Cost Proling of Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia Treatment in South Africa: Medicines That Are Still Too Expensive to Swallow

Background The development of tyrosine kinase inhibitors (TKIs) has improved chronic myeloid leukemia (CML) management and increased CML prevalence due to low mortality rates. CML management is potentially lifelong and expensive and requires pharmacoeconomic approaches and regular review of therapy to ensure that patients obtain cost-effective therapeutic outcomes. Although the introduction of TKIs generics has improved the availability of TKIs, the high-cost implications continue to hinder TKIs accessibility and translate into poor quality of life. To improve the availability and accessibility of TKIs in South Africa, interventional programs have been instrumental. A notable intervention is the collaborative effort of Novartis pharmaceuticals and The Max Foundation which has provided free access to Imatinib to patients in need. In recognition of the needs of CML patients, this study aimed to provide an overview of TKIs regulatory approval, availability, and cost prole in the South African (SA) context for the 2019 period.


Introduction
Tyrosine kinase inhibitors (TKIs) have radically improved the treatment of chronic myeloid leukemia (CML), a rare myeloproliferative disease de ned by the excessive production of myeloid cells, both mature and immature, in the bone marrow, blood, and spleen [1]. CML has three phases, namely the chronic phase (CP), accelerated phase (AP), and the blast phase (BP). In greater than 90% of CML cases, diagnosis is made during the CP; if untreated CML will progress into the initial AP and thereafter to the more aggressive BP [1]. Widespread and successful use of TKIs has resulted in an increased number of CML patients surviving with a near-normal life expectancy, subsequently increasing the prevalence of this disease [2]. The ultimate goal of CML treatment is normal survival and good quality of life without lifelong treatment. In resource-poor developing countries, the unavailability of effective drugs and limited essential monitoring systems result in the goal of treatment remaining as survival [3].
The treatment of CML with TKIs therapy attracts high costs coupled with recommended lifelong therapy [4], which translates to a signi cant burden on health care systems. In South Africa (SA) there are three active pharmaceutical ingredients of cellular TKIs registered by the South African Health Products Regulatory Authority (SAHPRA); namely Imatinib, Dasatinib, and Nilotinib [5]. All three TKIs are available in the private health sector whereas only two TKIs (Imatinib and Nilotinib) are available on tender in the public health sector [6]. Access to TKIs signi cantly impacts the management of CML. Therefore, only two TKIs for CML treatment are readily available in the SA public sector.
The SA access to TKIs has increased through patient assistance programs and clinical trials. Patient assistance programs such as the Glivec International Patient Assistance Program (GIPAP), which was set up as a partnership between Novartis and The Max Foundation in 2002, have supplied Imatinib at no cost to poorer patients [7,8]. The two organizations collaborated to ensure that patients with CML or Gastrointestinal Stromal Tumor (GIST) received treatment. The GIPAP was a direct-to-patient access program introduced after Novartis recognized the impact that Glivec had on CML and GIST.
Novartis assumed responsibility of managing the supply chain for the medicine and interacted with local stakeholders such as physicians, pharmacists, treatment centers, non-governmental organizations (NGOs), private companies, and governments (in countries where it operated) whilst The Max Foundation provided psychosocial support and education.
In 2017, it was reported that since the inception of GIPAP, the program had served the CML treatment needs of approximately 75,000 patients [8]. Over time, Novartis and The Max Foundation recognized a more exible approach to treatment access was needed, which led to a new collaboration in 2017 called the CMLPath to Care™ that replaced GIPAP. Under the new collaboration, The Max Foundation was responsible for supply chain management and treatment delivery to patients, whilst Novartis provides funding and medicine donation support. CMLPath to Care™ aims to support continued access to treatment at no cost for the nearly 34 000 previously registered patients in GIPAP with CML, GIST, and other rare cancers that responded to Imatinib. The program has been reported to run in 68 countries in the following regions: East Asia, Paci c, Europe, Central Asia, Latin America, Caribbean, Middle East, North Africa, South Asia, and Sub-Saharan Africa [9].
Due to TKIs use and the subsequent improved global CML survival rates, there has been an increase in the prevalence of CML [2]. The 2040 prevalence of CML has been estimated to be 250 000 patients in the United States of America (USA) due to the success of Imatinib increasing survival [10]. As TKI treatment attracts a high cost and against a backdrop of recommended lifelong therapy [4], this can translate to a signi cant burden on healthcare systems. A systematic review that focused on the economic burden associated with CML treatment in the United States noted that CML poses a signi cant economic burden in uenced by prescriptions, inpatient and outpatient costs, adherence and costs related to adverse events, switching between medications, and treatment failure [11]. As per the European LeukemiaNet (ELN), the ultimate goal of CML treatment is normal survival and good quality of life without lifelong treatment. However, in resourcepoor countries, which are affected by the unavailability of effective drugs and limited essential monitoring, the goal of treatment remains as survival [12].

Aim and objectives
The aim was to compare the cost pro les of TKIs registered in SA for the treatment of CML.
To achieve this, the following speci c objectives were outlined: To track the regulatory approvals of TKIs in SA (up to 2019).
To compare the 2019 cost pro les of TKIs available in the private and public sectors of SA.

Study design
The study was descriptive, quantitative, and retrospective in nature. The study employed a secondary research design in that existing data available from public domain documents were collected, analysed, and interpreted.

Public domain website
The South African Health Products Regulatory Authority (SAHPRA) website was searched on 20 August 2019 to track the regulatory approval of TKIs used in CML (CP) treatment in SA, by searching the active pharmaceutical ingredient terms "Imatinib", "Nilotinib" and "Dasatinib" under the registered health products portal.

Public domain documents
The 2019 Medicines Price Registry [13] and Department of Health (DOH) awarded tenders for oncology medication for the 2019 period [6] were reviewed to extract pricing data of TKIs in the private and public sectors respectively.

Data Analysis
Medicines' registration and pricing data of TKIs available in the South African private and public health care sectors were collected and entered into Microsoft Excel→ (version 2016), periodically sorted and analysed after complete entry.

Ethical Considerations
Ethical approval for the study was obtained from the University of KwaZulu-Natal's Biomedical Research Ethics Committee (BREC/00000486/2019) under the expedited approval process as the nature of the study involved data available in the public domain.

Registered TKIs in South Africa
There were three (3) TKI active pharmaceutical ingredients (APIs) registered in South Africa: Imatinib, Nilotinib, and Dasatinib. These APIs are formulated in different strengths and dosage forms, and the South African market had 21 duly registered TKI formulations (Table 1). Imatinib had been presented in 50 mg, 100 mg, and 400 mg; Nilotinib in 150 mg and 200 mg; and Dasatinib in 20 mg, 50 mg, 70 mg, and 100 mg strengths of capsules and tablets.

Discussion
It is well known that the health care framework in South Africa is divided into the private and public sectors, each with varying medicine funding sources and pricing systems [14]. The most prominent observation from the study was that all private sector Single Exit Prices (SEP) were consistently higher than public sector tender contract prices.
The recommended rst-line treatment for CML-CP is Imatinib 400 mg/daily, which costs between ZAR 12 593.64 -ZAR 44 563.16 per month in the private sector, compared to ZAR 454.25 per month in the public sector. The private health care sector is funded largely by private medical insurance and out-of-pocket funding. The private sector does not utilize a tendering system and therefore usually does not realize the bene t of lower procurement costs as seen in the public sector [15]. Louw et al. (2011) noted a concerning trend where patients in the private sector were refused TKI therapy due to cost implications. Unfortunately, this resulted in poor patient outcomes because these patients did not qualify for the patient assistance programs provided in the public sector [2]. It is therefore important that stakeholders engage in valuable discussions to address and lower these cost and access inequalities.
Imatinib-resistant or intolerant patients are generally treated with 400 mg of nilotinib twice daily. In 2019 nilotinib 200 mg was only available as the originator product in SA, costing ZAR 257.35/unit (or ZAR 28 823.04/month) for private-sector patients, whereas the same medicine translated to a 92.4% decrease in price at ZAR 19.43/unit (or ZAR 2176.28/month) for public sector patients. The public sector is funded by the South African government and utilizes a pharmaceutical tendering system where medicines are purchased in bulk and at xed prices over speci c periods of the contract. This in turn provides the public sector with the advantage of pricing competition and achieving economies of scale for a larger number of patients [15]. Unfortunately for private-sector patients, access to treatment will still be hindered by affordability and generic availability. It is noted that four nilotinib patents were granted in . The study ndings also noted that no quotes were received for all strengths of Dasatinib in the public sector, and a retender was applicable. It is therefore important that stakeholders (pharmaceutical companies, patient advocating organizations, the National Department of Health, clinical treaters, policymakers, and public and private health care sectors) engage in conversations on how to achieve equitable treatment accessibility.
Access to TKIs has had a signi cant impact on the management of CML in SA [7]. In SA, additional avenues to improve access to TKIs include access through clinical trials and patient assistance programs. A successful patient assistance program called Glivec International Patient Assistance Program (GIPAP) was set up as a partnership between Novartis and The Max Foundation in 2002, which supplied imatinib at no cost to poorer patients [7,8]. Smaller patient assistance programs were also established in South Africa to facilitate access to Nilotinib and Dasatinib for patients intolerant or resistant to Imatinib. However, challenges remain and include patient illiteracy, language barriers, co-infection with HIV, and far travel distances from treatment centres [7].
Although TKI prices appear more favourable to the public health sector, overall TKIs remain unaffordable in the SA public healthcare setting as it is accessed by approximately 80% of the population. Additionally, the public sector is burdened by a high prevalence of communicable, non-communicable diseases and HIV, which inherently limits resources available to procure and access expensive oncology medicines [7]. As with the advancement of medicine, the aim of developing TKIs was to alleviate pain and suffering by slowing disease progression, further the introduction of TKI generics should provide affordable treatment options. However high TKI costs in the 21st century still result in a signi cant economic burden in uenced by prescription, inpatient and outpatient costs, adherence and costs related to adverse events, switching, poor compliance, treatment failure, which has been noted in both developing and developed countries [11].
CML and TKI usage data in SA is scant and therefore the direct economic burden on the private versus public health care system could not be established. The study focused on TKIs used for CML treatment in the CP and not the AP and BP stages. Data regarding the available TKIs through a donation program was not detailed in the results. Basic cost comparisons were done between TKIs; however, the cost of monitoring and patient management has not been established in the study and requires further investigation for a full economic evaluation.

Conclusion
In general, and across all TKIs available in SA, treatment for CML-CP patients in the private sector is largely more expensive than treatment in the public sector. Imatinib generics are available, which results in more competitive pricing and affordable treatment options for patients. However, there were no generics available for Nilotinib and Dasatinib in SA at the time of the study. It is well known that patent monopolies create barriers to generic entry globally; however in the context of targeted oncology therapy, the high cost of oncology treatment including monitoring, and management, further strains the health care systems. Previously CML experts expressed that high CML treatment costs are unsustainable, may compromise treatment access to highly effective therapy, and is harmful to the sustainability of national health care systems [17]. This study highlights that urgent discussions between stakeholders on improving approval regulation, pricing regulation, use of risk-sharing health care models, and policy changes are required between stakeholders in both the private and public health care sectors so that patients can access the highly effective TKI therapy that is currently available.