Conducting Clinical Trials in Turkey

Conducting Clinical Trials in Turkey A Resource for Sponsors Prepared by: Ömer Sadun Okyaltırık Pharm-Olam Turkey Country & Clinical Operations Manager Yamin Mo Khan Pharm-Olam International, Executive Vice President, Clinical Development

Table of Contents Forward... 2 Country Overview... 3 Demographics...4-5 Incidence of Disease Leading Causes of Death... 6 Disease Profile... 7 Healthcare Agenda... 8 Health Infrastructure Types of Hospitals...9-12 Healthcare Professionals... 13 Regulatory Process... 15 Why Turkey? Opportunities and Challenges...20-21 Conclusion... 21 About the Authors... 21 Forward This paper is intended to serve as a resource for research-oriented pharmaceutical companies planning to sponsor international clinical research projects in Turkey. It presents a broad overview of the country s clinical research environment encompassing: population demographics; disease burden; access to medicine; and the country s healthcare agenda, infrastructure, legislation, and experience with clinical trials. R&D-oriented companies developing new medicines must, of course, generate reliable data through their trial process. Doing so requires access to a sufficiently large patient population and experienced investigators working in compliance with internationally accepted guidelines, local regulations, ethical principles, and common considerations. For this reason, we believe that clinical research professionals searching new regions for suitable research sites should consider Turkey; in our view, it is a favorable environment for conducting clinical research studies. 2 I Clinical Trials in Turkey: A Resource for Sponsors

Country Overview Turkey, officially known as the Republic of Turkey, covers a large area lying between Europe and Asia with a population of over 76 million. The capital of Turkey is Ankara, and Istanbul is its largest city with over 10 million people. Other major metropolitan areas each with over one million residents include Izmir, Bursa, and Adana. Healthcare services have emerged as one of the country s most important business areas in the 21st century, due to the aging population and worldwide changes in socioeconomic structures. Inevitably, the risk of chronic diseases increases with the extended average life expectancy. Thus, it is expected that innovative new treatments will gain increasing importance over time as they help to prevent disease and reduce treatment costs. 1 Turkey is located at the center of an emerging region where the number of industry-sponsored clinical trials is steadily increasing. Many multinational pharmaceutical companies which do not yet have offices in Turkey are looking for ways to conduct their clinical research projects in Turkey. They recognize the systematic and organized work Turkey has been doing to enhance TURKEY the country s healthcare sector. The first clinical research activities in the country date back to the 1990 s, and the first regulation in pharmaceutical research was published in 1993. Turkey can contribute significant patient data to future clinical trials as it offers: A large and eager patient population with high enrollment rates A growing middle class Competitive trial budgets A high number of investigators trained in Good Clinical Practices (GCPs) and having multinational/multi-center experience A modern and developed technical infrastructure Ethics Committees with standard principles Newly updated, comprehensive regulations 1 www.turkstat.gov.tr/start.do Clinical Trials in Turkey: A Resource for Sponsors I 3

Demographics The portion of the patient population requiring new medications in Turkey is increasing every day along with the population s longevity. The median age is 29.2 years, and the average life span, which has increased by 24% over the last 30 years, is now 74 years. Roughly three-quarters of the Turkish people live in urban centers, and nearly all are literate. 4 I Clinical Trials in Turkey: A Resource for Sponsors

Table 1: Turkish Demographics, 2013 Population 80,694,485 Age Structure 0-14 years 25.9 (10,682,900 male, 10,201,965 female) 15-24 years 17% (6,979,955 male, 6,703,689 female) 25-54 years 42.7% (17,375,544 male, 17,097,927 female) 55-64 years 7.9% (3,189,731 male, 3,169,450 female) 65 years and over 6.6% (2,422,983 male, 2,870,341 female) Median Age Total 29.2 years Male 28.8 years Female 29.2 years Population Growth Rate 1.16% Birth Rate 17.22 births (per.000 population) Death Rate 6.11 deaths (per.000 population) Urbanization Urban population 71.5% of total population Rate of urbanization 2.4% annual rate of change Major Cities - Population Istanbul 10.378 million Ankara 3.846 million Izmir 2.679 million Bursa 1.559 million Adana 1.339 million Sex Ratio At birth 1.05 male(s) / female 0-14 years 1.05 male(s) / female 15-24 years 1.04 male(s) / female 25-54 years 1.02 male(s) / female 55-64 years 1.01 male(s) / female 65 years and over 0.84 male(s) / female Total population 1.02 male(s) / female Life Expectancy at Birth Total population 73.03 years Male 71.09 years Female 75.07 years Ethnic Groups Turkish 70-75% Kurdish 18% Other Minorities 7-12% Literacy Definition Age 15 and over can read and write Total population 94.1% Male 97.9% Female 90.3% Source: Turkish Agency of Statistics (TurkStat), 2013. Clinical Trials in Turkey: A Resource for Sponsors I 5

Incidence of Disease Leading Causes of Death Diseases of the circulatory system are responsible for nearly 40 percent of deaths in Turkey. 2 Indeed, Turkish women have the highest mortality from coronary heart disease in Europe. 3 Causes of Death 2010 2011 2012 Diseases of the Circulatory System 39.6 38.8 37.9 Malignant Neoplasms 21.3 21.1 21.1 Disease of the Respiratory System 8.3 10.1 9.7 Endocrine, Nutritional, and Metabolic Diseases 6.4 6.3 6.0 External Causes in Injury and Poisoning 4.4 4.1 4.1 Other (Infectious and Parasitic Diseases, Mental and Behavioral Disorders, Diseases of the Musculoskeletal System and Connective Tissue, etc.) 16.3 15.9 16.9 TOTAL (Percentage) 100.0 100.0 100.0 6 I Clinical Trials in Turkey: A Resource for Sponsors

Disease Profile IMS Health also reports, Turkey s health disease burden and health indicators vary significantly from major urban centers, where they are approaching European standards, to outlying rural areas, particularly in Eastern Turkey, where tuberculosis (TB) and similar infections still occur. 4 According to a Report by the UCL School of Pharmacy 5 : The disease profile in Turkey is shifting away from infectious diseases toward non-communicable diseases, which account for 70 percent of all mortality in the country. 6 The incidence of Type 2 Diabetes has doubled in a little more than a decade, above the rate of increase in the U.S. More of the population is becoming obese (particularly less advantaged women) and about one quarter of adults in the country have clinically significant raised cholesterol levels. At least a third of the population have clinically significant hypertension, nearly half of whom are unaware of their condition. Nearly 150,000 new cancer patients are diagnosed each year in Turkey (with lung cancer being the most frequent tumor type), as indicated by the World Health Organization. 7 2 Causes of Death Statistics, 2010, 2011, and 2012, Turkish Statistical Institute, No: 15847, April 16, 2013. 3 Transforming Health in Turkey: 21st Century Opportunities, UCL School of Pharmacy, September, 2012. 4 IMS Health, Country Report: Turkey, Pharmaceutical Market Europe, May 2011. 5 Transforming Health in Turkey: 21st Century Opportunities, UCL School of Pharmacy, September, 2012. 6 Transforming Health in Turkey: 21st Century Opportunities, UCL School of Pharmacy, September, 2012. 7 World Health Organization International Agency for Research on Cancer, Globocan 2012: Estimated Cancer Incidence, Mortality, and Prevalence Worldwide in 2012. Clinical Trials in Turkey: A Resource for Sponsors I 7

Healthcare Agenda The Turkish Government aims to make Turkey one of the world s top ten economies in health services by 2023 by 1) increasing R&D expenditures to three percent of GDP and 2) by increasing exports to USD $500 billion. Moreover, according to a Strategy Report from the Turkish Ministry of Science, Industry, and Technology (AIFD), Turkey is slated to become the Eurasian production base for medium- and high-level technology products. Taking into account Turkey s current macroeconomic conditions, political stability, and increasing economic efficiency, AIFD considers these R&D targets to be realistic. 8 Turkey s Healthcare Transformation Program, which was implemented in 2004, marked a major development in public access to health services and treatments. Physician consultation per capita increased five times from 1.7% in 1994 to 7.7% in 2011. And, innovative treatments are playing a significant role in increasing life expectancy. Based on a study of conducted by Professor Lichtenberg of Columbia University and the National Bureau of Economic Research, innovative drugs accounted for 75% of the increase in life expectancy in the 30 countries surveyed, including Turkey. 9 8 www.aifd.org.tr/pdf/2023_rapor/2023_strat_en.pdf 9 www.aifd.org.tr/pdf/2023_rapor/2023_strat_en.pdf 8 I Clinical Trials in Turkey: A Resource for Sponsors

Health Infrastructure Types of Hospitals The number of hospitals in the country has climbed steadily since 2002. As of 2010, there are more than 1,400 hospitals in Turkey across three basic types of facilities, as seen in Figure 1: University Hospitals (62) Ministry of Health (843) Private and Foundation Hospitals (489) Figure 1: Number of Hospitals in Turkey Number of Institutions 1500 1000 500 0 1.7% BYBO 42 43 56 57 59 62 50 50 52 53 56 261 267 365 400 450 489 271 274 278 293 331 861 870 774 789 829 793 767 848 847 834 843 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 MOH Private University Health Expenditures Source: Report on Turkey s Health Sector, Deloitte, June 2012. Clinical Trials in Turkey: A Resource for Sponsors I 9

Together, these institutions have 2.5 beds per 1,000 population and maintain a total bed occupancy rate of around 64%. Most of the hospital admissions are to hospitals affiliated to the Ministry of Health (MOH) as seen in Figures 2 and 3. Figure 2: Number of Inpatients by Year and Sector Number of Inpatients by Year and Sectors (.000) Number of Patients Hospitalized (.000) Source: Health Statistics Yearbook 2012, Turkish Ministry of Health General Directorate for Health Services, p. 98. 10 I Clinical Trials in Turkey: A Resource for Sponsors

Figure 3: Distribution of Hospitalized Patients by Hospital Type Distribution of Hospitalized Patients Source: Health Statistics Yearbook 2012, Turkish Ministry of Health General Directorate for Health Services, p. 98 Clinical Trials in Turkey: A Resource for Sponsors I 11

Distribution of Hospitals The number of private hospitals is growing rapidly, and they hold much potential as future trial sites. The distribution of private hospitals is heavily weighted toward three leading cities: Istanbul, Ankara, and Izmir, which together have 48% of the country s private hospitals and 56% of the total available beds. See Figure 4. Figure 4: Distribution of Private Hospitals Across Metropolitan Areas in Turkey 2% Istanbul 38% 3% Izmir 5% 2% 2% Ankara 6% 3% 3% 2% 2% 2% Source: Turkish Yearbook of Statistics, 2010 (2008 data), Turkish Agency of Statistics As a matter of fact, providing medical care to social security patients is becoming more costly each day, and the costs are reflected to the patients at the end of the day. This brings additional burdens to the patients. Therefore participation in clinical trials is becoming more attractive in Turkey, as a mutual benefit both for the hospitals and for the patients, because as all trial related expenses can be reimbursed to the hospitals by the sponsors, while patients are being provided with full medical care at no cost at all. Likewise the sponsors have the chance this way to obtain adequate data for their clinical trials. This has also some positive impact on triggering clinical trials in private settings. The legislation allowing clinical research to be conducted in private hospitals is rather new 10, thus few have conducted studies to date, and most of the clinical research projects have been conducted so far in university hospitals and those affiliated with the MOH. 10 Turkish Official Gazette, 13 April 2013, issue no 28617 Amended on 25 June 2014, issue no: 29041. 12 I Clinical Trials in Turkey: A Resource for Sponsors

Healthcare Professionals Currently there are a total of 130,000 physicians in Turkey, according to research conducted by the Turkish Health Union. 11 Of these, 75,000 doctors are working in the MOH setting. And of those, 33,812 are specialists, 32,607 are general practitioners and 8,500 are assistants. Istanbul, Ankara, and Izmir are the leading cities in terms of the number of doctors: 30% of the total number of doctors is found in these three large cities. Figure 5: Distribution of Healthcare Professionals by Institution Type As seen in Figure 5, slightly less than two thirds (59%) of physicians in Turkey work in state hospitals affiliated with the Ministry of Health, while 20% work in the private settings. 12 Distribution of Healthcare Professionals According to the Institutions % 100 90 80 70 60 50 40 30 20 10 0 1.2%.7% 3.5% 3.7% 8.4% 19.5% 22.8% 15.0% 20.6% 7.5% 13.8% 60.6% 88.7% 90.4% 58.7% 5.7% 69.7% 67.5% 33.0% 7.0% 0.8% Physician Dentist Pharmacist Medical Officer Nurse Midwife Ministry of Health University Private Other 1.1% 11 http://www.sabah.com.tr/saglik/2014/03/13/turkiyede-bir-doktora-590-kisi-dusuyor 12 Annual of Health Statistics, 2010 Clinical Trials in Turkey: A Resource for Sponsors I 13

Clinical Trials The first regulations for conducting clinical trials in Turkey were introduced in 1993, and over the past 20 years, the country has come a long way in supporting clinical research. Today Turkey is a serious candidate to become a clinical research hub in the Eastern Europe - Middle East - North Africa triangle. Organizations such as the Foundation of Research-Based Pharmaceutical Companies (AIFD), the Foundation for Clinical Research, and the Foundation of Contract Research Organizations all work to enhance the clinical trial environment in Turkey. The AIFD s vision for Turkey is that it will become an R&D and manufacturing center on a global scale, a goal reflected in its slogan, 2023 Will Come as the Remedy. (See Figure 6). Figure 6: Projection of Pharmaceutical R&D in Turkey, through 2023 Pharmaceutical Research and Development in Turkey Vision 2023 Projection Million $ Amount of Investment 2000 1800 1600 1400 1200 1000 2,400 848 3,600 1,650 1,117 4000 3500 3000 2500 2000 800 700 1500 599 600 1000 400 180 136 197 240 300 200 500 7 47 49 82 0 0 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 Number of Clinical Trials Investment in Clinical Total Pharmaceutical R&D Number of Clinical Research (million $) Spendings (million $) Research Projects Source: Projection of the Association of Research-Based Pharmaceutical Companies 14 I Clinical Trials in Turkey: A Resource for Sponsors

Number of Trials As of September 2014, approximately one percent (1,616) of the world s 174,221 clinical research projects has been conducted in Turkey. 13 According to the World Economic Forum s Global Competition Index (2011-2012), while the Turkish pharmaceutical sector is ranked 16th in terms of market value, it is 36th in terms of the clinical research conducted and the volume of pharmaceutical exports. 14 As seen in Figure 7, the number of clinical trials in Turkey has been climbing steadily for the past several years. Between 2012 and 2013, the number increased 12%. Figure 7: Number of Clinical Trials in Turkey, 2006 Feb. 2013 1400 Number of Clinical Trials in Turkey 1200 1176 1000 800 798 600 400 372 200 0 Q1 06 Q3 06 Q3 07 Q3 08 Q3 09 Q3 10 Q3 11 Q3 12 Feb 13 Total Industry Other (University, EORTC etc.) NIH Source: AIFD data derived from clinicaltrials.gov 13 www.clinicaltrials.gov 14 www.aifd.org.tr/pdf/2023_rapor/2023_strat_en.pdf Clinical Trials in Turkey: A Resource for Sponsors I 15

Trial Types and Locations Sponsors are conducting clinical trials of all phases in Turkey, as shown in Figure 8, although most are in Phase III. Figure 8: Clinical Trials by Phase, 2014 Number of Clinical Phase Studies Source: Clinicaltrials.gov; as of August 20, 2014 16 I Clinical Trials in Turkey: A Resource for Sponsors

Figure 9 illustrates that the vast majority of trials in the country are interventional while nearly 20% are observational. Figure 9: Types of Clinical Trials in Turkey Source: Clinicaltrials.gov; as of August 20, 2014 Phase I clinical trials and bioavailability bioequivalence studies are conducted within the Ministry of Health hospitals and universities. These facilities must be approved by the regulatory authority, offer emergency treatment, and satisfy all applicable standards. These studies are conducted by teams with training and experience in good clinical practices and by pharmacologist physicians who have completed specialty education or a doctorate degree. Currently in Turkey, there are only two approved and certified Phase I centers; ARGEFAR - Ege University and Ege University Hospital of Pediatrics Department of Hematology. This number is likely to increase in the near future, as cities in Turkey are developing as centers of advanced technology. Clinical Trials in Turkey: A Resource for Sponsors I 17

Regulatory Process Recent measures to improve the applicable regulations have strengthened interest in conducting clinical research in Turkey. The country has taken major steps towards harmonizing its research legislation with that of the European Union, and Turkish regulations are now totally in line with EC Directives (EC 2001/20 and EC 2005/28). Regulations on clinical trials are reviewed periodically and amended as required to comply with the most stringent international standards and ethical principles. The MOH has created a clinical research unit which serves as the Country Authority to assess and grant approvals for clinical trials. Submissions must be made to both the MOH and a local Ethics Committee (EC). ECs have also been established in all localities, with 99 being approved at the time of writing. Members are required to have had education in Good Clinical Practices (GCPs). Applications can be submitted to any approved EC, and the decision of one Ethics Committee shall be sufficient for multi-center clinical trials. (See Figure 10.) Figure 10: Site Evaluations Site Selections Collection of Submission Documents Submissions Coordinating Site Ethics Committee MOH Ethics Committee Electronic Submission Physical Submission 60 days from Submission 90 days from Submission Import License Application (2-3 weeks) 18 I Clinical Trials in Turkey: A Resource for Sponsors

Sponsors must apply to the MOH for the license to import the Investigational Product(s). Importing IP requires a pro forma invoice for the shipment, an Import Customs Declaration, and relevant international shipping documents. Under normal circumstances, approval is granted in about 15 days. The entire process is expected to take between 45 to 60 days, as indicated in the regulation published by the Ministry of Health. However, from time to time this period is likely to extend to around 90 days depending on the workload of the Ethics Committees. Generally the best case is to be able to initiate a project within 75 days, including receipt of the import license. In the worst case, full approval might take 90 to 120 days, depending on the workload of the assessment committees. Trial Sites Clinical trials may only be conducted at suitable sites having the appropriate staff, equipment, laboratory capabilities, and emergency care to ensure the safety of research volunteers. These include: Centers for health practice and R&D established within universities Military training and research hospitals Ministry training and research hospitals Private hospitals Updated Legislation The current Turkish regulation on clinical research (originally published on 13 April 2013 in #28617) was updated 25 June 2014 in #29041, making it even easier to start and conduct clinical trials in the country, through the following changes: Both the MOH submission and the EC submission can now be completed in parallel, saving considerable time for sponsors and CROs. Submissions to the Ministry of Health can be made electronically another timesaver for sponsors. Applications can be sent to any EC, whether or not it is to be involved in the particular research project. Clinical trials can be performed in private settings Clinical trial documents must be archived for 5 years (instead of 14) The update also mandates that all clinical trials must be published in a public Internet database managed by the MOH. However, the Clinical Research Association in Turkey has also created a similar site, http://www.clinicaltrials-tr.org/, in cooperation with the clinicaltrials. gov database. Clinical Trials in Turkey: A Resource for Sponsors I 19

Why Turkey? Opportunities Turkey is one of the most convenient and productive countries in which to invest for clinical research and is aiming to become one of the foremost countries in the clinical research area. 15 The economy is one of the fastest growing in the world, and the volume of pharmaceuticals imported and exported has increased two fold in the last five years. Turkey represents a fertile market in the clinical research business, boasting: A developing clinical research profile supported by new regulations in clinical research that are in accordance with international standards and European Directives. A large and diverse patient population of almost 80 million, a large percentage of which are treatment naïve. Consequently, the people of Turkey are highly motivated to participate in studies, and ready access to them makes for rapid enrollment. A high number of sites with the capacity to conduct clinical research 62 university hospitals, 489 private hospitals and 843 government hospitals 16 Highly motivated research teams trained in GCP and capable of producing high quality, reliable data Comparatively low costs, relative to EU countries and the U.S. Challenges Although most of the physicians in Turkey work in hospitals affiliated with the MOH, conducting clinical research in such settings requires approval from the Association of Public Hospitals. Because the Association is also involved in Clinical Trial Agreements, this may sometimes delay study start up. Fortunately, the Turkish Ministry of Health is working to create common standards in such hospitals, where current fees for physical examinations, tests, and procedures vary from one facility to another. Other restrictions that may impede site and patient enrollment include: No payments can be made to assistant personnel No advertising can be done to recruit patients for clinical trials No payments can be made to patients in return for their participation in clinical trials 15 http://www.klinikarastirmalar.org.tr/admin/spaw/uploads/files/recent-changes-in-clinical-trials-regulations-in-turkey-areshortening-the-start-up-period-of-clinical-trials.pdf 16 TurkStat, Turkish Agency of Statistics Hospital Number Report, June 2012 20 I Clinical Trials in Turkey: A Resource for Sponsors

Another possible limiting factor is that investigators cannot be paid directly for their trial involvement; payments must be made to the circulating capital department of the relevant institutions. Ultimately, investigators only receive an average of 60 percent of the investigator fees that sponsors pay. There are still a number of inexperienced Ethics Committees in Turkey, so sponsors must take care to select ones that are properly prepared. This is easier now that applications can be sent to any Ethics Committee (rather than only the ones involved in particular project). Conclusion When considering clinical trial locations, sponsors seek countries with a well-established structure, a solid understanding of and adherence to global clinical trial management practices, and sufficient numbers of the targeted patients. They, of course, want to ensure that their research project delivers high-quality data in a timely manner. Turkey meets all of these basic requirements as well as offers an expedient regulatory process, a competitive cost structure, and a government committed to advances in public health and economic progress. The challenges to operating trials in Turkey are minor when weighed against the advantages and can easily be surmounted with the help of a partner familiar with the local practices and restrictions. Sponsor companies would do well to fully explore what Turkey has to offer their research programs. About the Authors Sadun Okyaltırık has developed knowledge and experience in the pharmaceuticals industry since beginning his career in 1994. He has focused on clinical research since 2001. Having started at Roche Turkey as a sales representative, Okyaltırık has been assigned to several positions such as Product Manager, Clinical Research Associate (CRA), and Sr. CRA positions in companies such as Pfizer, Aventis / Sanofi-Aventis, PPD, and finally Pharm-Olam. Currently he is conducting the Country Manager & Clinical Operations Manager duties in Pharm-Olam Turkey. Yamin Mo Khan is the Executive Vice President of Global Clinical Development at Pharm-Olam International, based in the UK. He has a PhD in Biochemistry and started in the industry in 1996. Prior to Pharm-Olam, Mo worked at a global CRO and a small biotech company. He has been with the Pharm-Olam for the last 14 years, during which time the company has grown from a small niche provider to a mid-sized global full service CRO with over 500 personnel. At Pharm-Olam, Mo has worked in Clinical Operations, Project Management, and Business Development. His major responsibility has been to ensure global project delivery and to build the Project Management group. In addition, he works with both new and current clients to build long-term relationships and assist in Business Development activities. Clinical Trials in Turkey: A Resource for Sponsors I 21

About Pharm-Olam International Pharm-Olam International is a global contract research company with a presence in over 40 countries, offering a wide range of comprehensive clinical research services to the pharmaceutical, biotechnology, and medical device industries. For more information on planning successful trials within Turkey, contact info@pharm-olam.com. Pharm-Olam International 450 North Sam Houston Parkway E., Suite 250 Houston, TX 77060, USA T: 713.559.7900 F: 713.559.7901 Pharm-Olam International (UK) The Brackens, London Road Ascot, Berkshire, SL5 8BJ, UK T: +44 (0) 1344 891121 F: +44 (0) 1344 890335 www.pharm-olam.com