Osteoarthritis: A Serious Disease: Submitted to the U.S. Food and Drug Administration

EXECUTIVE SUMMARY The global impact of osteoarthritis (OA) constitutes a major worldwide challenge for health systems in the twenty-first century. In 2005, 26.9 million US adults were estimated to have OA, up from 21 million in 1990. OA accounts for 2.4% of all years lived with disability (YLD) and has been ranked as the 10th leading contributor to global YLDs. The global prevalence of hip and knee OA is approaching 5% and is projected to increase as the population ages. Obesity rates are also rising globally, and as obesity is a strong risk factor for knee OA and may also increase the rates of hip, hand and spinal OA, rates of these painful conditions, together with their associated disability and loss of function, will continue to increase. The trends in OA YLDs from 1990 to 2013 showed a 75% increase, the third most rapidly rising condition associated with disability, just behind diabetes at 135% and dementia at 84%. The most recent update of the Global Burden of Disease figures, (GBD 2013) estimated that 242 million people were living in the world with symptomatic and activity limiting OA of the hip and/or knee, accounting for 13 million YLDs. These figures are likely to be an underestimate of the true global burden of OA, as these rates only consider hip and knee OA, and not OA at other sites. The economic burden of arthritis on patients and society is high in every country that it has been estimated. In 2003 the total costs attributable to arthritis and other rheumatic conditions (AORC) in the US was approximately $128 billion equalling 1.2% of the 2003 US gross domestic product. Direct costs totalled $80.8 billion (i.e., medical expenditures) and indirect costs were $47.0 billion (i.e., lost earnings). A US study in 2009 estimated costs due to hospital expenditures of total knee and hip joint replacements to be $28.5 billion and $13.7 billion respectively. When compared to age and gender matched peers, patients with OA have higher out of pocket health-related expenditures with the average direct costs of OA per patient estimated at approximately $2,600 per year. Additionally, job-related indirect costs due to loss of productivity have been estimated to cost from $3.4 to $13.2 billion per year. These figures are likely to be far greater in 2016 given the increasing prevalence of OA, the ageing population and the greater demands for and costs of medical and surgical interventions. Presently there are no drugs approved that can prevent, stop, or even restrain progression of OA. Moreover, the available medications that promise to mitigate the pain of OA have a number of risk/benefit considerations. Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with a clinically relevant 50 –100% increase in the risk of myocardial infarction or cardiovascular death compared with placebo [CNT Collaboration]. As a consequence of these treatment related adverse events and the paucity of other effective treatments, there is an urgent need for clinical studies of new and existing agents that might intervene in the pathophysiology and progression of OA. In 2014 an FDA Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics was released providing the FDA’s current thinking on four programs intended to facilitate and expedite the development and review of new drugs to address unmet medical need in the treatment of a serious or lifethreatening condition; specifically fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation. The FDA first articulated its thinking on expediting the availability of promising new therapies in regulations codified at part 312, subpart E (21 CFR part 312). Qualifying criteria for accelerated approval were a “drug that treats a serious condition and generally provides a meaningful advantage over available therapies and demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit (i.e., an intermediate clinical endpoint)”. The term serious has been defined by the FDA as “a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Shortlived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.” (21 CFR 312.300(b)(1). 3 OA has all the hallmarks of a serious condition. It is associated with a range of levels of disability severity from mild, when it may cause intermittent pain with only minimal difficulty performing daily activities, to severe with chronic pain, progressive irreversible structural damage and progressive loss of function, often with associated decline in mental health as well as an increase in mortality when a person is no longer able to walk or live independently. Pain from arthritis is one of the key barriers to maintaining physical activity and can be considered a key factor in onset of frailty in the elderly. The impact of OA is multi-factorial and depends on different contexts. Disability and loss of function associated with OA is higher in women, those with lower education levels, and the socially disadvantaged. Those reliant on manual labor, weight-bearing, or positions that involve walking or knee bending for their livelihood, are also more affected by the disability associated with OA. While there are numerous non-pharmacologic and pharmacologic interventions for OA, and integrated models of patient-centered multi-disciplinary care have been shown to reduce pain and improve function and quality of life among individuals with OA, we have no known cure or proven strategy for reducing progression from early to end-stage OA. We have no proven remedy for preventing the need for total hip or knee joint replacement, which is the end result for millions of OA patients worldwide. It is well documented that the actual rate of total joint replacement may significantly underestimate the true need. Many individuals may be in a health state that would be considered severe enough for total joint surgery, but a variety of personal and system factors are barriers to appropriate care. Further, it is also recognized that undergoing a joint replacement does not equate with remission or reversal of disability, but rather a lessening of disease severity in the replaced joint; it does not solve the problem. Most people continue to suffer some physical impairment following joint replacement and while there are improvements in pain and physical function, they do not reach the comparable level of their population peers. As many as 20-30% continue to experience pain and disability after total joint replacements and one in five require joint replacement in another joint within two years. OA is also associated with increased comorbidity. A recent systematic review found people living with OA had a pooled prevalence for overall cardiovascular disease pathology of 38.4% (95% confidence interval (CI): 37.2% to 39.6%) and were almost three times as likely to have heart failure (relative risk (RR): 2.80; 95% CI: 2.25 to 3.49) or ischemic heart disease (RR: 1.78; 95% CI: 1.18 to 2.69) compared with matched non–OA cohorts. In addition, OA significantly limits a person’s ability to self-manage other conditions, such as diabetes, and hypertension given that OA related pain is associated with reduced physical activity, which in turn is associated with increased all cause mortality. The presence of these comorbidities present contraindications to the use of existing OA therapies such as NSAIDs. Compared with the general population, people with OA have shown excess all cause mortality (standardized mortality ratio 1.55, 95% confidence interval 1.41 to 1.70). The more severe the walking disability, the higher was the risk of death (p value for trend <0.001), largely due to cardiovascular disease. Global and national health policies need to urgently address the rising burden of OA. OA has the potential to deny the sufferer the basic human rights as outlined in the United Nations Charter for Rights of Persons with Disability. OA sufferers should have the right to life, to accessibility to activities, to work, to be mobile, to be independent and be part of the community. OA-related disability threatens these rights. Access to interventions to prevent this threat are urgently needed. In the 2015 World Health Organization(WHO) publication World Report on Ageing and Health, “healthy ageing” was defined as ‘the process of developing and maintaining the functional ability that enables well being in older age. Functional ability comprises the health-related attributes that enable people to be and do what they have reason to value.’ It is clear that the pain and loss of mobility associated with OA becomes more apparent as people age and hence, people with OA are denied the right to healthy ageing. The World Health Organization Global Disability Action Plan 2014-2021, also calls for ‘better health for all people with disability’ and recognizes disability as a human rights issue. The following White Paper provides an in-depth review of the current literature and analyses of numerous OA cohorts, all supporting the designation of OA as a serious disease with no known cure and no interventions currently available to stop the progression or therapies to manage the pain and loss of mobility with an acceptable benefit:risk profile.

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