孩子的藥品使用情況已被認(rèn)為是一個主要關(guān)注的問題，因為醫(yī)療保健專業(yè)人士認(rèn)識到，缺乏必需的藥品質(zhì)量保證會對兒童繼續(xù)構(gòu)成重大威脅。

世界各地成千上萬的孩子每一天都發(fā)生不必要的死亡，這是不能接受的，因為他們沒有能救他們的基本藥物。在世界許多不同地區(qū)許多孩子的生命仍處于疾病威脅的高風(fēng)險。例如，許多孩子甚至沒有進(jìn)行疫苗免疫。

藥物是治療疾病和改善人體健康的重要組成部分。他們是在拯救生命的最具成本效益的醫(yī)療干預(yù)措施之一，并且減輕患者痛苦。

The issue of children?s access to medicines has been considered as one of major concern, because health care professionals recognise that a lack of access to essential medicines of assured quality continues to form significant risks to children(1).

It is unacceptable that thousands of children around the world still die needlessly every day because they do not have access to the essential medicines that could save them(2). In many different parts of the world children are still at high risk from many life- threatening diseases. Many children, for example, are not even immunised (3).

Medicines are an important component in treating diseases and in improving human health. They are one of the most cost-effective health-care interventions in saving lives and alleviating the suffering of patients.

Medicines must be effective, safe and of acceptable quality, as well as being used rationally to produce the desired effect (4, 5).

1 Medicines for Children兒童用藥
Accessing appropriate medicines for ill children has always been a significant problem. The challenges to develop safe, appropriate, and effective pharmacotherapy for children are still a major global concern (6). Children suffer different diseases from adults, such as bronchopulmonary dysplasia in neonates and bronchiolitis in infants, and effective treatments are often not available (7, 8).
The use of medicines for children is in general less evidence-based than for adults (1). It is recognised that few medicines are licensed for children, whereas most medicines are licensed for adult use. This is one of the reasons why off-label prescribing of medicines is more common for children than adults .

Unlicensed and off-label medicines are licensed medicines being used outside the terms of the product licence (10). For example, they may be licensed for adults but not for paediatric patients. Children suffer from different diseases from adults and therefore require different medicines.

Unlicensed medicines may not have been subjected to the licensing process at all (10). The safety, efficacy and quality of these prescriptions therefore cannot be guaranteed, since no pharmaceutical company has performed any clinical trials on them. However, the terms off-label and unlicensed medicines do not necessarily imply disapproval of, or improper practice in, their use.

Using off-label and unlicensed medicines for children is a matter of considerable concern within the United States and Europe (13). Many formulations dispensed in hospitals to treat children are considered as off-label or unlicensed medicines (10). For example, diazepam rectal solution, which has been used for children under one year of age is not licensed for this age group (14).

A study was conducted in five centres in Europe where 624 children were admitted to the paediatric wards and received 2262 prescribed drugs (14). About 46% of these drugs were off-label [872] or unlicensed [164]. Two thirds [421] of the inpatient children received off-label or unlicensed drugs.

More studies have been conducted in relation to medicines given to children (15). For example, studies conducted in the UK, Australia and New Zealand showed some improvements in children?s access to medicines and the number of medicines licensed for children between 1998 and 2002, but a serious imbalance between children?s and adults? access still exist in all three countries (16).

2 Challenges of age and formulation年齡和配方的挑戰(zhàn)
The size of a dose administered to a child varies with age and weight (17), and therefore different formulations are required for children of different ages.
Formulations for children are needed in different ranges of concentrations, and different forms including liquids and solids. However, the availability of appropriate forms may be limited by factors such as solubility, chemical and physical stability, formulation microbiology and homogeneity. The volume and dose of liquid medicines may be limited by the solubility of the active ingredients of a drug in solvents or flavouring and sweeteners (17). The development of these formulations has also been limited by the financial returns for such a small market.
Appropriate formulations for children, such as suitable oral formulations, are essential in medical treatment. Such formulations result in better adherence to treatment and enable individualised dosing. Lack of availability of suitable dosage forms can impair children?s access to safe medicines.

The persistent problems of limited numbers of paediatric medicines and inappropriate dosage forms can result in difficulties in the availability and supply of appropriate medicines for children (18). Therefore, regulatory authorities and the pharmaceutical industry need to ensure that children have access to appropriate formulations of medicines (19, 20).
 

 WHO and Make Medicines Child Size誰來制定兒童用藥劑量
The World Health Organisation (WHO) has taken many steps to map the global situation concerning children?s access to, and use of, medicines. It has also designed specific strategies to fill existing gaps, and to raise awareness and accelerate action to address the importance of improved access to and availability of safe and specific medicines for children (1). WHO has launched a campaign in 2007, entitled „Make Medicines Child Size? (21). A key feature of this campaign is the importance of access to health care and medicines for children, an area that has been inadequately explored (22). For example, world-wide two million children die each year from pneumonia (3, 23). The majority of these children would survive if they received an appropriate antibiotic.

The World Health Assembly (WHA) discussed the topic of paediatric medicines in depth and the Department of Essential Medicine and Pharmaceutical Policies initiated many actions to lead to 'better medicines for children'. These actions include many aspects such as ensuring that existing and new medicines are safe for use with children, ensuring that requirements of labelling and licensing for medicines are upgraded, and ensuring that skills and resources are available to improve use of medicines in children .

2 Regulation of Children?s Medicines兒童的藥品監(jiān)管
1The US regulations
Several tragedies involving children have led to an increase in drug regulation in the US. In 1902, the contamination of diphtheria toxin with live tetanus bacilli led to the deaths of many children (24). Therefore, the Biologics Control Act was passed to ensure the safety and purity of vaccines. In 1939, at least 105 people, 33% of them children, died after ingesting poisonous diethylene glycol mixed as a vehicle with sulphanilamide elixir and distributed for use without safety testing (24). This episode led to legislation by the Food and Drug Administration (FDA), which required new medicines to be tested for safety (25). Since this time the US has led the way in new legislation to promote the testing of all appropriate new medicines for children (24, 25).

In 1997, the US Congress enacted the Food and Drug Administration Modernisation Act (FDAMA). It contained provision establishing economic incentives for the pharmaceutical industry to conduct paediatric studies. This was soon recognised to be an insufficient incentive therefore the 1998 Paediatric Rule was enacted. This required the pharmaceutical industry to test drugs and biological products for children. It applied to new licensing applications for active ingredients, dosage forms, indications, and routes of administration (24). This was an important change to try to ensure paediatric safety in drug dosing, and efficacy (24, 26).

In support of these initiatives, guidelines were passed by the National Institute of Health (NIH) to increase the number of child participants in federally-funded research (27). Consequently, the FDA was authorised by Congress to grant a six month extension to patent protection of new pharmaceutical products that were labelled for use in children. This rule was applied through the programme of paediatric exclusivity for pharmaceutical industries completing FDA-requested paediatric studies. The success of this programme led to an increase in paediatric drug studies, in addition to an increase in the number of drugs that had labelling changes for use with children. Consequently, the net economic return to the companies from the participation in this programme was high due to the extension to patent protection .

European regulations were strongly influenced by both the experiences of the US paediatric exclusivity and the European regulation in 1999 on orphan medicines (24). The major goal of the European regulation was the improvement of children?s health in Europe, by improving the development of medicines, increasing information on the use of medicines with children and ensuring the appropriate evaluation and labelling of medicines. 

European regulations歐洲章程
After the US efforts at the end of the last century, European regulatory changes were seen as the start in improving knowledge of drugs given to children. In the latest development (2007) (30), the European regulation on paediatric medicines added a legal requirement that all commonly used medicines are tested on children. The regulation requires that the pharmaceutical company?s paediatric investigation plan describes measures to develop an appropriate formulation for paediatrics and make its use more acceptable, safer, easier and more effective .

Within the January 2007 updated European legislation, new regulations were introduced to govern the authorisation and development of medicines for use in children aged 0 to 18 years (30). The European Medicines Agency (EMA) established a Paediatric Committee (PDCO) to support the legislation on children?s medicines. Their aims are to ensure that there is scientific evidence for using medicines in children and that they have an appropriate formulation (13, 30). All these efforts set the scene for more developments affecting legislation covering the clinical trials for paediatric medicines in the EU .

Access to medicines under International Human Rights Law

Access to essential medicines is considered a basic human right. However, these essential medicines are often denied to poor people in low- and middle- income countries (31).
The lack of full access to essential medicines or vaccines due to economic problems raises new issues in human rights among both high income countries and the rest of low- and middle-income countries (31).

According to human rights principles, health care must be provided without distinction of any kind on the basis of ethnic group, race, religion, language, colour or any other status. A human rights framework also emphasises the importance of non-discrimination for marginalised and vulnerable groups. Moreover, it sets out the connection between access to medication and the right to adequate standards of health care (32).

Both the Convention on the Rights of the Child and the European Convention for the Protection of Human Rights state that access to
appropriate medication is a critical component of children?s rights to standard health(32). The international framework of child rights also, plays a major role in taking action to improve child health and ensure that all children have the same opportunity to access necessary medical assistance and health care (33).
All the efforts in this area go towards improving health care services and access to appropriate medication. Equality and human rights legislation have been passed by the British government to ensure that health staffs do not discriminate against individuals because of their race, religion or colour, and that equal opportunities exist for optimum treatment. This legislation gives everyone the right to equal treatment (34).

 Essential Medicines
1.5.1 Definition of essential medicines
Essential medicines are considered as fundamental to every public health programme (35). The main aim of these medicines is to reduce morbidity and mortality rates in all countries around the world. Most of the important public health programmes which mainly depend on essential medicines include child health and survival programmes, control of epidemic diseases such as tuberculosis and malaria, antenatal care, and medications for respiratory and enteric pathogens (31).

Essential medicines are defined, by the World Health Organisation (WHO) as those “medicines that satisfy the priority health care needs of the population?? (36). They are selected according to strict criteria:
• evidence of safety and efficacy
• prevalence of disease
• with due regard to cost effectiveness.
The first WHO Model List of Essential Medicines for Children, the purpose of which was to 'make medicines child size', was published in October 2007. In compiling the list, preparatory work was carried out by a special subcommittee formed to work on the selection and use of essential medicines based on the WHO treatment guidelines. The subcommittee also emphasised the importance of establishing mechanisms to control the prices of these essential medicines for children (1, 18). The WHO library for essential medicines is considered to be one of the most valuable information databases for drug and therapeutic committees in all member states, international organisations and health insurance organisations (37, 38). Model lists of essential medicines are also used by the United Nations High Commission for Refugees (UNHCR), the United Nations International Children's Emergency Fund (UNICEF) and many other non-governmental organisations (NGOs) to raise awareness of, and to promote, the availability, affordability, accessibility, and quality of medicines (38).

Careful selection of essential medicines leads to better health care, better access to medicines and acceptable prices. All essential medicines should be available at all times in sufficient amounts and suitable dosage forms, with assured quality and at an affordable price to all individuals in the community(31).

 The concept of essential medicines基本藥物的概念
The concept of essential medicines is international. It was launched with the first publication of the Model List of Essential Medicines in 1977 by WHO (37). Since then the List remains a strong tool within public health and has been revised and updated every two years (38). Both its process and the content by which it is updated are intended as models for low- and middle-income countries. Today, many of these countries have their own national list of essential medicines, most of which have been updated in the past five years. The original concept of essential medicines is seen nowadays as a breakthrough in global public health (37, 38).

It is recognised that in many low-and middle-income countries the lack of a free and accessible health care system and poor access to essential drugs result in many children being deprived of appropriate treatment. Today, over one-third of the world?s population, and over half of the poorest people in Africa and Asia, still suffer from lack of access to essential medicines (1)

Problems of access to essential medicines in low-and middle-income countrie
低收入和中等收入國家藥物使用問題

Essential medicines for the main diseases should be both available and affordable in the low- and middle-income countries. Problems related to access to essential medicines in many low-and middle-income countries around the world include the lack of availability. This is due to prohibitive cost, poor quality and counterfeit medicines, and the potential impact of the agreements of the World Trade Organisation (WTO) on drug availability world-wide. These agreements resulted in patents for many medicines which invariably are associated with higher prices and often result in such medicines being too expensive for poor countries. All these issues may result in significant difficulty in accessing essential medicines in low- and middle-income countries (31, 39). The following sections highlight these issues in detail.

 Withdrawal of essential drugs基礎(chǔ)藥物的撤回
Essential medicines which have been used for the treatment of diseases, including tuberculosis and African trypanosomiasis, have become unavailable because they are no longer considered to be profitable (31). Many old essential medicines are no longer available in high-income countries. An example of this was in Nigeria in 1996 when more than 100,000 cases were reported in an epidemic of Neisseria meningitis. An effective treatment for meningococcal meningitis is chloramphenicol in oily suspension. This medication is a tenth of the cost of ampicillin. Its simple administration orally makes it a suitable treatment for patients in rural areas in low-income countries. However, the manufacturer (Roussel-Uclaf) stopped producing chloramphenicol in oily suspension in 1995 and the availability of this product is no longer guaranteed (31, 39).

Prohibitive costs
The purchase of medicines represents a major expenditure of total health spending for both individuals and governments (31). It is also one of the main causes of household impoverishment in high-income countries as well as low- and middle- income countries. The high price of medicines affects access to them, even in countries such as the UK which have universal insurance with co-payments (40).

Prohibitive pricing is another issue in access to essential medicines in many low- and middle-income countries (31). This is well known with regard to acquired immunodeficiency syndrome, which is best treated with antiretroviral medicines that are, however, often inaccessible due to their high cost. New vaccines such as the ones against Haemophilus and hepatitis B are other examples of essential medicines which are not

affordable to many of the poorest and most at risk populations around the world, due to their high cost (31, 41).
Since 1979, Shigella dysenteriae type 1 has been the cause of large epidemics in the poorest countries in Africa. Unfortunately, this disease became resistant to nalidixic acid, the traditional medication, and the only effective treatment today is fluoroquinolones (31). Fluoroquinolones are approximately ten times more expensive than nalidixic acid ($20 vs $2) per course of treatment (31). Without introducing regulations and changes into the pharmaceutical market, significant improvements will not be achieved.

Patent of medicines藥品專利
Patents of pharmaceutical products give the owners the exclusive right to make, sell and distribute their products. The price of a medicine only comes down when the patent expires. Therefore, essential medicines are initially less affordable for the poor in low- and middle-income countries (31).
Furthermore, access to essential medicines remains poor, mainly due to inadequate purchasing power and infrastructure (transportations to clinics, and storage places) (31, 39). Directors of pharmaceutical industries in high-income countries also indicate that the lack of

protection for innovations is the main reason for their limited investments in low- and middle-income countries (31).
Pharmaceutical companies must be compelled to choose whether to protect their patents of new medicines in high-income countries, or in low- and middle-income countries, but not have the option of both. For diseases which affect countries all around the world like cancer, companies could choose to protect their patents in high-income countries. However, for those diseases which almost entirely affect low- and middle-income countries like malaria, they could choose to protect their patent in high-income countries only, so the treatment cost would not be prohibitive(34, 39).

Formerly, many low- and middle-income countries and some high-income countries excluded medicines from being patented, even if they met the criteria of being inventive and new. Today, all these countries are members of the WTO and implement the agreement to trade-related aspects of intellectual property rights (TRIPS) in their systems. This agreement probably has the greatest effect on the access to medicines. It set some standards, such as 20 years of patent for pharmaceutical products, by dealing with the laws of patent (29, 42). By establishing the priorities of public health, expensive medicines similar to other medicines which are supplied by international organisations like UNICEF must now be provided to poor countries. This can be achieved by cooperation between pharmaceutical companies and governments, or between the companies themselves. For example, Bayer laboratories and Medecins Sans Frontieres (MSF) reached a special agreement in 1997 to produce ciprofloxacin treatment for 50,000 patients with a price of $2 per treatment. Such examples demonstrate the ability of pharmaceutical companies to find short-term solutions between themselves