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mixture. Whether it has an impact on the efficacy and safety of protiramer is not yet clear.1


Proof of equivalence requires detailed evaluation of generics in clinical trials, which must run over a sufficient period of time to reveal any potential impacts.


Efficacy


to demonstrate the conformity of the pharmacokinetic profiles of the investigational product (generics) with the original. Comparable efficacy and safety is assumed on the basis of this equivalence. For NBCDs, the situation is further complicated.3 The basis is to describe the pharmacokinetics and


pharmacodynamics of the drug. Glatiramer acetate (GA; Copaxone) shows consistent immunological pharmacodynamic effects, such as specific antibodies against cerebral spinal fluid (CSF) stimulation of peripheral blood lymphocytes, formation of GA-specific T cells etc. However, correlation between these markers and clinical efficacy has not yet been demonstrated. In the absence of validated pharmacokinetic or pharmacodynamic markers, pharmacodynamic or pharmacokinetic studies cannot be used to demonstrate clinical efficacy of generic GA or therapeutic equivalence between generics and GA.3


Immunogenicity


Immunogenicity is the ability to induce a humoral or cellular immune response. A particular problem is formation of neutralising antibodies, which may reduce the drug’s effectiveness or lead to serious side effects. Immunogenicity is influenced by many factors (for example, the chemical nature of the substance, route of administration, dosing regimen, etc). The


administration of glatiramoids is associated with high risk (the polypeptide is administered subcutaneously and in the long term, which has immunomodulatory effects and induces high IgG response). Formation of aggregates and dimers or contamination during the


manufacturing processes increase the possibility of immunogenicity further.1 This emphasises that for various glatiramoids, but also for the same glatiramoids synthesised by another manufacturer, it is necessary to expect a specific profile of immunogenicity. Administration of GA results in all treated patients developing anti-CSF antibodies. Their concentration reaches a peak between three and six months of administration and then gradually decreases. These antibodies do not appear to be neutralising – the effects of the formation of anti-CSF antibodies were evaluated in several preclinical and clinical studies that have shown the presence of antibodies to interfere with pharmacodynamic or clinical effects of treatment with GA. It was also found that the presence of anti-CSF antibodies correlated with a risk of local or systemic side effects. With protiramer, the highest levels of antibodies are reached between two and three months of therapy; this then plateaus and the concentration is maintained at the same value for nine months or more. The differences between GA and protiramer may reflect differences in dosing or polypeptide compositions of the


Another pitfall can be evaluation of the efficacy. For multiple sclerosis (MS), the efficacy of any drug is best expressed as its ability to limit progression in the Expanded Disability Status Scale (EDSS) and reduction in the frequency of relapses. Lesser indicators are effect on quality of life of patients and changes in MRI. Changes in MRI cannot be accepted as the primary endpoint of clinical trials, especially not for glatiramoids, the effects of which are highly pleiotropic. Favourable changes in MRI therefore do not indicate clinical efficacy of the drug. Last, but not of least importance, is


safety. Safety and good tolerance in the treatment of MS is indeed essential, because it is a chronic disease that requires long-term therapy. Follow-up time of at least two years and a sufficiently large sample of patients is required in demonstrating safety. Most drugs used to treat patients with MS are immunomodulators and special attention should be paid to the incidence of severe infections and autoimmune diseases, especially in situations where individual immunomodulators are combined.


GA and generics: results of practice and clinical studies We will try to outline the complexity and difficulties in the implementation and use of generic GA. Patients treated with Probioglat at Hospital la Raza in Mexico City reported an increase in the incidence of injection site reactions, painful local reactions, erythema or diffuse flushing, itching and chest pain (symptoms consistent with post- infectious immediate reactions) associated with this treatment. In the course of two to four months from the transfer of treatment from Copaxone to Probioglat, relapse occurred in more than half of patients and increased the total number of hospitalisations due to MS relapse by 200%.4


Gene expression studies comparing www.hospitalpharmacyeurope.com 15


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