Access to and Affordability of World Health Organization Essential Medicines for Cancer in Sub-Saharan Africa: Examples from Kenya, Rwanda, and Uganda

Abstract Background Cancer mortality is high in sub-Saharan Africa (SSA), partly due to inadequate treatment access. We explored access to and affordability of cancer treatment regimens for the top 10 cancers utilizing examples from Kenya, Uganda, and Rwanda. Materials and Methods Population, healthcare financing, minimum wage, and cancer incidence and mortality data were obtained from the WHO, World Bank, public sources, and GLOBOCAN. National Essential Medicines List (NEML) alignment with 2019 WHO EML was assessed as a proportion. Cancer regimen pricing was calculated using public and proprietary sources and methods from prior studies. Affordability through universal healthcare coverage (UHC) was assessed as 1-year cost <3× gross national income per capita; and to patients out-of-pocket (OOP), as 30-day treatment course cost <1 day of minimum wage work. Results A total of 93.4% of the WHO EML cancer medicines were listed on the 2019 Kenya NEML, and 70.5% and 41.1% on Uganda (2016) and Rwanda (2015) NEMLs, respectively. Generic chemotherapies were available and affordable to governments through UHC to treat non-Hodgkin’s lymphoma, cervical, breast, prostate, colorectal, ovarian cancers, and select leukemias. Newer targeted agents were not affordable through government UHC purchasing, while some capecitabine-based regimens were not affordable in Uganda and Rwanda. All therapies were not affordable OOP. Conclusion All cancer treatment regimens were not affordable OOP and some were not covered by governments. Newer targeted drugs were not affordable to all 3 governments. UHC of cancer drugs and improving targeted therapy affordability to LMIC governments in SSA are key to improving treatment access and health outcomes.


Introduction
In 2020, an estimated 11 of 19 million new cancer cases (59.1%) and 7 of 10 million (71.0%) cancer deaths, occurred in low-and middle-income countries (LMICs). 1 Sub-Saharan Africa (SSA) has a disproportionate burden of cancer mortality with the annual number of cases projected to increase from 727 000 to 1.4 million from 2020 to 2040, while annual mortality will more than double from 484 000 to 967 000 during this same time period. 1 Reasons for the high case fatality rate in SSA are multifactorial and partly due to the patient and diagnostic delays leading to advanced cancer stage at diagnosis and suboptimal access to treatment. [2][3][4][5][6][7][8][9][10] The World Health Organization's (WHO) essential medicines list (EML) includes drugs deemed to be safe and effective in meeting the needs of a healthcare system. Many countries use the WHO EML to prioritize medicines for inclusion in national essential medicine lists (NEML), which is the first step to improving access to medications, including cancer drugs. However, the inclusion of a drug on the WHO EML does not guarantee its inclusion in NEMLs or availability at the point of care delivery. 11 While the WHO EML traditionally included generic chemotherapies and hormone therapies, the more updated EMLs include newer and more expensive cancer medicines supported by clinical trial data showing the superior efficacy of these drugs despite their high costs. [12][13][14] Even when a drug is included in the NEML, barriers to access include high out-of-pocket costs, drug stockouts, and inefficiencies in procurement and other chemotherapy supply chain challenges. 15 The 2019 WHO EML included 61 recommended antineoplastic and supportive agents to treat 28 disease cancer sites in adults (Table 1). 12,13 Many of the drugs that were recently added will continue to be on patent or will come off patent in the next couple of years. It is expected that the inclusion of higher-cost therapies in the WHO EML will result in strategies to negotiate the cost of these drugs. 16 Few studies have systematically explored affordability and access to these newer drugs in SSA in reference to health financing metrics for specific countries. [17][18][19] Our aim is to evaluate cancer medicine access in SSA as a function of both inclusion on the NEML and affordability by both governments and individual patients, who often pay for these medications out-of-pocket (OOP). We conducted these analyses using publicly available data from Kenya, Rwanda, and Uganda, focusing on the 10 most common cancers. We selected these 3 countries in East Africa because each had a different mechanism for financing cancer medicines. Medications on the NEML are covered in full by the government in Uganda, only for patients who purchase government health insurance in Kenya, and through a partnership with a non-profit organization with no cost-sharing by the government in Rwanda.

Population, Health Care, and Financing Metrics
Population and health care metrics including per capita gross national income (GNI), healthcare spending expenditure, and respective proportions of internal and external funding for healthcare were obtained from the World Bank database and World Health Organization databases. 20,21 Data on cancer incidence and mortality was obtained from GLOBOCAN 2020. 1

NEMLs Alignment with the WHO EML
The 2019 WHO EML was used as a reference for comparison of the most recent WHO registered lists of national essential medicines for Kenya, Rwanda, and Uganda. [22][23][24] Data were extracted from the NEMLs by 2 authors, with drugs limited to cytotoxic/antineoplastic agents, cancer supportive treatments, hormone and anti-hormone agents, targeted therapies, and immunotherapies. Extraction was limited to the drug name and used to provide a descriptive analysis of the proportion of WHO EML drugs listed on NEML for treatment of the 10 most common cancers in each country. If the NEML was published prior to 2019, a sensitivity analysis was done comparing alignment with the WHO EML published closest to the publication year of the NEML.

Affordability of Cancer Medicines
The annual cost of a treatment regimen per patient for the 10 most common cancers in each country was estimated using the 2019 WHO EML supplementary cancer treatment guidelines, 13 the median buyer price for a unit of medication, available through "Management Sciences for Health (MSH) International Drug Price Indicator Guide-2015," 25 and methodology and assumptions described in our prior study. 26 When the price of a drug was not available in the 2015 MSH, the lowest available price (US pricing) was used as listed on UptoDate . 27 Given large variations in cancer drug prices by world/income region, 28 we performed sensitivity analysis compared median price listed on the MSH to listed prices on UptoDate and used descriptive analysis to summarize differences in price and assumptions made in our estimates. For metastatic disease, the duration of treatment for a particular regimen was determined based on median progression-free survival (PFS) from the respective clinical trials.
Most countries in SSA do not have universal health coverage (UHC) for cancer medicines, 29 and patients in Kenya, [30][31][32][33] Uganda, 33,34 and Rwanda, 35,36 may have to pay for medications OOP in the private sector when they are not available in the public sector. Thus, we assessed both the affordability of cancer treatment if purchased through UHC funded by the respective governments and OOP costs to individual patients if privately purchased. Using the WHO threshold for program cost-effectiveness, drug regimens where the annual cost of treatment per patient was higher than 3× the GNI per capita, were considered unaffordable. Since we regard to access to cancer care as a human right, for annual treatment costs exceeding 3× GNI per capita, we estimated price reductions required to ensure affordability (ie. ratio ≤ 3). 37 Affordability of cancer medicines to patients paying OOP was assessed by using the WHO and Health Access Initiative (HAI) methodology, where a 30-day treatment course that cost more than the daily wage of the lowest unskilled government worker, was considered unaffordable. 38 Since information about the wage of the lowest unskilled government worker was not available, a conservative estimate of daily wage was estimated using publicly available annual minimum wages for the respective countries. 39

Affordability of Cancer Medicines
Cervical, breast, prostate, colorectal, ovarian cancer, non-Hodgkin's lymphoma, and leukemia were 7 of the top 10 cancers in all 3 countries that had recommended regimens on the WHO EML. (Fig. 1). There are no WHO EML indications for liver cancer, stomach cancer, and esophagus cancer. Mortality-to-incidence ratios (MIR) for these cancers were similar in all 3 countries. For comparison, MIRs for all these cancers except for liver, stomach, and esophagus cancer were lower in Europe compared to Kenya, Uganda, and Rwanda ( Fig. 1). Generic cytotoxic medications were available to treat 9 of the 13 most diagnosed cancers (7 in common between Kenya, Uganda, and Rwanda, and 6 others that varied across countries), and were all assessed as being affordable to governments if procured through a funded UHC program (Tables 3 and 4). All currently recommended treatments for prostate cancer, including leuprolide,  bicalutamide, and abiraterone were not affordable through government procurement mechanisms. In addition, treatment regimens that included bendamustine, trastuzumab, rituximab, imatinib, dasatinib, and EGFR tyrosine kinase inhibitors (TKIs), were not affordable through government purchasing in all 3 countries, while capecitabine-based regimens were not affordable through government purchasing in Uganda and Rwanda only (Tables 2 and 3). All WHO EML recommended medications used for the treatment of the top 10 cancers in Kenya and Uganda that were not listed as part of these NEMLs were also unaffordable to national governments without significant price reductions. The exception was nilotinib for CML, which was assessed as affordable through government procurement in both Uganda and Rwanda. Treatment regimens used for metastatic breast cancer, leukemia, and non-small cell lung cancer and that were not part of Rwanda's NEML were below the affordability threshold (Tables 2 and 3) None of the treatment regimens for all the 10 most common cancer diagnoses for which there was a WHO EML indication were affordable to patients if paying out of pocket. (Table 4)

Discussion
In this study, we used WHO tools for cost assessments and applied it to cancer care to evaluate cancer medicines access and affordability of WHO essential medicines for cancer treatment in SSA, drawing on data from Kenya, Rwanda, and Uganda and focusing on the 10 most common cancers in each country. Overall, NEML alignment varied across the different East African countries, even after consideration of the different years of NEML publication. Furthermore, cancer medicines were only affordable through government-financed procurement, such as through a UHC program, and no medicines were affordable through OOP individual purchases from patients. Newer targeted therapies were not affordable using current cost estimates and will require substantial reductions to make them affordable even through government purchasing.
Generic cytotoxic chemotherapies and hormone therapies included in the WHO EML were affordable to governments of the 3 countries, except for some capecitabine-based regimens in Uganda and Rwanda, which were not affordable for government purchasing. Newer targeted medicines and immunotherapies, except for nilotinib, were not affordable to the 3 country governments without significant price reductions of up to 99% for some drugs. Despite the high prices, all the newly added therapies are listed on the Kenya NEML except for dasatinib. Trastuzumab, rituximab, and imatinib are also part of the Rwanda NEML, while rituximab, leuprolide, bicalutamide, and capecitabine were listed on the Uganda *Incidence and mortality rate per 100,000 using age-standardized rate (World) ASR(W) from IARC GLOBOCAN  NEML. None of the cancer treatment regimens were affordable to patients paying OOP, however ESMO data, 42 suggests that most patients in SSA pay OOP for cancer medicines, which would thus force many patients in the 3 countries to forgo basic necessities or result in foregoing treatment, resulting in financial toxicity and potentially avoidable deaths. This study has several limitations. We used publicly available data, which may not represent the actual availability and pricing of medications in the respective countries. However, the MSH median price index considers multiple countries and sources of price data and has been used in prior studies. 18,26 In addition, when we compared prices available on UptoDate and prices listed in MSH, there was overlap in ranges of generic chemotherapies and less so targeted therapies, suggesting that our results for regimens that included abiraterone, trastuzumab, leuprolide, goserelin, dasatinib, gefitinib should be interpreted with caution. Ultimately, given that actual medication prices can vary widely, 19 including within countries, 19,43 with countries in Africa paying higher prices for anti-cancer drugs, 28 these studies will be strengthened by follow-up surveys of actual pricing and availability to inform cancer procurement policies for the specific countries. Furthermore, cancer outcomes depend on many factors, including multidisciplinary care coordination, 44 access to surgery, and radiation therapy. Other treatment modalities and inpatient admissions may account for the bulk of cancer treatment costs. 31 Therefore, we predict our analyses represent conservative estimates, and total cancer care costs will exceed those provided in this analysis. While we based our analysis on the 2019 WHO EML treatment indications focusing on the 10 most common cancers, we recognize that other guidelines could be used for the purpose, including the NCCN Harmonized Guidelines for Sub-Saharan Africa. 45 Our analysis does not include medicines on the 2021 WHO EML which was recently published, and includes newer patented medicines, 46 which are likely to not be affordable at current costs. Finally, mortality-to-incidence ratios for the most common cancers in all 3 countries were similar despite differences in cancer medicine access, and generally higher than mortality-to-incidence ratios for these cancers in Europe, likely reflecting differences in cancer early diagnosis and access to treatment. An analysis of the impact of cancer medication access on cancer outcomes is outside of the scope of our study.
Despite the above limitations, we believe that our results are robust and will be valuable to governments and other key stakeholders in SSA and other LMICs in selecting strategies to improve access and affordability of cancer medicines in their countries. This study is novel in providing a potential evaluation model for providing estimates of access and affordability of specific guideline-recommended cancer treatment regimens for the 10 most common cancers diagnosed in the specific countries. The analysis was applied to countries in Sub-Saharan Africa with different NEML cancer medicine financing mechanisms. This model can be extended readily to other countries in the region and to other low and middle-income countries (LMICs), as well as to cancers outside of the top 10 list.
It also provides further justification for including cancer treatment coverage as part of a UHC program, since our analysis supports that no cancer drugs or treatment regimens are affordable through OOP purchasing by individual patients. In fact, a recent study of 148 countries showed that one of the predictors of improved breast cancer survival was the increased coverage of essential health services for cancer care. 47 In all 3 countries, there are ongoing efforts to make cancer treatment more affordable, including through partnerships with philanthropic foundations and working to expand access to chemotherapy as is being done in Rwanda. 35 In Kenya, efforts are underway to negotiate drug prices with pharmaceutical companies and expand access to the National Health Insurance, which is purchased OOP and includes coverage for the equivalent of up to US $50 000 per lifetime for cancer treatment. 30   the retail cost for all the medications, except for capecitabine, irinotecan, and oxaliplatin, which were discounted 50-100%, and imatinib, which was free, suggesting that even generic drugs listed on the NEML may not be provided free of charge to patients by governments in the respective countries. However, a more recent study published in 2021 reported that all cancer medicines are free and available at the Uganda Cancer Institute. 34 These efforts are necessary but remain insufficient to alleviate the financial toxicity associated with a cancer diagnosis in SSA. Although inclusion in the NEML is the first step to increasing access, data suggests that it does not reflect the actual availability of the drugs at the point of care delivery. According to the 2017 ESMO survey, most medications from the 2015 WHO EML were "usually available" and only 6 "always available" in Kenya, with unreliable suppliers reported as the main barrier. 42 In Uganda, about half of the medications on the 2015 WHO EML were reported as usually available and about half as always available, including imatinib, while irinotecan was only available half of the time, with barriers including unreliable suppliers, government capitation for capecitabine, irinotecan, oxaliplatin, trastuzumab; no commercial motive for imatinib and manufacturing problems for vinorelbine and cyclophosphamide tablet. 42 A study done in Uganda in 2021 reported that 85.8% of all NEML medications were available as a result of a centralized national procurement system. 34 No data is available about the availability of cancer medications in Rwanda. Studies suggest that stockouts in all 3 countries pose a challenge and result in patients paying higher OOP prices in the private sector if the free drugs are out of stock in the public sector. 19   Our results highlight important gaps in the availability and affordability of cancer medicines that impair the ability of SSA countries to address the growing burden of cancer-associated morbidity and mortality. Several studies have used the WHO/HAI methodology to estimate the affordability of cancer medications to patients paying OOP in other LMICs. In India, pediatric lymphoma and leukemia were unaffordable OOP. 49 In South Africa, analysis of individual drug prices and not regimens showed that the originator brand (OB) prices were affordable OOP only for paclitaxel 300 mg and fluorouracil 500 mg, while the lowest price generic (LPG) was affordable only for paclitaxel 300 mg, doxorubicin 10 mg, and oxaliplatin 100 mg in the private sector. 18 A study in Kenya estimated that the entire cost of treatment for locally advanced breast and cervical cancer was unaffordable OOP and 6× higher in the private compared to the public sector. 19 Cancer medicine affordability cannot be achieved solely through inclusion on the WHO EML 28 or respective NEMLs. Potential regional, national, and international strategies to improve cancer medicine access include: (1) strengthening pricing policies across healthcare sectors, including price caps for cancer medicines and optimizing a healthcare system's ability to review and adjust medication prices; (2) implementation of differential pricing based on healthcare systems' purchasing power; (3) increasing transparency around cancer medicine prices 28,50 ; (4) pooling resources between MOH and other key partners, including non-governmental organizations, 51,52 the WHO, multilateral financing entities to subsidize healthcare budgets, and academic institutions 53 for joint cancer drug price negotiation and pooled procurement 16,54 ; (5) using voluntary and compulsory licensing and applying World Trade Organization Trade-Related Property Rights flexibilities to patented cancer medicines 54,55 ; (6) promoting health services research and program implementation to improve system efficiencies related to cancer drug procurement, 26 and rational use, including by partnering with philanthropic foundations 56 and academic institutions 34,35 ; and (7) removing incentives for prescribing cancer medicines of limited clinical value. 50,57,58 Healthcare policies that make cancer medicines more accessible can improve population-level cancer outcomes when they are tailored to the country context, including cancer epidemiology and healthcare system financing, resources, and priorities. 50 While significant work has been done to improve cancer medicine access in Kenya, Rwanda, and Uganda, our analysis points to additional specific steps forward that may be helpful in improving access and affordability of essential cancer medicines and ultimately clinical outcomes.

Conclusion
Our study shows that cancer treatment regimens based on WHO EML indications that include novel cancer drugs are not affordable to LMIC governments in Sub-Saharan Africa, and almost all cancer treatment regimens are not affordable to individuals paying OOP. Thus, a universal health insurance scheme is essential to ensuring access to cancer care and treatment in countries of sub-Saharan Africa. As cancer emerges as an increasing global epidemic, more research about effective programs and interventions for improving access and reducing costs to cancer medicines is urgently needed.

Funding
None declared.