1. Off-Label and Non-Licensed Endocrinology Medicine Use in Turkey: A Retrospective Analysis of Computer Records in the Turkish Ministry of Health Kockaya, Guvenc; Tanyeri, Pelin; Vural, İsmail Mert; Akbulat, Akif; Akar, Halil; Tokaç, Mahmut; Kerman, Saim guvenckockaya@yahoo.com General Directorate of Pharmaceuticals and Pharmacy, Turkey

2. Abstract Objectives: Off-label is defined by the Turkish Ministry of Health (MoHT) as the use of licensed pharmaceutical products in doses outside of or exceeding the scope of the registered indication, and the use of non-licensed, but imported medicinal products for the purpose of individual treatment. Methods: The use of off-label or non-licensed endocrinology medicines was evaluated to provide an understanding of Turkey’s perspective within this area of health care provision. A computer search was performed of IEGM’s database. A patient base using off-label endocrinology medicine applications from 19 June 2009 to 19 June 2010 were searched. The key word “endocrinology” was used in the search. Outcomes were evaluated in the light of indications for use.

3. Abstract Results: The computer search showed that 357 applications were submitted for off-label endocrinology medicine use. It was concluded that the highest application percentage was established by “osteoporosis” in all of the applications (43%, 155/357). The highest application was established by Ankara province (28%, 44/155). University hospitals had the highest off-label osteoporosis medicine use applications within the given timeline (65%, 102/155). Specialized physicians in the fields of endocrinology and metabolism (adult and paediatric) had the highest number of off-label osteoporosis applications (71%, 111/155). It was concluded that the highest application percentage was established by “teriparatide use in osteoporosis” (87%, 136/155) in all of the osteoporosis applications; 92 of 136 applications were approved. There was a significiant difference between the T score (L1-4) of rejected and approved applications for patients (3,07 ± 1,85 and 3,23 ± 1.63, respectively; p < 0.001).

4. Abstract Discussion and conclusion: Yet, there was not a significiant difference between ages of patients for whom applications were rejected or approved. In addition, it could be said that off-label use can lead to reimbursement restrictions in endocrinology, especially for teriparatide-like oncology medicines. In Turkey, physicians who want to prescribe an off-label or non- licensed pharmaceutical or a medicine that has a different use from reimbursement indications needs to apply through the off-label medicine use process. Funding sources: There was not any funding source or conflict of interest for the manuscript

5. Introduction & Objectives In Turkey, physicians can prescribe medications off- label or unlicensed under the control of the Ministry of Health, General Directorate of Pharmaceuticals and Pharmacy (IEGM) (http:// www.iegm.gov.tr). The IEGM evaluates off-label and unlicensed medication use for each patient by using application procedures. The physician who wants to prescribe an off-label or unlicensed pharmaceutical has to apply to the IEGM for patient base approval. If the IEGM approves the off-label or unlicensed prescription, it will be reimbursed by the Turkish Social Security Institution (SSI) (http://www.sgk.gov.tr).http://www.sgk.gov.tr Off-label is defined by the Turkish Ministry of Health (MoHT) as the use of licensed pharmaceutical products in doses outside of or exceeding the scope of the registered indication, and the use of non-licensed, but imported medicinal products for the purpose of individual treatment.

6. Methods The use of off-label or non-licensed endocrinology medicines was evaluated to provide an understanding of Turkey’s perspective within this area of health care provision. A computer search was performed of IEGM’s database. A patient base using off-label endocrinology medicine applications from 19 June 2009 to 19 June 2010 were searched. The key word “endocrinology” was used in the search. Outcomes were evaluated in the light of indications for use.

7. Results The computer search showed that 357 applications were submitted for off-label endocrinology medicine use. It was concluded that the highest application percentage was established by “osteoporosis” in all of the applications (43%, 155/357). The highest application was established by Ankara province (28%, 44/155). University hospitals had the highest off-label osteoporosis medicine use applications within the given timeline (65%, 102/155). Specialized physicians in the fields of endocrinology and metabolism (adult and paediatric) had the highest number of off-label osteoporosis applications (71%, 111/155). It was concluded that the highest application percentage was established by “teriparatide use in osteoporosis” (87%, 136/155) in all of the osteoporosis applications; 92 of 136 applications were approved. There was a significiant difference between the T score (L1-4) of rejected and approved applications for patients (3,07 ± 1,85 and 3,23 ± 1.63, respectively; p < 0.001).

8. Disease Aplication Number Osteoporosis155 Acromegaly40 Osteogenesis imperfecta21 Hiperparatiroidism (Primer&Sekonder)14 Hipoparatiroidism (Primer&Sekonder)13 Paget Disease9 Puberty Abnormalities8 Turner Sendrom8 Hypophysis adenoma (TSH releasing)7 Growth Hormone Deficiency6 Cushing Sendrom5 Others71 Total357 Table 1: Application Numbers of Off-label Medicine Use in Different Diseases Area

9. CityNumbers of Application Ankara44 Adana4 Afyon2 Afyonkarahisar2 Antalya1 Aydın3 Bursa17 Denizli4 Düzce1 Edirne1 Eskişehir1 Hatay3 Isparta1 İstanbul39 İzmir12 Kayseri4 Kocaeli2 Malatya3 Manisa4 Mersin4 Samsun3 Trabzon1 Table 2: Osteoporosis Applications from Cities

10. Conclusion Yet, there was not a significiant difference between ages of patients for whom applications were rejected or approved. In addition, it could be said that off-label use can lead to reimbursement restrictions in endocrinology, especially for teriparatide-like oncology medicines. In Turkey, physicians who want to prescribe an off- label or non-licensed pharmaceutical or a medicine that has a different use from reimbursement indications needs to apply through the off-label medicine use process.