PBAC (Australia)
Gilenya was registered by the Therapeutic Goods Administration (TGA) on 1 February 2011.
Gilenya is indicated for the treatment of RRMS and Secondary Progressive Multiple Sclerosis with superimposed relapses to delay the progression of physical disability and reduce the frequency of relapse. Safety and efficacy of Gilenya beyond 2 years are unknown.
The efficacy of Gilenya has been demonstrated in two trials which evaluated once daily doses of Gilenya 0.5 mg and 1.25 mg in patients with RRMS. Both trials included patients who had experienced at least 2 clinical relapses during the 2 years prior to randomization or at least 1 clinical relapse during the 1 year prior to randomization, and had an Expanded Disability Status Scale (EDSS) between 0 to 5.5.
Study D2301 (FREEDOMS) was a 2-year randomized, double-blind, placebo-controlled Phase III trial in patients with RRMS who had not received any interferon beta or glatiramer acetate for at least the previous 3 months and had not received any natalizumab for at least the previous 6 months.
Study D2302 (TRANSFORMS) was a 1-year randomized, double-blind, double-dummy, active (interferon beta-1a 30 micrograms, intramuscular, once weekly)-controlled Phase III trial in patients with RRMS who had not received any natalizumab in the previous 6 months. (Gilenya Product Information (Australia), 2011. Accessed from TGA website.)
The PBAC considered a submission to list Gilenya on the Pharmaceutical Benefits Scheme (PBS) at its March 2011 meeting. The submission presented one direct randomised comparative trial (plus its extension study) comparing fingolimod and interferon beta-1a (TRANSFORMS) and one direct randomised comparative trial (plus its extension study) comparing fingolimod and placebo (FREEDOMS).
The submission nominated intramuscular interferon beta-1a (Avonex) as the main comparator. The submission also nominated interferon beta-1b (Betaferon) and natalizumab (Tysabri) as secondary comparators. The PBAC considered that the main comparator, intramuscular interferon beta-1a, was appropriate, and that the comparison presented with natalizumab as a secondary comparator, was informative.
The PBAC considered the base case ICER to be unacceptably high to recommend listing. The PBAC considered that the uncertainties in the modelled economic evaluation could be managed with a lower price offer and that an acceptable ICER for fingolimod based on the current model would need to be in the range of $15,000- $45,000 per QALY.
The PBAC deferred its decision on the submission for fingolimod pending further negotiation with the sponsor. The PBAC acknowledged and noted the consumer comments on this item.
Subsequent to the meeting, the sponsor offered a further price reduction. The PBAC therefore recommended out-of-session the PBS listing of fingolimod as an Authority Required benefit for the initial and continuing treatment of clinically RRMS in a patient who meets certain criteria on the basis of an acceptable cost-effectiveness ratio compared with interferon beta-1a. (PBAC Public Summary Document for Gilenya (fingolimod), 2011).
The PBAC considered the base case ICER to be unacceptably high to recommend listing. The PBAC considered that the uncertainties in the modelled economic evaluation could be managed with a lower price offer and that an acceptable ICER for fingolimod based on the current model would need to be in the range of $15,000- $45,000 per QALY.
The PBAC deferred its decision on the submission for fingolimod pending further negotiation with the sponsor. The PBAC acknowledged and noted the consumer comments on this item.
Subsequent to the meeting, the sponsor offered a further price reduction. The PBAC therefore recommended out-of-session the PBS listing of fingolimod as an Authority Required benefit for the initial and continuing treatment of clinically RRMS in a patient who meets certain criteria on the basis of an acceptable cost-effectiveness ratio compared with interferon beta-1a. (PBAC Public Summary Document for Gilenya (fingolimod), 2011).
Gilenya was listed on the PBS on 1 September 2011.
NICE (UK)
Gilenya was approved by the European Commission on 17 March 2011.
Gilenya is indicated as single disease modifying therapy in highly active RRMS for the following adult patient groups:
- Patients with high disease activity despite treatment with a beta-interferon.
These patients may be defined as those who have failed to respond to a full and adequate course (normally at least one year of treatment) of interferon beta. Patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gadolinium-enhancing lesion. A “non-responder” could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year.
or
- Patients with rapidly evolving severe RRMS defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.
As was the case in Australia, its registration in the UK was supported by 2 clinical trials; FREEDOMS and TRANSFORMS. (Gilenya Summary of Product Characteristics, 2011. Accessed from www.emedicines.org.uk)
In provisional draft guidance published on 5 August, NICE recommended that fingolimod should not be prescribed on the NHS for patients with RRMS. This is because there are uncertainties over its clinical effectiveness and, based on the available evidence, it would not be a cost effective use of NHS resources.
While clinical trials have shown that fingolimod can reduce the number of relapses in some people who have highly active RRMS, it is unclear how much the drug may help the specific groups of people for whom it is licensed - i.e. adults with RRMS who experience at least one relapse in a year despite being treated with beta interferons, and adults with rapidly evolving severe RRMS who experience two or more disabling relapses regardless of their treatment. The evidence submitted by its sponsor mainly looked at a subgroup of the former.
NICE's Appraisal Committee could not determine how much fingolimod reduces the rate of relapses compared with some of the treatments already available. This is because its sponsor only submitted evidence which compared fingolimod with a placebo, and fingolimod with a specific type of interferon (interferon beta-1a, Avonex) that is not believed to be widely prescribed in the NHS.
The Appraisal Committee believes that the sponsor should have submitted a comparison of fingolimod with other interferons for people with highly-active RRMS, as well of fingolimod with natalizumab (Tysabri) for the subgroup of people with rapidly evolving severe RRMS. (NICE, 2011).
Summary
Whilst NICE is yet to make its final decision (i.e. issue a Final Appraisal Determination), its provisional assessment of fingolimod is different to that made by the PBAC. This is despite the assessments in both jurisdictions being based on the same clinical evidence (FREEDOMS and TRANSFORMS trials). The cause appears to be the difference in the approved label for fingolimod in Australia and the European Union rather than any differences in the policies, methods or values of the 2 P&R/HTA agencies. The sponsor may be at fault here for not having compared fingolimod with other treatment options. In is defence, its submission to NICE was made before fingolimod had been approved for use within the European Union and the label that was approved might not have been what it sought.
NICE (UK)
Gilenya was approved by the European Commission on 17 March 2011.
Gilenya is indicated as single disease modifying therapy in highly active RRMS for the following adult patient groups:
- Patients with high disease activity despite treatment with a beta-interferon.
These patients may be defined as those who have failed to respond to a full and adequate course (normally at least one year of treatment) of interferon beta. Patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gadolinium-enhancing lesion. A “non-responder” could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year.
or
- Patients with rapidly evolving severe RRMS defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.
As was the case in Australia, its registration in the UK was supported by 2 clinical trials; FREEDOMS and TRANSFORMS. (Gilenya Summary of Product Characteristics, 2011. Accessed from www.emedicines.org.uk)
In provisional draft guidance published on 5 August, NICE recommended that fingolimod should not be prescribed on the NHS for patients with RRMS. This is because there are uncertainties over its clinical effectiveness and, based on the available evidence, it would not be a cost effective use of NHS resources.
While clinical trials have shown that fingolimod can reduce the number of relapses in some people who have highly active RRMS, it is unclear how much the drug may help the specific groups of people for whom it is licensed - i.e. adults with RRMS who experience at least one relapse in a year despite being treated with beta interferons, and adults with rapidly evolving severe RRMS who experience two or more disabling relapses regardless of their treatment. The evidence submitted by its sponsor mainly looked at a subgroup of the former.
NICE's Appraisal Committee could not determine how much fingolimod reduces the rate of relapses compared with some of the treatments already available. This is because its sponsor only submitted evidence which compared fingolimod with a placebo, and fingolimod with a specific type of interferon (interferon beta-1a, Avonex) that is not believed to be widely prescribed in the NHS.
The Appraisal Committee believes that the sponsor should have submitted a comparison of fingolimod with other interferons for people with highly-active RRMS, as well of fingolimod with natalizumab (Tysabri) for the subgroup of people with rapidly evolving severe RRMS. (NICE, 2011).
Summary
Whilst NICE is yet to make its final decision (i.e. issue a Final Appraisal Determination), its provisional assessment of fingolimod is different to that made by the PBAC. This is despite the assessments in both jurisdictions being based on the same clinical evidence (FREEDOMS and TRANSFORMS trials). The cause appears to be the difference in the approved label for fingolimod in Australia and the European Union rather than any differences in the policies, methods or values of the 2 P&R/HTA agencies. The sponsor may be at fault here for not having compared fingolimod with other treatment options. In is defence, its submission to NICE was made before fingolimod had been approved for use within the European Union and the label that was approved might not have been what it sought.
