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The Osteoarthritis Research Society International initiated a number of working groups to address a call from the US Food and Drug Administration (FDA) on updating draft guidance on conduct of osteoarthritis (OA) clinical trials. The development of disease-modifying osteoarthritis drugs (DMOADs) remains challenging. The Assessment of Structural Change (ASC) Working Group aimed to provide a state-of-the-art critical update on imaging tools for OA clinical trials.
The Group focussed on the performance metrics of conventional radiographs (CR) and magnetic resonance imaging (MRI), performing systematic literature reviews for these modalities. After acquiring these reviews, summary and research recommendations were developed through a consensus process.
For CR, there is some evidence for construct and predictive validity, with good evidence for reliability and responsiveness of metric measurement of joint space width (JSW). Trials off at least 1 and probably 2 years duration will be required. Although there is much less evidence for hip JSW, it may provide greater responsiveness than knee JSW. For MRI cartilage morphometry in knee OA, there is some evidence for construct and predictive validity, with good evidence for reliability and responsiveness. The responsiveness of semi-quantitative MRI assessment of cartilage morphology, bone marrow lesions and synovitis was also good in knee OA.
Radiographic JSW is still a recommended option for trials of structure modification, with the understanding that the construct represents a number of pathologies and trial duration may be long. MRI is now recommended for clinical trials in terms of cartilage morphology assessment. It is important to study all the joint tissues of the OA joint and the literature is growing on MRI quantification (and its responsiveness) of non-cartilage features. The research recommendations provided will focus researchers on important issues such as determining how structural change within the relatively short duration of a trial reflects long-term change in patient-centred outcomes.
The development of disease-modifying osteoarthritis drugs (DMOADs) is faced with many challenges. There remains an inadequate understanding of the primary endpoint for demonstrating DMOAD efficacy. The actual result of clinical OA symptomatic progression, arthroplasty, is associated with multiple problems as an endpoint in clinical trials including the variability in rates of surgery, in part related to socioeconomic disparities, different healthcare environments and the relatively low incidence rate of arthroplasties compared with the total OA burden1,2. Alternative clinical endpoints for DMOAD clinical trials have therefore been considered and the Food and Drug Administration (FDA) previously provided regulatory draft guidelines for use in DMOAD development3. The FDA Clinical Development Programs for Drugs, Devices and Biological Products Intended for the Treatment of OA draft guidelines defined the current acceptable structural endpoint for DMOAD clinical trials as a slowing in the loss of knee or hip joint space narrowing (JSN) using conventional radiographs (CR); depending on the structural change this would need to be accompanied by symptom improvement. Similar recommendations were adopted by the European Medicines Agency (EMEA) in Europe4 (also adopted by the Therapeutic Goods Administration (TGA) in Australia) and remain in their recently revised Guideline5.
The current hierarchy of claims for structural outcome as defined by the FDA Clinical Development Programs for Drugs, Devices and Biological Products Intended for the Treatment of OA draft guidance is as follows:
CR have traditionally been the method of choice in clinical trials because of their relative feasibility. Until recently, it was widely accepted that alteration in progression of JSN implies preservation of hyaline cartilage and consequently clinical benefit; measurement of joint space width (JSW) by X-ray was determined as the most appropriate structural endpoint measure6,7. However it was recognized that the nature and magnitude of structural changes that are likely to be clinically relevant remain uncertain. Whether parallel clinical outcomes should be included in the claim depends on what JSW outcome is achieved, but collection of these data (including measurement of pain, a patient global assessment, a self-administered questionnaire and the time to the need for total joint replacement surgery) was strongly recommended regardless of the anticipated outcome since their assessment is critical for analysis of the overall risks and benefit of a product3. Since the concept of structural improvement connotes an element of durability, trials to demonstrate structure improvement were recommended to last at least 1 year3.
As well, owing to the rapid growth of magnetic resonance imaging (MRI) studies in the last decade, there has been an increased awareness that symptomatic OA represents a process involving all the tissues in the OA joint, not just cartilage8,9. MRI has evolved substantially over the last decade and its strengths include its ability to visualise individual tissue pathologies, as well as the interrelationship between tissue pathologies.
Although a product showing a slowing of JSN would be expected to also affect symptoms, it is possible that certain products may affect structural progression without associated symptomatic evidence10. It is also possible that slowing of structural progression may occur at an earlier time-point with later reduction in symptoms (acknowledged in the recent EMEA Guideline5). A claim of structural improvement (i.e., slowing of JSN) might conceivably be dissociated from other claims when the mechanism of action of the product, and/or the size of the effect on slowing of JSN, are suggestive of future clinical benefits. If products are not anticipated to have different effects on these parameters or show only small improvements in JSN without demonstrated effects in symptoms they will not generally be considered for approval or for separate claims. In other words, as long as an observed delay in JSN progression is correlated to an improvement of clinical outcomes it is considered as an appropriate primary endpoint and as a surrogate endpoint for total joint replacement, the critical event characteristic of medical treatment failure for OA. It is assumed that a delay in JSN will consequently delay the need for total joint surgery, and can hence be interpreted as a treatment success for DMOADs.
The use of JSN measured by CR as a structural endpoint is associated with some concerns. Since disease progression is generally slow, minimal and variable within and between subjects10,11, the use of JSW as an endpoint measurement requires long-term treatment periods (>1 year) and inclusions of large patient numbers. Moreover, the inability of radiographs to visualise cartilage leads to lack of sensitivity to detect early and small changes in this tissue12. There is difficulty in obtaining high quality reproducible images of OA joints, despite state-of-the-art standardisation of radiographic protocols to reduce the variability related to joint repositioning13. MRI studies have demonstrated that JSN represents a complex of hyaline cartilage loss, meniscal extrusion and meniscal degeneration14. Although structure is a critical component of OA assessment, the relationships between structure and pain and/or function and between structure and future outcomes (e.g., arthroplasty) are not well developed and the definition of a clinically relevant change in JSN has not been established.
The use of JSW alone may not be entirely relevant as an outcome measure for DMOAD efficacy since it fails to capture the multi-tissue nature of OA9,15. As such, potential early beneficial changes in other components of the joint are missed by the use of JSN alone as the structural endpoint. Moreover, the insensitivity of JSN to early changes in cartilage and meniscus means that even “moderate” OA knees (Kellgren–Lawrence ≥2) may already represent a stage of the disease too molecularly and biochemically advanced for alteration of disease course by pharmacological intervention. Previous attempts at OA disease modification using JSN as an endpoint have provided important lessons about the design and conduct of such trials, including issues on radiographic positioning, measurement methods, and study “enrichment” for progressors in order to ensure progression in the placebo group; this has been previously well reviewed7,16. Despite the limitations as a measure for DMOAD efficacy, delay in JSN has been reported for a small number of potential DMOADs to date7,16. However the lack of associated symptomatic benefit in these studies has prevented any of these agents from being successfully registered.
In the last decade since the FDA produced its draft guidance for industry, much evidence has been accumulated on the assessment of structural change in OA. The Osteoarthritis Research Society International (OARSI) FDA OA Assessment of Structural Change (ASC) Working Group comprised a wide range of expertise including clinical trialists, methodologists, academics, imaging experts and pharmaceutical company representatives with relevant trials experience; the Group was tasked with:
The following summary and derived recommendations attempts to overview the large amount of literature reviewed during this process. Much of the work summarised below is detailed in the more detailed accompanying systematic reviews of both radiography and MRI17–20; for this reason, individual references supporting each statement are not provided in this summary.
The underlying assumption of these recommendations is that the manifestations of joint pain and disability currently associated with OA are strongly related to the pathophysiology of OA seen in joint structures. This postulate is to some extent supported by epidemiological evidence of the association between radiographic OA, joint pain and disability in the general population.
Much of the published evidence on imaging ASC relates to OA of the knee, with much less evidence (especially for modern imaging modalities) relating to OA of the hip and very limited information available for hand OA. This summary must therefore be seen as largely related to trials for OA of the knee and to a lesser extent, the hip.
Importantly most of the therapeutic studies on OA have included symptomatic and radiographically moderate to severe OA, so there is an absence of literature and definitions for “early” OA, especially studies entering people before the currently recognized clinical syndrome is apparent and when structural pathology is presumably minimal. So the literature on the performance of existing imaging modalities at this important stage of the OA process is sparse.
When mentioned, the term `therapies' refers to drugs, devices and biological products entered into the treatment of OA and regulated by the FDA; this could also include interventions such as weight loss.
To further understand the relationship between JSN and symptoms, future studies should focus on the following areas:
For Knee OA:
For Hand OA:
As well as the areas recommended above, including research into `whole organ' or multi-tissue assessment (currently via semi-quantitative scores) and improving the quantification of non-cartilage pathologies, the MRI OA field needs:
The potential for non-CR or MRI modalities to assess relevant non-cartilage tissues should be considered. Ultrasound is currently the other recent imaging modality with most information available, and at this stage it appears it is most promising as a tool for evaluating OA synovitis. Ultrasound-detected pathologies have been associated with current OA symptoms. Further work is required to better understand the performance metrics of ultrasonographic quantification of pathology, with such work requiring improved pathology definitions.
The amount of publications assessing OA structural change has dramatically increased over recent years, related to the availability of large cohort studies. Though we now understand CR JSW represents a complex of pathologies, gaps still remain in our understanding of both construct and predictive validity. The growth of MRI as an OA imaging biomarker has evolved to a point where it can be recommended for clinical trials in terms of cartilage morphology assessment. Much still needs to be understood about compositional cartilage measures and just as importantly, quantification of non-cartilage features. The literature reviews performed by the ASC Working Group, together with attention to the research recommendations listed here, should ensure that the current gaps in our knowledge regarding the performance metrics and clinical importance of existing tools will be filled.
We acknowledge the contributions of the Assessment for Structural Change working group to this work: Jeffrey Duryea, PhD, Assistant Professor, Harvard Medical School; Garry Gold, MD, Associate Professor Radiology & Bioengineering, Stanford University; Steven Mazzuca, PhD, Director – Education, Epidemiology & Health Services, Indiana University; Timothy Mosher, MD, Professor of Radiology & Orthopaedics, Penn State University; Hollis Potter, MD, Chief, Division of MRI, Hospital for Special Surgery; David Felson, MD, MPH, Professor of Medicine & Public Health, Boston University; Gayle Lester, PhD, Program Director, Osteoarthritis & Diagnostic Imaging, NIAMS/NIH; Erika Schneider, PhD, Diagnostic Radiology, The Cleveland Clinic Foundation; Helen Keen, MBBS, Senior Lecturer, University of Western Australia; Ali Guermazi, MD, Associate Professor Radiology, Boston University; Felix Eckstein, MD, Director, Institute of Anatomy & Musculoskeletal Research, Paracelsus Medical Center; Jean Pierre Pelletier, MD, Prof of Medicine, Hopitalier de l'Universite de Montreal; Saara Totterman, MD, PhD, Chief Medical Officer, 4QImaging; Wayne Tsuji, MD, Director & Early Development Leader Medical Science Amgen; John Randle, PhD (Previous), Senior Director Commercial Development, CombinatoRx; Rose Maciewicz, PhD, Chief Scientist, Respiratory & Inflammation, AstraZeneca; Bernard Dardzinski, PhD, Senior Director – Merck & Co; Mona Wahba, MD, Executive Director, US Arthritis, Novartis; Elisabeth Morris, DVM (Previous), Senior Director Osteoarthritis Research, Wyeth; Jeffrey Kraines, MD, Senior Medical Director, Genzyme Corporation; Marie-Pierre Hellio Le Graverand-Gastineau, MD, PhD, DSc, Pfizer Global Research & Development.
Declaration of funding and role of funding source The OARSI FDA OA Initiative received financial support from the following professional organization:
Additionally the OARSI FDA OA Initiative received financial support from the following companies:
While individuals from pharmaceutical, biotechnology and device companies actively participated in on-going working group discussions, due to the conflict of interest policy enacted by OARSI, these individuals were not allowed to vote on the final recommendations made by OARSI to the FDA.
DH: receives research or institutional support from DonJoy, NIH, and Stryker.
Author contributions PC: conception, drafting, critical revision, final approval of the manuscript.
DH, JFM, WR, EL: critical revision, final approval.
Conflict of interest statement PC, JFM, WR, EL: no conflict of interest to declare.