Off-Label Uses of Ranibizumab and Aflibercept for Age-Related Macular Degeneration in Turkey.

Purpose: To evaluate the clinical and demographic aspects of off-label drug use applications for age-related macular degeneration (AMD) in Turkey. Methods: Applications for off-label drug use in the treatment of AMD to the Turkish Medicines and Medical Devices Agency (TITCK) in 2018 were retrospectively analyzed. Demographic characteristics, requested drugs, previous treatment regimens, and reasons for applications were evaluated. Results: The mean age of the patients (n = 209) was 64.9 ± 15.7 years, of which 48.8% were male and 51.2% were female. Ranibizumab (n = 113) comprised 54.1% and aflibercept (n = 96) 45.9% of off-label use applications. No application was made for bevacizumab. The most frequent reasons for application were switchback (49.3%), nonreimbursement of indicated drugs in cases under 50 years of age (24.4%), and failure to complete the loading dose (14.4%). Conclusions: Ranibizumab was the most requested off-label drug for AMD. There was no application for off-label bevacizumab since its use does not require approval from TITCK. In Turkey, new rules were established for the reimbursement of intravitreal drugs for AMD in 2019. Three doses of intravitreal bevacizumab were required initially for aflibercept and ranibizumab to be covered for reimbursement. There is not enough data in the English literature regarding the off-label use of ranibizumab and aflibercept for AMD. This study provides information about drug regulations and the off-label treatment options preferred by physicians for AMD in Turkey.

Biological therapy for ocular Behçet's disease with off-label drug prescription in Turkey.

OBJECTIVE: The use of biological agents in the treatment of ocular Behçet's disease has recently become more frequent. The use of two agents, infliximab (IFX) and adalimumab (ADA), for the treatment of Behçet's disease requires prior approval by the Turkish Medicines and Medical Devices Agency. We report on a review of such applications with a view to informing on how such agents are used off-label in Turkey. METHODS: Prescriptions for off-label use of IFX or ADA sent from hospitals in Turkey to the Turkish Medicines and Medical Devices Agency in 2018 were evaluated. Demographic data, previous treatment regimens and reasons for referral were extracted from the files of the cases. RESULTS: A total of 662 patients were considered for off-label use of IFX or ADA for the treatment of ocular Behçet's disease. The mean age of the patients was 35.7±10.8 years (range 12-76); 61.5% of patients were men and 38.5% were women. Of the applications, 345 (52.1%) were for IFX and 317 (47.9%) for ADA. Among the referring hospitals, the public university hospitals ranked first, accounting for 77.9% of IFX and 88.6% of ADA prescriptions. Most applications were made after the failure of conventional therapy, which included steroids and immunosuppressive agents. CONCLUSION: IFX and ADA are rarely used as initial therapy. Stepwise treatment is still preferred in the treatment of ocular Behçet's disease in Turkey. Our report informs on the management of this difficult-to-treat condition.

Evaluation of off-label anti-vascular endothelial growth factor and steroid implant medication uses in macular edema due to retinal vein occlusion in Turkey.

WHAT IS KNOWN AND OBJECTIVE: Retinal vein occlusion (RVO) is one of the most common causes of vision loss. Anti-vascular endothelial growth factor (anti-VEGF) drugs, ranibizumab and aflibercept, and corticosteroid implants are approved treatment options for RVO-related macular edema (ME) in Turkey. To the best of our knowledge, there is no data regarding the off-label use of these drugs for RVO in English literature. We aimed to evaluate the clinical and demographic characteristics of off-label drug use applications in Turkey for RVO. METHODS: Applications made to the Turkish Medicines and Medical Devices Agency between January 1 and December 31, 2018, for the use of off-label drugs (ranibizumab, aflibercept, dexamethasone implant) for the diagnosis of RVO from hospitals across Turkey were retrospectively analysed. Data of the applications, such as demographic characteristics, previous treatment regimens, reasons for applications, applicant hospitals and their regions, were recorded. RESULTS: There were 291 approved applications for RVO. The mean age of the patients was 64.88 ± 10.78 years, 48.8% were male, and 51.2% were female. Of these applications, 44.7% were for aflibercept, 35.7% for ranibizumab and 19.6% for dexamethasone implant. No application was made for bevacizumab since it could be used without needing for an application. The most common reasons for applications were due to dose limitations, failure to complete loading doses, and glaucoma, respectively. In terms of the distribution of the applicant hospitals, public university hospitals ranked first with 72.5%, training and research hospitals ranked second with 14.7% and foundation university hospitals ranked third with 13.1% rates. WHAT IS NEW AND CONCLUSION: The practice of drug use in RVO in Turkey has changed as of the beginning of 2019. Stepwise therapy has been accepted by the drug regulatory agency Turkish Medicines and Medical Devices Agency. Utilization of licensed drugs, aflibercept, ranibizumab and dexamethasone has been allowed only after administration of 3 doses of intravitreal bevacizumab. After 3 doses of bevacizumab, the physician may continue either with bevacizumab again or a dexamethasone implant. If there is a reason such as the presence of glaucoma, the physician may skip dexamethasone and switch to aflibercept and ranibizumab, but in this case, dexamethasone cannot be administered to the patient for life. The evaluation of the off-label treatments of RVO, which is one of the most frequently followed diseases in retina clinics, not only contributes to the literature but also provides information regarding the most frequently applied treatments and the physicians' off-label drug preferences for RVO.

Off-label uses of Aflibercept, Ranibizumab and Dexamethasone implant for diabetic retinopathy in Turkey.

Objective: Diabetic retinopathy (DRP) is the most common retinal vascular disease leading to blindness. There is limited data about the off-label drug use for DRP and diabetic macular edema (DME) in literature. The aim of the article was to evaluate the applications for off-label drug use in patients with DME and DRP in Turkey in terms of demographic and clinical characteristics. Methods: Applications for off-label drug use from hospitals across Turkey to the Turkish Medicines and Medical Devices Agency for DRP in 2018 were reviewed retrospectively. Results: 112 approved applications for 167 eyes were included in our study. The mean age of the cases was 61.24 ± 10.23 years, of them 57.1% were males and 42.9% were females. Of these applications, 41.1% were for aflibercept (n:46), 33.9% for ranibizumab (n:38), and 25% for dexamethasone implant (n:28). There was no application for bevacizumab. In terms of referring hospitals, public university hospitals were in the first place with a rate of 70.5%. The most common reasons for applications were drug switchback request and failure to complete loading dose, respectively. Discussions: DRP treatment can sometimes be challenging. The effectiveness of the intravitreal drugs may decrease over time and drug switching may be necessary. In Turkey, intravitreal drugs are only approved and reimbursed for DRP patients in case of macular edema. Off-label drug use may be preferred in non-approved indications and for reasons such as the need for additional drug doses to the determined limits. However, permission must be obtained from TMMDA for off-label drug use in Turkey. Conclusion: Anti-vascular endothelial growth factor drugs are the first-line treatment options for DME. TMMDA currently approves stepwise therapy for diabetic macular edema, initiated with bevacizumab. Bevacizumab administration does not require approval for off-label application. Additionally, ranibizumab, aflibercept, and dexamethasone implant are reimbursed only in case of failure to respond to 3 doses of bevacizumab injection. Our report provides information about off-label drug preferences and drug use regulations in DRP treatment in Turkey. Abbreviations:DME = diabetic macular edema, DRP = Diabetic retinopathy, FFA = fundus fluorescein angiography, TMMDA = Turkish Medicines and Medical Devices Agency, VEGF = vascular endothelial growth factor.

Assessment of quarter billion primary care prescriptions from a nationwide antimicrobial stewardship program.

We described the significance of systematic monitoring nationwide antimicrobial stewardship programs (ASPs) in primary care. All the prescriptions given by family physicians were recorded in Prescription Information System established by the Turkish Medicines and Medical Devices Agency of Ministry of Health. We calculated, for each prescription, "antibiotics amount" as number of boxes times number of items per box for medicines that belong to antiinfectives for systemic use (i.e., J01 block in the Anatomical Therapeutic Chemical Classification System). We compared the antibiotics amount before (2015) and after (2016) the extensive training programs for the family physicians. We included 266,389,209 prescriptions from state-operated family healthcare units (FHUs) between January 1, 2015 and December 31, 2016. These prescriptions were given by 26,313 individual family physicians in 22,518 FHUs for 50,713,181 individual patients. At least one antimicrobial was given in 37,024,232 (28.31%) prescriptions in 2015 and 36,154,684 (26.66%) prescriptions in 2016. The most common diagnosis was "acute upper respiratory infections (AURI)" (i.e., J00-J06 block in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems) with 28.05%. The average antibiotics amount over prescriptions with AURI decreased in 79 out of 81 provinces, and overall rate of decrease in average antibiotics amount was 8.33%, where 28 and 53 provinces experienced decreases (range is between 28.63% and -3.05%) above and below this value, respectively. In the most successful province, the highest decrease in average amount of "other beta-lactam antibacterials" per prescription for AURI was 49.63% in January. Computational analyses on a big data set collected from a nationwide healthcare system brought a significant contribution in improving ASPs.

Evaluation of more than one billion outpatient prescriptions and eight-year trend showing a remarkable reduction in antibiotic prescription in Turkey: A success model of governmental interventions at national level.

PURPOSE: To present the antibiotic prescription trend between 2011-2018 at primary healthcare in Turkey in order to evaluate the effects of interventions at national level for providing rational prescription of antibiotics. METHODS: Electronic prescription data of the family physicians collected from January 1, 2011 to December 31, 2018 in 81 provinces of Turkey were recorded through the Prescription Information System and screened for the antimicrobial drugs. The interventions to promote rational antibiotic use during 2011-2018 in Turkey includes reminding the legislation to stop access of antibiotics without prescription, monitoring of antibiotic prescription behaviors of primary healthcare physicians, and education of healthcare workers and the public on the appropriate use of antibiotics. RESULTS: A total of 1 054 261 396 prescriptions for outpatients of all age groups were recorded during this period. Of the prescriptions written by family physcians, 34.94% were containing at least one antibiotic in 2011, which declined to 24.55% in 2018. Antibiotics constituted 13.99% of all the items in prescriptions in 2011 and 10.47% in 2018. Percentage of total antibiotic expenditure to the total drug expanditure decreased from 14.14% to 4.12% during 2011-2018. The most commonly prescribed antibiotics were amoxicillin and enzyme inhibitor combination, cefdinir, and cefuroxime during 2011-2018, with an increasing trend for prescription of first-line antibiotic, amoxicillin, in recent years. CONCLUSIONS: Governmental interventions at national level have contributed to reducing antibiotic prescription and increasing preference of first-line antibiotics at primary healthcare level in Turkey over a course of 8 years. Turkey's model of governmental interventions may set an example for other countries with high consumption of antibiotics, and contribute to the actions against antimicrobial resistance worldwide.

Relative risk of tuberculosis in patients with rheumatic diseases managed with anti-tumour necrosis factor-alpha therapy: A nationwide cohort study.

WHAT IS KNOWN AND OBJECTIVE: Anti-tumour necrosis factor-alpha (anti-TNF-α) therapy is known to raise the risk of granulomatous infections, leading to development of risk management strategies at national or global level. This study aimed to determine the relative risk (RR) of tuberculosis (TB) due to anti-TNF-α usage in patients with rheumatologic diseases (RDs) in a nationwide basis. METHOD: This retrospective cohort study included patients with rheumatoid arthritis (RA), ankylosing spondylitis, juvenile idiopathic arthritis or psoriatic arthritis (PsA) that treated with or without anti-TNF-α agents, as registered in the national prescription information system between years 2013 and 2015. Two-year RR of TB after anti-TNF-α therapy initiation was calculated in this RD population, including main subgroups. RESULTS AND DISCUSSION: The study cohort included 413 500 RD patients, where anti-TNF-α(+) arm (n = 2117) had mean age of 41.9 ± 13.4 years and male distribution of 54.3%. Four patients among anti-TNF-α users developed TB compared to 128 patients in anti-TNF-α-naïve group (189 vs 31 cases per 100 000 patients, respectively), yielding a 2-year RR of 6.07 (95% CI, 2.25-16.42) with an attributable risk of 0.16%. These RRs (95% CI), which were particularly pronounced, were 5.39 (1.69-7.17) in men, 6.12 (2.26-16.55) in adults, and 5.70 (1.41-23.08) in RA and 13.46 (1.58-114.40) in PsA patients. There was no difference between the anti-TNF-α users who developed and undeveloped TB regarding drug utilization characteristics, except significantly less immunosuppressive drug exposure in TB patients. WHAT IS NEW AND CONCLUSION: This study is the first prescription-based nationwide study to suggest an elevated RR of TB in a comparably younger population with a broad spectrum of RDs managed with any approved anti-TNF-α drug in Turkey.

Evaluation of the Performance of the Turkish Regulatory Agency: Recommendations for Improved Patients' Access to Medicines.

BACKGROUND: This study was to evaluate the Turkish regulatory review process and timelines between 2016 and 2018 with a view to assess the changes that had taken place since the previous study, which evaluated the Turkish review processes and timelines 2013 to 2015. METHODS: Data related to the Turkish Medicines and Medical Devices Agency (TITCK) organizational structure and general information were collected from publicly available sources. A standard questionnaire was then used to collect data with the aim of identifying the TITCK's review practices and key milestones for the marketing authorization process. Subsequently, a comparison with the previous study was conducted to identify the key changes and developments that had taken place from 2015- 2018. RESULTS: The TITCK has made considerable efforts to improve its regulatory capacity since 2016, which has contributed to the overall decrease in the agency review times. The overall median approval time for new active substances; however, increased from 529 calendar days (2016) to 663 calendar days (2018), with the review time in the agency decreasing from 408 calendar days to 326 calendar days, while the company time increased from 137 to 268 calendar days, respectively, over this period. CONCLUSIONS: For the TITCK to become an international reference agency, they will need to fully implement good review practices and a structured framework for benefit-risk assessment and decision making; consider implementing verification and abridged reviews based on a reliance model and expedite the PIC/S mutual recognition process as well as become a full member of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

The Turkish Medicines and Medical Devices Agency: Comparison of Its Registration Process with Australia, Canada, Saudi Arabia, and Singapore.

Introduction: Regulatory agency comparisons can be of more value and facilitate improvements if conducted among countries with common challenges and similar health agency characteristics. A study was conducted to compare the registration review model used by the Turkish Medicines and Medical Devices Agency (Türkiye Ilaç ve Tibbi Cihaz Kurumu; TITCK) with those of four similar-sized regulatory agencies to identify areas of strength and those requiring further improvement within the TITCK in relation to the review process as well as to assess the level of adherence to good review practices (GRevP) in order to facilitate the TITCK progress toward agency goals. Methods: A questionnaire was completed and validated by the TITCK to collect data related to agency organizational structure, regulatory review process and decision-making practices. Similar questionnaires were completed and validated by Australia's Therapeutic Goods Administration (TGA), Health Canada, Singapore's Health Science Authority (HSA), and the Saudi Arabia Food and Drug Administration (SFDA). Results: The TITCK performs a full review for all new active substance (NAS) applications. Submission of a Certificate of Pharmaceutical product (CPP) with an application is not required; however, evidence of approval in another country is required for final authorization by the TITCK. Pricing data are not required by the TITCK at the time of submission; however, pricing must be completed to enable products to be commercially available. Mean approval times at the TITCK exceeded the agency's overall target time suggesting room for improved performance, consistency, and process predictability. Measures of GRevP are in place, but the implementation by the TITCK is not currently formalized. Discussion: Comparisons made through this study enabled recommendations to the TITCK that include streamlining the good manufacturing practice (GMP) process by sharing GMP inspection outcomes and certificates issued by other authorities, thus avoiding the delays by the current process; removing the requirement for prior approval or CPP; introducing shared or joint reviews with other similar regulatory authorities; formally implementing and monitoring GRevP; defining target timing for each review milestone; redefining the pricing process; and improving transparency by developing publicly available summaries for the basis of approval.

A nationwide evaluation of off-label drug utilization in Turkey

Background/aim: Off-label drug use (OLDU) is under the control of the Turkish Medicines and Medical Devices Agency (TMMDA) in Turkey. It was aimed to investigate demographic and medical features of patients with OLDU applications in Turkey. Materials and methods: A total of 4426 electronic OLDU application records of the TMMDA were evaluated retrospectively. Information regarding patients? demographic characteristics, diagnoses, requested drugs, institutions, and specialties of the physicians were evaluated. Results: OLDU applications were mostly made by rheumatologists (21.5%) and 95.2% of them were approved by the TMMDA. The mean age of the patients was 35 years and 54.4% of them were female. Off-label drugs were mostly prescribed for patients aged 18?64 years (62.1%) and were most frequently prescribed by physicians from university medical centers (81.0%). Systemic lupus erythematosus (10.1%) was the most common diagnosis. Mycophenolate (16.1%) and rituximab (10.1%) were the most frequently prescribed off-label drugs. There were differences regarding some characteristics of patients and their physicians among most frequently prescribed off-label drugs (P < 0.05). Conclusion: It is noteworthy that OLDU applications showed demographical and institutional differences. It is expected that this study will provide important contributions to physicians working in the relevant area with respect to treatment alternatives of diseases with treatment challenges.

Cost Evaluation of Inhaler Therapies Used in Respiratory Diseases: 1998--2015 Period in Turkey.

BACKGROUND: With the rise in life expectancy, the burden of chronic diseases, including obstructive pulmonary diseases, has increased throughout the world. OBJECTIVES: To evaluate the sales trends of inhaler pharmaceuticals. METHODS: The changes in box sales and sales amounts (in Turkish lira) of inhaler pharmaceuticals during the period 1998 to 2015 were examined and sales were projected for the next 3 years. Pharmaceuticals were classified according to form and pharmacological groups. RESULTS: The sales of inhaler pharmaceuticals have increased rapidly since 2008. The fastest increase in consumption has occurred in short-acting ß2 agonist preparations and nebulizer pharmaceuticals. Inhaled corticosteroid and long-acting ß2 agonist combination sales have been the highest since 2002, when these products entered the Turkish market. CONCLUSIONS: The inhaler pharmaceutical market has grown over the years, and this growth will continue in the future. The increased use of short-acting preparations, which should be used as symptom relievers, indicates that treatment management continues to be inadequate.

ADHD Medication Trends in Turkey: 2009-2013.

OBJECTIVE: To investigate the change of ADHD medication prescriptions in Turkey between 2009 and 2013. METHOD: Consumption data of ADHD medications, immediate release (IR) methylphenidate (MPH; Ritalin), OROS MPH (Concerta), and atomoxetine (Strattera) were obtained from IMS Health database for the November 2008 to October 2013 period. Defined daily dose (DDD) of each drug was calculated according to WHO definitions and time-series analysis was conducted. RESULTS: There was a significant seasonal effect for prescription of all drugs. Annual use of ADHD medications increased 2.18 times for all ADHD medications combined. DDDs per 1,000 population per day for all ADHD medications were 0.28 in 2009, 0.41 in 2010, 0.52 in 2011, and 0.59 in 2012. OROS MPH represented almost 75% of all ADHD medication utilization. CONCLUSION: As reported from several other countries, ADHD medication use increased in Turkey. Results suggested that over- and underdiagnosis might be seen at the same time.

Impact of Health Policy Changes on Trends in the Pharmaceutical Market in Turkey.

BACKGROUND: The implementation phase of the Turkish Health Transformation Program (HTP) began in 2003, with the aim of organizing, financing, and delivering health care services effectively, efficiently, and equally. The HTP impacted all clinical and economic outcomes of health, including pharmaceutical sales, by improving access to health services. OBJECTIVES: To understand the impact of five selected major policy changes that made an impact on supply, demand, or price in the pharmaceutical market between 1998 and 2012. METHODS: Monthly sales data (in units and value in US $) of a total of 180 pharmaceuticals covering the period between 1998 and 2012 were used for statistical analysis. Five major policies that could affect health expenditures and the demand and supply of pharmaceuticals were selected and led by the Ministry of Health. A P value of less than 0.05 was considered as the cutoff value for statistical significance. RESULTS: There was a growing trend in pharmaceuticals value and units in years, possibly as a result of the HTP implementation. Supply- and demand-related policies had a negative impact on the trends for value, whereas the pricing policy had a positive impact. CONCLUSIONS: It could be said that the HTP had an impact on units for improved access to health care services. Although this access increased the consumption of pharmaceuticals in units, the policies implemented were successful in controlling pharmaceutical expenditures.

Introduction and Utilization of High Priced HCV Medicines across Europe; Implications for the Future.

BACKGROUND: Infection with the Hepatitis C Virus (HCV) is a widespread transmittable disease with a diagnosed prevalence of 2.0%. Fortunately, it is now curable in most patients. Sales of medicines to treat HCV infection grew 2.7% per year between 2004 and 2011, enhanced by the launch of the protease inhibitors (PIs) boceprevir (BCV) and telaprevir (TVR) in addition to ribavirin and pegylated interferon (pegIFN). Costs will continue to rise with new treatments including sofosbuvir, which now include interferon free regimens. OBJECTIVE: Assess the uptake of BCV and TVR across Europe from a health authority perspective to offer future guidance on dealing with new high cost medicines. METHODS: Cross-sectional descriptive study of medicines to treat HCV (pegIFN, ribavirin, BCV and TVR) among European countries from 2008 to 2013. Utilization measured in defined daily doses (DDDs)/1000 patients/quarter (DIQs) and expenditure in Euros/DDD. Health authority activities to influence treatments categorized using the 4E methodology (Education, Engineering, Economics and Enforcement). RESULTS: Similar uptake of BCV and TVR among European countries and regions, ranging from 0.5 DIQ in Denmark, Netherlands and Slovenia to 1.5 DIQ in Tayside and Catalonia in 2013. However, different utilization of the new PIs vs. ribavirin indicates differences in dual vs. triple therapy, which is down to factors including physician preference and genotypes. Reimbursed prices for BCV and TVR were comparable across countries. CONCLUSION: There was reasonable consistency in the utilization of BCV and TVR among European countries in comparison with other high priced medicines. This may reflect the social demand to limit the transmission of HCV. However, the situation is changing with new curative medicines for HCV genotype 1 (GT1) with potentially an appreciable budget impact. These concerns have resulted in different prices across countries, with their impact on budgets and patient outcomes monitored in the future to provide additional guidance.

Assessment of the Turkish health care system reforms: a stakeholder analysis.

BACKGROUND: The Turkish health care system has been undergoing a significant transformation with the Health Transformation Program (HTP) since 2003. The HTP's overall objective is to improve governance, efficiency, user and provider satisfaction, and long-term fiscal sustainability of the health care system in Turkey. OBJECTIVES: To systematically evaluate the effects of the HTP Phase I reforms on various stakeholders, and to outline strategic options for the implementation of the second phase of health transformation in Turkey. METHODS: A total of 47 formal structured stakeholder interviews, representing 29 different institutions, are conducted between December 2008 and January 2009. Five main components of the HTP were examined: strengthening of the Ministry of Health (MoH) capacity for stewardship, universal health insurance, reorganizing health service delivery, human resources development, and national health information system. RESULTS AND CONCLUSIONS: There is a general agreement among stakeholders that the progress made thus far is the greatest in the national health information system and the slowest in strengthening the MoH capacity for stewardship. It appears that the HTP has the capacity to deliver cost-effective health care services and the implementation progress, so far, is in congruence with the overall economic development and growth in Turkey.