PALIPERIDONE, prolonged release tablets, 3mg, 6 mg, 9 mg, 12 mg, Invega, November 2007
Public summary document for PALIPERIDONE, prolonged release tablets, 3mg, 6 mg, 9 mg, 12 mg, Invega, November 2007
Page last updated: 29 February 2008
Public Summary Document
Product: PALIPERIDONE, prolonged release tablets, 3mg, 6 mg, 9 mg, 12 mg, Invega
Sponsor: Janssen-Cilag Pty Ltd
Date of PBAC Consideration: November 2007
1. Purpose of Application
The submission sought a Section 85 Authority required (Streamlined) listing for schizophrenia.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Paliperidone’s TGA registration commenced on 17 September 2007. Paliperidone prolonged release tablets are indicated for the treatment of schizophrenia, including acute treatment and recurrence prevention.
4. Listing Requested and PBAC’s View
Authority Required (Streamlined)
Schizophrenia
The PBAC had no comments on the requested restriction wording.
5. Clinical Place for the Proposed Therapy
Paliperidone prolonged release is a once daily oral atypical antipsychotic medication for the treatment of schizophrenia.
6. Comparator
7. Clinical Trials
The submission presented four pivotal, head-to-head trials of paliperidone and olanzapine
in patients with schizophrenia and experiencing an acute attack: three of the trials
employed a fixed dosing regimen (Kane et at (2007), Marder et al (2007) and Davidson
et al (2007)) and the remainder a flexible dosing regimen for 6 weeks (dose range:
paliperidone 3-12 mg/day and olanzapine 5-15 mg/day, unpublished study). Nine supportive
trials were presented: one placebo-controlled flexible dose trial in patients ≥65
years, one placebo-controlled flexible dose trial in relapse prevention, five open
label extension studies (being open-label single-arm paliperidone extensions of the
three pivotal head-to-head fixed dose and two supportive placebo controlled flexible
dose trials), one cardiovascular safety trial and one sleep architecture trial. One
pooled analysis of the three pivotal fixed dose trials was also presented.
The trials published at the time of submission are as follows:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
Pivotal direct randomised trials |
||
|
Kane et al 2007 |
Treatment of schizophrenia with paliperidone extended-release tablets: A 6-week placebo-controlled trial. |
Schizophr Res; 90 (1-3):147 – 61. |
|
Marder et al 2007 |
Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomised, placebo-controlled study. |
J.Biopsych (E-publication ahead of print) |
|
Davidson et al 2007 |
Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): Results of a 6-week, randomised, placebo-controlled study. |
Schizophrenia Research 93; 93: 117-130.c |
|
Supportive trials and studies |
||
|
Kramer 2007 |
Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia: A randomised, double-blind, placebo-controlled study. |
Journal of clinical psychopharmacology 27(1):6-14. |
8. Results of Trials
The pooled results for paliperidone versus placebo from the key fixed-dose trials are summarised in the table below:
|
Trial |
Change from baseline total PANSS score – mean (SD) |
||||
|---|---|---|---|---|---|
|
Placebo |
Pali 3 mg/day |
Pali 6 mg/day |
Pali 9 mg/day |
Pali 12 mg/day |
|
|
Kane et al 2007 |
N = 126 -4.1 (23.16) |
N = 123 -17.9 (22.23) |
N = 122 -17.2 (20.23) |
N = 129 -23.3 (20.12) |
|
|
Marder et al 2007 |
N = 105 -8.0 (21.48) |
N = 110 -15.7 (18.89) |
N = 111 -17.5 (19.83) |
||
|
Davidson et al 2007 |
N = 120 -2.8 (20.89) |
N = 123 -15.0 (19.61) |
N = 123 -16.3 (21.81) |
||
|
Pooled analysis |
|||||
|
N |
351 |
123 |
233 |
245 |
240 |
|
Baseline |
93.9 (11.68) |
91.6 (12.19) |
93.4 (11.22) |
93.6 (12.55) |
94.4 (11.16) |
|
Week 6 |
-4.8 (21.95) |
-15.0 (19,61) |
-16.9 (20.70) |
-16.8 (21.00) |
-20.6 (20.15) |
PANSS = Positive and Negative Syndrome Scale
The submission provides unpublished pooled analyses of different doses of paliperidone
versus olanzapine from the three fixed dose trials. The results of these analyses
for change from baseline in total PANSS score showed no significant differences between
any dose of paliperidone and olanzapine. However, the primary comparison in each of
the trials was between each paliperidone group and placebo, and as such, the trials
may not have been powered to detect any differences between paliperidone and olanzapine.
An unpublished non-inferiority trial comparing paliperidone and olanzapine was presented.
The non-inferiority limit of the trial, as specified in the protocol was 7 points
in the total PANSS scores. The upper limit of the 95% confidence interval for the
differences between the two treatment groups indicated that the non-inferiority criteria
had been met and the results indicated that paliperidone is non-inferior to olanzapine
for the outcome of change in total Positive and Negative Syndrome Scale (PANSS) score
at 6 weeks.
The PBAC agreed that the sponsor’s argument in support of a 7 point difference in
PANSS as a clinically unimportant difference for non-inferiority was reasonable. Overall,
the confidence intervals around the treatment differences in the four key trials are
reasonably narrow suggesting that paliperidone is non-inferior to olanzapine at the
doses used in the trials.
In terms of comparative toxicity, the pooled analysis indicated that the occurrence
of serious adverse events was comparable across all treatment groups. Metabolic system
adverse events (body weight increase ≥ 7%, triglyceride abnormality), occurred in
a statistically significantly greater proportion of patients treated with olanzapine
compared with paliperidone in the pooled analysis. Nervous system adverse events (akathisia
and any EPS syndrome) occurred in a statistically significantly greater proportion
of patients treated with paliperidone compared with olanzapine.
For the PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The submission claimed that paliperidone is non-inferior to olanzapine in terms of
efficacy and safety. The dose relativity between paliperidone and olanzapine was claimed
to be 1:1.31 mg.
For the PBAC’s view of this claim, see Recommendation and Reasons.
10. Economic Analysis
A trial-based economic evaluation was presented. The choice of a cost-minimisation
approach was considered valid. The resources included were drug costs only. The submission
calculated that the drug cost per patient per year was less than $15,000 for both
paliperidone and olanzapine.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of scripts/year to be in the range of 100,000
– 200,000 by Year 5.
The submission estimated financial savings/year to the PBS (excluding co-payments)
of up to $1 million over 5 Years. The overall market is not expected to grow or to
grow more rapidly as a result of listing paliperidone.
12. Recommendation and Reasons
The PBAC recommended the listing of paliperidone on the PBS for schizophrenia on a
cost-minimisation basis compared with olanzapine and that the equi-effective doses
were paliperidone 9.83mg per day and olanzapine 12.91mg per day.
The PBAC considered that paliperidone is non-inferior to olanzapine in the PANSS score
at 6 weeks as the score was below the non-inferiority limit of 7 points.
The PBAC noted that there was a statistically significant difference between paliperidone
and olanzapine for weight gain (favouring paliperidone) and the incidence of extrapyramidal
symptoms (EPS) (favouring olanzapine).
Based on the supporting data, despite accepting the clinical claim, the PBAC considered
there was some uncertainty with respect to the claim that paliperidone was no worse
than olanzapine in terms of effectiveness and having quantitatively similar, but different
toxicity profile. This was because the dosing of olanzapine may have been suboptimal
and there was uncertainty regarding whether the patients enrolled in the trials forming
the primary source of evidence in the submission are representative of those for whom
PBS listing is sought, as the patients enrolled in the trials were experiencing an
acute attack.
The PBAC noted that the pivotal trials were all of 6 weeks duration, and considered
that the data may only represent equi-effectiveness of paliperidone and olanzapine
in the acute phase, however listing is requested for both the acute and maintenance
phases of the disease.
The PBAC noted that a flat pricing structure was proposed and recommended a risk share
agreement be put in place.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia.
It considers submissions in this context. A PBAC decision not to recommend listing
or not to recommend changing a listing does not represent a final PBAC view about
the merits of the medicine. A company can resubmit to the PBAC or seek independent
review of the PBAC decision.
14. Sponsor’s Comment
The sponsor welcomes the decision by the PBAC to recommend listing of an additional treatment option for patients with schizophrenia.
