Interferon Beta – 1b, injection set comprising 1 vial powder for injection 8,000,000 i.u. (250 micrograms) and solvent, Betaferon®, March 2007
Public summary document for Interferon Beta – 1b, injection set comprising 1 vial powder for injection 8,000,000 i.u. (250 micrograms) and solvent, Betaferon®, March 2007
Page last updated: 13 July 2007
Public Summary Document
Product: Interferon Beta – 1b, injection set
comprising 1 vial powder for injection 8,000,000 i.u. (250
micrograms) and solvent, Betaferon®
Sponsor: Schering Pty Limited
Date of PBAC Consideration: March 2007
1. Purpose of Application
The submission requested a review of the eligibility criteria of
drugs for the treatment of Multiple Sclerosis (MS) to allow
patients diagnosed using the McDonald criteria to access treatment.
This would allow for a second attack in time to be defined by a new
lesion appearing on Magnetic Resonance Imaging (MRI) rather than a
second clinical attack.
2. Background
Interferon beta-1b was first listed on the PBS on 1 November 1996
after consideration at the September 1996 PBAC meeting.
3. Registration Status
Betaferon is registered for:
- the treatment of ambulatory patients with relapsing-remitting multiple sclerosis (MS) characterised by at least two attacks of neurologic dysfunction over a two year period followed by complete or incomplete recovery.
- the reduction of frequency and severity of clinical relapses, and for the slowing of progression of disease in patients with secondary progressive multiple sclerosis.
- the treatment of patients with a single clinical event suggestive of multiple sclerosis and at least two clinically silent magnetic resonance imaging (MRI) lesions characteristic of multiple sclerosis, if alternative diagnoses have been excluded.
4. Listing Requested and PBAC’s View
Two listing alternatives were proposed:
Alternative One:
Authority required
Initial treatment of relapsing-remitting multiple sclerosis in
ambulatory (without assistance or support) patients who have
experienced documented neurological dysfunction believed to be due
to the multiple sclerosis.
- Two or more attacks believed to be due to multiple sclerosis with objective clinical evidence of two or more lesions.
- Two or more attacks believed to be due to the multiple sclerosis with objective clinical evidence of one lesion plus dissemination in space demonstrated by MRI, or two or more MRI lesions plus positive CSF or a further clinical attack implicating a different site.
- One attack believed to be due to the multiple sclerosis with objective clinical evidence of two or more lesions plus dissemination in time demonstrated by MRI or a second clinical attack suggestive of multiple sclerosis.
- One attack believed to be due to the multiple sclerosis with objective clinical evidence of one lesion plus dissemination in space demonstrated by MRI or two or more MRI-detected lesions plus positive CSF and dissemination in time demonstration by MRI or a second clinical attack.
- MRI lesions should be consistent with multiple sclerosis. MRI dissemination in space criteria should include three of the following, (1) at least one gadolinium-enhancing lesion or nine T2 hyperintense lesions (2) at least one infratentorial lesion (3) at least one juxtacortical lesion (4) at least three periventricular lesions. A spinal cord lesion can be considered equivalent to a brain infratentorial lesion: an enhancing spinal cord lesion is considered equivalent to an enhancing brain lesion and individual spinal cord lesions can contribute together with individual brain lesions to reach the required number of T2 lesions. MRI dissemination in time criteria can be satisfied by (a) detection of gadolinium enhancement at least three months after the onset of the initial clinical event at a new site or (b) detection of a new T2 lesion if it appears at any time compared to a reference scan done at least 30 days after the onset of the initial clinical event.
The dates of scans must be 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.
Continuing treatment of multiple sclerosis 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. The authority will be limited to the
maximum quantity and number of repeats indicated in the
schedule.
Alternative two:
Authority required
Initial treatment of relapsing-remitting multiple sclerosis in
ambulatory (without assistance or support) patients who have
experienced one or more documented attacks of neurological
dysfunction believed to be due to the multiple sclerosis.
The diagnosis must be confirmed by magnetic resonance imaging (MRI)
unless there have been two attacks with objective evidence of two
or more lesions. MRI lesions should be consistent with multiple
sclerosis.
For a single neurological attack with objective clinical evidence
of two or more lesions, a positive MRI disseminated in time is
required. For a single neurological attack with objective clinical
evidence of one lesion, positive MRIs disseminated in space and
time are required.
The dates of MRI scans must be 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.
Continuing treatment of multiple sclerosis 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. The authority will be limited to the
maximum quantity and number of repeats indicated in the
schedule.
See Recommendation and Reasons for PBAC’s view
5. Clinical Place for the Proposed Therapy
By revising the current eligibility criteria, patients who are
already diagnosed with multiple sclerosis using the McDonald
criteria would have access to treatment.
6. Comparator
The submission nominated placebo as the appropriate
comparator.
7. Clinical Trials
The primary source of evidence was a single trial (the BENEFIT
trial) comparing interferon beta-1b (INFN beta-1b) (8 million IU
every other day) and placebo over 24 months in the treatment of
patients with one clinical attack of neurological dysfunction
suggestive of demyelinating disease within the last 60 days and at
least two clinically silent lesions on MRI.
The BENEFIT trial had been published at the time of submission as
follows:
| First author | Publication title | Publication citation |
| Kappos et al. | Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. | Neurology; 2006;67(7):1242-124 |
| Blaeser-Kiel et al. | First clinical manifestation of multiple sclerosis. BENEFIT: Good prospects of therapy ‘on suspicion’. | Neurologue & Rehabilitation 2005; 6:356-357. |
| Anonymous | The BENEFIT study: Betaferon can delay outbreak of multiple sclerosis. | Deutsche Apotheker Zeitung 2005; 145(44):47-49 |
8. Results of Trials
The results of the BENEFIT trial are summarised below:
Cumulative probability (%, Kaplan-Meier estimates) of being diagnosed with MS according to the McDonald criteria and CDMS according to the altered Poser criteria
| Cumulative probability of CDMS according to the modified Poser criteria (%) | Cumulative probability of being diagnosed with MS according to the McDonald criteria (%) | |||
| Days of treatment | INFN-1b (N=292) | Placebo (N=176) | INFN-1b (N=292) | Placebo (N=176) |
| 0 | 0 | 0 | 0 | 0 |
| 90 | 6.6 | 9.2 | 12.2 | 21.2 |
| 180 | 11.2 | 19 | 28 | 50.6 |
| 270 | 14.4 | 26 | 46.5 | 66.1 |
| 360 | 18.4 | 31.9 | 55.6 | 73.1 |
| 450 | 22.1 | 34.3 | 62.6 | 76.6 |
| 540 | 24 | 39.1 | 63.4 | 77.8 |
| 630 | 25.8 | 40.9 | 76 | 79.7 |
| 720 | 27.5 | 45.3 | 69.4 | 84.5 |
The Kaplin-Meier estimates for the probability of MS according to
the McDonald criteria over time suggest that the majority of
patients in both groups were diagnosed with MS in the first year of
the trial.
The following table shows mean and median scores for the Kurtzke
Expanded Disability Status Scale (EDSS) observed over 2 years of
the trial.
EDSS scores
| INFN-1b (N=292) | Placebo (N=176) | |||||
| Observation point | N | Mean (SD) | Median (Q1-Q3) | N | Mean (SD) | Median (Q1-Q3) |
| Baseline | 292 | 1.59 (0.86) | 1.50 (1.0;-2.0) | 176 | 1.49 (0.88) | 1.50 (1.0;-2.0) |
| Month 6 | 253 | 1.30 (0.93) | 1.50 (1.0;-2.0) | 152 | 1.30 (0.90) | 1.50 (1.0;-2.0) |
| Month 12 | 229 | 1.24 (0.89) | 1.50 (1.0;-2.0) | 120 | 1.32 (0.85) | 1.50 (1.0;-2.0) |
| Month 18 | 210 | 1.24 (0.87) | 1.0 (1.0;-2.0) | 111 | 1.18 (0.81) | 1.0 (1.0;-2.0) |
| Month 24 | 196 | 1.26 (0.96) | 1.0 (1.0;-2.0) | 91 | 1.18 (0.83) | 1.0 (1.0;-2.0) |
| End of study | 277 | 1.49 (1.05) | 1.50 (1.0;-2.0) | 167 | 1.56 (1.08) | 1.50 (1.0;-2.0) |
Q1–Q3 = range (1st to 3rd quartile).
9. Clinical Claim
The submission claims INFN-1b has significant advantages in
effectiveness over and less (sic) toxicity than placebo in the
treatment of MS when diagnosed according to the McDonald
criteria.
See Recommendation and Reasons for PBAC’s
view.
10. Economic AnalysisA series of preliminary economic
evaluations were presented. The resources included were drug costs.
The trial-based incremental discounted cost per extra discounted
patient avoiding a diagnosis of Clinically Definite Multiple
Sclerosis (CDMS) at 2 years was estimated to be in the range of
$105,000 – $200,000.
Two modelled economic evaluations were presented. The PBAC noted
that one model was not relevant to the current requested
restriction while the other model did not provide any estimate of
incremental costs and benefits of the proposed algorithm for
treating MS compared with the current algorithm.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be <
10,000 in Year 4, while the financial cost per year to the PBS was
estimated to be < $10 million in Year 4.
12. Recommendation and Reasons
The PBAC noted that the submission proposed that the PBS
restriction for interferon beta-1b (INFN-1b) be amended in line
with current clinical practice as represented by the McDonald
criteria. The PBAC acknowledged, as stated in the hearing, that the
Poser criteria for diagnosing multiple sclerosis (MS) had now been
superseded by the McDonald criteria using magnetic resonance
imaging (MRI) and one attack of neurological dysfunction. However,
there was concern about the specificity of the McDonald criteria in
differentiating between MS and other neurological conditions, which
could lead to inappropriate use of INFN-1b.
The PBAC indicated that to support any change to the PBS
restriction to adopt the McDonald criteria, evidence would be
required that the incremental efficacy gained from earlier
treatment with INFN-1b, balanced by the incremental harm of
exposing more patients to INFN-1b for a longer period of time than
they would have been under the Poser criteria, is
cost-effective.
However, the PBAC agreed that the evidence from the BENEFIT trial
was not informative in relation to the question of replacing the
Poser criteria with the McDonald criteria because patients were not
enrolled in the trial according to either of these criteria.
Patients were considered eligible for enrolment if they had
symptoms suggestive of MS, in other words, at baseline (Day 1) of
the trial they had “probable/possible” MS, but did not
have confirmed MS using either the McDonald or Poser diagnostic
criteria. Enrolled patients then followed over time to determine
whether the earlier treatment with INFN-1b delays progression of
disease more than would have been achieved by treating later. After
1 year (360 days of treatment) 55.6% of patients treated with
INFN-1b had a MS diagnosis confirmed according to the McDonald
criteria, but only 18.4% of those had the MS diagnosis also
confirmed according to the Poser criteria. The only conclusion that
can be drawn from these data is that treatment with INFN-1b delays
the diagnosis of MS, regardless of which criteria for diagnosis of
MS are used, in comparison with placebo.
The PBAC also noted that there was uncertainty whether this delay
in MS diagnosis (regardless of which criteria for diagnosis are
used) observed with INFN-1b translates into a slower progression of
disability. At 2 years there was no statistically significant
difference in EDSS scores between patients with
“probable/possible” MS treated with INFN-1b in
comparison with similar patients on placebo.
On the other hand, the PBAC acknowledged that the relevance of a
PBS restriction based on the Poser criteria for the current
clinical management of MS in Australia is likely to be eroded over
time, especially given that the clinical trials of future MS drugs
will likely recruit patients according to the newer McDonald
criteria.
- The economic uncertainties about the submission arose from the clinical uncertainties.
The PBAC concluded that the submission’s claim that it is
cost-effective to initiate treatment with INFN beta-1b upon
diagnosis of MS by the McDonald criteria was not adequately
supported by the evidence presented. The PBAC therefore rejected
the submission because of uncertain clinical benefit and uncertain
cost effectiveness.
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 general acceptance of the McDonald criteria, for the
diagnosis of multiple sclerosis, the sponsor will work with the
PBAC to justify updating the wording of the authority for Betaferon
to reflect current best practice in multiple sclerosis
treatment.
