Patient based method of assessing adverse events in clinical trials in rheumatology: the revised Stanford Toxicity Index

We describe the progress towards developing a patient rated toxicity index that meets all of the patient-important attributes defined by the OMERACT Drug Safety Working Party. These attributes are frequency, severity, importance to patient, importance to the clinician, impact on economics, impact on activities, and integration of adverse effects with benefits. The Stanford Toxicity Index (STI) has been revised to collect all attributes with the exception of impact on activities. However, since the STI is a part of the Health Assessment Questionnaire (HAQ), impact on activities is collected by the HAQ. In particular, a new question asks patients to rate overall satisfaction, taking into consideration both benefits and adverse effects. The next step in the development of this tool is to ensure that the STI meets the OMERACT filter of truth, discrimination, and feasibility. Although truth and feasibility have been confirmed by comparisons within the ARAMIS database, discrimination needs to be assessed in clinical trials.     

Standardizing assessment of adverse effects in rheumatology clinical trials. Status of OMERACT Toxicity Working Group March 2000: towards a common understanding of comparative toxicity/safety profiles for antirheumatic therapies

This paper describes the background and current status of an OMERACT facilitated effort to improve the consistency of adverse event reporting in rheumatology clinical trials. The overall goal is the development of an adverse event assessment tool that would provide a basis for use of common terminology and improve the consistency of reporting severity of side effects within rheumatology clinical trials and during postmarketing surveillance. The resulting Rheumatology Common Toxicity Criteria Index encompassed the following organ systems: allergic/immunologic, cardiac, ENT, gastrointestinal, musculoskeletal, neuropsychiatric, ophthalmologic, pulmonary and skin/integument. Before this tool is widely accepted, its validity, consistency, and feasibility need to be assessed in clinical trials.     

OMERACT consensus-based operational definition of contextual factors in rheumatology clinical trials: A mixed methods study

ObjectivesTo develop an operational definition of contextual factors (CF) [1].MethodsBased on previously conducted interviews, we presented three CF types in a Delphi survey; Effect Modifying -, Outcome Influencing - and Measurement Affecting CFs. Subsequently, a virtual Special Interest Group (SIG) session was held for in depth discussion of Effect Modifying CFs.ResultsOf 161 Delphi participants, 129 (80%) completed both rounds. After two rounds, we reached consensus (≥70% agreeing) for all but two statements. The 45 SIG participants were broadly supportive.ConclusionThrough consensus we developed an operational definition of CFs, which was well received by OMERACT members.     

Harms reported by patients in rheumatology drug trials: a systematic review of randomized trials in the cochrane library from an OMERACT working group

BackgroundUnderreporting of harms in randomized controlled trials (RCTs) may lead to incomplete or erroneous assessments of the perceived benefit-to-harm profile of an intervention. To compare benefit with harm in clinical practice and future clinical studies, adverse event (AE) profiles including severity need to be understood. Even though patients report harm symptoms earlier and more frequently than clinicians, rheumatology RCTs currently do not provide a reporting framework from the patient's perspective regarding harms. Our objective for this meta-research project was to identify AEs in order to determine harm clusters and whether these could be self-reported by patients. Our other objective was to examine reported severity grading of the reported harms.MethodsWe considered primary publications of RCTs eligible if they were published between 2008 and 2018 evaluating pharmacological interventions in patients with a rheumatic or musculoskeletal condition and if they were included in Cochrane reviews. We extracted data on harms such as reported AE terms together with severity (if described), and categorized AE- and severity-terms into overall groups. We deemed all AEs with felt components appropriate for patient self-reporting.ResultsThe literature search identified 187 possible Cochrane reviews, of which 94 were eligible for evaluation, comprising 1,297 articles on individual RCTs. Of these RCTs, 93 pharmacological trials met our inclusion criteria (including 31,023 patients; representing 20,844 accumulated patient years), which reported a total of 21,498 AEs, corresponding to 693 unique reported terms for AEs. We further sub-categorized these terms into 280 harm clusters (i.e., themes). AEs appropriate for patient self-reporting accounted for 58% of the AEs reported. Among the reported AEs, we identified medical terms for all of the 117 harm clusters appropriate for patient reporting and lay language terms for 86%. We intended to include severity grades of the reported AEs, but there was no evidence for systematic reporting of clinician- or patient-reported severity in the primary articles of the 93 trials. However, we identified 33 terms suggesting severity, but severity grading was discernible in only 9%, precluding a breakdown by severity in this systematic review.ConclusionsOur results support the need for a standardized framework for patients’ reporting of harms in rheumatology trials. Reporting of AEs with severity should be included in future reporting of harms, both from the patients’ and investigators’ perspectives.RegistrationPROSPERO: CRD42018108393     

Standardizing assessment and reporting of adverse effects in rheumatology clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0

OBJECTIVE: The OMERACT Drug Safety Working Group focuses on standardization of assessment and reporting of adverse events in clinical trials and longitudinal and observational studies in rheumatology. This group developed the Rheumatology Common Toxicity Criteria (RCTC) in 1999, building on the Oncology Common Toxicity Criteria. At OMERACT 8, a workshop group reviewed the use of the RCTC and other instruments in rheumatology clinical trials to date, to revise and to stimulate its implementation. METHODS: The Working Group drafted a revision of the RCTC after an iterative examination of its contents, terms, and definitions. The RCTC were compared with the Oncology Common Toxicity Criteria (CTC v.2.0), and the Common Terminology Criteria for Adverse Events (CTCAE v.3.0). In addition a pharmaceutical company focus group met to clarify the challenges of application of RCTC terms and definitions, relative to the standard in pharmaceutical clinical trials, i.e., verbatim recording of adverse events followed by mapping to Medical Dictionary of Drug Regulatory Activities (MedDRA) terms. The workshop focused on the proposed revision of RCTC to version 2.0 and on the research agenda, including a validation of the RCTC in future trials. RESULTS: At OMERACT 8, breakout groups amended the contents of the 4 current and 2 new categories of adverse event terms within the draft RCTC v.2.0. Participants recognized the need to standardize the definitions for disease flares, infection, malignancy, and certain syndromes such as drug hypersensitivity and infusion reactions. Moderate consensus (62%) was reached in the final plenary session that the amended RCTC v.2.0 should be promulgated and tested in available trials of anti-tumor necrosis factor agents. CONCLUSION: The RCTC has face validity and construct validity. However, documentation of discrimination and feasibility (the other elements of the OMERACT filter) is needed. Collaboration with drug safety working groups in rheumatology professional organizations is necessary to enable this project.     

Toward development of a fibromyalgia responder index and disease activity score: OMERACT module update

Following development of the core domain set for fibromyalgia (FM) in Outcome Measures in Rheumatology Clinical Trials (OMERACT) meetings 7 to 9, the FM working group has progressed toward the development of an FM responder index and a disease activity score based on these domains, utilizing outcome indices of these domains from archived randomized clinical trials in FM. Possible clinical domains that could be included in a responder index and disease activity score include pain, fatigue, sleep disturbance, cognitive dysfunction, mood disturbance, tenderness, stiffness, and functional impairment. Outcome measures for these domains demonstrate good to adequate psychometric properties, although measures of cognitive dysfunction need to be further developed. The approach used in the development of responder indices and disease activity scores for rheumatoid arthritis and ankylosing spondylitis represents heuristic models for our work, but FM is challenging in that there is no clear algorithm of treatment that defines disease activity based on treatment decisions, nor are there objective markers that define thresholds of severity or response to treatment. The process of developing candidate dichotomous responder definitions and continuous quantitative disease activity measures is described, along with participant discussions from OMERACT 10. Final results of this work will be published in a separate report pending completion of analyses.     

特发性肺纤维化治疗药物临床试验进展

特发性肺纤维化(IPF)是一种慢性进行性纤维化性肺疾病,预后不良.目前抗肺纤维化药物吡非尼酮和尼达尼布已获批上市,能够部分地延缓IPF患者肺功能的下降.随着对肺纤维化机制的认识,针对不同部位、不同靶点的抗肺纤维化药物研发速度加快,呈现多元化的趋势.本文就IPF抗肺纤维化新药临床试验进展进行综述.     

The prevalence of underpowered randomized clinical trials in rheumatology

OBJECTIVE: The conduct of underpowered randomized controlled trials (RCT) has recently been criticized in medical journals. We investigated the current prevalence of underpowered RCT in rheumatology. METHODS: We searched to identify randomized, prospective RCT assessing clinical efficacy of treatments for adult rheumatic diseases published in English in 2001 and 2002. RCT were assessed as positive or negative based on the result of the primary outcome measure. For phase III RCT with negative results without power analysis, we calculated adequate sample size using beta = 0.20 and alpha = 0.05. We also examined trial quality by assessing the adequacy of reported random sequence generation, allocation concealment, and analysis, and compared the quality of reporting of RCT with adequate and inadequate sample size. RESULTS: A total of 228 RCT met inclusion criteria; of the 205 phase III trials, 119 were positive, 81 were negative. The remaining 5 trials made no statistical comparison between interventions, and did not supply enough information for a result to be calculated. Of the 86 negative or indeterminate RCT, 37 reported sample size calculations (all but 4 had adequate power). Of the 49 remaining phase III trials that did not report power calculations, we conducted sample size calculations; only 10 were adequately powered. Few of the underpowered RCT studied rare rheumatic diseases. Negative RCT with inadequate sample size were less likely to describe adequate random sequence generation or allocation concealment than positive RCT or negative RCT with adequate sample size. CONCLUSION: The conduct of underpowered trials is not an infrequent occurrence in rheumatology, with only 50% of negative or indeterminate phase III rheumatology RCT in 2001-2002 having adequate sample size.     

Endorsement of the OMERACT core domain set for shared decision making interventions in rheumatology trials: Results from a multi-stepped consensus-building approach

ObjectiveTo gain consensus on the Outcome Measures in Rheumatology (OMERACT) core domain set for rheumatology trials of shared decision making (SDM) interventions.MethodsThe process followed the OMERACT Filter 2.1 methodology, and used consensus-building methods, with patients involved since the inception. After developing the draft core domain set in previous research, we conducted five steps: (i) improving the draft core domain set; (ii) developing and disseminating white-board videos to promote its understanding; (iii) conducting an electronic survey to gather feedback on the draft core domain set; (iv) finalizing the core domain set and developing summaries, a plenary session video and discussion boards to promote its understanding; and (v) conducting virtual workshops with voting to endorse the core domain set.ResultsA total of 167 participants from 28 countries answered the survey (62% were patients/caregivers). Most participants rated domains as relevant (81%-95%) and clear (82%-93%). A total of 149 participants (n = 48 patients/caregivers, 101 clinicians/researchers) participated in virtual workshops and voted on the proposed core domain set which received endorsement by 95%. Endorsed domains are: 1- Knowledge of options, their potential benefits and harms; 2- Chosen option aligned with each patient's values and preferences; 3- Confidence in the chosen option; 4- Satisfaction with the decision-making process; 5- Adherence to the chosen option and 6- Potential negative consequences of the SDM intervention.ConclusionWe achieved consensus among an international group of stakeholders on the OMERACT core domain set for rheumatology trials of SDM interventions. Future research will develop the Core Outcome Measurement Set.Clinical significancePrior to this study, there had been no consensus on the OMERACT core domain set for SDM interventions. The current study shows that the OMERACT core domain set achieved a high level of endorsement by key stakeholders, including patients/caregivers, clinicians and researchers.     

Secular changes in the quality of published randomized clinical trials in rheumatology

OBJECTIVE: To assess the quality of published randomized clinical trials (RCTs) in rheumatology and to determine whether there has been improvement in quality between 2 time periods, 1987-1988 and 1997-1998. METHODS: Using MEDLINE and a hand search of selected rheumatology journals, we identified RCTs of adult rheumatic diseases published in English in 1987-1988 or 1997-1998. We examined trial quality with an expanded version of the Jadad scale, which assesses the adequacy of reported random sequence generation, allocation concealment, blinding, and analysis. All trials were read by 1 reviewer, with prior standardization using a random sample read by 2 reviewers. We also evaluated "high"- versus "low"-impact journals based on citation index. RESULTS: Two hundred forty RCTs (1987-1988 119 RCTs, 1997-1998 121 RCTs) were assessed. Results showed improvement in the quality of the trials, but the rates of reported random sequence generation, allocation concealment, power, and intent-to-treat analyses were persistently low. Low rates of reports of random sequence generation, allocation concealment, and intent-to-treat analyses were present even in the high-impact journals. CONCLUSION: There has been improvement in the quality of reporting of RCTs in rheumatology between 1987-1988 and 1997-1998. However, methodologic problems such as lack of allocation concealment, inadequate random sequence generation, lack of reporting of power, and lack of intent-to-treat analyses remain common. Many of these problems are established sources of bias in RCTs and are easily rectifiable.     

2021 clinical trials update: Innovations in hemophilia therapy

Therapies engineered to prolong clotting factor protein circulation time, manipulate the balance of pro‐coagulant and anti‐coagulant proteins, or introduce new genetic material to enable endogenous factor protein production dominate the clinical trial landscape of hemophilia. The availability of clotting factor concentrates and the establishment of primary prophylaxis have dramatically improved health outcomes for hemophilia patients. But, the burden of hemostatic therapy remains significant, and many barriers to consistent longitudinal use of prophylaxis exist. Several types of emerging therapeutics including engineered factor concentrates, substitutive therapies, rebalancing therapies, and gene transfer/editing all aim to reduce the challenges of current hemophilia treatment. Emerging treatment options may reduce treatment frequency or need for intravenous administration. They may also introduce new challenges in laboratory assessment of hemostasis. These novel therapies must not introduce significant new health risks and continue to support similar or improved outcomes. The potential ramifications of rebalancing the coagulation cascade, particularly in a stress or inflammatory state, or introduction of new genetic material are not trivial. The focus of this review is to provide an overview of active and recently completed clinical trials as well as emerging preclinical data investigating new therapeutic possibilities for hemophilia patients and potentially other rare bleeding disorders.     

Incorporating the patient perspective into outcome assessment in rheumatoid arthritis--progress at OMERACT 7

The Patient Perspective Workshop at OMERACT 7 addressed the question of assessing the outcomes of intervention in rheumatoid arthritis (RA) from the perspective of those who experience the disease. A particular emphasis at this workshop was placed on fatigue, but other areas included well-being, real-time assessment, patient priorities, and needs in early and late disease. Through a series of overview presentations, discussion groups, and plenary sessions, workshop participants (who included 19 patients) clarified what is known and what are the outstanding issues for future research. The importance of further work on clarifying the validity of fatigue measurements in RA has been confirmed, and with at least one suitable instrument available there will be strong pressure to include fatigue in a redefined core set of outcome measures in RA. In the other 4 areas covered there are important issues that can be addressed by enquiry and experiment and that together provide a challenging research agenda. At the final plenary session the OMERACT conference endorsed, by a large majority, the proposal that fatigue may warrant consideration for inclusion in the OMERACT core set for RA.     

Clinimetric concepts in outcome assessment: the OMERACT filter

Validation is the process by which the clinical measurement (clinimetric) properties of an assessment procedure are formally evaluated. In the case of outcome measures, this process traditionally establishes the reliability, validity, and responsiveness of the measurement technique. Although the statistical methods used are diverse, the principles to be followed have been well established and are generally accepted. The basic issues are similar and transcend outcome measurement in different medical conditions. In addition to fulfilling clinimetric requirements, outcome measures are required to be practical in their application. The OMERACT group have recently proposed a novel user-friendly paradigm to capture the essential elements of truth, discrimination, and feasibility. This paradigm is termed the OMERACT filter.     

Selection of controls in clinical trials: introduction and conference summary

Understanding the strengths and weaknesses of the control group used in a randomized clinical trial is essential because comparisons of outcomes between the investigational and control groups form the basis of inferences regarding the safety and efficacy of the investigational treatment. For its 2007 International Conference, the American Thoracic Society (ATS) sponsored a scientific symposium in which the strengths and limitations of different types of control groups in clinical trials of pharmacotherapy, procedures, devices, and behavioral interventions were discussed. In this section, the co-chairs of this ATS symposium provide an overview of the presentations, including a brief historical perspective on the use of control groups in clinical trials.