Pharmaceutical Legislation and Regulation 7 Pharmaceutical Production Policy 8 Pharmaceutical Supply Strategies Financing and Sustainability

Part I: Policy and economic issues Part II: Pharmaceutical management Part III: Management support systems Policy and legal framework 1 Toward sustainable access to medicines 2 Historical and institutional perspectives 3 Intellectual property and access to medicines 4 National medicine policy 5 Traditional and complementary medicine policy 6 Pharmaceutical legislation and regulation 7 Pharmaceutical production policy 8 Pharmaceutical supply strategies Financing and sustainability

chapter 6 Pharmaceutical legislation and regulation

Summary 6.2 illustrations 6.1 The role of pharmaceutical legislation and Figure 6-1 Resources for medicine registration in twenty-six regulation 6.2 African countries 6.13 Why pharmaceutical laws and regulations are Figure 6-2 Reports of counterfeit medicines by therapeutic necessary • Differences between pharmaceutical laws, class received in 2007 6.15 regulations, and guidelines • Evolution of policy and Table 6-1 Resources required for effective administrative law • Globalization and harmonization • Drafting and control 6.17 revising pharmaceutical legislation and regulations country studies 6.2 Basic elements of national pharmaceutical legislation 6.7 CS 6-1 The evolution of pharmaceutical legislation 6.4 CS 6-2 Harmonization efforts in the Americas 6.5 6.3 Key provisions of national pharmaceutical CS 6-3 Revising registration procedures in legislation 6.7 Namibia 6.12 Defining the roles of various parties • Licensing, inspection, CS 6-4 Regulatory interventions in Lao P.D.R. 6.14 and quality control • Pharmacovigilance • Advertising and promotion • Sanctions boxes 6.4 Medicine registration, licensing, and marketing Box 6-1 Elements of a comprehensive drug law 6.7 authorization 6.10 Box 6-2 Adverse drug reaction monitoring 6.9 Classifying pharmaceuticals for dispensing • Regulating Box 6-3 Stages in the evolution of a medicine registration traditional and herbal medicines system 6.11 Box 6-4 Interchangeability 6.12 6.5 Controlling alternative and informal distribution Box 6-5 Regulatory hurdles in the development of channels 6.13 microbicides for HIV/AIDS 6.16 6.6 Substandard and counterfeit medicines 6.14 6.7 Establishing effective administrative control 6.15 Required resources • Financing • Guiding principles for small national drug regulatory authorities 6.8 Evaluating the effectiveness of pharmaceutical legislation 6.18 References and further readings 6.19 Assessment guide 6.20

summary

Realistic and effective laws and regulations are needed • Inventory the laws and regulations already in force for the pharmaceutical sector because— • Determine what type of legislative instrument is required • Pharmaceuticals concern the whole population • Involve both legal and health experts • Many parties are involved: patients, health provid- • Keep all interested parties informed ers, manufacturers, and salespeople • Serious consequences, including injury and death, National drug legislation generally includes provisions can result from the lack or misuse of medications relating to the manufacturing, importing, distribution, • The consumer has no way to determine product marketing, prescribing, labeling (including language), quality dispensing, and sometimes pricing of pharmaceutical • Informal controls are insufficient products, as well as the licensing, inspection, and control of personnel and facilities. A regulatory authority is usu- Countries may choose to develop new legislation or to ally established for administrative control. Medicine revise existing laws. When starting afresh, it is useful to registration is often a major element in legislation, to prepare a general law. Models exist, and expert assistance ensure that individual products meet the criteria of effi- is readily available. After the law is passed, regulations cacy, safety, and quality. made under it can bring its various provisions into operation, one by one, as the necessary resources and experi- Countries that need to introduce comprehensive legisla- ence are acquired. tion can seek guidance from the experiences of others and from WHO (2001a) guidelines. In drafting or revising legislation, a country should—

6.1 The role of pharmaceutical legislation language that enables the government to issue regulations and regulation based on the law. Passing new laws may require a lengthy process, with the country’s legislative branch giving final The role of pharmaceuticals has become more prominent approval. Regulations can be passed more rapidly and sim- on international agendas as health indicators have been ply than laws, sometimes requiring, for example, only the increasingly linked with a country’s successful development. approval of a single government minister on the advice of In addition, the legal and economic issues that surround experts. They can also be altered more easily. After approval, pharmaceuticals have become more complex and politi- a regulation has the same power as the law itself. Guidelines, cized because of the increase in global trade. which do not carry the force of law, can be more easily modified and updated and offer informal information on what Why pharmaceutical laws and regulations are the government’s thinking is regarding the best way to necessary implement regulations. Following guidelines will help avoid misinterpretation of and facilitate compliance with laws and The use of ineffective, poor-quality, or harmful medicines regulations. can result in therapeutic failure, exacerbation of disease, Pharmaceuticals involve many parties, including patients, resistance to medicines, and sometimes death. It also under- doctors, other health workers, salespeople, and manufactur- mines confidence in health systems, health professionals, ers. The field also involves important risks: people can suf- pharmaceutical manufacturers, and distributors. To protect fer or die not only from a lack of medicines, but also from public health, governments need to approve comprehensive drugs that are impure, wrongly prescribed, or used incor- laws and regulations and to establish effective national regu- rectly. Thus, it is easy to see why laws and regulations are latory authorities to ensure that the manufacture, trade, and needed. However, some argue that medicines—like many use of medicines are regulated appropriately and that the other commodities—should be subject only to the control public has access to accurate information on medicines. of the ultimate user. But medicines are indeed different, as discussed in Chapter 1. Differences between pharmaceutical laws, Additionally, informal controls are insufficient: charla- regulations, and guidelines tanism or quackery (that is, the deliberate sale of remedies known to be worthless) is centuries old, and firm action Laws today are usually written in fairly general terms to may be needed to put a stop to it; however, as discussed meet present and possibly future needs. Laws usually have later in the chapter, the Internet presents new challenges in 6 / Pharmaceutical legislation and regulation 6.3 controlling deceitful drug promotion. Counterfeiting, also, • What are the most important goals to achieve within has been on the rise in developed and developing countries. five, ten, and fifteen years? U.S. customs officials, for example, report that pharmaceu- • What means are available to achieve them? ticals are one of the fastest-growing categories of counterfeit • In which order can they best be tackled? goods coming into the country illegally. Pharmaceuticals • What help is available? accounted for 10 percent of total seizures in 2008 to become the third-largest category, compared to 6 percent in 2007 The answers to these questions provide a good starting (Mui 2009). point in developing both policies and the laws needed to The approach to pharmaceutical regulation should not be support them. simply punitive: rules creating a positive situation tend to Laws and regulations are intended to be used together to be more effective. Finally, laws and regulations are effective achieve their objective. It is appropriate to begin with passing only to the extent that they meet society’s needs. a broad law, emphasizing the requirement that pharmaceutical products be safe and effective. The various provisions Evolution of policy and law of the law are then brought into operation through regulation, step by step, addressing the most important things first. There may be a long preparatory period before the sort of For instance, in resource-constrained countries, setting up consensus develops that can form the basis for a law. It is a new pharmaceutical distribution system may be urgently sometimes preferable to work for a while with informal necessary, but pharmaceutical registration can wait for sev- agreements among parties or with government guidelines, eral years, while procuring essential medicines in the mean- so that generally accepted rules of behavior can develop in time through reputable channels where product quality is practice; the law then serves to confirm and formalize them controlled. (see Country Study 6-1). Whether or not a national drug policy exists, countries Globalization and harmonization need effective, enforceable legislation and regulation. These legislative acts may take the form of a single national drug Laws and regulations evolve within countries over time, but law that deals with all the issues or a series of complemen- in recent years, the trend has been toward the globalization tary laws, each introduced when the time is right. In some of pharmaceutical issues, which affects national legislation. countries, certain aspects of the pharmaceutical sector are This globalization, exemplified through changes in inter governed by national laws, and other aspects, such as phar- national trade, patent protection, and pricing, has resulted macy and medical practice, are governed by state or provin- in a number of initiatives that must be considered by coun- cial laws. This chapter focuses on a single, comprehensive tries developing pharmaceutical regulations. Some exam- drug law at the national level. Most of the issues discussed ples of these initiatives follow. are also applicable in situations where legal responsibility TRIPS Agreement. The TRIPS Agreement (Agreement is divided between national and state or provincial govern- on Trade-Related Aspects of Intellectual Property Rights) ments. of the World Trade Organization (WTO) has greatly A law on medicines must, first and foremost, clearly affected international pharmaceutical regulation. TRIPS is define what all the parties—manufacturers, doctors, an attempt to reduce gaps in the way intellectual property pharmacists—are required to do, so that no serious mis rights are protected around the world and to bring them understanding is possible. Medicine registration laws and under common international rules; however, the impli- regulations, for example, make clear what a manufacturer cations of the agreement’s provision on patents caused needs to do to obtain a license to sell a product. They define concerns in developing countries. In response to those how a registration agency should assess both the manufac- concerns, at the Doha Conference in 2001, WTO mem- turer and the product to determine if they meet society’s bers adopted a special affirmation—known as the Doha needs. Declaration—on issues related to TRIPS and public health. A good law also creates administrative bodies to put The declaration affirms that the TRIPS Agreement should rules into practice—for example, a national drug regulatory be implemented in ways that protect public health and authority with broad competence, or separate organs to deal promote access to medicines. Chapter 3 on intellectual with the various aspects of pharmaceutical regulation such property and access to medicines goes into more detail on as practice of pharmacy, inspection of factories, and adver- these issues. tising of medicines. Driven by the increase of global trade in pharmaceutical Trying to achieve too much, too quickly, can be tempting. products and the subsequent complexity of technical regu- It took more than a hundred years for pharmaceutical poli- lations related to medicine safety and quality, several initia- cies and laws to evolve to current levels in the industrialized tives have been established to promote the harmonization world. Sensible questions to ask are— of international pharmaceutical guidelines and regulations 6.4 Policy and legal framework

by intergovernmental organizations at regional and inter- and provide a platform to develop international consensus regional levels. on pharmaceutical regulation. The conferences are a unique International Conference on Drug Regulatory forum that assemble all drug regulatory authorities, regard- Authorities. Organized by WHO, the International less of their organizations’ stage of development. The ICDRA Conference on Drug Regulatory Authorities (ICDRA) pro- has been instrumental in guiding regulatory authorities on vides officials from the drug regulatory authorities from all how the harmonization of regulation can improve the safety, WHO member states with a forum to work on strength- efficacy, and quality of medicines. ening cooperation and collaboration. Held since 1980, the International Conference on Harmonisation. The annual conferences promote the exchange of information International Conference on Harmonisation of Technical

Country Study 6-1 The evolution of pharmaceutical legislation

Venezuela’s first medicine-related law was issued in were also created by law, for example the Pharmacy 1883 as the Ordinance of the Council of Physicians on and Medicines Directorate in 1981, the National Secret Medicines and Patents. Pharmaceutical laws have Pharmacovigilance Center in 1984, and the National been revised regularly; a significant number of phar- Medicines Control Laboratory in 1990. maceutical laws were adopted over the course of the twentieth century. The law that established the medicine In the Netherlands, the legal basis for licensing of registration system—the Law on the Exercise of the pharmaceutical manufacturing and distribution was Pharmacy—was passed in 1928, before the Ministry established in 1956. The Medicines Act of 1958 there of Health was set up in 1936. The National Institute of after regulated the admission of medicines to the Dutch Hygiene was established in 1938 to serve as the nation’s market through the Medicines Evaluation Board. But the national regulatory agency. Over the years, new rules board started to operate only after 1963, triggered by the and organizations have been created to expand the scope thalidomide disaster of 1961. European pharmaceutical of regulation and to add capacity for executing the laws. regulation is now playing a growing role. In 1995, the The section on pharmacological advice, the Laboratory European Medicines Evaluation Agency was founded to for Pharmacological Analysis, and the Center for coordinate the tasks of the drug regulatory authorities Pharmacological Surveillance were established in 1944, of European Union member states. Certain aspects of 1946, and 1962, respectively. Rules for good manufactur- the Netherlands’ pharmaceutical regulation now follow ing practices (GMP) were drawn up in 1990. A pharma- European Union rules. For example, GMP inspection is ceutical law was approved in 2000 that addressed certain based on the 1983 European Union guidelines for GMP. concepts for the first time, such as generic and essential Since January 1, 1995, a European procedure for registra- medicines. tion has operated in the Netherlands. Now two types of trade licenses exist: a European license and a national Tunisia first introduced pharmaceutical regulation in license. Products with a European license may be sold 1942, in the form of a decree on medical and pharma- throughout the European Union, while the national ceutical promotion and medicine control. All finished licenses are valid only for the country in which the pharmaceutical products, whether manufactured in license was issued by means of the national registration Tunisia or imported, must undergo a technical com- procedure. mittee review and obtain a certificate of approval from the Ministry of Health before they may be placed on Estonia’s drug regulatory framework began to take shape the market. Registration is also required for homeo- only over the two decades since the country gained inde- pathic drugs, and some herbal medicines are registered pendence. However, the pace of regulatory development with the status of allopathic medicines. Key legislation has been rapid. The Licensing Board of Pharmaceutical includes the 1961 Law on Inspection of Pharmacies Activities and the Center of Medicines were both created and Manufacturers, the 1969 Poisonous Drug Law, and in 1991. Registration and licensing were introduced that the 1985 Law on Production of Drugs for Human Use. year. In 1993, the State Agency of Medicines was created Between 1985 and 1991, several legal texts were pro- to become the Drug Regulatory Authority. The main leg- mulgated concerning GMP, clinical trials, medical and islation—the Medicinal Products Act—came into force scientific information, procedures to obtain licensing in 1996. of manufacturing and registration. New organizations Source: Ratanawijitrasin and Wondemagegnehu 2002. 6 / Pharmaceutical legislation and regulation 6.5

Requirements for Registration of Pharmaceuticals for medicines, while maintaining regulatory obligations to Human Use (ICH) is a project that brings together the safeguard the products. Although intended for new prod- regulatory authorities and experts from the pharmaceutical ucts, ICH guidelines are also being used to register exist- industry of Europe, the United States, and Japan to discuss ing products. The guidelines, formally produced by and for scientific and technical aspects of product registration. The ICH member countries, reflect the technical capabilities purpose is to promote harmonization in the application of of their well-developed regulatory agencies and pharma- technical guidelines and requirements for new product reg- ceutical industries. Thus, other countries should consider istration in order to reduce the duplication of and facilitate their local situations before trying to apply ICH guidelines. the evaluation of testing carried out during the research However, the ICH guidelines do end up affecting all coun- and development of new medicines. Harmonization con- tries, particularly as they relate to the quality specifications serves resources and increases the availability of new of medicinal products, including generic medicines, the

Country Study 6-2 Harmonization efforts in the Americas

Although subregional harmonization activities have been As PANDRH secretariat, PAHO supports the member under way in a number of countries in the Americas (for countries with— example, Mercosur, the Andean Community, NAFTA), • Information on pharmaceutical legislation no overarching mechanism existed for exchanging infor- • Collection and dissemination of documents, experi- mation and promoting harmonization in the Americas. ences, and procedures on drug regulatory harmoni- In 1999, a hemispheric forum was established, with zation in each country and subregion the Pan American Health Organization (PAHO) as • Research to document compliance with existing har- its secretariat, to communicate about pharmaceutical monization agreements regulation among the different subregions. The result- • Definition of the analytical methodology for ing organization, known as the Pan American Network addressing common problems for Drug Regulatory Harmonization (PANDRH), has • Exchange of information among the harmonization a steering committee that represents the drug regula- efforts of the different integration processes tors of subregional groups active in the pharmaceutical Subregional and technical meetings are held often, and regulatory harmonization process and formulates recom- PAHO convenes periodic conferences that bring together mendations on how to promote coordination among the all the groups to share information and advance har- countries. PANDRH includes all representatives involved monization efforts. The Pan American Conference is a in addressing the problems connected with pharma meeting open to all interested stakeholders, including ceuticals: regulatory authorities, industry (domestic and consumers, industry representatives, and nongovern- multinational), consumers, and professional associations. mental organizations. Providing an open forum helps In addition, PANDRH has formed a number of work- ensure the successful adoption and implementation of ing groups to address issues of importance to phar- harmonized outcomes. maceutical regulations including good manufacturing One of the major issues of concern to PANDRH mem- practices, bioequivalence, good clinical practices, drug bers is the recognition that serious limitations exist in counterfeiting, pharmacopoeias, and external quality some subregions, such as Central America, where no control. Examples of working group activities include legal framework exists to authorize and operationalize harmonizing good manufacturing practices guidelines the commitments made by technical groups; therefore, for inspectors and making the guidelines easily available PANDRH takes the particular needs of each subregional on the PANDRH website (http://new.paho.org/hq/index. bloc and the different degrees of development of their php?option=com_content&task=view&id=1054&Item constituent countries into account to implement the id=513); developing specific criteria to prioritize neces- subregional agreements. This specificity means that the sary bioequivalence studies; and developing inspection agreements must be implemented gradually. guidelines for audits on good clinical practices, including establishing legal penalties for noncompliance. Sources: PAHO 2005; PANDRH Steering Committee 2009. The PANDRH steering committee adopted statutes in 2009, which are available on the website. 6.6 Policy and legal framework

requirements for which vary considerably across countries The second step is for drafters and experts to meet to (Gray 2004). WHO, with its observer status on the ICH decide what type of legislative instrument is required. The steering committee, is expected to act as a link between most straightforward model is likely to be a comprehensive ICH and non-ICH countries (through the ICDRA) and to law that deals in outline with all the relevant issues, each disseminate information to non-ICH countries. The ICH main section taking up a particular matter. Sections can has also established a Global Cooperation Group that pro- then be implemented one at a time, through the passage of motes ICH guidelines by acting as an information resource regulations. for nonmembers. In countries with a long history of regulation, laws on Country Study 6-2 discusses regulatory harmonization pharmacists and the registration of medicines as well as reg- efforts in the Americas. ulations on prices and costs are likely to be separate, because Pharmacopoeias. Pharmacopoeias are documents that they came into being at different times. In starting afresh, outline technical information, manufacturing and testing however, and particularly if the laws on these matters are procedures, and standards for active pharmaceutical sub- outdated or incomplete, it may be easier to pull together all stances and products. Some countries, such as Germany and relevant elements into a single law. Thailand, also have pharmacopoeias specifically for herbal Ideally, the task of writing or revising the law should be products. A pharmacopoeia is usually recognized as part entrusted to a group of legal and health experts who are of a country’s national pharmaceutical laws; therefore, the familiar with all the issues, but not all countries can assem- standards and procedures are legally enforceable. WHO has ble such a group. Rather than solving the problem by copy- also developed an international pharmacopoeia that, unlike ing laws from abroad, countries with limited expertise can other pharmacopoeias, has no legal status, but is meant as obtain assistance from international and bilateral agencies a reference for member countries that may adapt it and to draft new pharmaceutical legislation that meets the coun- incorporate it into their national legislation. Because of the try’s own needs. International and regional meetings of drug extensive resources required to produce and maintain these regulatory authorities (for example, ICDRA) also provide complex documents, most countries do not have national opportunities for learning how to approach the problem pharmacopoeias and rely on one or more internationally and identifying expert colleagues who can be called on for recognized pharmacopoeias, such as those from the United advice. In addition, WHO has a number of publications that States, the European Union, Japan, or WHO. The organiza- can assist countries in developing national medicine poli- tions that publish pharmacopoeias, pressured by the need to cies (available at http://apps.who.int/medicinedocs/en/cl/ facilitate international trade, are actively working to harmo- CL1.1.1.1.2/clmd,50.html#hlCL1_1_1_1_2). nize their requirements. At all stages of the process, it is important to discuss early drafts of the law with all interested parties, including the Drafting and revising pharmaceutical legislation health professions, trade and industry groups, other con- and regulations cerned government departments (such as those handling commerce and education), and consumer groups. The Regulatory authorities are continually faced with new greater the consensus, the greater is the chance that a law issues—such as globalization and extension of free trade— will be passed and will work in practice. Sometimes, coun- while increased responsibilities from market expansion tries react to a crisis by rushing through the enactment of and the sophistication and new categories of products place a new law without putting it through a consensual process heavy demands on regulatory systems. The development of or carefully evaluating its effect on other sectors. However, cutting-edge technologies and health care techniques and this attempt to respond quickly may backfire if the law is not the extensive use of the Internet as a source of information carefully thought through. and commerce impose further complex challenges. When the law is approved, regulations are developed to As a first step before drafting any new law, it is important guide the implementation of the law. Regulations can be to inventory the laws and regulations already in force. Even modified more easily than laws as the local situation evolves. if no general drug law exists, pieces of legislation are likely When a regulation is revised, it is important to research to touch on the field—for example, laws on narcotics and and take into account what other laws will be affected by the licensing and responsibilities of pharmacists. An out- the revision. Declaring that a revision nullifies all previous of-date general drug law may exist that should be replaced laws and regulations in conflict, without making sure what rather than merely amended. Determining the extent to those previous laws cover, can result in confusion. It is easier which existing laws and regulations contribute to attaining to track revisions when a country’s laws are well codified, the national policy objectives is essential. Because concepts such as in the U.S. Code of Federal Regulations. Following the of pharmaceutical policy are modern, legislation more than adoption of regulations, guidance documents may be devel- twenty years old may not be relevant; starting over may be oped to provide more flexible and detailed information on simpler. how to comply with regulations. 6 / Pharmaceutical legislation and regulation 6.7

Box 6-1 Elements of a comprehensive drug law

A. General provisions 3. Controls, incentives, disincentives for local manufacture 1. Title* 4. Control of distribution, supply, storage, and sale* 2. Purposes* 3. Territorial extent D. Drug control administration 4. Application of other laws 1. Organization and function* 5. Definitions* 2. Appeals against decisions of the drug control B. Control of availability and marketing authority* 1. Drug registration* E. Powers of enforcement 2. National essential medicines list/national 1. Prohibition of specified activities* formulary 2. Penalties for each offense based on magnitude and 3. Scheduling prescription, and dispensing occurrence* authority* 3. Legal procedures for offenses* 4. Labeling* 5. Generic labeling, manufacturing, and F. Powers to make rules and regulations substitution 1. Who has authority* 6. Pharmacovigilance 2. Under which circumstances* 7. Information and advertising* 8. Public education G. Repeals and transitional provisions 9. Imposition of fees 1. Repeal of sections of existing laws in conflict with 10. Price control the act 11. Special products (herbal medicines, medicines 2. Transitional period to implementation* for clinical trials, orphan drugs) H. Exemptions from provisions of the law* C. Control of supply mechanisms * Elements for which model legislation has been developed by WHO. 1. Importation of medicines* 2. Exportation of medicines* Sources: Adapted from WHO 1998b, 1999c.

6.2 Basic elements of national universally recognized as being different from ordinary pharmaceutical legislation items of commerce, such as clothing or household appli- ances, and therefore in need of handling by specially trained A well-defined set of elements constitutes the initial require- health professionals. These requirements make pharmaceu- ments for a strong and comprehensive national pharma- ticals subject to numerous controls at all levels, and legal ceutical law. These elements, though basic, are sufficiently authority is granted to regulate their manufacture, distri- wide and varied in their scope to meet most of the objec- bution, marketing, prescribing, labeling, dispensing, and tives of a national pharmaceutical policy. Box 6-1 presents a related activities, such as pricing. model for national pharmaceutical legislation, showing the An effective national pharmaceutical law is a primary various key elements. This model can be adapted to support means of ensuring that pharmaceutical policy goals are the efforts of small national drug regulatory authorities in achieved while the unique character of pharmaceutical countries where only one or two professionals are available products, personnel, and facilities is preserved. The law to deal with pharmaceuticals and related products. may specify what products can legally be imported—for example, those included on the national medicines list and possessing a WHO-type certificate of quality—and which 6.3 Key provisions of national individuals are legally qualified to prescribe and dispense pharmaceutical legislation them, thus promoting certain national pharmaceutical policies. Because a consumer cannot independently assess the safety, Likewise, control of the manufacture, storage, distribution, efficacy, or quality of pharmaceuticals, these products are and sale of pharmaceutical products enables a government 6.8 Policy and legal framework

to better ensure compliance with a national policy of having the people who import, distribute, and sell medicines are essential medicines of appropriate quality, safety, and properly qualified, approved, registered, and inspected. efficacy available for their intended purposes. The processes Pharmaceuticals themselves require a special form of of licensing and registration can grant authorization only inspection. An inspector visiting a pharmacy or warehouse to those personnel, products, and facilities that conform to may have reason to suspect that medicines are not of suffi- the national pharmaceutical law. For example, counterfeit cient quality or in good condition: they may be damp, dirty, or dangerous medicines can be taken off the market, or disintegrating. More often, samples need to be obtained and sanctions can be taken against those responsible for for testing in the quality-control laboratory, an essential part introducing them illegally. of the inspection system. In addition, countries that host clinical trials to test Some countries have their own quality-control laborato- new medicines should incorporate regulations on how ries, either specifically for medicines or shared with other the studies should be conducted, including an applica- commodities (such as foods). A number of countries use tion process that explains the purpose and protocol of the regional laboratories, such as the ones serving sub-Saharan intended research and the creation of an ethics committee Africa or the Caribbean. Whatever the structure, the phar- to approve and monitor any study protocol that includes maceutical law needs to designate a quality-control labora- human participants. For countries needing assistance in this tory that has the capacity and equipment to do the job. area, WHO publishes guidelines on good clinical practices Countries that have pharmaceutical manufacturing (WHO 2005b). operations should enforce good manufacturing practices The promulgation of regulations, the collection of licens- (GMP), which is a system to ensure that products are con- ing and registration fees, and the enforcement of the national sistently produced and controlled according to quality law and its regulations are legally delegated to an agency— standards. GMP covers all aspects of production from the usually called the national drug regulatory authority— starting materials, premises, equipment, and quality test- headed by a commissioner or director who is responsible to ing to the training and personal hygiene of staff.W HO a cabinet-level person, such as the minister of health. For has established detailed guidelines for good manufactur- example, in the United States, the basic national pharmaceu- ing practice, and many countries have formulated their tical law is called the Federal Food, Drug, and Cosmetic Act, own requirements based on WHO’s GMP. Other regions, which is enforced by the Food and Drug Administration. such as the Association of Southeast Asian Nations and the For controlled substances, additional restrictions are European Union, have harmonized their GMP require- imposed by the Drug Enforcement Administration. In the ments. United States, wholesale distributors, pharmacy practice, Although important, GMP monitoring sometimes and medical practice are regulated by individual states. receives more resources than the inspection of distribution channels; however, the consumer’s interest is not served Defining the roles of various parties by manufacturing a product under GMP but then storing and distributing it under adverse conditions. Inspection of Because so many parties are involved with medicines, the distribution channels, including the importation of phar- laws need to clearly state the roles, responsibilities, and rights maceuticals, should also be emphasized, particularly in of each, ranging from practitioners, auxiliaries, nurses, and countries where the distribution system has several inter- pharmacists to importers, manufacturers, and distributors. mediate levels or the climate is unfavorable. WHO has Countries approach prescribing and dispensing differently, produced guidelines relating to good storage practices for depending on their circumstances; for example, in Canada, pharmaceuticals (WHO 2003a). a physician must be the medicine prescriber, but in areas Chapter 19 has more information on quality-control and where physicians are scarce, legal authority may be granted inspection procedures. to nurses or other health practitioners to prescribe essential medicines. The legislation should establish the qualifications Pharmacovigilance required for those handling medicines, or it must state who has the authority to set these standards by passing appropri- The law should also provide a basis for a pharmacovigi- ate regulations (for example, a government minister). lance (that is, postmarketing surveillance) system to report problems with adverse reactions and product quality. Licensing, inspection, and quality control Pharmacovigilance is defined by WHO (2002a) as “the science and activities relating to the detection, assessment, The law should create mechanisms to ensure that relevant understanding and prevention of adverse effects or any parties are licensed and inspected so the community can other drug-related problems.” have confidence in them. Doctors and nurses may be cov- Pharmacovigilance is an overarching concept that encom- ered by other laws, but the medicine law needs to ensure that passes any system used to monitor medicine safety, use, 6 / Pharmaceutical legislation and regulation 6.9 and efficacy. For example, adverse drug reaction monitor- through informal channels or the sale of powerful medi- ing as part of a product’s postmarketing surveillance con- cines without prescription. Drug regulatory agencies should tributes to the assessment of benefit, effectiveness, and risk have access to information from the WHO Programme of medicines. A pharmacovigilance system is difficult—if for International Drug Monitoring (http://www.who.int/ not impossible—to implement in an unregulated market medicines/areas/quality_safety/safety_efficacy/Joining that allows the importation and sale of pharmaceuticals WHOProgrammeforInternationaDrugMonitoring.pdf),

Box 6-2 Adverse drug reaction monitoring

An adverse drug reaction (ADR) is a harmful and un- • Dose, frequency, and route expected reaction to a drug taken at a normal dosage. • Therapy date The research done on medicines before they are allowed • Diagnosis for use on the market is incomplete; generally fewer than 5,000 • Event abated after use stopped or dose reduced people have been exposed to the medicine in premarket • Batch number tests, an insufficient number to detect less common • Expiration date ADRs. In addition, information on chronic toxicity and • Event reappeared after reintroduction of the treat- reactions in special groups, such as pregnant women ment and children, is often unavailable from this premarket • Concomitant medical products and therapy dates research, because these groups are usually not included Reporter— as subjects in clinical trials. Postmarketing surveillance, therefore, allows for the detection of rarer, but possibly • Name, address, telephone number critical ADRs. In addition, postmarketing monitoring • Specialty and occupation may detect counterfeit or substandard products. Often, It can take years or even decades before adverse events a country’s national drug regulatory authority is respon- are linked to the use of particular medicines. For exam- sible for ADR monitoring and reporting. ple, several years passed before certain birth defects were To facilitate information gathering, the drug regulatory associated with thalidomide use by pregnant women; authority should provide case report forms to health decades passed before aspirin was linked to gastro providers on adverse drug reactions. The completed intestinal problems. In some cases, medicines are with- case report form is then sent to the national or regional drawn from the market, as was the case with bromfenac, ADR center or to the manufacturer of the product. These terfenadine, and encainide after they were connected forms vary by locale, but should include the following to serious health outcomes. In other cases, labeling is minimum information. changed to include the new information on effects, contraindications, or dosage as a result of information Patient information— received through postmarketing surveillance. • Patient identifier Clearly, the usefulness of a postmarketing surveillance • Age at time of event or date of birth program depends on cooperation from health profes- • Gender sionals. All health care providers, including physicians, • Weight pharmacists, nurses, dentists, and others, should report Adverse event or product problem— ADRs as part of their professional responsibility. Even when some doubt exists about the relationship between • Description of event or problem the product and the ADR, all suspected ADRs, especially • Date of event related to new medicines, should be reported as soon • Date of report as possible. Many countries provide an easy system for • Relevant tests/laboratory data reporting ADRs to their drug regulatory authorities, such • Other relevant patient information/history as a dedicated phone line as provided in Ghana and a • Outcomes attributed to adverse event special reporting website as in Brazil. Suspected medication(s)— Source: WHO 2002c. • Name (international nonproprietary name and brand name) 6.10 Policy and legal framework

which provides a clearinghouse for the millions of adverse To be effective, the drug regulatory authority must be able drug reaction reports received from almost 100 countries. to apply sanctions on a timely basis, so it must have either International pharmacovigilance activities have had a nota- the legal staff to ensure compliance or the necessary links ble effect on international drug regulation. Box 6-2 describes with the relevant government department charged with the elements that comprise an adverse drug reaction pro- enforcement. Therefore, the law governing pharmaceutical gram, and Chapter 35 has more information on implement- products must give legal authority to the appropriate per- ing a pharmacovigilance program. sonnel to carry out any necessary enforcement activities. In addition, because the pharmaceutical sector is vulner- Advertising and promotion able to corruption, a country should not only include an anticorruption mechanism in its regulatory framework, but Although many countries have rules to ensure that advertis- also have sanctions in place for bribery, fraud, collusion, and ing is not misleading, these rules are generally not sufficient other dishonest acts (WHO/PSM 2006). Many countries to cover pharmaceuticals. With consumer products, a cer- have specific laws that address corruption in the public sec- tain degree of exaggeration is often tolerated as the normal tor or provisions in their procurement regulations to ensure practice of the marketplace. But for medicines that have the transparency and provide sanctions against, for example, capacity to kill or cure, and with claims that people cannot bribery. easily verify, it is important that advertising to health professionals and to consumers be objective and reliable; misleading and extravagant pharmaceutical advertising claims may 6.4 Medicine registration, licensing, and pose significant risks to the public. marketing authorization For these reasons, most laws on pharmaceuticals now include a clause empowering regulation on advertising. The licensing and inspection of manufacturers and import- In many countries, it is illegal to advertise to consumers ers, although important, do not provide assurance about medicines intended to be prescribed by health profession- the products. Many countries have evolved systems of drug als. However, direct promotion of pharmaceutical products registration to ensure that individual products approved for through the Internet is practically impossible to control; sale meet the following criteria— therefore, the national regulatory agency should educate consumers on identifying reliable sources of information, Efficacy: The medicine should be shown to be effective for preferably in collaboration with national consumer and pro- the indications claimed. However, note that no product fessional organizations. All advertising and labeling must be is ever 100 percent effective for all users. In practice, effi- consistent with the information verified when the pharma- cacy means that in a majority of cases the product meets ceutical product was registered or approved for marketing, its therapeutic claim. with modifications required by the regulatory authority on Safety: The medicine should not present risks that are dis- the basis of postmarketing experience. proportionate to its benefits. Some patients may suffer Useful guides to the principles that should underlie hon- severe reactions even to medicines shown to be safe in est pharmaceutical promotion have been issued by WHO clinical studies. However, in the great majority of cases, and separately by manufacturers (WHO 1988, 1999b). adverse effects are minor or very infrequent. Quality: The medicine should be well made, as specified in Sanctions the official pharmacopoeia chosen as a standard. If not listed in an official pharmacopoeia, the product’s manu- Because constant vigilance is needed if the public is to be facturing should comply with the quality documentation protected, pharmaceutical laws must be properly enforced submitted by the applicant that demonstrates its safety with appropriate penalties for violators. There is no use and efficacy. establishing that medicine quality is poor, a warehouse is Clinical use information: All the clinical information needed rat infested or damp upon inspection, or an advertisement to use the medicine properly, including indications, is untruthful unless something is done about it. The drug doses, precautions, and adverse effects, should be pro- regulatory agency must use its authority to impose appro- vided as part of the packaging, in language understand- priate penalties when necessary: sanctions may be penal able to the health professional or patient, as appropriate. (fines, imprisonment, or both) or simply corrective (ban- ning the drug, closing down the warehouse). Sometimes a Medicine registration, also referred to as licensing or mar- party has contravened the law so seriously that the appropri- keting authorization, is often a major element in national ate sanction is determined to be loss of license to prescribe, pharmaceutical law. In its fully developed form, however, manufacture, import, or distribute. On occasion, all of the it is costly and labor intensive. Establishing a drug registra- penalties may be imposed. tion system is generally not justified until a country has a 6 / Pharmaceutical legislation and regulation 6.11

insert. Having a complete register of what is on sale in the Box 6-3 marketplace allows the regulatory agency to evaluate infor- Stages in the evolution of a medicine mation from other countries or from WHO about problems registration system with a particular medicine (for example, toxicity, contami- nation, evidence of inactivity), to determine whether the Stage 1: Notification procedure. Standard infor product is on sale in their country, and what actions might mation is obtained on all pharmaceutical products be taken. currently marketed in the country and entered into a Stage 2 requires assessment for new pharmaceutical prod- register. No judgment is made at this time regarding ucts. Because this procedure is costly and time-consuming, the appropriateness of the drugs for sale in the country. countries can rely on decisions made in other countries Stage 2: Basic authorization procedure. Products with well-developed regulatory agencies, such as those that listed in the register are provisionally authorized to are members of the ICH. Is the drug approved for sale in remain on sale. All other drugs that are to be sold its home country? If so, what claims have been made for require a license, which is issued after an appropri- it? Does it carry a WHO-type certificate indicating that it ate assessment of the efficacy, safety, and quality and is manufactured under satisfactory conditions? The firm a review of truth and completeness of packaging and wishing to import the product must provide documented labeling information. answers to these questions. Regulatory authorities may con- sult other countries directly before deciding to accept or Stage 3: Full registration or licensing procedure. reject a product. WHO and other bodies hold international Full evaluation of individual products is conducted by and regional meetings of regulatory authorities from differ- examining detailed data submitted by the manufac- ent countries, which helps create trust across borders and turer and obtained from the literature to assess their facilitates informal work sharing. Approval of locally manu- quality, safety, and efficacy. factured pharmaceuticals requires inspection of the manu- Stage 4: Reevaluation of older drugs. All older phar- facturing premises and staff. maceutical products on the market are systematically The task of full registration described in stage 3 should reassessed for compliance with the standards. never be taken up lightly—even a large regulatory agency can be overwhelmed by the vast amount of material that needs to be examined. Some groups of countries handle assessment jointly; others look at where else in the world the significant volume of private-sector pharmaceutical sales. medicine is licensed, and under what conditions. Countries The primary concern of many resource-limited countries is that have the resources to handle registration and licensing ensuring a reliable flow of essential generic drugs from repu- independently can often obtain technical advice and practi- table suppliers into the public health system. cal help from WHO and support from other countries with As a country’s economic development proceeds and well-developed regulatory agencies. more resources become available, priorities may change. Stage 4, the reevaluation of older products on the market, The private sector may become more active, and local and is the final stage in the development of a registration system multinational firms may begin actively promoting their new and is very ambitious. Few industrialized countries have yet products to prescribers and even to the public. At this point managed to complete it. the need for a medicine registration system arises. If a medicine is intended to be generically equivalent As proposed in the WHO (1999c) guidelines for small to another already on the market, regulations must stipu- drug regulatory authorities, a medicine registration system late the evidence needed to support their equivalence (see can best be developed in stages, starting with an inventory Box 6-4). WHO has a resource for countries without a fully of all pharmaceutical products on the market, followed by a functioning system for premarket evaluation and mar- provisional authorization that allows products to continue ket authorization that wish to assess and authorize multi- to be sold until they complete the full registration procedure source (generic) pharmaceutical products (WHO 1998b). as shown in Box 6-3. Country Study 6-3 shows how Namibia WHO also makes available findings from assessment maximized its resources by streamlining its medicine regis- reports generated as part of its program to prequalify medi- tration system. cines for HIV/AIDS, tuberculosis, and malaria, including In stage 1, the information requested initially may be sim- information based on product data showing compliance ply the international nonproprietary name; product trade with international standards for quality, safety, and effi- name, if any; name of the manufacturer; and country of cacy, bioequivalence (for generic products), and findings origin. Later, this can be expanded to include composition, resulting from inspections of production sites according including inactive ingredients; pharmacological action; to GMP standards (see http://mednet3.who.int/prequal/). therapeutic classification; and claims made in the package TheW HO prequalification process should be useful to 6.12 Policy and legal framework

Country Study 6-3 Revising registration procedures in Namibia

In its first fifteen years of independence, Namibia devel- ucts already registered in International Conference on oped very comprehensive pharmaceutical regulatory Harmonisation countries or South Africa; for example, procedures, considering its small population and limited the new policy permits the MCC to accept certain qual- resources. Unfortunately, human resources capacity did ity requirements that have already been approved by not keep pace with administrative requirements, and the recognized authorities, such as through WHO’s prequali- number of medicine registration applications quickly fication program. Other interventions included training created a huge backlog of about 1,000 medicines awaiting nonprofessional staff to take on some application pro- marketing approval, including antiretroviral (ARV) med- cessing responsibilities and creating a drug registration icines. At that time, forty-nine ARVs were on the market, database. but the backlog prevented access to valuable fixed-dose Within a year after RPM Plus’s intervention began, 1,392 combinations and pediatric products. One estimate applications for new medicines were evaluated. Of those, showed that at the current capacity, it would take eigh- fourteen ARVs and twenty-four generic ARVs were teen years to review all outstanding applications. reviewed and approved (which increased the number The Rational Pharmaceutical Management (RPM) Plus of ARVs on the market by 75 percent). The fourteen Program worked with the government on interven- approvals included much-needed pediatric dosage forms tions to streamline the registration process. Key was a and fixed-dose combinations; the addition of generic policy change allowing the Medicines Control Council products helps reduce prices. (MCC) to give priority to ARVs for registration and Source: Pereko and Nwokike 2006. create a proxy evaluation process to quickly accept prod-

Box 6-4 Interchangeability

New multisource (generic) pharmaceutical products quality standards and at least compliance with relevant must be of good quality and at least as safe and efficacious pharmacopoeial standards; stability; possible differ- as existing products. The need for interchangeability ences in sensitizing potential caused by the use of dif- arises when a patient changes from one brand to another, ferent excipients; therapeutic equivalence in terms of, as for example, when— appropriate, bioequivalence, pharmacodynamic studies, • Physicians prescribe by generic name clinical studies, or in vitro dissolution rate; and product • Generic substitution is permitted by national legisla- information and labeling. tion By their nature, different brands of modified (sustained-, • The same brand is not always available, for example, continuous-, prolonged-, slow-) release products are in remote areas of the country more likely not to be equivalent than are different brands • Patients in hospitals are given whatever brand of immediate, conventional-release products. Some drug the hospital has in stock, and sometimes different regulatory agencies take the view that such products brands on different occasions should never be considered interchangeable, while oth- • Patients receive a different brand after discharge ers define a series of studies that should be conducted, from the hospital including in some circumstances comparative clinical tri- A number of features are important to interchangeability, als. For delayed-release products, such as enteric-coated although the science behind demonstrating interchange- tablets, interchangeability is more easily demonstrated. ability is still evolving: compliance with appropriate Source: WHO 1998b. 6 / Pharmaceutical legislation and regulation 6.13

Figure 6-1 Resources for medicine registration in twenty-six African countries

25 Adequate 20 Existing but inadequate 15 Not existing

10 No information or not applicable 5 Number of NMRAs

0 Legal basis Guidelines SOPs for Assessors Secure IT system outline (tech. detail) assessment ling space NMRAs = national medicine regulatory authorities; SOPs = standard operating procedures; IT = information technology. Source: Adapted from WHO 2010b. developing-country regulatory authorities that do not have and psychotropic drugs is available from the International sufficient capacity to fully assess products and determine Narcotics Control Board (http://www.incb.org). their acceptability before licensing. The registration systems of many African countries are Regulating traditional and herbal medicines still lagging. For example, in twenty-six countries surveyed, the technical standard of evaluations, if they existed, were As discussed in Chapter 5, countries are increasingly rec- not in line with WHO standards; only 11 percent had ade- ognizing the large role that traditional and complementary quate standard operating procedures for assessment, 85 per- medicine plays in their health care systems. An important cent did not have enough space to store data securely, and challenge is the evaluation and assurance of the quality, only one-quarter of the countries had functioning comput- safety, and efficacy of herbal and traditional medicines. erized registration systems (WHO 2010b) (see Figure 6-1). Since the earliest days of humankind, herbal medicines have been applied in health care throughout the world. Many Classifying pharmaceuticals for dispensing are still widely used and have become important in international trade. Significant quantities of herbal products are As part of the marketing authorization process, the national now imported by countries in the European Union, North drug regulatory agency is also responsible for classify- America, and Asia. However, the use and production of ing each pharmaceutical product in terms of how it is dis- herbal products remains largely unregulated, and their pensed and sold. For example, prescription-only medicines safety and therapeutic value cannot always be guaranteed. require a directive from an authorized health practitioner; Recognition of the clinical, pharmaceutical, and eco- pharmacist-only medicines are available without prescrip- nomic value of herbal medicines is growing, although tion, but only under a pharmacist’s supervision; and over- the level of official recognition through legislation varies the-counter medicines are available without a prescription widely among countries. WHO published a reference on the in retail outlets besides the pharmacy, such as a grocery or national experiences of fifty-two countries in formulating licensed drug seller. This classification affects the product’s policies on traditional and herbal medicinal products and in availability and appropriate use. Factors to consider in the introducing measures for their registration and regulation classification include— (WHO 1998c). WHO also published a summary of the legal status of traditional and complementary medicines in 141 • The safety of the active ingredient countries (WHO 2005c) and guidelines on how to develop • The need for professional counsel before use national policies on the safety, efficacy, and quality of herbal • The nature of the ailment or symptoms the medicine is medicines (WHO 1998a). intended to treat • The risk/benefit ratio G(T A 2003) 6.5 Controlling alternative and informal Consideration should also be given to the restrictions distribution channels for prescribing and dispensing controlled drugs as provided in the international drug control treaties, namely the In some countries, unregulated, informal, or even illegal 1961 Single Convention on Narcotic Drugs and the 1971 distribution (including sales in marketplaces and on streets) Convention on Psychotropic Substances. The list of narcotic and smuggling of medicines are widespread. Another major 6.14 Policy and legal framework

problem is that medicines may be traded through several the government in the Lao People’s Democratic Republic intermediaries and free-trade zones and are sometimes (P.D.R.) has instituted regulations to improve the quality of repackaged and relabeled to hide their true source or iden- private pharmacies. tity, leading to the circulation of substandard and counter- Another challenge to drug regulators that has emerged feit medicines. in recent years is the widespread use of the Internet to sell As the volume of expensive medicines such as for HIV/ uncontrolled pharmaceuticals across national borders AIDS and malaria increases in formal distribution chan- (WHO 2003b). Regulation and enforcement can deter nels, there will be an increase in leakage of these medicines illegal practices, although it requires cooperation among to informal channels. A WHO study of regulations in ten national agencies such as those handling drug regulations, countries (Ratanawijitrasin and Wondemagegnehu 2002) customs, and the postal service. Because of the transnational showed that pharmaceuticals distributed through the infor- nature of e-commerce, international cooperation in its con- mal sector received little regulatory attention from govern- trol is also needed. ments compared with those distributed through the formal sector. Products of substandard quality and incorrect information—especially exaggeration about efficacy—are often 6.6 Substandard and counterfeit medicines found in the informal sector. It is important for countries to assess the influence of Substandard medicines are products whose composition alternative and informal distribution channels on their and ingredients do not meet the correct scientific specifica- health care systems. If citizens purchase most of their medi- tions and consequently may be ineffective, dangerous to the cines from informal dealers, they may be getting substan- patient, or both. Substandard products may occur as a result dard-quality products, which may adversely affect public of negligence, human error, insufficient human and finan- health. Medicine regulation can be used to promote quality cial resources, or counterfeiting. criteria for medicines and health commodities by establish- Counterfeit medicines are considered a subset of substan- ing and enforcing standards for all distribution channels and dard medicines, but the difference is that they are deliber- encouraging the public to be careful about where they buy ately and fraudulently mislabeled regarding their identity pharmaceutical products. Chapter 32 discusses how initia- or source. Counterfeiting can apply to both branded and tives can improve the quality of products and services from generic products, and counterfeit medicines may include private-sector drug sellers. Country Study 6-4 describes how products with the correct ingredients but fake packaging,

Country Study 6-4 Regulatory interventions in Lao P.D.R.

In Lao P.D.R., private pharmacies make up the majority A follow-up study in 1999 used the same indicators to of the retail market for medicines. However, little or no assess the effect of the new policies and activities on pri- control of private pharmacies existed until 1996, when vate pharmacy services. The results showed significant such regulation was incorporated into the National improvement in almost all indicator values, including Drug Policy. District pharmacists became responsible the organization in the pharmacy; availability of essential for inspecting and monitoring private pharmacies, and a medicines and essential materials for dispensing, such as special unit was created at the provincial level to oversee a hygienic counter; and information given to the custom- the regulations. Inspectors made sure that the pharma- ers. Analysis of samples from the 115 pharmacies showed cies had up-to-date regulatory documents. In addition, a decrease in the proportion of substandard medicines— the central drug regulatory authority instituted a number from 46 percent in 1997 to 22 percent in 1999—still high, of policies to improve the quality assurance system in but substantially better. the country. These included the development of a good Before the regulatory interventions, the quality of phar- manufacturing practices regulation with associated maceutical service was low in Savannakhet province. training, improvements in the medicine registration sys- The development of a regulatory framework with regular tem, and the institution of fines and sanctions to enforce inspections and enforcement through sanctions was not the new regulations. only possible to initiate in a resource-limited country, but In 1997, a baseline assessment was conducted in 115 of also appeared to be an important catalyst for better qual- 214 licensed private pharmacies in Savannakhet prov- ity medicines and pharmacy practices. ince before the new regulations had fully taken hold. Sources: Stenson et al. 2001; Syhakhang et al. 2001. 6 / Pharmaceutical legislation and regulation 6.15

Figure 6-2 Reports of counterfeit medicines by guidance from the experiences of others, but problems therapeutic class received in 2007 have arisen when overly complex provisions were adopted. Legislation and administrative practices must be attuned to available resources, and every opportunity must be taken to understand and use the information provided by regulatory authorities in other countries (WHO 1990). The example of approving microbicides to control HIV infection shows the Other 21% regulatory difficulties faced by resource-constrained countries (Box 6-5). Genito-urinary 37% Required resources

Anti-infectives 12% To perform effectively, national regulatory authorities must have the necessary political support, legal power, human and financial resources, and independence in decision making. They also must have strong public support and Central nervous proper management. Where national regulatory authori- system 12% Cardiovascular ties have a high profile within the government, they are Gastro- organized as a commission, board, statutory authority, or intestinal 9% 9% department, with the legal power from government to acquire and use resources, including hiring qualified full- time staff at a salary scale that discourages corruption and Total number of cases: 1,513. One case re ects at least one production lot (e.g., thousands of tablets, capsules, or other forms). conflicts of interest. Data from the Pharmaceutical Security Institute (http://www.psi-inc.org). Ideally, one central, autonomous agency should be accountable for the overall effectiveness of pharmaceutical regulation. In countries whose regulatory functions are split with the wrong ingredients, without active ingredients, or among two or more agencies, the fragmentation can lead to with insufficient active ingredients. duplication of effort, lapses in implementation, inconsistent In wealthier countries, the most frequently counterfeited regulation, and wasted resources. In recent years, several medicines are new, expensive lifestyle medicines. In devel- countries (for example, Argentina and Brazil) have success- oping countries, the most counterfeited medicines are those fully established such centralized agencies to regulate food, used to treat life-threatening conditions such as malaria, medicines, and consumer products. However, a survey of tuberculosis, and HIV/AIDS. Figure 6-2 gives the number twenty-six countries in sub-Saharan Africa showed that of reports of counterfeit medicines, by therapeutic class, most countries’ regulatory systems were uneven—with gaps submitted in 2007 and shows that the highest percentage and overlaps in responsibilities spread over several bod- reported concerned genito-urinary medicines. ies other than the drug regulatory authority, including the Trade in these medicines is more prevalent in countries ministries of trade and health, pharmaceutical councils, and with weak pharmaceutical regulatory control and enforce- regional authorities, especially for licensing and inspection ment, scarce or erratic supply of basic medicines, unregu- (WHO 2010b). lated markets, and unaffordable prices. Governments need Table 6-1 details the resources required to achieve effec- to develop strategies and put appropriate legislation and tive administrative control; at a minimum, these needs sanctions into place to reduce corruption and criminal include a drug regulatory authority with staff, a team of activity. As in the case of e-commerce, enforcement of these inspectors to visit warehouses and retailers, and access to a laws requires cooperation among regulatory authorities, laboratory capable of performing quality-control testing. police, customs services, and the judiciary to control more Personnel are the key resource for making effective phar- effectively the pharmaceutical market. maceutical regulation possible. Because of the technical nature of their work, the law often prescribes that inspectors be pharmacists or have other relevant education and train- 6.7 Establishing effective administrative ing. Others can be trained to undertake licensing, registra- control tion, and enforcement duties. Depending on the size of the country and the degree of pharmaceutical development, the In many countries, medicine legislation and regulation are entire staff may consist of only a few individuals. Sometimes not regularly updated or are imported from other countries contracting out specific duties may be appropriate; however, and do not reflect national realities. Countries can draw it is important for the contractor not to have any conflicts of 6.16 Policy and legal framework

Box 6-5 Regulatory hurdles in the development of microbicides for HIV/AIDS

More women than men account for new HIV infections To help fill the gaps, the European Parliament approved in many parts of the world. In certain places, women’s an initiative for the European Medicines Agency (for- lack of power means they cannot insist on condom use merly known as the European Medical Evaluation to protect themselves, and even if they have a single part- Agency) to scientifically assess products such as micro- ner or husband, they are still at risk. This situation has bicides that are proposed for use primarily in developing resulted in much interest in the development of micro countries. The drug regulatory agencies in developing bicides—a topical medicine used vaginally to prevent countries would then use the scientific assessments to HIV transmission—that gives women control of usage. make decisions about licensing. Other steps that could help overcome these regulatory hurdles would be collab- A major obstacle to the approval of an effective micro- oration between regulatory authorities in developing and bicide is the fact that those now in clinical testing are industrialized countries to jointly review product profiles new medicines that have not been on the market yet. and to help resource-limited countries develop the capac- Many developing countries do not have the resources or ity to make drug registration decisions autonomously. regulatory framework available to perform the testing and review of new medicines themselves, so they rely Although results of clinical trials of microbicides for HIV on product reviews from the United States or Europe to have been mixed, research continues, and the European determine acceptability for their countries. However, assessment mechanism is one that could be used with because microbicides will be marketed primarily in other similar products. developing countries, developed countries have no incen- Sources: Coplan, Mitchnick, and Rosenberg 2004; Davis 2009; Fox, tive to review and license them for their own markets. Beasley, and Kelland 2010.

interest, such as an ongoing consultancy with a pharmaceu- percent, 100 percent, and about 50 percent, respectively, tical company that could specifically benefit from the con- of their regulation costs (WHO 2003b). Because of their tracting arrangement. large markets, developed countries tend to charge higher Computer software now greatly simplifies many of the fees than developing countries. In addition, in developing administrative tasks of the regulatory agency. Personnel countries, fee revenues are often added to the general trea- should have access to the latest scientific and technical infor- sury rather than being assigned specifically to the drug reg- mation to facilitate their work. ulatory agency, which makes it hard to adequately finance regulation. However, regulatory agencies should not be Financing completely dependent on fees to fund all of their activities; they should receive some financial support from their gov- The law must provide a realistic mechanism for funding ernments to help ensure their independence and ability to regulatory functions. Funds may be provided from general carry out basic responsibilities. Most of the twenty-six drug tax income and from charges levied on the manufacturers, regulatory authorities surveyed in Africa get their funding importers, and distributors to cover the bulk of the costs of from more than one source (e.g., fees, government, donors); the pharmaceutical control system. The level of charges may however, none had sufficient or sustainable operating funds be set from year to year, but the nature of the charges can be (WHO 2010b). defined in the law. For example, the law may set lower fees for essential medicines; importers can be required to pay Guiding principles for small national drug a fee when they submit a new medicine application to the regulatory authorities regulatory authority for consideration, a supplementary fee when the license is issued, and an annual fee for as long as Regulation is not the only component of pharmaceutical the medicine remains on sale; and manufacturers might be policy, and sometimes in resource-limited settings, it is not required to relicense their products periodically (for exam- even the most pressing one. Nonetheless, the existence of a ple, every five years). well-functioning national drug regulatory authority to help Fees and charges substantially fund the cost of operat- ensure medicine quality, safety, and efficacy is the best guar- ing the national regulatory agencies in most developed antee that the public is getting the medicines it deserves. A and some developing countries. In Canada, the United national regulatory authority needs a clear mission state- Kingdom, and the United States, the agencies recover 70 ment including goals and objectives to direct its work. Goals 6 / Pharmaceutical legislation and regulation 6.17

Table 6-1 Resources required for effective administrative control

Resources required Specific function or purpose Personnel • Regulatory activities (licensing, registration, and so forth) • Monitoring, inspection, and surveillance • Enforcement Physical and infrastructure • Office space for regulatory and enforcement personnel • Access to appropriate analytical laboratory resources • Computers, software, sampling equipment, and office equipment • Vehicles for distribution, inspection, and enforcement activities Technical • Preservice and in-service training • Knowledge of pharmaceutical manufacturing processes, packaging, and so forth • Collation of data • Dissemination of information • Reference library (books, journals, bulletins) Financial • Capital and recurrent expenditures • Technical programs • Payments for patents and royalties • Payments for consultants • Payments for quality-control samples • Publications (forms, licenses, pharmacopoeia) • Travel for inspection and enforcement activities Source: Adapted from Jayasuriya 1985. usually include protecting public health by ensuring the products, manufacturers, importing agents, and distributors safety, efficacy, and quality of medicines and their appro- is in place. A small authority has limited capacity to under- priate use. Plainly outlined objectives provide a measure to take these tasks. For imported pharmaceutical substances, evaluate how well the agency is functioning. a small authority is dependent on information generated in Primary pharmaceutical regulation activities should not the exporting country. The WHO certification scheme on be compromised by other nonregulatory tasks with which the quality of pharmaceutical products moving in inter the national regulatory authority may be charged. If the national commerce (WHO 2000) was designed to provide authority responsible for pharmaceutical regulation has this information, although recommendations have been nonregulatory functions, such as manufacturing, procure- made on how to update the scheme (WHO 2008). As dis- ment, or service delivery, conflicts of interest may occur cussed in Chapter 19, this scheme must be supplemented by regarding mandates and resource allocation. direct contacts with international agencies and other regula- When a country is ready to introduce pharmaceutical tory agencies to obtain necessary information; however, the regulation, work by WHO (1990) provides useful guidance certification scheme is only as good as the certifying author- for authorities with limited human, financial, scientific, ity. WHO’s prequalification program provides information and technological resources. To be effective, a small drug on approved sources for products related to HIV/AIDS, regulatory authority needs to operate within the national malaria, tuberculosis, and reproductive health. pharmaceutical laws and policies that have been established Many national regulatory authorities do not make pub- and must relate to other interested bodies, including orga- licly available their regulatory policies, administrative nizations responsible for pharmaceutical procurement in procedures, guidelines, and criteria for decisions. Lack of the public sector and the national formulary committee. As transparency means that communication is probably lack- mentioned, effectively enforcing pharmaceutical legislation ing on medicine regulation between national regulatory requires national regulatory authorities and other govern- authorities and their stakeholders. Moreover, transparency ment enforcement agencies, such as customs, police, and is required to make the agency accountable for its actions prosecutors, to work together. National regulatory agen- and to limit the influence of political pressures and per- cies should also seek the cooperation of health profession- sonal favors in the decision-making process. Transparency als, pharmaceutical and consumer associations, and other will also contribute to the credibility and authority of com- interested parties through stakeholder workshops, meet- munications between the agency and those affected by ings addressing specific issues, or other venues open to the its actions: manufacturers, importers, distributors, health public. professionals, and consumers. An assessment tool is avail- A drug regulatory authority’s objectives can be accom- able to measure transparency in the pharmaceutical sectors plished effectively only if a mandatory system of licensing (WHO 2009a) and a report describes the assessment of four 6.18 Policy and legal framework

countries’ pharmaceutical registration, selection, and pro- outlets to ensure that they comply with prevailing curement systems: Lao P.D.R., Malaysia, Philippines, and regulations and guidelines Thailand (WHO 2006a). To increase the amount of information and communica- To implement these responsibilities, the authority must tion, WHO is helping drug regulatory authorities develop have the power to order that certain things be done and to websites with information on— prosecute those who disregard the law. To retain public confidence and respect, the authority must be seen as operating • Lists of approved medicines in an independent, authoritative, and impartial manner. It • National pharmaceutical regulations should be concerned exclusively with the determination of • Methods to ensure safe, efficacious, and rational use of standards and the implementation of controls. Although it specific medicines needs to work closely with the body responsible for public • Lists of approved companies and their authorized pharmaceutical procurement, it should not be responsible activities for procurement and should remain independent in its • Details of persons and institutions with responsibility operations and decisions. for pharmaceutical regulation

WHO resources available for drug regulatory authorities 6.8 Evaluating the effectiveness of include— pharmaceutical legislation

• A model website for drug regulatory authorities that Evaluating the effectiveness of pharmaceutical legislation aims to enhance communication and transparent and accompanying regulations is not always easy. The pro- dialogue among national drug regulatory authorities, cess of evaluation depends on the types of performance indi- industry, consumers, and health professionals (http:// cators and criteria used and on the availability of adequate www.who.int/medicines/areas/quality_safety/ data. The questions in the Assessment Guide at the end of regulation_legislation/model_site/en) this chapter provide a framework. • A list of recognized drug regulatory authorities’ The most important factor in the effectiveness of phar- websites (http://www.who.int/entity/medicines/ maceutical laws and regulations is the extent to which the areas/quality_safety/regulation_legislation/ legislative framework is in tune with national policy and the ListMRAWebsites.pdf) existing situation in the pharmaceutical sector. Changes in • A tool to assess regulatory authorities (http://www. policy need to be reflected in the legislation and in its imple- who.int/medicines/areas/quality_safety/regulation_ mentation. legislation/assesment/en/index.html) Measuring the effectiveness of a law on pharmaceuticals is • Practical guidance for conducting a review (based easier for certain elements than for others. For instance, the on the WHO Data Collection Tool for the Review of registration process can be evaluated in relation to quantita- Drug Regulatory Systems) (http://www.who. tive targets and time schedules to see whether the agency is int/medicines/areas/quality_safety/regulation_ on schedule. legislation/GuideAssessRegSys.pdf) The degree of noncompliance with a law or regulation • A drug regulatory status database (http://www.who. may suggest not only the need to take action against those int/hiv/amds/patents_registration/en/index.html) responsible but also the desirability of identifying the causes of noncompliance: it may be related to technical defects In summary, the regulatory authority should be vested in the law or in its wording, or to operational problems of with legal powers to— implementation, such as lack of transparency or poor communication, which can be resolved. Enforcement person- • Issue, vary, and revoke licenses for pharmaceutical nel should periodically report on their perception of how products on grounds of quality, safety, and efficacy the law functions and the types of problems encountered to • Ensure the safe and effective use of each product by facilitate any necessary revisions. Many legislative and regu- controlling, through the terms of the license, the con- latory provisions can be improved and updated when the tent of all labeling (including package inserts, associ- legislation is sufficiently flexible to allow for modifications ated prescribing information, and advertising) and the by the regulatory agency. channels through which the product may legitimately Responsibility for evaluating the effectiveness of a drug be supplied law often falls on the regulatory authority established by • Inspect and license all manufacturing premises, law for policy making, implementation, or both. The level importing agents, wholesalers, distributors, hospital of accountability and transparency under which the drug dispensaries, independent pharmacies, and other retail regulatory authority operates can be evaluated by examining 6 / Pharmaceutical legislation and regulation 6.19 reporting requirements, external reviews of performance, Stenson, B., L. Syhakhang, C. S. Lundborg, B. Eriksson, and G. Tomson. processes involved with lodging complaints, and appeals 2001. Private Pharmacy Practice and Regulation: A Randomized Trial in Lao P.D.R. International Journal of Technology Assessment in procedures. Periodic self-evaluation to identify weaknesses Health Care 17(4):579–89. in policy making and implementation activities is impor- Srivastava, D. 2008. A Country Level Report on the Pharmaceutical tant. The body must devise its own systems to judge whether Sector in India. Part One: Institutions Involved in Pharmaceutical it receives sufficient feedback and whether its operational Regulation. London: UK Department for International Development. effectiveness can be improved.n Syhakhang, L., B. Stenson, R. Wahlström, and G. Tomson. 2001. The Quality of Public and Private Pharmacy Practices: A Cross-Sectional Study in the Savannakhet Province, Lao PDR. European Journal of References and further readings Clinical Pharmacology 57:221–7. TGA (Therapeutic Goods Administration). 2003. Australian Regulatory Guidelines for OTC Medicines. Woden, A.C.T., Australia: H = Key readings. TGA. Coplan, P. M., M. Mitchnick, and Z. F. Rosenberg. 2004. Regulatory H TCM/HTP/WHO (Department of Technical Cooperation for Challenges in Microbicide Development. Science 34:1911–2. Essential Drugs and Traditional Medicine/Health Technology and Davis, S. 2009. Microbicide Hopes Fade with Poor Trial Results. Science Pharmaceuticals/World Health Organization). 2007. Report of the and Development Network 16 December. Regulatory Decision Making, WHO Headquarters, Geneva 27–29 Feeley, R., B. O’Hanlon, A. Stene, and Y. Sezgin. 2009. Finding November 2006. Sector Through More Effective Regulations. Bethesda, Md.: Private WHO (World Health Organization). 2010a. Medicines: Counterfeit Sector Partnerships (PSP)-One, Abt Associates. Report.pdf> ————. 2010b. Regulatory Harmonization: Updating Medicines Fox, M., D. Beasley, and K. Kelland. 2010. AIDS Gel with Gilead Regulatory Systems in Sub-Saharan African Countries. WHO Drug Drug Protects Women in Study. 20 July. Vienna: Reuters. Information 24(1):6–20. Sector: Assessment Instrument. Geneva: WHO. Countries. London: UK Department for International Development ————. 2009b. Annex 3: Procedure for Prequalification of Pharma- Health Systems Resource Centre. Pharmaceutical Preparations. 43rd Report. the Tenth International Conference of Drug Regulatory Authorities ————. 2008. WHO Certification Scheme on the Quality of (ICDRA), Hong Kong, China, 24–27. Geneva: World Health Pharmaceutical Products Moving in International Commerce. Organization. WHO Drug Information 22(3):207–18. Hill, S., and K. Johnson. 2004. Emerging Challenges and Opportunities H ————. 2007a. Practical Guidance for Conducting a Review. in Drug Registration and Regulation in Developing Countries. [Based on the WHO Data Collection Tool for the Review of London: UK Department for International Development Health Drug Regulatory Systems.] Geneva: WHO. GuideAssessRegSys.pdf> Jayasuriya, D. C. 2002. Medicinal Products and the Law in Developing H ————. 2007b. WHO Data Collection Tool for the Review of Countries—Concepts, Issues and Approaches. New Delhi: Har- Drug Regulatory Systems. [To Be Used Jointly with Practical Anand Publications. Guidance for Conducting a Review.] Geneva: WHO. Kaplan, W., and R. Laing. 2003. Paying for Pharmaceutical Registration ————. 2006a. Measuring Transparency in Medicines Registration, in Developing Countries. Health Policy and Planning 18:237–48. Selection and Procurement: Four Country Assessment Studies. Mui, Y. Q. 2009. “Crackdown Targets Counterfeit Drugs: Fake Geneva: WHO. PAHO (Pan American Health Organization). 2005. Proceedings of IV ————. 2006b. Annex 7: Multisource (Generic) Pharmaceutical Pan American Conference on Drug Regulatory Harmonization. Boca Products: Guidelines on Registration Requirements to Establish Chica, Dominican Republic, March 2–4. Interchangeability. In WHO Expert Committee on Specifications for PANDRH Steering Committee (Pan American Network for Drug Pharmaceutical Preparations. 40th Report. Geneva: WHO. American Health Organization. ————. 2005a. Annex 5: Guidelines for Registration of Fixed-Dose Pereko, D., and J. Nwokike. 2006. “Improving the Availability of Combination Medicinal Products. In WHO Expert Committee on ARVs in Namibia by Using Policy Change to Streamline the Drug Specifications for Pharmaceutical Preparations. 39th Report. Geneva: Registration Process.” Paper presented at the XVI International WHO. Ratanawijitrasin, S., and E. Wondemagegnehu. 2002. Effective ————. 2005b. Handbook for Good Clinical Research Practice (GCP): Drug Regulation: A Multicountry Study. Geneva: World Health Guidance for Implementation. Geneva: WHO. 6.20 Policy and legal framework

assessment guide

Policy, legislation, and regulation manufacturing, distribution, and dispensing facilities? • Is there a national medicine policy approved by the • Do inspectors use a checklist for inspecting different government? Is the policy suitable to regulate the types of pharmaceutical establishments? market? When was it last updated? • How many inspections were made during each of • Is there a comprehensive medicine law? Is it appro- the last three years for the different types of pharma- priate? Is it a new law or a revision of an existing law? ceutical establishments? When was it last updated? • Is there an audit system to evaluate the inspection • Is the legislation flexible in allowing for the passage system? and revision of regulations in response to new scientific information and market changes? Advertising and promotion • Is there a drug regulatory authority responsible for • Is there any specific regulation regarding therapeutic the promulgation of regulations and for enforce- claims in drug labeling and promotion? ment? Does the necessary political will and funding • Is there any legal provision for the compulsory use exist to support it? of generic names in medicine labeling and promo- • Are regulatory policies, procedures, and criteria for tion? decisions available to all stakeholders? • Are there controls on pharmaceutical promotion, Medicine selection and registration and are these consistent with the WHO ethical criteria for medicinal drug promotion? • Is there a system for medicine registration? Is this a notification procedure? A basic authorization pro- Compliance and enforcement cedure? A full registration procedure? Is periodic • What measures exist for enforcement of pharma- renewal required? ceutical laws and regulations? Are they enforceable • Is medicine registration based on an assessment of a administratively or through court actions? Are medicine’s efficacy, safety, quality and truth of pack- statistics available about compliance and enforce- aging information? Are pharmacological or thera- ment? peutic standards used? • During the last three years, how many pharmaceu- • Are there different registration procedures for essen- tical products were eliminated from the register? tial medicines, generic products, multisource drugs, How many batches of pharmaceutical products were or imported products from selected countries? recalled from the market? • Is the WHO certification scheme on the quality of • Is there a system for reporting pharmaceutical prod- pharmaceutical products moving in international uct problems? What types of and how many com- commerce used systematically for the registration of plaints were registered in the past three years, and imported medicines? what corrective measures were taken? • Are relevant medicines procured from suppliers • How many violations have occurred with regard to prequalified by WHO? pharmaceutical advertising and promotion in the • Is there a system for the collection of data regarding past three years? What corrective measures were the efficacy and safety (adverse effects) of marketed taken? medicines? • Are there any statistics about the reaction of the Licensing, inspection, and control industry and consumers to regulatory actions? • Do mechanisms exist for the licensing, inspection, and control of pharmaceutical personnel and for 6 / Pharmaceutical legislation and regulation 6.21

————. 2005c. National Policy on Traditional Medicine and Regulation ————. 1998a. Guidelines for the Appropriate Use of Herbal Medicines. of Herbal Medicines—Report of a WHO Global Survey. Geneva: Manila: WHO Regional Office for the Western Pacific. whqlibdoc.who.int/wpro/-1993/9290611103.pdf> ————. 2003a. Annex 9: Guide to Good Storage Practices for H ————. 1998b. Marketing Authorization of Pharmaceutical Pharmaceuticals. In: WHO Expert Committee on Specifications for Products with Special Reference to Multisource (Generic) Products: Pharmaceutical Preparations. 37th Report. Geneva: WHO. A Manual for Drug Regulatory Authorities. Geneva: WHO. Medicines Regulation: Ensuring Safety, Efficacy and Quality. ————. 1998c. Regulatory Situation of Herbal Medicines: A Worldwide Geneva: WHO. WHO_TRM_98.1.pdf> ————. 2002a. Annex 3: Good Practices for National Pharmaceutical ————. 1990. Guiding Principles for Small National Drug Regulatory Control Laboratories. In WHO Expert Committee on Specifications Authorities. In WHO Expert Committee on Specifications for for Pharmaceutical Preparations. 36th Report. WHO. ————. 2002b. The Importance of Pharmacovigilance: Safety Monitoring ————. 1988. Ethical Criteria for Medicinal Drug Promotion. Geneva: of Medicinal Products. Geneva: WHO. WHO/IMPACT (World Health Organization/International Medical ————. 2002c. Safety of Medicines: A Guide to Detecting and Reporting Products Anti-Counterfeiting Taskforce). 2008. Counterfeit Drugs Adverse Drug Reactions. Geneva: WHO. WHA2008a.pdf> H ————. 2001a. How to Develop and Implement a National Drug H WHO/PSM (World Health Organization/Department of Policy. 2nd ed. Geneva: WHO. Good Governance in the Public Pharmaceutical Sector: Working ————. 2001b. Pharmaceuticals and the Internet: Drug Regulatory Draft for Field Testing and Revision. Geneva: WHO/PSM. hq/2001/a74987.pdf> H WHO/QSM (World Health Organization/Quality Assurance and ————. 2000. WHO Certification Scheme on the Quality of Pharma Safety of Medicines). 2004. WHO Medicines Regulatory Package. ceutical Products Moving in International Commerce. Geneva: WHO. Geneva: WHO. Western Pacific). 2004. Enhancing Health Policy Development: ————. 1999b. Medical Products and the Internet. Geneva: WHO. A Practical Guide to Understanding the Legislative Process. Manila: WHO/WPRO. Guiding Principles for Small Drug Regulatory Authorities. In WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-Fifth Report. Geneva: WHO.