Effectiveness of tumor necrosis factor inhibitors in rheumatoid arthritis in an observational cohort study: Comparison of patients according to their eligibility for major randomized clinical trials

Abstract

Objective. Randomized clinical trials (RCTs) evaluate the efficacy of treatments in selected groups of patients defined by strict inclusion criteria. The value of these trials in predicting therapeutic effectiveness in "real world" patients is limited. This observational cohort study was designed to complement the knowledge obtained in RCTs by evaluating the effectiveness of tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA) according to their eligibility for the major trials.Methods. Using the data from the German biologics register Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT [in German]), we investigated how many of the RA patients who were treated with a TNF inhibitor (infliximab, etanercept, or adalimumab) would have been eligible for the major clinical trials that led to approval of the drugs. In addition, therapeutic effectiveness was compared in the eligible and ineligible patients using the American College of Rheumatology 20% (ACR20) and 50% (ACR50) improvement response criteria.Results. Only 21-33% of the patients in the RAB-BIT register would have been eligible for the major trials. In these patients, the ACR20 and ACR50 improvement responses, indicating therapeutic effectiveness, were comparable with the response rates in the published trials. ACR response rates were lower in those patients considered ineligible for the trials; however, absolute improvement was similar to that in eligible patients. Ineligible patients had lower baseline disease activity, more comorbidity, and lower functional status.Conclusion. RCT cohorts reflect only a minor proportion of the patients treated with biologic agents in routine care. In the clinic setting, the indications for treatment with biologic agents are not identical to the inclusion criteria for trials. Despite the smaller relative improvement achieved in these patients with longstanding, severe RA who would not fulfill the inclusion criteria of a major trial, the majority of such patients would nevertheless benefit from biologic therapy.Randomized clinical trials (RCTs) are generally considered the gold standard for evaluating the efficacy of new therapeutic interventions for defined medical conditions. Standardized trial designs are necessary to ensure that patients randomly allocated to the treatment arms are as similar as possible. The setting of the RCT is therefore artificial, due to restrictive inclusion and exclusion criteria, fixed treatment regimens, and rigidity of followup (1,2). In rheumatology, as in many other fields of medicine, trials cannot reflect effectiveness of treatments in the real world (3), since a majority of

Effectiveness of Rituximab for the Treatment of Rheumatoid Arthritis in Patients with Prior Exposure to Anti-TNF: Results from the CORRONA Registry

“…In clinical practice, many patients initiating RTX have lower disease activity levels compared with those enrolled in anti-TNF RCT, a factor that further influences evaluations of effectiveness 12,13,14 . Most observational data examining the effectiveness of RTX in routine clinical practice have been reported from European registries 15,16,17,18,19,20,21,22 , with scant information currently available from the United States 23 .…”

Biologics registers in RA: methodological aspects, current role and future applications

“…However, they restrict patient inclusion, usually in an attempt to recruit a homogenous group of patients and thus are not always representative of the cohort of patients who will eventually go on to receive biologic therapies. 4,5 They are usually not powered to study the risk of less common outcomes, such as serious infection. As recruitment and follow-up are usually over a short period of time, latent effects, such as the risk of malignancy, may not be observed.…”

“…4,5 This was explained by both a proportion of patients who were too ill or disabled to participate, but there was also a proportion of patients whose disease was not active enough to be eligible. More recent data from the British register have shown that patients who start rituximab or tocilizumab as a first line biologic, as opposed to a TNFI, have higher frequencies of important comorbidities such as prior cancer or interstitial lung disease, conditions which often preclude participation in RCTs.…”

Generalization and Extrapolation of Treatment Effects From Clinical Studies in Rheumatoid Arthritis

“…Randomized clinical trials (RCTs) are widely accepted as the gold standard to evaluate the effectiveness of treatment (1). This design ensures the internal validity of results, i.e., the results cannot be explained by confounding (2).…”

“…However, observational studies are often viewed as less (internally) valid because of confounding, especially confounding by indication. It has also been shown that well-designed observational studies might not systematically over-or underestimate the magnitude of the effects of treatment as compared to RCTs (1)(2)(3)(4)(5)(6)(7). Hence, we are still in need of a methodology for estimating the treatment effect that fits both the need for internal validity and for generalizability (also sometimes referred to as external validity).…”