Institutional and Regional Variations in Access to Clinical Trials and Next-Generation Sequencing in Turkish Oncology Centers

Introduction

Cancer is an escalating global health issue and ranks as the second leading cause of death worldwide. According to GLOBOCAN 2022 data, lung, breast, and colorectal cancers are the 3 most prevalent types of cancer [1]. Between 1991 and 2021, there was a notable decline in cancer mortality rates. This reduction is more pronounced in high-income countries (HICs) than in low- and middle-income countries (LMICs) [2]. Nonetheless, the World Cancer Report indicates that future projections for LMICs are less favorable than current statistics, highlighting significant disparities in cancer care between nations. These inequalities in cancer care remain a critical issue [3].

Despite the increasing financial burden associated with cancer care, most HICs manage to accommodate these costs and continue to support research and development initiatives, such as through the official Cancer Moonshot program [4,5]. These research and development operations include mainly cancer clinical trials performed in HICs, with a growing number being performed in LMICs. These trials assessing new treatment strategies provide an opportunity for many patients to reach novel therapeutics and testing facilities for LMICs. The key barriers to conducting clinical trials in LMICs are limited funding and insufficient research capacity. Limited access to next-generation sequencing (NGS) is a significant barrier that restricts therapeutic options for oncology patients in LMICs. However, collaborative solutions between LMICs and HICs may provide innovative solutions tailored to the local needs of LMICs and may create a cost-effective strategy to expand treatment options. Finding an appropriate clinical trial – and gaining access to it – can be challenging for many patients and health care providers [6].

Turkey has a social health policy, and almost all diagnostic tests are reimbursed through government-provided general health insurance (GHI) in GHI-based public hospitals, including university hospitals, training and research hospitals, city hospitals, and state hospitals [1]. Nevertheless, health expenditures in private hospitals are not covered by GHI, or a limited proportion is covered occasionally. Moreover, tests such as genomic profiling in adjuvant therapy for breast cancer, large panel NGS, and several novel anti-neoplastic agents considered to be expensive in many other countries are not reimbursed by GHI [7–10]. As a result, clinical trials remain one of the best opportunities for patients with cancer to receive optimal treatment in certain circumstances. These opportunities may also extend to the control arms of clinical trials, depending on the underlying cancer type and the availability of accessible treatment options within the country. Additionally, the presence of regionally accessible and affordable NGS-capable centers can promote equity and facilitate the delivery of cancer care. The uniform distribution of clinical trials and NGS across a country, along with their allocation independent of hospitals’ GHI coverage, represents an important aspect of the principle of equity in healthcare. However, the availability of clinical trials and NGS in oncology hospitals in Turkey has not yet been comprehensively analyzed, and such an analysis could inform future development plans at both regional and national levels.

This study aimed to evaluate the distribution of clinical trials and NGS availability in Turkish oncology clinics and their impact on healthcare equity, with a particular focus on the coverage provided by GHI and the geographical location of these clinics. This investigation was conducted through a survey-based questionnaire administered to medical oncologists.

Material and Methods

SURVEY METHOD AND DATA COLLECTION:

This study was conducted in accordance with Good Clinical Practice guidelines, and ethics approval was obtained from the Antalya Training and Research Hospital Ethics Committee (Approval No: 10/36, dated July 11, 2024).

This study was conducted as a cross-sectional survey targeting medical oncologists practicing in Turkey between July 15 and August 22, 2024. After an initial item pool was drafted based on a targeted literature review, 2 independent medical oncology specialists, each with 5 or more years of experience, reviewed all items for relevance, clarity, and coverage of prespecified domains, including work setting and institutional resources, numbers of ongoing/active clinical trials, NGS availability, and pathways to access. Consequently, a questionnaire with 14 questions was developed. Based on expert feedback, the wording and ordering of the questions were refined (content/face validity). Prior to launch, the questionnaire underwent cognitive checks with 4 medical oncologists to confirm comprehensibility and response processes; minor edits were made accordingly. The survey, titled “Cancer Groundshot – Turkish Oncology Clinics Perspective”, ensured personal anonymity by not collecting any personally identifiable information. Following ethics approval from the local ethics committee, the survey link was sent to medical oncologists through email and messaging application groups previously created by the Turkish Society of Medical Oncology and other oncology associations. Above the survey link, an information text clarified the purpose of the survey and affirmed that participation was voluntary. It was also stated that the answers would be evaluated on a center basis rather than at an individual respondent level. Answering all questions was not mandatory to complete the survey. All participants were asked to specify their workplace and region, which ensured their privacy and anonymity while allowing the sorting of answers for each hospital.

MISSING DATA AND CENTER-LEVEL SELECTION PROTOCOL:

Prespecified rules were applied to handle missing data and address item non-responses. The survey questions that lacked essential identifying information – specifically, the center name and region – were excluded from the analyses. For the main study variables, such as the number of ongoing or active clinical trials per center and the availability of NGS testing, we included only records with complete data (complete-case analysis) and did not perform any data imputation. For secondary, descriptive variables, we used an available-case approach: analyses were based on all responses provided, and the proportion of missing data (no-response) was explicitly reported. To avoid duplicate center representations, we prespecified a center-level selection protocol: incomplete responses were excluded (region and center were mandatory); when 2 or more respondents represented the same hospital, we retained the individual with the highest academic rank; if tied, the one with longer oncology experience was selected. As a result, each oncology hospital was represented by 1 individual’s survey participation. A total of 162 medical oncologists completed the survey, which was distributed online. After a no-response elimination, answers from 150 survey participants were valid to be included in the analyses. These 150 participants were subjected to the center-level selection protocol (described above). As a result, 86 survey participants represented the 86 medical oncology centers (regardless of being an academical or non-academical center) in 38 cities (including the metropolitan areas) across Turkey in the final analyses.

STUDY ANALYSES DESIGNATION AND METROPOLITAN DEFINITIONS:

The represented medical oncology centers were divided into 2 groups based on their GHI coverage status as GHI-based public hospitals or private hospitals, and by their location as located in the 3 large metropolitan areas, Ankara, Istanbul, and Izmir, or in the rest of Turkey, which consists of 81 cities. The metropolitan status of Ankara, Istanbul, and Izmir is reflected in their large populations, concentration of higher-order economic and public functions, and their consistent designation as the country’s 3 benchmark cities in scholarly analyses of urban growth and governance [11]. Comparative analyses were performed to evaluate differences between GHI-affiliated public hospitals versus private hospitals, and between oncology centers situated in metropolitan versus non-metropolitan regions (other cities).

STATISTICAL ANALYSES:

IBM SPSS version 24.0 was used for data analyses. Descriptive statistics are presented as percentages and frequency distributions. Continuous variables are reported as median values (range). Comparative analysis of the independent categorical variables was performed using the chi-square or Fischer exact test. Continuous variables were compared between groups using the independent-samples t test or Mann-Whitney U test depending on normality tests. A P value <0.05 was considered statistically significant.

Results

SURVEY PARTICIPANTS: MEDICAL ONCOLOGISTS AND HOSPITALS:

To evaluate the distribution of clinical trials and NGS availability across the country, 162 medical oncologists were included in this survey, most of whom were medical oncology fellowship residents and academicians. The median duration of occupational experience in medical oncology was 5 years, with a range of 0.1 to 40 years (Table 1). Of the 162 participants, 150 (92.6%) were affiliated with 86 distinct oncology hospitals. However, 9 participants (5.6%) did not specify their region and workplace, 2 (1.2%) provided irrelevant responses regarding their workplace, and 1 (0.6%) was employed in a private office that was not an oncology center. These 86 hospitals were distributed across 38 cities. Sixty-three hospitals (73.3%) were GHI-based public hospitals (university hospitals, training and research hospitals, city hospitals, and state hospitals) and 23 (26.7%) were private hospitals. Thirty-three hospitals (38.4%) were located in the 3 largest metropolitan areas, whereas 53 (61.6%) were located in other cities.

There were 47 hospitals (54.7%) with 3 or fewer medical oncologists, while 21 hospitals (24.4%) had 4 to 10 medical oncologists on duty, and 11 hospitals (12.8%) had more than 10 medical oncologists. In most centers, the daily patient volume exceeded 100. None of the private hospitals were the sole oncology center in their region (Table 1).

COMPARISON OF GHI-BASED PUBLIC HOSPITALS AND PRIVATE HOSPITALS:

The question regarding the number of clinical trials conducted at their respective hospitals was addressed by 61 of 63 public hospitals (96.8%) and 22 of 23 private hospitals (95.7%). The median number of ongoing clinical trials at public and private hospitals was comparable: 1 (0–50) and 2 (0–50), respectively, P=0.961 (Figure 1A). The response rates to the question concerning the number of clinical trials actively recruiting patients were 60 of 63 (95.2%) for public hospitals and 21 of 23 (91.3%) for private hospitals. The median number of clinical trials actively recruiting patients was similar between public and private hospitals: 0 (0–42) and 0 (0–30), respectively (P=0.862) (Figure 1B). The ability to include patients in clinical trials via the facilities of other centers was similar (Table 2). NGS availability was comparable, although a small subset of public hospitals reported a complete lack of access (15.9% vs 0%) (Figure 2A, Table 2). These results showed that distrubition and accessibility of clinical trials and availability of NGS was not significantly influenced by GHI coverage of the hospitals.

COMPARISON OF HOSPITALS IN 3 LARGEST METROPOLITAN AREAS AND HOSPITALS IN OTHER CITIES:

The response rate to the question concerning the number of clinical trials was 100.0% for hospitals located in metropolitan areas and 50 of 53 (94.3%) for hospitals in other cities. The median number of ongoing clinical trials in hospitals located in metropolitan areas was significantly greater than the number in other cities: 2 (0–50) versus 0 (0–25), respectively (P=0.002) (Figure 3A). In relation to the survey question regarding the number of clinical trials actively recruiting patients, the response rate was 31 of 33 (93.9%) for metropolitan areas and 50 of 53 (94.3%) for hospitals in other cities. Hospitals in metropolitan areas had a significantly higher median number of clinical trials actively recruiting patients than did hospitals in other cities: 2 (0–42) and 0 (0–25), respectively (P=0.008) (Figure 3B). Hospitals in metropolitan areas reported significantly higher rates of patient inclusion in clinical trials at other centers, in addition to a higher number of clinical trials (Table 3). Most hospitals in the 3 metropolitan areas reported the availability of NGS at their centers, and none of the hospitals in these metropolitan areas reported an inability to access NGS. These figures were significantly lower for hospitals in other cities, where 11 hospitals (20.8%) had NGS available, and 10 centers (18.9%) reported a general inability to access NGS, even when necessary (P<0.001) (Figure 2B, Table 3).

Discussion

Our study, which investigated the distribution of clinical trials and NGS availability, revealed that the number of clinical trials and availability of NGS did not differ among oncology centers based on GHI coverage. However, hospitals located in the largest metropolitan areas had a significantly higher number of ongoing clinical trials and trials actively recruiting patients than did hospitals in other cities across Turkey. Furthermore, the availability of NGS was significantly greater in the 3 major metropolitan regions.

Access to cancer care and affordability are the major causes of inequities and disparities in oncology practice. The global expansion of clinical trials increases population representation, enhances diversity, and provides more patients with access to novel treatment options [12,13]. In some cases, even the control arms of clinical trials may provide patients with treatment options that are otherwise unaffordable or inaccessible in routine practice, depending on the setting and the country. Turkey ranks 18th globally in the number of clinical trials, with a total of 17 530 trials conducted between 1999 and 2024 [14]. Despite these statistics, we demonstrated that 17% of hospitals outside the largest metropolitan areas have issues reaching a clinical trial for their patients. However, we found that 75.8% of representatives from hospitals in the metropolitan areas reported that they could easily enroll their patients in clinical trials in other hospitals. Given the strong connections among oncologists, particularly via online communication platforms, the lack of clinical trial reach in non-metropolitan areas is not due to inadequate inter-hospital communication but rather to insufficient resources. In line with the Cancer Groundshot philosophy, these numbers may be improved by addressing local needs and considering the cumulative population-adjusted numbers [15].

Turkey’s healthcare system has undergone several important changes over the last 2 decades. The integration of the 3 different types of public insurance in the GHI led to improved equity. However, the lack of coverage of private hospital expenses by GHI is a socioeconomic concern [16]. No study has directly assessed the effects of hospital geographic location and insurance coverage on institutional resources, which limits a direct comparison with our study results. However, several investigations from different countries have indirectly examined hospital characteristics and health expenditures and explored the implications of these factors on patient prognosis. Similar concerns have been highlighted in many other countries regarding the equity and delivery of cancer care. In Australia, despite being an HIC, median overall survival was found to be significantly longer for patients with pancreatic cancer treated in private hospitals than for those in public hospitals [17]. In Brazil, both the 5-year and 10-year breast cancer survival rates were almost 10% higher in the private healthcare facilities than in the public facilities [18]. Moreover, a study on colorectal cancer treatment in South Africa showed that a greater proportion of patients in private hospitals were able to receive second- and third-line therapies compared with those in public hospitals, despite the high costs [19]. In contrast to these studies, our results did not directly reflect patient outcomes. However, we observed no significant difference between private and public healthcare facilities in terms of access to clinical trials and NGS, both of which may play a critical role in enabling patients to receive the best available treatment options. Obviously, there are many factors, such as preventive actions and radiological and surgical interventions, that influence the outcomes of cancer beyond access to the best systemic therapies. However, the data show that many steps in cancer care, from radiological assessments to surgical procedures, are affected by financial factors and the ability to pay [20].

The substantial impact of social determinants of health, such as residential and occupational locations, on health outcomes has been acknowledged by 93% of oncology and hematology specialists in the United States [21]. Local inequalities were observed at both the national and regional levels in the European Union, which has a policy of solidarity. However, Western European countries have demonstrably better cancer prevention and care facilities than Central and Eastern European countries, leading to lower cancer mortality rates. Moreover, cancer mortality rates vary by up to 37% between regions in the same country [22]. The prominent reasons behind the inequalities are counted as economic and educational differences between areas [23]. This may also be a reasonable explanation of regional differences that we found in our study.

NGS enables detailed genomic profiling of tumors, identifies genetic alterations that drive cancer progression, and facilitates personalized treatment plans. It has become an essential tool for many cancer types and is now recommended in updated clinical guidelines [24]. The availability of NGS has been the subject of many studies, since these tests may significantly influence both clinicans’ treatment choice and cancer outcomes [25–27]. In a global assessment, Turkey ranked among the top 5 Middle Eastern countries in terms of access to NGS [28]. Moreover, Bayle et al conducted a survey on 201 representatives from 48 countries to investigate the availability of biomolecular tests. Turkey has been reported to be one of the top countries in terms of NGS availability, reporting that small panel NGS was “usually available”, and large panel NGS/whole-exome sequencing was “occasionally available” [29]. However, we demonstrated that 18.9% of the hospitals located outside the largest metropolitan areas had serious problems in reaching NGS. It should be noted that Turkey was represented by only 1 field reporter in this study, while many other countries were represented by up to 10 field reporters. Moreover, this study was designed to reveal heterogeneity among European countries, unlike the single-country focus of our study.

The primary limitation of our study was the use of a non-validated survey instrument. Because the questionnaire is primarily formative and center-based, internal consistency metrics for the full instrument are not applicable; test–retest reliability could not be completed within the study window and is planned for future research. Additionally, the voluntary nature of survey participation may have contributed to self-reporting anxiety and potential selection bias. Implementing a more comprehensive survey design could potentially mitigate self-reporting anxiety, and increasing the number of participating centers could enhance the robustness of the data collected. A notable strength of our study is the inclusion of 86 oncology hospitals across 38 cities. Given that Turkey has 81 cities, our study includes a significant portion of Turkish oncology hospitals, thereby providing a representative analysis of the national landscape.

Conclusions

Our study revealed that GHI coverage is not a limiting factor for the distribution of clinical trials or the availability of NGS. However, larger cities possess more facilities for accessing NGS and clinical trials than do smaller cities. Ensuring equity in cancer care has gained increasing importance in recent years, which may positively influence future outcomes and help reduce disparities [30]. In light of our study findings, focusing on region-specific needs, such as expanding NGS access and strengthening inter-hospital collaboration in directing patients to clinical trials, may inform future healthcare developments. Considering that all equity efforts and development plans ultimately aim to improve patient outcomes rather than institutional capacity, future studies may investigate the survival outcomes of patients treated in different regions and types of hospitals. This approach would allow for more accurate identification of areas requiring urgent improvement.