Fingolimod (1) – Gilenya®

• Clinical trials
  • During the commenting procedure, the pharmaceutical manufacturer submitted a new analysis of the data on the TRANSFORMS study already set out in Module 5 of the dossier.

a) Glatiramer acetate in patients with highly active relapsing-remitting multiple sclerosis (RRMS) who have not responded to a complete and appropriate course of beta-interferons (IFN-β 1a or 1b), normally lasting at least one year

• An additional benefit over the appropriate comparator therapy, glatiramer acetate, is not proven.
• As there are no direct comparative studies between fingolimod and glatiramer acetate, the pharmaceutical manufacturer carried out an indirect comparison in the dossier on which the benefit assessment is based.
• This indirect comparison does not take into account prior treatment with beta-interferons, which is, however, a fundamental prerequisite both for the marketing authorisation and for the appropriate comparator therapy to which it relates.
• The pharmaceutical manufacturer therefore does not base its analyses on the relevant patient population a), as it predominantly includes patients who have not been treated with beta-interferons.
• The indirect comparison and the results it presents are therefore not usable for the benefit assessment.
• Nor are the data subsequently submitted by the pharmaceutical manufacturer during the written and oral commenting procedure suitable for providing proof of additional benefit.

b) IFN-β (1a or 1b) in patients with highly active RRMS who have not yet received adequate treatment with IFN-β

• The direct comparison between fingolimod and beta-interferon carried out by the pharmaceutical manufacturer in the dossier does not represent the relevant patient population, as the patient population analysed consists largely of patients who have already been treated with IFN-β (1a or 1b) for one year or longer.
• These patients have therefore received adequate treatment and do not belong to patient population (b).
• The direct comparison and the results presented therein are therefore not usable for the benefit assessment.
• Nor are the data subsequently submitted by the pharmaceutical manufacturer during the written and oral commenting procedure suitable for providing proof of additional benefit.

c) IFN-β 1a in patients with rapidly progressive severe RRMS

• Here, in the area of side effects, there is a hint of a minor additional benefit in the form of flu-like symptoms.
• The dossier analyses for this patient population could be used for the benefit assessment.
• The pharmaceutical manufacturer’s decision to restrict the patient population to treatment-naive patients results, amongst other things, in a smaller number of patients in both the fingolimod arm (27 patients) and the IFN-β arm (30 patients).
• In the authorised therapeutic indication for fingolimod, this patient population is characterised by c) not only the number of relapses and lesions detected on brain MRI, but also by the presence of disability progression.
• For the endpoints assessed as relevant in the benefit assessment report on fingolimod, a statistically significant difference in favour of fingolimod could only be demonstrated for the side effects of flu-like symptoms.
• Flu-like symptoms are not classified as serious adverse events and are non-specific in terms of their distinction from other symptoms of the disease.
• In view of the preceding comments on the data available, the minor number of patients and the lack of clarification regarding the patient population c) in relation to the endpoint of disability progression, as well as indications of an increased cardiac risk, including for the overall patient population (see ‘red-hand’ letter of 26 January 2012, Novartis Pharma GmbH), the results are subject to a high degree of uncertainty.
• Taken as a whole, therefore, there is merely a hint of a minor reduction in the risk of influenza-like symptoms.
• Side effects
  • For the endpoints assessed as relevant in the benefit-risk assessment report on fingolimod, a statistically significant difference in favour of fingolimod could only be demonstrated for the side effects of flu-like symptoms.
  • Flu-like symptoms are not classified as serious adverse events and are non-specific in their distinction from other symptoms of illness.
• Overall assessment
  • In the overall assessment, there is therefore only a hint of minor harm with regard to flu-like symptoms.

Courtesy translation only, please refer to the German original.