Summary Report. on health technology assessment

Transcription

1 Summary Report on health technology assessment pursuant to art. 17, paragraph 7 of Ordinance 9 of of the Ministry of Health of Republic of Bulgaria for medicinal product LARTRUVO 190 mg/19 ml concentrate for sol. inf. Adopted by the Commission on health technologies assessment pursuant to art. 5 of Ordinance 9 of on the conditions and the procedure for health technologies assessment at a session, held on

2 I. Health problem analysis. 1. The health problem analysis incorporates the following elements: 1.1. Health problem description, based on a review of scientific and epidemiological data. The Soft Tissue Sarcomas (STS) are a heterogenic group of over 50 rare malignant tumours, originating from tissues, produced by the mesoderm. STSs have various place of origin, including connective tissue, adipose tissue, muscles, vessels, peripheral nervous tissue and visceral tissue. Although the STS can occur anywhere in the body, it is the most common in the lower extremities. Most STSs have no clear etiology and occur de novo. In isolated cases, genetic factors and factors of the environment, such as radiation, viral infections and immunodeficiency, are related with general malignant STSs. There are also isolated reports of sarcomas, occurring in the tissue of the scar in case of a fracture and near surgical implants. Some angiosarcomas occur in areas with chronic lymphedemas. The risk of sporadic STSs increases after previous radiotherapy, as the chemical agents thorotrast, vinyl chloride and arsenic are confirmed carcinogens for hepatic angiosarcoma. Soft tissue sarcomas occur more often in patients with the following hereditary syndromes: Nevoid basal cell carcinoma syndrome (Gorlin syndrome: PTC genetic mutation) Gardner Syndrome (APC mutation) Li-Fraumeni Syndrome (mutation with р53) Tuberous sclerosis (Bourneville s disease: TSC1 or TSC2 mutation) Von Recklinghausen disease (Type 1 neurofibromatosis: NF1 mutation) Werner Syndrome (adult progeria: WRN mutation). Data from the RARECARE project show that the 5-year relative survival rate, related to the STSs in Europe, is evaluated at 55,8% in the period and 58% in the period Rare types of cancer amount to 21% of all cancer diagnoses in Bulgaria. In Bulgaria there were a total of new cases of rare cancer types in The incidence rate is 85,4 per man-years (lower than the European average). This may be due to a different distribution of risk factors and different preventive/screening activities. The most recent data on the estimated number of new cases of rare cancer types in Bulgaria is for Most of the cases of cancer (56,6% of all diagnoses) are defined as very rare with an incidence rate of less than 1 in Three cancer types, considered rare on an European level, have a higher rate of 6 in people in Bulgaria (squamous cell carcinoma of the cervix, squamous cell carcinoma of the larynx and adenocarcinoma of the ovaries). 21 Tumour Incidence rate х Generalized estimated data for Bulgaria 95% CI Expected 2

3 /per annum Lower limit Upper limit number of new cases, 2013 Soft Tissue Sarcoma (STS) 4, , , STS of the head and neck 0, , , STS of the extremities 1, , , STS of the superficial trunk 0, , , STS of the mediastinum 0, , , STS of the heart 0, , , STS of the breast 0, , , STS of the uterus 0, , , Other STS of the bladder 0, , , STS of the viscera 0, , , STS of paratestis 0, , , STS of the retroperitoneum and peritoneum 0, , , STS of the pelvis 0, , , STS of the skin 0, , , STS of the paraorbit 0, , , STS of the brain and other parts of the nervous system 0, , , Embryonal rhabdomyosarcoma 0, , , Alveolar rhabdomyosarcoma 0, , , Soft tissue Ewing s sarcoma 0, , , Description of the proposed health technology. Оlaratumab is a human IgG1 monoclonal antibody, derived in murine (NS0) cells through recombinant DNA technology. Оlaratumab belongs to the following pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies ATC code: L01XC27. Оlaratumab is marketed as sterile concentrate for infusion solution. 1 ml of the concentrate for infusion solution contains 10 mg olaratumab. Each 50 ml vial contains 500 mg olaratumab. Оlaratumab in combination with doxorubicin is indicated for the treatment of adult patients with advanced soft tissue sarcoma, who are not eligible for radical treatment through surgery or radiotherapy and who are doxorubicin treatment naive. In Bulgaria the medicinal product olaratumab is promoted under the tradename Lartruvo. The marketing authorization holder is Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, the Netherlands. 3

4 1.3. Description of the other health technologies, reimbursed in Bulgaria, which may be used as a therapeutic alternatives or as combination therapy, together with the proposed health technology The main compared technologies, included in the Pharmacotherapeutic guidelines on medical oncology and available in the Positive Drug List (PDL) in Bulgaria, applied as a therapeutic alternative and could be replaced by the implementation of the new: - Ifosfamide - Doxorubicin - Epirubicin - Pazopanib 2. Selection of the main comparative therapeutic alternative. The оlaratumab + doxorubicin therapy is compared with respect to the following alternatives: Doxorubicin, as the first and second-line treatment of all the STS subtypes; Gemcitabine + Docetaxel, as the first-line treatment of all the STS subtypes; Pazopanib, as the second-line treatment of lyposarcoma, angiosarcoma, synovial sarcoma and leiomyosarcoma. Analyses show that the new technology has a better therapeutic efficiency and is a cost-effective therapy for the treatment of patients with STS. The оlaratumab + doxorubicin therapy is also compared to the BAT -best available therapy, according to the current guidelines and consensuses. It is a cost-effective alternative and dominant for the treatment of patients with STS. 3. Perspective of the evaluation the perspective is that of the institution - payer. Analyses from the public s perspective is used as auxiliary. The available pharmacoeconomic analyses from a third-party payer s perspective (NHIF), have been properly used from a methodological point of view, to assess the health technology оlaratumab + doxorubicin. 4. Number of potential patients, to be eligible for treatment with the new health technology. The data provides the potential total number of the target population, distributed by therapy alternatives. II. Comparative analysis of the therapeutic efficiency/effectiveness and safety. 1. Health outcomes: 1.1. The analysis evaluates the health outcomes, which are clinically significant endpoints and play a significant role in the reviewed health problem. 4

5 The platelet-derived growth factor (PDGF) and the PDGF-receptor (PDGFR) play a significant role in the mesenchymal biology, including differentiation, growth and angiogenesis of mesenchymal stem cells. Olaratumab is an antagonist of the receptor-α of the Platelet-derived growth factor (PDGFR-α), expressed on tumour and stromal cells. Olaratumab is a targeted, recombinant, fully-human immunoglobulin G subclass 1 (IgG1) monoclonal antibody, which specifically binds the PDGFR-α, blocking the binding to PDGF AA, -BB and -CC and the activation of the receptor. As a result, in vitro olaratumab inhibits the PDGFR-α single path in tumours and stromal cells. In addition, in vivo olaratumab shows that it destroys the PDGFR-α path in tumour cells and inhibits tumour growth Clinical endpoints: clinically significant long-term outcomes are considered, which - on their own - are or characterize the respective health outcomes; The analysed and summarized results of the conducted phase I-III clinical trials, bring to the following conclusions: The olaratumab+doxorubicin combination shows a significant improvement in the median of the Progression-Free Survival (PFS). The olaratumab+doxorubicin combination is the first and sole therapeutic regimen, showing a clear benefit, in terms of survival, compared to doxorubicin. The olaratumab+doxorubicin combination shows higher degrees of objective response, compared to the doxorubicin monotherapy (no statistically significant difference is achieved). The analysis of the combined data of both clinical trials of ЕORTC shows that the treatment with pazopanib results in PFS 6 months in 124 (36%) of the patients and up to OS 18 months in 116 (34%) of the patients. 76 (22.1%) patients reported both a long-term response to the therapy and survival. 2. The comparative analysis included a systematic review for: 2.1. comparing at least one reimbursed therapeutic alternative, and if this is not currently available another alternative technology; The olaratumab s clinical programme includes: Phase 1 clinical trial I5B-IE-JGDI, conducted on adult patients with metastatic or locally advanced soft tissue sarcoma, ineligible for surgery or radiotherapy. The main objective of the trial is to evaluate the effects of olaratumab on doxorubicin s pharmacokinetics. Phase 1b clinical trial I5B-IE-JGDG, conducted on adult patients with a potentially resectable STS, for whom olaratumab and doxorubicin would be a suitable treatment option. Phase 3 clinical trial JGDJ (ANNOUNCE): a randomized, double-blind, parallel, placebo-controlled trial, evaluating the efficiency of the monotherapy with doxorubicin against olaratumab in combination with doxorubicin in adult patients with advanced or metastasized soft tissue sarcoma. Number of patients, participating in the trial: 509. This trial is still ongoing and there are no officially published outcomes. Phase 1b/2 clinical trial I5B-IE-JGDL, evaluating the therapeutic efficiency of olaratumab in combination with doxorubicin vs. doxorubicin monotherapy in adult patients 5

6 with advanced soft tissue sarcoma, ineligible for surgery or radiotherapy. The number of patients, participating in the trial is 133. The clinical trial (I5B-IE-JGDL) includes two phases, as primary and secondary endpoints are specified for each phase: Phase 1b primary endpoint: evaluation of the safety profile of olaratunab+doxorubicin in patients with advanced STS, who are ineligible for surgical intervention or radiotherapy. The patients from phase 1b do not take part in phase 2. Secondary endpoint: evaluation of the pharmacokinetics and immunogenicity of olaratunab in combination with doxorubicin. Phase 2 primary endpoint: comparison of the progression-free survival (PFS) in patients with advanced STS, ineligible for surgical intervention or radiotherapy, when taking olaratumab + doxorubicin or doxorubicin as a monotherapy. Secondary endpoint: evaluation and comparison of the PFS at month 3, objective response rate (ORR), change in the tumour size from baseline to the best overall response and overall survival (ОS) when taking olaratumab+doxorubicin vs. doxorubicin monotherapy; evaluation of the pharmacokinetics and immunogenicity of olaratumab + doxorubicin; association between the tumour PDGFRα expression and clinical outcomes. The clinical trial includes patients, meeting the following criteria: - Patients 18 years - Patients with histologically or cytologically confirmed advanced STS (with the exception of Kaposi s Sarcoma and gastrointestinal stromal tumour), ineligible for surgical treatment or radiotherapy - Patients with ECOG performance status Patients with previous therapy lines (irrespective of their number) - Antracycline treatment naive - Available tumour tissue for determining the PDGFRα status Patients with histologically or cytologically confirmed Kaposi s Sarcoma, not treated for metastases in the central nervous system, previous intake of doxorubicin, daunorubicin, idarubicin and/or other anthracyclines and anthracenediones (e.g. mitoxantrone) and with HIV infection are not eligible for participation in the trial. The final analysis of the primary endpoint (PFS), based on evaluator s assessment, was performed after 103 events. The PFS median is 6,6 months (95% CI, 4,1-8,3; IQR, 2,7-10,2) for patients, treated with olaratumab+doxorubicin and 4,1 months (95% CI, 2,8-5,4; IQR, 1,6-7,4) for those, treated with doxorubicin monotherapy. An external independent analysis of the X-ray images did not show any systematic deviation in the evaluator s assessment, regarding the PFS, which would result in a change in the results (PFS median 8,2 months in the olaratumab+doxorubicin group vs 4,4 months in the doxorubicin monotherapy arm). The olaratumab+doxorubicin combination results in a 3,8 months improvement in the PFS vs doxorubicin. The olaratumab+doxorubicin therapy demonstrates a statistically significant improvement in the OS duration. The double combination is the first and only therapeutic scheme, providing clinically significant benefits in the overall survival of patients with STS vs. doxorubicin. Olaratumab+doxorubicin reduces the risk of death by 53.7% (stratified HR=0,463; 95% CI, 0,301, 0,710; p=0,0003) 11,8 months longer median survival in the test arm (26,5 months vs 14,7 months in the control arm). 6

7 The оlaratumab+doxorubicin combination has an acceptable and controllable safety profile. The absence of direct comparisons of оlaratumab+doxorubicin vs. therapeutic alternatives, makes it necessary to conduct a network meta-analysis, providing the opportunity to make a comparison of the therapeutic efficiency and safety. The meta-analysis results showed a significantly longer duration of OS for olaratumab + doxorubicin vs doxorubicinwhen compared to gemcitabine + doxorubicin and three of the four different therapeutic regimens with ifosfamide + doxorubicin. From the NMA, there is evidence, supporting the fact, that olaratumab+doxorubicin performs as the most efficient therapy in terms of OS (HR-analysis and fractional polynomial analysis) and PFS (SUCRA and fractional polynomial analysis). With regards to the safety profile, the combination olaratumab+ doxorubicin is associated with fewer cases of discontinued treatment due to adverse reactions vs gemcitabine + doxorubicin and ifosfamide + doxorubicin. The results of the main clinical trial for оlaratumab (I5B-MC-JGDL) show that the olaratumab plus doxorubicin combination showed a significant improvement in the median Progression-Free Survival, as well as higher objective response rates, compared to the doxorubicin monotherapy (no statistically significant difference is achieved). The olaratumab+doxorubicin combination is the first and sole therapeutic regimen, showing a clear benefit, in terms of survival, compared to doxorubicin. The treatment with the olaratumab+doxorubicin combination showed an acceptable and controllable safety profile. Level 3 and 4 neutropenia is the most common adverse reaction in both therapeutic arms (olaratumab+doxorubicin and doxorubicin monotherapy, 53% and 32%, respectively). The frequency of febrile neutropenia and cardiac adverse reactions is similar in in both therapeutic arms. A lower number of patients, taking olaratumab+doxorubicin, discontinued the treatment due to adverse reactions vs those, taking doxorubicin monotherapy (13% vs 19%, respectively). There was no increase in either the number or duration of the hospitalizations in the olaratumab plus doxorubicin arm, vs the doxorubicin monotherapy arm identification of all clinical trials, concerning the efficiency, effectiveness and safety; The comparative analysis of the therapeutic efficiency/effectiveness and the safety of the new health technology was performed, based on the following databases: MedLine, PubMed and ClinicalTrials.gov 2.3. description of the searching criteria in the reference databases; Based on publications, issued in English, in the period description of the process of data selection and explanation of the data ineligibility; The search strategy applied, had a wide scope in order to include all the completed, ongoing and pending clinical trials. No limitations, regarding the phase, outcomes, trial types, location and demographic characteristics of the patients, were applied to the databases. The trials found were analysed vs. pre-set eligibility and ineligibility criteria. The clinical trial data reviewed included patients with the same diagnosis and characteristics. The 7

8 results of three clinical trials are described below characteristics of each clinical trial in order to prove supremacy, equivalence or lower efficiency of the health technology: The following trials were analysed: Trial Phase Population patients Comparators Objective I5B-EW- Phase NA JGDI 1 Adult patients with metastatic or locally advanced STS, ineligible for surgery or radiotherapy The main objective of the trial is to evaluate the effects of olaratumab on doxorubicin s pharmacokinetics. Participating countries Duration America (US) January present, ongoing I5B-MC- JGDL Phase 1b/2 Adult with advanced or metastatic STS Gemcitabine Docetaxel The main objective of the phase 1b part of the trial was to determine the recommended is olaratumab dose for phase 2, which can be safely applied in combination with gemcitabine and docetaxel in patients with advanced or metastatic STS. The main objective of the phase 2 part was to compare the overall survival in patients with advanced or metastatic STS, treated with olaratumab plus gemcitabine and docetaxel vs placebo plus gemcitabine and docetaxel. America (US) EU/AMERIT (8 countries) AP (Australia) March present, ongoing I5B-MC- JGDM Phase 1b Adult patients with a potentially resectable STS, for whom olaratumab and doxorubicin would be a suitable treatment option NA Main objectives: The number of circulating cancer cells in the whole blood in patients with a potentially resectable STS changes before and after the monotherapy with olaratumab. Characterization of the change in the expression of PDGFRα and PDGFRβ and the canonical ligands (PDGF-A, B, C, and D) before and after monotherapy with olaratumab in patients with potentially resectable STS America (US) EU/AMERIT (4 countries) October present, ongoing information on the number of participants, who have discontinued their participation in the clinical trial before completion in order to objectivise the efficiency and safety; The оlaratumab+doxorubicin Combination has an acceptable and controllable safety profile, irrespective of the difference in the median cumulative exposure of doxorubicin between the two therapeutic arms, with a higher median cumulative dose in the оlaratumab+doxorubicin arm (7 infusions; 487,6 mg/m 2 ) vs the doxorubicin monotherapy arm (4 infusions; 299,6 mg/m 2 ). 8

9 The percentage of patients, experiencing at least one treatment-related ADR, was similar between the two therapeutic arms. ADR 3 degree, ADR resulting from the treatment, degree 3 and serious ADR 3 degree were more common in patients, treated with olaratumab+doxorubicin, vs those, treated only with doxorubicin. No ADR, resulting in death, were observed in the olaratumab+doxorubicin arm, while there were 5 such cases (7,7%) in the doxorubicin arm. More ADRs 3 degree, resulting in treatment discontinuation, were observed in the doxorubicin arm (12.3%) vs the olaratumab + doxorubicin arm (6,3%). A higher frequency of some of the known toxic effects of doxorubicin (mucositis, nausea, vomiting, diarrhoea) was observed in the olaratumab+doxorubicin arm. These toxic effects, however were mainly 2 degree and were controlled. The most common ADRs (of any degree), observed in the olaratumab+doxorubicin arm, were nausea (73,4%), fatigue (68,8%), musculoskeletal pain (64,1%), neutropenia (59,4%) and mucositis (53,1%). The most common ADRs in the doxorubicin arm were fatigue (69,2%), nausea (52,3%), infections and infestations (41,5%), alopecia (40%), neutropenia (38,5%) and anaemia (36,9%). ADR 3 degree, occurring in at least 10% of the patients in the olaratumab+doxorubicin arm, included neutropenia (54,7%), anaemia (12,5%), febrile neutropenia (12,5%) and thrombocytopenia (10,9%). In the doxorubicin arm, ADRs 3 degree, occurring in at least 10% of the patients, included neutropenia (33,8%) and febrile neutropenia (13,8%). The frequency of neutropenia (of any degree and 3 degree) was higher in the olaratumab+doxorubicin arm (54,9% for any degree and 54,7% for 3 degree) vs the monotherapy (doxorubicin) arm (38,5% for any degree and 33,9% for 3 degree). This, however, is not associated to an increased risk of life-threatening complications such as febrile neutropenia and infections or with more cases of discontinuation of the treatment or death. III. Pharmacoeconomic indicators analysis. 1. The pharmacoeconomic analysis includes systematic review of published economic analyses, in accordance with the target patient population, and relies on some of the following analytical techniques: 1.1. cost - effectiveness analysis; The preferred method for health technology assessment conforms to the published recommendations, EUnetHTA s guidelines and is appropriate, considering the method of measuring the health outcomes from the application of the OLA /olaratumab/. The analysis contains summarized data of the applied model and a margin metaanalysis was applied for the relative therapeutic efficiency of the OLA for the treatment of patients with STS. The clinical efficiency data is included in the model as the relative risk ratio, taking into consideration the available epidemiological data. 9

10 1.2. Cost utility analysis. The data on the utility is divided into phases of pre- and post-progression of the disease Cost benefit analysis. The cost-effectiveness analysis performed shows that the application of the new health technology OLA in the treatment of STS is related to higher costs and more health benefits for the patient Cost minimum analysis. The cost-minimum analysis demonstrates an increase in the total costs after switching to olaratumab therapy, but patients live longer, without progression of the disease. 2. The pharmacoeconomic analysis takes into consideration the health perspective of the institution payer of the respective treatment, using public funds, or the public perspective. This analysis was prepared from the perspective of the National Health Insurance Fund (NHIF), including the direct costs based on public funds. The medicinal products, used for the treatment of soft tissue sarcoma are 100% reimbursed. Therefore if the medicinal product is included in Schedule No. 2 to the Positive Drug List the medicinal therapy with Lartruvo 10mg/ml concentrate for infusion solution shall be at the expense of NHIF s budget for oncological products, i.e. the treatment shall be fully funded, using public funds. In order to calculate the costs for the medicinal therapy with Lartruvo 10mg/ml, the acquisition cost, based on Eli Lilly Nederland B.V. s own data, as well as the costs per unit for the medicines with a separate component for the treatment plans, were used. It should be noted that as a medicinal product with a new international non-patented name, Lartruvo 10mg/ml is subject to mandatory discount negotiation as per art. 21, para. 2 of Ordinance No. 10 of on the terms and conditions for the payment for medicinal products, as per art. 262, para. 6, item 1 and item 2 of the Medicinal Products in Human Medicine Act, of medical devices and dietary foods for special medical purposes, as well as of medicinal products for health activities, pursuant to art. 82, para. 2, item 3 of the Health Act (promulgated in State Gazette, No. 24 / 2009) as a precondition for the inclusion of the medicinal product in the positive drug list in accordance with art. 262, para. 10 of the MPHMA. 3. The time horizon of the pharmacoeconomic analysis is such that it allows reliable and justified conclusions regarding the assessment of the costs and outcomes vs the alternative technologies. The time horizon, specified in the analysis is 5 years. The time horizon is justified, based on the analyses, conducted with the aid of the datalink for the trial of the clinical practice and is supported by analyses, performed with the aid of the epidemiology and endpoints in soft tissue sarcoma. The analysis of the basic model follows-up patients until their death. 10

11 4. When it is necessary to extrapolate the results, beyond the time horizon of the clinical trials, as well as for the evaluation of the outcomes in real-life practice, this is done by utilizing various models. The results of the cost-effectiveness analysis are presented as the incremental ratio of the incremental costs and health benefits of the evaluated health technology OLA vs the alternative STS treatment therapies. 5. When the analysis is from the public perspective, both the direct and indirect medical costs are included. The model includes the costs for the medicinal therapy OLA and alternatives. No other hospital or non-hospital health costs are included, since these are identical for all different medicinal alternatives, and therefore these have been neglected for the needs of this health technology assessment. The costs for the compared medicinal therapies have been calculated based on registered dosage regimens and reference prices in the Positive Drug List (PDL) in Bulgaria as of June 2017 of all medicines. 6. The future costs and outcomes are discounted by 5%. In accordance with recommendations of the Bulgarian legislation in the pharmacoeconomic studies, the discount rate, used for the costs and health effects, is 5%. The future costs are discounted at an annual discount factor of 5% without long-term modelling. 7. The benefits of the health technology are presented as final health outcomes. Positive evaluations of the health technologies in Germany and the UK are attached. As of June 2017 no evaluation had been submitted in France. Olaratumab+doxorubicin is the first and sole therapeutic regimen, providing more than 2 years of average overall survival vs doxorubicin as a monotherapy. 8. A sensitivity analysis was performed and the sustainability of the results was tested. The sensitivity analysis of the costs and benefits with respect to the stochastic variations in the values the OLA+DOX therapeutic line, was based on a Monte Carlo simulation with normal and gamma distribution of the values of the costs and benefits. The input parameters were obtained from the analysis cost-effectiveness. A one-way sensitivity analysis was performed with varying indicators. 9. The standardized tool for measuring the health condition (benefits) EQ-5D was used. Also allowed are direct methods for measuring the quality of life among the Bulgarian population "standard lottery" or "visual analogue scale". No results from the use of the standardized tool EQ-5D for evaluating the health condition among the Bulgarian population, were presented. 10. All data is presented as tables or diagrams. 11

12 The data is clearly presented both as tables and diagrams. 11. All the results of the efficiency/ therapeutic effectiveness and safety analysis are presented, as well as all costs between the compared health technologies, as well as the incremental cost effectiveness ratio. The strengths of the model used are that the input data is the result of multi-centre clinical trials. Additional strengths of the analysis are the use of the results of margin metaanalysis and indirect comparison of the different comparators, improving the external validity of the results obtained. The modelling of data for the health costs and benefits in the period after the completion of the clinical trials, results in a degree of uncertainty, regarding the therapeutic efficiency and safety in the long term. IV. Budget Impact Analysis. 1. The budget impact analysis includes the following key components: 1.1. epidemiology and therapy of the disease, clinical impact, economic impact; The analysis uses Bulgarian epidemiological data. It is indicated that the STS is a form of sarcoma, developing in connective tissue. It is considered part of the rare cancer disease (<1% of all new cases of cancer). In accordance with the data, provided by the Bulgarian National Cancer Register, the incidence rate in Bulgaria as of 2014 was 2,4/ (178 patients per annum). As with other oncological conditions, STS is an age-specific disease. The incidence rate increases significantly after the age of 50, reaching its peak in the age group years (14,4/ ). The actual death rate, registered in Bulgaria as of 2014 was 0,5/ (33 patients). The five-year relative survival with STS in Bulgaria is 51,1%. The average five-year survival of the patients in Europe is 7,6% higher. The risk factors for the occurrence of STS remain unknown. There are insufficiently justified suggestions of high doses of radiation exposure, which may cause STS in certain patients. The specified recommended dose of Olaratumab is 15 mg/kg, administered as an IV infusion on day 1 and day 8 and every 3-week cycle afterwards until progression of the disease or inacceptable toxicity. Lartruvo is administered in combination with doxorubicin for up to 8 treatment cycles, followed by Lartruvo monotherapy in patients, whose disease is not progressing. Doxorubicin is administered 1 per day in each cycle, followed by a Lartruvo (Olaratumab) infusion analysis design and methods: patient population, therapeutic mix, time horizon, perspective, description of the analytical framework, input data, collection and sources of data, analyses, evaluation of the uncertainty; The financial impact on the budget is determined as the incremental costs. The mathematical expression of the budget impact is provided by deducting the total cost of the treatment of STS before the reimbursement of OLA from the total cost of the treatment of STS after reimbursement of OLA. Therefore the financial impact on the budget is determined incrementally (net budget impact). The budget impact is calculated based on two scenarios the first, where the new 12

13 health technology is included in the Positive Drug List (PDL) and reimbursed by the National Health Insurance Fund (NHIF) and the second where OLA is not included in the PDL and is not reimbursed with public funds. The number of patients is estimated, based on the following significant assumptions: - Prevalence in Europe, expressed in percentiles, in patients with soft tissue sarcoma 4/ ; - Incidence (incidence) of soft tissue sarcoma in Bulgaria 2,3/ ; - Death rate 1,8; - The population of Bulgaria in The data regarding these assumptions was obtained from the respective official sources and quoted in the references to this report. The time horizon of the analysis is five years. The calculation of the incremental costs in the analysis is based on the following factors: 1. The costs, incurred for specialist health services during the period of the analysis were neglected, because they are with the same value for all reviewed comparators for the treatment of STS. 2. The cost of the evaluated STS technology is related to the group of patients, targeted by the technology, in each of the respective years, after the decision for the use of the technology is made. 3. Reduction of the value of the budget impact of the new technology by the costs, which would be fully or partially replaced by the assessed STS technology, as well as each possible increase of the additional payments by patients. 4. Other costs, related to the assessment of the technology (costs for the follow-up of patients, changes in the number of days in hospital, costs for supplies, costs for the personnel, costs for nurses, depreciation, travel costs, related to the access to specialist health services, administrative costs, costs for lost productivity etc.) are not included in this analysis, because there are no significant differences between the competitive technologies in this respect, and furthermore these are methodologically incompatible with the third-party payer (NHIF) perspective adopted. The input data for the analysis originates from a number of sources, properly referred to by the applicant. The costs for the compared medicinal therapies in the analysis, have been calculated based on registered dosage regimens and reference prices in the Positive Drug List (PDL) in Bulgaria as of June 2017 г. An evaluation of the costs as a result of the change of some of the main determinants in the budget impact analysis has been performed: number of patients in a five-year period, average cost of the therapy with comparators and cost of the therapy with OLA+DOX. In order to add stochastic noise, an interval has been determined, in which the deterministic variables vary ± 20 %. The sensitivity analysis shows the following results: - the budget impact is determined to the highest extent by the average cost of the therapy with OLA+DOX and the average cost of the comparators. - the increase of the cost of the therapy by up to 20% would result in an increase of the costs for the implementation of the OLA. - the fluctuations of the number of patients, potentially receiving the OLA+DOX therapy, within ± 20%, have a negative impact on the budget in all possible cases. 13

14 - in case of a moderate increase in the cost of the OLA+DOX therapy or reduction in the cost of the comparators, the reimbursement of the new technology by the NHIF will result in increased costs evaluation of the annual numbers of the target population; The expected patient population varies in the five years of the analysis. The number of patients is estimated, based on the following significant assumptions: - Prevalence (prevalence) in Europe, expressed in percentiles, in patients with soft tissue sarcoma 4/ ; - Incidence rate (incidence) of STS in Bulgaria 2,3/ ; - Death rate 1,8; - The population of Bulgaria in evaluation of the annual number of patients, to be administered the new health technology; The estimated number of patients, to receive treatment with the new technology, if it is accepted, is calculated for a future 5-year period evaluation of the current annual costs of public budget money for the treatment of patients; The analysis contains an evaluation of the current annual costs for the treatment of the patient population. On a national level there are different alternatives in the treatment of STS. Based on the main assumptions in the model and the costs for the comparators, an evaluation of the current costs, covered by public budget funds has been performed evaluation of the costs, covered by public funds, in the five-year period; There is data on the costs before and after the implementation of the proposed health technology, as the analysis was made for a five-year period. As evidenced by the analysis, the increase in the budget funds, to be used for the treatment of STS is significant. The budget impact of the possible implementation of the new technology is presented results; The results of the analysis show a positive budget impact for the NHIF in the five-year period, following the possible inclusion of the proposed product in the PDL conclusions and limitations; In conclusion of the budget impact analysis, it can be stated, with the assumption that the basic epidemiological indicators will remain largely unchanged in the reviewed period, that the net budget impact of the proposed product would be positive submission of the results in the form of tables and diagrams. 14

15 The applicant has submitted the results of the budget impact analysis in the form of tables and diagrams. The budget impact is determined to the highest extent by the average cost of the therapy with OLA+DOX and the average cost of the comparators. The fluctuations of the number patients, potentially receiving the OLA+DOX therapy, within ±20%, have a negative impact on the budget in all possible cases. The model shows that in case of a moderate increase in the cost of the OLA+DOX therapy or a reduction in the cost of the comparators, the reimbursement of the new technology by the NHIF will result in increased costs. V. Recommendation. Inclusion of the medicinal product LARTRUVO 190 mg/19 ml Concentrate for Sol. Inf. (оlaratumab) in the positive drug list of the Republic of Bulgaria. The recommendation is made, based on a thorough review and evaluation of the submitted analysis pursuant to art. 16, para. 1, item 5 of Ordinance 9 / of the Ministry of Health for the therapeutic efficiency/effectiveness, safety, pharmacoeconomic indicators and budget impact analysis of the new health technology. RESOLUTION of the Committee under Art. 5 of Ordinance No. 9 of on the terms and procedure for conduct of health technology assessment of : The commission ACCEPTS the draft Health Technology Assessment Report for the medicinal product LARTRUVO 190 mg/19 ml concentrate for sol. inf, submitted with Application No. 2877/ г. to the National Center of Public Health and Analyses and RECOMMENDS the inclusion in Positive Drug List. 15