Off-Label Prescription Drugs Use in Pediatric Rheumatology

Written on 15 October 2016. Posted in Rheumatology News & Perspectives

Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration [1]. While approved drugs remain the exception for children with rheumatic diseases, the off-label use is sometimes standard practice.

A child with a juvenile idiopathic arthritis today is expected to have a significantly better prognosis than was the case in previous decades. This is due to the improvement of the care structures, the development and application of guidelines and recommendations, and the existence of a pathogenetically oriented pharmacotherapy [2,3] proven to be effective in clinical trials with standardized test criteria. In general, therapeutic goals can now be formulated which go far beyond symptom control. The needs and expectations of patients, parents and physicians are often met targeting: 

• remission or reaching an inactive disease stage of rheumatic disease, 
• normal growth and normal development, 
• good to very good quality of life, 
• minimizing side effects and risks.

However, this applies to only a part of the patients with certain rheumatic diseases particularly because of the increasing number biologics available on the market for more than 15 years. Thus, four biologics are approved for the treatment of polyarticular juvenile idiopathic arthritis (JIA) with abatacept, adalimumab, etanerept and tocilizumab, two systematic JIAs, canakinumab and tocilizumab, and two, adalimumab, for the beeses-assisted JIA (juvenile spondylarthropathy) And etanercept, and for psoriasis arthritis only etanercept. As studies on other biologics do not exist or are not finalized, for example, certolizumab, golimumab, infliximab, rituximab or ustekinumab are not approved for children under 18 years of age with rheumatic diseases, although a comparable therapeutic value can be assumed as in adults.

Off-label use in numerous clinical situations

This is the case, for example, for the JIA-associated chronic uveitis, where methotrexate and anti-TNF antibodies are necessary but not approved, as well as for other significant diseases such as systemic lupus erythematosus and lupus nephritis, genetic autoinflammatory diseases (except CAPS) and vasculitides in childhood. As a consequence, children and adolescents with rheumatic diseases are treated too late or inadequately, or are not treated according to the current treatment options. This leads to a further necessity for the use of off-label therapy in numerous clinical situations. 

In a study conducted at a German university clinic, 41 per cent of in-patients treated in the first year were treated with non-approved substances [4]. In ambulatory care, 61 percent of patients (253 of 417) received at least one off-label use prescription and the proportion of off-label use drugs out of all prescriptions was 31 percent (553 from 1812). This high rate is also confirmed by the analysis of health insurance data, according to which the off-label use regulation was 10 to 20 percent in outpatient pediatric care and 30 to 70 percent in hospitals [5]. The off-label therapy is therefore a daily practice in the care of children, and in particular in cases of seriously ill, in-hospital treated children.

In addition to the problem of cost-taking, off-label use therapy also involves a safety risk for the patient. In an analysis, the incidence of adverse drug reactions in off-label therapies was significantly higher. [6]

For the specific situation in pediatric rheumatology, a small number of innovative drugs are approved for individual diseases and few approvals may be expected in the coming years. Alternatives for therapy failure or intolerance are often lacking.

While many rheumatic diseases are rare in adults, this is even more pronounced for children. Often these very rare diseases are particularly severe. This creates a dilemma, because in the case of rare diseases, the development and monitoring of therapies for the pharmaceutical industry is uneconomical. The "pediatric investigation plan" of the European Medicines Agency (EMEA) can not solve this problem, since it is based on diseases of adults and their parallels in the childhood and not by the special requirements of children affected.

In conclusion, especially children with severe diseases are at a risk for a permanent injury in our society because they are poorly treated as adults. The elements of the society involved, from politics to medicine to industry, must be responsible for this situation.

Tags: off-label, pediatrics, biologics, anti-TNF, JIA, drugs

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