Introduction

Osteoarthritis (OA), the most common of all arthritides, is a heterogeneous disease characterised by the failure of the synovial joint organ. The risk of mobility disability (defined as needing help walking or climbing stairs) attributable to knee OA alone is greater than that due to any other medical condition in people aged 65 and over . Recent estimates suggest that the global burden of knee OA affects approximately 250 million people . Although ageing is a significant risk factor, the majority of those affected with OA (64%) are of working age (15–64 years) accounting for 11% of the workforce . There are presently no therapies approved by regulatory authorities that modify the onset or progression of OA structural damage, and the available symptom-modifying (analgesic) treatments have only moderate long-term effect sizes with the majority of patients dissatisfied with their efficacy . As a result of the failure of pharmacological approaches to manage the condition, the number of joint replacement surgeries, over 95% of which are done for OA, is increasing by ∼10% annually. In the USA alone, the financial burden has been estimated to be US$81 billion in medical costs and US$128 billion in total cost, given approximately 21 million people with OA-associated limitations, 36 million outpatient visits and 750,000 hospitalizations per year . This formidable individual and socioeconomic impact of OA will continue to increase as the population ages and obesity rates continue to grow, with the number of persons affected predicted to double by 2020 .

Despite the urgency driven by its frequency, individual impact of disability, and societal cost, current treatment paradigms are limited to palliative measures broadly focussed on analgesia and, when this fails, surgical knee replacement. It is clear that finding effective disease- and symptom-modifying therapies for OA is a global unmet need whose amelioration should be an international medical priority. There have been major research advances that have significantly increased our understanding of the molecular pathophysiology of joint destruction and pain in OA. Despite this pre-clinical progress, however, no new structure-modifying therapies have translated into treatments for patients. Indeed, the recent failure of a number of phase II and III clinical trials for OA structure-modifying drugs has resulted in a considerable decline in the number and size of pharmaceutical company research programmes in this area . The reasons for the translational failure of anti-OA drugs are likely multifold, but include the poor relationship in individual patients between joint structural pathology (especially joint space narrowing (JSN) on radiographs) and symptomatic disease, and limited responsiveness of existing biological markers (biomarkers) .

This narrative chapter outlines the rationale for why we need OA biomarkers and work done in OA with regard to biomarker validation and qualification. The main biomarkers in current development for OA are biochemical and imaging markers. It then describes an approach to biomarker validation and qualification for OA clinical trials that has recently commenced with the Foundation for the National Institutes of Health (FNIH) OA Biomarkers Consortium study cosponsored by the Osteoarthritis Research Society International (OARSI).

Introduction

Osteoarthritis (OA), the most common of all arthritides, is a heterogeneous disease characterised by the failure of the synovial joint organ. The risk of mobility disability (defined as needing help walking or climbing stairs) attributable to knee OA alone is greater than that due to any other medical condition in people aged 65 and over . Recent estimates suggest that the global burden of knee OA affects approximately 250 million people . Although ageing is a significant risk factor, the majority of those affected with OA (64%) are of working age (15–64 years) accounting for 11% of the workforce . There are presently no therapies approved by regulatory authorities that modify the onset or progression of OA structural damage, and the available symptom-modifying (analgesic) treatments have only moderate long-term effect sizes with the majority of patients dissatisfied with their efficacy . As a result of the failure of pharmacological approaches to manage the condition, the number of joint replacement surgeries, over 95% of which are done for OA, is increasing by ∼10% annually. In the USA alone, the financial burden has been estimated to be US$81 billion in medical costs and US$128 billion in total cost, given approximately 21 million people with OA-associated limitations, 36 million outpatient visits and 750,000 hospitalizations per year . This formidable individual and socioeconomic impact of OA will continue to increase as the population ages and obesity rates continue to grow, with the number of persons affected predicted to double by 2020 .

Despite the urgency driven by its frequency, individual impact of disability, and societal cost, current treatment paradigms are limited to palliative measures broadly focussed on analgesia and, when this fails, surgical knee replacement. It is clear that finding effective disease- and symptom-modifying therapies for OA is a global unmet need whose amelioration should be an international medical priority. There have been major research advances that have significantly increased our understanding of the molecular pathophysiology of joint destruction and pain in OA. Despite this pre-clinical progress, however, no new structure-modifying therapies have translated into treatments for patients. Indeed, the recent failure of a number of phase II and III clinical trials for OA structure-modifying drugs has resulted in a considerable decline in the number and size of pharmaceutical company research programmes in this area . The reasons for the translational failure of anti-OA drugs are likely multifold, but include the poor relationship in individual patients between joint structural pathology (especially joint space narrowing (JSN) on radiographs) and symptomatic disease, and limited responsiveness of existing biological markers (biomarkers) .

This narrative chapter outlines the rationale for why we need OA biomarkers and work done in OA with regard to biomarker validation and qualification. The main biomarkers in current development for OA are biochemical and imaging markers. It then describes an approach to biomarker validation and qualification for OA clinical trials that has recently commenced with the Foundation for the National Institutes of Health (FNIH) OA Biomarkers Consortium study cosponsored by the Osteoarthritis Research Society International (OARSI).

The role of the critical path initiative and the biomarkers consortium in biomarker development

Cognisant of the challenges involved, stakeholders in the pharmaceutical enterprise (health-care providers, regulatory authorities, industry and payers) recognised the need for a shift in the approach to drug development . New investigational paradigms in drug development have advanced to facilitate both discovery and clinical development, without sacrificing basic regulatory standards of safety and efficacy . The US Food and Drug Administration (FDA) put forward a Critical Path Initiative that identified a choice between the status quo, ‘stagnation,’ and a new path, ‘innovation’, and described critical path research as being ‘directed towards improving the product development process itself by establishing new evaluation tools’.

The many challenges related to biomarker research and development have been clearly articulated by the FDA Critical Path Initiative and The Biomarkers Definitions Working Group . Several consortia in recent years have taken on the challenges related to biomarker development for a variety of diseases ; our own initiative, the FNIH OA Biomarkers Consortium, endeavours to identify, develop and qualify biomarkers to support new drug development, preventive medicine, and medical diagnostics for OA. The OA Biomarkers effort is part of the broader FNIH Biomarkers Consortium, a major public–private biomedical research partnership with broad participation from stakeholders across the health enterprise, including government, industry, academia and patient advocacy and other non-profit private sector organisations and is managed by the FNIH ( http://www.FNIH.org ).

Outlining the need for change in OA

Historically, disease knowledge development and treatment innovation in OA have been considered to be slow . One of the many reasons purported as responsible for this slow pace has been the alleged lack of valid and responsive biomarkers to ascertain efficacy, which itself has been dependent upon the slow evolution of the understanding of the complex nature of joint tissue biology.

The lack of valid and responsive biomarkers not only slows therapeutic advances but also blocks development of strategies to stem the tide of rising clinical trial costs. The time and cost needed to develop new compounds have increased in recent years . DiMasi et al. calculated that the average cost of bringing a drug to the market increased from US $ 318 million in 1991 to US $ 802 million in 2003 (inflation adjusted, including opportunity cost of capital) . The cost calculation comprises the expenses for failures of drug candidates in the development process. The average probability that a drug candidate will successfully pass clinical phase I studies is in the range of 75%; the respective values for phase II and III trials are 50% and 65% . In total (including further probabilities, e.g., for the regulatory review), the cumulative probability that a leading drug candidate will successfully proceed from the preclinical phase to approval is about 8% (i.e. for every 12–13 compounds that were serious candidates in preclinical research, only one drug will make it to the market) . The rising cost of drug development is imposing a significant burden on the industry engaged in therapeutic development. The attraction of integrating valid and responsive biomarkers into the therapeutic development process includes the expectation that less promising projects may be stopped earlier (especially, before they enter into costly clinical phase III ) and that the total cost of drug development will be optimised.

Some barriers to the development of OA therapeutics are unique to the OA biomarker field. First, our current reference standard for disease diagnosis and severity is often the radiograph, which has a low responsiveness to change and at most moderately correlates with clinical endpoints. Second, there is a lack of consensus for surrogate measure and efficacy of intervention development and the definition as to what constitutes a meaningful clinical endpoint. Third, OA is extraordinarily complex with marked heterogeneity in onset, clinical presentation, rate of disease progression, pattern of joint involvement and synovial tissue structure affected. These issues will be described in more detail later in the manuscript.

This vicious cycle, of imperfect biomarkers to test the efficacy of disease modifying therapies in clinical trials and the lack of effective therapies to demonstrate the validity of biomarkers, has challenged therapeutic development for years. What remains clear, however, is that it creates exciting opportunities to refine existing biomarker methods and identify new biomarkers for accelerating the development of safe and effective treatments for OA.

Challenges in OA

Many hurdles exist within OA research and development that pertain to biomarker validation and qualification. The draft regulatory (FDA) guidance and current gold standard for measuring clinical efficacy in disease modifying therapy development in OA is radiographic JSN . From JSN outcomes, the health, integrity and thickness of hyaline articular cartilage are inferred . This FDA guidance describes a process for drug approval for specific indications in OA, including treatment of symptoms and delays in structural progression and even discusses prevention of OA. The JSN measure is currently recommended by both the FDA and the European Agency for the Evaluation of Medicinal Products (EMEA) guidance documents as the imaging endpoint for clinical trials of disease-modifying OA drugs (DMOADs). At present, an alteration in structural progression would likely be determined by plain radiography, but it is possible that newer technologies may be approved including biochemical markers or magnetic resonance imaging (MRI), once appropriately validated.

If we choose the current recommended endpoint, namely JSN, due to limited responsiveness we would require many hundreds of subjects, followed for at least 2–3 years, to demonstrate a significant incremental benefit of a novel therapy over and above that provided by the currently available therapies. The direct costs of conducting such trials and the costs resulting from the overall duration of the therapeutic development and regulatory review process has dampened the enthusiasm for development of therapeutic agents in this area and, in some instances, has rendered advancement of novel treatments prohibitively expensive. On the other hand, if other, more efficient means of establishing the benefit of new drugs exist, the promise of timely access to new therapies remains. There is, therefore, potentially tremendous value to public health in accelerating the discovery and development processes for OA therapeutics through shorter studies, using validated endpoints other than radiographic JSN. The use, in part, of clinical trial evidence based on biomarker and surrogate endpoint effects (in lieu of morbidity endpoints such as joint replacement or virtual joint replacement ) has the potential to revolutionise the OA drug development process and to thereby enhance the armamentarium of safe and effective therapeutics.

This accelerated path to new therapies in OA needs to be balanced by global concerns. Unlike other diseases where surrogate endpoints exist, OA does not have a mortality endpoint but rather affects a person’s quality of life . Therefore, the ‘clinical endpoint’ is harder to establish. Furthermore, improvement in quality of life over the long interval of time that persons with this chronic disease receive therapy, can be easily dampened by toxicity . Thus, the need for therapeutic advance needs to be balanced by not only demonstrating early efficacy but also ensuring sustainability of the effect and adequate safety.

Another challenge with the radiograph as the current reference standard is that it creates an imperfect reference for comparison with other methodologies for the purposes of validation . Progression in joint space width (JSW) loss also reflects OA changes in joint tissues other than articular cartilage, particularly extrusion and degenerative changes of the menisci associated with OA development and progression . If a purported therapeutic targeted synovium or bone marrow lesions directly, ascertaining its therapeutic benefit by the measurement of JSW may not be appropriate.

Another challenge is that the current approval of potential therapies in OA requires that this structural alteration be linked to some clinical benefit either at the time when the structure was measured or at a later time-point. With this concept in mind it is obviously important that improvements in OA structural features are ascertained that are more likely linked to the clinical symptoms experienced by patients or alternatively can serve as a surrogate for a clinically meaningful outcome. Currently, there is little consensus on what constitutes a meaningful clinical endpoint for OA structure modifying trials; some suggest that the development of symptomatic radiographic OA should suffice whereas others are developing definitions for what would constitute a virtual total joint replacement . The lack of clear consensus creates an enormous challenge with regard to defining and validating the efficacy biomarkers, let alone the development of surrogate endpoints. Although the use of surrogate outcomes in clinical trials reduces sample size requirements and trial duration, they can only be justified if there is strong evidence that therapeutic targeting of the surrogate will translate into a beneficial patient outcome .

Current State of the Art

In 2008, an effort by the Osteoarthritis Research Society International (OARSI) to evaluate the science around the design of clinical development programs for the treatment and prevention of OA was launched in response to a 2007 Federal Register notice posted by the FDA seeking a critical appraisal of these issues. Among the outputs were reviews of the state of the science as it relates to both imaging and biochemical markers.

The OARSI–FDA OA Assessment of Structural Change (ASC) Working Group reviewed and synthesised published data on the performance metrics of the most common imaging tools used to assess structural change in OA, focussing predominantly on conventional radiographs and MRI. A search of plain radiography and MRI literature in OA was conducted using articles published up to the time of the search, April 2009. These systematic reviews depict the responsiveness of quantitative JSW on plain radiographs, and the responsiveness, reliability and validity of MRI measurements . A meta-analysis of the plain radiographic literature demonstrated:

• 1.
  

  Insufficient data to make any conclusion on the predictive validity of JSW and change in JSW for clinical outcomes beyond a specific trial duration (typically 1–2 years). There were, however, some trends identified including:

  
  
  
  
  • a)
    

    Baseline JSW may predict treatment outcomes, with patients with smaller JSW showing less symptomatic and structural efficacy in treatment trials.

    
    
  • b)
    

    For example, in one study the amount of JSW loss may be predictive of requirement for knee replacement surgery . In this 5-year cohort following two 3-year randomised trials, a 0.5 mm or more joint space loss during the 3-year trial was predictive of joint replacement during 5 subsequent years: four out 15 patients (26.7%) with an initial joint space loss above 0.5 mm underwent later knee surgery during the 5 years following, nine out of 118 patients (7.6%) in those with a previous joint space loss below 0.5 mm ( p = 0.019, relative risk (RR ) = 3.5, 95% confidence interval (CI) = 1.23–9.97).

  
  
  
  
• 2.
  

  Responsiveness of JSW measures pooled over multiple studies was low for all knee radiography techniques and without significant differences between techniques. Head-to-head comparisons suggested higher responsiveness with fluoroscopic semi-flexed views. Longer studies (∼2 years) offered better responsiveness. Responsiveness is assessed by calculating the standardised response mean (SRM), which is defined as the mean change divided by the standard deviation of change.

MRI measures of cartilage morphology were recommended by the Working Group for clinical trials of knee OA treatments with structural outcomes on the basis of their preferable validity and responsiveness . 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 most promising MRI measures identified in systematic reviews with respect to reliability, responsiveness and validity were quantitative cartilage morphometry, cartilage defects and bone marrow lesions on semi-quantitative analysis, bone shape/attrition and subchondral bone area; these particular parameters were subsequently selected for inclusion in the FNIH OA Biomarkers Consortium study. Research recommendations were developed through a consensus process by the ASC Working Group.

The biomarkers group of the OARSI–FDA initiative stated that there are no FDA qualified OA-related biochemical biomarkers, although there are many that have shown associations with some aspects of OA and that fulfil one or more aspects of the BIPEDS classification scheme; this scheme classifies the major types of biomarkers into six categories corresponding to B urden of disease, I nvestigational, P rognostic, E fficacy of Intervention, D iagnostic and S afety biomarkers (the latter category added as part of the OARSI-FDA initiative) . To date, a total of 12 distinct molecular biomarkers of bone and cartilage turnover that can be quantified by commercially available kits have been shown to have an association with some aspects of OA based on the BIPEDS classification scheme. These represent the best-qualified OA-related biomarkers to date but few of them have been compared in the same sample set.