SUMMARY. Health Technology Assessment Report

Transcription

1 SUMMARY OF Health Technology Assessment Report subject to Art.17, par.7 of Ordinance No.9 / of the Ministry of Health of the Republic of Bulgaria ON MEDICINAL PRODUCT Esbriet 267 mg hard capsule 1

2 I. Health problem analysis. 1. Health problem analysis Idiopathic Pulmonary Fibrosis (IPF): 1.1. Description of the health problem based on a review of scientific and epidemiological data. Idiopathic pulmonary fibrosis (IBF) is one of the most common diseases with unspecified etiology and high mortality rate in adult paients, among the idiopathic interstitial pneumonias (IIP). It is a heterogeneous disease with a various course, having a median survival period between 2.5 and 3.5 years after diagnosing, and it is a diagnosis of exclusion. IIP is not synonymous with IPF, as these diseases include a heterogeneous group of diffuse parenchymal lung disorders with similar clinical, radiological, physiological and histological characteristics, but with clarified etiology. There are no accurate epidemiological data of IPF prevalence. According to US Population Studies, IPF incidence ranges between and cases per 100,000 man-years, depending on the scope of the disease definition. The disease ranges between (narrow definition) and (broad definition) per 100,000 people. According to various sources, the incidence in Europe varies from 2 to 29 per 100,000. The wide variability of these data is due to undiagnosed cases or diagnostic errors. Currently, there are no official epidemiological data on IPF in Bulgaria, as there is no official register. About 5 to 6% of the total diagnosed IPF cases are due to family IPF. In family cases, several rare genetic variants (the rare heterozygous variants of the SFTPA2 and SFTPC genes), and in sporadic IPF single nucleotide polymorphism (SNP) of the MUC5B gene have been established. IPF affects more often men over the age of 60 from all ethnic groups, irrespective of whether they live in rural or urban areas, with the frequency increasing with age. In terms of pathomorphology, the disease is characterized by a disorder of the regenerative processes in the lung tissue resulting in fatal accumulation of fibroblasts and extracellular matrix in the lung, which destroys its tissue architecture and functional capacity. Histologically, the picture is heterogeneous areas of normal parenchyma, mixed with areas of paraseptal and subpleural fibrosis, and formation of honeycomb-type changes, with or without bronchiectases. At cellular level, a damage of the alveolar epithelial cells (AEC) is detected; unlocking of the inflammatory cascade; enhanced expression of fibrosis stimulating cytokines; increased deposition of extracellular matrix and development of fibrous lesions, known as fibroblast focuses. Clinically, IPF is characterized by two main but non-specific symptoms, which cause its delayed diagnosis: o Unexplained shortness of breath during physical efforts, which begins gradually and progresses rapidly over time (observed in about 50% of the patients); o Cough, usually non-productive and resistant to treatment with antitussives - observed in over 80% of the patients. The physical methods of examination reveal crackles in both lung bases and clubbing of the fingers. IPF is a rare, chronic, progressive, irreversible disease, which causes severe lung function impairment and the following complications: poor quality of life; reduced physical capacity and tolerance; disability; exacerbations and frequent hospitalizations, when the 2

3 disease becomes more severe; need of constant oxygen therapy at home for advanced disease (currently payable by the patient) and fatal outcome between 2 and 3.5 years on average after the diagnosis Description of the proposed health technology. The health technology being assessed relates to the use of the medicinal product Esbriet (pirfenidone), hard capsules, in patients with IPF. Esbriet (pirfenidone) belongs to the following pharmacotherapeutic group - Immunosuppressants, other immunosuppressants, АТС code: L04AX05. Esbriet is indicated for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in adults. At the start of the treatment, the dose should be titrated to the recommended daily dose of nine capsules per day over a period of 14 days, as follows: Days 1 to 7 one capsule three times a day (801 mg/day); Day 8 to 14 two capsules three times a day (1602 mg/day); From Day 15 onward three capsules three times a day (2403 mg/day). Dose titration is performed in outpatient settings and does not require hospitalization (data from the health technology owner and summary of product characteristics). The recommended daily dose of Esbriet for patients with idiopathic pulmonary fibrosis is three capsules of 267 mg three times daily taken orally during a meal with one glass of water, which makes a total of 2403 mg/day. Doses above this one are not recommended for any patients. Patients, who miss 14 consecutive days of treatment with Esbriet or more, should start the treatment from the beginning by going through the initial titration regimen for 2 weeks, until they reach the recommended daily dose. If the treatment is discontinued for less than 14 consecutive days, the dose remains the same as the previous recommended daily dose without any need for titration. No dose adjustment is needed in older patients. Pirfenidone is a new drug technology, which is indicated for the treatment of patients with IPF - the first approved drug therapy with an indication for IPF. Pirfenidone was approved for the treatment of mild to moderate IPF in adults under a centralized procedure for all EU Member States on 28 February 2011 by ЕMА (EMA, 2011). The health technology was authorized for use in Bulgaria on 28 February 2011, a centralized procedure. Esbriet (pirfenidone) is indicated for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in adults, when the following NICE criteria are met: - Forced vital capacity (FVC) of the patient between 50% and 80% of the predicted value; - In case of disease progression in any twelve-month treatment period (proven FVC decline of 10% or more), it is discontinued. 3

4 1.3. Description of other health technologies, which are reimbursed in Bulgaria and which can be used as a therapeutic alternative or a combination therapy with the proposed health technology. As of April 2017, there is no reimbursement of any IPF therapy. 2. Choice of basic comparative therapeutic alternative: 2.1. As of April 2017, there is no reimbursement of any IPF therapy Reimbursed pharmacotherapeutic analogue used for the treatment of the same disease or first-choice therapy Currently, there are no data on completed clinical trials directly comparing pirfenidone with other health technologies. The main comparative product is Ofev (nintedanib). No head-to-head clinical trials for pirfenidone and nintedanib have been conducted and any comparison of the results between trials conducted with different patient groups and using different methodologies should be interpreted with caution. In EU, pirfenidone is indicated in adults for the treatment of mild to moderate idiopathic pulmonary fibrosis. In EU, nintedanib is indicated in adults for the treatment of idiopathic pulmonary fibrosis with no limit to any specific severity The most commonly prescribed reimbursed health technology with the same or equivalent therapeutic indication As of April 2017, there is no reimbursed therapy for IPF in Bulgaria. At the same time, the reimbursement status of the medicinal product in other EU countries and outside EU, according to the data provided by the Marketing Authorization Holder (Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom; represented by Roche Bulgaria ЕООD within the meaning of Art. 26, par. 2 of the Law on Medicinal Products in Human Medicine) reveals the following: as of June 2016, pirfenidone is reimbursed in 20 EU Member States, as well as in the USA, Canada, Iceland, Norway Non-drug therapies and non-treatment, when it is most commonly used in therapeutic practice or when there are no other treatment alternatives. Based on the national clinical practice, Ofev (nintedanib) is mentioned as the main comparative product The choice of the main comparative therapeutic alternative is in accordance with the national clinical practice, national consensus and pharmacotherapy guidelines. On the basis of completed multicentre trials, in 2015 new guidelines were accepted, and pirfenidone has Conditional Recommendation for use. 4

5 In 2015, Bulgarian Society of Pulmonary Diseases participated in the issue of an Update of 2011 Clinical Practical Guideline IDIOPATHIC PULMONARY FIBROSIS, based on the official statement of the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALAT). 3. Assessment perspective Pirfenidone is a new drug technology, which is indicated for treatment of patients with IPF and was authorized for use in Bulgaria on 28 February centralized procedure. This health technology will not lead to a change in the diagnostic methods. Diagnosis requires high-resolution computed tomography. A multidisciplinary approach with the participation of a pulmonary specialist, radiologist and pathologist will be needed. Currently, there is no reimbursed therapy for IPF and this health technology will lead to a change in the way of treatment. It will enable specialists to use approved drug technology for IPF in their practice. 4. Number of potential patients, who will be eligible for treatment with the new health technology. Idiopathic pulmonary fibrosis is a rare disease. The literature review of the published studies did not find any publications, which can be used to establish the incidence of the disease in Bulgaria. In the submitted documents by Bulgarian authors, there are single publications, which provide data with insufficient probative value, as in most of the cases they are review materials or case studies. II. Comparative analysis of therapeutic efficacy / effectiveness and safety. 1. Health results: 1.1. This analysis is based on data, which represent clinically significant outcomes and play an important role in the health problem being reviewed. The clinical efficacy of pirfenidone has been studied in patients with IPF in three large, double-blind, placebo-controlled, randomized, Phase III studies funded by InterMune: PIPF- 004 (CAPACITY 2) and PIPF-006 (CAPACITY 1), which have almost identical design, and another confirmatory study with a similar design, PIPF-016 (ASCEND). Phase III study (SP3), sponsored by Shionogi (holders of the rights to develop pirfenidone in Japan, Taiwan and South Korea); Phase II study (SP2) (using the tablets formulation), sponsored by Shionogi; Study PIPF-012 (RECAP) contributes evidence of the long-term pirfenidone treatment in a 7-year prospective follow-up period. These studies are the main studies of pirfenidone, which are currently available and are of the greatest importance for answering the basic question of the HTA analysis. The primary endpoint is the annual decline in the forced vital capacity (FVC). The main secondary endpoints are the change from the baseline of the total score of the quality of life 5

6 questionnaire Saint George's Respiratory Questionnaire (SGRQ) at 52 weeks, and the time to the first acute exacerbation of IPF Clinical outcomes: Clinically significant long-term outcomes: - quality of life (SGRQ) - mortality - safety Intermediate clinical outcomes of economic importance, which are associated with the long term outcomes: - absolute change in FVC decline, expressed as a percentage of predicted FVC; - category assessment of the absolute change in FVC decline, expressed as a percentage of predicted FVC; - progression free survival; - deterioration; - change in the distance in the 6-minute walk test; - change in the lowest levels of oxygen saturation in the 6-minute walk test; - a change in the percentage of pulmonary diffusion capacity (DLСО); - manifested dyspnea, measured by the total sum of the dyspnea indicators; - mean change in vital capacity. 2. In the comparative analysis, a systematic review was carried out for: 2.1. Comparison with at least one reimbursed therapeutic alternative, and when there is no such alternative comparison with another alternative technology. The identification of the studies assessing the efficacy, therapeutic effectiveness and safety of pirfenidone in the treatment of IPF has been performed through a study protocol in compliance with PRISMA standard for conducting systematic reviews and meta-analyses. (Moher, 2009). A systematic review of the scientific literature concerning the efficacy, therapeutic effectiveness and safety of pirfenidone has been carried out. A search for clinical trials in the U.S. National Institutes of Health (Clinicaltrials.gov) database using the key phrase pirfenidone AND IPF has been made to identify the relevant clinical trials as of July The choice of this database is consistent with the fact that not all completed studies were published at the time of the preparation of this health technology assessment report. The criteria, according to which the studies are included in the analysis of the efficacy, therapeutic effectiveness and safety of pirfenidone, are relatively open - the main criterion is that the patients must be diagnosed with IPF. The comparison is between pirfenidone and placebo, with no restrictions to the reported outcomes. The analysis excludes Phase I and II studies, in vitro studies, reviews, studies not on people and studies, which have not been completed Identification of all clinical trials concerning efficacy, effectives and safety. 23 studies have been found in clinicaltrials.gov 8 ongoing studies, 5 studies with other medicinal products, 3 Phase II studies, 4 Phase III studies, 2 observational studies and 1 program of extended patient access to pirfenidone. The further efficacy, therapeutic 6

7 effectiveness and safety analysis includes the 4 Phase III clinical trials, 1 additionally identified Phase III study and 1 additionally identified Phase II study. The identified studies have been analyzed according to the inclusion and exclusion criteria in the further analysis. As a result of that, the following studies have been accepted for analysis and assessment: - three large, double-blind, placebo-controlled, randomized, Phase III studies of pirfenidone for IPF, funded by InterMune: PIPF-004 (CAPACITY 2) and PIPF-006 (CAPACITY 1), which have almost identical design, and another confirmatory study with a similar design, PIPF-016 (ASCEND). - Phase III study (SP3), sponsored by Shionogi (holders of the rights to develop pirfenidone in Japan, Taiwan and South Korea); - Phase II study (SP2) (using the tablet formulation), sponsored by Shionogi; - Study PIPF-012 (RECAP) contributes evidence of the long-term pirfenidone treatment in a 7-year prospective follow-up period Objective analysis of the health outcomes in each study. The purpose of the main working hypothesis is to demonstrate the clinical superiority of pirfenidone versus placebo. Only PIPF-012/RECAP aims at assessing the long-term efficacy and safety of the product in the treatment of IPF. A wide range of statistical tools have been used to determine the sample size, calculate correlations and manage data. The objective analysis of the health outcomes in each of the studies was carried out by appropriate statistical methods rank-based ANOVA analysis, descriptive statistics, Hochberg s multiple comparison procedure, log-rank test, hazard ratio based on Cox proportional hazards model, the least significant difference method based on one-way ANOVA, Kaplan-Meier method, Fisher s exact test, Wilcoxon test, chi-square test, Welch test. The missing values due to death are given the worst rank in ANOVA analyzes and the worst possible score in the average change analyses (e.g. FVC = 0) and the analyses by category. Other missing data are entered with the average value of three patients having the smallest sum of the differences in the squares of each visit with available data. The last observation carried forward (LOCF) was used as a sensitivity analysis. The main outcomes indicate that: Pirfenidone statistically significantly reduces the decline in the percentage of predicted FVC from the baseline; Pirfenidone statistically significantly reduces IPF-related mortality; Pirfenidone statistically significantly reduces the risk of death or disease progression vs. placebo; Pirfenidone statistically significantly reduces the decline in the distance walked in 6- MWT vs. placebo; The proportion of patients with poor quality of life according to San Diego Shortness of Breath Questionnaire (SOBQ) (increase 20 points or mortality) is lower in the pirfenidone group vs. placebo group. The efficacy outcomes from the clinical trials of pirfenidone are applicable to a large number of various markets. Three main Phase III studies (PIPF-016, PIPF-004, PIPF-006) demonstrate the efficacy of pirfenidone in approximately 1600 patients from all over Asia, North and South America and Europe (King, 2014a; Noble, 2011; Noble, 2014), with additional evidence from SP2 and SP3 two Japanese clinical trials (Azuma, 2005; Taniguchi, 2010). 7

8 1. Timely and consistent pirfenidone treatment slows the decline in the pulmonary function: The benefit of pirfenidone treatment for the pulmonary function is distinct within 12 weeks as of the onset of the treatment and is maintained throughout the study with a progressively increasing difference of the decline in the percentage of predicted FVC in favor of pirfenidone over the 52 weeks (Noble, 2014); The mean change in FVC from baseline to week 52 is -216 ml altogether for the pirfenidone group vs ml in the placebo group (absolute difference, 148 ml; relative difference, 40.7%) (Noble, 2014); Patients, who have 10% or higher decline in FVC, have a significantly reduced risk of death and improved disease stabilization, if they continue their treatment with pirfenidone (and not with placebo) (Nathan, 2015); The trend of slowing the decline in the percentage of predicted FVC with pirfenidone is sustainable in many different subgroups, including patients with mild to moderate disease (Albera, 2015). 2. Pirfenidone improves the symptom control: The overall findings of the three Phase III studies provide constant and consistent evidence that pirfenidone offers a clinically significant improvement in the exercise tolerance of IPF patients. In the pooled analysis, there is a clinically significant effect of pirfenidone on the reduction of the declined in the distance walked in 6-MWT vs. placebo (p < 0.001) (Noble, 2014); Fewer patients treated with pirfenidone had worsening of the dyspnea vs. placebo. Pirfenidone reduced by 23.7% vs. placebo (p = 0.047) the number of the patients, who had worsening of the dyspnea, defined as increase of the scores in the shortness of breath questionnaire (SOBQ) by 20 points or death cases (Noble, 2014). 3. Pirfenidone improves progression free survival and overall survival: When comparing pirfenidone to placebo, the risk of death for any reason is reduced by 48% (HR 0.52; 95% CI, ; p = 0.01) at week 52, and by 39% (HR 0.61; 95% Crl ) at week 72 (Noble, 2014; King, 2014); In the pooled analysis of PIPF-016, PIPF-004, and PIPF-006, the risk of disease progression or death is reduced by 38% for pirfenidone vs. placebo (HR 0.62; 95% CI ; p < ) (Noble, 2014); The mean time to progression from the date of diagnosis is assessed at 3.2 years with pirfenidone (95% CI ) and 2.1 years with the best supportive care (95% CI ). This means that pirfenidone could be able to extend the time to progression by about 1 year (Fisher, 2015); The mean overall survival from the date of diagnosis is assessed at 9.2 years with pirfenidone (95% CI ) and years with the best supportive care (95% CI ). This means that pirfenidone could be able to extend the survival by about 3 years (Fisher, 2015). 4. Safety of Pirfenidone Pirfenidone is well tolerated and has manageable side effect profile: The most common side effects observed during pirfenidone treatment include nausea, rash, stomach ache, upper respiratory tract inflammation, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, decreased / loss of appetite, gastroesophageal reflux disease, sinusitis, insomnia, decreased weight and arthralgia (ЕМА, 2011), and they are similar to the side effects reported for nintedanib (FDA, 2014b); The complete safety analysis performed during five clinical trials with 1299 patients 8

9 exposed to treatment for up to 9.9 years showed that the long-term pirfenidone treatment is safe and well tolerated (Lancaster, 2015); Adverse events may be managed through reduction of the pirfenidone dose; Pirfenidone related adverse events, which require immediate treatment, are mostly mild to moderate and can be well managed by dose reduction (King, 2014a; Costabel, 2014), which means that the patients can continue with the therapy and benefit from the improved survival outcomes. 3. In the cases, where there is no alternative health technology, the analysis involves a comparison with the natural course of the disease according to the indications, for which the assessed health technology is approved. According to the latest update of the IPF Guideless of the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association of 2015, Pirfenidone is only approved, together with Nintedanib, for treatment of IPF. Based on this fact and according to the data above, we give our positive statement for the inclusion of the drug Pirfenidone in the Positive Drug List. References: Albera, C., Bradford, W.Z., Costabel, U., etal. PirfenidoneIsEfficaciousinPatientsWithIdiopathicPulmonaryFibrosis (IPF) andmildrestrictivedisease: BenefitofEarlyIntervention. Abstract A15. American ThoracicSociety 2015 International Conference, May Denver. Azuma A, Nukiwa T, Tsuboi E, etal. Double-blind, placebocontrolledtrialofpirfenidoneinpatientswithidiopathicpulmonaryfibrosis. Am J RespirCrit Care Med 2005; 171: Costabel, U., Bendstrup, E., Cottin, V. etal. Pirfenidoneinidiopathicpulmonaryfibrosis: expertpaneldiscussiononthemanagementofdrug-relatedadverseevents. AdvTher 2014; 31(4): dubois, R. M., Weycker, D., Albera, C. etal. Six-minutewalktestinidiopathicpulmonaryfibrosis: testvalidationandminimalclinicallyimportantdifference (a). Am.J.Respir.Crit Care Med. 2011c; 183(9): EuropeanMedicines Agency. EPAR foresbriet. LastupdatedJune 2015a. _Product_Information/human/002154/WC pdf [lastaccessed 08th September 2015] EuropeanMedicines Agency. Publicsummaryofopiniononorphandrugdesignation - Pirfenidoneforthetreatmentofidiopathicpulmonaryfibrosis Availableat: 821/human_med_ jsp&mid=WC0b01ac058001d124 Publicsummaryofopiniononorphandrugdesignation - Pirfenidoneforthetreatmentofidiopathicpulmonaryfibrosis. FederalDrugsAdministration (FDA) Ofev (nintedanib) PrescribingInformationOctober 2014b. Availableat Dateaccessed 06th August

10 FederalDrugsAdministration (FDA) Esbriet (pirfenidone) ProductInformation, LastrevisedOctober 2014c; Availableat [dateaccessed 08th September 2015]. Fisher, M. (a), Maher, T., Hill, C., etal. Diseaseprogressionmodelinginidiopathicpulmonaryfibrosis: a predictionoftimetodiseaseprogressionandlifeexpectancywithpirfenidone. Am.J.Respir.Crit Care Med. 191; 2015: A4413. King, T. E., Bradford, W. Z., Castro-Bernardini, S. etal. A Phase 3 TrialofPirfenidoneinPatientswith IPF. N Engl J Med 2014a; 370: Lancaster, L. H., Albera, C., Bradford, W. Z., etal. Safety ofpirfenidoneinpatientswith IPF: IntegratedAnalysisof Data fromfiveclinicaltrials. Am.J.Respir.Crit Care Med. 191; 2015: A15. Lancet. New Guidelinesfor IPF 2015; 386. Nathan, S.D.(b), dubois, R.M., Albera C., Bradford, W.Z, etal. Validationoftestperformancecharacteristicsandminimalclinicallyimportantdifferenceoft he 6-minute walktestinpatientswithidiopathicpulmonaryfibrosis. RespiratoryMedicine 2015; 109: Noble, P. W., Albera, C., Bradford, W. Z. etal. Pirfenidoneinpatientswith IPF (CAPACITY): tworandomizedtrials. Lancet 2011; 377(9779): Noble, P. W., Albera, C., Bradford, Z. W. etal. Pirfenidonefor IPF: AnalysisofpooleddatafromthreemultinationalPhase III trialseurrespir J Jan;47(1): Pharmaceutical andmedicaldevices Agency (PDMA). GlaspiaTablets (pirfenidone): Reportonthedeliberationresults. September Availableat DateAccessed 05 August Roche Data onfile, SystematicReviewandMixedTreatmentComparisonofTreatmentsfor IPF. July 2015 [unpublished]. Swissmedic, EsbrietProductInformation; September 2015, Availableat DateAccessed [21 September 2015]. Taniguchi H, Ebina M, Kondoh Y, etal. Pirfenidonein IPF. EurRespir J 2010; 35: Vancheri, C.. IPF: a diseasewithsimilaritiesandlinkstocancerbiology. EuropeanRespir J 2010; 35(3): III. Analysis of the pharmacoeconomic indicators of ESBRIET (PIRFENIDONE) 267 mg hard capsule 1. Pharmacoeconomic analysis including a systematic review of published economic analyzes tailored to the target patient population, using some of the following analytical techniques: 1.1. cost-effectiveness analysis; 1.2. cost utility analysis; 1.3. cost - benefit analysis; 1.4. minimum cost analysis. The first pharmacoeconomic analysis applied by the marketing authorization holder is based on the analytical technique cost effectiveness analysis (CEA). A search in EMBASE, EMBASE Alert and Medline database was conducted as to identify pharmacoeconomic analyses of the economic effectiveness of pirfenidone. As a result of this, 2 cost 10

11 effectiveness analyses of pirfenidone have been identified. Both publications are made by the same team with the same results and conclusions. This analysis is based on a systematic review of the outcomes of 14 studies comprising azathioprine, NAC (alone or in combination), pirfenidone, nintedanib, sildenafil, thalidomide, pulmonary rehabilitation and IPF comprehensive management program. The authors have come to the conclusion that only pirfenidone and nintedanib show statistically significant improvements in the treatment of IPF. The model shows increased survival rate at increased costs for the five studies drug therapies (pirfenidone, triple NAC therapy, inhaled NAC, nintedanib and sildenafil) vs. the best supportive care. In respect of the reimbursement status of the product in other countries, there is evidence that by June 2016, pirfenidone has a positive statement for reimbursement and is reimbursed in 20 of the EU Member States, as well as in the USA, Canada, Iceland, and Norway. Pirfenidone is paid by public funds in a large number of EU Member States from Eastern Europe - the Czech Republic, Estonia, Lithuania, Latvia, Slovenia, Romania. Two analyses were used for the health technology assessment: cost-effectiveness and cost-utility. The time horizon chosen for the cost-effectiveness analysis is 1 year, and the time horizon chosen for the cost-utility analysis is 30 years. The first analysis is based on direct observation, and the second one is based modeling using a 30-year Markov model. The health outcomes are expressed in a single unit, which allows the estimation of the value of the money in a wide range of therapeutic areas. In this case, the units are improved qualityadjusted life-years (QALY) gained. The improved quality-adjusted life-year gained is a measure of the severity of the disease, for which the number of the life-years has been weighed with the quality of life during that period. The price of the life-year gained (LYG) and avoided exacerbations are also taken into account. The choice of this time horizon is justified by the fact that the only published data on QALYs gained with IPF therapy with pirfenidone result from exactly such a timeframe. An attempt has been made to assess the cost-benefit ratio adapted to Bulgarian conditions using baseline data from the 30-year Markov model and the discounted costs associated with the treatment of one patient for this period. The analysis is carried out from NHIF s perspective, including the direct costs with public funds for the therapy of IPF patients. Due to the lack of studies for direct comparison of pirfenidone with other IPF treatments, a network meta-analysis (NMA) was performed to compare the efficacy of pirfenidone against other available treatments. A literature review has been carried out to identify all relevant pirfenidone studies and comparison indicators, which may be of interest for inclusion in the NMA. NMA shows that pirfenidone is more efficient than placebo in respect of the outcomes of FVC, 6-MWT difference, health-related quality of life, PFS and some mortality outcomes. The quality of life indicator used for the purposes of this analysis is QALY. Due to a lack of direct data from the included studies of efficacy, therapeutic effectiveness and safety, the analysis has used the QALY outcomes from a study of Loveman et al. of

12 In the analysis of cost-utility indicators, the health effects and costs were discounted by 3.5% on an annual basis. The reason for choosing such a discount rate is the results used from a published 30-year Markov model. Titration with pirfenidone until reaching the optimal therapeutic dose in the first month of treatment is conducted in outpatient settings and does not require hospitalization. Thus, no extra costs are accounted for. The introduction of pathogenetic treatment with the new technology or the alternative medicinal product reduces the cost of complex maintenance treatment in these patients. Only direct and additional costs are taken into account. In conclusion, there is no evidence of indirect costs to be valued because it is an innovative therapy with an orphan drug status. One-way sensitivity analysis was performed. Health outcomes are varied within the range of +/-5%. The results of the cost-effectiveness and cost-utility analyzes were tested with no significant fluctuations in the pharmacoeconomic indicators of pirfenidone, which shows the sustainability of the results. 2. The pharmacoeconomic analysis takes into account the health perspective of the institution, which pays for the treatment by public funds, or the public perspective. The presented pharmacoeconomic analyses take into account the health perspective of the institution, which pays for the relevant treatment by public funds. The first analysis was designed for the purposes of the UK and Wales reimbursement system, which assesses the costs and outcomes from the point of view of the National Health Service (NHS) of England and Personal Social Services (PSS) in Wales, and the second one assesses the costs and outcomes from the point of view of the National Health Insurance Fund (NHIF) in Bulgaria. 3. The time horizon of the pharmacoeconomic analysis allows for reliable and reasonable conclusions on cost and outcome assessment compared to the alternative technologies. The time horizon of the pharmacoeconomic analysis conducted for England and Wales is for life, whereas the applied Bulgaria-adapted analysis is for 12 months. In the first case, the time horizon is sufficiently long to identify and measure all important health costs and benefits. The time horizon allows for reliable and reasonable conclusions on cost and outcome assessment compared to the alternative drug therapy and other health technologies. 4. Different models are used when it is necessary to extrapolate the results beyond the time horizon of the clinical trials and assess the results in the real-life practice In the applied Bulgaria-adapted analysis carried out for the time horizon of 12 months there is no data of extrapolation of the results beyond the time horizon of the clinical trials. 12

13 5. When the analysis is from the public point of view, both direct and indirect medical costs are included. The analyses are not from the public, but from the payer s point of view, therefore only direct medical costs are included. 6. Future costs and results are discounted by 5 %, respectively. Health benefits and costs are discounted by 3.5% from the prepared pharmacoeconomic analysis. The results of the pharmacoeconomic analysis of pirfenidone should be interpreted in the light of the specific characteristics of the product and the disease, for which it is intended. This is an orphan drug intended to be used for a rare disease. IV. Budget Impact Analysis. 1. Budget Impact Analysis includes the following main components: 1.1. Epidemiology and therapy of the disease, clinical impact, economic impact Epidemiology of the disease Idiopathic pulmonary fibrosis (IPF) is a rare ( cases per 100,000 man-years) specific form of chronic progressive fibrosing interstitial pneumonia of unknown cause occurring in adults. IPF belongs to the group of Interstitial Pulmonary Diseases (IBB), which are a heterogeneous group of diffuse parenchymal lung disorders with similar clinical, radiological, physiological and histological characteristics. IPF is the most common and deadliest form. In its essence, it is a heterogeneous disease with a heterogeneous course and an average survival after diagnosis between 2.5 and 3.5 years. It is a diagnosis of exclusion. According to US Population Studies, IPF incidence ranges between and cases per 100,000 man-years depending on the scope of the disease definition. According to some studies, IPF incidence ranges between (narrow definition) and (broad definition) per people. IPF affects more often men over the age of 60 from all ethnic groups, irrespective of whether they live in rural or urban areas, with the frequency increasing with age Clinical impact of the disease Clinically, IPF is characterized by two main but non-specific symptoms, which cause its delayed diagnosis: - Unexplained shortness of breath during physical efforts, which begins gradually and progresses rapidly over time - observed in about 50% of the patients; - Cough, usually non-productive and resistant to treatment with antitussives - observed in over 80% of the patients. 13

14 Other symptoms, such as chest pain, rash, increased body temperature, muscle and joint pain are not characteristic of IPF, and their presence directs the diagnostic investigation to other nosological units. IPF, however, is characterized by progressive, irreversible course leading to disability, chronic respiratory and heart failure, need of constant oxygen therapy at home, which is not included in any form of treatment and is not reimbursed Economic Impact The direct economic impact of the disease is not unequivocally described and presented in the attached HTA report. Indirectly, it can be concluded that the disease leads to serious economic consequences for the patients due to the limitation of their beneficial activity and occurrence of concomitant diseases. IPF is a severe, progressive disease with a fatal outcome and a huge impact on the quality of life of the patients. Its expected survival is much worse than that of a number of oncology diseases. Such conditions directly affect the economic aspect of the patient's disease - the complications and necessary complex symptomatic treatment and frequent hospitalizations, which further affect patient's economic well-being and budget expenditure as a whole Analysis design and methods: patient population, therapeutic mix, time horizon, perspective, description of the analytical framework, input data, collection and data sources, analyses, uncertainty assessment. The analysis design includes the following methods: Patient population is clearly limited by the following criteria and includes patients with proven IPF based on the clinical picture, high-resolution computed tomography, and restrictive ventilatory syndrome (decreased FVC and DLCO). The expected number of patients is presented in the text. The time horizon of the analysis is 1 year for Bulgaria, which includes the patient s perspective. One-way sensitivity analysis has been carried out Assessment of the annual number of the target population. The target population was calculated on the basis of epidemiological data. The assessment has used mainly studies of the expected incidence of the disease as well as expert assessments by leading Bulgarian pulmonologists Estimate of the actual annual costs from the public budget for the treatment of patients. As of April 2017, the positive drug list does not include any product, which is reimbursed with public funds for the treatment of idiopathic pulmonary fibrosis. 14

15 1.6. Estimated costs from public funds over a five-year period. The described costs of the new health technology exceed the cost of treatment with the best supportive care available on the market. At the same time, the product partially shows better results for the treatment of IPF patients in terms of its long-term effects - FVC improvement, quality of life, longer time to severe exacerbation and longer survival Results As a result of the conducted analysis, it can be concluded that the calculations and proposals made in respect of the budget impact are correct. The main aspects required for the assessment have been reviewed. 1.8 Conclusions and restrictions. The product can be submitted for reimbursement but under certain conditions, namely compliance with the NICE criteria for inclusion and continuation of pirfenidone treatment in patients with IPF. V. Recommendation. On the basis of the report presented by the members of the Working Committee on Health Technology Assessment for the Medicinal Product Esbriet 267 mg hard capsules, entered by Application No. 3266/ with the National Center of Public Health and Analyses (NCPHA), we propose the inclusion of the medicinal product in the Positive Drug List. RESOLUTION of the Committee under Art. 5 of Ordinance No. 9 of on the terms and procedure for conduct of health technology assessment of : ACCEPT the draft Health Technology Assessment Report for the medicinal product Esbriet 267 mg hard capsules /INN Pirfenidone/, entered by Application No. 3266/ with the National Center of Public Health and Analyses and RECOMMENDS its inclusion in the Positive Drug List. 15