在高收入國(guó)家基本藥物可獲得性問(wèn)題
Problems of access to essential medicines in high-income countries

1.全球藥品的質(zhì)量和造假的問(wèn)題
The Global Problem of the Quality of Medicines and Counterfeiting
藥品的成本上升和需求增加是國(guó)際問(wèn)題不僅僅局限于低收入和中等收入國(guó)家。在過(guò)去的十年中，由于人口老齡化，美國(guó)的藥品的基本成本（每年5-6 %）支出增加和廣告的消費(fèi)急劇上升。在高收入國(guó)家的藥品和保健問(wèn)題與生活在農(nóng)村的設(shè)施有關(guān)，屬于一定的少數(shù)民族，社會(huì)經(jīng)濟(jì)地位和交流問(wèn)題。在一些高收入國(guó)家的東道國(guó)的移民由于對(duì)健康保險(xiǎn)和衛(wèi)生保健系統(tǒng)知識(shí)的匱乏受到了不成比例的影響。最近在美國(guó)北部的研究已經(jīng)表明，在美國(guó)和加拿大，無(wú)醫(yī)療保險(xiǎn)的多民族兒童可能是不太可能獲得藥物的。

藥品的質(zhì)量是一個(gè)綜合性的概念，包括特性，純度，和所有醫(yī)學(xué)中的化學(xué)產(chǎn)品的療效和安全性。歷史已經(jīng)證明，在低收入和高收入國(guó)家仍然存在質(zhì)量差的產(chǎn)品。因此，藥品的質(zhì)量是藥品監(jiān)管機(jī)構(gòu)醫(yī)療衛(wèi)生機(jī)構(gòu)和醫(yī)療保健專(zhuān)業(yè)人士的一個(gè)主要的擔(dān)憂。

The increasing demand for medicines and their rising costs are international problems not limited to low- and middle-income countries. Over the last decade, expenditure on pharmaceutical products in the USA rose dramatically due to an ageing population, an increase in the basic cost of medications (5-6% per year) and consumer advertising (38). Problems of access to medicines and health care in high-income countries are related to living in rural settings, belonging to certain minority ethnic groups, socioeconomic status and communication issues (43). Immigrant populations in some high-income countries are affected disproportionately by the lack of health insurance and their inadequate knowledge of the health care system in the host country (43, 44). More recent research in North America has revealed that in both the United States and Canada,
children of different ethnic groups or without insurance may be less likely to receive medicines

The quality of medicines is a comprehensive concept which includes the identity, purity, efficacy and safety of all chemical products contained in each medicine. History has shown that poor quality products still exist in both low- and high-income countries. Therefore, the quality of medicines is a major concern for drug regulatory agencies, health organisations and healthcare professionals.

The assessment of drug quality is a very complex process. Scientific regulation is essential from the pharmaceutical manufacturing operation till the pharmacovigilance stage (49). Poor manufacturing practices or inappropriate storage can result in products of poor/low quality (50). For this reason all governments should make it a priority to regulate the process of drug manufacturing, storage and distribution. Medicinal preparations must be prepared according to good manufacturing practices (51). These standards assure the quality of administered medicines. The three most important criteria for medicines are quality, safety and efficacy. These criteria are used by governments to regulate pharmaceutical products (52), and should be verified at all stages throughout all the processes of manufacturing, distributing, storage and dispensing. Such specifications are cornerstones of the functioning of each public health care system (48, 53

Medicines, unfortunately, are not exempt from counterfeiting (54). The problem of substandard and counterfeit medicines has a long history. In earlier centuries, herbal medicines were often adulterated; for example, Valeriana officinalis root was adulterated by mixing congeners with root to treat cholera which reduced their effectiveness and led eventually to loss of faith in genuine treatment (55). In the 17th century, the first effective treatment of malaria, Peruvian Cinchona bark (48), was adulterated with aloes and other astringent barks. Huge demand from Europe for the bark, because of endemic malaria, precipitated this adulteration. After a while, loss of confidence in this herbal medicine induced a decrease in demand and a price decline, leading to a temporary ruin of the exporting markets (48-50).

Any manufactured medicinal product is at risk of imitation. Such medicines are often marketed under the name of the original commercial product (54). Pharmaceutical companies worry about the imitation of their products because they may lose the confidence of both prescribers and patients. Since these counterfeit products may be difficult to distinguish from the genuine products, they present great danger to the public and patients? health (54).

The dangers to public health of counterfeit and substandard drugs have been well documented and crucially the problem has now reached global proportions due to easy access of these products through internet technology and the ease of transportation and travel (54).

Counterfeiting is the mimicking of an original product (56). The WHO defines counterfeit medicines as those which are mislabelled deliberately and fraudulently with respect to identity or source (51, 57). Counterfeit medicines may include products without active ingredients, with insufficient active ingredients, the wrong ingredients or even the correct ingredients. They may also include products with fake packaging (58).

Substandard medicines are genuine medicines produced by legitimate manufacturers that fall short of meeting the required quality specifications (50). Substandard medicines may contain less or even more of the active ingredient than specified on the package. Unfortunately, many low- and middle-income countries do not possess sufficient resources (financial, technical, or human) to apply appropriate manufacturing standards and controls which safeguard medicines. Furthermore, some pharmaceutical companies in some industrialised countries such as India and China tend to apply fewer restrictions to manufactured products designed for exportation (56) because this lowers

the cost of production, thereby giving them a competitive advantage in the global market.
For example, Malaria is an infection which is curable when an anti-malarial drug with the correct quality is taken. A recent study by Nayyar et al (59) reported that one-third of anti-malarial medicines were fake. The study included anti-malarial drugs from 28 countries sold between 1999-2010. 36% of 1437 tested drugs from Southeast Asia and 20% of tested drugs in the sub-Saharan Africa were fake (59

2. How big is the problem?
The WHO has said that it is difficult to estimate the level of medicinal counterfeiting accurately (60). 15% of all medicines worldwide are believed to be substandard or counterfeit (54). A wide variation has been noticed in the prevalence of counterfeiting between countries. In the markets of low- and middle-income countries, 10-30% of medicines are estimated to be counterfeit (60). This percentage increases with the high demand during epidemics and the presence of poor drug regulations. For example, approximately 30% to 50% of an important anti-malarial treatment Artesunate? bought in Southeast Asia was counterfeit (54). Moreover, a high percentage of discovered counterfeit medicines in central Africa were the antiretroviral agents, such as lamivudine-zidovudine and stavudine-lamivudinenevirapine

In contrast, in high-income countries, the percentage of counterfeit medicines is estimated to be only 1% (60). This is clearly related to the strict enforcement of drug regulations in countries in North America, European Union, and Japan which enhance protection against counterfeiting(60).

Underlying causes of counterfeit and substandard medicines
The prevalence of counterfeit medicines is a global problem(60). Intellectual Property (IP) Laws and the global markets of medicines create the opportunity for counterfeit medicines. Counterfeiters always follow the money. High pricing ratios attract them to counterfeit expensive patented and trademark medicines (58).
In sub-Saharan Africa many counterfeit and substandard medicines are sold at lower prices than expensive patented products. For example, in the US the triple combination of antiretroviral treatment costs over $11,000 per year. However in Africa, unlicensed generic companies sell an annual supply of a similar but poorer quality treatment for $244 (a “pricing ratio” of 45:1) (58). Others have found that vaccines and contraceptives are much more highly priced (pricing ratio 200:1). Despite the efforts of relevant pharmaceutical companies and IP laws, criminal counterfeiting is still present (58).

The increasing pharmaceutical trade via the Internet has a significant impact on the entry and availability of counterfeit products into the international markets (61). This facilitates the availability and the spread of counterfeit medicines worldwide.

Less quality assurance in low-and middle-income countries are the most common reasons for producing substandard medicines (50). Poor quality control, a limited number of Good Manufacturing Practice (GMP) certified manufacturers and the challenges of limited resources result in a widespread use of substandard and counterfeit drugs and few child-friendly formulations in these poor countries (1, 50).

The problem is not confined to low- and middle-income countries. Individuals from high-income countries are at risk, especially those who purchase substandard or counterfeit medicines from poorly regulated markets when travelling or through ordering via the Internet (61). Recently, in North America, a number of drugs such as atorvastatin, filgrastim, growth hormone, erythropoietin, paclitaxel, and gemcitabine were found to be counterfeit (54 Unfortunately these poor quality products still exist in both low-income and high-income countries. In the UK, counterfeit Serotide 250mcg,

There are many other reasons for the spread of substandard and counterfeit medicines worldwide. High costs often coupled with a shortage of genuine products, additionally, lack of legislation, inadequate liaison between drug regulatory authorities, police, customs, and a lack of publicised information among health professionals and the public, all encourage the counterfeiting of medicines and make detection difficult (48, 52). Presence of counterfeit and substandard drugs in the international markets is a result of ineffective regulations and inadequate quality control by both importing and exporting countries (51). For this reason all governments need to make the regulation of drug manufacturing, storage and distribution a priority.

2.1Global efforts for detecting counterfeit medicines
Drug regulatory authorities and the pharmaceutical industry have been criticised for not doing enough to tackle the problem of counterfeit medicines (54). In the mid-19th century, widespread adulteration of medicines in the UK and USA, particularly quinine, enhanced both the regulation of medicine?s trade, and detection techniques of counterfeit medicine (52). The first resolution against substandard and counterfeit medicines was adopted by the WHA at an international health meeting in 1988 (50, 63, 64).
In the UK, regulatory guidelines were introduced in order to deal with counterfeit medicines. The Trademark and Copyright Act was also passed in 1988 to protect owner copyright and patent (54).

A cooperation between the MHRA and the Royal Pharmaceutical Society creates a system for checking random samples both from pharmacists? shelves and during their inspections of the facilities of manufacturers and distributers. The Medicines Testing Unit of MHRA and the Defective Medicines Report Centre (DMRC) collaboratively analyse and assess these collected samples in order to detect counterfeit medicines. The MHRA has also collaborated with the Royal Pharmaceutical Society to publish guidance for helping pharmacists to ensure the security of a legitimate supply chain and to recognise counterfeit medicines (60).

2.2Information sharing on counterfeit medicines
Pharmaceutical companies often keep the information they have about counterfeit medicines secret. They believe that informing the public about counterfeit medicines deters them from taking genuine medications (54).

It is difficult to obtain factual data on the extent of the drug counterfeiting problem. Unfortunately, information on the epidemiology of counterfeit medicines is also hidden from the public by governmental agencies. Health workers and the public do not have access to the databases which would tell them which products are being counterfeited at any particular time (54).
Legal pressure on the pharmaceutical industry to take more responsibility for informing the public about the counterfeiting of their products has increased. Fortunately, some noticeable changes have occurred. The Pharmaceutical Security Institution has been established under the authority of the International Federation of Pharmaceutical Manufacturers Association (IFPMA) to investigate the incidence of counterfeiting and report their findings. Most of their reports are only provided to the pharmaceutical industry. However, they should make their information available both to the competent authorities to enable them to take action, and, ideally to the public (54).

In the UK in 1989, after discovery of counterfeit Ventolin inhalers for asthma, the British Department of Health and Glaxo Wellcome pharmaceutical company faced strong criticism for hiding information from the public. In the UK it has been suggested that a charge of „corporate killing? should be applied to pharmaceutical companies who do

not take responsibility for alerting the public to counterfeit products which may contribute to the deaths of patients (54).
In the USA in 2005, the Partnership for Safe Medicines started an information programme to alert the public to counterfeit medicines. This indicates the importance of reporting unexpected therapeutic failure, in case it is related to substandard or counterfeit medicines (48, 63).

2.3Possible actions against counterfeit problem
The quality of purchased pharmaceutical products is now accepted as an important issue (49). Global efforts should be made to combat counterfeit drugs and ensure that high quality drugs are readily available (61).

Industry should collaborate with governments and support them financially and technically; and share their information in order to curb drug counterfeiting (54). Moreover, the availability of inexpensive or even free essential medicines, with international technical or financial support, will contribute to prevent the spread of counterfeit medicines (52, 63).
With the high prevalence of counterfeit medicines, regulatory authorities recognise that they have to be stricter in identifying areas of risk and beradicating these illegal products (61). Drug regulators in each country should have analytical laboratories for testing suspect samples. Collaboration with police forces and customs to create a network for exchanging relevant information may help to detect the illegal importation or exportation of counterfeit and substandard pharmaceutical products (54). Low- and middle-income countries with limited resources must make the effort to verify the quality of imported medicines in order to reduce the rate of mortality and morbidity caused by substandard and counterfeit medicines (51, 53).

Every person who deals with medicines should be alert. Drug prescribers and pharmacists should report any incidence of ineffectiveness or absence of quality to the national adverse drug reactions monitoring system(54).
1  Counterfeiting threat
2  Pharmaceutical innovation
Drug counterfeiting is a concomitant risk to innovation. It is growing rapidly in the global pharmaceutical markets. In 2000, the value of pharmaceutical counterfeiting in the EU was estimated at around €1.5bn. In 2003, it had been estimated by the UK-based Anti-Counterfeiting Group that pharmaceutical companies lost 5.8% of their annual income to drug counterfeiting. Recent estimates of the global market for medicines indicated that it exceeded $500bn, and the annual loss of this market from counterfeiting may be over $30bn (58). If true, drug counterfeiting must be recognised not only as a major threat to public health care, but to innovation also. Therefore, criminal counterfeiting must be challenged (58

3 Therapeutic treatments
Substandard medicines may have a detrimental effect on the success of treatments. This is mainly due to the complete absence of quality assurance during their manufacturing process. Many low- and middle-income countries in particular suffer from insufficient financial, technical or human resources to apply such standards. Therefore, they are more likely to have substandard and counterfeit products on their markets (54).

In many low- and middle-income countries, treatment failure has been linked to the use of substandard and counterfeit drugs. It has been estimated that malaria kills 1,000,000 people every year in Africa, predominantly children under five (54). It is largely acknowledged that the high percentage of substandard or counterfeit anti-malarial drugs contributes to these deaths (52).
Serious implications for health may arise from poor quality medicines, such as drug resistance, adverse drug reactions and treatment failure

(50). For example, the poor quality counterfeit pyrazinamide and rifampicin was one of the reasons for the common resistance of Mycobacterium tuberculosis (48, 63).
The high prevalence of substandard or counterfeit anti-infective medications containing a subtherapeutic quantity of active components, exacerbates the increasing rate of drug resistance (52). In Burma, substandard cotrimoxazole and chloramphenicol may be the reason for the resistance of typhoid to these antibiotics. These negative therapeutic results will lead eventually to the failure of treatment and increase the demand for the development of new treatments (63).

4 Health
The prevalence of counterfeiting appears to be increasing and responsible for a large impact on public health. It is a major cause of unnecessary morbidity and mortality in poorer countries (54). The most vulnerable and poorest people in low- and middle-income countries are at the greatest risk of counterfeit drugs because these countries have the weakest drug regulatory programmes (61).

The threat of counterfeit medicines on patients and public health are difficult to evaluate and quantify. In 2001, it was estimated that 192,000 patients were killed in China by counterfeit medicines (54). Chinese authorities investigated 480,000 cases of counterfeit medicines estimated to cost $57m(US). Consequently, they closed 1300 factories involved in this tragedy (54). This gives an indication of the scale of the problem and the attendant health risk.

Vaccination programmes in many low- and middle-income countries may be jeopardised by counterfeit vaccines. In 1995, Niger received a donation of meningitis vaccines from Nigeria. Local health authorities working with Medicines Sans Frontieres (MSF) discovered these vaccines were counterfeit after more than 60,000 people were inoculated with fake ones with no traces of active product (31).

5 Children?s access to safe medicines
The problem of access to safe essential medicines in many low- and middle-income countries is often associated with substandard and counterfeit medicines (52). The following tragedies involving drug counterfeiting indicate the scale of the problem and the need to apply quality control on drug manufacturing to ensure drug safety and efficacy for children (51). A high percentage of deaths in children around the world are associated with acute infectious diseases treated with fake paediatric formulations (65). Therefore, counterfeit medicines are considered to be a serious threat to children worldwide (66, 67

History has indicated that replacing or adulterating intended components with toxic ones is responsible for several major incidents of severe mortality and morbidity in both adults and children (54). The catastrophic results which occurred during the last few decades after giving medications containing the industrial solvent diethylene glycol (DEG) are clearly illustrated by the large number of deaths (51, 64).

In this thesis, I will explore the effect of substandard and counterfeit medicines containing diethylene glycol (DEG) in children. A systematic literature review will be performed in order to identify all cases and provide guidance to health professionals to hopefully identify future cases quickly.

Problems with acccess to health care and medicines are well recognised in some developing countries and in developed countries (45-47). Accessibility is dependent on attitudes towards childhood illness as well as access to health professionals. For example, a health professional/parent who does not consider that a child is in pain is highly unlikely to ensure that the child receives analgesia. Medical conditions such as epilepsy are, unfortunately, associated with a considerable degree of stigma in certain societies. Parents may therefore choose not to have their child treated (68-70).

We therefore also aimed to study two groups of children who might be less likely to have full access to medicines and health care than others. These are: (1) children of Asylum Seekers and Refugees; (2) children of Gypsies and Travellers. The Royal College of Paediatrics and Child Health have identified these two groups as children who are likely to experience inequalities in their state of health (71) resulting from significant problems in accessing health care and medical treatment (72, 73). There have been relatively few studies looking at access to health care for children from these groups and to date there have been no studies in the UK on whether these children receive satisfactory drug therapy.
The research reported in this thesis investigates whether children from the “at risk” groups (children of Asylum Seekers, Refugees and Traveller communities) are likely to receive fewer medicines than other children. It seeks to fill a gap in the literature regarding children?s access to medicines and analyses the impact of identified factors on their access to health care and medical treatment (43, 73, 74).

My study aims to identify the potential barriers to access to safe medicines, then determine whether they are due to problems in relation to access to health care. It also will explore attitudes towards the treatment of medical conditions such as pain, asthma and epilepsy.

The results of my study will have direct implications for healthcare services and seeks to develop better health care for children (67). This study will also give individuals who have difficulty accessing health care the opportunity to state their opinions on any barriers they have encountered to their children receiving the medicines that they require.