Pregabalin, capsule, 75, 150 & 300 mg, LyricaŽ, July 2005

Public Summary Document for Pregabalin, capsule, 75, 150 & 300 mg, LyricaŽ, July 2005.

Page last updated: 24 October 2005

Public Summary Document
Product: Pregabalin, capsule, 75, 150 & 300 mg, LyricaŽ

Sponsor: Pfizer Australia

Date of PBAC Consideration: July 2005

1. Purpose of Application

The application sought listing of Pregabalin on the Pharmaceutical Benefits Scheme (PBS) as an authority required benefit for the treatment of partial epileptic seizures which are not satisfactorily controlled by other anti-epileptic drugs.

2. Background

This was the first time a listing application for Pregabalin had been considered by the Pharmaceutical Benefits Advisory Committee (PBAC).

3. Registration Status

Pregabalin was registered by the Therapeutic Goods Administration on 13 April 2005 for adjunctive therapy in adults with partial seizures with or without secondary generalisation. It is also registered for the treatment of neuropathic pain in adults.

4. Listing Requested and PBAC’s View

The sponsor’s requested listing was:

Authority Required

Treatment of partial epileptic seizures which are not controlled satisfactorily by other anti-epileptic drugs.

The PBAC did not comment on the wording of the requested restriction.

5. Clinical Place for the Proposed Therapy

There are a number of different types of epileptic seizures. Partial seizures involve only one part of the cerebral cortex and can occur with or without secondary generalisation. Pregabalin represents a further choice to clinicians and patients for the treatment of partial seizures which are not controlled by other available therapies.

6. Comparator

The submission nominated gabapentin as the comparator. This was considered appropriate by the PBAC.

7. Clinical Trials

The submission presented an indirect comparison of Pregabalin with gabapentin in the treatment of refractory partial seizures with placebo as the common comparator.

The submission presented the results of four fixed dose randomised placebo controlled trials for Pregabalin and four fixed dose randomised placebo controlled studies for gabapentin.

The submission also presented a number of meta-analyses based on the results of these trials.

All eight individual studies were published at the time of submission as follows:

Trial/first author

Protocol title

Publication citation

1008-009/ Beydoun APregabalin add-on trial: double-blind, multi-centre study in patients with partial epilepsy. Epilepsia 41:253-54, Suppl. 7, 2000.
1008-011/

Arroyo S

Pregabalin Add-on Treatment; A Randomised, Double-blind, Placebo-controlled, Dose-Response Study in Adults with partial Seizures. Epilepsia 45 (1): 20-27, 2004.
1008-034/

French J

Dose-response trial of Pregabalin adjunctive therapy in patients with partial seizures. Neurology 2003; 60:1631-1637
1008-157/Elger A Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multicentre Study in Patients With Partial Seizures (Pregabalin BID Add-On Titration Trials).Epilepsia 2004; 45 (supplement 3): 67-68 Abstract 054
945-5/McLean Gabapentin as add-on therapy in refractory partial epilepsy: A double-blind, placebo-controlled, parallel-group study. Neurology 1993; 43: 2292-2298
877-210P/ Chadwick Gabapentin in partial epilepsy.Lancet 1990; 335: 1114-1117
945-6/Anhut Gabapentin (Neurontin) as Add-On Therapy in Patients with Partial Seizures: A Double-Blind, placebo-Controlled Study.Epilepsia 1994; 35(4): 795-801
945-9 and 945-10/ SiveniusDouble-Blind Study of Gabapentin in the Treatment of Partial Seizures. Epilepsia 1991; 32 (4) 539-542

8. Results of Trials

The primary analysis of efficacy presented in the submission compared responder ra tes for Pregabalin 600 mg/day with gabapentin 1,800 mg/day based on the fact that these represent maximum doses. Responder rate was defined as patients achieving a greater than or equal to (?) 50% reduction in seizures. The indirect rate difference compar ing Pregabalin 600 mg and gabapentin 1800 mg showed a statistically significant difference in favour of Pregabalin. However, there was no statistically significant difference in the corresponding indirect relative rate and indirect odds ratio.

The submission also presented an indirect comparison of withdrawal rates due to adverse events for Pregabalin and gabapentin. The indirect comparison of 600 mg/day Pregabalin and 1800mg gabapentin showed a statistically difference in the risk difference for patients withdrawing due to adverse events (more withdrawals due to adverse events in the Pregabalin 600mg group than the gabapentin 1800mg group).However, no significance difference was observed for the relative risk.

The PBAC had a number of concerns with the evidence presented in relation to efficacy and safety (see Recommendations and Reasons).

9. Clinical Claim

The submission claimed that Pregabalin 600mg is significantly more effective compared with gabapentin 1800mg but patients treated with Pregabalin have a higher risk of withdrawing due to adverse events than patients treated with gabapentin.

The PBAC did not agree with the claim that Pregabalin 600 mg is significantly more effective than gabapentin 1800mg.

10. Economic Analysis

Several preliminary economic evaluations were presented in the submission. The resources included were drug costs only. The submission estimated that the trial-based incremental cost per extra responder gained over 84 days was dominant (ie.Pregabalin was more effective at a lower cost).

Two modelled economic evaluations were presented, a 12 week model (corresponding to the duration of the key clinical trials) and a 1 year model. The 1-year model included effects of withdrawal of therapy due to adverse events.

The submission estimated that the base case modelled incremental cost per extra quality adjusted life year (QALY) gained over 12 weeks was dominant (ie.Pregabalin was more effective at a lower cost).

The submission estimated that the base case modelled incremental cost per extra quality adjusted life year (QALY) gainedover one year was<$15,000.

As the Committee did not accept the clinical claim made in the submission, they could not accept the results of the economic analysis.

11. Estimated PBS Usage and Financial Implications

The submission estimated that <10,000 patients will be treated with Pregabalin by the fourth year of listing.

The submission estimated that the net cost to government of Pregabalin listing would be <$10 million per year by the fourth year of listing. This took into account the expectation that the overall antiepileptic market is expected to grow as a result of listing Pregabalin. This document presents only a broad estimate for the net financial impact of Pregabalin listing. The submission provided a more precise estimate of the net financial impact. The PBAC had some concerns about the accuracy of the net impact estimate provided in the submission, but these concerns likely do not apply to the estimate presented in this document.

The PBAC noted that Pregabalin is also registered for the management of neuropathic pain, but listing is not requested for these patients. This introduces potential for use of Pregabalin beyond the PBS restriction.

12. Recommendation and Reasons

The PBAC recommended listing on a cost-minimisation basis compared with gabapentin, with the equi-effective doses being Pregabalin 349 mg daily and gabapentin 1188 mg daily.

The PBAC noted the request of the submission to list Pregabalin on a cost-effectiveness basis was through an indirect comparison involving placebo as the common reference, thus it was not possible to ensure internal validity by minimising systematic error, which means that the strength of the evidence presented is weak. The PBAC further noted that the indirect rate difference comparing Pregabalin 600 mg and gabapentin 1800 mg (the dose comparison emphasised in the submission) shows a statistically significant difference, but the corresponding indirect relative rate and indirect odds ratio do not, which means that the play of chance cannot be confidently excluded as an alternative explanation of the reported numerical differences. The PBAC considered that, in relation to assessing whether treatment effects vary across drugs, the more appropriate measures of treatment effect are the relative rate or the odds ratio, and noted that, for these summary statistics, the indirect estimates of comparative treatment effect are not statistically significant between the two drugs at the nominated doses for either effectiveness or toxicity.

The PBAC concluded the indirect comparison provided insufficient evidence to conclude that Pregabalin 600 mg has therapeutic advantages over gabapentin 1800 mg.

The PBAC noted that the likely doses used in practice may be closer to Pregabalin 349 mg daily (from the only dose titration trial presented) and gabapentin 1188 mg, which, as the inferred PBS daily prescribed dose, also incorporates dose titration.

Recommendation

List

Restriction: Authority Required

Treatment of partial epileptic seizures in patients 18 years of age or older whose seizures are not controlled satisfactorily by other anti-epileptic drugs.

Maximum Quantity:

Repeats:

56 (all strengths)

5

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

Pregabalin is a novel medicine for add-on treatment of partial epilepsy. Pfizer Australia (the sponsor) believes that the data we provided in our March 2005 reimbursement application demonstrated that pregabalin is more effective than gabapentin. In contrast, the PBAC did not conclude that pregabalin is superior to gabapentin. Given the current disparity in viewpoints, the sponsor is re-evaluating its options regarding future PBS-listing of pregabalin. Please contact Pfizer Australia Medical Affairs at 1-800-675-229 for further enquiries about the sponsor's comment.