“WHO continues to establish and develop authoritative norms and standards to assist countries in the assurance of the quality, safety and efficacy of medicines. This is a goal supported and pursued by all parts of WHO.”

WHO Director-General Dr Gro Harlem Brundtland, keynote address, 9th International Conference of Drug Regulatory Authorities, April 1999. ⁵⁴

Effective drug regulation promotes and protects public health by ensuring the quality, safety and efficacy of medicines before they reach consumers. WHO's major contribution in this area relates to development of internationally recognized norms, standards and guidelines. These are then adapted by countries to meet their specific drug regulatory needs and, provided they are adequately enforced, help maintain public confidence in pharmaceuticals.

Component 6: Norms, standards and guidance for pharmaceuticals

Strengthen global norms, standards and guidelines for the quality, safety and efficacy of drugs, including traditional medicine, and provide guidance for global harmonization efforts

Progress

The development of norms, standards and guidelines to promote quality assurance and quality control is an integral part of WHO's Constitution and a unique responsibility. It has been endorsed and supported through numerous World Health Assembly resolutions, and more recently in those on the Revised Drug Strategy.

Much of the work is ongoing since it involves providing advice as information becomes available. For example, development of quality control specifications for essential drugs - for inclusion in The International Pharmacopoeia - started in the 1950s. The fifth volume will soon be published. Similarly, WHO's contribution to quality control in laboratories was initiated in 1970, and has included drafting of guidelines for national quality control laboratories, and provision of further guidance on samples and validation. Thereafter, in 1975, the first edition of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce was issued. Since then the scheme has been revised twice, and now boasts a total of 142 Member State participants.

Development of the WHO system of International Nonproprietary Names (INN) is another ongoing activity. Introduced by WHO in 1950, this system is a means of identifying each pharmaceutical substance or active pharmaceutical ingredient by a unique name that is universally recognized and universally accessible as public property. Given the growth in global pharmaceutical markets and international pharmaceutical trade, use of INNs by all countries has become increasingly important. Conversely, the existence of several names for the same pharmaceutical substance can be a source of considerable confusion (Figure 17). To date more than 7000 INNs for generic and newly developed products have been selected, published and translated into five languages. WHO is also working in close collaboration with WIPO to protect INNs against use as trademarks.

Figure 17: International nonproprietary name one name worldwide

Good manufacturing practices (GMP) have also been actively promoted by WHO. All WHO GMP texts are now available in a single publication for easy reference, a revision of the text on sterile products is being finalized, and additional GMP guidance is being developed for inspectorates, as well as draft pre-approval inspection and quality system requirements for national GMP inspectorates.

In terms of actual pharmaceutical products, activities to ensure the quality of starting materials are well under way, including the development of a model certificate of analysis and mechanisms to improve quality assurance and relevant commercial trading practices.

WHO has also provided guidance on the selection of comparator pharmaceutical products for equivalence assessment of generic products. This is an important area of activity given WHO's support for generic products ^c and their potential to increase access to essential drugs.

^c More generally termed “multisource” products by drug regulators.

Regarding use of pharmaceutical products, WHO has developed the ATC/DDD system (Anatomical Therapeutic Chemical Classification system/defined daily dose) to collect drug use data. This data is essential for assessing trends in drug use and cost, assessing use in light of existing guidelines, measuring the impact of interventions against misuse, and ultimately measuring access, quality and cost-effectiveness of care.

Challenges

The increasing globalization of commerce and trade, and the merging of pharmaceutical companies, are internationalizing pharmaceutical production. Pharmaceutical norms and standards are thus more important than ever before since they serve as a common reference point for ensuring minimum safety and quality. One of WHO's roles is to continue to define such norms and standards, and to help countries apply them.

Safety and quality of pharmaceuticals are also being promoted through regional and international efforts to harmonize drug regulation, such as those led by the International Conference on Harmonisation (ICH), the European Union, ASEAN (Association of South-East Asian Nations), CAN (Andean Community), CADREAC (The Collaboration Agreement of Drug Regulatory Authorities in European Union Associated Countries), and MERCOSUR (Southern Common Market). These efforts are to be welcomed since international consensus on quality, safety and efficacy standards can speed up access to new medicines. It also favours price competition among generic pharmaceutical products.

That said, quality assurance levels differ from country to country - not all countries have the same capacity and resources for implementing agreements on drug regulation harmonization. Drug regulation experts accordingly recommend a step-wise approach for achieving the highest level of drug regulation and quality control in each country. WHO's role is to identify areas in which further guidance needs to be developed for preliminary and intermediate steps. Simple screening tests for detecting substandard and counterfeit drugs are just one example.

More generally, WHO's task is to help countries consider the implications of the relevant harmonization agreements. This is particularly true with regard to ICH, which currently does not include representatives from all developing countries. WHO needs to evaluate the impact of ICH guidelines, and advise non-ICH Member States on how to adapt existing guidelines to their own needs and conditions.

At the same time WHO must ensure that its own normative guidelines, such as its guidelines on good clinical practice (GCP), are maintained and updated. The GCP guidelines aim to provide globally accepted and applicable standards for biomedical research involving human subjects, and must therefore take recent developments in science and technology fully into account.

Rapidly evolving science and technology are likewise creating problems for regulatory authorities everywhere. Training and specialization requirements for dealing with the ever increasing complexity of assessing technologically advanced products can be especially burdensome. But by developing norms and standards for use in new areas of health technology and product development, WHO can reduce this problem, while at the same time helping to minimize unnecessary duplication of scientific expertise and effort.

Globalization of the pharmaceutical industry is also bringing other safety issues to the fore. For example, nonprescription medicines are becoming increasingly available to the general public in all countries, including through such channels as the Internet. Yet resources for monitoring their safety are often lacking.

Expected outcomes for 2000 - 2003

6.1: Norms, standards and guidelines developed or updated including: norms and standards for pharmaceutical legislation and regulation, for assessment of quality, safety and efficacy, and for quality assurance; standards for safe trade in starting materials and finished drug products; and guidelines concerning sale of medical products on the Internet.

• Specific work will include developing guidelines on safe trading in the context of globalization, and on the purchase and sale of medical products on the Internet. The WHO guidelines on good clinical practice will be revised, and guidelines produced by other institutions or regional collaborative groups evaluated.

6.2: Quality control specifications, basic tests, screening tests and international chemical reference materials for pharmaceuticals developed. The quality control specifications will be included in The International Pharmacopoeia.

• Work will include development of pharmacopoeial monographs, publication of the sixth volume of The International Pharmacopoeia, and creation and maintenance of international reference materials, screening tests and basic tests.

Figure 18: Antibiotics and other essential drugs are commonly counterfeited leading to treatment failure and sometimes even death

Note: By April 1997, WHO had received reports of 771 cases of counterfeit drugs, as broken down above.

Source: World Health Organization, 1999. ⁵⁸

6.3: Drug nomenclature and classification efforts continued through assigning, promoting and protection of international nonproprietary names (INNs) and promotion and development of ATC/DDD system (Anatomical Therapeutic Chemical Classification system/defined daily dose).

• INNs will be assigned to new pharmaceutical substances, their use promoted and measures for protecting against their misuse strengthened. ATC/DDD classification will continue to be developed and promoted, particularly for drug use studies, by the International Working Group on Drug Statistics Methodology.

6.4: Promotion of WHO norms, standards, guidelines, nomenclature and WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce at national and international levels.

• WHO will provide support for workshops, conferences, publications and other promotional measures to ensure adoption and implementation by countries and international organizations of WHO norms, standards, guidelines and nomenclature, and also the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce.

6.5: Coordination of regional and international harmonization of norms through networking with interested parties, and regular review of WHO’s position on global harmonization.

• WHO will continue to collaborate with the International Conference on Harmonisation, and support regional drug regulatory networks.

Component 7: Drug regulation and quality assurance systems

Support countries to establish and maintain effective drug regulation and quality assurance systems

“Today, the quality of drugs and, therefore, their effectiveness and safety are less and less certain, especially for the poorest populations, who are attracted by lower-priced drugs sold outside pharmacies.”

Bernard Pécoul et al., 1999. Access to Essential Drugs in Poor Countries. A Lost Battle? ³⁵

Progress

WHO's experience in drug regulation has shown that countries generally develop drug regulatory capacity in phases and over a long period of time. For countries with limited resources it is therefore particularly important to set priorities. Drug regulatory activities can later be expanded gradually, in line with development of the pharmaceutical sector, and as resources become available. ⁵⁵

In an attempt to find means of accelerating the development of drug regulation capacity, WHO has created a multicountry working group. Consisting of ten WHO Member States, the group is assessing the drug regulation performance - both strengths and weaknesses - of a variety of drug regulatory authorities. The ultimate aim is to develop alternative strategies for decision-makers for improving drug regulation, and for promoting a culture of mutual problem-solving.

WHO is also establishing collaborative projects with the European Agency for the Evaluation of Medicinal Products (EMEA), to develop methodologies for strengthening pharmaceutical inspectorates, and computerized systems to support the work of drug regulatory authorities.

Meanwhile, provision of training for national regulatory officials in GMP inspection, good distribution practices inspection, drug registration and quality control, is doing much to enhance existing drug regulation capacity. WHO's basic training modules for GMP are nearing completion and will be used to train trainers to enable more rapid spread of GMP implementation.

At the same time WHO has been helping countries to combat the growing problem of counterfeit and substandard drugs. Activities have included establishing a network of anti-counterfeit pharmaceutical liaison officers, expanding the WHO database on counterfeits, organizing workshops and international meetings on the issue, and helping countries to implement the Organization's Guidelines for the Development of Measures to Combat Counterfeit Drugs. ⁵⁶

The quality and safety aspects of traditional medicine - particularly herbal medicines - is another emerging issue for many drug regulation authorities, and reflects the increased use of and interest in this type of health care. WHO has responded by producing a number of authoritative reference materials, such as the Regulatory Situation of Herbal Medicines: Worldwide Review. ⁵⁷ Containing information from 50 countries on the regulation of herbal medicines, it is proving to be an invaluable reference for other countries seeking to develop their own systems for regulation and registration of herbal medicines.

Challenges

But despite all the efforts made to improve drug regulation at national and international levels, fewer than one in six WHO Member States have well-developed drug regulation. Those that do are usually wealthy, industrialized countries. About three in six Member States undertake drug regulation of varying levels of development and operational capacity, while two in six have either no drug regulatory authority or very limited drug regulation capacity.

Given this picture it is not surprising that in many developing countries the quality, safety and efficacy of both imported and locally manufactured medicines cannot be guaranteed. This is because pharmaceutical manufacturers, importers and distributors do not comply with the regulatory requirements, and smuggling and illegal importation of drugs are often rife.

Substandard ^d and counterfeit drugs ^e are then not only sold in these countries but also exported or re-exported. By April 1999, reports of 771 cases of substandard drugs had been entered into the WHO database on counterfeit drugs, 77% of which were from developing countries (Figure 18). (Data analysis showed that in 60% of the 325 cases for which detailed data were available, an active ingredient was lacking.) ⁵⁸

^d A substandard drug is a pharmaceutical product that does not comply with established standards.

^e A counterfeit pharmaceutical product is a product that is deliberately and fraudulently mislabelled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products. Counterfeit products may include products with the correct ingredients or with the wrong ingredients, with no or incorrect quantities of active ingredient, or with fake packaging.

The situation is worsened by the fact that medicines exported from industrialized countries are not regulated to the same level as those domestically consumed, while export of drugs to developing countries via free trade zones is increasing. Relabelling of products to mask details of their origin is also known to occur. Tackling these issues will require effective partnerships between WHO, national authorities and the pharmaceutical industry.

Strengthened drug regulation efforts at international level are also required following the concentration of pharmaceutical manufacturers within a limited number of large corporations, and increased pharmaceutical trading following international and regional trade agreements. Some policy-makers now believe that drug regulation represents an unnecessary barrier to trade and should be reduced to a minimum. Pharmaceuticals, however, cannot be considered a standard commodity since consumers and prescribers are unable to assess their quality, safety and efficacy.

This is well illustrated by the problem of how to protect consumers from substandard and dangerous drugs moving on international markets, and increasingly distributed via the Internet, over which there is little jurisdiction. Even if a product can be sold legally over the Internet within the country in question, the quality, safety and efficacy of pharmaceuticals sold in this way cannot be assured by the consumer. ⁵⁹

Growing international and national trade in alternative medicines, including herbal products, is also becoming more complex, following rapid increases in demand. Significant quantities of herbal products are now imported by countries in Europe, North America and Asia. For example, between 1992 and 1996, Australia's importation of Chinese herbal medicines increased fourfold, while Korea now imports about 30,000 tons of medicinal plants every year. ^{60, 61} As in the case of any other pharmaceutical material or product, their safety and therapeutic value must be assured if their full health benefits are to be attained. A growing number of countries are developing national policies on traditional medicine that cover quality and safety, but much remains to be done.

Figure 19: A growing number of countries report having laws and regulations covering herbal medicines, but many more are needed

Expected outcomes for 2000 - 2003

7.1: Drug regulation effectively implemented and monitored through better organization, financing, staffing and management of regulatory functions.

• Activities will include the development and promotion of drug regulation tools and training courses, facilitation of workshops and seminars, participation in regional and international conferences, such as the International Conference of Drug Regulatory Authorities and the Eastern Mediterranean Drug Regulatory Authorities Conference, and support to drug regulatory networks.

7.2: Drug manufacturing, distribution and inspection practices improved through provision of training modules and other tools for promoting good manufacturing practices, good distribution practices, inspection practices and other related enforcement mechanisms.

• WHO will finalize the good manufacturing practices (GMP) training modules, and continue to help countries implement GMP.

7.3: Substandard and counterfeit drugs combated by raising decision-makers’ awareness of the issue, increasing the capacity of enforcement authorities to take necessary action, and encouraging the different stakeholders, including the pharmaceutical industry, to work together on common solutions.

• WHO will continue to promote the WHO guidelines on counterfeit drugs 56 at national, regional and global levels. It will also maintain and extend its database on counterfeit drugs, and support the network of anti-counterfeit pharmaceutical liaison officers.

7.4: Regulatory Situation of Herbal Medicines: Worldwide Review updated following completion of data collection on regulatory situation of herbal medicines from Member States.

• As well as updating and extending its review of the regulatory situation of herbal medicines, WHO will encourage all countries to ensure the quality and safety of herbal medicines through development and implementation of suitable regulations.

Component 8: Information support for pharmaceutical regulation

Improve the access of national regulatory and pharmaceutical control authorities to reliable information management systems, and to mechanisms for exchange of independent information on drug quality, safety and efficacy

Progress

Reliable and rapid information exchange, as well as efficient data management, are essential to the effective operation of drug regulatory authorities. WHO is successfully using several means to promote such exchange.

The International Conference of Drug Regulatory Authorities (ICDRA) is a good example of WHO's networking activities. Supported by WHO, ICDRA is the only international forum where representatives of national and regional drug regulatory authorities can exchange information and debate drug regulatory matters. Held biennially since 1980 - the most recent in April 1999, in Berlin, attracted over 250 participants - the conferences have often been the starting point for development of World Health Assembly resolutions on drug regulation.

WHO also supports regional technical cooperation and networking. Examples include ASEAN technical cooperation among countries (TCAC) and the African Drug Regulatory Authorities Network (AFDRAN). Both ASEAN and AFDRAN have been active in human resource development, harmonization issues, and development of regulatory and quality assurance tools in their regions.

The WHO Programme on International Drug Monitoring is another good example of information support for pharmaceutical regulation - but on a very specific issue. The Global Database on Adverse Drug Reactions is situated within the programme, in Uppsala, Sweden. The data collected is used to generate early warning signals of potential adverse drug reactions. More generally, the programme offers WHO Member States a tool for developing and reporting on activities concerned with adverse drug reaction monitoring. Additionally, the programme provides guidance and training courses on pharmacovigilance. ⁶² These are carried out jointly with the Uppsala Monitoring Centre, and supported by the network of national centres in 56 countries.

WHO also provides information on regulatory matters to Member States through regular publications such as WHO Drug Information (quarterly journal), the WHO Pharmaceuticals Newsletter (monthly) and WHO Drug Alerts.

With so many drugs circulating on national and international markets, and in view of the growing quantity of pharmaceutical information, electronic information support has become a necessity. WHO has developed SIAMED, a model system for computer-assisted drug registration, to help countries harmonize regulatory systems and improve the drug registration efficiency of their drug regulatory authority. The system can record information and decisions, and helps create a global overview of drugs that have been authorized to date. When this system is in operation, drug regulatory decisions are much more likely to be made consistently and transparently. In Africa, SIAMED is being used to help harmonize registration procedures for generic essential drugs.

Challenges

The main challenge in terms of information support to drug regulatory authorities in developing authorities is how best to help them access the safety and efficacy information they most need. Currently, the best means would be for WHO to liaise with selected Collaborating Centres to establish a network of sources of readily accessible, summarized unbiased information, in at least three widely used languages. This would be an invaluable resource and reference to support the work of national drug regulatory authorities.

Many drug regulatory authorities also experience problems in maintaining a clear picture of the drugs circulating on their markets. Yet without a complete and comprehensive inventory of these drugs countries cannot hope to define, let alone operate, a rational drug policy. WHO's task, therefore, is to continue to introduce SIAMED where needed and to keep up to date with information technology developments that could be of use and relevance to drug regulatory authorities.

Not only the proliferation of pharmaceutical information, but also the ever-growing number of new medicines calls for a WHO response. Various regulatory guidelines relating to safety are needed. Guidelines currently planned include Safety Monitoring of New Drugs in the Immediate Postmarketing Phase, Guidelines on the Safe Use of Drugs in Pregnancy and Guidelines on the Safe Use of Drug Combinations. However, many others will be needed.

With spontaneous postmarketing surveillance extending to most countries, there is an urgent need to react positively to early warning signals about adverse drug reactions. A standing committee needs to be set up with the necessary expertise to analyse reports made by the WHO Programme on International Drug Monitoring. This will require networking within WHO, with the WHO Regions, as well as with individual Member States.

Expected outcomes for 2000 - 2003

8.1: Increased exchange of information on quality, safety and efficacy of medicines through provision of access to a multilingual database system containing information on quality, safety and efficacy of medicines, supported by WHO and WHO Collaborating Centres.

• WHO will continue to gather and disseminate information through its WHO Drug Information periodical, WHO Drug Alerts and the WHO Pharmaceuticals Newsletter and expand activities relating to electronic distribution of drug quality and drug safety information.

8.2: Reliable information management systems created for national drug regulatory and control authorities through provision of computerized database systems and assistance to establish computer-assisted drug registration and licensing.

• Activities will include support to countries, as well as collaboration with the European Union, to develop standard drug registration systems for the European Agency for the Evaluation of Medicinal Products, and for European countries.

8.3: Access to international adverse drug reaction monitoring system extended to drug regulatory authorities of additional countries.

• WHO will guide national authorities in monitoring adverse drug reactions, and further develop its international programme on adverse drug reaction monitoring.

Component 9: Guidance for control and use of psychotropics and narcotics

Provide advice and guidance on psychotropic and narcotic substances in accordance with WHO’s mandate under international treaties

Progress

Three international drug control treaties now provide the legal basis for the international prevention of drug abuse.

WHO undertakes medical and scientific review of psychotropic and narcotic substances before the United Nations Commission on Narcotic Drugs makes decisions on their control status. Since 1949, through its Expert Committee on Drug Dependence, WHO has reviewed more than 400 substances. Between 1948 (when WHO was established) and 1999 the number of narcotic drugs under international control increased from 18 to 118, and the number of psychotropic substances from 32 to 111.

Concurrently, WHO is developing guidelines to improve the prescribing of controlled drugs, with the aim of preventing dependence and abuse.

Challenges

However, overly restrictive drug control regulations can hamper access to controlled medicines for therapeutic use. A balance must therefore be struck between medical and regulatory requirements. For example, overly strict control of psychotropics and narcotics can render them unobtainable during emergency situations. Emergency victims may then be deprived of adequate pain relief and sedation, particularly during or following emergency surgery. WHO's role is to balance the conflicting concerns and interests of the various stakeholders, be they regulators, manufacturers, prescribers, patients or law-enforcement authorities, when control regulations are being developed.

Expected outcomes for 2000 - 2003

9.1: Psychoactive substances assessed for international control through joint updating with United Nations of lists of controlled narcotic drugs and psychotropic substances.

• WHO will support the Expert Committee on Drug Dependence, and produce guidelines for WHO review of dependence-producing psychoactive substances for international control, as well as for early warning systems for abuse. It will also collect information on new psychoactive substances.

9.2: Rational use of controlled medicines promoted to optimize the risk benefit ratio.

• WHO will promote rational use of controlled medicines by finalizing and disseminating its document on Achieving Balance in National Drug Control Policy: Guidelines for Self-assessment and the Model Guidelines for the International Provision of Controlled Medicines for Emergency Care.