Date of first round report: 1 September 2016 Date of second round report: 30 January 2017

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  1. No discussion of the data by SOC collating MedDRA preferred terms was provided for TEAEs.

  2. The use of TEAEs, rather than laboratory abnormalities underreports these treatment-related events and these should be included, especially for the haematological abnormalities.

Table 24: Study A5481023 Summary of the all-causality, treatment-emergent adverse events experienced by at least 10% of patients, presented by maximum severity grade and frequency (Source Table 7, 90-day safety update)


  1. The most prominent adverse events for the palbociclib and fulvestrant arm are those related to bone marrow suppression when palbociclib is added to fulvestrant. The rates and severity of bone marrow suppression are so significant that all patients must be monitored closely and dose interruption and reduction considered. This is clearly stated in the PI. This is a side effect profile familiar to all oncologists and is considered manageable, especially with dose reduction. The duration of treatment attests to the effectiveness of these management strategies.

  2. The strikingly different AE profile is likely effectively to lead to unmasking of treatment allocation. It would have been better to have had a 100% BICR of the efficacy data for this reason to ensure investigator bias is completely ruled out.

  3. An update infection rate/febrile neutropenic rate has not been presented in this safety update for Study 1023 and this is needed, to ensure the figure quoted in the PI is accurate (Clinical Questions and PI comments). There needs to be a sentence describing the increased risk of neutropenia and longer duration of neutropenia with longer treatment as this may require closer monitoring for patients on longer term treatment.

  4. Table 5 of the draft PI presents out of date data for Adverse Drug Reactions which is in the SOC format which needs to be updated. The collapsing of similar terms is useful but needs updating with the latest tables which are listed in the supporting tables for the 90-day safety update. No updated SOC data formatted or presented in that same way that is, as in Table 5, has been provided for evaluation in the 90-day safety update. This is required in the s31 response and to be inserted in the PI (see PI comments and Clinical Questions).

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