Elements Of Trial Design Research Articles

Advancing Transthyretin Amyloidosis Drug Development in an Evolving Treatment Landscape: Amyloidosis Forum Meeting Proceedings.

Hereditary transthyretin amyloidosis (ATTRv, also referred to as hATTR; ORPHA 271861) and wild-type ATTR amyloidosis (ATTRwt; ORPHA 330001) are rare, progressive, systemic protein misfolding disorders with heterogeneous clinical presentations. ATTRv and ATTRwt amyloidosis are characterized by the deposition of amyloid fibrils in multiple organs including the heart, nerves, eyes, and soft tissues. The management of ATTR amyloidosis is complex because of its multisystemic nature and progression despite available treatment options. Morbidity is high and there are many unmet medical needs for patients. While contemporary ATTR amyloidosis cohorts are diagnosed earlier, have lower risk disease and lower mortality compared with the previous era, these advances coupled with the emergence of effective disease-modifying therapies have confounded the design of future prospective clinical trials and interpretation of historical control data. The Amyloidosis Forum is a public-private partnership between the US Food and Drug Administration Center for Drug Evaluation and Research and the nonprofit Amyloidosis Research Consortium ( www.arci.org ). This article summarizes proceedings from the 21 June 2023 Amyloidosis Forum on advancing drug development in ATTR amyloidosis in an evolving treatment landscape. The Forum focused on elements of clinical trial design to address these challenges and discussed their strengths and weaknesses from multiple stakeholder perspectives (i.e., patient, sponsor, statistician, clinician, and regulatory authorities). Given rapid evolution of natural history in ATTR amyloidosis, the utility of historical control data is limited. Leveraging contemporary real-world data is essential for clinical trial design. Evidence generation from clinical trials should address clinically relevant questions. Key factors in successful trial design must be informed by up-to-date data on natural history, prognostic factors, clinically meaningful thresholds, and sharing available clinical trial data. The Amyloidosis Forum includes the community of patients with ATTR amyloidosis, the physicians who treat them, and the sponsors and regulators who collectively stand ready to support further studies in order to develop novel effective therapies.

Patient engagement in clinical trial design for rare neuromuscular disorders: impact on the DELIVER and ACHIEVE clinical trials

BackgroundEngaging individuals living with disease in drug development and regulatory processes leads to more thoughtful and sensitive trial designs, drives more informative and meaningful outcomes from clinical studies, and builds trust between the public, government, and industry stakeholders. This engagement is especially important in the case of rare diseases, where affected individuals and their families face many difficulties getting information, treatment, and support. Dyne Therapeutics is developing therapeutics for people with genetically-driven muscle diseases. During the development of potential treatments for Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1), Dyne sought the opinions of individuals living with these diseases to inform its clinical trial design and to decrease the difficulties that participants and families might experience participating in them.MethodsDyne engaged individuals and families living with DMD and DM1 as expert partners in its clinical development programs. Dyne convened panels of affected individuals and care partners/parents of individuals living with DMD (n = 8) or DM1 (n = 18). Workshops focused on how affected individuals and their families evaluate and select clinical trials for participation, the importance, quality, and burden associated with individual trial design elements, participation considerations such as site location and the study visit design, patient privacy, the suitability and scope of travel and participant support programs, and the accessibility of content in the informed consent (or assent) forms. Dyne also engaged the DMD Community Advisory Board (CAB) to collect feedback and advice on designing optimal and meaningful clinical trials and measuring relevant outcomes.ResultsThe issues most important to individuals living with DM1 and DMD regarding clinical trials were the ability to participate/access to the trial, perceptions of benefit and risk of trials and potential treatments, the flexibility of participation, clear communication from the sponsor, availability of information from trusted sources, and patient enrollment. In response to the patient advisory workshops and CAB feedback, Dyne refined clinical trial inclusion/exclusion criteria and clinic visit design, developed a travel service program to address the burden of clinical trial travel and enable long-distance and cross-border participation, planned for home visits when feasible, and allowed for adequate rest before clinic visit initiation and between assessments. Additionally, Dyne developed and implemented a transparent and consistent communications plan (including age-appropriate content) for trial participants and community members, and assessed and adjusted procedures to provide maximum participant comfort and lower anxiety, particularly with younger participants.ConclusionsOngoing communication with the Duchenne CAB and with DMD and DM1 patient advisory committee members allows Dyne to stay current with disease community perspectives and feedback on the needs and preferences of those affected and has provided valuable insights into the participant experience thereby helping Dyne initiate clinical trials that better meet the needs of affected individuals and their families.

Protocol in a Day: An Educational Institutional Workshop for Protocol Development

The Protocol-in-a-Day (PIAD) workshop was developed to support junior faculty and residents with clinical trial protocol design, with the main goal of providing initial feedback during development to reduce time for review and approval from institutional oversight committees. Our objectives are to mentor and educate participants and to evaluate the time to institutional approval by oversight committees. PIAD provided concurrent educational feedback on 6 key elements of trial design. These included: (1) regulatory aspects; (2) institutional scientific review committee (SRC) and institutional review board (IRB); (3) clinical research and data coordination (including nursing); (4) statistics; (5) correlatives including imaging, biospecimens, and health services research/patient-reported outcomes; and (6) operations. The average number of days from submission to IRB approval or study activation for PIAD protocols was compared to other protocols submitted between January 2018 - January 2022 within the Division of Radiation Oncology. Participants were also given a 15-question survey to assess their perspective of the impact of the workshop. A total of 25 protocols went through the PIAD workshop between January 2018-January 2022. Of the 25 protocols, 7 (28%) were excluded from this study due to not being submitted possibly after participants benefited from education on the limitations of their design. Eighteen protocols were included in our final analyses. These protocols included phase II (n = 11), phase 1 (n = 5), and phase III (n = 2). At the time of this report, all protocols (n = 18) have received IRB approval and have been activated. Protocol elements that could impact study activation included protocols requiring investigational new drug (IND) approval (n = 8) and multicenter studies (n = 1). Analyzing the time of submission to request for activation showed a decrease in time for protocols that went through PIAD vs those that did not [PIAD protocols, 254 days vs All other protocols, 262 days]. Likewise, those who attended PIAD had a lower average time from submission to IRB Approval [ PIAD protocols, 40 days vs All other protocols, 59 days]. All participants (100%) of the PIAD workshop responded that the educational program "improved the overall quality of the study design." The most commonly cited changes were protocol language (n = 17), statistics (n = 15), consent language (n = 8), and study design (n = 8). Aspects participants identified as the most educational included mentorship from regulatory, clinical research finance, and IRB review. PIAD from participant surveys provided high educational value in the areas of improving trial quality, language and statistical design. When analyzing the average time, from 'submission to IRB initial approval' and 'submission to activation', PIAD protocols had a shorter time for approval, and thus suggests PIAD is effective in improving the overall design of protocols.

Characteristics of Scientific Success in Phase 1 Pediatric Oncology Clinical Trials: Establishing a Need for Integrated Patient-Reported Outcomes Even in Early Phase Trials

Background: Pediatric clinical trials are particularly vulnerable to challenges in participant accrual, making them more likely to encounter early termination. Objective: To describe clinical trial characteristics of phase 1 pediatric oncology clinical trials registered in ClinicalTrials.gov through 2017. Method: We identified a retrospective cohort and abstracted key clinical trial characteristics from this data source. We calculated a bivariate logistic regression to explore factors related to early trial termination. Results: Over 1400 phase 1 trials were included in this analysis. Only 3.2% of trials included any type of patient-reported outcome (PRO) as a secondary outcome and 21.6% of phase 1 trials did not meet scientific success due to early termination. National Institutes of Health (NIH)-funded phase 1 trials had the lowest percentage of early termination. Conclusions: Phase 1 clinical trials for pediatric patients with cancer are at risk of early termination due to lack of enrollment. A deeper understanding of clinical trial design elements, characteristics, and eligibility determination may contribute to a higher proportion of trials meeting successful enrollment. Implications for Practice: Oncology nurses and nurse scientists uniquely contribute to an understanding of family-centered approaches and should take an active role in trial design for pediatric cancers that could help capture meaningful PROs during a vulnerable clinical trajectory. What Is Foundational: Very little attention has been given to understanding characteristics of phase 1 clinical trials for pediatric cancers that may impact the state of the science and care delivery for patients with advanced pediatric cancer diagnoses.

Landscape Analysis of the Application of Artificial Intelligence and Machine Learning in Regulatory Submissions for Drug Development From 2016 to 2021.

Landscape Analysis of the Application of Artificial Intelligence and Machine Learning in Regulatory Submissions for Drug Development From 2016 to 2021.

Protocol Design Variables Highly Correlated with, and Predictive of, Clinical Trial Performance.

Tufts Center for the Study of Drug Development (Tufts CSDD) collected data on trial design elements and clinical trial performance outcomes from 187 protocols provided by 20 companies. 10 design variables were tested for correlations with 11 performance variables, and regression models of each performance variable were tested. Results: Many significant correlations were found (p < .01, p < .05). The number of countries and the number of sites were each positively correlated with amendment frequency, longer screening and study duration as well as study participant dropout rates. The number of internal reviews prior to protocol finalization was also positively correlated with these same performance outcomes. In regression modeling, scientific and operational design characteristics were significant predictors of cycle time, enrollment and retention outcomes, and amendment frequency, even when controlling for phase and therapeutic area. These predictors included the number of endpoints, eligibility criteria, procedures per visit, number of countries, and investigative sites. The results of this analysis suggest practical considerations for optimizing protocol performance.

Quantifying Efficiency Gains of Innovative Designs of Two-Arm Vaccine Trials for COVID-19 Using an Epidemic Simulation Model

Clinical trials of a vaccine during an epidemic face particular challenges, such as the pressure to identify an effective vaccine quickly to control the epidemic, and the effect that time-space-varying infection incidence has on the power of a trial. We illustrate how the operating characteristics of different trial design elements may be evaluated using a network epidemic and trial simulation model, based on COVID-19 and individually randomized two-arm trials with a binary outcome. We show that “ring” recruitment strategies, prioritizing participants at an imminent risk of infection, can result in substantial improvement in terms of power in the model we present. In addition, we introduce a novel method to make more efficient use of the data from the earliest cases of infection observed in the trial, whose infection may have been too early to be vaccine-preventable. Finally, we compare several methods of response-adaptive randomization (RAR), discussing their advantages and disadvantages in the context of our model and identifying particular adaptation strategies that preserve power and estimation properties, while slightly reducing the number of infections, given an effective vaccine.

Palliative radiotherapy combined with stent insertion to reduce recurrent dysphagia in oesophageal cancer patients: the ROCS RCT.

Most patients with oesophageal cancer present with incurable disease. For those with advanced disease, the mean survival is 3-5 months. Treatment emphasis is therefore on effective palliation, with the majority of patients requiring intervention for dysphagia. Insertion of a self-expanding metal stent provides rapid relief but dysphagia may recur within 3 months owing to tumour progression. Evidence reviews have called for trials of interventions combined with stenting to better maintain the ability to swallow. The Radiotherapy after Oesophageal Cancer Stenting (ROCS) study examined the effectiveness of palliative radiotherapy, combined with insertion of a stent, in maintaining the ability to swallow. The trial also examined the impact that the ability to swallow had on quality of life, bleeding events, survival and cost-effectiveness. A pragmatic, multicentre, randomised controlled trial with follow-up every 4 weeks for 12 months. An embedded qualitative study examined trial experiences in a participant subgroup. Participants were recruited in secondary care, with all planned follow-up at home. Patients who were referred for stent insertion as the primary management of dysphagia related to incurable oesophageal cancer. Following stent insertion, the external beam radiotherapy arm received palliative oesophageal radiotherapy at a dose of 20 Gy in five fractions or 30 Gy in 10 fractions. The primary outcome was the difference in the proportion of participants with recurrent dysphagia, or death, at 12 weeks. Recurrent dysphagia was defined as deterioration of ≥ 11 points on the dysphagia scale of the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire oesophago-gastric module questionnaire. Secondary outcomes included quality of life, bleeding risk and survival. The study recruited 220 patients: 112 were randomised to the usual-care arm and 108 were randomised to the external beam radiotherapy arm. There was no evidence that radiotherapy reduced recurrence of dysphagia at 12 weeks (48.6% in the usual-care arm compared with 45.3% in the external beam radiotherapy arm; adjusted odds ratio 0.82, 95% confidence interval 0.40 to 1.68; p = 0.587) and it was less cost-effective than stent insertion alone. There was no difference in median survival or key quality-of-life outcomes. There were fewer bleeding events in the external beam radiotherapy arm. Exploration of patient experience prompted changes to trial processes. Participants in both trial arms experienced difficulty in managing the physical and psychosocial aspects of eating restriction and uncertainties of living with advanced oesophageal cancer. Change in timing of the primary outcome to 12 weeks may affect the ability to detect a true intervention effect. However, consistency of results across sensitivity analyses is robust, including secondary analysis of dysphagia deterioration-free survival. Widely accessible palliative external beam radiotherapy in combination with stent insertion does not reduce the risk of dysphagia recurrence at 12 weeks, does not have an impact on survival and is less cost-effective than inserting a stent alone. Reductions in bleeding events should be considered in the context of patient-described trade-offs of fatigue and burdens of attending hospital. Trial design elements including at-home data capture, regular multicentre nurse meetings and qualitative enquiry improved recruitment/data capture, and should be considered for future studies. Further studies are required to identify interventions that improve stent efficacy and to address the multidimensional challenges of eating and nutrition in this patient population. Current Controlled Trials ISRCTN12376468 and Clinicaltrials.gov NCT01915693. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 31. See the NIHR Journals Library website for further project information.

On Clinical Trials.

On Clinical Trials.

Adaptive designs for clinical trials

The gold standard for interventional studies is the randomized controlled trial (RCT). The RCT follows a linear path with prespecified plans and a little option for flexibility within its implementation. The RCT is also resource and time-intensive and can be a limitation in epidemics or pandemics where more rapid responses can reduce adverse effects. Adaptive designs (ADs) allow for continuous evidence-based modifications to key elements of trial design even as data collection is going on. Reduced use of resources, reduced time to complete the trial, flexibility in the allocation of participants to study arms and improved likelihood for scientifically valid trial results are added advantages with AD. ADs can be applied from early-phase trials to confirmatory trials. In this paper, we introduce key aspects of AD that Ophthalmologists can apply to clinical trials in Ophthalmology. We briefly introduce the rationale for AD, commonly used terminology, and design elements.

Standardized definitions for evaluation of heart failure therapies: scientific expert panel from the Heart Failure Collaboratory and Academic Research Consortium.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation.

Highly efficient clinical trial designs for reliable screening of under-performing treatments: Application to the COVID-19 Pandemic

The COVID-19 pandemic presents challenges for clinical trials including urgency, disrupted infrastructure, numerous therapeutic candidates, and the need for highly efficient trial and development designs. This paper presents design components and rationale for constructing highly efficient trials to screen potential COVID-19 treatments. Key trial design elements useful in this circumstance include futility hypotheses, treatment pooling, reciprocal controls, ranking and selection, and platform administration. Assuming most of the many candidates for COVID-19 treatment are likely to be ineffective, these components can be combined to facilitate very efficient comparisons of treatments. Simulations indicate such designs can reliably discard underperforming treatments using sample size to treatment ratios under 30. Methods to create very efficient clinical trial comparisons of treatments for COVID-19 are available. Such designs might be helpful in the pandemic and should be considered for similar needs in the future.

Patients' preferences of cutaneous leishmaniasis treatment outcomes: Findings from an international qualitative study.

BackgroundCutaneous leishmaniasis (CL) is a disease that often affects exposed skin areas and may heal leaving lifelong scars. Patients’ expectations from treatment are rarely considered in drug development for CL. An initiative aiming to address shortcomings in clinical trial design and conduct for CL treatments involving the researchers’ community is on-going. This manuscript presents patient-preferred outcomes for CL and an assessment on how to consider these in the conduct of future trials.Methodology/Principal findingsWe report preferred treatment outcomes by 74 patients with confirmed CL in endemic regions of Brazil, Burkina Faso, Colombia, Iran, Morocco, Peru and Tunisia during individual in-depth interviews. Beyond outcomes customarily considered in trials (such as lesion appearance and adverse events), patients talked about a large number of outcomes related to quality of life, such as pain, scar formation, and others affecting their work and daily activities. They also reported fears around getting rid of the parasite, disease recurrence, and possible sequelae.Conclusions/SignificanceThe study results provide a rich insight into important outcomes for CL treatments, as well as related topics, from the perspective of a diverse patient population. Among the outcomes identified, we argue that those related to quality of life as well as recurrence should be included to a greater extent for assessment in clinical trials, and discuss the suitability of measurement instruments such as the Dermatology Quality of Life Index (DLQI). Interviews also point out the potential need to address concerns related to parasitological cure or scar formation, such as social stigmatization and disability. In addition, patients should be given information in order to clarify reported misconceptions. This study therefore suggests a methodology for consulting CL patients on outcomes as elements of clinical trial design, and how to incorporate these outcomes in trials. It also discusses how reported outcomes could be addressed in clinical care.

Altered functional activation during happy face processing in youth at risk for bipolar disorder

Increasing rates of antimicrobial-resistant infections and the dwindling pipeline of new agents necessitate judicious, evidence-based antimicrobial prescribing. Clinical trials represent a vital resource for establishing evidence of safety and efficacy, which are crucial to guiding antimicrobial treatment decisions. The objective of this study was to comprehensively evaluate the characteristics of antimicrobial research studies registered in ClinicalTrials.gov. Primary outcome measures, funding sources, inclusion criteria and the reporting of study results were evaluated for 16 055 antimicrobial studies registered in ClinicalTrials.gov as of mid 2012. Interventional studies accounted for 93% of registered antimicrobial studies. Clinical trials of drugs (82%) and biologics (9%) were most common. Antibacterial, antiviral and antifungal studies accounted for 43%, 41% and 16% of drug trials, respectively. Among interventional drug trials, 73% featured randomised allocation to study arms and 71% included measures of safety and/or efficacy as primary endpoints. Children were eligible for enrolment in 26% of studies. Among the studies, 60% were sponsored primarily by non-profit organisations, 30% by industry and 10% by the federal government. Only 7% of studies reported results; however, 71% of these were sponsored primarily by industry. Antimicrobial studies commonly incorporated elements of high-quality trial design, including randomisation and safety/efficacy endpoints. Publication of study results and updating of ClinicalTrials.gov should be encouraged for all studies, with particular attention paid to research sponsored by non-profit organisations and governmental agencies. Leveraging the application of these data to guide the careful selection of antimicrobial agents will be essential to preserve their utility for years to come.

Clinical trials in end-stage renal disease—priorities and challenges

Patients with end-stage renal disease (ESRD) experience extremely high morbidity and mortality and there are virtually no therapeutic interventions besides dialysis treatment that are proven in properly designed randomized controlled trials (RCTs) to improve patients' outcomes. Historically, the number of RCTs performed in the ESRD population has been very low compared with other medical subspecialties, and several of the few large RCTs have yielded inconclusive or negative results, dampening enthusiasm for future investment in similar trials. Recent initiatives promoting a focus on patient-centered outcomes and more active patient and caregiver involvement in the planning and conduct of clinical trials may result in more clinically relevant RCTs and broader participation from patients representing the diversity of the ESRD population. The adoption of novel clinical trial design elements characteristic of pragmatic clinical trials and platform trials could help improve both the internal and external validity of RCTs in ESRD, ultimately resulting in the adoption of therapeutic interventions that can be rapidly translated to clinical practice.

Methods for measuring patient preferences: an update and future directions.

The current review highlights the growing number of available methods used to measure patient preferences and discusses how this impacts preference research in rheumatology. Spurred by the growing role of preferences in regulatory decisions and drug development, researchers have begun applying preference methods to study questions beyond the clinical context. We explore these trends, provide case studies highlighting changes in measuring patient preferences, compare strengths and weaknesses of common stated-preference methods, and discuss considerations for the future use of these methods. Early literature on patient preferences often mimicked clinical practice, asking whether treatment A is better or worse than treatment B for a patient. Early applications of patient preference methods in rheumatology aimed to value different attributes of treatments, but remained focused on informing clinical questions. Spurred by interest in preferences by regulatory agencies and patient-centeredness throughout the product lifecycle, there are now a wide array of methods available to measure preference. Although these different preference methods have strengths and weaknesses, they serve to highlight the broad number of questions that could help rheumatology beyond the clinical context. Researchers in rheumatology now have the opportunity to better serve diverse stakeholders by considering how these methods could aid in clinical trial design, regulatory policy, and other elements of the medical product life cycle.

Perspectives on Adjuvant Therapy in Renal Cell Carcinoma

Perspectives on Adjuvant Therapy in Renal Cell Carcinoma

Clinical trial design for cutaneous neurofibromas.

Several clinical trials targeting cutaneous neurofibromas (cNF) have been conducted; however, none has resulted in meaningful changes to care. The Clinical Trial Design and Development subgroup's goals were to (1) define key considerations in the design of clinical trials for cNF, (2) summarize existing data in relation to these considerations, and (3) provide consensus recommendations about key elements of trial design to accelerate the clinical development of therapies for cNF. The subgroup, with experts from genetics, dermatology, neurology, oncology, and basic science, spanning academia, government research, and regulatory programs, and industry, reviewed published and unpublished data on clinical trials for cNF and other diseases in the skin. Discussions of these data resulted in formulation of a list of priority issues to address in order to develop efficient and effective clinical trials for cNF. The subgroup identified 2 natural history studies of cNF, 4 priority outcome measures, and 6 patient-reported outcome tools for potential use in efficacy trials of cNF. Time to initiate intervention, patient eligibility, mechanism of action, route of administration, safety monitoring, and regulatory agency interactions were identified as key factors to consider when designing clinical trials for cNF. Alignment on endpoints and methods for the measurement and quantification of cNF represent a priority for therapeutic development for cNF. Advances in technological methods and outcome tools utilized in other skin diseases may be applicable to cNF studies. Patient age is an important factor guiding trial design and clinical development path.

Identification of approval conditions for orphan drugs for neurological disorders by the Japanese regulatory agency

ABSTRACTBackground: Orphan drugs are used to treat rare diseases. Since consistent criteria for regulating these drugs are not clarified, we sought to identify the regulatory requirements and trial design elements of clinical trials for orphan drugs approved by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan.Research design and methods: We identified orphan drugs approved to treat neurological disorders during April 2006–March 2016, using PMDA data. We investigated characteristics of pivotal trials from drug labels and drug approval packages, and identified six elements of clinical trial design: use of controls, blinding, randomization, size, analysis type, and end point. The evidence for efficacy provided by the PMDA was also collected for each drug.Results: PMDA has approved orphan drugs for neurological diseases in a flexible manner. Randomized, double-blinded, placebo-controlled pivotal trials were not always included in the new drug application package. The PMDA tended to make a positive judgment decision when a controlled trial was performed in Japan, regardless of the existence of foreign data.Conclusions: We provide a review of the Japanese regulatory environment for orphan drug approval in the neurological field by assessing the characteristics of clinical trials for orphan drugs indicated for neurological diseases in Japan.

Emerging Treatment Models in Rheumatology: Challenges for Osteoarthritis Trials.

At a time when advancing understanding of osteoarthritis (OA) has created opportunities for new treatments, development of treatments has remained considerably behind advances in other rheumatic diseases. We describe elements of trial design and measurements that have inhibited success and offer suggestions that may help break the log jam. Among the problems with trials that include pain as an outcome measure are reliance on a single, non-optimal pain outcome, overestimation of likely effects of treatments on pain, and failure to identify patient subgroups most likely to respond to specific treatments. With regard to the use of structure modification as an outcome measure, demonstrating structure modification is often highly challenging, even with the use of magnetic resonance imaging. Many OA patients have advanced disease that is unlikely to respond to treatments that prevent cartilage loss. Further, prevention of cartilage loss and reduction of pain correlate weakly at best, and in at least some patients, reduction in pain may actually increase joint damage, making it impossible to demonstrate dual treatment effects on structure and pain in such scenarios. For structure outcomes, treatment effects on pain-sensitive structures such as bone and synovium may be more achievable than preventing cartilage loss. We suggest that changes in trial design related to some of these issues may increase the chances that new exciting and effective OA treatments will become available.