Discussion
In this cross-sectional study, we evaluated the scope of essential medicines for childhood cancers listed in use in facilities within 50 countries encompassing different WHO world regions and income groups, as well as the availability of these medicines for clinical use at the point of care. Consistent with prior studies, our analyses showed significant variability in medicine availability and higher rates of suboptimal access in LMICs compared with HICs22 24 as well as variability in prices within countries and between countries of similar economic status.17 36–38
Furthermore, in a detailed assessment of medicine prices and corresponding prices of treatment regimens for common paediatric cancers, our comparative price analysis highlights the significant variability in the cost of treatment across and within different income groups, even for generic formulations. Generic medicines were not always cheaper than the innovator product, perhaps reflecting manufacturer discounts and rebates for brand-name products, loss-leader pricing and bundled purchasing of some products, or small numbers of generic manufacturers and little competition.39 40 Official list prices do not take account of confidential discounts and rebates.23 Difficulties with acquisition of data on prices also highlight challenges with addressing problems with prices if there is lack of transparency and no reliable data to describe the extent of the problem.36 41 At the World Health Assembly in May 2019, Member States adopted a resolution (WHA72.8) to improve the transparency of markets for medicines, vaccines, and other health products.42
In our initial assessment of drugs listed in use, SIOP core medicines were the most likely group to be listed in use in facilities across all income groups. However, the proportion of facilities listing these medicines in use was significantly higher in high-income and middle-income settings. Although these medicines were listed in use, UMCs were more likely, along with LMCs and LICs to list these medicines as being unavailable and out of stock with suppliers. This may reflect more efficient supply lines and larger buffer stocks held in HIC institutions. By performing these two analyses we capture not only the listing of a drug in use but provide data on the ability of a patient at the point of care to receive these drugs from the specific facilities.
There are several possible reasons for lower levels of reported availability of key medicines in LMCs than LICs. LICs may use a narrower range of clinical protocols or manage lower stages of disease and therefore rely on a smaller number of agents. This is consistent with the observations that LICs use fewer SIOP ancillary and WHO EMLc medicines than LMCs. More LICs may also be part of twinning arrangements with cancer care centres in HICs that facilitate access to medicines. Some LICs reported donor programmes supplying medicines at reduced cost to LIC facilities. These external supply mechanisms may overcome some of the challenges of national centralised procurement processes and limited government budgets for purchase of cytotoxic medicines.
Stockout was most prevalent in UMCs, LMCs and LICs, especially for SIOP ancillary medicines for which a median of 40% of facilities reported stockout in LMC facilities. Of note, however, 31% of HIC2 facilities reported stockout of asparaginase, one of the key medicines in treating paediatric ALL, which is the most common childhood cancer with a survival rate of 90% for patients who complete specified treatment regimens in HICs.43 These analyses highlight global issues with paediatric cancer drug stockout most prevalent in UMCs, LMCs and LICs, but specific key drug shortages in HICs could pose significant challenges and result in inferior survival outcomes for childhood cancer patients.4
The mechanisms for drug shortages and stockouts may be different across income groups and it is likely that both international and local disruptions contribute to vulnerabilities in the supply chain.15 25 Our results show that, for drugs which are out of stock at the time of the survey in UMCs, LMCs and LICs, suppliers being out of stock, sometimes for more than 3 months, contribute to extended stock out periods of specific drugs. HICs are also affected, with shortages of vincristine, methotrexate and Erwinia asparaginase threatening delivery of care for children with ALL.44–46 In some cases these shortages are attributed to decrease in production because of low profits associated with the manufacturing of generic formulations.46–49
Few studies have examined the prices of essential medicines for specific diseases within individual countries.27 50 51 This study adds to the current literature by performing a detailed examination of the price of essential medicines for childhood cancers across different income groups and world regions. Similar to prior data on medicine prices for adult cancers41 and MSH prices,16 this study showed significant heterogeneity in the costs for treating two of the three most common cancers. Differences in median treatment costs between HIC, UMC and LMC+LIC facilities were much smaller when expressed in PPP-adjusted costs, with median costs being higher in UMCs than HICs for BL and WT. However, costs for treating BL in HIC and UMC will be underestimated as we applied costs to a treatment regimen that would mostly be used in LICs. It is difficult to directly compare treatment costs with other studies that have included medical and non-medical costs in addition to pharmaceutical costs.5 52 However, we are reassured that our country estimate of ALL treatment costs was broadly similar to that calculated by Faruqui et al27 using a similar but not identical treatment regimen and recognising wide variations in prices of different brands of the same anticancer drug in the same dose and dosage form manufactured in India.37
This study has several limitations. It is based on the accuracy of self-reports provided by health professionals in different facilities and could be subject to inaccuracies. We believe that the expertise of the participants and their interest in the problem being investigated ensures the collection of valid and reliable data. Furthermore, the lead study investigators had interim meetings to review data quality and discrepancies. When the data were discrepant, follow-up enquiries were made to reach the relevant respondent and healthcare facilities to clarify any issues identified. Another limitation of this study is the challenge of comparing different formulations of the same drug across income groups and countries. For instance, asparaginase in HICs is unlikely to be the same native product used in LMCs and LICs, with differences in products noted even within Europe.36 53 The special issue with asparaginase is compounded by the marketing and distribution in LMICs of substandard products54 which have deleterious effects on children with ALL.55 Significant additional challenges were apparent in obtaining price data. The response rates were much lower on price data, with some facilities unable to provide data due to commercial-in-confidence arrangements and agreements with group purchasing organisations.56
The limited sample size may misrepresent the true access to chemotherapy in individual countries but may be accurate for LMICs where there are few paediatric cancer centres. However, it may be inaccurate for HICs where substantial regional heterogeneity exists.24 Therefore, we are cautious about generalising price data for a single institution as representative of the whole country. Finally, these prices do not take into consideration public/private insurance coverage and out-of-pocket expenses or some drug access programmes available to patients. Moreover, lower prices in certain LMICs may not reflect affordability for patients if 100% of drugs are covered out-of-pocket by families.21 22 41 57 The data are still important for highlighting variability in price regulatory structures and costs for treatment in different countries, even for generic formulations.
Despite these limitations, the study has several strengths. We are unaware of any other studies which have measured the comparative scope of the prices and costs in different regions of the world and in different economic settings. By bringing together information on the extent of the problems and potential cost implications of shortages of drugs for the care of children with cancers, we aim to heighten awareness and promote discussions on practical solutions to ensure that essential, effective and affordable cytotoxic medicines continue to be marketed and available. Traditional donor funding is unlikely to be a useful mechanism for providing access to cytotoxic medicines in LMICs.58 59 However, mechanisms such as those used by GAVI (The Vaccine Alliance), with Advance Market Commitments which commit to purchase quality-assured products at negotiated prices, may encourage manufacturers to plan for longer periods knowing that demand exists and there is a sustainable business case with a guaranteed affordable long-term price.60 WHO will have an important role to play in advancing these discussions along with professional societies such as SIOP and ISOPP.
Many of the issues we have identified here are not new and confirm the persistent disadvantage for children requiring care for treatable cancers, especially in LMICs. Medicine costs are only one aspect of cancer care provision. However, irregular medicine availability, unreliable supply chains, high prices relative to GNI per capita, confidential medicine pricing that conceals benefits to governments able to negotiate effectively with industry, out-of-pocket costs to patients and their families, and limited government budgets to purchase cytotoxic medicines all contribute to problems in providing care. Documenting relative disadvantage is a starting point, but reluctance to provide medicine cost information and/or reliance on list prices severely limit the usefulness of comparisons of medicine and treatment costs and inhibit progress in ensuring equitable and affordable access to essential cancer medicines and treatments.
