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



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Safety clinical question 7


QUESTION 7

There needs to be a heading and discussion of the rates of infection and febrile neutropenia (0.6% of patients receiving palbociclib and fulvestrant reported at 5 December 2014 cut-off – but what is it now with the later dataset?) An updated 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).

Sponsor Response


Please refer to Safety Question 5.

Evaluator comment:


The sponsor’s response is accepted.
      1. Safety clinical question 8


QUESTION 8

Table 5 of the draft PI presents out of date data for Adverse Drug Reactions which is in the SOC format which needs to be updated with the 90-day safety update. Where there are clinical laboratory findings (eg for biochemical and haematological events), these should be included in any data presented as these are more accurate than TEAEs. It must be shown clearly how the figures used in the ADR table were reached and why any treatment-related events were discounted. This is required in the response (clearly indicating how these figures were reached) and to be inserted in the PI.

Sponsor Response


the scope of the Day-90 SU was primarily to provide the US FDA with updated safety information on Study A5481023 which was the pivotal study of the Supplementary NDA under assessment. Thus, a comprehensive safety update was conducted only for the pivotal Study A5481023. The Adverse Drug Reactions (ADRs) table for Study A5481023 reported in the PI has been updated accordingly.

With regards to the ADRs table for the combination of palbociclib with letrozole, based on data from Study A5481003 and Study A5481008, the most recent cutoff have been used (please refer to PI Question 21 for further details) [not included in this document].

In general, adverse drug reactions were determined by the sponsor based on whether an AE could be reasonably associated with palbociclib treatment. The sponsor evaluated this potential association by examining the frequencies of all-causality AEs reported in the palbociclib plus letrozole combination in comparison with the placebo plus letrozole arm (Studies A5481003 and A5481008) and the palbociclib plus fulvestrant combination in comparison with the placebo plus fulvestrant arm (Study A5481023). Further, the sponsor considered the mechanism of action of palbociclib, the available nonclinical toxicity data, and the overall assessment of AEs by the investigators in considering whether reported AEs were reasonably associated with palbociclib treatment. In cases of uncertainty or for confirmation, the AE experience from palbociclib monotherapy studies was also considered.

This is consistent with the ICH guidance E6 definition of Adverse drug reactions ‘In the preapproval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, that is, the relationship cannot be ruled out.’

. the sponsor proposes to include Laboratory abnormality tables for Study A5481008 and Study A5481023 under the Adverse Effects section of the PI, which is the appropriate location for this information and is aligned with the USPI.



The sponsor has already addressed the apparent discrepancy noted between the frequency of laboratory test abnormalities and the frequency of corresponding treatment emergent adverse events (TEAEs) in Safety Question 10, Safety Question 31 ….

References

ICH GUIDELINE FOR GOOD CLINICAL PRACTICE E6 (R1) Current Step 4 version dated 10 June 1996 https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_ R1_Guideline.pdf

Evaluator comment:


The sponsor’s response is accepted.
      1. Safety clinical question 9


QUESTION 9

Study A5481023: Without a table providing side-by-side comparison of the adverse events of lower frequency, presented with similar terms collapsed to provide a single figure (as in the SOC presentation with like MedDRA terms collated, it is very difficult to determine whether there have been additional clinically significant adverse events occurring more commonly in the experimental arm. Given the importance of understanding these for both clinicians and patients, the sponsor is requested to present all the adverse events, (including all grades frequency, as well as Grade 3 and Grade 4) that occurred more often in the palbociclib and fulvestrant arm than the placebo and fulvestrant arm (Clinical Questions). These adverse events’ preferred terms should be clustered to capture the same event being classified by a range of different terms.

Sponsor Response


The sponsor created a table with a side-by-side comparison of any Grade adverse events and Grade 3/4 adverse events experienced by subjects enrolled in the palbociclib plus fulvestrant arm (N=345) and the placebo plus fulvestrant arm (N=172) of Study A5481023.

Adverse events of lower frequency occurring more commonly in the experimental arm were examined for clinical significance. Note that the adverse event frequencies were not adjusted for the significantly longer median treatment duration in the palbociclib arm compared to the placebo arm (330 days vs. 137 days, respectively).

Twice as many subjects were randomised to the palbociclib plus fulvestrant arm than to the placebo plus fulvestrant arm and the median treatment duration was 2.4 times as long on the palbociclib arm. It is therefore not surprising that a variety of adverse events were reported on the palbociclib arm at low frequencies, which either were reported at lower frequencies or were not reported at all on the placebo arm, both for any Grade and for Grade 3 or 4 events.

A careful review of these events did not suggest that the creation of additional adverse event clusters would result in grouping adverse events that are truly medically related and/or that might constitute heretofore unidentified adverse drug reactions of palbociclib.

Evaluator comment:


Tables 1023.684.1 and 1023.684.2 have been provided by the sponsor and summarise the data side-by-side as requested, both for all AEs and for Grade 3 or 4 events, but have not been reproduced herein due to their length.

The sponsor’s response is accepted.


      1. Safety clinical question 10


QUESTION 10

For Study A5481023: It is difficult to determine whether the difference between the rates of thrombocytopenia from laboratory findings compared with the TEAEs of thrombocytopenia indicates a level of under-reporting of the events for the population as a whole for lower grade AEs of thrombocytopenia as it would be unusual for such a high percentage of patients who have received endocrine therapy as their last treatment to be thrombocytopenic (even Grade 1 or 2) at baseline; however, the reporting of TEAEs appears to match the total number with Grade 3 or 4 TEAEs although the distribution is different (one patient more is reported to be Grade 4 not Grade 3). The sponsor is requested to provide an explanation.

Sponsor Response


The sponsor agrees that some differences exist between the frequency of laboratory test abnormalities (for example, decrease in platelets) and the frequency of corresponding TEAE. During the data review/cleaning process queries had been generated for laboratory abnormalities that were not reported as a TEAE. This process mainly concerned the laboratory abnormalities with Grade 3 and 4 severity which may lead to a change in study drug dosing. Of note, the Study protocol (Section 8.4) includes guidelines for investigators to determine whether a laboratory test abnormality should be reported as an AE. In summary, an abnormality is to be reported as an AE or SAE if associated with accompanying symptoms, requiring additional diagnostic testing or medical intervention, leading to a change in study drug dosing or discontinuation from the study, or if necessitating additional concomitant therapy, or if considered to be an AE by the investigator or sponsor.

It is the responsibility of investigators to decide when a laboratory test abnormality is to be considered a TEAE. This decision may be based on the clinical conditions of the patient or on the investigator’s perspective as to whether an observed laboratory abnormality is clinically relevant. In many instances, the investigators may not have considered laboratory abnormalities with a Grade ≤2 severity as medically relevant and thus may not have reported these abnormalities as an AE.

As for thrombocytopenia at baseline, only 1 patient in the palbociclib plus fulvestrant arm had a Grade 1 thrombocytopenia at baseline while 2 patients in the placebo plus fulvestrant arm had thrombocytopenia at baseline, one of Grade 1 and the other of Grade 2 in severity (Table 14.3.4.1.5.4 [Shift Summary Results of Labs by Maximum CTC Grade - Hematology, All Cycles]).

In conclusion, consistent with the study protocol, not all laboratory test abnormalities are reported as AEs. The differences between the frequency of observed laboratory test abnormalities and the frequency of corresponding reported TEAEs are likely due to the investigator’s clinical decision of what laboratory test abnormalities were reported as a TEAE rather than a level of under-reporting of events.

Evaluator comment:


The sponsor’s response explains the differences between adverse event counts and laboratory abnormalities.

It is recognised that the methodology, definitions and criteria for adverse event reporting used by the sponsor may result in some laboratory events not being reported as adverse events. However, this is in keeping with the ICH guidelines, which are generally accepted by the TGA. The converse of the ‘underreporting’ of adverse event terms is that this system prevents the inclusion of reports that were not considered to be clinically relevant according to the investigator, thus increasing the significance of the events that are reported, and reducing signal noise.

The issue with this modus operandi is that prescribers reading the PI are not experts in MedDRA, adverse event reporting or CTCAE definitions, and are not likely to differentiate between ‘adverse event’ and ‘laboratory abnormality’. This particularly true with something like thrombocytopenia, where by definition the adverse event IS a laboratory abnormality. In these cases, clinical assessment of the grade would be related to whether symptoms were associated with the abnormal reading and the extent of intervention – for example, if neutropenia extended a hospital stay as the count was so low the clinical decision was that isolation was required preventatively to avoid infection/febrile neutropenia. The inclusion of the laboratory abnormality tables in the PI in addition to the existing adverse event tables assists in addressing this issue, as both sets of data are then available for the prescriber.

The sponsor’s response is accepted.


      1. Safety clinical question 11


QUESTION 11

Study A5481023: The rates of epistaxis and thrombocytopenia are both noted to be increased in Study 1008 for the palbociclib arm and sponsor is requested for Study 1023, to state the rates for bleeding events by:

    1. broadening the search criteria beyond ‘Haemorrhage’ and to use all MedDRA terms that are designed to cover the event of bruising, bleeding in any organ ( including petechiae)

    2. how many of these were associated with the events of thrombocytopenia in Study 1023?

Sponsor Response


As noted in Table 33 A5481023 90 Day Safety Update neither Grade 3 nor Grade 4 THROMBOCYTOPENIA (cluster term comprising the PT of Thrombocytopenia and Platelet count decreased) events were associated with bleeding episodes (based on Haemorrhage terms, excluding laboratory terms, within Standardized MedDRA Queries [Narrow]). Note: this SMQ contains the Preferred Terms of Contusion (bruising), and Petechiae.

Further information regarding the concurrence of bleeding events and thrombocytopenia can be found in the response to Efficacy Question 21.

Evaluator comment:


The sponsor’s response is accepted.
      1. Safety clinical question 12


QUESTION 12

Study A5481003: the sponsor is requested to provide the platelet count for the patient at the time of requiring a dose reduction for petechiae.

Sponsor Response


The platelet count was 83 x 109/L (reference range: 150-400 x 109/L) on 24 Jul 2012 (Cycle 17 Day 1) for the patient (Patient [information redacted]) who had palbociclib dose reduced from 100 mg to 75 mg due to Grade 3 Petechiae (previously dose reduced from 125 mg to 100 mg due to Grade 3 Fatigue at Cycle 16) ….

Evaluator comment:


The sponsor’s response is accepted.
      1. Safety clinical question 13


QUESTION 13

Study A5481008: table 6, (Summary of all-causality treatment-related adverse events) states that 6.1% and 5.0% of patients permanently discontinued letrozole due to an AE in the experimental and comparator arms, respectively. This figure exceeds that for those permanently discontinuing the study due to an AE for those arms (2.5% and 1.8%, respectively). The sponsor is requested to provide explicit details regarding how these patients were treated and followed up from this point of discontinuation.

    1. Was palbociclib or placebo continued as monotherapy in any patients? If so, how many in each arm?

    2. If both letrozole and the placebo or palbociclib were discontinued, what is the difference between the group who permanently discontinuing the study and those labelled as permanently discontinuing letrozole?

Sponsor Response


Study A5481008 includes two distinct post-randomisation periods: (1) the active treatment phase which is the period from randomisation until the last dose of study treatment and (2) the overall survival follow up phase which is the period from last dose of study treatment until patient’s death, withdrawal of consent, or loss to follow-up. A patient is considered to have permanently discontinued study when they are no longer receiving study treatment and are no longer being followed-up for overall survival.

Question a):

Palbociclib or placebo was not continued as monotherapy in any patients who either ‘permanently discontinued study due to AE’ or ‘permanently discontinued letrozole due to AE’. Per protocol, patients discontinuing letrozole treatment due to a treatment-related toxicity could not continue on blinded therapy alone and were to be permanently discontinued from the active treatment phase of the study at which point they would enter the overall survival follow-up phase of the study unless the patient withdrew consent. As a result none of the patients who permanently discontinued letrozole continued with palbociclib or placebo as monotherapy.

Question b):

In Table 6, ‘permanently discontinued study due AE’ and ‘permanently discontinued letrozole due to AE’ represent 2 distinct scenarios.

Permanently discontinued study due to AE’ represent the number of patients who not only permanently discontinued study drug due to an adverse event but also withdrew study consent as a result of the adverse event. No additional data could be collected from these patients once they withdrew consent. This included information on anticancer treatment administered beyond study discontinuation.



Permanently discontinued letrozole due to AE’ represent the number of patients who permanently discontinued letrozole treatment as a result of an adverse event regardless of whether patients continue to be followed-up on study in the overall survival follow-up phase or withdrew consent as a result of the AE.

The number of patients reported under ‘permanently discontinued study due to AE’ is a subset of the patients reported under ‘permanently discontinued letrozole due to AE’.

During the follow-up period the following information were collected every 6 months: post study survival status, patient reported outcome questionnaires, and details of any new anticancer therapies. The choice of follow-up anticancer therapy was left at the investigator’s discretion. Follow-up systemic treatments are summarised in Section 10.4 A5481008 Clinical Study Report.

Evaluator comment:


The sponsor’s response is accepted.
      1. Safety clinical question 14


QUESTION 14

Study A5481008: Events rates for TEAEs of thrombocytopenia were not reported as occurring below 10% in Study 1008. This is an artefact of the high cut-off threshold of ≥ 10% in either arm and use of separate MedDRA terms for TEAE reporting; the combination of treatment-related thrombocytopenia/platelet count decreased was 14.9% in the experimental arm and 1.4% in the comparator that is, a 10-fold increase in risk, with the lower cut-off of 5% reporting the treatment-related AEs. Furthermore with the lower threshold in the treatment-related events table, the adverse event of epistaxis also emerges which could be linked to the low platelets (any correlation of these 2 adverse events should be addressed in the clinical overview and safety section when providing the CSR for Study 1008). When submitting the CSR for Study 1008, the sponsor is requested to include a table of TEAEs with a cut-off of 1% in either arm, treatment-related AEs with a cut-off of 1% in either arm to be consistent with the Grade 3/4/5 TEAE reporting provided. This will assist in identification of events that may require inclusion in the PI to inform clinicians and patients. The assessment of attribution of AEs considered treatment-related cannot be made without knowing the baseline percentage listed as treatment-emergent.

Sponsor Response


A5481008 Clinical Study Report Tables 14.3.1.1.3.1 and 14.3.1.2.4.1 provide the Summary of Treatment-Emergent Adverse Events by MedDRA Preferred Term (including Clusters of Preferred Terms) and Maximum CTCAE Grade in Descending Frequency Order (All causalities - All cycles and Treatment Related – All Cycles, respectively) without a frequency cut-off for the As Treated population. The following summary tables provide similar information but with a 1% cut-off as per the TGA’s request.

      • Table 1008.4083.1: Summary of Treatment-Emergent Adverse Events by MedDRA Preferred Term (including Clusters of Preferred Terms) and Maximum CTCAE Grade in Descending Frequency Order (All Causalities - All Cycles) reported in ≥ 1% of Patients.

      • Table 1008.4083.2: Summary of Treatment-Emergent Adverse Events by MedDRA Preferred Term (including Clusters of Preferred Terms) and Maximum CTCAE Grade in Descending Frequency Order (Treatment Related - All Cycles) reported in ≥ 1% of Patients.

An evaluation of whether bleeding episodes (based on Standardized MedDRA Query of Hemorrhage terms, excluding laboratory terms) were associated with Thrombocytopenia events is discussed in the A5481008 Summary of Clinical Safety and Clinical Overview. A summary of the findings is provided below.

Thrombocytopenia experienced by patients in Study A5481008 as of 26 February 2016 is summarised below based on the cluster term THROMBOCYTOPENIA comprising the MedDRA Preferred Terms (PTs) of Thrombocytopenia and Platelet count decreased. All causality THROMBOCYTOPENIA was reported in each treatment arm, with the frequency being higher in the palbociclib plus letrozole arm (15.5%) than in the placebo plus letrozole arm (1.4%) (A5481008 CSR Table 14.3.1.1.3.1).

Most AEs of THROMBOCYTOPENIA reported for patients in the palbociclib plus letrozole arm were of Grade 1 or Grade 2 severity (A5481008 CSR Table 14.3.1.1.3.1). THROMBOCYTOPENIA (14.6%) were considered to be related to treatment in most patients who had these events (A5481008 CSR Table 14.3.1.2.4.1). No events of THROMBOCYTOPENIA were assessed as serious (A5481008 CSR Table 14.3.1.4.1). There were no permanent discontinuations associated with THROMBOCYTOPENIA in either treatment arm (A5481008 CSR Table 14.3.1.5.1). Neither Grade 3 (1.4% of patients) nor Grade 4 (0.2%) THROMBOCYTOPENIA was associated with bleeding episodes (based on the Standardized MedDRA Query of Hemorrhage terms, excluding laboratory terms) in the palbociclib plus letrozole arm (Table 1) [Table 44 below].

Table 44: Summary of thrombocytopenia of Grade 3 or Grade 4 maximum severity (all cycles) reported in the palbociclib plus letrozole arm of Study A5481008 as of 26 February 2016 All treated patients.



Overall, the review of THROMBOCYTOPENIA in Study A5481008 is consistent with the known safety profile of palbociclib.

Evaluator comment:


Thrombocytopenia is included in the draft PI in adverse event tables and is described under ‘myelosuppression’ as an identified risk in the RMP.

The sponsor’s response is accepted.


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