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



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Treatment-related adverse events (adverse drug reactions)

  1. Integrated safety analyses


None provided.
        1. Main/pivotal studies that assessed safety as the sole primary outcome


None provided
        1. Pivotal and/or main efficacy studies

Combination of palbociclib and fulvestrant – Study 1023

Overall, 94.2% of patients in the palbociclib plus fulvestrant arm and 67.4% of patients in the placebo plus fulvestrant arm experienced at least 1 treatment-related AE as of the 31 July 2015 data cutoff date.

As shown in the table below, the most frequently reported treatment-related AEs (that is, >20% of patients) in the palbociclib plus fulvestrant arm were neutropenia (65.2%) and neutrophil count decreased (22.6%), fatigue (31.0%), white blood cell count decreased (29.3%) and leukopenia (25.8%), anaemia (26.4%), and nausea (25.2%). Nausea (22.1%) and fatigue (21.5%) were the most frequently reported treatment-related AEs for the placebo plus fulvestrant arm.

The following common treatment-related AEs were reported substantially more frequently as calculated by the clinical evaluator’s calculation (that is, >9% difference in treatment-related AE frequency) for the palbociclib plus fulvestrant arm than for the placebo plus fulvestrant arm:


  • neutropenia (65.2% versus 1.7%, respectively)

  • neutrophil count decreased (22.6% versus 1.2%)

  • white blood cell count decreased (29.3% versus 4.1%)

  • leukopenia (25.8% versus 1.2%)

  • anaemia (26.4% versus 8.1%)

  • thrombocytopenia (12.8% versus 0.0%)

  • platelet count decreased (10.1% versus 0.0%)

  • alopecia (16.2% versus 5.8%)

  • fatigue (31% versus 21.5%)

  • stomatitis (11.6% versus 1.7%)

A rash occurred in 4.9% more (7.8% versus 2.9%) patients in the palbociclib and fulvestrant arm. The remainder of the treatment-related toxicities occurring at a frequency of at least 5 percent were similar (90-day safety update).

Comment: By altering the cut-off for the difference in rates from 10% to 9%, 2 more clinically relevant AEs were identified as occurring’ more commonly in the experimental arm: stomatitis and fatigue.

No presentation of the less commonly occurring treatment-related adverse events could be located in the 90-day safety update, and a review of the main CSR provided a table with a cut-off of TEAEs occurring in at least 5% based on the older data cut-off of 5 December 2014) but no additional tables with discussion for less common events were presented.

The clinical evaluator has reviewed treatment-related events by SOC supplied (as of cut-off 31 July 2015) which revealed:


  • hepatobiliary disorder events of 5.3% in each arm; however, the palbociclib and fulvestrant arm included one case of drug-induced liver injury and one case of hepatocellular injury and one of liver failure. No such cases were reported for the comparator arm, which included more general terms of hepatic pain, cholecystitis etc. It is noted that the drug-induced liver injury (Grade 3) was not considered an SAE, but the patient permanently discontinued.3 The liver failure was listed as an SAE.

  • The source tables with the data by SOC contain multiple terms that could be used to describe the same event eg ‘neutropenia’ and ‘neutrophil count decreased’. The rate of ‘dyspnoea’, if that term plus ‘dyspnoea exertional’ are combined leads to a rate of 15% not 13.3% in the palbociclib and fulvestrant arm, and 8.7% in the comparator arm as reported. No grades of severity for these events of dyspnoea could be located but for the dyspnoea at the 5 December 2014, the event rates 10.7% in palbociclib and fulvestrant arm (0.3% Grade 4); 6.4% in the comparator (0.6% Grade 3).

Comment: 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 collated to capture the same event being classified by a different term.
Combination of palbociclib and letrozole – Study 1008 top-line summary (no CSR available)

2973 adverse events were reported as related to treatment in the palbociclib and letrozole arm. The sponsor reported the following in the summary provided: ‘Treatment-related adverse events were reported for 96.4% of patients in the palbociclib plus letrozole arm and for 80.6% of patients in the placebo plus letrozole arm. Treatment-related serious adverse events were reported for 24 (5.4%) patients in the palbociclib plus letrozole arm and for 2 (0.9%) patients in the placebo plus letrozole arm. Permanent discontinuation from the study associated with treatment-related adverse events was reported for 1 (0.2%) patient in the palbociclib plus letrozole arm and for 1 (0.5%) patient in the placebo plus letrozole arm.’

Table 27: Study A5481008 Summary of Treatment-related, Treatment-emergent adverse events (As treated population)



The limited data available from the table summarising treatment-related TEAEs of any grade reported at ≥ 5% frequency in either arm introduced new adverse events in the palbociclib arm which were more frequent than in the comparator over and above those presented in the TEAE table with its cut-off reporting threshold of events occurring in ≥ 10% of patients in either arm. The Grade 3/4/5 was presented with a differing threshold again, of ≥ 1% in either arm. New events identified as a result:



  • epistaxis (6.3% versus 2.7%);

  • thrombocytopenia (9.0% versus 0.9%) /platelet count decreased (5.9% versus 0.5%);

  • pruritus (5.0% versus 2.3%)

Comment:

  1. The clinical evaluator was unable to evaluate attribution of causality made by the sponsor because:

  1. the ≥ 10% frequency (in either arm) threshold for cut-offs for baseline TEAEs was higher than the treatment-related (≥ 5%) resulting in:

  2. new events being reported;

  3. no baseline figures for comparison between the two assessments for example, for epistaxis, pruritus;

  4. the only links and data provided in support are the source tables for these figures which do not provide a side-by-side comparison of AE rates between arms;

  5. no link to any narratives to assess the cases by the evaluator;

  6. all narratives are blinded and not evaluable;

  7. No comments on these data and no recommendations for the PI can be made to reflect the proposed usage.

  8. Table 10, top-line summary provide frequencies for treatment-related adverse events by frequency of at least 5% in either arm. Given rare events will be missed by presentation this way, the sponsor is requested to provide a table where the cut-off is 1% in either arm when submitting the CSR for Study 1008. THE same threshold should be used for the TEAEs – it would be acceptable to add in a table to capture this rate of events. It is recommended that these issues be addressed when submitting the Study 1008 to facilitate any evaluation.

  9. These, and all subsequent data with relation to causality, could not be evaluated by the TGA.

The sponsor also provided a discussion and table for ‘Adverse Drug reactions’ in the palbociclib and letrozole arm, without a comparison with the placebo and letrozole arm.

The sponsor states (Study 1008 top-line summary):



‘Adverse drug reactions (ADRs) were identified based on whether adverse events were reasonably associated with palbociclib treatment. The sponsor evaluated this potential association by examining the all-causality reporting frequencies on the palbociclib plus letrozole arm in comparison with the placebo plus letrozole arm. Further, the sponsor considered the mechanism of action of palbociclib, the available nonclinical toxicity data, and the overall assessment of adverse events by the investigators when judging whether reported adverse events were reasonably associated with palbociclib treatment. In cases of uncertainty or for confirmation, the adverse event experience from Studies 1003 and 1023, and from palbociclib monotherapy studies was also considered. The ADRs reported in Study 1008 are summarised in Table 14. In earlier determinations of ADR frequencies, Febrile neutropenia was listed as ‘Uncommon’ and Dysgeusia as ‘Common’. Febrile neutropenia is now listed as ‘Common’ and Dysgeusia as ‘Very Common’; no other changes in ADR frequencies were noted.’

Comment:

  1. The sponsor has not provided the data, analyses or narratives on which these attributions were made;

  2. It is not possible to establish and evaluate how these figures were reached (see above discussion on differing presentations of thresholds for different AE data);

  3. No information about the comparator arm is included in the table for comparison.

  4. These adverse events have not been presented adequately described elsewhere, and the attribution of what constitutes an ADR appears to be different from the ‘treatment-related TEAE’ classification for example, the rates of epistaxis here are presented as 9.3% whereas in Table 10 for the Treatment-related TEAEs, the frequency was 6.3%. This could be due to reporting terms but it is very unclear as to why there are different rates for the same term. The sponsor is requested if presenting such analyses in the CSR, to make it very clear as to how these two classifications differ.

  5. Reference in the paragraph above is made to differences between this and ‘earlier determinations of ADR frequencies’, but there is no link or reference to where these ‘earlier determinations can be found’ for the evaluator to check that earlier data, noting this is a new chemical entity submission to the TGA and no prior submissions have been made for palbociclib.
        1. Other efficacy studies

Combination of palbociclib and letrozole
Study 1003 Phase II

Overall, 78 patients (94.0%) in the palbociclib plus letrozole arm and 33 patients (42.9%) in the letrozole alone arm were reported to have experienced at least 1 treatment-related AE in this portion of the study. The most frequently reported treatment-related AEs (>10% of patients) in the palbociclib plus letrozole arm were neutropenia (73.5%), leukopenia (41.0%), anaemia (28.9%), fatigue (25.3%), Alopecia (21.7%), Hot flush (20.5%), thrombocytopenia (19.3%), arthralgia (16.9%), nausea (15.7%), and decreased appetite (10.8%). The most frequently reported treatment-related AEs in the letrozole alone arm were fatigue (14.3%), hot flushes (11.7%), and arthralgia (10.4%).

A summary table of treatment-related, treatment-emergent adverse events by MedDRA PT for at least 5 patients in the palbociclib and letrozole arm was presented.



Comments:

No additional information has been presented in the summary discussion to represent the outcomes when clinically related events are merged. A more clinically meaningful table would be generated by presenting the data by clustered MedDRA PT by SOC – it is noted that the ADR table proposed in the PI for fulvestrant and palbociclib usage uses this approach (although cannot be evaluated due to the data not being presented in the same way for the treatment-related events in that trial) – this, and any proposed table for inclusion in the PI based on this study or Study 1008 when it is submitted, should present the data by clustered MedDRA PT by SOC to allow evaluationComparison of treatment-emergent rather than treatment-related events avoids the possibility of biases in attribution of causality. Study 1010

In the Ph1P2 portion of Study 1010, all patients experienced at least 1 treatment-related AE.

The most frequently reported (that is, ≥ 2 patients [33.3%]) treatment-related AEs were neutrophil count decreased and white blood cell count decreased (100% each) as well as platelet count decreased (50.0%) and fatigue (33.3%).

No update is provided in the 90-day safety update.


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