Drug Labeling in Developing Countries. (1993)

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Codes of Conduct and Voluntary Guidelines for Pharmaceutical Information | 137 dent, two vice-presidents, and an executive vice- president. The Code also notes that the commit- tee is counseled by three independent reviewers (111); however, the Jen Year Report on the IFPMA Code (110) makes no mention of the in- dependent reviewers and the executive director of the IFPMA has stated it is not feasible to have outsiders review the complaints (187). When the President’s Committee has reviewed a case, a for- mal reply is sent to the complainant. The IFPMA states that no member company or member asso- ciation has failed to take corrective action when found to be in violation of the Code (110). Because the Code is voluntary, IFPMA relies on adverse publicity as a “stick” to keep mem- bers in compliance. Status reports on the Code (the list of all complaints made, the companies involved, and the actions taken) are public and can be obtained from IFPMA, though they are not distributed widely. Code-related activities are also summarized (by number and type of com- plaint, and by action taken) in the IFPMA newsletter, Health Horizons, and certain interna- tional pharmaceutical publications also report on complaints brought under the IFPMA Code (e.g., SCRIP World Pharmaceutical News). § Reporting and Resolution of iFPMA Code Violations The IFPMA complaint procedure has been used by consumer groups, WHO, and by individ- uals. Between 1982 and 1991, the IFPMA re- ceived 72 complaints, comprising 926 separate cases. Forty percent of the complaints (account- ing for 86 percent of the cases) were brought by consumer groups, with WHO accounting for an- other 35 complaints (involving 100 cases) (110). In 1987, 13 complaints involving 509 separate in- stances were filed. The majority of these com- plaints were filed by the Medical Lobby for Appropriate Marketing (MaLAM), an interna- tional doctors lobbying network (See ch. 7.) (130). Most of their complaints referred to adver- tisements in prescribing guides (110). Approximately 56 percent of complaints (535 citations) concern Section IV of the IFPMA Code. In particular, these complaints have fo- cused on the lack of full disclosure of active ingredients, the nature of indications and the dis- closure of side effects, precautions, and contra- indications. Many of the complaints have focused on reminder advertisements, which need not carry complete information unless the pharma- ceutical’s use entails specific precautionary mea- sures (110). MaLAM, one of the groups whose complaints have focused on reminder advertise- ments, Claims that the IFPMA has refused to clar- ify the exact definition of a reminder or the phrase “specific precautionary measures.” Ac- cording to MaLAM, IFPMA has permitted rela- tively long advertisements (more than 200 words) to be classified as reminders, exempting them from the more inclusive requirements for full advertisements. MaLAM also cited examples of reminders that, as required, state “further in- formation is available on request,” but either fail to provide an address, or refer readers to informa- tion available only if the drug is purchased (130,196). From August 1989 through August 1990, over half of the 34 breaches of the Code (out of 74 cases resolved) were for failure to adequately support claims for a product with scientific evi- dence, or for making claims not in accordance with “needs of public health.” Six advertisements were cited for using the word “safe” without proper qualification. Twelve other advertise- ments failed to include all the information re- quired by the Code (109). U.S. pharmaceutical companies were responsible for six of the 34 breaches: one for failing to use the non-propri- etary name, three for failing to include complete information in advertisements, one for including advertising claims that were stronger than justi- fied, and one for using the word “‘safe”’ in an un- qualified manner (109). Not all complaints are found by the President’s Committee to violate the Code. Of the 926 cases resolved between 1982 and 1991, approximately

138 | Drug Labeling In Developing Countries 56 percent were declared by the IFPMA to be breaches; 21 percent were not breaches; 10 per- cent were declared invalid because the complaint was based on false or out-of-date information, or was a repeat complaint about the same advertise- ment; and 13 percent did not involve member as- sociation companies.” i Criticisms of the Code fhe IFPMA Code has been criticized by both pharmaceutical associations and health activists because its requirements lack specificity and are prone to subjective interpretation (103,196,223). The Code requires, for instance, that information on products conform to “ethical standards and standards of good taste” (111), without further explanation. On another point, the Code states that a product should not be promoted as safe and effective for a particular indication before it has been approved officially for that indication, but also states that the scientific community and the public have a right to be “fully informed” of the results of investigational studies (111). So while the Code does not permit a company to market a drug for indications not approved by a regulatory authority, the company may disseminate the re- sults of studies that support unapproved indica- tions. : With respect to pharmaceutical sales represen- tatives, the Code does not define what constitutes “sufficient training” or the type of information sales representatives must provide, and it does not provide guidance on what might be a reason- able amount of free samples. According to one activist, the only provision that is not ambiguous is the requirement that the word “safe” be quali- fied (103). IFPMA has also been criticized for the amount of time it takes to make a determination on al- leged infractions; MaLAM has claimed that the delays permit companies to continue running advertisements that violate the Code (130). MaLAM filed 208 complaints in January 1987, and the IFPMA responded with an interim report on 165 of them 7 months later. This interim re- port listed 89 infringements, and 28 “invalid complaints.” The remaining 43 complaints were not acted on because the companies involved were not members of IFPMA associations. In April 1987, MaLAM filed another 254 complaints, and the IFPMA responded to 111 of them almost a year later, in March 1988, leaving 143 complaints unresolved. This response in- cluded findings of 44 new breaches and 42 repeat advertisements from the first submission by MaLAM (130). IFPMA classified these 42 repeat submissions as invalid complaints, rather than continued infractions, as MaLAM contended they were (130). One activist, who filed 259 com- plaints between November 1985 and April 1988, reported that the average time taken to resolve 222 of his complaints was about 7 months (195). IFPMA explains that the large number of com- plaints received in 1987 could be interpreted as an attempt to “break the system,” as many of them did not include documentation, making res- olution of those cases more difficult (110). IFPMA also points out that a delay in issuing a decision does not necessarily delay remedy of a breach. IFPMA claims that companies often take remedial action soon after being informed of a complaint, before the IFPMA decision is made. Perhaps the most controversial aspect of the Code is IFPMA’s interpretation of provisions re- quiring deference to national laws. IFPMA ac- knowledges that it would be desirable for label- ing, packaging, leaflets, and data sheets used in developing countries to be consistent with the ones used in industrialized countries. However, it recognizes that a company ultimately must fol- low the regulations of the country in which the drug is marketed. According to IFPMA, regulato- 9 Although the IFPMA may contact the member association in the country where the company is located, the complaint is not a breach un- less the company is part of a member association of the IFPMA (110).

Codes of Conduct and Voluntary Guldelines for Pharmaceutical Information | 139 ry requirements differ among countries for good reasons (111): . . .[tJhe decision of a national authority with re- gard to the permitted indications and precau- tionary information to be provided about the product must take precedence. Furthermore, when a product has been evaluated and registered by an established regulatory au- thority, the approval by itself is accepted as ade- quate evidence of the product’s efficacy. IFPMA does not challenge the decisions or judgments of national regulatory agencies in any country (9). MaLAM asserts that the IFPMA position is flawed, noting that the Code recognizes that “Third World countries are not aware of the indi- cations, contra-indications, side-effects, etc. of individual drugs that have been adopted in devel- oped countries” (111), yet IFPMA advocates de- ferring to regulatory bodies of developing coun- tries on those issues. MaLAM contends that the point of self-regulation is to develop a voluntary standard that is compatible with, but different from, the government standard. According to MaLAM, industry standards should meet or ex- ceed those of the government, especially when the government agency has limited resources for drug regulation (139). Despite the criticisms of the Code, it remains one of the few formal mechanisms for challieng- ing specific advertisements. The complaint pro- cedure has been responsible for at least some im- provements in pharmaceutical promotion. In the past 2 years, IFPMA has received only 17 com- plaints involving 34 different instances (110). Consumer groups, however, still report violations of the Code and continue to push for stronger mechanisms for controlling promotion of phar- maceutical products (39). SUMMARY Codes of conduct offer a possible means of setting international standards for drug labeling without compromising the sovereignty of indi- vidual countries. However, even though the codes are voluntary, they are not necessarily easy to de- velop, as the Transnational Code demonstrates. While not binding legally, they are formal pro- nouncements and will not be endorsed by gov- ernments that do not agree with their provisions. The most relevant precedent for a pharmaceutical labeling code is the Breast-Milk Substitutes Code. That Code was devised at a time of public outrage at the behavior of certain MNCs, howev- er, and addressed a less complex issue than that of drug labeling. Codes of conduct provide general guidance and principles for behavior. A code of conduct for pharmaceutical labeling might define the cat- egories of information that should be on a label and create some uniformity in labeling format. It could also address the type of information that should be presented to a developing country reg- ulatory body with an application for registration. A code would not, however, define the content or wording of the label for each individual product. The overall impact of such a code would depend to a great extent on how it was implemented and monitored over the long term.

Efforts to Improve Drug Information In Developing Countries | / rug labeling is not the only, or necessarily the most im- portant, pharmaceutical issue facing developing coun- tries, but it is recognized as an essential component of effective drug regulation. The World Health Organiza- tion (WHO), national governments, and private organizations have made efforts to promote the rational use of drugs, and with- in that broad objective, to improve the prescribing information available in developing countries. The activities of WHO, the U.S. Food and Drug Administration (FDA), and private groups related to drug labeling are discussed in this chapter. THE WORLD HEALTH ORGANIZATION In the past decade, pharmaceutical programs of the World Health Organization (WHO), in conjunction with other donors, have assisted developing countries in formulating comprehen- sive national drug policies (135). The focus of many national programs is pharmaceutical supply and consumption in the pub- lic sector, but strengthening regulation has been another priority. The following discussion covers briefly the main WHO activi- ties directed specifically at improving drug regulation and pre- scribing information for physicians. — Action Program on Essential Drugs WHO direct country support for pharmaceutical issues is pro- vided primarily through the Action Program on Essential Drugs (APED). APED promotes the rational use of drugs all over the world, especially in developing countries.’ The core of the ' For an overview of the history of the APED and the political constraints on WHO's efforts in this area, see reference number 183. 141

PH OT O CR ED IT : T. FA RK AS , WH O 142 | Drug Labeling in Deveioping Countries Action Program is WHO’s “Model Essential Drug List,” which can be adopted by countries, modified to fit their health needs, and used to promote the rational use of a limited number of pharmaceuticals. APED also promotes improved registration systems to better ensure that only safe, effective, and properly labeled products enter the market. WHO provides training materials and semi- nars to achieve its goals. Among the publications relevant to drug labeling are: the Model Guide to Good Prescribing (286), developed in conjunc- tion with the Gréningen University in the Netherlands, and designed to be used in under- graduate medical education; the Manual for Rural Health Workers: Diagnosis and Treatment with Essential Drugs (47); and The Essential Drugs Monitor, a quarterly newspaper that dis- cusses all aspects of essential drug programs, fo- cusing on existing programs in developing coun- tries. The Essential Drugs Monitor is distributed to 28,000 subscribers and is read by 180,000 people worldwide (286). APED also has a Documentation Center that distributes more than 20,000 publications a year and issues a periodi- cally updated bibliography of available materials (on diskette and in printed form) (286). i Drug Management and Pollcies WHO’s Division of Drug Management and Policies (DMP), which is independent of the Action Programme on Essential Drugs, is re- sponsible for a number of functions involving pharmaceutical issues. The DMP’s units include Biological Standardization, Drug Regulatory Support, Drug Safety and Efficacy, and Quality Assurance. The DMP develops the Model Prescribing Information used by APED and co- ordinates the exchange of information on safety and efficacy of pharmaceuticals. In addition, the DMP is responsible for monitoring and further developing WHO’s Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce, which is discussed below. i WHO Certification Scheme In 1969, WHO endorsed requirements for “Good Practices in the Manufacture and Quality Control of Drugs” (Guidelines on Good Manu- facturing Standards) (285). These guidelines were the starting point for the “Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce,’ which was adopted in 1975 (275). The Certifica- tion Scheme was designed to assist countries lacking a comprehensive or effective drug con- trol or registration system to ensure the safety and quality of imported drugs. Under the Certifi- cation Scheme, an importing country may re- quest that the regulatory authority of the country in which the drug is manufactured provide a cer- Sample of WHO essential drugs.

Efforts to Improve Drug Information In Developing Countries | 143 tificate assuring that it was manufactured in ac- cordance with good manufacturing practices. As originally designed, the certificate included the name and dosage form of the drug, the active in- gredients, and either certified that the product was approved for marketing in the country of ori- gin, or explained why it was not. In addition, the Drug prescribing by village health worker in Bangladesh. regulatory authority certified that the factory pro- ducing the drug was inspected regularly and complied with WHO guidelines on good manu- facturing practices. In 1984, the Third International Conference of Drug Regulatory Authorities (cosponsored by WHO and the U.S. FDA) recommended that the product labeling information approved in the country of origin be submitted with the certifi- cate. They also recommended that the Certification Scheme be broadened to include imports of raw materials and unfinished products (275). These recommendations were adopted in 1988 (277). The new certificates require copies of all labeling supplied with the product in the country of origin, including approved packaging materials and package inserts (277). WHO recently issued proposed new guide- lines for the Certification Scheme, which were endorsed by the World Health Assembly (266). The new guidelines call for the issuance of one of three different certificates: certificate of a phar- maceutical product (see figure 7-1), statement of licensing status of a pharmaceutical product, and batch certificate of a pharmaceutical product (285). The certificate of a pharmaceutical prod- uct is used by an importing country when: 1) the country is evaluating whether to approve a prod- uct for import and sale and 2) when administra- tive action is required to renew, extend, vary, or review an existing license for import and sale (285). The company exporting the product is re- sponsible for requesting that a certificate be is- sued. So, if OTA, Inc. wished to export a drug to Thailand, and the Thai regulatory authority wanted a WHO certificate of a pharmaceutical product, OTA, Inc. would ask the FDA to issue a certificate to Thailand. Under WHO’s Guide- lines, the certificate is considered a confidential document. Man purchasing low-priced essential drugs in Nepal. O H M ‘ S L L N S S W : LI GS HO O L O H d

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Efforts to Improve Drug Information In Developing Countries | 145 The statement of licensing status of a product attests that the product has been licensed for sale in the country of export. The statement is intend- ed to be used by importers considering bids made in response to an international tender for drugs (285). The batch certificate of a pharmaceutical product provides information on the quality and expiration date of a specific batch of the product, including results of any analyses undertaken on the batch. For most products, the batch certificate is issued by the manufacturer. For vaccines, sera, and other biological products, the certificate is is- sued by the regulatory authority (285). By 1990, 129 countries had notified WHO that they intended to use the Certification Scheme; however, most of the countries opted to use it as a means of controlling imports, not as a means to support exports (52). Countries were regularly requesting certificates for imports, but did not have a policy of providing certificates with ex- ports. This is not surprising because in order to issue a certificate a country must ensure that: e the authorization for sale or distribution is subject to appropriate testing, e its pharmaceutical industry conforms with recommended standards for the manufacture and quality control of pharmaceuticals, e the competent authority is given the authori- ty to carry out complete inspections of the pharmaceutical manufacturing facilities, and e the country’s inspectors are qualified and experienced. It is likely that only those countries with devel- oped drug regulatory bodies could provide cer- tificates that meet these criteria (285). In addi- tion, evidence suggests that the Scheme is not used optimally by developing countries, particu- larly in Africa, which relies heavily on imported pharmaceuticals (275,200). The Certification Scheme has limitations. Certificates may be difficult to obtain for drugs manufactured in more than one country or manu- factured in one country and packaged in another. Donated drugs or drugs procured from whole- salers and brokers with a wide variety of sources may not be easily certified. Products manufac- tured specifically for a foreign agency or govern- ment may differ from the manufacturer’s stan- dard products and labeling from the standard product may not be appropriate for the special product (275). If a country requests a certificate only at the time of first import or when a drug is reregistered, the country may not obtain updated Transport of essential drugs in Latin America information about the drug (164). Countries with inadequate administrative or legal infrastructure for drug regulation may be unable to use the Certification Scheme effectively (164). APED and DMP have initiated activities to improve the Certification Scheme and expand its adoption. The United States Agency for Inter- national Development (USAID) is supporting a WHO evaluation of the Certification Scheme in

146 | Drug Labeling in Developing Countries developing countries and the DMP is carrying out field trials in a number of countries (259, 286). E Distribution of Prescribing Information In addition to labeling provided with a drug, compendia of pharmaceutical information from industrialized countries are useful sources of pre- scribing information for officials and physicians. WHO is working to provide national drug regula- tory authorities in developing countries with three of these compendia, which contain infor- mation approved by the regulatory authorities in those countries: the Dictionnaire Vidal (249) (in- formation approved by the French Ministry of Health); Association of the British Pharmaceu- tical Industry Data Sheet Compendium (10) (in- formation in compliance with the regulations of the United Kingdom), and the Physicians’ Desk Reference (information in compliance with regu- lations of the U.S. FDA) (258). DMP has also begun work on a series of publi- cations entitled WHO Model Prescribing Information for those drugs on the essential drugs list that are of particular interest to devel- oping countries. The first one, Drugs Used in Anesthesia (280), was published in 1989; Drugs Used in Parasitic Diseases (282) was released during 1990; and Drugs Used in Mycobacterial Diseases (284) in 1991, with more in prepara- tion.” l Access to New Information on Safety and Efficacy of Pharmaceuticals Most industrialized countries have formal pro- grams for monitoring adverse reactions associat- ed with pharmaceuticals. Developing countries typically do not have the resources to do this in their own countries, and as a result, may not be able to respond to the need to revise labeling, or even withdraw a drug from the market. One WHO priority is to secure the regular exchange of information on the safety and efficacy of phar- maceuticals and to promptly transmit new infor- mation on serious side effects to national health authorities (258). The DMP receives information regularly on decisions of regulatory authorities and voluntary decisions of manufacturers related to the safety of pharmaceuticals. During 1986, for example, WHO received information on deci- sions about 360 pharmaceutical products from 35 countries (258). This information is disseminated monthly to the drug regulatory authorities of member countries through the WHO Pharma- ceutical Newsletter (285). DMP also produces WHO Drug Information, a quarterly journal that provides discursive commentaries on the more important actions of national drug regulatory bodies (258,285). WHO has established collaborating centers in each of its five regions for the purpose of infor- mation dissemination, training, and operational research. The most recent collaborating center was established in India in 1988 to serve 11 countries in Southeast Asia (131,274). These collaborating centers are distinct from the WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden, which is an international center for monitoring adverse drug reactions. Thirty-three countries, including the United States, provide case reports on ad- verse drug reactions to the Uppsala Centre where the data are combined and analyzed to detect re- lationships between drugs and rare adverse reac- tions (290). The information in the database at Uppsala, which as of 1991 contained 950,000 in- dividual case reports (290), is available only to the countries that participate in reporting. Nonparticipating countries may learn about the adverse reactions through medical journals or through the regulatory actions of participating 2 WHO is currently working on prescribing guid-s for drugs used in treating sexually transmitted diseases, including AIDS, and other bac- terial diseases, and in neurology and dermatology (285).

Efforts to Improve Drug Information in Developing Countries | 147 countries, but there is no guarantee that they, in fact, will (290). THE U.S. FOOD AND DRUG ADMINISTRATION The FDA is primarily a domestic agency, but being the regulatory agency for one of the largest pharmaceutical markets in the world, it is also in- volved in international pharmaceutical issues. The FDA is not a development agency and it does not generally help other countries with projects specifically designed to improve the marketing and labeling of drugs, but it does assist develop- ing countries by sharing its expertise with their drug regulatory personnel. Most of FDA’s international activities are co- ordinated by its International Affairs Staff (IAS) under the Associate Commissioner for Health Affairs. The IAS is principal FDA contact point and liaison with foreign counterpart agencies, foreign embassies, international regional organi- zations, U.S. Government agencies (e.g., the Office of Intemational Affairs, U.S. Public Health Service; USAID, the U.S. Trade Representative), and U.S. embassies. IAS arranges the participa- tion of FDA officials in U.S. delegations to inter- national meetings, such as those held by WHO. Four IAS officials are responsible for bilateral li- aison within broad geographic regions. One of FDA’s most visible international activ- ities is the dissemination of information about regulatory actions. FDA sends monthly updates to WHO and representatives of the European Community on important regulatory develop- ments, including proposed regulations and poli- Clies; reports of serious adverse reactions from pharmaceuticals; the monthly list of approvals for new drugs, medical devices, and biologics; and other public information. WHO may incor- porate this information in its newsletters, which are distributed internationally. The FDA also sends its Medical Bulletin (see, e.g., ref. 150) to more than 800 government and academic organizations around the world. Many of these institutions are in industrialized coun- tries (e.g., more than 129 Canadian institutions are on FDA’s mailing list), but a number are in developing countries. The Medical Bulletin fo- cuses on new FDA policies and findings on par- ticular drugs and devices. For example, a recent issue discussed the dangers of angiotensin con- verting enzyme (ACE) inhibitors during the sec- ond and third trimesters of pregnancy, allergic re- actions with dialysis and ACE inhibitors, new Halcion labeling, warnings about sporicidin products, FDA proposed food labeling reforms, recommendations on silicone breast implants, and foodbome diseases in nursing homes (150). Until the end of 1991, the FDA sent quarterly information packets to WHO, the Pan American Health Organization (PAHO), and approximately 70 drug regulatory authorities throughout the world (95). This policy has now modified to sending important policy papers to WHO and to 62 foreign embassies located in Washington, DC. The material sent by FDA does not necessarily focus on labeling for specific drugs but instead highlights regulatory decisions that U.S. regula- tors believe are important (32). The FDA also has a special procedure for noti- fying foreign purchasers that a drug or medical device has been withdrawn from the U.S. market for safety reasons. FDA contacts the U.S. compa- ny for a list of foreign individuals, institutions, and government agencies that have imported the product. The IAS works with the U.S. De- partment of State to provide the U.S. embassies in the countries in which the product is sold with a list of the purchasers so that the purchasers can be notified (168). FDA provides a summary of the reasons for withdrawal, and encourages the U.S. company to provide foreign purchasers with complete information. FDA may evaluate the effectiveness of the company’s notice by request- ing that the U.S. embassies follow up with for- eign purchasers to see whether information was provided. If the company has not provided ade- quate information, FDA may ask them to send it but does so without legal authority. There have

148 | Drug Labeling in Deveioping Countries been few drug withdrawals in which FDA has used this special notification procedure (31). FDA also responds to requests for information from other countries. FDA is currently setting up an electronic bulletin board that will contain all public information issued by the FDA including: Enforcement Report (weekly recall list), a drug and device product approval list, Medical Devices and Radiological Health news, FDA Medical Bulletin, FDA Consumer Information, FDA's Federal Register summaries, speeches by FDA officials, FDA congressional testimony, special AIDS information, Veterinary Medicine news, and notice of upcoming FDA public meet- ings. The electronic information will be available through INTERNET, a worldwide research com- puter network of government, military, academic, and other organizations (32). The IAS administers the FDA International Visitors Program. In the year ending September 1991, FDA was visited by 603 representatives from 61 countries. In 1990, the IAS arranged vis- its to the FDA by 789 foreign officials represent- ing 65 countries and multinational organizations (168). FDA cooperates with WHO in various activi- ties. In 1980, the FDA and WHO cosponsored the first International Conference of Drug Regu- latory Authorities, held biannually since then, bringing together regulatory authorities from all over the world. FDA representatives have provid- ed advice and other assistance to various WHO programs including the Action Program on Essential Drugs, WHO’s Management Advisory Committee, the Certification Scheme, the Ethical Criteria for Medicinal Drug Promotion, the prep- aration of Model Drug Prescribing Information, the Model Lists of Essential Drugs, and the Global Program on AIDS (166). FDA is also a WHO Collaborating Center for Monitoring of Adverse Drug Reactions, providing WHO with a monthly accounting of all serious adverse reac- tion reports (168). FDA staff have also assisted WHO with drug regulation projects in developing countries (17). In 1988, for example, the FDA provided a drug specialist for 2 years to PAHO, a regional office of WHO, to assist with formal training programs designed to strengthen national drug agencies and improve pharmaceutical manufacturing (57). Most recently, the FDA agreed to assist USAID in its support of a WHO evaluation of the Certification Scheme (see above) (24,259), and USAID and the FDA will assist in a WHO evalu- ation of its “Guiding Principles for Small Na- tional Authorities” (24, 278). THE U.S. AGENCY FOR INTERNATIONAL DEVELOPMENT Until recently, USAID was not involved di- rectly with WHO’s pharmaceutical work, but has just begun funding a WHO evaluation of both the Certification Scheme and the “Guiding Prin- ciples for Small National Authorities.” USAID is also supporting a WHO project to develop coun- try-specific research on current pharmaceutical use in developing countries. The research will be carried out by the International Network for the Rational Use of Drugs (INRUD) (see below for description of INRUD), which will develop a Drug Use Indicators Manual. The manual will include background, definitions, methodologies for collecting drug use indicators,’ and extensive appendices containing data collection methods, drug and problem lists, and data collection forms (24,113). A report on these activities should be available by the end of 1992. USAID 1s also engaged in a 5-year cooperative agreement with the U.S. Pharmacopoeia to assess and facilitate the distribution of pharmaceutical 3 Drug use indicators include: average number of drugs used per facility; percent of antibiotics or injections, percent of patients not pro- vided drugs; number of essential drugs in stock, patients reporting correct dosing, etc. (113).

Efforts to Improve Drug Information In Developing Countries | 149 information in developing countries, including both information provided to the drug regulatory authorities and to health workers (24). Finally, USAID has requested proposals for a 5-year con- tract addressing three areas of pharmaceutical distribution in developing countries: drug regula- tion and registration; rationalization of procure- ment strategies; and the development of pharma- ceutical information for prescribers, consumers, and drug regulatory authorities (24). CONSUMER HEALTH ADVOCATES A variety of organizations and individuals ad- dress themselves to pharmaceutical issues in de- veloping countries. This section concentrates on groups that act as advocates for political change or focus on the role of multinational pharmaceu- tical companies in the area of drug information. The many organizations that provide health care or focus on health issues other than pharmaceuti- cals are not discussed here. Public health advocacy may take several forms. The most common form is the dissemina- tion of information to the public and the press about actions of industry, international organiza- tions, or governments, that are inconsistent with consumer interests. Consumer boycotts, while difficult to organize, can also be powerful. In ad- dition, public interest organizations may operate as information clearinghouses and many provide educational programs in developing countries. Numerous public interest groups operate in in- dividual countries. Many of the individual health and consumer groups in both developing and in- dustrialized countries are part of a larger interna- tional network, Health Action International (HAI), which itself works closely with the International Organization of Consumers Unions, an umbrella group that helps promote consumer issues and consumer advocacy in many countries. These two groups and selected smaller consumer groups are discussed below. i The International Organization of Consumers Unions The International Organization of Consumers Unions (IOCU) was formed in 1960 as a multi- purpose resource for its membership of 130 con- sumer groups in 51 countries. IOCU’s central of- fice is in the Hague, and its two regional offices are in Penang, Malaysia, and Santiago, Chile. IOCU acts as an information network, coordi- nates consumer activities, holds a triannual world congress, and organizes international seminars and workshops. In 1973, IOCU published one of the first studies on drug labeling in developing countries (see app. A) (61,116) and it continues to be active in drug information as well as other issues of pharmaceutical distribution. In August 1990, IOCU sponsored an International Work- shop on Consumer Health and Drug Information and Education in Penang, Malaysia. The major objective of the workshop was to determine how media could be used effectively to communicate information to parents about children’s health and the rational use of drugs (54). IOCU drug labeling activities include collect- ing relevant information (e.g., general prescrib- ing information, lists of banned or restricted pharmaceuticals, reports of adverse effects) and passing this information on to developing coun- tries. IOCU also publishes reports related to the pharmaceutical industry and rational drug use. In 1981, IOCU published a Consumer Action and Resource Kit on Pharmaceuticals, which focused on 44 “problem” drugs, that could be used by groups in developing countries to lobby against the sale of dangerous drugs (154). IOCU also maintains a network called Con- sumer Interpol, consisting of approximately 260 correspondents in 79 developing and developed countries (117). The correspondents monitor in- formation on newly discovered or newly regulat- ed hazardous consumer products, including phar- maceuticals, such as notifications of banning, restriction, withdrawal, or nonapproval of prod- ucts. This information is received by the Con-

150 | Drug Labeling in Developing Countries sumer Interpol office in Penang and may become the basis for Consumer Alerts sent to all mem- bers of the network. As of March 1991, 85 Consumer Alerts had been sent out, covering hazardous toys, cosmetics, pharmaceuticals, electrical goods, food products, pesticides, and other items (4). Consumer Interpol also distrib- utes a Consumer Interpol Memo, relating select- ed articles and news briefs on consumer issues, and a quarterly Consumer Interpol Focus, with feature stories on specific safety problems or major international initiatives to restrict global trade in hazardous products (3). IOCU has published many books and pam- phliets on technical aspects of pharmaceutical use. In 1988 it published several short pamphlets written by it pharmaceutical adviser, K. Balasubramaniam, including: Policy Options in Pharmaceutical Patents for Developing Asian Countries (14); The Rational Use of Drugs: A Universal Concept (15); Global Marketing of Pharmaceuticals: Prescription for Disaster (12); and Policies and Strategies On Drug Pricing Regulations: International Experiences (13). IOCU also supports publications by other con- sumer organizations. With respect to pharmaceutical issues, IOCU plays a major role in one of the primary intema- tional consumer health organizations, Health Action International. fi Health Action international In 1981, 50 consumer organizations and indi- viduals founded Health Action International (HAI) as an “international antibody” to the ad- verse effects of pharmaceutical marketing. HAI has coordinating offices in Europe, Asia, and Latin America. HAI’s original agenda included (102): 1. developing an information clearinghouse; 2. responding to the IFPMA Code of Pharma- ceutical Marketing Practices; 3. coordinating activist campaigns regarding specific drugs and companies; 4. promoting full implementation of WHO’s Action Program on Essential Drugs; 5. pressuring industry to market drugs that meet “real medical needs,” have “signifi- cant medical value,” and are acceptably safe and efficacious; and 6. supporting nondrug solutions to health problems. HAI has coordinated international advocacy for essential drug policies in lobbying WHO, UNICEF, the European Parliament, and other in- ternational and regional bodies (16,97). For a number of years, HAI lobbied WHO to pass a code of pharmaceutical marketing. In 1982, HAI published its own code of conduct that it hoped would be the basis for a U.N. or WHO international code. The HAI code demon- strates the degree of specificity that consumer groups seek. With respect to labeling, HAI’s code calls for package labels with: 1. specific information on whether the prod- uct is for prescription or OTC use; 2. the non-proprietary name for all active in- gredients printed in equal or greater size than the print used for the manufacturer’s name; 3. information on the class and category of therapeutic use; 4. an explanation of all contraindications that may endanger life or severely endanger health; and 5. a list of all active ingredients. HAI also would limit claims about efficacy, safety, or potency of the product unless they were qualified. In addition, the HAI Code would re- quire that package inserts include: 1) only those indications approved by public health authorities or generally endorsed by reputable and indepen- dent scientific publications, 2) all contraindica- tions that are not included on package label, and 3) a list of active and inactive ingredients (84). Finally, HAI would require graphic warning symbols on all promotional material indicating

Efforts to Improve Drug Information In Developing Countries | 151 products that should be avoided during pregnan- cy or lactation, on all prescription-only products to indicate changes in product information, and on new products for which reports of any adverse reactions or events are required (86). HAI has published a detailed critique of the IFPMA Code and WHO’s Ethical Criteria for Medicinal Drug Promotion (see ch. 6) (86). Another report by HAI presents evidence that the IFPMA Code is not effective in controlling ad- vertising (39). In 1992, HAI carried out the first phase of an international survey of pharmaceuti- cal marketing standards that will evaluate the im- plementation of WHO’s Ethical Criteria for Medicinal Drug Promotion (97). Initial results in- dicate that the Ethical Criteria have not been ef- fective because they have not been implemented at the national level (89). HAI member groups also focus on problems with specific products or categories of product, trying either to have the products removed from the market or to change their labeling or promo- tion. Their campaigns usually consist of docu- menting problems with drug products, challeng- ing the companies involved to respond to their criticisms and, if the company responses are not satisfactory, using public education campaigns “built on solid information and powerful emo- tional pleas” (102). The organization communi- cates through an international newsletter, HAI News. One HAI international campaign was directed at removing inappropriate antidiarrheals from the market. Following a WHO paper on the limited efficacy of antidiarrhea drugs, HAI members in Latin America published a survey of antidiarrhea drugs marketed in Bolivia, Brazil, Chile, Colombia, Costa Rica, Ecuador, Guatemala, Mexico, Peru, Uruguay, and Venezuela. A num- ber of products that WHO said were not effica- cious, and potentially harmful, were widely available in those countries (87). HAT has published various resource books on pharmaceuticals. Problem Drugs (38), a HAI “‘in- formation and campaign pack” on various cate- 330-065 0 - 93 - 6 QL 3 gories of “problem” pharmaceuticals, was first published in 1986. It has since been translated into 8 languages and a new edition is scheduled for release in 1993 (97). Other publications in- clude: Peddling Placebos: An Analysis of Cough and Cold Remedies (36), Antibiotics: The Wrong Drugs for Diarrhoea (35), Cleared for Export (33), The Provision and Use of Drugs in Developing Countries (71), Drugs and Primary Health Care (63), Promoting Health or Pushing Drugs? A Critical Examination of Marketing of Pharmaceuticals (39), A Question of Control (261), and Bitter Facts About Drugs (5). Andrew Chetley, a prominent consumer advocate who has worked with a number of consumer groups, is the author of several of these publications and has re- cently written a book analyzing the role the phar- maceutical industry has played in health care in the developing world (37). In addition to its publications and lobbying, HAI groups help promote and develop national drug policies and sponsor a wide variety of train- ing and education programs. HAI seeks to pro- mote the WHO Ethical Criteria for Medicinal Drug Promotion, and continues to expand and strengthen its ties to local consumer organiza- tions in developing countries (88). SOCIAL AUDIT Social Audit, based in the United Kingdom, is an active HAI member. It has concentrated on the marketing practices of British multinational pharmaceutical corporations in developing coun- tries, but it also has examined their activities in industrialized countries. In 1979, Social Audit published Insult or Injury? An Enquiry into the Marketing and Advertising of British Food and Drug Products in the Third World (142), a work funded largely by IOCU. In 1982, the group pub- lished Drug Diplomacy: Decoding the Conduct of a Multinational Pharmaceutical Company (148). This book chronicles Social Audit’s cam- paign against the marketing claims made by Searle Pharmaceuticals for its antidiarrhea drug

152 | Drug Labeling In Developing Countries Lomotil, a campaign that Social Audit maintains resulted in changes in the labeling (154). In 1980, Social Audit published Drug Disinformation: What British and Multinational Drug Companies Tell Doctors About Their Products, At Home and Abroad (143). This book compared the information for about 900 drugs listed in MIMS prescribing guides in England and Ireland. Although over half of the entries were identical, the study found what they be- lieved to be significant discrepancies for the pre- scribing entries for over 200 products. The main force behind Social Audit is its Director, Charles Medawar. He continues to pub- lish books and articles that keep the work of Social Audit visible. In addition to the titles listed above, he has written: The Wrong Kind of Medicine? (144), Drugs and World Health (146), “International Regulation of the Supply and Use of Pharmaceuticals” (145), and with the support of IOCU, One Drug at A Time: A Report on the Limitation of Fixed Ratio Combination Drugs (149). In 1991, Social Audit published Power and Dependence (147), an examination of the history of benzodiazepine (a class of sedatives that includes diazepam) marketing, focusing on the problems of dependence. BUKO BUKO (the Federal Congress of Development Action Groups), one of the founding members of HAI, is a West German network of approximate- ly 200 consumer groups that focuses on “global malpractice in drug marketing by the multina- tional pharmaceutical companies” (62), in partic- ular Swiss and German companies. In 1987, it published a short report on Hoechst, a German pharmaceutical company, with evidence that Hoechst was marketing drugs in developing countries that had potentially severe side effects, or which had been banned in developed coun- tries, often without complete warnings (62). The study also attacked Hoechst’s practices in Germany, such as the delay of a warning letter to German doctors about several reported adverse reactions (including six deaths) caused by one of its antidepressant products (62). In 1990, BUKO, together with HAI, helped disseminate a study by two German physicians that examined more than 2,000 German and Swiss pharmaceutical products marketed in 26 developing countries. The majority of these prod- ucts were marketed by large multinational corpo- rations. The authors determined whether these drugs met the health needs of the countries in which they were marketed by comparing the sample drugs to those on WHO’s Essential Drug List. The authors also evaluated the efficacy and safety of the drugs using authoritative pharma- ceutical reference books from several countries (7,28,30,75). They reported significant problems in all areas. (See app. A, “The Hartog and Schulte-Sasse Study.”) In addition to its publications, BUKO pro- duces a monthly newsletter Pharma-Brief. The newsletter contains summaries of research on pharmaceutical issues in developing countries and reports on consumer activities (64). BUKO also helps facilitate dialogue on pharmaceutical policies in developing countries. In 1987, for ex- ample, BUKO held a conference in Germany that brought together representatives of nongovern- mental organizations from various developing countries, academia, and industry. The confer- ence focused on the relationship among the num- ber of pharmaceuticals on the market in a coun- try, the quality of those products, and the need for essential drug policies ir countries with limited budgets for health care (85). i Medical Lobby for Appropriate Marketing (MaLAM) MaLAM is an international network of physi- cians that acts as a watchdog for advertising by pharmaceutical companies (199). MaLAM works to encourage companies to provide what they consider “sufficient, consistent, and accurate in- formation” about their products, and primarily

Efforts to Improve Drug Information In Developing Countries | 153 targets marketing claims made in developing countries (254). Each month, MaLAM’s approximately 700 subscribers in more than 40 countries receive a draft letter addressed to a senior executive in a pharmaceutical company questioning a particular marketing practice. MaLAM’s subscribers are asked to sign the letter and return it to MaLAM. A final letter is sent after review by an interna- tional editorial board (153,254). The letters ask the company to provide evidence supporting the contested advertising claim. MaLAM publishes the responses it receives from industry in its newsletter. (Results of some of MaLAM’s work are discussed in ch. 4 and 6.) i International Network for the Rational Use of Drugs (INRUD) Developing countries typically lack the re- sources needed to evaluate national programs, in- cluding drug policies. An organization that pro- vides support for evaluative research is the International Network for the Rational Use of Drugs (INRUD), a nonprofit group based in Boston. INRUD is a cooperative organization of health professionals, administrators, and re- searchers from developing countries who are in- terested in implementing new, innovative pro- grams to improve the use of pharmaceuticals, and is supported by the development agencies of a number of countries (including USAID) and pri- vate foundations (127). INRUD’s strategy is to first engage in research designed to clarify the “dynamics of drug use and. . .the underlying motivations, expectations, and incentives of providers and consumers” (128). According to INRUD, although a number of countries have tried to improve drug use by de- veloping standard treatment protocols, providing drug information, drug bulletins, implementing changes in health training curricula, restricting drug advertising, and using public education, there has been little evaluation of these strategies; they are assumed to have a positive impact. However, studies in industrialized countries have revealed that some of these same interventions have not been very effective (127). The initial INRUD network is limited to seven countries that have demonstrated a commitment to the rational use of essential drugs: Bangladesh, Ghana, Nigeria, the Sudan, Tanzania, Indonesia, and Nepal. Each country has a “Country Core Group” of four to eight people representing vari- ous professional disciplines and organizations. A “Central Support Group” is staffed by Manage- ment Sciences for Health and the Harvard Medical School in Boston. INRUD anticipates that other individuals and organizations interest- ed in the program will become affiliate members and share in information gathering, training, and other activities (128). INRUD also is developing a number of indica- tors of drug use to facilitate comparisons of drug use among countries and identify drug use prob- lems. The study involves field work in Indonesia, Bangladesh, Nepal, Nigeria, and Tanzania. WHO plans to publish a manual on standard drug use indicators based on the results of this study (115). INRUD recently received a grant from USAID to conduct country-specific research with WHO on current pharmaceutical use in developing coun- tries (see section on USAID, above). INRUD publishes a newsletter, INRUD NEWS, reporting on its own activities and on other recent drug utilization studies, and has de- veloped a computerized bibliography of pub- lished and unpublished literature relating to drug use in developing countries (114). In addition, INRUD has developed training materials to pro- mote rational drug use, which it has used in Nepal and will use in Zimbabwe in 1993. INRUD’s future plans include studies of the fac- tors that influence drug prescribing behavior (129). SUMMARY Developing countries face many obstacles to maintaining effective pharmaceutical programs,

154 | Drug Labeling in Developing Countries including lack of political commitment, poor planning capabilities, lack of trained personnel, inadequate financial resources, irrational pre- scribing and dispensing practices, and lack of public awareness of the problems (286). WHO programs and private groups have attempted to help countries by providing information and other services to improve drug regulation, includ- ing the regulation of drug labeling.

Appendix A: Major Pharmaceutical Labeling in Developing Countries he 1970s marked the rise of the consumer movement and a time of increased attention to the operations of multinational corporations (MNCs) in developing countries. Concern was growing that many MNCs operated in a virtually unregulated environment in developing countries, in some cases to the detriment of consumers. A number of consumer groups, health care workers, and repre- sentatives from international organizations raised con- cerns about certain corporate practices in developing countries. One issue raised with respect to pharmaceu- tical companies was the quality of their prescribing in- formation. Small studies began to disclose that a num- ber of pharmaceutical MNCs had labeling standards for developing countries that differed from those for industrialized nations. These studies are discussed below. B 1OCU: The Chloramphenicol Study The first comprehensive study of pharmaceutical labeling in the developing world was carried out by member groups of the International Organization of Consumers Unions (IOCV) in 1972 (116). IOCU ex- amined 55 packs of chloramphenicol marketed by MNCs in 21 countries. Chloramphenicol is an antibi- Otic that can cause aplastic anemia, a serious blood condition. Although aplastic anemia is rare, when it does occur it has a fatality rate of 40 percent or more (210). Since the discovery of this connection in the 1950s, use of chloramphenicol has been limited in the United States and other industrialized countries to treating serious infections when alternative treatments failed. IOCU did not find a single label that included 155 Studies of all the necessary contraindications, and they found wide variation in the wamings given with identical brands sold in different countries (34,61). — IOCU: The Clioquinol Study A larger study was done during 1974 and 1975 on clioquinol, a drug originally introduced for treatment of amoebic dysentery, but often used for treatment of traveler’s diarrhea (53). By the early 1970s, clioquinol was implicated in an epidemic of subacute myelo- optic neuropathy (SMON), an often fatal condition that causes blindness and paralysis. The epidemic claimed the lives of about 10,000 people in Japan. As a result, where it was still available, clioquinol was recommended only for treating acrodermatitis entero- pathica, a serious chronic condition affecting the skin and bowels of young people. At the time of the study, clioquinol had been banned in the United States and Japan, and was avail- able only from a pharmacy in Norway, Sweden, Austria, Finland, France, Iceland, Italy, the Nether- lands, Yugoslavia, New Zealand, some places in Australia, the Philippines, and Denmark. It was avail- able without prescription, but in most cases only from a pharmacy, in the United Kingdom, Belgium, Ire- land, Guatemala, Ghana, South Africa, Tanzania, Egypt, Lebanon, Zambia, Malaysia, Mexico, Sri Lanka, Israel, Greece, Tunisia, Thailand, Taiwan, Iraq, and Brazil. The IOCU researchers obtained 107 drugs contain- ing clioquinol from 39 countries, of which 83 samples from 34 countries included package inserts. Almost all of the package inserts recommended the drug for

156 | Drug Labeling in Developing Countries the treatment of diarrhea and 50 of them recommend- ed it as a prophylactic. The indications were often vague, e.g., “for specific medically indicated prophy- lactic use.” The dosage recommendations on 63 leaflets ranged from 400-1,500 mg per day for 3 to 28 days, despite the fact that the clinical literature recom- mended an adult dose of only 750 mg a day for 14 days (169). Twenty of the leaflets had no recommend- ed dosage. Thirty-two leaflets mentioned the most im- portant contraindications: hyperthyroidism, iodine al- lergy, and malfunctioning of the liver or kidneys; however, 37 leaflets listed no contraindications, in- cluding those from the United Kingdom, New Zealand, Belize, Brazil, Tanzania, Taiwan, Kenya, Spain, Malaysia, and Singapore. One explanation of- fered for the lack of contraindications on certain of these package inserts was that the insert recommend- ed a maximum treatment of 3 days, after which it rec- ommended consulting a doctor if the diarrhea was not cleared up. The risk of an adverse effect from clio- quinol was relatively small if used in low dosage for a few days. Information on side effects was also analyzed. Forty-five leaflets listed the major side effect, periph- eral and optic neuropathy, but only 34 recommended stopping the drug at the first sign of peripheral neuri- tis or optic neuritis. The researchers concluded that wamings were deficient on inserts from the United Kingdom, Bahamas, Belize, New Zealand, Brazil, Indonesia, Thailand, Tanzania, Taiwan, Iraq, Kenya, Malaysia, and Singapore. However, the lack of com- plete warnings in the United Kingdom, Belize, Bahamas, and New Zealand was tempered by the fact that there were instructions that the drug be taken for no more than 3 days. The study also looked at four other halogenated hydroxyquinoline drugs (the same chemical class as clioquinol) because there was some evidence that these drugs also could cause neurological illness. The researchers examined 44 leaflets from 24 countries. Again, there were many differences in indications, contraindications, and warnings on the package leaflets. There were differences among labels within the same country and among labels provided by the same manufacturer for a drug marketed in different countries. Some of the differences might have been attributable to different national regulations, but the differences within countries indicated that differing regulatory requirements were probably not the sole explanation. A number of lawsuits were brought against MNCs that marketed products containing clio- quinol (primarily Ciba-Giegy, a Swiss company, and Takeda and Tanabe from Japan). Damage awards eventually reached almost $900 million. Today, clioquinol is banned in the United States and United Kingdom, and in other industrialized and developing countries. However, a recent study found many products containing clioquinol in India, Indonesia, Thailand, the Middle East, Egypt, Mexico, Central America, Colombia, Venezuela, and Brazil. A number of these products are marketed by domestic companies and their labeling carries little or no wam- ing of possible neurological damage. Despite clio- quinol’s history, it is considered safe and effective in a number of developing countries, and in India is con- sidered an essential drug (212). — !OCU: The Anabolic Steroid Study In 1983, IOCU released a study about the market- ing of anabolic steroids in Germany, Australia, the United Kingdom, the United States, and a number of Asian countries (118).! According to the cited clinical literature, anabolic steroids were recommended only for treatment of certain serious anemias resulting from bone marrow failure, and for treating osteoporo- sis in the elderly. Anabolic steroids were also recom- mended for children with certain growth disorders, but because they can cause subsequent infertility, pre- cocious or abnormal sexual development, and stunt growth, this indication was very limited. Other known side effects of anabolic steroids include ireversible symptoms of masculinization in women (deepening of voice, body hair growth, male-pattern baldness), and in men, atrophy of the testicles, inhibition of sperm development, and impotence. Anabolic ste- roids were also linked to liver tumors, jaundice, acne, and nausea. IOCU examined 38 anabolic steroid products mar- keted in Indonesia, Bangladesh, the Philippines, ' This was not the first study to examine the labeling and marketing of anabolic steroids in developing countries. See also references 134,163,208.

Major Studies of Pharmaceutical Labeling in Developing Countries | 157 Thailand, Mexico, Malaysia, the United States, and West Germany. Fifteen samples came from a single Dutch company, Organon, and the remaining drugs were marketed by Winthrop, a U.S. company, and Schering, a West German company. Package inserts, advertisements, and other promotional literature were examined. The study found examples of these companies mar- keting the same product with complete wamings in developed countries and less-than-complete warnings in developing countries. Anabolic steroids were pro- moted in the developing countries for poor appetite in children, poor weight gain, listlessness, and lack of energy, sometimes using pictures of healthy, well- nourished children. In a number of countries, the drugs were available in easy-to-take drops and syrups, often flavored to make them more palatable to chil- dren. Package inserts in Bangladesh and the Philip- pines stated specifically that there were no contraindi- cations in children. Another 16 package inserts failed to caution against use in children or to recommend that skeletal maturation be checked periodically by x- ray. A majority of the package inserts also failed to wam against use in patients with kidney or liver dis- ease. Side effects were also minimized. Nine package in- serts from developing countries listed no side effects. The majority of products that did include wamings about side effects failed to warn against impotence, enlargement of breasts, liver damage, jaundice, or the more common side effects found in children. i The Yudkin Study In the late 1970s, a British physician, J.S. Yudkin, compared the prescribing information in the African Monthly Index of Medical Specialties (MIMS) with information on the same drugs in the British MIMS (292). He found significant discrepancies in indica- tions and warnings. For example, tetracycline was marketed in Africa with no waming about the risk of tooth discoloration in children. In Britain, anabolic steroids, whose side effects include stunting of growth, virilization (appearance of secondary male sexual characteristics in women) and liver tumors, were rec- ommended only to treat osteoporosis, renal failure, terminal malignancies, and aplastic anemia. In Africa they were also indicated for treatment of malnutrition, weight-loss, as appetite stimulants, and for excessive fatigue. In the African MIMS several different brands of liothyronine, a drug recommended for “severe thy- roid deficiency” in Britain, were marketed for “low- ered metabolic states.” Methadone, which was recom- mended in Britain for severe pain, was marketed in Africa as a cough suppressant. — The Social Audit Studies A 1978 study by the British consumer group, Social Audit, funded principally by IOCU, focused on products of the major British pharmaceutical MNCs: Beecham, Boots, Fisons, Glaxo, ICI, Reckitt and Colman, and Wellcome (142). The study compared the information from British MIMS with MIMS guides from Africa, the Caribbean, and the Middle East. When available, the researchers also looked at detailed prescribing instructions in India and Malay- sia. They found that dosage recommendations in de- veloping countries tended to be greater, even double the dosages recommended in the United Kingdom. The study also found a marked lack of detail about contraindications. For example, the British official prescribing information for Ancoloxin (meclizine), an antiemetic, warned against use in pregnant women ex- cept in cases of severe vomiting. U.S. labeling also wamed against use during pregnancy because animal studies had indicated the drug might cause birth de- fects. However, in Africa and some developing coun- tries in other areas, it was indicated specifically for the treatment of nausea and vomiting in pregnancy. Even the detailed prescribing information in India did not contain warnings about potential birth defects. Another example was the painkiller, Paramol 118 (di- hydrocodeine). In Britain this drug required warnings against use by children, people with impaired liver or kidney function, or during an asthma attack. This same drug was marketed in Africa without these wamings. In contrast, indications were often more expansive in the developing country guides than in the U.K. 2 MIMS are commercial prescribing guides distributed free to physicians. Their prescribing information is supplied by the pharmaceuti- cal manufacturers and edited by the publishers. Production of the guides is paid for by advertisements.