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J Clin Epidemiol Vol.44, Suppl.II, pp. 49S-55% 1991 Printedin Great Britain
DRUG
PROMOTION AND LABELING IN DEVELOPING COUNTRIES: AN UPDATE
PHILIP R. LEE, PETER LURIE, MILTON M. SILVERMANand MIA LYDECKER Institute for Health Policy Studies, University of California, San Francisco, CA, U.S.A.
Abstraet-Recent studies of drug promotion and labeling in Third World countries since 1972 have observed important changes in the policies of multinational corporations. Earlier studies found that multinational and national drug companies often grossly exaggerated the indications for the drugs and minimized or ignored the hazards. In the latest study, initiated in 1987, considerable improvement in promotional practices of the multinational corporations has been found, but little or no improvement on the part of the national companies. As a result, physicians are still provided with grossly exaggerated claims and the hazards of prescription drugs are covered up or glossed over. A very serious problem-the marketing of fraudulent drug products-has been identified in a number of Third World countries. Drug products are shaped and colored to resemble the original multinational company product, but contain only a small percentage of the active ingredient stated on the label, or perhaps none at all. In Indonesia fraudulent drug products may represent 20-30% of all drug products in the market. Similar fraudulent products have been reported in Brazil, Thailand, Bangladesh and Malaysia. Prescription
drugs
Promotion
Labeling
INTRODUCTION
The goal of drug promotion and labeling was clearly defined by Lionel and Herxheimer a decade ago [l]: “Accurate and objective information on drugs must be available to help those prescribing drugs to make proper decisions in selecting the drugs and to learn how to use them to the best effect.” The growing concern about the availability of accurate information for those dispensing and prescribing drugs arises within the context of rapid scientific advances, the development of an increasing number of effective drugs that carry significant risks, and a reexamination of drug regulation. Drug regulation is widespread throughout the industrialized and developing 49s
Fraudulent
drug products
nations of the world. It is based on the premise that regulation is needed to ensure that new drugs will be safe and effective, labeled accurately and marketed responsibly. In short, the potential benefits and risks of modern drugs are too important to be left to the competitive market and the unregulated activity of the pharmaceutical industry. That concern is reflected in the growing emphasis placed on the role of drugs and drugrelated issues in the international arena. Forty years ago the focus was on the quality of drugs moving in international commerce. In the 196Os, discussion shifted from the use of national quality standards as artificial barriers to trade to the dangers posed by drugs of low quality, particularly those destined for marketing in developing countries. In 1963, for example, the World Health Assembly passed a resolution
SOS
PHILIP
R. LEEet al.
asking for an examination of the “ways and were compared with the materials used in the means of ensuring that drugs exported from a U.S. In a nutshell, the Silverman study found producing country comply with the drug control glaring differences between the promotion of requirements which apply in that country for selected prescription drugs in the U.S. and in the domestic use” [2]. Latin American countries studied. The decadeThe Third World nations that expressed con- and-a-half following that report was notable cern shared certain characteristics: they had for studies that corroborated its findings [4-6], serious unmet health needs that created a large, followed by attempts to rectify the practices potential market for modern pharmaceutical described. products; most were poor with a very small In this paper we summarize the findings of amount of foreign exchange available and hence our follow-up surveys and review initiatives were under great pressure to get the most advanby the World Health Organization and other tageous price possible on imported drugs; they governmental authorities, the pharmaceutical had few, if any, trained inspectors to monitor industry, and consumer groups to reduce the the quality of imported pharmaceuticals and proliferation of misleading claims. lacked the infrastructure necessary to support a reliable quality control system. Although FOLLOW-UP SURVEYS regulation of the marketplace for prescription After Silverman’s initial report in 1976, we and nonprescription drugs in Third World initiated a study of information distribution in countries resembles that of the industrialized 1980 to physicians in 27 countries-6 in Latin nations on paper, in practice the effect is far America, 15 in Central Africa and 4 in different. Asia (Malaysia, Singapore, Indonesia and the Except for China, Mexico, India, Indonesia, Philippines), together with the U.S. and U.K.Brazil and Egypt, the pharmaceutical sector in most Third World countries is dependent for covering 34 drug entities or fixed combinations marketed as 5 15 different products by 149 comdrugs mainly on multinational pharmaceutical panies. Of these drug firms, about one-half were firms based in Europe, Japan and the U.S. engaged in multinational operations. In comBecause of this dependence, attention began parison with the information given to American to focus on the role of exporting nations and and British physicians, materials provided to multinational pharmaceutical firms in relation physicians in the Third World were found to be to the needs of Third World countries. marked by grossly exaggerated claims of efficacy By the mid- 197Os, attention increasingly and a glossing over of hazards [7]. centered not only on the export of drugs not In-depth interviews in those countries approved for domestic use, but also on the with pharmacologists and many clinical authmanner in which pharmaceutical companies orities-internists, pediatricians, hematologists, promoted and labeled their products, especially endocrinologists, infectious disease experts and in developing countries. Critics vociferously pathologists-brought forth sharp criticisms of denounced the companies for puffing up their the irrational promotion that was so prevalent claims of efficacy and failing to disclose the in the developing nations. We denounced the dangers of the drugs. Industry spokesmen promotion of so-called “luxury products” and denied such charges. other nutritional elements that were widely Most of the early dispute involved a few drugs and inappropriately promoted in Third World marketed in only one or two nations. In 1976, countries. the results of a broader study carried out in 1974 We identified some specific problems related by Dr Milton Silverman were published [3]. The to dispensing and to the marketing and prostudy covered about 40 drug products marketed motion of drugs. Problems related to the by two dozen multinationals in Mexico and 11 dispensing of drugs included: other countries in Latin America. (1) Rapid disintegration of the drugs in pharIn that study, the labeling and promotion macies, and even in storage facilities. of seven major drug classes (antibiotics, oral (2) In some cases containers labeled for a contraceptives, non-steroidal anti-inflammatory specific drug contained totally different drugs, antipsychotics, antidepressants, selected drugs. In other cases the drugs, although steroids and anticonvulsants) were examined. properly labeled, contained from 10 to The materials used to promote the drug prod90% of the labeled ingredients. ucts by the same multinational corporations
Drug Promotion and Labeling in Developing Countries
(3) Brand name drugs were often dispensed when generic drug products were equally appropriate and far less expensive. (4) Pharmacists often dispensed drugs without prescription, and also appeared to dispense some of the most expensive, marginally useful drugs. These drugs, which we refer to as “luxury drugs”, often contained multivitamins, minerals, iron and multiple antibiotics. (5) Injections were often offered on the premises; untrained attendants gave injections on demand for calcium, vitamins, glucose and other drugs. Problems related to the marketing motion of drugs included:
and pro-
(1) Exaggerated claims made for some drugs (e.g. chloramphenicol, “tissue building” anabolic hormones, oral contraceptives). (2) Known dangers were not disclosed to physicians, pharmacists, or the public (e.g. dipyrone, tetracycline, clioquinol). (3) Luxury drugs were promoted and sold by the drug companies. (4) Injectable forms of vitamins, minerals, amino acids and other agents were promoted when they could be equally effective, safer and less costly when taken by mouth. (5) Gross over-promotion and over-use of vitamins, especially complex combinations. A third study, based on information given to physicians in the U.S., U.K. and 28 developing countries in 1984 covered 63 drug entities or fixed combinations, marketed as 1069 drug products by 303 drug companies. Drug products covered in our 1984 survey included analgesics/ antipyretics, anti-arthritis agents, anti-diarrhea agents, anti-infective agents, appetite stimulants, cardiovascular agents, cerebral vasodilators, psychoactive agents, anabolic hormones, anti-impotency agents and “sex tonics”. The study revealed that a number of pharmaceutical companies had made improvements in their promotional practices in developing countries. They exhibited more restraint in making claims to physicians for the clinical value of their products and far more willingness to discuss serious hazards. Our data indicated that most cases (60%) of irrational promotion in developing countries involved domestic (indigenous) firms [S].
51s
Our fourth study, based on information given to physicians in 1987 and 1988 has been completed recently. Preliminary information indicates that most multinational firms are more willing to restrict claims of efficacy for their products to what is scientifically justifiable and appear more willing to disclose the major hazards of their products. However, domestic firms have not changed their policies and practices with respect to drug promotion and labeling to the same degree. As a result, physicians are still provided with grossly exaggerated claims and the hazards of prescription drugs are covered up. Recently, attention has been focused on the problem of what may be termed fraudulent drug products. These products are shaped and colored to resemble the original multinational company products, and packaged to imitate the original product, but contain only a small percentage of the active ingredient stated in the label-or perhaps none at all. The problem has been of growing concern in Brazil. In Indonesia, it has been disclosed that fraudulent products represent 20-30% of all drug products on the market. They have been found not only in street stores but even in government hospitals. So far, the government has found no effective method of keeping them off the market. Similar fraudulent products have been reported in Bangladesh, Thailand and Malaysia. Recent investigations have shown that most of the fraudulent products come from supposedly reputable domestic drug companies. No multinational drug company has yet been implicated [9]. WORLD HEALTH ORGANIZATION-THE ESSENTIAL DRUGS PROGRAM
In 1975, the Director-General of the World Health Organization (WHO) issued a report at the annual meeting of the World Health Assembly that identified national drug policies as a priority issue for Third World countries. The Director-General was instructed by the World Health Assembly “to develop means by which the organization can be of greater direct assistance to member states in advising on the selection and procurement, at reasonable cost, of essential drugs of established quality corresponding to their national needs” [lo]. The World Health Assembly proposed that WHO establish a program on essential drugs in 1978.
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P~LIP
R. LEEet al.
In 1981 the Essential Drugs Program was expanded to become the Action Program on Essential Drugs and Vaccines or the Drugs Action Program (DAP), which seeks to ensure “the availability of a regular supply to all people, of a selected number of safe and effective drugs of acceptable quality at lowest cost” [l 11. By promoting the availability of these so-called essential drugs, WHO sought also to address the widespread problem of irrational drug use [12]. In 1985, a WHO-sponsored Conference of Experts on Rational Use of Drugs was held in Nairobi, Kenya. The Conference extended the scope of rational drugs policies by stressing the need to provide objective information on drugs to health workers and the public. In 1986 the World Health Assembly approved a revised drug strategy, which added rational use of drugs to the distribution of essential drugs as an element of the Drugs Action Program. The DAP has been supported in its local work within countries by its relationship with UNICEF, which has been largely involved in the supply and, to a lesser extent, distribution of essential drugs since the mid-1980s. In 1987, UNICEF expanded its focus and developed the Bamako Initiative in order to strengthen primary health care through the provision and sale of essential drugs. Under the terms of the initiative, essential drugs would be sold at two to three times the cost price and the proceeds devoted to the maintenance of local primary health care and maternal and child health programs and the procurement of more drugs for the community [13]. Strains developed because of the lack of adequate consultation with WHO, and sharp criticism greeted the announcement of the initiative. Critics asserted that charging for drugs would exclude substantial numbers of people already lacking basic health resources. Health workers would depend on drug sales for their salaries and would thus have an incentive to overprescribe [ 141. Attempts to promote the essential drugs concept have consistently met opposition from the pharmaceutical industry. In 198 1, Jay Kingham of the U.S. Pharmaceutical Manufacturers’ Association (PMA) claimed that an essential drug list “will have everbody go third-class in drugs. It won’t save money and it won’t meet real health needs” [15]. Indeed, the PMA insisted that such lists “would have a very adverse impact on the practice of medicine, the
level of competition in the pharmaceutical industry, the rate of pharmaceutical innovation, and the overall cost of illness in human and economic terms” [ 163. More objective observers have found otherwise. Researchers in Democratic Yemen found that health units with essential drugs programs carried greater numbers of essential drugs and had larger stocks of them. In addition, rational prescribing was promoted; this was reflected in fewer injections, less antibiotic prescribing, and fewer drugs per prescription [ 121. More recently, the DAP has been evaluated by researchers from the London School of Hygiene and Tropical Medicine and the Koninklijk Instituut voor de Tropen in the Netherlands [l I], as well as by Reich [17]. The U.K./Netherlands group concluded that the program “has been successful both in promoting the essential drugs concept and providing support to those countries concerned with formulating and implementing essential drugs policies”. However, that report noted a persistent tension within the WHO between those supporting continuing advocacy of the essential drugs concept and those who would have the DAP assume the role of technical consultant to countries interested in developing essential drugs policies. The latter approach seems to have gained some support by the removal of the DAP from within the Director-General’s office by the new Director-General, Dr Nakajima. At the World Health Assembly meeting in May 1990, a resolution was passed to continue WHO’s advocacy role regarding the essential drugs concept. This position was reconfirmed by DAP’s Management Advisory Committee in February 199 1. THE INTERNATIONAL FEDERATION OF PHARMACEUTICAL MANUFACTURERS’ ASSOCIATIONS (IFPMA) CODE OF MARKETING PRACTICES AND THE RESPONSE OF CONSUMER GROUPS
Placed on the defensive by the adoption of the essential drugs concept and continuing reports of promotional abuse in developing countries, the pharmaceutical industry promulgated the IFPMA Code of Pharmaceutical Marketing Practices in 1981 [18]. Member companies were called upon to conduct all their dealings with “complete candor” and to restrict their claims to those that could be supported by scientific fact. The code requires printed advertisements
Drug Promotion and Labeling in Developing Countries
to include: “A succinct statement of the side effects, precautions and contraindications” [19]. Clinically important risks were to be disclosed. This was an attempt by the manufacturers to promote self-regulation rather than regulation by WHO actions. Another significant development occurred in 1981-the establishment of Health Action International (HAI). HA1 was formed as a consumer advocacy and public interest organization “to further the safe, rational and economic use of pharmaceuticals worldwide” [17]. While HA1 actively lobbied the WHO in support of the DAP, it was also critical, as were other consumer groups, of the IFPMA code. Critics noted the absence of any monitoring mechanism or punitive recourse. “The major sanction against any company that transgresses the code will continue to be the sanction of adverse publicity,” declared the IFPMA [20]. The industry has long touted governmental agencies in the developing world as appropriate loci for the regulation of drug sales and marketing. Such an approach appears impractical. According to Arthur Yellin, assistant to the acting director of the U.S. Food and Drug Administration’s Division of Drug Advertising and Labeling, the “vast majority” of promotional materials are false or misleading [21]. Nevertheless, even in a wealthy nation like the U.S., he said, regulatory action has been taken in only 5% of cases, due to lack of resources. Some activist groups have sought to use the IFPMA code to address misleading pharmaceutical marketing. The Medical Lobby for Appropriate Marketing (MaLAM) has filed over 450 alleged breaches of the code with the IFPMA. The industry association acknowledged that 168 were indeed code infringements, but their response time was so slow that in many cases the advertising run may have been completed. Many alleged code breaches were left unaddressed as the companies were not members of the IFPMA [20]. Health activist Andrew Chetley also has filed complaints with the IFPMA about advertisements in alleged contravention of the code. Of his initial group of 189 complaints, the industry replied to 167 (88.4%) 58% of which were ruled valid. In 1988 he filed an additional 70 complaints [22]. The results of the consumer groups’ analysis of the response to the IFPMA code is not surprising in view of the experience in Great Britain with a similar code adopted
53s
in 1958 by the Association of the British Pharmaceutical Industry (ABPI). A recent analysis by Herxheimer and Collier revealed 379 breaches between 1983 and 1988. The authors estimated that the Medicines Act had been broken over 1200 times between 1972 and 1988 and they concluded [23]: “The evidence suggests that the code has failed to deter promotional excesses. The ABPI’s wish to secure compliance with the code seems weaker than its wish to preempt outside criticism and action; its self regulation seems to be a service to itself rather than to the public.” REGULATORY
ACTIVITY OF EXPORTING NATIONS
The regulatory policies of exporting nations are of growing importance to developing nations. The first legislation to control drugs was enacted in England little more than a century ago. Switzerland followed suit in 1900 and the U.S. in 1906. Increased regulation and scientific advances have evolved together, although not always harmoniously, ever since [24]. Although most European countries developed some form of drug regulation in the early years of this century, several had only limited systems as late as 1960. Norway and Sweden were the first countries to develop regulations relevant to safety and efficacy in the 1920s. It was not until 1938, with enactment of the Food, Drug and Cosmetic Act in the U.S., that physicians assumed a central role as agents for consumers. While few countries followed Norway, Sweden and the U.S. in the 1920s and 1930s virtually all European nations developed regulations regarding safety and efficacy after the thalidomide tragedy in Europe in the late 1950s and early 1960s. One means for addressing irrational drug promotion practices in the developing world is through the regulatory authorities of the industrialized exporting nations. Despite the development of strong regulatory policies for drugs used domestically, industrialized countries, with the exception of the U.S. until 1986, have permitted export of drugs not approved for use within the country. Indeed, many governments consider the export of pharmaceuticals highly desirable and often regulate exports differently than drugs approved for domestic use.
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R. LEEet nl.
In 1986 the Drug Export Amendments Act (Public Law 99-660) was ratified by the U.S. Congress. For the first time it permitted the export of drugs unapproved for use in the U.S. After lengthy debate, a list of 21 receiving countries, mostly in Europe, was designated. Those countries were precluded from reexporting unapproved U.S. pharmaceuticals. The U.S. Office of Technology Assessment is currently completing a study of the labeling of 500 approved and unapproved drugs exported by U.S. corporations to Kenya, Thailand, Panama and Brazil. The report is expected to be released in the fall of 199 1. In recent years, attention in Europe has centered on the report of the Committee on the Environment, Public Health and Consumer Protection (Banotti Report) of the European Parliament on the Export of Pharmaceuticals from the European Community to the Developing World [25]. Three principles endorsed by the report were subsequently incorporated into draft legislation, passed unanimously by the European Parliament’s Environment Committee, and presented to the full Parliament for further debate: (1) Package inserts with exported drugs should contain information of the same standard as that required in the exporting country. (2) Manufacturers would be required to inform importing nations that a given preparation had been withdrawn or restricted for safety reasons. (3) Drugs banned in the European Community could only be exported if, after receiving all information relevant to the ban, the importing country specifically requested the drug (the doctrine of “prior informed consent”). With broad support from across the political spectrum, the amendments garnered 240 votes in favor to 63 against. However, 260 votes (an absolute majority) were required and the amendments were defeated. The issue will surely return. THE DRUGGING CONTINUES
Our recent findings do indeed suggest an manuals improvement in the prescribing being used by physicians around the world. While this is a useful index of overall trends in drug marketing and promotion in the
developing world, it does not adequately account for certain realities of drug use in that setting. Information contained in the regional prescribing manuals may differ from other advertising material provided by the company. In Nigeria, for example, product package inserts tend to make added claims of efficacy and omit dangers listed in the U.S. Physicians Desk Reference [26]. Detailers have incentives to promote drug use for indications beyond those listed in the prescribing guides [27]. While there is one company “rep” for every 10 physicians in developed nations, ratios of one detailer to three physicians are not uncommon in the Third World [7]. Another technique is the “promotional clinical trial” in which third rate clinical trials are conducted in order to forestall possible governmental regulation [28]. The double standard of promoting a drug only for scientifically based indications in developed countries while expanding its indications in developing ones persists. The marketing of anabolic steroids by the Dutch multinational, Organon [29], and the promotion of Sibelium (flunarizine dihydrochloride) for pityriasis versicolor by Janssen in the Philippines [30] testify to the resilience of such practices. Unjustified claims of efficacy or safety continue to proliferate. In Pakistan, Janssen markets Imodium (loperamide) drops for the treatment of diarrhea. A report in the Lancet documented 19 cases of severe abdominal distension and paralytic ileus associated with at least six deaths in infants administered the drug [30]. Numerous reports document misleading promotion in Pakistan [32], Asia and the Middle East [33], Kenya [34] and Francophone Africa 1351. Thus, while changes in the prescribing guides may be significant, advertising through other methods and prescribing practices in the local setting may be little altered [36]. The combination of overzealous promotion, unjustifiable claims of efficacy, physicians with little opportunity for continuing medical education, and widespread over-the-counter drug availability has potentially lethal implications for the patient [37]. Even when multinational corporations remove unsafe or questionable drugs from the market, or improve their promotional practices, it is no guarantee that indigenous companies will follow suit or
Drug Promotion and Labeling in Developing Countries
the drug regulatory agencies in Third World countries will be able to control their practices. CONCLUSION
The past decade-and-a-half has seen the issue of pharmaceutical use in the developing world rise from obscurity to one intermittently occupying the headlines across the globe. Solutions to the issues raised have been offered by the WHO, developing and developed world governments, consumer activists and the industry itself. While some progress has indeed been made, particularly among multinational companies and in the prescribing guides, evidence of continued abuse is legion. It will take concerted effort by all affected parties before satisfactory resolution of the remaining issues can be realized. REFERENCES 1. Lionel W, Herxheimer A. Coherent policies on drugs: formulation and implementation. In: Blum R ef al., Eds. Pharmaceuticals and Health Policy. London: Croom Helm; 1981: 24&267. 2. Stenzel C. The role of international organizations in medicines policy. In: Blum R et al., Eds. Pharmaceutlcals and Health Policy. London: Croom Helm; 1981: 21 l-239. 3. Silverman M. The Drugging of the Americas. Berkeley: University of California Press; 1976. 4. Medawar C. Insult or Injury? London: Lithosphere Ltd; 1979. 5. Yudkin JS. Provisions of medicines in a developing country. Lancet 1978; April 15: 81&812. 6. Melrose D. Bitter Pills. Oxford: Oxfam Publications; 1982. 7. Silverman M, Lee PR, Lydecker M. Prescriptions for Death: The Drugging of the Third World. Berkeley: University of California Press; 1982. 8. Silverman M, Lee PR, Lydecker M. Drug promotion: the third world revisited. Intern J Health Serv 1986: 16(4): 659667. 9. Silverman H, Lyaecker M, Lee PR. The drug swindlers. Intern J Health Serv 1990; 20(4): 561-572. 10. Mahler H. Report to the 28th World Health Assembly. official Records of the World Health Organization 1975; 226 (Annex 13): 96110. 11. London School of Hygiene and Tropical Medicine, Koninklijk Instituut voor de Tropen. An Evaluation of WHO’s Action Programme on Essential Drags. Copenhagen: DANIDA; 1989. 12. Hogerzeil HV, et al. Impact of an essential drugs programme on availability and rational use of drugs. Lancet 1989; Jan 21: 141-142.
5%
13. Grant JP. Africa: the Bamako Initiative. In: The State of the World’s Children 1989. Oxford: Oxford University Press; 1989. 14. The Bamako Initiative. Lancet 1988; Nov 19: 1177. 15. Radolf A. UN has bitter pill in mind for international drug firms. San Francisco Examiner; 1981 Sept 16. Manufacturers’ Association. The 16. Pharmaceutical health consequences of restricted drug lists. Washington, November; 1985. 17. Reich MR. Essential drugs: economics and politics in international health. Health Policy 1987; 8: 39-57. 18. IFPMA Code of Pharmaceutical Marketing Practices. In: Silverman M, Lee PR, Lydecker M, Eds. Prescrlp tions for Death: The Dragging of the Third World. Berkeley: University of California Press: 1982: 157-160. 19. International Federation of Pharmaceutical Manufacturers’ Associations. IFPMA Code of Pharmaceutical Marketing Practices. Geneva; 1987. 20. International drug marketing code. Lancet 1988; April 30: 988. 21. FDA’s drug promotion problems. Scrip 1989; Feb 24. 22. 70 breaches of IFPMA code alleged. Scrip 1988; April 5. 23. Herxheimer A, Collier J. Promotion by the British pharmaceutical industry, 1983-8: A critical analysis of self regulation. Br Med J 1990; 300: 307-311. 24. Lee PR, Herzstein J. International drug regulation. Ann Rev Public Health 1986; 7: 217-235. 25. Committee on the Environment, Public Health and Consumer Protection. Draft report on the export of pharmaceutical products from the European Community to the countries of the Third World. European Parliament, Feb 13; 1986. 26. Nosakhare GO. Overpromotion of drugs in international product package inserts. Tropical Doctor 1983; 13: 5-8. 27. Lexchin J. Doctors and detailers: therapeutic education or pharmaceutical promotion? Intern J Health Serv 1989; 19: 663-679. 28. Kiatboonsri P, Richter J. Unethical trials of dipyrone in Thailand. Lancet 1988; Dee 24/31: 1491. 29. Werkgroep Medische Ontwikkelngs Samenwerking. Anaholic Steroids. Amsterdam: WEMOS: 1987. 30. Tan ML. Dying for Drugs: Pill Power and politics in the Philippines. Quezon City: Health Action Information Network; 1988. 31. Bhutta TI, Tahir KI. Loperamide poisoning in children. Lancet 1990; Feb 10: 363. 32. Birley JLT. Drug advertisements in developing countries. Lancet 1989; Jan 28: 220. 33. Hosking G. Drug marketing in the third world. Lancet 1986; July 19: 164. 34. Misuse of antidiarrhoeal medicines. Lancet 1989; Ott 21: 35. “Misleading promotion” in Africa attacked. Scrip 1990; Jan 26. 36. Tomson G, Sterky G. Self-prescribing by way of pharmacies in three Asian developing countries. Lancet 1986; Sept 13: 620-621. 37. Greenhalgh TK. Drug marketing in the third world: Beneath the cosmetic reforms. Lancet 1986; June 7: 1318-1320.
J Clin Epidemiol Vol.44, Suppl.II, pp. 49S-55% 1991 Printedin Great Britain
DRUG
PROMOTION AND LABELING IN DEVELOPING COUNTRIES: AN UPDATE
PHILIP R. LEE, PETER LURIE, MILTON M. SILVERMANand MIA LYDECKER Institute for Health Policy Studies, University of California, San Francisco, CA, U.S.A.
Abstraet-Recent studies of drug promotion and labeling in Third World countries since 1972 have observed important changes in the policies of multinational corporations. Earlier studies found that multinational and national drug companies often grossly exaggerated the indications for the drugs and minimized or ignored the hazards. In the latest study, initiated in 1987, considerable improvement in promotional practices of the multinational corporations has been found, but little or no improvement on the part of the national companies. As a result, physicians are still provided with grossly exaggerated claims and the hazards of prescription drugs are covered up or glossed over. A very serious problem-the marketing of fraudulent drug products-has been identified in a number of Third World countries. Drug products are shaped and colored to resemble the original multinational company product, but contain only a small percentage of the active ingredient stated on the label, or perhaps none at all. In Indonesia fraudulent drug products may represent 20-30% of all drug products in the market. Similar fraudulent products have been reported in Brazil, Thailand, Bangladesh and Malaysia. Prescription
drugs
Promotion
Labeling
INTRODUCTION
The goal of drug promotion and labeling was clearly defined by Lionel and Herxheimer a decade ago [l]: “Accurate and objective information on drugs must be available to help those prescribing drugs to make proper decisions in selecting the drugs and to learn how to use them to the best effect.” The growing concern about the availability of accurate information for those dispensing and prescribing drugs arises within the context of rapid scientific advances, the development of an increasing number of effective drugs that carry significant risks, and a reexamination of drug regulation. Drug regulation is widespread throughout the industrialized and developing 49s
Fraudulent
drug products
nations of the world. It is based on the premise that regulation is needed to ensure that new drugs will be safe and effective, labeled accurately and marketed responsibly. In short, the potential benefits and risks of modern drugs are too important to be left to the competitive market and the unregulated activity of the pharmaceutical industry. That concern is reflected in the growing emphasis placed on the role of drugs and drugrelated issues in the international arena. Forty years ago the focus was on the quality of drugs moving in international commerce. In the 196Os, discussion shifted from the use of national quality standards as artificial barriers to trade to the dangers posed by drugs of low quality, particularly those destined for marketing in developing countries. In 1963, for example, the World Health Assembly passed a resolution
SOS
PHILIP
R. LEEet al.
asking for an examination of the “ways and were compared with the materials used in the means of ensuring that drugs exported from a U.S. In a nutshell, the Silverman study found producing country comply with the drug control glaring differences between the promotion of requirements which apply in that country for selected prescription drugs in the U.S. and in the domestic use” [2]. Latin American countries studied. The decadeThe Third World nations that expressed con- and-a-half following that report was notable cern shared certain characteristics: they had for studies that corroborated its findings [4-6], serious unmet health needs that created a large, followed by attempts to rectify the practices potential market for modern pharmaceutical described. products; most were poor with a very small In this paper we summarize the findings of amount of foreign exchange available and hence our follow-up surveys and review initiatives were under great pressure to get the most advanby the World Health Organization and other tageous price possible on imported drugs; they governmental authorities, the pharmaceutical had few, if any, trained inspectors to monitor industry, and consumer groups to reduce the the quality of imported pharmaceuticals and proliferation of misleading claims. lacked the infrastructure necessary to support a reliable quality control system. Although FOLLOW-UP SURVEYS regulation of the marketplace for prescription After Silverman’s initial report in 1976, we and nonprescription drugs in Third World initiated a study of information distribution in countries resembles that of the industrialized 1980 to physicians in 27 countries-6 in Latin nations on paper, in practice the effect is far America, 15 in Central Africa and 4 in different. Asia (Malaysia, Singapore, Indonesia and the Except for China, Mexico, India, Indonesia, Philippines), together with the U.S. and U.K.Brazil and Egypt, the pharmaceutical sector in most Third World countries is dependent for covering 34 drug entities or fixed combinations marketed as 5 15 different products by 149 comdrugs mainly on multinational pharmaceutical panies. Of these drug firms, about one-half were firms based in Europe, Japan and the U.S. engaged in multinational operations. In comBecause of this dependence, attention began parison with the information given to American to focus on the role of exporting nations and and British physicians, materials provided to multinational pharmaceutical firms in relation physicians in the Third World were found to be to the needs of Third World countries. marked by grossly exaggerated claims of efficacy By the mid- 197Os, attention increasingly and a glossing over of hazards [7]. centered not only on the export of drugs not In-depth interviews in those countries approved for domestic use, but also on the with pharmacologists and many clinical authmanner in which pharmaceutical companies orities-internists, pediatricians, hematologists, promoted and labeled their products, especially endocrinologists, infectious disease experts and in developing countries. Critics vociferously pathologists-brought forth sharp criticisms of denounced the companies for puffing up their the irrational promotion that was so prevalent claims of efficacy and failing to disclose the in the developing nations. We denounced the dangers of the drugs. Industry spokesmen promotion of so-called “luxury products” and denied such charges. other nutritional elements that were widely Most of the early dispute involved a few drugs and inappropriately promoted in Third World marketed in only one or two nations. In 1976, countries. the results of a broader study carried out in 1974 We identified some specific problems related by Dr Milton Silverman were published [3]. The to dispensing and to the marketing and prostudy covered about 40 drug products marketed motion of drugs. Problems related to the by two dozen multinationals in Mexico and 11 dispensing of drugs included: other countries in Latin America. (1) Rapid disintegration of the drugs in pharIn that study, the labeling and promotion macies, and even in storage facilities. of seven major drug classes (antibiotics, oral (2) In some cases containers labeled for a contraceptives, non-steroidal anti-inflammatory specific drug contained totally different drugs, antipsychotics, antidepressants, selected drugs. In other cases the drugs, although steroids and anticonvulsants) were examined. properly labeled, contained from 10 to The materials used to promote the drug prod90% of the labeled ingredients. ucts by the same multinational corporations
Drug Promotion and Labeling in Developing Countries
(3) Brand name drugs were often dispensed when generic drug products were equally appropriate and far less expensive. (4) Pharmacists often dispensed drugs without prescription, and also appeared to dispense some of the most expensive, marginally useful drugs. These drugs, which we refer to as “luxury drugs”, often contained multivitamins, minerals, iron and multiple antibiotics. (5) Injections were often offered on the premises; untrained attendants gave injections on demand for calcium, vitamins, glucose and other drugs. Problems related to the marketing motion of drugs included:
and pro-
(1) Exaggerated claims made for some drugs (e.g. chloramphenicol, “tissue building” anabolic hormones, oral contraceptives). (2) Known dangers were not disclosed to physicians, pharmacists, or the public (e.g. dipyrone, tetracycline, clioquinol). (3) Luxury drugs were promoted and sold by the drug companies. (4) Injectable forms of vitamins, minerals, amino acids and other agents were promoted when they could be equally effective, safer and less costly when taken by mouth. (5) Gross over-promotion and over-use of vitamins, especially complex combinations. A third study, based on information given to physicians in the U.S., U.K. and 28 developing countries in 1984 covered 63 drug entities or fixed combinations, marketed as 1069 drug products by 303 drug companies. Drug products covered in our 1984 survey included analgesics/ antipyretics, anti-arthritis agents, anti-diarrhea agents, anti-infective agents, appetite stimulants, cardiovascular agents, cerebral vasodilators, psychoactive agents, anabolic hormones, anti-impotency agents and “sex tonics”. The study revealed that a number of pharmaceutical companies had made improvements in their promotional practices in developing countries. They exhibited more restraint in making claims to physicians for the clinical value of their products and far more willingness to discuss serious hazards. Our data indicated that most cases (60%) of irrational promotion in developing countries involved domestic (indigenous) firms [S].
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Our fourth study, based on information given to physicians in 1987 and 1988 has been completed recently. Preliminary information indicates that most multinational firms are more willing to restrict claims of efficacy for their products to what is scientifically justifiable and appear more willing to disclose the major hazards of their products. However, domestic firms have not changed their policies and practices with respect to drug promotion and labeling to the same degree. As a result, physicians are still provided with grossly exaggerated claims and the hazards of prescription drugs are covered up. Recently, attention has been focused on the problem of what may be termed fraudulent drug products. These products are shaped and colored to resemble the original multinational company products, and packaged to imitate the original product, but contain only a small percentage of the active ingredient stated in the label-or perhaps none at all. The problem has been of growing concern in Brazil. In Indonesia, it has been disclosed that fraudulent products represent 20-30% of all drug products on the market. They have been found not only in street stores but even in government hospitals. So far, the government has found no effective method of keeping them off the market. Similar fraudulent products have been reported in Bangladesh, Thailand and Malaysia. Recent investigations have shown that most of the fraudulent products come from supposedly reputable domestic drug companies. No multinational drug company has yet been implicated [9]. WORLD HEALTH ORGANIZATION-THE ESSENTIAL DRUGS PROGRAM
In 1975, the Director-General of the World Health Organization (WHO) issued a report at the annual meeting of the World Health Assembly that identified national drug policies as a priority issue for Third World countries. The Director-General was instructed by the World Health Assembly “to develop means by which the organization can be of greater direct assistance to member states in advising on the selection and procurement, at reasonable cost, of essential drugs of established quality corresponding to their national needs” [lo]. The World Health Assembly proposed that WHO establish a program on essential drugs in 1978.
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In 1981 the Essential Drugs Program was expanded to become the Action Program on Essential Drugs and Vaccines or the Drugs Action Program (DAP), which seeks to ensure “the availability of a regular supply to all people, of a selected number of safe and effective drugs of acceptable quality at lowest cost” [l 11. By promoting the availability of these so-called essential drugs, WHO sought also to address the widespread problem of irrational drug use [12]. In 1985, a WHO-sponsored Conference of Experts on Rational Use of Drugs was held in Nairobi, Kenya. The Conference extended the scope of rational drugs policies by stressing the need to provide objective information on drugs to health workers and the public. In 1986 the World Health Assembly approved a revised drug strategy, which added rational use of drugs to the distribution of essential drugs as an element of the Drugs Action Program. The DAP has been supported in its local work within countries by its relationship with UNICEF, which has been largely involved in the supply and, to a lesser extent, distribution of essential drugs since the mid-1980s. In 1987, UNICEF expanded its focus and developed the Bamako Initiative in order to strengthen primary health care through the provision and sale of essential drugs. Under the terms of the initiative, essential drugs would be sold at two to three times the cost price and the proceeds devoted to the maintenance of local primary health care and maternal and child health programs and the procurement of more drugs for the community [13]. Strains developed because of the lack of adequate consultation with WHO, and sharp criticism greeted the announcement of the initiative. Critics asserted that charging for drugs would exclude substantial numbers of people already lacking basic health resources. Health workers would depend on drug sales for their salaries and would thus have an incentive to overprescribe [ 141. Attempts to promote the essential drugs concept have consistently met opposition from the pharmaceutical industry. In 198 1, Jay Kingham of the U.S. Pharmaceutical Manufacturers’ Association (PMA) claimed that an essential drug list “will have everbody go third-class in drugs. It won’t save money and it won’t meet real health needs” [15]. Indeed, the PMA insisted that such lists “would have a very adverse impact on the practice of medicine, the
level of competition in the pharmaceutical industry, the rate of pharmaceutical innovation, and the overall cost of illness in human and economic terms” [ 163. More objective observers have found otherwise. Researchers in Democratic Yemen found that health units with essential drugs programs carried greater numbers of essential drugs and had larger stocks of them. In addition, rational prescribing was promoted; this was reflected in fewer injections, less antibiotic prescribing, and fewer drugs per prescription [ 121. More recently, the DAP has been evaluated by researchers from the London School of Hygiene and Tropical Medicine and the Koninklijk Instituut voor de Tropen in the Netherlands [l I], as well as by Reich [17]. The U.K./Netherlands group concluded that the program “has been successful both in promoting the essential drugs concept and providing support to those countries concerned with formulating and implementing essential drugs policies”. However, that report noted a persistent tension within the WHO between those supporting continuing advocacy of the essential drugs concept and those who would have the DAP assume the role of technical consultant to countries interested in developing essential drugs policies. The latter approach seems to have gained some support by the removal of the DAP from within the Director-General’s office by the new Director-General, Dr Nakajima. At the World Health Assembly meeting in May 1990, a resolution was passed to continue WHO’s advocacy role regarding the essential drugs concept. This position was reconfirmed by DAP’s Management Advisory Committee in February 199 1. THE INTERNATIONAL FEDERATION OF PHARMACEUTICAL MANUFACTURERS’ ASSOCIATIONS (IFPMA) CODE OF MARKETING PRACTICES AND THE RESPONSE OF CONSUMER GROUPS
Placed on the defensive by the adoption of the essential drugs concept and continuing reports of promotional abuse in developing countries, the pharmaceutical industry promulgated the IFPMA Code of Pharmaceutical Marketing Practices in 1981 [18]. Member companies were called upon to conduct all their dealings with “complete candor” and to restrict their claims to those that could be supported by scientific fact. The code requires printed advertisements
Drug Promotion and Labeling in Developing Countries
to include: “A succinct statement of the side effects, precautions and contraindications” [19]. Clinically important risks were to be disclosed. This was an attempt by the manufacturers to promote self-regulation rather than regulation by WHO actions. Another significant development occurred in 1981-the establishment of Health Action International (HAI). HA1 was formed as a consumer advocacy and public interest organization “to further the safe, rational and economic use of pharmaceuticals worldwide” [17]. While HA1 actively lobbied the WHO in support of the DAP, it was also critical, as were other consumer groups, of the IFPMA code. Critics noted the absence of any monitoring mechanism or punitive recourse. “The major sanction against any company that transgresses the code will continue to be the sanction of adverse publicity,” declared the IFPMA [20]. The industry has long touted governmental agencies in the developing world as appropriate loci for the regulation of drug sales and marketing. Such an approach appears impractical. According to Arthur Yellin, assistant to the acting director of the U.S. Food and Drug Administration’s Division of Drug Advertising and Labeling, the “vast majority” of promotional materials are false or misleading [21]. Nevertheless, even in a wealthy nation like the U.S., he said, regulatory action has been taken in only 5% of cases, due to lack of resources. Some activist groups have sought to use the IFPMA code to address misleading pharmaceutical marketing. The Medical Lobby for Appropriate Marketing (MaLAM) has filed over 450 alleged breaches of the code with the IFPMA. The industry association acknowledged that 168 were indeed code infringements, but their response time was so slow that in many cases the advertising run may have been completed. Many alleged code breaches were left unaddressed as the companies were not members of the IFPMA [20]. Health activist Andrew Chetley also has filed complaints with the IFPMA about advertisements in alleged contravention of the code. Of his initial group of 189 complaints, the industry replied to 167 (88.4%) 58% of which were ruled valid. In 1988 he filed an additional 70 complaints [22]. The results of the consumer groups’ analysis of the response to the IFPMA code is not surprising in view of the experience in Great Britain with a similar code adopted
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in 1958 by the Association of the British Pharmaceutical Industry (ABPI). A recent analysis by Herxheimer and Collier revealed 379 breaches between 1983 and 1988. The authors estimated that the Medicines Act had been broken over 1200 times between 1972 and 1988 and they concluded [23]: “The evidence suggests that the code has failed to deter promotional excesses. The ABPI’s wish to secure compliance with the code seems weaker than its wish to preempt outside criticism and action; its self regulation seems to be a service to itself rather than to the public.” REGULATORY
ACTIVITY OF EXPORTING NATIONS
The regulatory policies of exporting nations are of growing importance to developing nations. The first legislation to control drugs was enacted in England little more than a century ago. Switzerland followed suit in 1900 and the U.S. in 1906. Increased regulation and scientific advances have evolved together, although not always harmoniously, ever since [24]. Although most European countries developed some form of drug regulation in the early years of this century, several had only limited systems as late as 1960. Norway and Sweden were the first countries to develop regulations relevant to safety and efficacy in the 1920s. It was not until 1938, with enactment of the Food, Drug and Cosmetic Act in the U.S., that physicians assumed a central role as agents for consumers. While few countries followed Norway, Sweden and the U.S. in the 1920s and 1930s virtually all European nations developed regulations regarding safety and efficacy after the thalidomide tragedy in Europe in the late 1950s and early 1960s. One means for addressing irrational drug promotion practices in the developing world is through the regulatory authorities of the industrialized exporting nations. Despite the development of strong regulatory policies for drugs used domestically, industrialized countries, with the exception of the U.S. until 1986, have permitted export of drugs not approved for use within the country. Indeed, many governments consider the export of pharmaceuticals highly desirable and often regulate exports differently than drugs approved for domestic use.
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In 1986 the Drug Export Amendments Act (Public Law 99-660) was ratified by the U.S. Congress. For the first time it permitted the export of drugs unapproved for use in the U.S. After lengthy debate, a list of 21 receiving countries, mostly in Europe, was designated. Those countries were precluded from reexporting unapproved U.S. pharmaceuticals. The U.S. Office of Technology Assessment is currently completing a study of the labeling of 500 approved and unapproved drugs exported by U.S. corporations to Kenya, Thailand, Panama and Brazil. The report is expected to be released in the fall of 199 1. In recent years, attention in Europe has centered on the report of the Committee on the Environment, Public Health and Consumer Protection (Banotti Report) of the European Parliament on the Export of Pharmaceuticals from the European Community to the Developing World [25]. Three principles endorsed by the report were subsequently incorporated into draft legislation, passed unanimously by the European Parliament’s Environment Committee, and presented to the full Parliament for further debate: (1) Package inserts with exported drugs should contain information of the same standard as that required in the exporting country. (2) Manufacturers would be required to inform importing nations that a given preparation had been withdrawn or restricted for safety reasons. (3) Drugs banned in the European Community could only be exported if, after receiving all information relevant to the ban, the importing country specifically requested the drug (the doctrine of “prior informed consent”). With broad support from across the political spectrum, the amendments garnered 240 votes in favor to 63 against. However, 260 votes (an absolute majority) were required and the amendments were defeated. The issue will surely return. THE DRUGGING CONTINUES
Our recent findings do indeed suggest an manuals improvement in the prescribing being used by physicians around the world. While this is a useful index of overall trends in drug marketing and promotion in the
developing world, it does not adequately account for certain realities of drug use in that setting. Information contained in the regional prescribing manuals may differ from other advertising material provided by the company. In Nigeria, for example, product package inserts tend to make added claims of efficacy and omit dangers listed in the U.S. Physicians Desk Reference [26]. Detailers have incentives to promote drug use for indications beyond those listed in the prescribing guides [27]. While there is one company “rep” for every 10 physicians in developed nations, ratios of one detailer to three physicians are not uncommon in the Third World [7]. Another technique is the “promotional clinical trial” in which third rate clinical trials are conducted in order to forestall possible governmental regulation [28]. The double standard of promoting a drug only for scientifically based indications in developed countries while expanding its indications in developing ones persists. The marketing of anabolic steroids by the Dutch multinational, Organon [29], and the promotion of Sibelium (flunarizine dihydrochloride) for pityriasis versicolor by Janssen in the Philippines [30] testify to the resilience of such practices. Unjustified claims of efficacy or safety continue to proliferate. In Pakistan, Janssen markets Imodium (loperamide) drops for the treatment of diarrhea. A report in the Lancet documented 19 cases of severe abdominal distension and paralytic ileus associated with at least six deaths in infants administered the drug [30]. Numerous reports document misleading promotion in Pakistan [32], Asia and the Middle East [33], Kenya [34] and Francophone Africa 1351. Thus, while changes in the prescribing guides may be significant, advertising through other methods and prescribing practices in the local setting may be little altered [36]. The combination of overzealous promotion, unjustifiable claims of efficacy, physicians with little opportunity for continuing medical education, and widespread over-the-counter drug availability has potentially lethal implications for the patient [37]. Even when multinational corporations remove unsafe or questionable drugs from the market, or improve their promotional practices, it is no guarantee that indigenous companies will follow suit or
Drug Promotion and Labeling in Developing Countries
the drug regulatory agencies in Third World countries will be able to control their practices. CONCLUSION
The past decade-and-a-half has seen the issue of pharmaceutical use in the developing world rise from obscurity to one intermittently occupying the headlines across the globe. Solutions to the issues raised have been offered by the WHO, developing and developed world governments, consumer activists and the industry itself. While some progress has indeed been made, particularly among multinational companies and in the prescribing guides, evidence of continued abuse is legion. It will take concerted effort by all affected parties before satisfactory resolution of the remaining issues can be realized. REFERENCES 1. Lionel W, Herxheimer A. Coherent policies on drugs: formulation and implementation. In: Blum R ef al., Eds. Pharmaceuticals and Health Policy. London: Croom Helm; 1981: 24&267. 2. Stenzel C. The role of international organizations in medicines policy. In: Blum R et al., Eds. Pharmaceutlcals and Health Policy. London: Croom Helm; 1981: 21 l-239. 3. Silverman M. The Drugging of the Americas. Berkeley: University of California Press; 1976. 4. Medawar C. Insult or Injury? London: Lithosphere Ltd; 1979. 5. Yudkin JS. Provisions of medicines in a developing country. Lancet 1978; April 15: 81&812. 6. Melrose D. Bitter Pills. Oxford: Oxfam Publications; 1982. 7. Silverman M, Lee PR, Lydecker M. Prescriptions for Death: The Drugging of the Third World. Berkeley: University of California Press; 1982. 8. Silverman M, Lee PR, Lydecker M. Drug promotion: the third world revisited. Intern J Health Serv 1986: 16(4): 659667. 9. Silverman H, Lyaecker M, Lee PR. The drug swindlers. Intern J Health Serv 1990; 20(4): 561-572. 10. Mahler H. Report to the 28th World Health Assembly. official Records of the World Health Organization 1975; 226 (Annex 13): 96110. 11. London School of Hygiene and Tropical Medicine, Koninklijk Instituut voor de Tropen. An Evaluation of WHO’s Action Programme on Essential Drags. Copenhagen: DANIDA; 1989. 12. Hogerzeil HV, et al. Impact of an essential drugs programme on availability and rational use of drugs. Lancet 1989; Jan 21: 141-142.
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13. Grant JP. Africa: the Bamako Initiative. In: The State of the World’s Children 1989. Oxford: Oxford University Press; 1989. 14. The Bamako Initiative. Lancet 1988; Nov 19: 1177. 15. Radolf A. UN has bitter pill in mind for international drug firms. San Francisco Examiner; 1981 Sept 16. Manufacturers’ Association. The 16. Pharmaceutical health consequences of restricted drug lists. Washington, November; 1985. 17. Reich MR. Essential drugs: economics and politics in international health. Health Policy 1987; 8: 39-57. 18. IFPMA Code of Pharmaceutical Marketing Practices. In: Silverman M, Lee PR, Lydecker M, Eds. Prescrlp tions for Death: The Dragging of the Third World. Berkeley: University of California Press: 1982: 157-160. 19. International Federation of Pharmaceutical Manufacturers’ Associations. IFPMA Code of Pharmaceutical Marketing Practices. Geneva; 1987. 20. International drug marketing code. Lancet 1988; April 30: 988. 21. FDA’s drug promotion problems. Scrip 1989; Feb 24. 22. 70 breaches of IFPMA code alleged. Scrip 1988; April 5. 23. Herxheimer A, Collier J. Promotion by the British pharmaceutical industry, 1983-8: A critical analysis of self regulation. Br Med J 1990; 300: 307-311. 24. Lee PR, Herzstein J. International drug regulation. Ann Rev Public Health 1986; 7: 217-235. 25. Committee on the Environment, Public Health and Consumer Protection. Draft report on the export of pharmaceutical products from the European Community to the countries of the Third World. European Parliament, Feb 13; 1986. 26. Nosakhare GO. Overpromotion of drugs in international product package inserts. Tropical Doctor 1983; 13: 5-8. 27. Lexchin J. Doctors and detailers: therapeutic education or pharmaceutical promotion? Intern J Health Serv 1989; 19: 663-679. 28. Kiatboonsri P, Richter J. Unethical trials of dipyrone in Thailand. Lancet 1988; Dee 24/31: 1491. 29. Werkgroep Medische Ontwikkelngs Samenwerking. Anaholic Steroids. Amsterdam: WEMOS: 1987. 30. Tan ML. Dying for Drugs: Pill Power and politics in the Philippines. Quezon City: Health Action Information Network; 1988. 31. Bhutta TI, Tahir KI. Loperamide poisoning in children. Lancet 1990; Feb 10: 363. 32. Birley JLT. Drug advertisements in developing countries. Lancet 1989; Jan 28: 220. 33. Hosking G. Drug marketing in the third world. Lancet 1986; July 19: 164. 34. Misuse of antidiarrhoeal medicines. Lancet 1989; Ott 21: 35. “Misleading promotion” in Africa attacked. Scrip 1990; Jan 26. 36. Tomson G, Sterky G. Self-prescribing by way of pharmacies in three Asian developing countries. Lancet 1986; Sept 13: 620-621. 37. Greenhalgh TK. Drug marketing in the third world: Beneath the cosmetic reforms. Lancet 1986; June 7: 1318-1320.
