify patients’ choices of less important outcomes (specificity). Physicians’ sensitivity was highest for social functioning (84%) and lowest for mental functioning (59%), while specificity was highest for physical functioning (82%) and lowest for symptom status (42%). Overall, mental functioning was the dimension showing the lowest set of sensitivity (48%) and specificity (59%) values. Clearly, differences exist between clinicians’ and patients’ outcome priorities. Part of the difficulty with the assessment of nontraditional PRO-based endpoints in RA RCTs is the choice of PRO instrument. As our review demonstrated, in the case of endpoints less frequently assessed in RA, existing PROs may be lacking in some or all aspects of validation. In these cases, although candidate tools have been identified, additional knowledge of the tools’ properties is needed. To overcome the paradox whereby on the one hand it is difficult to validate instruments until they have been used in interventions, while on the other hand the effectiveness of interventions cannot be assessed without valid instruments, researchers should consider undertaking development or validation studies. This is particularly important in cases where instrument validity (or lack thereof) may compromise the assessment of effectiveness or fail to pass criteria required for PRObased label claims. Further, only by including these endpoints into RA trials can it be established to what extent they enable knowledge to be gained (beyond what is possible using the traditional core set of endpoints for RA trials). This paper identified the set of endpoints that is most important to patients with RA and potential PRO measures to assess these endpoints. As explained in the most recent FDA guidance on the use of PROs in clinical trials9, the strength of PRO-based evidence will be evaluated in the context of study-specific characteristics, such as its objectives, design, and population, and the conceptual framework and measurement properties of the PRO in question. It is hoped that the review presented here will call researchers’ attention to the current gaps in the implementation of PROs in RA clinical trials. ! 2014 Informa UK Ltd www.cmrojournal.com

July 2014

Transparency Declaration of funding Support for this study and manuscript development was provided by Pfizer Inc. Declaration of financial/other relationships T.K., S.H.Z., and G.V.W. have disclosed that they are employees of Pfizer Inc., the sponsor of this study. R.R.-B., M.B., A.R., and M.K. have disclosed that they are employees of QualityMetric and acted as paid consultants to Pfizer Inc. in connection with the development of this manuscript. CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships. Acknowledgments This study was sponsored by Pfizer Inc. Editorial assistance was provided by Kate Silverthorne PhD of Complete Medical Communications and funded by Pfizer Inc.

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The impact of endpoint measures in rheumatoid arthritis clinical trials.

Provisional guidelines for measuring disease activity in clinical trials on rheumatoid arthritis.

Longterm followup of rituximab therapy in patients with rheumatoid arthritis: results from the Belgian MabThera in Rheumatoid Arthritis registry.

Novel methods of measuring clinical outcomes from psoriasis and psoriatic arthritis clinical trials.

Assessment of the Effect of Methotrexate Therapy on Bone Metabolism in Patients with Rheumatoid Arthritis.

Combination therapy for early rheumatoid arthritis: a treatment holiday perspective.

Reasons for discontinuation of subcutaneous biologic therapy in the treatment of rheumatoid arthritis: a patient perspective.

The Mechanisms Underlying Chronic Inflammation in Rheumatoid Arthritis from the Perspective of the Epigenetic Landscape.

Evaluating quality of care in rheumatoid arthritis: the patient perspective.

Randomized clinical trials as reflexive-interpretative process in patients with rheumatoid arthritis: a qualitative study.

Clinical trials documenting the efficacy of low-dose glucocorticoids in rheumatoid arthritis.

Changes in serum creatinine in patients with active rheumatoid arthritis treated with tofacitinib: results from clinical trials.

Interleukin-34 in rheumatoid arthritis: potential role in clinical therapy.

Rheumatoid Arthritis: The Stride from Research to Clinical Practice.

Clinical restenosis trials: a perspective from the pharmaceutical industry.

Clinical trials of new drugs for the treatment of rheumatoid arthritis: focus on early disease.

Rheumatoid arthritis: Testing the inflammation-insulin resistance link in clinical trials.

Is radiographic progression in modern rheumatoid arthritis trials still a robust outcome? Experience from tofacitinib clinical trials.

Chronic Lyme arthritis. Clinical and immunogenetic differentiation from rheumatoid arthritis.

Diet therapy in rheumatoid arthritis.

Gold therapy in rheumatoid arthritis.

Gold therapy in rheumatoid arthritis.

Corticosteroid therapy in rheumatoid arthritis.

Triple therapy in rheumatoid arthritis.