Critical appraisal of intra-articular glucocorticoid injections for symptomatic osteoarthritis of the knee.

OBJECTIVE: Intra-articular (IA) injections of glucocorticoids (GCs) have been shown to decrease pain, increase mobility, and improve quality of life in patients with osteoarthritis (OA) of the knee. Concerns about cartilage loss with IA GCs have prompted reconsideration of their use in knee OA. This review has three objectives: 1) critically review the clinical, molecular, and structural effects of IA GCs in knee OA; 2) provide a design for a clinical trial aimed at improving our understanding of the long-term consequences of IA GCs; and 3) provide practical guidance on the use of IA GCs in patients with knee OA based on current information. DESIGN: A narrative review of current literature on the use of IA GCs for OA of the knee. RESULTS: Important questions remain to be fully answered with respect to IA GCs, including long-term effects on all aspects of the structural and molecular environment of the knee, and identification of factors that can reliably predict a positive or negative response to IA GCs. CONCLUSIONS: While awaiting results from an appropriately designed study, several provisional statements regarding IA GCs can be put forward: 1) IA GCs appear to be a relatively safe option that is effective in specific patients with symptomatic knee OA; 2) there is no definitive evidence that IA GCs accelerate joint deterioration to an important extent or hastens the requirement for knee replacement; and 3) there are few contraindications to IA GCs and injection-associated complications are rare when IA GCs are delivered with proper technique.

Proposed study designs for approval based on a surrogate endpoint and a post-marketing confirmatory study under FDA's accelerated approval regulations for disease modifying osteoarthritis drugs.

In 1992, the Food and Drug Administration (FDA) instituted the accelerated approval regulations that allow drugs or biologics for serious conditions that fill an unmet medical need to be approved on the basis of a surrogate endpoint or an intermediate clinical endpoint. The current definition of a serious condition includes chronic disabling conditions, such as osteoarthritis (OA), and thereby provides expanded opportunities for the use of biomarkers for regulatory approval of drugs for OA. The use of surrogates or intermediate clinical endpoints for initial regulatory approval of a drug or biologic requires confirmation in a post-marketing study of a drug effect on a clinically relevant outcome, such as on how a patient feels, functions or survives. Current FDA guidance requires that the post-marketing approval (PMA) study be ongoing during the time of initial drug approval. This white paper arose out of the need to brainstorm trial designs that might be suitable for PMA of drugs initially approved, on the basis of a surrogate or intermediate clinical endpoint, for treatment of OA to alter disease progression, abnormal function or pathological changes in the morphology of the joint. In this white paper we define the concept and regulations regarding accelerated approval and propose two major study design scenarios for PMA trials in OA. The long-term goal is to discuss and refine these designs in consultation with regulatory agencies in order to facilitate development of drugs to fill the large unmet need in OA.

A critical review of clinical trials in systemic lupus erythematosus.

One challenge in caring for patients with systemic lupus erythematosus (SLE) is a paucity of approved therapeutics for treatment of the diverse disease manifestations. In the last 60 years, only one drug, belimumab, has been approved for SLE treatment. Critical evaluation of investigator initiated and pharma-sponsored randomized controlled trials (RCTs) highlights barriers to successful drug development in SLE, including disease heterogeneity, inadequate trial size or duration, insufficient dose finding before initiation of large trials, handling of background medications, and choice of primary endpoint. Herein we examine lessons learned from landmark SLE RCTs and subsequent advances in trial design, as well as discuss efforts to address limitations in current SLE outcome measures that will improve detection of true therapeutic responses in future RCTs.

OARSI Clinical Trials Recommendations: An abbreviated regulatory guide to the clinical requirements for development of therapeutics in osteoarthritis.

In this brief abbreviated review of regulatory issues regarding the development of drugs and or devices for the treatment of osteoarthritis (OA), the steps that are expected by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are discussed.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hip osteoarthritis.

The ability to assess the efficacy and effectiveness of an intervention for the treatment of hip osteoarthritis (OA) requires strong clinical trial methodology. This consensus paper provides recommendations based on a narrative literature review and best judgment of the members of the committee for clinical trials of hip OA. We provide recommendations on clinical trial design, outcome measures, including structural (radiography), and patient and physician global assessments, performance based measures, molecular markers and experimental endpoints including MRI imaging. This information can be utilized by sponsors of trials for new therapeutic agents for hip OA.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hand osteoarthritis.

Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing "good" clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future.

Outcome measures in placebo-controlled trials of osteoarthritis: responsiveness to treatment effects in the REPORT database.

INTRODUCTION: Treatment response in randomized clinical trials (RCT) of osteoarthritis (OA) has been assessed by multiple primary and secondary outcomes, including pain, function, patient and clinician global measures of status and response to treatment, and various composite and responder measures. Identifying outcome measures with greater responsiveness to treatment is important to increase the assay sensitivity of RCTs. OBJECTIVE: To assess and compare the responsiveness of different outcome measures used in placebo-controlled RCTs of OA. SEARCH STRATEGY: The Resource for Evaluating Procedures and Outcomes of Randomized Trials database includes placebo-controlled clinical trials of pharmacologic treatments (oral, topical, or transdermal) for OA identified from a systematic literature search of RCTs published or publicly available before August 5, 2009, which was conducted using PubMed, the Cochrane collaboration, publicly-available websites, and reference lists of retrieved publications. DATA COLLECTION AND ANALYSIS: Data collected included: (1) pain assessed with single-item ratings and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale; (2) patient and clinician global measures of status, improvement, and treatment response; (3) function assessed by the WOMAC function subscale; (4) stiffness assessed by the WOMAC stiffness subscale; and (5) the WOMAC and Lequesne Algofunctional Index composite outcomes. Measures were grouped according to the total number of response categories (i.e., <10 categories or ≥10 categories). The treatment effect (difference in mean change from baseline between the placebo and active therapy arms) and standardized effect size (SES) were estimated for each measure in a meta-analysis using a random effects model. RESULTS: There were 125 RCTs with data to compute the treatment effect for at least one measure; the majority evaluated non-steroidal anti-inflammatory drugs (NSAIDs), followed by opioids, glucosamine and/or chondroitin, and acetaminophen. In general, the patient-reported pain outcome measures had comparable responsiveness to treatment as shown by the estimates of treatment effects and SES. Treatment effects and SESs were generally higher for patient-reported global measures compared with clinician-rated global measures but generally similar for the WOMAC and Lequesne composite measures. CONCLUSIONS: Comparing different outcome measures using meta-analysis and selecting those that have the greatest ability to identify efficacious treatments may increase the efficiency of clinical trials of treatments for OA. Improvements in the quality of the reporting of clinical trial results are needed to facilitate meta-analyses to evaluate the responsiveness of outcome measures and to also address other issues related to assay sensitivity.

Safety issues in the development of treatments for osteoarthritis: recommendations of the Safety Considerations Working Group.

OBJECTIVE: The symptomatic treatment of osteoarthritis (OA) remains to be improved, as many patients do not respond well to current palliative therapies and/or suffer unacceptable adverse events. Given the unmet need for innovative, effective and well-tolerated therapies, it is important to develop the means to estimate the ongoing safety profile of novel therapeutic agents over short- and longer term use. DESIGN: Methods are presented to estimate the number of serious adverse events (SAEs) of interest considered as "acceptable" per 1000 patient-years exposure and to estimate the numbers of patient-years needed in a randomized controlled trial (RCT) to meet objectives. As exposure is increased, more evidence is accrued that the overall risk is within study limits. It is equally important that requirements for delineating the safety of promising new therapies not create barriers that would preclude their development. Therefore, ongoing surveillance of occurrence of SAEs of interest during clinical development is proposed, for example after every incremental 500 patient-years exposure are accrued. RESULTS: This paper and others in this special issue focus on identification of safety signals for symptomatic treatments of OA. Much less information is available for agents aimed at slowing/preventing structural progression but it is expected that a higher risk profile might be considered acceptable in the context of more promising benefit. CONCLUSION: This paper provides a proposal and supporting data for a comprehensive approach for assessing ongoing safety during clinical development of both palliative and disease-modifying therapies for OA.

Toward a valid definition of gout flare: results of consensus exercises using Delphi methodology and cognitive mapping.

OBJECTIVE: To identify, in people known to have gout, the testable, key components of a standard definition of gout flare for use in clinical research. METHODS: Consensus methodology was used to identify key elements of a gout flare. Two Delphi exercises were conducted among different groups of rheumatologists. A cognitive mapping technique among 9 gout experts with hierarchical cluster analysis provided a framework to guide the panel discussion, which identified the final set of items that should be tested empirically. RESULTS: From the Delphi exercises, 21 items were presented to the expert panel. Cluster analysis and multidimensional scaling showed that these items clustered into 5 concepts (joint inflammation, severity of symptoms, stereotypical nature, pain, and gout archetype) distributed along 2 dimensions (objective to subjective features and general features to specific features of gout). Using this analysis, expert panel discussion generated a short list of potential features: joint swelling, joint tenderness, joint warmth, severity of pain, patient global assessment, time to maximum pain, time to complete resolution of pain, an acute-phase marker, and functional impact of the episode. CONCLUSION: A short list of features has been identified and now requires validation against a patient- and physician-defined gout flare in order to determine the best combination of features.

A modified Delphi exercise to determine the extent of consensus with OMERACT outcome domains for studies of acute and chronic gout.

OBJECTIVES: To reach consensus with recommendations made by an OMERACT Special Interest Group (SIG). METHODS: Rheumatologists and industry representatives interested in gout rated and clarified, in three iterations, the importance of domains proposed by the OMERACT SIG for use in acute and chronic gout intervention studies. Consensus was defined as a value of less than 1 of the UCLA/RAND disagreement index. RESULTS: There were 33 respondents (61% response rate); all agreed the initial items were necessary, except "total body urate pool". Additional domains were suggested and clarification sought for defining "joint inflammation" and "musculoskeletal function". Items that demonstrated no clear decision were re-rated in the final iteration. There were six highly rated items (rating 1-2) with four slightly lower rating items (rating 3) for acute gout; and 11 highly rated items with eight slightly lower ratings for chronic gout. CONCLUSIONS: Consensus is that the following domains be considered mandatory for acute gout studies: pain, joint swelling, joint tenderness, patient global, physician global, functional disability; and for chronic gout studies: serum urate, gout flares, tophus regression, health-related quality of life, functional disability, pain, patient global, physician global, work disability and joint inflammation. Several additional domains were considered discretionary.

OMERACT: an international initiative to improve outcome measurement in rheumatology.

OMERACT is the acronym for an international, informally organized network aimed at improving outcome measurement in rheumatology. Chaired by an executive committee it organizes consensus conferences in a 2-yearly cycle that circles the globe since 2002. Data driven recommendations are prepared and updated by expert working groups. Recommendations include core sets of measures for most of the major rheumatologic conditions. Since 2002 patients have been actively engaged in the process. OMERACT 8 will take place in Malta, May 2006 (www.omeract.org).

Randomized controlled trials in systemic lupus erythematosus: what has been done and what do we need to do?

The study of systemic lupus erythematosus (SLE) is a challenging undertaking. It is difficult to assess outcomes in SLE randomized controlled trials (RCTs), and this is illustrated by the lack of new therapies approved for use in lupus. In a disease that is waxing and waning, and requires constantly changing medications, identifying treatment effects of new therapies may be difficult, and the use of potentially toxic therapies requires a rigorous understanding of the benefit to risk ratio. Some issues that need to be considered by the investigator in designing these studies include: 1) should the trial focus on patients with active or inactive disease; 2) which of the measures of disease activity should be used or should prevention of flares be examined; 3) should the study focus on defined organ specific endpoints or utilize one of the available disease activity indices to identify changes in disease activity; 4) should the trial be a superiority trial or an equivalence trial. This review summarizes the critical issues involving the design of studies in lupus and provides the reader with suggestions and recommendations for consideration before embarking on trials in this area.

Low dose glucocorticoids in early rheumatoid arthritis.

The use of glucocorticoid therapy in the treatment of rheumatoid arthritis [RA] remains controversial. There has been much data accumulated over the years describing both the risks and benefits of acute and chronic glucocorticoid therapy. Initially there was significant enthusiasm for this type of therapy given the extent of the anti-inflammatory effects. However, use was then modified as chronic therapy with higher doses was associated with frequent reports of important safety concerns. More recently low dose glucocorticoid therapy (e.g. < or = 5 mg prednisone per day) is being reconsidered in particular for patients with early disease. This paper will review the historical experience with higher dose therapy along with the evolving evidence of an improved benefit to risk ratio with the advent of concomitant therapies to minimize some of the more problematic adverse events associated with chronic use of even low dose glucocorticoid therapy. It is suggested that with appropriate monitoring and careful concomitant prophylactic therapy to prevent osteoporosis, adjunctive therapy using low dose glucocorticoids along with the appropriate disease modifying anti-rheumatic drug may be a reasonable treatment plan for select patients.

Gastrointestinal toxic side effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2-specific inhibitors.

Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammation but are frequently associated with gastrointestinal side effects, including life-threatening bleeding or perforation of gastroduodenal ulcers. Conventional NSAIDs are nonselective inhibitors of two isoforms of cyclooxygenase (COX): COX-1 and COX-2. The inhibition of COX-1 is believed to be responsible for inducing mucosal injury primarily by impairing prostaglandin-dependent mucosal protective mechanisms. The latest development in reducing the incidence of ulcers and ulcer complications associated with conventional NSAIDs is the use of recently approved COX-2-specific inhibitors (CSIs). This article critically reviews the data on gastrointestinal toxic side effects for conventional NSAIDs without as well as with prevention therapy. In addition, we compare these data with those for the CSIs, namely, celecoxib and rofecoxib. Finally, we offer recommendations on the clinical use of these drugs, emphasizing the need to balance clinical effectiveness with the avoidance of potential gastrointestinal side effects.

COX-2 inhibitors. Are they nonsteroidal anti-inflammatory drugs with a better safety profile?

In the treatment of arthritis, NSAIDs are some of the most commonly used drugs, although the prescription of such drugs has been questioned due to their inherent risks for gastrointestinal compromise, platelet effects, and the potential for renal toxicity with long-term use. With the availability of celecoxib and rofecoxib, 2 cyclooxygenase (COX-2) inhibitors (or COX-1 sparing agents) as new forms of NSAIDs, these issues have become magnified not only in the context of risk-to-benefit ratios but also interms of pharmacoeconomics because they have been proven to be equally efficacious as the nonselective NSAIDs, with an improved safety profile particularly within the gastrointestinal tract, but at a significantly increased cost.