Around one-third of WHO's Member States have either no drug regulatory authority (DRA) or very limited regulation capacity. Work to increase regulatory capacity is thus a high priority. Evidence shows, however, that interventions to improve regulation that have been successful in one country, work best if customized, rather than being imported "wholesale".
In 2001, WHO finalized a data collection tool for reviewing regulatory capacity to regulate not only medicines, but also vaccines.2 The tool enables realistic assessment of a country's medicines and vaccines regulation needs (i.e. its priorities), and what it can reasonably be expected to develop and implement (i.e. what it can plan).
2 It is supported by an assessment recently undertaken in the Americas of different DRA models by PAHO and Temple University, USA. The results suggest that integrated regulatory agencies - covering medicines, technical devices and food - and financially independent agencies, operate the most effectively.
Reviews of medicines and vaccines regulatory capacity were carried out in Indonesia, Morocco, Nepal, the Philippines, Tunisia and Viet Nam, and led to rapid improvements in regulatory capacity. For example, in Viet Nam, assessment showed an absence of written procedures, slowing staff performance of day-to-day regulatory tasks. Also, staff lacked capacity to assess new medicines and access to reliable technical literature. Six months later, Tunisia's procedures for DRA staff had been revised, freeing up their time for other technical work. And DRA staff had received tailor-made training on assessing new medicines and accessing technical literature. The outcome of 2001 activities confirmed that joint medicines and vaccines regulatory assessments are useful and cost-effective.
Other training for DRAs included an international training course on assessing applications for marketing authorizations. Organized by WHO and the Philippine Bureau of Food and Drugs, the course was attended by representatives of ASEAN (Association of South-East Asian Nations) countries and China.
Harmonization of medicines regulation requirements is another means of improving the cost-effectiveness of regulatory activities - by minimizing their duplication between countries and accelerating access to medicines, particularly new medicines. In the Americas, such harmonization has supported harmonization within the region's various economic integration groups in a number of related technical areas. These include bioequivalence, good manufacturing practice, good clinical practice, defining counterfeits and development of pharmacopoeias.
In Asia, an ASEAN-WHO project was set up to improve the public health impact of medicines regulation, especially harmonization. Activities included developing a common set of requirements for new chemical entities and multisource medicines, and creating a common technical dossier for applications. Sharing of expertise was also actively promoted, principally through use of resource centres within ASEAN to support weaker DRAs.
Harmonization of medicines registration and quality control also continued within the Southern African Development Community Common technical documents for both registration and quality control were drafted, and will be finalized in 2003.
In terms of medicines quality WHO's Good Manufacturing Practices (GMP) Project is having an impact worldwide. During 2000-2001, more than 400 people from 50 countries were trained in GMP implementation. In 2001 alone, courses were held in Bosnia Herzegovina, China, Egypt, India, Jamaica and Uganda. Additionally, national GMP seminars were held in Colombia, Costa Rica, Cyprus, the Dominican Republic, Honduras, Oman, the Philippines and Syria, at which more than 180 people from the public and private sectors were trained.
Ensuring access to quality HIV/AIDS medicines
Dramatic decreases in supplier prices for medicines for HIV/AIDS - particularly antiretroviral (ARV) medicines - has brought with it the need to ensure the quality of these products. In March 2001, WHO launched a project to prequalify manufacturers of ARVs, including generic producers. Working closely with the International Pharmaceutical Coordination (IPC) group (WHO, UNICEF, UNAIDS, UNFPA and the World Bank), WHO established consensus on standards that products submitted by suppliers must attain for prequalification status, and on the need for a list of prequalified HIV/AIDS medicines and their suppliers.
Other elements in a comprehensive programme to promote access to quality medicines for HIV/AIDS and other priority health problems included:
• creating a WHO Model Quality Assurance System for procurement
• development of quality specifications for nine priority ARV agents, in collaboration with national and regional pharmacopoeial authorities
• expansion to include a prequalification process for antituberculosis and antimalarial medicines
• feedback to regulators regarding information collected during assessments, to increase their capacity to ensure the quality of ARVs on their national market
• regional workshops for drug regulators on registration of generic ARVs.
The GMP training modules are now backed up with a video and a CD-ROM, so that after attending workshops participants can continue to learn about and also guide others on GMP implementation. Progress in China has been particularly rapid - only around 800 of the country's 6300 pharmaceutical manufacturers met GMP standards in 2000. But thanks to increasing collaboration between China's State Drug Administration and WHO, all pharmaceutical manufacturers are projected to become GMP-compliant by 2004 (Figure 3).
Strengthening official medicines control laboratories is another major element of quality assurance. WHO's external quality control programme counted 36 participating laboratories by the end of 2001. International Chemical Reference Materials were provided to all participating laboratories in order to enhance then-capacity to carry out pharmacopoeial tests for essential medicines.
Work carried out in 2001 showed that counterfeit and substandard medicines continue to be a major concern globally, with a number of specific problems, such as no active ingredient, or wrong level of active ingredient observed. For example, a survey completed in 2001 in Cambodia showed that of the samples of 24 pharmaceutical products collected from the market, about 50% (115/230) were unregistered. Laboratory tests based on registration status showed that of 98 imported registered products, 6 (6.1%) failed the laboratory test. Results of tests on 112 imported but unregistered products showed that the active ingredients in 22.3% of the samples were lower than the amount indicated by the label. The overall failure rate for the total of 230 samples was 13%. Studies such as these serve as a starting point for formulating national strategies for fighting counterfeit drugs.
Another counterfeits survey was carried out by the WHO-Industry-NGO Working Group on Counterfeits in a Western Pacific country. Samples have been analysed by an independent laboratory and the survey results will be made available in 2002.
Activities to combat counterfeits included an intercountry workshop organized by WHO in Phnom Penh, Cambodia, to enable South-East Asian, and Western Pacific countries to share experience and information, to identify areas of collaboration and draw up an anti-counterfeits workplan. A similar workshop was held in Nairobi, Kenya for African drug regulatory authorities.
Other quality-related activities focused, on improving the quality of medicines for treating specific diseases. Malaria was one of these. Between 800 and 900 thousand people die every year of malaria in Africa - not simply because antimalarials are unavailable but also because the quality of antimalarials is often poor. In 2001, specifications for testing antimalarial agents promoted for use by the Roll Back Malaria initiative were finalized, including full pharmacopoeial monographs.
Suspecting that the problem of poor-quality antimalarials is widespread, WHO initiated a pilot project to collect data at country level on the quality of antimalarials. Six countries, from the African and Eastern Mediterranean regions, each representing a different geographical area, were selected for inclusion in the project. Evaluation focused on the antimalarial products most widely used (chloroquine tablets and syrup, and sulfadoxine/pyrimethamine (SP) tablets) in those countries. It also included sampling from various levels of the distribution chain (i.e. household, private sector pharmacy, peripheral health units, district hospitals, teaching/referral hospitals and district and/or medical stores). Samples were examined using a screening test tool (known as a "mini-lab") and, if results were significant, they were verified at a central laboratory (using pharmacopoeial tests) in South Africa.
Results showed that the biggest problem is with SP tablets - for more than 60% of samples, for all countries, the dissolution rate was unacceptably slow (see Figure 4). The countries' DRAs are now being encouraged to continue post-marketing surveillance of antimalarials in order to detect substandard products, to stipulate a dissolution rate that an antimalarial must attain if it is to be approved, and to develop capacity in ensuring GMP compliance. Two more African countries are scheduled for similar investigations in 2002. The technical "sensitivity" of the mini-lab and pharmacopoeial tests for antimalarials will also be harmonized to ensure data comparability.
Figure 2 More than 400 professionals in 50 countries received training in good manufacturing practice (GMP) during 2000-2001
Tuberculosis (TB) is another disease which afflicts poor countries disproportionately. In 2001, WHO medicines support to the Stop TB Partnership for operation of the Global TB Drug Facility included development of application materials, product selection and development of quality specifications for TB medicines (in cooperation with the US Pharmacopeia).
Other work on promoting quality of medicines resulted in the adoption, by the WHO Expert Committee on Specifications for Pharmaceutical Preparations, of nine new WHO guidance texts. These were on topics such as the certification scheme for pharmaceutical starting materials, GMP-related issues and storage practices. Work on proposing international nonproprietary names also continued.
Figure 3 Enhancing local pharmaceutical production in China - increasing and projected increase in GMP-certified pharmaceutical manufacturers
Drug safety was also actively promoted. The WHO Drug Dictionary provides information on all medicines that have been entered into the WHO database since 1968. National drug monitoring centres and many pharmaceutical companies around the world use it as the standard reference tool for coding drugs. In 2001, WHO strengthened its efforts to improve the database. In 1995, the European Union (EU) commissioned the European Agency for the Evaluation of Medicinal Products to set up an adverse drug reactions database for the EU. The first version of the Eudra Vigilance database was launched in December 2001. Concern has been raised over problems that could arise due to the existence of two levels of monitoring: international WHO monitoring and European regional monitoring.
Access to WHO's international adverse drug reaction (ADR) monitoring database was simplified during 2001. The database will become available as a website for national pharmacovigilance centres in 2002. It is the cornerstone of the WHO International Programme on International Drug Monitoring (in which 68 countries participate), operated by the Uppsala Monitoring Centre in Sweden.
"The global epidemics of HIV/AIDS, tuberculosis, and malaria continue to spread. Yet, there is a growing recognition of the vulnerability faced by poor and marginalized communities, and of the impact such vulnerability has on global stability and growth. We know now, more than ever, that there is no wall between the wealthy and poor nations of the world."
James D. Wolfensohn, President of the World Bank in foreword to Global Plan to Stop TB. Phase 1:2001-2005.
Additionally, growing awareness of the need to ensure the safety of herbal medicines stimulated efforts to increase safety monitoring and pharmacovigilance for this type of health care. WHO worked with the Uppsala Monitoring Centre to incorporate monitoring of herbal medicines in the Programme on International Drug Monitoring.