Assessing the potential impact of non-proprietary drug copies on quality of medicine and treatment in patients with relapsing multiple sclerosis: the experience with fingolimod

BACKGROUND: Fingolimod is a once-daily oral treatment for relapsing multiple sclerosis, the proprietary production processes of which are tightly controlled, owing to its susceptibility to contamination by impurities, including genotoxic impurities. Many markets produce nonproprietary medicines; assessing their efficacy and safety is difficult as regulators may approve nonproprietary drugs without bioequivalence data, genotoxic evaluation, or risk management plans (RMPs). This assessment is especially important for fingolimod given its solubility/bioavailability profile, genotoxicity risk, and low-dose final product (0.5 mg). This paper presents an evaluation of the quality of proprietary and nonproprietary fingolimod variants. METHODS: Proprietary fingolimod was used as a reference substance against which eleven nonproprietary fingolimod copies were assessed. The microparticle size distribution of each compound was assessed by laser light diffraction, and inorganic impurity content by sulfated ash testing. Heavy metals content was quantified using inductively coupled plasma optical emission spectrometry, and levels of unspecified impurities by high-performance liquid chromatography. Solubility was assessed in a range of solvents at different pH values. Key information from the fingolimod RMP is also presented. RESULTS: Nonproprietary fingolimod variants exhibited properties out of proprietary or internationally accepted specifications, including differences in particle size distribution and levels of impurities such as heavy metals. For microparticle size and heavy metals, all tested fingolimod copies were out-of-specification by several-fold magnitudes. Proprietary fingolimod has a well-defined RMP, highlighting known and potential mid- to long-term safety risks, and risk-minimization and pharmacovigilance procedures. CONCLUSION: Nonproprietary fingolimod copies produced by processes less well controlled than or altered from proprietary production processes may reduce product reproducibility and quality, potentially presenting risks to patients. Safety data and risk-minimization strategies for proprietary fingolimod may not apply to the nonproprietary fingolimod copies evaluated here. Market authorization of nonproprietary fingolimod copies should require an appropriate RMP to minimize risks to patients.