Public financing of new drug therapy in Poland is usually performed within a separate financial path – so-called ‘drug programmes’. A drug programme is allowed to be performed by medical entities by a decision made by the Minister for Health, made public by a Notice. The drug programmes provide a path for financing of new drugs under strictly controlled (specified) conditions. The clinical criteria, which have to be met by the patient for inclusion or exclusion from the therapy, and conditions for monitoring the treatment efficacy and toxicity are of key importance. Thus, the organization of the programme makes it somehow similar to the organization and implementation of clinical trials. A highly homogeneous group of patients subjected to a therapy with a specified drug/drugs participates in the drug programme.
The results of clinical trials allow the assessment of efficacy and safety of the therapy with a newly invented molecule (drug) and are usually different from the observations in daily clinical practice. The multiple illnesses, environmental factors and mainly a different general physical condition and prognosis than the one assumed in the trials translate into the primary endpoint values, including overall survival (OS) analysis. Observation of the OS indicator or the disease-specific survival indicator becomes the main problem in clinical trials owing to the long time of observation. Financing melanoma therapy with the use of new drugs, vemurafenib, ipilimumab and dabrafenib, is performed in Poland as part of drug programmes in hospitals. The analysis includes patients undergoing therapy as part of melanoma treatment drug programmes with the following molecules: vemurafenib (financed since 1 March 2013 in accordance with the decision by the Minister for Health); ipilimumab (financed since 1 March 2014 in accordance with the decision by the Minister for Health); dabrafenib (financed since 1 July 2015 in accordance with the decision by the Minister for Health); vemurafenib and dabrafenib are financed in one drug programme, and ipilimumab is financed in a separate drug programme.
Detailed criteria for inclusion in drug programmes for individual drugs in Poland are included in the annex to the main document (Supplementary Material, Supplemental digital content 1, http://links.lww.com/MR/A18).
The National Health Fund standardized database ‘on health services financed from public funds’ contains all data from Poland, which are reported to the payer on procedures provided to patients and financed from public funds, which enables a retrospective analysis and calculation of OS rates for patients treated with individual drugs as part of drug programmes.
Patients and methods
The reporting databases of the National Health Fund (single public payer in Poland) were used in order to download data for analysis from the 2013–2016 period for patients indicated to the payer with an ICD-10 code of C43% (the ‘%’ mark replaces any number) – malignant melanoma of skin. The PESEL number was considered a unique patient identifier. Then, information concerning the treatment of patients in drug programmes in hospital treatment was separated from these databases. The OS analysis was performed using the Kaplan–Meier estimator and survival tables. Data on deaths were obtained from the PESEL database kept by the Ministry of Internal Affairs. The date of the first (earlier) drug application in the drug programme was assumed as the commencement of observation. The end date of the observation for all observed patient populations was set to 31 December 2016. To prepare the results of statistical analyses, the SAS E.G., v. 5.1 (SAS Institute Inc., Cary, North Carolina, USA) software was used. The difference in OS was assessed by a two-sided log-rank test, assuming statistical significance at P less than 0.05. Observation time median was calculated based on the censored observation time. Median observation time value means the time during which the observation of 50% of patients was conducted at the analysis end time – that is, until 31 December 2016.
In the analysed period from 1 March 2013 to 31 December 2016 within the drug programmes, the vemurafenib therapy was conducted for 759 patients, ipilimumab therapy for 370 patients (in the period of 1 March 2014–31 December 2016) and dabrafenib therapy for 181 patients (in the period of 1 July 2015–31 December 2016) (Table 1).
The number of complete observation patients treated in the vemurafenib programme was 557 (73.4%), and observation time median was 26.2 months. OS median had a value of 9.8 months [95% confidence interval (CI): 8.8–10.6]. Probability of surviving 12 months was 40.5%, that of surviving 24 months was 21.1% and that of surviving 36 months was 15.4% (Fig. 1).
The number of complete observation patients treated in the ipilimumab programme was 259 (70%), and the observation time median was 17.1 months (95% CI: 5.7–9.2). The OS median had a value of 6.9 months. Probability of surviving 12 months was 35.1%, that of surviving 24 months was 21% and that of surviving 36 months was 18.8% (Fig. 1).
The number of complete observation patients treated with dabrafenib was 45 (24.8%), and observation time median was 7.8 months. The OS median was not reached. The probability of surviving 12 months amounted to 60.7% (Fig. 1).
We presented the OS time for all patients with advanced or metastatic melanoma in Poland receiving vemurafenib, ipilimumab or dabrafenib reimbursed from public funds. The overall median survival of patients who were receiving those drugs amounted to, respectively, 9.8, 6.9 months and not reached. The percentage of patients living for 12 months amounted to, respectively, 40.5, 35.1 and 60.7%; for 24 months it amounted to 21.1%, 21% and impossible to assess; and for 36 months it amounted to 15.4%, 18.8% and impossible to assess.
The Ministry of Health drug programmes – omitting the ‘new drug extended access’ programmes – are the only form of vemurafenib, ipilimumab and dabrafenib reimbursement in Poland. They place restrictions on doctors in the possibility of using the drug in question, as the requirements for commencement of therapy include appropriate values of laboratory parameters and physical condition. Moreover, in drug programmes, there are restrictions on, for example, the line of therapy where the given drug may be used. Although such criteria are much less restrictive than in clinical trials, they still force appropriate selection of patients. An advantage of this new drug financing system is the lower risk of achieving much worse effectiveness in practice than the one established by clinical trials, which form the basis for the registration.
According to the data from the National Cancer Registry in Poland, ∼1400 patients die annually from skin melanoma 1. Our analysis includes a total of 1310 patients, who have commenced treatment with vemurafenib, ipilimumab or dabrafenib within a period of almost 4 years; we may approximately assume that every fourth patient suffering from advanced, unresectable or metastatic melanoma in Poland receives one of the aforementioned drugs. This proportion demonstrates that despite the restrictions resulting from the drug programme inclusion criteria and the fact that the contracting does not apply to all oncology centres, this model of financing ensures quite good access to the therapy.
Dabrafenib was the last to be included in the reimbursement, which is why the number of patients receiving this drug is the smallest and the observation period the shortest. Unlike dabrafenib, both the number of persons treated with vemurafenib or ipilimumab and the observation time enable us to compare our results with the ones obtained in the registration trials.
Vemurafenib in Europe was authorized in February 2012 based on phase III trial results, where the OS median in previously systemically untreated patients with V600 BRAF mutation the OS median amounted to 13.6 months, and the percentage of patients surviving 12 months to 56% 2,3. The drug is also effective in a population not included in clinical trials; in a large group of patients (over 3000) who participated in the trial assessing the safety of vemurafenib therapy in a population similar to one encountered in clinical practice, the OS median had a value of 12 months, and the percentage of patients surviving 12 and 18 months amounted to, respectively, 52 and 36% 4. Half of those patients were treated earlier in the system. Until 1 March 2015, patients included in the drug programme in Poland were administered vemurafenib in first-line or second-line therapy, and afterwards only in first-line therapy. This may be the reason for which the OS median in our study (9.8 months) was slightly smaller than in referred publications, similarly to the percentage of patients surviving for a year. Almost 16% of patients treated with vemurafenib lived for at least 36 months.
In July 2011, European Medicines Agency registered ipilimumab based on a phase III clinical trial in patients previously treated for metastatic or unresectable melanoma – the drug enabled achieving an OS median of 10.1 months and the 1-year survival percentage of 46%, and 2-year survival of 24% 5. Patients treated with ipilimumab outside of clinical trials may, however, obtain significantly worse results from the therapy. In 193 patients included in the Expanded Access Programme in the UK, the OS median was only 6.1 months, and the percentage of 2-year survival was 14% 6. In our patients, the OS median (6.9 months) was lower than in the registration trial and comparable to the one obtained in the British Extended Access Programme, similarly as the percentage of 1-year survival (35.1%) was lower than the one obtained in the registration trial (45.6%); however, the percentage of patients surviving for 2 years (21%) was similar to the one obtained in registration trial (23.5%) and numerically larger than the one described in the extended access. Moreover, the 3-year survival, amounting to ∼19%, was similar to long-term results of phase II and III clinical trials, as in our patients the drug was used only in second-line therapy 7.
An obvious restriction of our analysis is the lack of detailed data concerning patient characteristics, prognosis, time free from progression, adverse events and the percentage of direct responses. We also do not know how many patients were treated with vemurafenib in the first-line treatment, and how many in the second-line treatment. However, our goal was to assess the effectiveness of therapy based on its most important parameter – that is, the OS in patients treated with new drugs within the scale of the entire country.
Financing of vemurafenib and ipilimumab under drug programmes with specific inclusion criteria allows obtaining results comparable to the ones described in the phase III clinical trials, enabling at the same time relative good access to innovative, expensive therapies.
Conflicts of interest
There are no conflicts of interest.
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