In July, 2009, CEDAC issued a recommendation that Duodopa be “not listed.”59 Key reasons for the recommendation included:
The manufacturer’s reported incremental cost per quality-adjusted life-year (QALY) estimate for Duodopa of ▬ to ▬ compared with conventional oral drug therapies. The manufacturer requested that specific results from the economic evaluation remain confidential pursuant to the CADTH Common Drug Review (CDR) confidentiality guidelines. Other published cost per QALY estimates for Duodopa were reported at approximately $1 million dollars.
The quality of two trials considered by the Committee was limited by open-label designs, high proportions of withdrawals in trials of small sample size, and patient populations that are not representative of those who are most likely to use Duodopa. Therefore, given concerns with the quality of these trials, the relevance of the results was limited.
Summary of Committee Considerations59
The Committee considered the results of a systematic review that included two randomized, open-label crossover trials evaluating the effects of Duodopa in patients with advanced PD and severe motor complications. The DIREQT trial (n = 25) compared Duodopa with patients’ pre-study conventional therapies. Treatment sequences were three weeks. The primary outcomes in the DIREQT trial were Unified Parkinson Disease Rating Scale (UPDRS) item scores and time spent in various motor states as assessed by video recording. QoL was also measured in the DIREQT trial. In the NPP-001-99 trial (n = 16), Duodopa was compared with long-acting levodopa/carbidopa, and the short-acting formulation was given to patients as needed. Long-acting levodopa/carbidopa is not considered an appropriate comparator in this patient population.
The validity of results from the two trials was limited by a number of factors, including open-label designs and high proportions of withdrawals in trials of small sample size. Furthermore, the generalizability of the study conclusions is limited because the patient populations included are not representative of those most likely to use Duodopa. It is likely that patients using Duodopa will be over age 70; i.e., those who do not qualify for DBS. However, these trials were conducted in a younger population with an average age ranging from 60 years to 68 years across trials and treatment groups. In both studies, Duodopa was administered by a nasoduodenal tube rather than by the intended PEG-J tube associated with the marketed product. It is not clear if the effect would be similar for nasoduodenal and PEG-J administration. Therefore, given concerns with trial quality, the relevance of the results was limited.
In the DIREQT trial, there were statistically significant improvements in QoL, UPDRS scores (range: 0 to 199), and motor function with Duodopa compared with conventional drug therapy. QoL, measured by the 39-item Parkinson’s Disease Questionnaire (PDQ-39) (range: 0 to 100), was statistically significantly improved with Duodopa compared with conventional treatment (median difference = −9.0, P < 0.01). Motor function, measured as the percentage of “on” time during video recording, was statistically significantly higher with Duodopa compared with conventional treatment [median difference (range) = 4.5% (−14.7 to 63.2; P < 0.01)]. The percentage of “off” time was statistically significantly lower with Duodopa compared with conventional drug therapy (median difference = −8.1%, P < 0.01). The magnitude of between-treatment differences for all measures was considered clinically important. However, the lack of blinding and the use of per-protocol analysis for most outcomes may have biased estimates of efficacy in favour of Duodopa.
The proportions of patients experiencing serious adverse events (SAEs) and AEs were similar between treatment groups in both studies. Common AEs included well-documented effects of levodopa/carbidopa involving the GI tract (i.e., constipation, diarrhea) and the central nervous system (i.e., depression, insomnia, somnolence), as well as administration-related complications (dislocated tubes and intolerance to or dislike of the nasoduodenal tube or pump). Withdrawal due to an AE occurred in three Duodopa patients and no patients in the conventional treatment group in the DIREQT trial.
The Committee also noted the results of two small (n = 13 and n = 22) uncontrolled studies with a pre-post design that provided clinical inputs for the manufacturer’s economic evaluation. Results were reported over time periods ranging from six months to two years. Statistically significant improvements were observed for only subjective patient-reported outcomes, such as QoL, ADL, and motor function (measured as “off” and “on” time). There were no statistically significant improvements in clinician-assessed motor function as measured by the UPDRS. The validity of these studies is limited due to their lack of control groups and reliance on observed case analysis when data were missing.
In the cost-utility analysis submitted by the manufacturer, Duodopa was compared with conventional oral drug therapies (i.e., levodopa/carbidopa, cabergoline, pramipexole, pergolide, entacapone, amantadine sulphate, and/or selegiline) for the treatment of advanced PD over a five-year period. The manufacturer’s results were highly dependent on the study selected to inform the clinical input parameters, with the manufacturer reporting incremental cost per QALY estimates for Duodopa ranging from approximately ▬ to ▬. The manufacturer requested that specific results from the economic evaluation remain confidential pursuant to the CDR confidentiality guidelines. The cost of Duodopa is $166 per day; in comparison, oral forms of levodopa/carbidopa cost less than $3 per day.
Basis of Resubmission
The basis of the resubmission, as indicated by the Drug Policy Advisory Committee Formulary Working Group (DPAC-FWG), is the new clinical information (systematic reviews, randomized controlled trials [RCTs], and observational studies) that has been available for the treatment of PD with LCIG since the original CDR review in 2009. The CDR-participating drug plans expressed the need for an updated review of the best available evidence and a formulary reimbursement recommendation from the CADTH Canadian Drug Expert Committee (CDEC) to address the use of LCIG for the treatment of PD. In response to DPAC-FWG formally requesting the manufacturer of LCIG (AbbVie Corporation) to file a resubmission for the review of LCIG through the CDR process, the manufacturer indicated that it did not plan to file a CDR resubmission for LCIG. Therefore, DPAC-FWG requested that CADTH undertake a review of LCIG through the CDR process. The CDR-participating drug plans submitted a resubmission for the review of LCIG (Duodopa) for the following Health Canada–approved indication:
For the treatment of patients with advanced levodopa-responsive PD:
who do not have satisfactory control of severe, debilitating motor fluctuations and hyper-/dyskinesia despite optimized treatment with available combinations of PD medicinal products, and
for whom the benefits of this treatment may outweigh the risks associated with the insertion and long-term use of the PEG-J tube required for administration.
The original CDR review of Duodopa in 2009 was based on the following Health Canada–approved indication: for the treatment of advanced levodopa-responsive PD in which satisfactory control of severe, disabling motor fluctuations and hyper-/dyskinesia cannot be achieved with available combinations of PD medicinal products.
An early-stage clinical development program for Duodopa (LCIG) provided preliminary efficacy and safety data (based on the DIREQT and NPP-001-99 trials) for the initial conditional marketing authorization of this product (i.e., Notice of Compliance with conditions) pending additional evidence, including the results of a 12-week, double-blind (DB) RCT where Duodopa was administered through a PEG-J tube. The conditions have since been removed based on the Duodopa phase III Clinical Development Program (Study 001/002 and Study 004) conducted subsequent to conditional marketing authorization to confirm the preliminary findings of the early-stage clinical development program.
