Drug regulation structures in existence today-drug laws, drug regulatory agencies, drug evaluation boards, QC laboratories, drug information centres, etc.-have developed over time. In some countries, such developments began centuries ago; in others, they are relatively recent, having started only in the 1990s. A timeline of drug regulatory events is shown in Figure 4.3 below.

Figure 4.3 Timeline of drug regulation events

4.5.1 Different evolutionary paths

Cuba has a long history of drug regulation. The first regulation relating to drugs, the royal act Real Tribunal Protomedicato was enacted in 1709. This law did not, however, attempt to control “drugs” themselves, but rather aimed to regulate pharmacists and medical activities. In 1833, the enactment of the Superior Royal Board of Pharmacy Regulation was aimed not only at regulating pharmacy and the medical profession, but also at regulating drugs. After the 1959 revolution, private manufacturers and pharmacies were nationalized. The current drug regulatory structures were established only recently. The National Regulatory Authority and NCDQC were created by ministerial decree in 1989. Rules for drug registration were instituted in 1995, also by ministerial decree.

Venezuela developed its drug regulation system relatively early. Its first drug-related law was issued in 1883 as the Ordinance of the Council of Physicians on Secret Medicines and Patents. Drug laws have been revised regularly; a significant number of drug laws were adopted over the course of the 20^th century. The law which established the drug registration system-the Law on the Exercise of the Pharmacy-was passed in 1928, before the Ministry of Health was set up in 1936. The National Institute of Hygiene was established in 1938 to serve as the nation’s DRA. Over the years, new rules and organizations have been created to expand the scope of regulation and to add capacity for executing the laws. The section on pharmacological advice, the Laboratory for Pharmacological Analysis and the Centre for Pharmacological Surveillance were established in 1944, 1946 and 1962, respectively. Rules for GMP were drawn up in 1990.

Tunisia first introduced drug regulation in 1942, in the form of a decree on medical and pharmaceutical promotion and drugs control. All finished pharmaceutical products, whether manufactured in Tunisia or imported, must undergo a technical committee review and obtain a certificate of approval from the Ministry of Health before they may be placed on the market. Registration is also required for homeopathic drugs, and some herbal medicines are registered with the status of allopathic medicines. Key legislation includes the 1961 Law on Inspection of Pharmacies and Manufacturers, the 1969 Poisonous Drug Law and the 1985 Law on Production of Drugs for Human Use. Between 1985 and 1991, several legal texts were promulgated concerning GMP, clinical trials, medical and scientific information, procedures to obtain licensing of manufacturing and registration. New organizations were also created by law, for example the Pharmacy and Medicines Directorate in 1981, the National Pharmacovigilance Centre in 1984 and the National Medicines Control Laboratory in 1990.

Regulatory controls over the pharmaceutical sector in Malaysia were introduced in the 1950s, starting with the promulgation of three ordinances: the Sales of Food and Drugs Ordinance of 1952, the Poisons Ordinance of 1952 and the Dangerous Drugs Ordinance of 1952. These were followed by the Medicines (Advertisement and Sale) Ordinance of 1956. Combined, the laws provided a legal framework to regulate the general handling of pharmaceuticals, including poisons and narcotics, in respect of importation, manufacture, compounding, storage, distribution and transportation. They also covered advertising, sales, record-keeping and use of pharmaceuticals.

The next wave of major legislative activities and capacity-building relating to drug regulation came in the late 1970s and 1980s. The National Pharmaceutical Control Laboratory was set up in 1978 for the purposes of regulatory control. New legislation was introduced in 1984 in response to increased concerns about the infiltration of products into the market and the inaccuracy of information provided by the pharmaceutical industry. This legislation was promulgated under the Control of Drugs and Cosmetics Regulations 1984. This Act provided for the establishment of the Drug Control Authority (DCA), which started registering pharmaceutical products in January 1985. But the initial implementation of this law was limited only to the states of Peninsular Malaysia (West Malaysia). In 1990 the law was extended to cover the states of Sabah, Sarawak and the Federal Territory of Labuan (in East Malaysia). The Poisons Ordinance, revised to become the Poisons Act 1952, was again revised in 1989, to include the Poisons Regulations (Psychotropic Substances Act 1989). Similarly, the Sales of Food and Drugs Ordinance was revised in 1959 to become the Sales of Drugs Act 1952 (revised 1989).

In the Netherlands, the legal basis for licensing of pharmaceutical manufacturing and distribution was established in 1956. The Medicines Act of 1958 thereafter regulated the admission of medicines to the Dutch market through the MEB. But the Board started to operate only after 1963, triggered by the thalidomide disaster of 1961. European drug regulation is now playing a growing role. In 1995, the European Medicines Evaluation Agency was founded to co-ordinate the tasks of the drug regulatory authorities of European Union Member States. Certain aspects of Netherlands drug regulation now follow European Union rules. For example, GMP inspection is based on the 1983 European Union guidelines for GMP. Since 1 January 1995, a European procedure for registration has operated in the Netherlands. Now two types of trade licences exist: a European licence and a national licence. Products with a European licence may be sold throughout the whole European Union, while the national licences are only valid for the country in which the licence was issued by means of the national registration procedure.

In Cyprus, the Pharmacy and Poisons Law was first promulgated in 1959. It established the framework for regulation of pharmacy practice, drug distribution, prescription and labelling. The principal legislation regulating pharmaceuticals today-the Drug Law-was introduced in 1967 following the thalidomide disaster. Several major regulatory activities, e.g. drug registration and licensing of manufacturers, began in 1970.

The “thalidomide disaster” was also a key factor in the development of the Australian drug regulatory system. Before the 1960s, drug regulation was predominantly the responsibility of the states and territories, rather than the Australian Commonwealth. There was considerable diversity in the level of control exercised. The first advisory committee to review drugs was set up by the state of Victoria in 1948. This committee reviewed all products sold in the state of Victoria, but had no jurisdiction over other states in Australia. The first Commonwealth advisory committee in Australia was established in 1964. Because of the legislative process, the Commonwealth limited its control to imported products and those included in the Government reimbursement list. The National Biological Standards Laboratory (the forerunner of the mechanisms established under the Therapeutic Goods Act) was established to test drugs provided on the Schedule for Quality. The first federal act relating to therapeutic goods was enacted in 1965. Lack of control over locally manufactured products emerged as a public policy issue in the mid-1980s, and the Therapeutic Goods Act was changed in 1989 in response.

Under the terms of the Act, the TGA was created. It combined the old Therapeutics Division within the Department of Health with the National Biological Standards Laboratory.

Uganda passed its first drug regulation law, Eddagala Luwangula, in 1952. A poisons guide was issued in 1960, a dispensary tariff imposed in 1962 and a trade guide issued in 1963. In 1970, the Pharmacy and Drugs Act was enacted to regulate the pharmacy profession. Currently, the major piece of drug regulatory legislation in use is the National Drug Authority Statute of 1993.

Regulation of medicines in Zimbabwe started in 1969, with the promulgation of the Drugs and Allied Substances Control Act, Chapter 320. This Act created the Drugs Control Council (a body corporate), which started operations in 1971. The 1997 amendment transformed the Drugs and Allied Substances Control Act into the Medicines and Allied Substances Control Act (MASCA), Chapter 15:03, which established the Medicines Control Agency of Zimbabwe (MCAZ), with increased authority.

Estonia’s drug regulatory framework has begun to take shape only over the last decade, since the country gained independence. However, the pace of regulatory development has been rapid. The Licensing Board of Pharmaceutical Activities and the Centre of Medicines were both created in 1991. Registration and licensing were introduced that year. In 1993, the SAM was created to become the DRA. The main legislation-the Medicinal Products Act-came into force in 1996.

4.5.2 Patterns of development

Some observations can be made on the basis of the country data relating to the historical development of drug regulation.

Objectives of the first drug law

Cuba, which has the longest drug regulation experience in this group, issued its royal act Real Tribunal Protomedicato in 1709 to control the conduct of professionals, rather than pharmaceutical products themselves. Before the industrialization of pharmaceutical production, drugs were made up and dispensed to individual patients in pharmacies. Accordingly, attempts to protect patients were aimed first at the activities of the professionals who practised pharmacy rather than at the products themselves, which at that time were being manufactured on a small scale only.

The first Venezuelan drug law, the Ordinance of the Council of Physicians and Secret Medicines and Patents (1883), stated its objective as the control and registry of medicines, in order to develop a pharmacopoeia of drugs with established pharmacological properties, composition, indication and dosage, for the purposes of standardization. A product registration system was developed and the DRA was created some decades later.

The specific feature of Tunisia’s first drug law-the 1942 Decree related to Medical and Pharmaceutical Promotion and Drug Control-was the control of drug information. It required authorization of product information on leaflets before a drug could be marketed.

Countries that developed their drug regulation more recently generally began with one or more relatively comprehensive pieces of legislation, which covered a larger number of functions relating to control of the pharmaceutical sector than legislation developed earlier. The drug laws of Australia, Malaysia and Zimbabwe are examples of such development.

Patterns of historical development

The 10 countries appear to follow some general patterns of development in their drug regulatory systems. Most countries started out with the enactment of a law specifying the scope of control, followed by institutionalization-the creation of a specialized organization to execute the law. They then built up capacity by establishing QC laboratories and other facilities to strengthen regulation. In some countries, for example Zimbabwe, the first law included comprehensive provisions for areas of control, as well as the creation of specialized drug regulatory institutions. The scope of drug legislation was then gradually expanded to cover such areas as manufacturing practice, drug promotion and drug prices.

In brief, drug laws in these 10 countries evolved, and regulatory capacities developed over time, to meet the growing complexity of the pharmaceutical sector, and to respond to societal concerns.

Crisis-led change

Regulatory policies are often developed in response to problems.

As mentioned above, significant changes in drug regulation in Australia, Cyprus and the Netherlands, were made as a result of the thalidomide disaster that occurred in Europe in 1961. This is a classic example of a crisis-led change. The disaster increased public concerns about pharmaceutical safety: governments responded by imposing more stringent controls on the pharmaceutical sector, and with less resistance from the industry than would normally have been the case.

Discrete versus continuous drug regulation development

Two distinctive patterns of drug regulation development can be identified from the timeline map in Figure 4.3: discrete development versus continuous development. Cuba, Tunisia and Venezuela offer examples of the latter: their laws were promulgated at more or less regular intervals. Australia, Malaysia and the Netherlands have displayed a pattern of discrete development, alternating between periods of massive change and relative quiet. For example, in Malaysia, several laws were enacted in the early 1950s, which laid the groundwork for drug regulation in the country. But the country’s drug laboratory was not established until 1978, with subsequent major amendments to the 1950s laws being adopted in the 1980s.

In Figure 4.3, the major milestones in drug regulatory development in the 10 countries are presented as a time-scale, to illustrate discrete development versus continuous development of drug regulation.

Trend towards harmonization

International collaboration in drug regulation has led to the creation of international instruments to facilitate cross-border drug control, particularly for narcotics. All the 10 countries in this study have signed a number of international conventions. The most commonly endorsed of these conventions relate to narcotic drugs and psychotropic substances, and illicit trafficking.

Recent regional activities indicate a trend towards harmonization of standards and laws. The European Union is the most advanced in fostering regional harmonization of drug regulation. In 1995, the European Medicines Evaluation Agency was created to co-ordinate drug regulatory affairs in its Member States. The influence of European Union guidelines and rules is evident in Estonia and the Netherlands. Because its drug regulatory structures have been developed recently, Estonian drug regulation has made rapid progress towards harmonization with European Union structures. In the Netherlands, on the other hand, the main regulatory framework was created in the 1960s, so that the country currently recognizes two drug regulation systems. Drugs registered by the MEB, and those registered by the European Commission (on the recommendation of the European Medicines Evaluation Agency) are both available on the Netherlands market. For GMP inspection, the Dutch regulatory body follows the relevant European Union guidelines. The Netherlands is also involved in the process initiated by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) by virtue of its membership of the European Union.

Venezuela also observes harmonization decisions made by a regional body, namely the Andean Community.

Australia has a formal process for adopting European guidelines for drug development and evaluation, including the ICH guidelines. It also has bilateral agreements with a number of countries, and its membership of the Pharmaceutical Inspection Convention allows it to exchange GMP information with other members.

Members of the Association of South-East Asian Nations (ASEAN), Malaysia included, have yet to formulate common rules for drug regulation. Nonetheless, efforts have been made towards harmonization in terms of voluntary standards. Through the ASEAN Technical Cooperation Project in Pharmaceuticals, a number of reference substances and guidelines have been developed (17). Furthermore, agreements made for the ASEAN Free Trade Area have harmonized and reduced import tariffs on a number of goods, including pharmaceutical raw materials and finished products.