Levodopa with carbidopa monohydrate, intestinal gel, 20 mg – 5 mg (base) per mL, 100 mL, Duodopa®, March 2009
Public summary document for Levodopa with carbidopa monohydrate, intestinal gel, 20 mg – 5 mg (base) per mL, 100 mL, Duodopa®, March 2009
Page last updated: 03 July 2009
Public Summary Document
Product:Levodopa with carbidopa monohydrate,
intestinal gel, 20 mg – 5 mg (base) per mL, 100 mL,
Duodopa®
Sponsor: Solvay Pharmaceuticals
Date of PBAC Consideration: March 2009
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drug) PBS
listing for initial treatment commenced in a hospital based
Movement Disorder Clinic for patients with advanced Parkinson
disease with severe disabling motor fluctuations not adequately
controlled by oral therapy.
The submission also sought a Section 85 authority required PBS
listing for continuing treatment for patients commenced in a
hospital based Movement Disorder Clinic.
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
At the March 2008 meeting, the PBAC rejected a submission seeking a
Section 100 Highly Specialised Drug listing for treatment by a
neurologist of patients with advanced Parkinson disease with severe
disabling motor fluctuations not adequately controlled by oral
therapy on the basis of the unacceptably high and uncertain
incremental cost effectiveness ratio for levodopa with carbidopa
gel compared to standard medical management.
3. Registration Status
Duodopa was TGA registered on 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. Listing Requested and PBAC’s View
Section 100 Public and Private Hospital Authority
Required
Initial treatment, commenced in a hospital based Movement Disorder
clinic specialising in the treatment of advanced Parkinson disease
with Duodopa
Patients should have adequate cognitive function to manage
administration with a portable continuous infusion pump.
NOTE:
Specialist Movement Disorder clinics are required to have the
following facilities for the provision of specialised clinical
support of advanced Parkinson’s patients:
(a) a Neurologist or Geriatrician experienced in the management of
advanced Parkinson’s Disease
(b) a Parkinson’s Disease Specialist nurse;
(c) a Gastroenterologist experienced in PEG-J insertion and
hospital facility equipped for this procedure
(d) 24 hour access by patients to medical advice
(e) a hospital pharmacy with adequate cold chain storage
Section 85 - Authority Required
Continuation of treatment with Duodopa intestinal gel commenced in
a hospital based specialised Movement Disorder clinic.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Parkinson disease (PD) is a chronic, progressive neurological
disease. PD causes the neurons in the substantia nigra cells to
die, leading to a lack of dopamine in the brain, especially in the
basal ganglia. This results in loss of the ability to control
normal body movements, with varying degrees of loss of muscular
control.
Patients with advanced PD experience daily changes in symptoms,
medication side effects that limit treatment and the loss of
independence in activities of daily living.
Duodopa would provide a treatment for advanced idiopathic PD in
patients who no longer respond to oral treatment.
6. Comparator
The submission nominated standard medical management and deep brain
stimulation as the main comparators. The PBAC considered this was
appropriate.
7. Clinical Trials
The March 2008 submission presented results from two randomised
trials (NPP-001-02 (DIREQT) and NPP-001-99) and five non-randomised
studies (NPP-001-92, NPP-002-02, DAPHNE, Antonini and Odin/Eggert).
No new clinical evidence for Duodopa was provided in this
submission.
New data on the clinical effectiveness of deep brain stimulation
(DBS) were included.
For the published direct randomised trials see the March 2008 PSD.
For the non-randomised trials and DBS trials published at the time
of March 2009 submission see below:
| Nonrandomised studies | ||
| Trial NPP-001-92 Nilsson et al | Long-term intraduodenal infusion of a water based levodopa-carbidopa dispersion in very advanced Parkinson’s disease. | Acta Neurologica Scandinavica 1998; Vol 97 (3): 175-83. |
| Nilsson et al. | Duodenal levodopa infusion in Parkinson’s disease – long-term experience. | Acta Neurologica Scandinavica 2001; Vol 104(6): 343-8. |
| Antonini study | Duodenal levodopa infusion for advanced Parkinson’s disease: 12-month treatment outcome. | Movement Disorders 2007; 22(6): 1-5. |
| Odin / Eggert study | Kongressreport, 5th German Parkinsons Congress. Besserung von motorischen und night-motorischen Symptonen. | Neurologie & Rehabilitation 2007, 2. |
| Deep Brain Stimulation trials – direct randomised trials/systematic reviews | ||
| Deuschl 2006 | A Randomized Trial of Deep-Brain Stimulation for Parkinson’s Disease | N Engl J Med 2006; 355:896-908. |
| Schupbach 2006 | Neurosurgery at an earlier stage of Parkinson disease | Neurology 2007; 68:267–271 |
| Deep Brain Stimulation systematic reviews and reports | ||
| Hamani 2005 | Bilateral subthalamic nucleus stimulation for Parkinson’s disease. A systematic review of clinical literature. | Neurosurgery 2005. 56(6):1313-1324 |
| Kleiner-Fisman 2006 | Subthalamic Nucleus Deep Brain Stimulation: Summary and Meta-Analysis of Outcomes | Movement Disorders Vol. 21, Suppl. 14, 2006, pp. S290–S304 |
| Temel 2006 | Behavioural changes after bilateral subthalamic stimulation in advanced Parkinson disease: A systematic review | Parkinsonism and Related Disorders 12 (2006) 265–272 |
8. Results of Trials
The key results presented for levodopa-carbidopa were unchanged
from the previous submission – see March 2008 PSD.
The submission also presented some comparative data of DBS versus
standard care. The results of the two trials (Deuschl 2006,
Schupbach 2006) are presented below. Their primary outcomes were PD
Questionnaire (PDQ-39) scores; the Unified PD Rating Scale
(UPDRS-III) scores were also used as outcomes in one trial (Deuschl
2006). Comparisons with the PDQ-39 and UPDRS-III results reported
in levodopa-carbidopa trial NPP-001-02 (secondary outcomes) are
also presented below.
Results of the Parkinson’s disease Questionnaire
(PDQ-39) summary index primary outcome measure for the DBS
randomised trials
| Treatment | Baseline | Endpoint | Δ Baseline to endpoint (SD) | WMD (95% CI) |
| NP-001-02: Endpoint = 6 weeks, Mean (SD) | ||||
| Duodopa | n =18 38.4 (12.1) | n =18 26.5 (9.4) | -11.9 (10.5) | -9.5 (-14.83, -4.17) |
| CM | n =18 36.0 (11.8) | -2.4 (4.8) | ||
| Deuschl et al (2006): Endpoint = 6 months, Mean (SD) | ||||
| Surgery | n =78 41.8 (13.9) | n = 71 31.8 (16.3) | -9.5 (15.3) | -9.3 (-13.69, -4.91) |
| CM | n =78 39.6 (16.0) | n = 73 40.2 (14.4) | -0.2 (11.2) | |
| Schupbach et al (2006): Endpoint = 18 months, Median (range) | ||||
| Surgery | n = 10 35.4 (24.4-51.5) | n = 10 28.9 (5.7-53.1) | -6.5 (NR) | NA |
| CM | n = 10 37.9 (23.4-53.1) | n = 10 41.9 (13.5-57.3) | 4 (NR) | |
Statistically significant differences between groups are
bolded
SD = standard deviation; CI = confidence interval; CM =
conventional medication treatment;
WMD = weighted mean difference, NR = not reported
The results of the UPDRS-III outcome measure from the randomised trials are summarised below:
Results of the Unified Parkinson’s Disease Rating Scale part III (UPDRS—III) (primary outcome measure for Deuschl 2006)
| Treatment | Baseline | Endpoint | Δ Baseline to endpoint (SD) | WMD (95% CI) |
| NP-001-02: Endpoint = 6 weeks, Mean (SD) | ||||
| Duodopa | NR | NR | NR | Mean Difference (SD) -6.9 (12.6) |
| CM | NR | NR | NR | |
| Deuschl et al (2006): Endpoint = 6 months, Mean (SD) | ||||
| On medication | ||||
| Surgery | n =78 18.9 (9.3) | n = 71 14.6 (8.5) | -4.0 (10.1) | -4.40 (-7.34, -1.46) |
| CM | n =78 17.3 (9.6) | n =73 17.5 (10.6) | 0.4 (7.7) | |
| Off medication | ||||
| Surgery | n =78 48.0 (12.3) | n =71 28.3 (14.7) | -19.6 (15.1) | -20.0 (-24.14, -15.86) |
| CM | n =78 46.8 (12.1) | n =72 46.0 (12.6) | -0.4 (9.5) | |
| Schupbach et al (2006): Endpoint = 18 months, Mean (SD) | ||||
| On medication | ||||
| Surgery | 2.9 (3.0) | NR | NR | NA |
| CM | 2.6 (2.8) | NR | NR | |
| Off medication | ||||
| Surgery | 32.7 (13.4) | NR | 69% | NA |
| CM | 25.3 (8.7) | NR | -29% | |
SD = standard deviation; CI = confidence interval; CM =
conventional medication treatment;
Δ = change in, NR = not reported, NA = not applicable
A formal indirect comparison of levodopa-carbidopa and DBS was not
undertaken because of differences in trial design, patient
populations and the inconsistent way time-points outcomes were
measured. This was appropriate.
The key adverse events results presented for levodopa-carbidopa
were unchanged from the previous submission – see March 2008
PSD.
The adverse events reported for DBS in Deuschl (2006) are presented below:
Summary of number of adverse events in Deuschl et al (2006)
| Deuschl et al (2006) | Surgery | Conventional Medication | RR (95% CI) |
| Serious Adverse Events Death Readmission to hospital | 10/78 3 7 | 3/78 1 2 | 3.3 (0.95, 11.65) 3.0 (0.32, 28.22) 3.5 (0.75, 16.32) |
| Non-serious adverse events Mild Moderate Severe | 77/78 35 32 10 | 96/78 8 39 49 | NA |
For PBAC’s view, see Recommendations and
Reasons.
9. Clinical Claim
The submission claimed 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 Parkinsonian health state
(‘off’ time), and health related quality of life as
measured by the 15D instrument.
For PBAC’s view, see Recommendations and
Reasons.
10. Economic Analysis
An updated modelled economic evaluation was presented. The methods
used in the modelled economic evaluation were substantially
unchanged from the previous submission. However updated estimates
were used to generate the results.
The submission excluded the costs of the DBS from the basket of
comparators in the base case. The PBAC had previously advised that
DBS should be included in the basket of comparators and that carer
utilities should be considered in a sensitivity analysis, rather
than the base case.
The revised base case calculated during the evaluation excluding
carer utilities and including DBS estimated the ICER to be in the
range of $75,000 – $105,000 per QALY over ten years. This was
considered likely to be an under-estimate and to be highly
uncertain because the model included costs associated with DBS, but
no effects of DBS were attributed.
The PBAC noted that as with the previous submission, the results of
the sensitivity analyses indicated that the model was most
sensitive to the estimated number of cartridges of
levodopa-carbidopa intestinal gel used per patient per day, the
transition probabilities associated with levodopa-carbidopa
intestinal gel improvements in Hoen and Yahr Scale status, the
costs of supportive care at home and nursing home costs, and the
disutility for caregivers. The model is moderately sensitive to the
discount rate and the use of utility values from the published
literature.
The PBAC considered that several other previously raised issues
regarding the economic evaluation remained unaddressed.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be well
below 2,000 in Year 5 and was lower than in the previous
submission.
The financial net cost per year to the PBS was estimated to be in
the range of $10 – $30 million in year 5 and was lower than
in the previous submission.
For PBAC’s view, see Recommendations and
Reasons.
12. Recommendation and Reasons
The comparator, standard medical management, which also includes
deep brain stimulation (DBS), was considered appropriate by the
Committee.
The PBAC noted that the clinical evidence presented was the same as
that for the March 2008 PBAC meeting and included results from two
randomised trials, NPP-001-02 (DIREQT) and NPP-001-99, and five
non-randomised studies (NPP-001-92, NPP-002-02, DAPHNE, Antonini
and Odin/Eggert). The results of two recently published randomised
trials (Deuschl 2006 and Schupbach 2006) were also provided in the
submission for comparison of the clinical effectiveness of DBS
versus standard care. The PBAC had a number of concerns with the
clinical efficacy data presented. In each of the randomised trials,
NPP-001-02 and NPP-001-99, the levodopa with carbidopa gel was
administered via a nasogastric tube (NG), rather than via
percutaneous endoscopic gastrostomy (PEG), which is the main
feature of the Duodopa formulation, and there were still concerns
regarding adverse events related to the pump and/or tubing as
identified in the March 2008 PBAC Minutes. As previously, the
Committee considered there was uncertainty with the clinical
importance of the trial results.
The PBAC noted that the PEG administration route has a high risk of
complications with insertion of the PEG tube, such as aspiration
pneumonia, and that sudden cessation of the infusion (if the pump
or tubing failed) could precipitate neuroleptic malignant syndrome.
Based on the evidence presented the Committee considered that there
are significant administration safety concerns with levodopa with
carbidopa intestinal gel.
The PBAC noted that carer utilities were again incorporated into
the base case for this re-submission, which was considered
inappropriate and instead should have been considered in a
sensitivity analysis. In addition, the PBAC considered that the
safety and quality of life issues associated with PEG
administration of the product should have been incorporated into
the economic evaluation. The PBAC also considered that the cost of
DBS should have been included in the mix of comparators in the base
case of the economic evaluation. The revised base case calculated
during the evaluation excluding carer utilities and including DBS
estimated the ICER to be in the range of $75,000 – $105,000
per QALY over ten years. This was considered likely to be
underestimated and highly uncertain as the model includes costs
associated with DBS, but no effects were attributed. The Committee
considered that a number of other issues previously raised with the
economic evaluation for this submission remained unaddressed in the
re-submission and that the cost effectiveness remained highly
uncertain.
The utilisation estimates for levodopa with carbidopa intestinal
gel for the treatment of advanced Parkinson disease were also
considered by the PBAC to be highly uncertain. The PBAC considered
that the proportion of patients with Parkinson disease who would be
eligible under the proposed listing was highly uncertain as the PEG
administration of the product may limit use due to concerns with
the safety of PEG tube insertion and the invasive nature of the
procedure.
The PBAC also noted advice from the Highly Specialised Drugs
Working Party that the product did not meet all the criteria for
listing under the Highly Specialised Drugs Program.
The PBAC rejected the submission for levodopa with carbidopa
intestinal gel on the basis of an uncertain clinical benefit and an
unacceptably high and uncertain cost effectiveness ratio.
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 continue to work with the PBAC to address the issues
identified in the Duodopa PBAC resubmission. Duodopa is an Orphan
Drug with limited clinical data and is suitable for a small number
of advanced Parkinson's disease patients. Solvay is disappointed
that the
Highly Specialised Drugs Working Party did not accept the highly
specialised drug status of Duodopa. Solvay strongly believes that,
by relegating carer burden from the base case cost-effectiveness
analysis to the sensitivity analysis, this devalues the importance
of carers in the management of Parkinson Disease. Duodopa is
reimbursed in all major European markets due to its proven benefits
to patients as well as cost-effectiveness.
