Fidaxomicin (1) – Dificlir®

• Clinical trials
  • Trials 101.1.C.003 and 101.1.C.004 were conducted in North America and North America and Europe, respectively. These were randomised, controlled, two-arm, multicentre, double-blind Phase III trials in which fidaxomicin was compared directly with vancomycin in a 1:1 ratio in a total of more than 1,100 adult patients.

a) Patients with mild, treatment-requiring cases of Clostridium difficile-associated diarrhoea

• For patients presenting with a mild, treatment-requiring course of Clostridium difficile-associated diarrhoea, there is no proof of additional benefit compared with the appropriate comparator therapy, metronidazole.
• The pharmaceutical manufacturer has not submitted any data for comparison with the appropriate comparator therapy, metronidazole; consequently, the additional benefit in this patient population is deemed not to have been demonstrated.

b) Patients with severe and/or recurrent courses of Clostridium difficile-associated diarrhoea

• For patients presenting with a severe and/or recurrent course of Clostridium difficile-associated diarrhoea, there is proof of considerable additional benefit compared with the appropriate comparator therapy, vancomycin.
• The certainty of the evidence (probability of additional benefit) is classified in the ‘Proof’ category.
• The G-BA classifies the extent of the additional benefit of fidaxomicin for patients with a severe and/or recurrent course of Clostridium difficile-associated diarrhoea as ‘considerable’, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the condition.
• mortality
  • No statistically significant difference in mortality was observed between the treatment groups, neither in the relevant patient population of patients with a recurrent course of the disease nor in that with a severe course of the disease – nor even for the combined patient population of patients with a severe and/or recurrent course of Clostridium difficile-associated diarrhoea – was found between the treatment groups.
  • Consequently, the additional benefit of fidaxomicin for patients with a severe and/or recurrent course of Clostridium difficile-associated diarrhoea, compared with the appropriate comparator therapy, vancomycin, is not proven in terms of mortality.
• Morbidity – Overall cure
  • The definition of the endpoint ‘overall cure’ considered for the benefit assessment is not equivalent to the concept of ‘cure of the disease’ as defined in the AM-NutzenV.
  • Due to its operationalisation, the endpoint ‘overall cure’ serves to assess the course of disease symptoms, which – based on the patient populations relevant to the benefit assessment – are clinically defined as severe or serious symptoms (multiple episodes of diarrhoea with at least three, and in severe cases more than ten, bowel movements per day; inflammatory damage to the intestinal mucosa; dehydration; fever; pain; and leukocytosis in the blood and stools).
  • The ‘Overall Resolution’ endpoint is a composite endpoint which, in addition to the ‘Cure’ endpoint at the end of the treatment phase (day 10 ± 2 days), also takes into account the proportion of relapses in patients with Clostridium difficile infection during a subsequent follow-up period of 28 ± 2 days.
  • Although there is no statistically significant difference between fidaxomicin and vancomycin when the two relevant patient populations are considered separately (this applies both at the level of individual studies and in the meta-analytic synthesis of the two studies), however, a comparison of the magnitude and location of the effect estimates shows a numerically favourable effect in favour of fidaxomicin in each case. A statistically significant effect is then observed for the meta-analytical assessment of the combined patient population of patients with severe and/or recurrent disease courses, due to greater statistical precision.
  • With regard to the combined patient populations with severe and/or recurrent disease courses, the G-BA assesses the extent of the additional benefit as considerable for the endpoint ‘overall health’, as, in these patients, against the background of the existing severity of the disease, a significant reduction in serious symptoms such as watery diarrhoea, abdominal discomfort, fever, vomiting and the resulting dehydration, as well as a reduction in the recurrence rate, is achieved.
• Health-related quality of life
  • The health-related quality of life endpoint was not assessed in any of the relevant studies. No data on health-related quality of life are available.
  • With regard to the health-related quality of life endpoint, the additional benefit of fidaxomicin is therefore deemed not proven.
• Side effects
  • The benefit assessment dossier did not present any detailed results on side effects for patients with severe and recurrent disease. Consequently, at the time of the dossier assessment, no data were available for populations with severe and/or recurrent disease courses regarding the overall rate of severe adverse events and discontinuations due to adverse events.
  • The data show no statistically significant difference between the treatment groups.
  • Overall, therefore, it is not proven that fidaxomicin causes greater or minor harm compared with vancomycin.
  • On balance, the side effects are classified as largely comparable to those of the appropriate comparator therapy, vancomycin, and therefore do not lead to a downgrading of the extent of the additional benefit in the G-BA’s assessment.
• Conclusion
  • A classification as ‘major additional benefit’ within the meaning of Section 5(7)(1) of the AM-NutzenV is not justified. The endpoint ‘overall mortality’ serves, by virtue of its operationalisation, to assess the course of disease symptoms, which are clinically categorised as serious or very serious on the basis of the relevant patient populations under consideration.
  • Based on these considerations, the information in the dossier, the results of the benefit assessment and the statements submitted, the G-BA assesses the results regarding overall survival, taking into account the data on overall mortality, quality of life and side effects as a significant improvement in treatment-related benefit for patients with Clostridium difficile infection compared with the appropriate comparator therapy, vancomycin, which has not yet been achieved, particularly in the context of a severe course of the disease and the occurrence of a first recurrence of Clostridium difficile infection.

Courtesy translation only, please refer to the German original.