Natalizumab, concentrated solution for IV infusion, 300 mg per 15 mL, Tysabri November 2006
Public summary document for Natalizumab, concentrated solution for IV infusion, 300 mg per 15 mL, Tysabri November 2006
Page last updated: 16 March 2007
Public Summary Document
Product: Natalizumab, concentrated solution for IV infusion, 300 mg per 15 mL, Tysabri
Sponsor: Biogen Idec Australia Pty Ltd
Date of PBAC Consideration: November 2006
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drug) authority required listing
for initial and continuing treatment, by neurologists, of clinically definite relapsing-remitting
multiple sclerosis in ambulatory patients eighteen years of age or older.
Highly Specialised Drugs are medicines for the treatment of chronic conditions, which,
because of their clinical use or other special features, are restricted to supply
to public and private hospitals having access to appropriate specialist facilities.
2. Background
The PBAC had not previously considered this drug.
3. Registration Status
Natalizumab was registered by the TGA on 1 November 2006 for the indication:
as monotherapy for the treatment of patients with relapsing remitting multiple sclerosis to delay the progression of physical disability and to reduce the frequency of relapse. The safety and efficacy of TYSABRI beyond two years are unknown.
4. Listing Requested and PBAC’s View
Public and private hospital authority required – Section 100
Initial treatment, by neurologists, of clinically definite relapsing-remitting multiple
sclerosis in ambulatory (without assistance or support) patients eighteen years of
age or older. The diagnosis must be confirmed by magnetic resonance imaging (MRI)
of the brain and/or spinal cord and the date of the scan included in the authority
application, unless the authority application is accompanied by written certification
provided by a radiologist that an MRI scan is contraindicated because of the risk
of physical (not psychological) injury to the patient.
In addition, to be eligible for initial treatment, patients must either:
- Have experienced at least 2 documented attacks of neurological dysfunction, believed to be due to multiple sclerosis, in the preceding 2 years, or:
- Have shown progression of disability while on an existing immunomodulatory therapy (eg. interferon-beta or glatiramer acetate), and are therefore required to cease that treatment in accordance with the current PBS listing, or:
- Have proven intolerant to, or unable to comply with, an existing immunomodulatory therapy, and are therefore required to cease that treatment in accordance with the current PBS listing, or:
- Have developed persistent neutralising antibodies to an existing immunomodulatory treatment, as demonstrated by two consecutive negative bioactivity measurements while on treatment, which are separated by at least three months.
Authority applications must be in writing and must include:
- a completed authority prescription form
- a completed 'Natalizumab Treatment for Multiple Sclerosis Supporting Information Form' which includes the patient's date of MRI scan at which multiple sclerosis was diagnosed, and results of any relevant supporting evidence to indicate the patient meets the initial treatment criteria.
- a copy of the signed patient acknowledgement form that declares that the patient understands and acknowledges that PBS-subsidised treatment with natalizumab for multiple sclerosis will cease if they fail to meet the PBS-defined continuation criteria.
A maximum quantity of 6 infusions will be issued with the initial authority (1 + 5
repeats).
Continuing treatment of clinically definite relapsing-remitting multiple sclerosis
in patients previously issued with an authority prescription for this drug who do
not show continuing progression of disability while on treatment with this drug, and
who have demonstrated compliance with, and an ability to tolerate, this therapy. Patients
who have been shown to develop persistent antibodies to natalizumab, as shown by two
consecutive positive anti-natalizumab antibody tests separated by at least 12 weeks,
should discontinue therapy as they receive no benefit from treatment.
Authority applications must be in writing and must include:
(1) a completed authority prescription form
A maximum quantity of 3 infusions will be issued with the continuing authority (1
+ 2 repeats).
See Recommendation and Reasons for PBAC’s view.
5. Clinical Place for the Proposed Therapy
Multiple sclerosis (MS) is an incurable, degenerative disease of the brain and spinal
cord, characterised by loss of areas of nerve-fibre covering (demyelination) and nerve
(axonal) destruction.
Advancement in the treatment of multiple sclerosis occurred in the early and mid 1990’s
following the introduction of immunotherapy in the form of recombinant beta-interferons
and, later, glatiramer acetate. Prior to this, the only mainstream therapies available
for multiple sclerosis were oral or intravenous corticosteroids for the management
of acute relapses, and a range of antispasmodics, antidepressants and other therapies
for symptom management.
Natalizumab is proposed as a further disease-modifying immunotherapy agent, specifically
directed at an early step in the formation of the inflammatory lesion: migration of
white cells across the blood brain barrier.
6. Comparator
The submission nominated interferon beta-1b as the main comparator. The PBAC accepted this as appropriate, however noted that it would have been informative for the submission to have included a comparison to interferon beta-1a as well.
7. Clinical Trials
The submission provided an indirect comparison of natalizumab and interferon beta-1b
(INFN beta-1b) using placebo as the common reference. One randomised placebo-controlled
trial of natalizumab (AFFIRM trial) and one randomised placebo-controlled trial of
interferon beta-1b (IFNB MSSG trial), both conducted in patients with relapsing-remitting
multiple sclerosis (RRMS), were used to conduct the indirect comparison.
The trial involving natalizumab had been published as follows:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
C-1801 AFFIRM |
||
|
Polman CH et al (2006) |
A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. |
New England Journal of Medicine, 2006; 354: 899-910 |
The trial involving INFN beta-1b had been published as follows:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
IFNB MSSG trial |
||
|
Duquette P et al (1993) |
Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. |
Neurology, 1993; 43(4 I): 655-661 |
|
Duquette P et al (1995) |
Interferon beta-1b in the treatment of multiple sclerosis: Final outcome of the randomized controlled trial. |
Neurology, 1995; 45(7): 1277-1285 |
8. Results of Trials
Key results of the indirect comparison for annualised relapse rates at one and two
years for both trials were presented.
The results of the key trials are summarised in the tables below.
Results of the indirect comparison– annualised relapse rate
|
Trial |
Rate ratio |
Natalizumab |
Placebo |
INFN beta-1b |
Rate ratio |
Indirect estimate of effect |
|---|---|---|---|---|---|---|
|
Results at 1 year |
||||||
|
AFFIRM |
0.341 |
N=627 |
N= 315 |
0.51 |
||
|
IFNB MSSG |
N=123 |
N=124 |
0.67 |
|||
|
Results at 2 years |
||||||
|
AFFIRM 2 years |
0.320 |
N=627 |
N= 315 |
|||
|
IFNB MSSGC |
N=110 |
N=107 |
0.720 |
0.444 |
||
|
N=112 |
N=115 |
0.66 |
0.485 |
|||
Bolded font indicates statistically significant differences
# Rates were annualised for actual time on study (Source: 1995 published report of IFNB MSSG trial)
Although the indirect comparison suggests that natalizumab is superior in terms of
relapse rate, the PBAC noted that the annualised relapse rate at one year in the placebo
group in the interferon trial was around double the risk for the AFFIRM trial.
Proportion of relapse-free subjects-ITT population 2 years
|
Trial |
Risk difference |
Natalizumab |
Placebo |
INFN beta-1b |
Risk difference |
Indirect estimate of effect |
|---|---|---|---|---|---|---|
|
AFFIRM |
0.26 |
418/627 |
129/315 |
|||
|
IFNB MSSG |
18/112c |
36/115c |
0.15 |
0.10 |
c Data presented are from the 1993 published report of the IFNB MSSG trial
The proportion of patients relapse-free at 2 years, was 66.7 per cent for natalizumab
as compared to 31.3 per cent for interferon. This difference was not statistically
significant.
The proportion of patients who remained relapse free at 2 years in the placebo arm
of the IFNB MSSG trial was 16.1% compared with 41% in the AFFIRM trial.
The PBAC considered that although both outcomes (relapse rates and proportion of
relapse-free subjects), were informative, making an indirect comparison, given the
difference between the placebo groups within each trial, requires the strong assumption
that the effectiveness of treatment does not depend on the underlying risk of relapse
in the patient population.
For PBAC’s further comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The submission claimed that natalizumab has significant advantages in effectiveness over interferon beta-1b and similar or less toxicity. The PBAC considered that while the evidence presented suggested that natalizumab may have superior efficacy in the treatment of multiple sclerosis as compared to INFN beta-1b, there were significant problems interpreting the evidence due to the use of the indirect comparison approach taken in the submission.
For PBAC’s comments, see Recommendation and Reasons.
10. Economic Analysis
The submission presented a preliminary economic evaluation using a cost-effectiveness
approach. The resources included were drug and drug administration costs. The PBAC
accepted this approach as valid.
The submission estimated that the incremental cost per extra relapse avoided over
one year (based on indirect comparison) would be in the range $45,000 – $55,000.
The submission estimated that the incremental cost per additional progression-free
patient over two years (based on indirect comparison) would be > $200,000 (this estimate
is based on an assumption in the submission that INFN beta-1b has no incremental effect
on disease progression over placebo).
A modelled economic evaluation was presented. The resources included were drug costs,
drug administration costs, specialist neurologist visits, other health and community
care costs, (Over-The-Counter (OTC) medications, hospitalisation, hospital in the
home, emergency department presentations, rehabilitation, visits to other specialist
and GPs, allied therapy, equipment, home modifications, community care, personal transport,
respite care, long-term care, etc.) and costs associated with relapse episodes.
The submission estimated that the base case modelled incremental cost per extra quality
adjusted life year (QALY) gained over 64.4 years would be in the range $75,000 – $85,000
(this estimate is based on an assumption in the submission that INFN beta-1b has no
incremental effect on disease progression over placebo).
For PBAC’s comments, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated that in Year 5 of listing the likely number of patients would
be
< 10,000 and the financial net cost to the PBS would be in the range $30 – $40 million.
The PBAC considered that the estimates of usage may result in net costs ≥ $10 million/year
to the PBS in the first year of listing at least.
12. Recommendation and Reasons
The PBAC agreed that the choice of comparator was appropriate but it would have been informative for the submission to have included a comparison to INFN beta-1a as well.
The PBAC considered that while the evidence presented suggested that natalizumab may have superior efficacy in the treatment of multiple sclerosis as compared to INFN beta-1b, there were significant problems interpreting the evidence due to the use of the indirect comparison approach taken in the submission. The Committee considered that patients recruited to the trials were not sufficiently comparable at baseline to support the conduct of an indirect comparison of natalizumab and INFN beta-1b, using placebo as the common reference.
Although patients in both trials were required to have a definite diagnosis of MS,
the natalizumab trial (AFFIRM) enrolled patients according to the McDonald criteria
which did not exist at the time the INFN beta-1b trial (IFNB MSSG) was conducted.
The PBAC remained uncertain as to whether the inclusion criterion in the AFFIRM trial
of at least one medically documented clinical relapse within the twelve months prior
to randomisation would be comparable with the requirement in the IFNB MSSG trial for
patients to have had at least two acute exacerbations during the previous two years.
The PBAC noted the Pre-PBAC Response to this issue stating that 96% of patients in
the AFFIRM trial had experienced two or more relapses and would have therefore satisfied
the older Poser criteria. Nevertheless, the PBAC considered that the issue of comparability
between the placebo groups remained uncertain and unresolved. The Committee also noted
that the cost-effectiveness of treating multiple sclerosis according to the McDonald
criteria has not been established in the context of PBS subsidisation.
The PBAC noted that patients in the IFNB MSSG trial appeared to have had multiple
sclerosis for a longer period of time with a greater disability at baseline. The Committee
also noted information on patient demographics included in the sponsor’s Pre-Sub-Committee
Response, providing evidence that the two populations are more comparable in terms
of time since diagnosis, than originally thought. The PBAC considered however, that
this did not eliminate other concerns raised in regard to differences in populations
between the trials. The mean EDSS at baseline was 2.3 in AFFIRM and 2.9 in IFNB MSSG.
However, the PBAC would have found it useful to know the distribution of EDSS scores
at baseline in both studies to assist in understanding the clinical significance of
this difference. Although this information was provided in the submission for the
AFFIRM trial, baseline EDSS score distribution data are not available for the IFNB
MSSG trial. The PBAC noted that the EDSS scale is non-linear over its range in comparison
with the actual level of function. For example, a 1-point EDSS change at the low end
of the scale reflects only a small change in function, compared to a similar change
at mid-point which reflects a substantial increase in disability.
The PBAC noted that the annualized relapse rate at one year in the placebo group in
the INFN trial was around double the risk in the AFFIRM trial. The PBAC considered
that making an indirect comparison given this difference, requires the strong assumption
that the effectiveness of treatment does not depend on the underlying risk of relapse
in the patient population.
The PBAC also noted that the IFNB MSSG trial was conducted more than a decade earlier
than the AFFIRM trial, and there may be reasons to believe that management of RRMS
could have changed in the time between the trials in ways that are likely to affect
some of the trial outcomes, for example management of relapses and the consequent
impacts on progression of disability. The PBAC noted the sponsor’s comment on this
issue in it Pre-Sub-Committee Response, however considered that this was not adequately
addressed in the submission.
The PBAC agreed that the indirect comparison suggested that natalizumab is superior
in terms of relapse rate, however noted that the magnitude of this superiority is
dependent on the effect measure used. The PBAC noted the proportion of patients relapse-free
at 2 years, with the difference between the trials not being statistically significant.
The PBAC noted the Pre-PBAC Response concern regarding the focus on the secondary
outcome of proportion of patients relapse free at one year ‘at the expense of” the
primary outcome of the annualised relapse rate, because the former loses information
on how many relapses a patient may have in a year. The PBAC considered that both outcomes
were informative in the context of an indirect comparison in which concerns were raised
about the comparability of the patients enrolled in the trials.
The PBAC noted the risk of developing progressive multifocal leukoencephalopathy (PML)
with natalizumab treatment. This risk is stated to be around 1 in 1000, but if it
occurs is highly likely to cause death or severe disability. Given the seriousness
of this adverse event, the Committee agreed that any restriction should include a
Cautionary NOTE and specify that treatment is restricted to monotherapy, as this is
thought to limit the risk of developing PML. The PBAC noted that the TGA registered
indication includes a statement that the safety and efficacy of natalizumab beyond
two years is unknown and that this should also be included in any PBS restriction
for natalizumab. The PBAC endorsed the prescribing education program proposed by the
sponsor noting that this was a condition of registration.
In regard to the requested restriction, the PBAC considered that the inclusion of
criteria 2 and 3 of the initial treatment restriction is not appropriate as they imply
that natalizumab should be used as second line therapy to interferon beta. The requested
restriction therefore did not match the patient population included in the AFFIRM
study, as almost all patients in the trial were treatment naﶥ, and the submission’s
proposed restriction would unnecessarily dictate clinical practice in an area where
a standard treatment algorithm has not been established.
The PBAC had concerns about the economic evaluation and considered overall that the
incremental cost-effectiveness ratio to be high at $75,000-$85,000 per QALY compared
with INFN beta-1b, uncertain and likely to be biased in favour of natalizumab.
The Committee was concerned that the economic model did not adequately reflect the
treatment pathways, disease progression or resource utilisation of patients in the
PBS setting. The question of whether the utilities were applied appropriately also
contributed to the uncertainty.
The PBAC considered that the structure of the model did not adequately represent the
natural history of multiple sclerosis. Firstly, there are differences in the transitions
assumed possible for patients having disease progression and ‘on treatment’ and patients
having disease progression and ‘off treatment’. Secondly, the model assumed that patients
discontinuing treatment will not commence treatment with other available therapies,
which is not substantiated in the submission. Thirdly the model did not include health
states that account for natalizumab-treated patients discontinuing therapy because
they develop neutralising antibodies, but who do not have progression of disability.
The Committee was also concerned that the discontinuation rule assumed by the model
did not adequately reflect the interpretation of the requested restriction.
The PBAC was concerned about the utilities derived from Fisk et al and whether the
submission adequately justifies the utilities assumed in the model. It noted the Pre-Sub-Committee
Response that the precise utility weights were sourced from the author, however the
utility of health states in the model were estimated by taking the average of the
EDSS scores and the submission did not provide sufficient detail to enable independent
verification of results. Resource utilisation by disability level was based on a small
unpublished study with a sample size of only thirty in an Australian setting while
the costs of managing a relapse episode was based on a US study, which raised concerns
about differences in practices between the two countries.
The PBAC noted that the submission relies on the fact that there is a non-significant
difference in disease progression in the IFNB MSSG trial between INFN beta-1b and
placebo, as a basis to use only the results of the AFFIRM trial to estimate the benefit
of natalizumab over IFNB beta 1b. The PBAC acknowledged the argument presented by
the Pre-PBAC Response that the ESC estimate of a cost per progression free patient
over two years of approximately $1,000,000 based on no difference in progression between
nataluzimab and IFNB beta 1b was extreme. However, the Committee felt that this does
not negate the fact that the comparison presented in the submission favoured natalizumab.
Hence the estimated cost-effectiveness ratio of $75,000-$85,000 per QALY is the best
case for natalizumab. This estimate is carried into the modelled economic evaluation,
and hence the cost per QALY favoured natalizumab, accordingly.
Overall, the PBAC acknowledged that natalizumab represents the first additional effective
treatment option in several years for this distressing disease and agrees that the
submission demonstrates a clinical benefit. However, notwithstanding this, the Committee
considered that the optimistic estimated base case cost-effectiveness ratio of $75,000-$85,000
per QALY to be high and uncertain, and rejected the submission on this basis.
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
Due to the clear clinical need for new therapeutic options in the management of multiple sclerosis, the sponsor will work with the PBAC with a view to ensuring access to TYSABRI through the PBS for this incurable, debilitating disease.
