What medicines are needed for the management of paediatric endocrine diseases and diabetes?

There are no Clinical Practice Guidelines that provide a master list of medicines used in our specialty. Therefore, a master list of most commonly used medicines was developed. The list was prepared by J-PC and discussed during a focus group by the paediatric endocrinologists at British Columbia Children's Hospital and by two paediatric endocrinologists in Central and South America (AA and JG-A). Each medicine was added to the master list based on consensus. Table 1 (left column) provides a list of medicines or groups of medicines that are deemed necessary for the management of the main paediatric endocrine conditions and of diabetes. Only the non-proprietary names of the medicines were considered. Chemically distinct medicines that have similar effects and are used interchangeably around the world were listed as one category and discussed as one medicine (for instance methimazole and carbimazole are used interchangeably as antithyroid medications). Chemically distinct medicines from the same family but with different potency (for instance, alendronate and pamidronate belong to the bisphosphonates family and have different potency and availability in different countries) were listed in the same category but discussed separately. Although paediatric endocrinologists might prefer to use one medicine over the other because of specific pharmacological characteristics, it was felt that hydrocortisone, prednisone or prednisolone can all be used for the replacement of cortisol. Similarly, most patients with diabetes can be treated with the human or the analogue form of a short-acting and a long-acting insulin.9 Some of the medicines are life-saving, such as insulin or corticosteroids. Others prevent severe morbidity, such as L-thyroxine or bisphosphonates. The cost of the medicines differs from setting to setting and can vary from a few cents a day (eg, thyroid hormones) to several dollars a day (eg, insulin).

Medicines used in paediatric endocrinology and diabetes do not all meet the criteria of ‘essential medicines’ as defined by an expert panel of the WHO which states that ‘An essential drug is a drug needed to satisfy the health needs of the majority of the population and it should be available at all times in adequate amounts and in the appropriate dosage forms’.10 However, while most conditions seen in paediatric endocrinology are not relevant to the majority of a population, they affect thousands of children around the world. Similar to CLAN, we feel that in 2016, children with chronic health conditions should be entitled to affordable access to appropriate medicines.6

Which medicines used in paediatric endocrinology and diabetes are included in the WHO Model Lists of Essential Medicines?

The WHO maintains two Model Lists of Essential Medicines (EMLs), one for children and one for adults.11 ,12 These lists were last updated in April 2015 by an Expert Committee on the Selection and Use of Essential Medicines.10 They are used as a model, non-binding guide for individual countries for the development of their own national EML. Since the publication of the first adult WHO EML for adults (1977) and for children (2007), the committee is constantly adapting to a changing scenery. Relevant to our analysis, the WHO has added expensive medicines to the EMLs when appropriate and has considered child-appropriate formulations.13

Table 1 compares the medicines included in our master list (left column) and the WHO EMLs for children and for adults (middle columns). Overall, the WHO EMLs include medicines that would enable appropriate management of vitamin D deficiency, type 1 and type 2 diabetes and most diseases of the adrenals, the thyroid gland and water metabolism. Medicines that are required for diseases of puberty and for contraception were included only in the WHO EML for adults as the age limit currently used as a cut-off for children is 12 years of age. We also identified several commonly used medicines that were not included in either of the two WHO lists: 1α vitamin D/calcitriol (eg, for hypocalcaemia secondary to hypoparathyroidism), diazoxide/somatostatin (eg, for hypoglycaemia secondary to hyperinsulinism), growth hormone (for neonatal hypoglycaemia secondary to growth hormone deficiency (GHD)) and bisphosphonates (eg, for osteogenesis imperfecta).

Similarities and differences between the WHO and national lists of essential medicines

According to the WHO, the “National lists of essential medicines guide the procurement and supply of medicines in the public sector, schemes that reimburse medicine costs, medicine donations, and local medicine production”.14 In most countries, national EMLs are prepared by a committee appointed by the Ministry of Health (MOH) and submitted to the WHO. They can be found on the WHO website in two complementary locations.14 ,15 Typically, the committee includes representatives from the MOH and from regional and local government health facilities in a multidisciplinary fashion (eg, physicians, nurses, pharmacologists, pharmacists, community health workers).16

We looked for all available national EMLs in Mexico, Central America, the Caribbean and South America and collected the following information for each country: date of the last revision of the EML, gross national income (GNI), and medicine names, form and dosage. Data were entered using the RedCap database (REDCap Software—Version 6.5.20—© 2016 Vanderbilt University). Information could not be obtained from some countries or territories. First, several independent countries did not seem to have published a national EML, including Antigua and Barbuda, Bahamas, Grenada, Saint Kitts and Nevis, and Saint Lucia in the Caribbean and Guatemala and Panama in Central America. Second, many territories that have privileged relationships with France (Guadeloupe, Martinique, French Guyana), Netherlands (Aruba, Curacao, Sin Maarten and the Netherlands Antilles), UK (Anguilla, the British Virgin Islands, the Cayman Islands, Montserrat, and Turks and Caicos), and the USA (Navassa, Puerto Rico and the US Virgin Islands) may rely on the national EML list of countries with which they have these privileged contacts.

Table 2 shows the 25 countries for which we could collect national data (Mexico, 5 countries in Central America, 7 in the Caribbean, and 12 in South America) as well as the date of the most recent revision for the national EMLs. Most national EMLs were current within 10 years (mean year 2010, range 2004–2014). However, some lists may no longer accurately reflect the situation in an individual country. For example Venezuela's list was last reviewed and updated in 2004, and since that time the country has been under sociopolitical unrest. As a consequence, the government has failed to uphold support for Venezuela's health delivery programmes.17 In Brazil, ‘long-standing problems in the country's health-care system have been exacerbated by the economic and political crises’.18 Individual data for each of the countries are available in online supplementary table S1.

For thyroid diseases, all countries listed L-thyroxine and antithyroid drugs. However, while propylthiouracil (PTU) is the only antithyroid medicine suggested by the WHO, many countries list methimazole (44%) and carbimazole (28%) in their national EMLs. In 2010, following the identification of rare but significant side effects of PTU (fatal liver failure), the Food and Drug Administration19 added a Boxed Warning to the label for PTU, which is not acceptable anymore as a first-line treatment for hyperthyroidism.20 We suggest that the inclusion of this medicine in the WHO EMLs should be reconsidered on the grounds that safer alternatives are available.

For adrenal diseases, all countries had at least one of the oral corticosteroids commonly used in paediatrics to replace cortisol (hydrocortisone, prednisone or prednisolone). However, fludrocortisone, an affordable medicine that is lifesaving for patients with a salt wasting form of congenital adrenal hyperplasia, remains difficult to access. Fludrocortisone was added to the WHO EMLs following a submission by CLAN in 2008 but is only included by 48% of the countries.21 Reasons for poor availability in countries such as Peru, Bolivia and Ecuador include lack of awareness of health authorities, cost of the medicine and cost to the pharmaceutical industry for registering a low-cost medicine that serves a small market.

For diabetes, all countries included at least one short-acting insulin and 96% included at least one long-acting insulin. Short-acting analogues were included in 11 (44%) national EMLs and long-acting analogues in 7 (28%) national EMLs. In contrast, glucagon, which is included in both the WHO lists, was only included in 12 countries (48%).

For diseases of calcium/bone, vitamin D3 (for the prevention and treatment of rickets due to vitamin D deficiency) is included in both the WHO EMLs but only in the national EMLs of 15 countries (60%).

To manage puberty, paediatric endocrinologists commonly use testosterone in boys, and oral contraceptives and oestradiol in girls. These medicines were available in most, but not all, of the national EMLs, but only testosterone and oral contraceptives were listed in the WHO EML for adults.

For the management of congenital hyperinsulinism, diazoxide and somatostatin were only available in a few countries (16%).

Bisphosphonates, essential for the treatment of osteogenesis imperfecta among other bone diseases, are not included in either of the WHO EMLs, but are included in 17 countries (68%). We agree on the importance of this medicine and suggest that the addition of bisphosphonates to the WHO EMLs should be considered, especially since many of the class are now off patent and prices have fallen substantially.

Growth hormone is included by 20% of the individual countries but is absent from the WHO EML for children or adults. In infants with true GHD, human growth hormone (hGH) is essential for the prevention and management of hypoglycaemia. In older GHD children, it improves final height and body composition. However, in HICs, the availability of hGH has led to the treatment of many thousands of short but healthy, non-GHD children with unclear benefits and potential long-term risks.22 A similar comment could be made about recombinant insulin-like growth factor 1 (rIGF-1) that is used so rarely in paediatric endocrinology that it was not included in our master list. In Ecuador, a small number of children present with growth hormone receptor deficiency (GHRD), a genetically inherited condition that results in a very short adult height and causes increased mortality at early ages.23 GHRD can be managed with rIGF-1.24 Since the vast majority of these patients are clustered in a small area of Ecuador (among the countries we surveyed), this medicine is specifically relevant for this population. hGH and rIGF-1 are expensive medicines and their inclusion in the EMLs could promote unwanted use resulting in inappropriate healthcare expenses. These two examples illustrate the challenges of designing a national EML for less common diseases requiring more expensive medicines. Clarifying the country's prevalence of a condition (often unknown in LMICs), achieving a formal diagnosis (that may challenge the country's capacity) and proposing an age at which the patient would most benefit from the medicine are issues that need to be considered when designing a national EML, acknowledging that such specific recommendations may be difficult to implement.

Comparison between the WHO and the national EMLs has been used as an indicator of whether countries are promoting access to paediatric medicines.25 ,26 Overall, there were discrepancies between the medicines included in the WHO and in the national EMLs (table 1, right column). National EMLs generally included fewer medicines than the WHO EMLs. Indeed, while essential medicines are selected by the WHO based on evidence of efficacy, safety, dose and cost-effectiveness, individual countries take into account additional factors such as local prevalence of disease, availability of treatment facilities, cost and health professional experience. Interestingly, more expensive medicines used for the management of less common diseases such as somatostatin, diazoxide and bisphosphonates and that are not included in the WHO EMLs were found in several EMLs from mostly richer countries (figure 1). This may reflect a proactive attitude of the MOH in these countries. Considering the worldwide recognition of the WHO lists as a benchmark, it may be important that in future meetings, the Expert Committee on the Selection and Use of Essential Medicines consider whether medicines included unilaterally by specific countries should also be included in the WHO EMLs. This may ultimately promote the adoption of a larger number of medicines by more individual countries.

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Figure 1

Per cent of countries including each medicine or category of medicines, as a function of the median GNI. The grey bars represent the 13 countries below the median GNI and the white bars represent the 12 countries above the median GNI. DDAVP, desmopressin acetate; GNI, gross national income; GnRH, gonadotropin-releasing hormone; HCT, hydrocortisone; IM, intramuscular; LA, long-acting; PDL, prednisolone; PDN, prednisone; SA, short-acting.

GNI influences the content of the national lists of essential medicines

GNI data were obtained from the World Bank, which calculates GNIs based on the World Bank Atlas Method.27 Figure 1 compares the availability of each medicine or category of medicines as a function of the national GNI. Overall, richer countries included more medicines than poorer countries (Spearman Rank Correlation Coefficient (r) 0.57 (95% CI 0.23 to 0.79), p<0.01) (figure 2). The per cent of countries including a specific medicine or category of medicines ranged from 16% to 100%. Medicines that address the most common needs (corticoid treatment, hypothyroidism and hyperthyroidism, type 1 and type 2 diabetes, and contraception) were included in most national EMLs irrespective of GNI. In contrast, fludrocortisone was available in nine (75%) of the richest countries and only in three (23%) of the poorest countries (figure 1). Among insulins, short-acting analogues were included in only five (39%) of the poorest countries, and long-acting analogues in only two (15%) of the poorest countries. Bisphosphonates were listed in 10 (83%) of the top 50% richer countries and 7 (54%) of the poorest 50%. However, intravenous bisphosphonates (newer and more potent than the oral form) were included in only eight (67%) of the richest countries, and in four (31%) of the poorest countries. Growth hormone is only included in the national EML of four countries which are all part of the upper middle income group.

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Figure 2

Relationship between gross national income and number of medicines that are included both in the WHO and national Model Lists of Essential Medicines (EMLs) for each of the 25 countries included in the analysis. Spearman Rank Correlation Coefficient (r) 0.57 (95% CI 0.23 to 0.79), p<0.01.

Policy implications and recommendations

The present analysis focuses on access to medicines in paediatric endocrinology and diabetes, an area that has received little interest in resources-limited settings until now. The increase in capacity in this paediatric specialty, the increasing relative importance of NCDs in overall child mortality, and the goal to achieve equitable access to healthcare are all driving the interest to improve care for the many thousands of children with paediatric endocrine conditions and diabetes living in LMICs. We expect that this trend will also develop for other paediatric specialties.

Paediatric endocrinology focuses on growth, which is related more to pubertal development than to age. The WHO presently sets 12 years of age as the limit between a child and an adult, with the rationale that older children can be given dosage forms of medications that are designed for adults.28 Accordingly, testosterone and contraceptives were included in the adult but not the paediatric WHO EML. We suggest that a definition based on physical maturity (end of pubertal development or final height) would be better suited. Indeed, pubertal development and growth are critical periods that present specific challenges best addressed by paediatricians. Although in many countries children are presently followed by adult physicians, capacity in paediatric specialties is increasing and revising the age cut-off would ensure that the EML for children truly meets their best interests.

Most national EMLs were written in the official language of the country (Spanish, Portuguese, English, French or Dutch). Although they used the category numbers and format proposed by the WHO, at least one list did not include the route of administration or the dose of the medicines. Formatting the lists in a similar manner or making an English translation available could promote collaborative projects around regional registration of medicines or use of medicines with the same characteristics.

Diabetes and several paediatric endocrine conditions require lifelong management and multifaceted approaches. For instance, diabetes requires insulin as well as glucagon (and other non-drug supplies such as metres and strips for blood glucose measurement). We propose that essential medicines be systematically presented in a disease-focused manner and be promoted together.29 ,30 This is the case for childhood cancer, where the WHO recently promoted a more effective disease-based approach compared with an agent-based approach.31 ,32 Addressing essential medicines in a holistic fashion may improve disease management.