Levodopa with Carbidopa, intestinal gel, 20 mg–5 mg per mL, Duodopa, March 2008
Public summary document for Levodopa with Carbidopa, intestinal gel, 20 mg–5 mg per mL, Duodopa, March 2008
Page last updated: 18 July 2008
Public Summary Documents
Product: Levodopa with Carbidopa, intestinal gel, 20 mg–5 mg per mL, Duodopa
Sponsor: Solvay Pharmaceuticals
Date of PBAC Consideration: March 2008
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drug) Public and Private Hospital Authority Required listing for the treatment by a neurologist for patients with advanced Parkinson’s disease with severe disabling motor fluctuations not adequately controlled by oral therapy.
2. Background
This formulation and method of administration had not previously been considered by the PBAC. Levodopa with carbidopa in a tablet formulation has been listed for many years.
3. Registration status
Duodopa was granted Orphan Drug status on 18 April 2006 and was registered by the TGA on the 27 February 2008 for the treatment of advanced idiopathic Parkinson’s disease with severe motor fluctuations despite optimised oral treatment. A positive clinical response to Duodopa administered via a temporary nasoduodenal tube should be confirmed before a permanent percutaneous endoscopic gastrostomy (PEG) tube is inserted.
4. Requested Listing and PBAC’s view
Section 100 (Highly Specialised Drug)
Public and Private Hospital Authority required
Treatment by a neurologist for patients with advanced Parkinson’s disease with severe
disabling motor fluctuations not adequately controlled by oral therapy.
The PBAC noted advice from the Highly Specialised Drugs Working Party that the product
did not meet all criteria for listing under the Highly Specialised Drug Program.
For the PBAC’s view, see Recommendation and Reasons.
5. Clinical place for the proposed therapy
6. Comparator
The submission nominated standard medical management, defined as a mix of suboptimal
oral medication (including oral levodopa and carbidopa) and continuous subcutaneous
apomorphine infusion.
For PBAC's comments see Recommendations and Reasons.
7. Clinical Trials
The submission presented two randomised cross-over trials comparing levodopa-carbidopa
intestinal gel with conventional medication in patients with advanced idiopathic levodopa-responsive
Parkinson’s Disease (PD), with severe motor fluctuations in spite of individually
optimised conventional treatment. A comparison of the trial interventions is shown
in the table below.
Interventions compared by the direct randomised trials
|
Trial |
Treatment |
Dosage regimen |
Duration of treatment |
Duration of follow-up |
|---|---|---|---|---|
|
Trial |
Group 1 (CM→D) |
3 weeks of conventional PD medicationa followed by 3 weeks of Duodopab or vice versa |
Maximum of 6 weeks |
6 weeks |
|
Trial |
Group 1 (CM→D) |
3 weeks of conventional PD medicationc followed by 3 weeks of Duodopab |
Maximum of 6 weeks |
6 weeks |
Notes: CM=conventional medication; D=Duodopa
a Conventional PD medication included levodopa, apomorphine, amantadine and dopamine
agonists such as ropinirole.
b Duodopa was administered via a nasoduodenal catheter only.
c Oral carbidopa/levodopa (Sinemet)
The following table lists the trials as published at the time of submission.
Trials presented in the submission
|
Trial ID |
Protocol title/ Publication title |
Publication citation |
|---|---|---|
|
Direct randomised trials |
||
|
Trial NPP-001-99 |
Nyholm et al. Optimising levodopa pharmacokinetics: intestinal infusion versus oral
sustained release tablets. |
Clinical Neuropharmacology 2003; Vol 26 (3):156-163 |
|
Trial NPP-001-02 |
Nyholm et al. Duodenal levodopa infusion monotherapy vs. oral polypharmacy in advanced Parkinson disease. |
Neurology 2005; Vol 64: 216-223 |
Trial NPP-00102 was open for the patient and the investigator. Two independent and blinded observers evaluated the video recordings. However, the electronic diaries, Unified Parkinson’s Disease Rating Scale (UPDRS), the Parkinson’s Disease Questionnaire (PDQ) and the fifteen-dimensional measure of health-related quality of life (15D) used unblinded assessments. Blinding was not used in trial NPP-001-99.
8. Results of trials
The primary outcome in trial NPP-001-02 was the between-treatment difference in the
percentage of video recordings during which the Treatment Response Scale (TRS) was
in the range -1 to +1 (defined interval of normal).
A statistically significant difference in the percentage time in the ‘normal’ motor
state (percentage of video recordings in the range -1 to +1 of the TRS) during the
6-week treatment period was observed between levodopa-carbidopa intestinal gel and
conventional medication in trials NPP-001-02 and NPP-001-99. The results showed that
subjects spent more time in the ‘on’ motor state on levodopa-carbidopa intestinal
gel. This difference in trial NPP-001-02 was statistically significant (p<0.01) in
favour of levodopa-carbidopa intestinal gel, in both the intention to treat (ITT)
and per protocol (PP) populations using various analyses and reliability test. However,
when the results of the two groups are compared separately for Trial NPP-001-02, there
was a significant difference at the 0.05 level in favour of levodopa-carbidopa intestinal
gel in patients who received 3 weeks of treatment with conventional medication and
a subsequent 3 weeks of treatment with levodopa-carbidopa intestinal gel (Group 1).
When the sequence of treatments was reversed (3 weeks of levodopa-carbidopa intestinal
gel followed by 3 weeks of conventional medication, Group 2), there were no significant
differences at the 0.05 level in the amount of time spent in the “normal” motor state
for patients enrolled in Trial NP-001-02. For patients enrolled in trial NPP-001-99,
a significant difference at the 0.05 level in the amount of time spent in the “normal”
motor state was observed regardless of the sequence of treatments. However the assessment
in this trial was unblinded and thus subject to observer bias.
Trial NPP-001-02 showed a statistically significant difference (p<0.01) in favour
of levodopa-carbidopa intestinal gel for the primary endpoint percentage of video
recordings in the range -1 to +1 of the TRS.
The primary outcome in trial NPP-001-99 was mean levels and variability (variance,
coefficient of variation) in plasma levodopa concentrations.
The variance in plasma levodopa concentrations was significantly less during levodopa-carbidopa
intestinal gel treatment. In addition, daily within-patient plasma levodopa coefficients
of variation were significantly lower during levodopa-carbidopa intestinal gel treatment.
The results show that intraduodenal administration of levodopa-carbidopa intestinal
gel is accompanied by decreased variability in plasma levodopa, measured as variance
and coefficient of variation.
No statistically significant difference in mean plasma levodopa during the 6-week
treatment period was observed between levodopa-carbidopa intestinal gel and conventional
medication in trial NPP-001-99.
Quality of life measures used in NPP-011-02 included electronic diary, PDQ-39 (Parkinson’s
disease questionnaire), and 15-D (a 15 item Quality of Life instrument).
A statistically significant difference in the PDQ-39 summary indices during the 6-week
treatment period was observed between levodopa-carbidopa intestinal gel and conventional
medication in trial NPP-001-02. Levodopa-carbidopa intestinal gel was also significantly
better than conventional therapy in regard to 7 of the 8 dimensions of the PDQ-39
(excluding ‘Social Support’).
Analysis of the electronic diary showed levodopa-carbidopa intestinal gel was significantly
better than conventional therapy in relation to responses to the morning question
regarding ability to turn in bed, and the morning and daytime questions regarding
difficulty walking, having been “off”, difficulty with chores and satisfaction with
functioning.
A statistically significant difference in quality of life as measured by 15D results
during the 6-week treatment period was observed between levodopa-carbidopa intestinal
gel and conventional medication in trial NPP-001-02.
The key adverse events results are summarised in the table below:
Summary of adverse events in the direct randomised trials
|
Trial ID |
Duodopa |
Conventional medication |
RRb |
|---|---|---|---|
|
Trial NPP-001-02a |
|||
|
Adverse events |
17/22a (77.3) |
16/21 (76.2) |
1.01 (0.73, 1.41) |
|
Trial NPP-001-99 |
|||
|
Adverse events |
10/12 (83.3) |
15/16 (93.8) |
0.89 (0.67, 1.18) |
a The study report for the pivotal trial NPP-001-02 used a denominator of 24 patients
when calculating AE rates for the Duodopa treatment period. However, only 22 patients
actually received Duodopa, 2 patients withdrew after the start of the Duodopa treatment
period but before receiving any medication.
b Calculated during the evaluation.
The extended assessment of comparative harms was based on the Periodic Safety Update
Report for the period 21 January 2007 to 20 July 2007. An estimated 600 patients were
exposed to Duodopa during the period covered by this report. During the reference
period a total of 59 serious and unlisted non-serious ADR-reports from healthcare
professionals were received, 55 (93%) of which were regarded as serious.
Of major concern to the PBAC is that adverse events related to the pump and/or tubing
may be substantial. The open-label NPP-002-02 trial which followed-up 65 patients
from 1991 to 2002 reported that tube dislocation occurred in 65.5% and tube occlusion
in 37.9% of patients. The Pre-Sub-Committee Response acknowledged that the delivery
of Duodopa is associated with more adverse events than the comparators, but claimed
that that new tubing is now used that is less prone to dislocation.
9. Clinical claim
The submission claimed that levodopa-carbidopa intestinal gel has significant advantages
in effectiveness over standard medical management with regards to ‘on’ time (treatment
success), time spent in the Parkinsonism health state (‘off’ time) , and health related
quality of life as measured by the 15D instrument.
For PBAC's views see Recommendations and Reasons.
10. Economic analysis
A cost-effectiveness approach was adopted and a modelled economic evaluation was presented.
The modelled economic evaluation took a societal perspective and included disutilities
to carers in the base case. The model also included an incremental gain in carer utility
associated with patients’ improvement in Hoehn & Yahr status (the Hoehn and Yahr scale
is a five stage disability scale used in Parkinson’s disease). The key factors driving
the results were the probability of transitioning to a nursing home and the probability
of improvement in Hoehn and Yahr status.
The base case incremental cost per extra QALY gained (including care burden) compared
to standard medical management was between $45,000 and $75,000. The submission estimated
that this cost would rise to between $130,000 and $150,000 when carer burden was excluded.
The PBAC was advised of several issues of economic uncertainty associated with the
model.
For the PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated that the likely number of patients per year would be well below 2,000, as the product is an orphan drug, as designated by TGA and suitable only for a small sub-group of the possible total population The total cost per year was estimated to be between $10 to 30 million.
12. Recommendations and Reasons
The PBAC noted advice from the Highly Specialised Drugs Working Party that the product
did not meet all criteria for listing under the Highly Specialised Drug Program.
The place of levodopa with carbidopa intestinal gel (Duodopa) was confirmed during
the hearing as being a last line treatment for Parkinson’s disease that would replace
such therapies as continuous subcutaneous apomorphine infusion, suboptimal oral treatment
or deep brain stimulation (DBS). The PBAC considered it was not appropriate that DBS
had been excluded from the mix of comparators in the submission and also noted that
the trial populations excluded patients with dementia or cognitive impairment who
would be eligible for PBS-subsidised treatment under the sponsor’s proposed listing.
The PBAC accepted that levodopa-carbidopa intestinal gel has statistically significant
advantages in effectiveness over standard medical management with regards to ‘on’
time (treatment success), time spent in the Parkinsonism health state (‘off’ time)
, and health related quality of life as measured by the 15D instrument. However, there
was uncertainty associated with the clinical importance of the trial results as the
two randomised trials presented were small, and, in the larger trial with 12 participants
in each treatment group, there were five treatment withdrawals. An additional area
of concern to the Committee was that the use of electronic diaries, the UPDRS, PDQ
and 15D were all unblinded, and there were no long term efficacy or safety data. The
Committee also noted that the 15D is a less preferred instrument than other instruments
(it is well documented to have poor correlation with other multi-attribute utility
instruments).
Of major concern to the PBAC was that adverse events related to the pump and/or tubing
may be substantial. The open-label NPP-002-02 trial which followed-up 65 patients
from 1991 to 2002 reported that tube dislocation occurred in 65.5% and tube occlusion
in 37.9% of patients. The Pre-Sub-Committee Response acknowledged that the delivery
of Duodopa is associated with more adverse events than the comparators, but claimed
that that new tubing is now used that is less prone to dislocation. However, no evidence
for this statement was provided, and the PBAC was advised that percutaneous endoscopic
gastrostomy into the duodenum is generally not as successful as into the stomach.
The PBAC was advised of several areas of uncertainty associated with the modelled
economic evaluation presented which calculated an incremental cost per extra QALY
gained of between $45,000 to $75,000 compared to standard medical management. Furthermore
this QALY included a cost for ‘carer burden’ and the incremental cost effectiveness
ratio excluding carer utilities was between $105,000 and $200,000. Although the PBAC
acknowledged that there is a significant carer burden related to the cost of care
with Parkinson’s disease and carer disutility, it considered carer utilities should
have been incorporated in a sensitivity analysis, distinct from the base case.
The PBAC also commented on the high cost of the drug in this presentation, and the
potential for wastage due to storage requirements.
The PBAC therefore rejected the submission on the basis of the unacceptably high and
uncertain incremental cost effectiveness ratio for levodopa with carbidopa gel compared
to standard medical management.
Recommendation
Reject
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
Solvay will work with the PBAC to address the key issues identified in the Duodopa
PBAC submission in order to make this orphan drug available for Advanced Parkinson’s
Disease patients. Duodopa has been granted Orphan Drug Status by the TGA and by definition,
it is suitable only for a small number of Parkinson’s disease patients, hence the
overall paucity in the availability of clinical data. Solvay is disappointed that
the Highly Specialised Drugs Working Party did not consider that Duodopa and its innovative
mode of delivery met the highly specialised drug criteria. The higher rate of device
complications reported in earlier trials has been addressed by Solvay with significant
product development and changes implemented over the last 10 years. Many issues with
the earlier systems including leakage, PEG/PEJ dislocation and occlusion has been
addressed and ongoing market acceptance testing results show reductions in complication
events over time. Solvay strongly believes that the base case cost effectiveness analysis
should include all the costs associated with Parkinson disease (including carer burden).
It should be noted, like all orphan drugs, there are very little economies of scale,
hence the commercial viability of drugs is often marginal. Given the lack of therapeutic
options available for advanced PD, Solvay believes there is a strong argument to make
Duodopa available on the PBS.
