Obinutuzumab (4) – Gazyvaro®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer has presented the results of the randomised, three-arm, open-label, multicentre Phase III trial CLL11 in the dossier.

Adult patients with previously untreated chronic lymphocytic leukaemia (CLL) who, due to comorbidities, are not suitable for treatment with a full dose of fludarabine

• Consequently, it is concluded that the additional benefit is not proven.
• Irrespective of the change to the appropriate comparator therapy in the present procedure, the presentation of the study data in the dossier proved to have a seriously inadequate and incomplete extent in terms of content, with the result that this precludes a proper assessment of the additional benefit.
• The dossier did not contain analyses for all the endpoints recorded for any of the data sets, in particular not for the final one.
• Furthermore, the analyses of patient-reported endpoints were inadequate.
• Moreover, the results presented on common adverse events were incomplete.
• It should also be noted that, with regard to side effects, only analyses for the overall population were submitted, but not for the relevant patient population.
• Nor were the analyses submitted subsequently with the written statement suitable for enabling a proper assessment of the additional benefit, due to their inadequate processing.
• mortality
  • For the patient population, data were submitted only for the endpoint categories of mortality, morbidity and health-related quality of life, but not for the category of side effects.
• morbidity
  • Data were submitted for the patient population only for the endpoint categories of mortality, morbidity and health-related quality of life, but not for the category of side effects.
  • The analyses submitted for patient-reported endpoints in the categories of morbidity and quality of life are based on the interim data cut-off date of 9 May 2013.
  • The pharmaceutical manufacturer has not provided an adequate justification in this regard.
  • It must be assumed that the extent of data added on patient-reported endpoints was significant by the time of the final data cut-off.
• Health-related quality of life
  • For the patient population, data were submitted only for the endpoint categories of mortality, morbidity and health-related quality of life, but not for the category of side effects.
  • The analyses submitted for patient-reported endpoints in the categories of morbidity and quality of life are based on the interim data cut-off of 9 May 2013.
  • The analyses of the EORTC QLQ-C30 were not adequate.
  • Although a longer-term follow-up was conducted, data in the follow-up were only presented for month 3, which had not been pre-specified for any analysis.
  • Furthermore, due to a lack of information on endpoint-specific observation periods, it is not possible to assess whether the analyses of the responder analyses using relative risk are adequate.
  • The analysis of the continuous data for the EORTC QLQ-C30 is also subject to uncertainties.
• Side effects
  • For this patient population, data were presented only for the endpoint categories of mortality, morbidity and health-related quality of life, but not for the category of side effects.
  • Furthermore, the data on adverse events submitted by the pharmaceutical manufacturer are incomplete.
  • In accordance with Annex II to Chapter 5 of the Rules of Procedure, all events occurring in ≥ 10 patients and in ≥ 1 % of patients in a study arm must be reported, regardless of severity.
  • The pharmaceutical manufacturer has failed to comply with this requirement and has reported only a subset of the adverse events.
  • Only adverse events, regardless of severity, that occurred in ≥ 10 % of patients in a study arm were reported.
  • For severe AEs and SUEs, the marketing authorisation holder provides analyses based on a threshold of ≥ 5 per cent of patients in a study arm.
  • Furthermore, data are missing in the ‘side effects’ category for the patient population of patients who were not eligible for a full dose of fludarabine.
  • Data are available only for the overall population, of which only 75 per cent represent the relevant patient population.
  • The pharmaceutical manufacturer has not provided a plausible justification as to how the results from the overall population can be extrapolated to the patient population.
  • Similarly, with regard to adverse events, only analyses using relative risk were submitted; however, the endpoint-specific observation periods are required to estimate these.
  • However, these are missing.

Courtesy translation only, please refer to the German original.