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(2004; 24 pages) [French] [Spanish]
Quality and Safety
Prequalification - vital to global goals for treating HIV/AIDS, malaria and tuberculosis
PHOTO: Irene R Lengui/L'IV Com
"Because it works hand-in-hand with national medicines regulatory authorities, our prequalification project is proving to be one of the best things we've done to help local producers improve antiretroviral (ARV) quality. The feedback they get from us has contributed substantially to scaling up production of good-quality ARVs," says André van Zyl, of WHO's Quality Assurance and Safety of Medicines team.
Partnered with UNICEF, UNAIDS and the UN Population Fund, and receiving support from the World Bank, the prequalification project provides a solid, scientific assessment of the quality of both generic and patented medicines, based on internationally harmonized standards for evaluating information on product quality and bioequivalence, inspecting manufacturing sites and undertaking quality control of pharmaceutical production. "The project provides a great opportunity for pharmaceutical manufacturers to prove that the assumed quality distinctions between innovative drugs and multi-source products are not valid," comments Mr van Zyl.
Increasing treatment options and simplifying treatment regimes
On World AIDS Day 2003, WHO announced that three new generic products for first-line AIDS treatment had been added to the list of prequalified products. The products are fixed-dose triple-therapy combinations and will contribute to simplifying HIV/AIDS treatment regimes. By the end of 2003, over 240 medicines for treating HIV/AIDS had been evaluated, and more than 50 of these products included in the list. The project now also covers medicines for treating tuberculosis and malaria.
The list means that procurement agencies can choose between several manufacturers offering the same quality product. Indeed, the Global Fund to Fight AIDS, Tuberculosis and Malaria considers the list to be vital to ensuring that its funds are spent on medicines of assured quality. Mr Van Zyl points out that, "The Fund is allowing countries who receive funds a period of grace in terms of procuring ARVs and other medicines. But after that funds must be spent only on products that have been prequalified by WHO." The list saves procurement agencies time since they don't have to assess the quality of products themselves.
Evaluations and inspections are carried out by a group of qualified external experts from national medicines regulatory agencies providing support to a core team at WHO. At all stages, WHO provides feedback to encourage the manufacturer to meet prequalification standards.
Publicly available standards for independent laboratories
Key also to the success of the prequalification project has been the issuing of pharmacopoeial monographs to provide independent laboratories with the information they need to be able to test product quality. In 2003, draft monographs were issued for some ARVs. Nine monographs were circulated for comments and further validation. Others will follow.
Comments Dr Sabine Kopp, a scientist with the Quality and Safety: Medicines team at WHO Headquarters, "Because ARVs are new substances and products, no internationally validated monographs are publicly available for them. We are collecting information from manufacturers in all regions so that we can develop tests for detecting any impurities. Of course there are commercial sensitivities, but we've had a good response from many manufacturers. Hopefully other manufacturers will come to recognize that this will contribute to not only ensuring that patients get quality medicines, but also to fighting counterfeiting."
Further information on the prequalification project:
André van Zyl - firstname.lastname@example.org
Further information on pharmacopoeial monographs:
Sabine Kopp - email@example.com
Quality antimalarials: meeting the challenge
Without the right medicines, there can be no effective treatment for malaria, and resistance to antimalarials will continue to grow. A WHO study, The Quality of Antimalarials, published in May 2003, revealed significant problems of substandard products in Africa.
The deeply disturbing results showed that many antimalarials for sale in the countries studied (Gabon, Ghana, Kenya, Mali, Mozambique, Sudan and Zimbabwe) often contain little or insufficient active ingredients. This appears to be due to failure of manufacturers of antimalarials to comply with good manufacturing practice (GMP), and to the high prevalence of counterfeiting.
"Such results cannot be ignored by Roll Back Malaria (RBM) partners - either at the global level or at the level of country action," says Dr Clive Ondari, one of the report's authors. He affirmed that WHO's RBM programme, and others working in malaria prevention, must actively support national regulatory authorities in strengthening GMP as well as good procurement and good distribution procedures.
Quality standards for many antimalarials are now in place. However, for a number of the newer antimalarial products, such standards have yet to be developed. The challenge will be to get the different RBM technical partners (including WHO, UNICEF, USAID and the United States Pharmacopeia) to work effectively together to improve production and distribution of safe, effective and good-quality antimalarials.
Safety tracking of the new antimalarials
Safety issues will be critical to effective use of the new generation of artemisinin-based combination (ACT) antimalarials, now being deployed in countries where resistance to chloroquine and sulphadoxine-pyrimethamine is high.
WHO and RBM are also developing pharmacovigilance reporting programmes for the new artemisinin combinations, in a bid to avoid the quality and resistance issues that have beset past drug responses. Pharmacovigilance identifies and quantitatively assesses the risks related to the use of medicines in an entire population or in specific population groups. It can pinpoint problems relating to misuse of a medicine, poor-quality or counterfeit production, or safety issues not picked up during a drug's development and initial testing.
Dr Mary Couper, who leads pharmacovigilance activities at WHO Headquarters in Geneva, comments that, "Any new drug on the market needs especial vigilance. No drug is completely safe. But there are certain effects with malaria medicines that we need to be on the look-out for such as blood disorders and Stevens-Johnson allergic skin disorders. This is especially true for African countries for which ACTs represent new products and which have not yet developed capacity to undertake pharmacovigilance."
Child being tested for malaria in the Congo
PHOTO: WHO/Harry Anenden
Further information on quality of antimalarials:
Clive Ondari - firstname.lastname@example.org; email email@example.com for a copy of The Quality of Antimalarials
Further information on pharmacovigilance:
Mary Couper - firstname.lastname@example.org
Quality assurance and safety - a cure for counterfeiting
Recent headline stories in the international press on counterfeit medicines touch only the tip of a very large and very dangerous iceberg. They are in part a response to WHO's efforts to raise awareness of the dangers of counterfeit medicines, defined as medicines that are "deliberately and fraudulently mislabelled with respect to identity and/or source".
Lucrative trade in counterfeit medicines
Some agencies estimate that up to 25% of all medicines in the developing world are counterfeit or substandard. Counterfeit medicines are often used - particularly in Africa and Asia - to treat life-threatening conditions such as HIV/AIDS, tuberculosis and malaria.
The lack of openness and poor information exchange on this issue means that fighting counterfeits is not easy. Sometimes, of course, the information is simply not available, because the necessary surveillance is not undertaken. And legitimate manufacturers worry that if concerns about counterfeit medicines are publicly highlighted, sales of their products will fall. So they can be reluctant to participate in campaigns against counterfeit medicines. Compounding these problems is the fact that many countries find it difficult to attract qualified personnel for regulatory positions, given that they can offer only low salaries. Law enforcement is another factor - all too often counterfeiting of medicines is classified merely as a trade violation, carrying a minor penalty only.
In 2003, WHO intensified its efforts to raise public and government awareness of the dangers of counterfeit and substandard medicines, and to improve collaboration between medicines regulatory agencies and law enforcement agencies in this area. It also continued to strengthen national regulatory authorities, through training, provision of advice, and development of guidelines and tools for improving regulatory systems.
Eshetu Wondemagegnehu is a WHO technical officer, working with the Quality and Safety: Medicines team at WHO Headquarters. Although he recognizes that public awareness of counterfeit medicines is increasing, he considers that enhanced country-level regulation, using WHO guidelines and advice, remains an urgent priority. "In most developing countries, there is a shortage of medicines. This encourages smuggling and counterfeiting. What's more, their regulatory system is often very weak. So medicines are easily sold over the counter without prescription or even on the street. In other words, we have to look at the whole pharmaceutical supply system, and encourage governments to strengthen and really enforce their medicines regulation and legislation, including where, how and by whom medicines can be sold."
Fakes in Central and Eastern Europe and the Newly Independent States
Counterfeit medicines plague not only Asia and Africa. Following the collapse of communism, under which the state had been the monopoly supplier and regulator of medicines, ensuring effective medicines regulation in Central and Eastern Europe (CEE), and in the Newly Independent States (NIS), proved to be extremely challenging. Although many of these countries have now created national medicines regulatory authorities, regulatory "gaps" are reflected in reports of increased incidence and variety of counterfeit medicines.
Accurate data on incidence of counterfeit medicines in NIS and CEE countries have yet to be collected. But we do know that in several countries in the Caucasus, Central Asia and South-Eastern Europe, medicines are sold on markets and from kiosks. Ministries of health in the region have limited funds for purchasing medicines and so populations must generally cover their health costs themselves. The temptation to buy medicines from these cheap sources is therefore very strong. Unfortunately, the medicines may be not only cheaper but fake and/or substandard as well. Kees de Joncheere, Regional Adviser for Pharmaceuticals in WHO's European Regional Office, observes that, "Ministries of health in CEE and the NIS are clearly aware of this problem and very concerned about it, but they lack the resources that would enable them to tackle this issue effectively."
Further information: Kees de Joncheere - email@example.com
Mr Wondemagegnehu continues, "We are very concerned about the persistence of counterfeits in developing countries. Not surprisingly, for many of them, national policies are driven by economic priorities and the need to ensure safe medicines to promote public health is forgotten. Production and sale of medicines can then take precedence over ensuring the quality and safety of medicines. In general, I think it's a question of political commitment…if the commitment is there it's easy to enforce regulation.
"China is a good example of effective political commitment and allocation of the resources needed. In just five years it has set up an independent regulatory authority (the State Drug Administration) and developed significantly in terms of infrastructure and qualified human resources. It has enacted the Drug Administration Law with provisions prohibiting the manufacture, sale and distribution of counterfeit and substandard medicines, and has also taken action against people and companies convicted of counterfeiting medicines."
Joining forces to fight counterfeits
In 2003, implementation of a WHO multi-country project to combat counterfeit medicines for the greater Mekong sub-region countries (Cambodia, China, Lao PDR, Myanmar, Thailand and Viet Nam) continued, with support from AusAID. The percentage of counterfeit artemisinin-based antimalarials exceeds 50% in parts of this region. Comments Dr Budiono Santoso, regional pharmaceuticals adviser in WHO's Western Pacific Regional Office, "It's hard to imagine what the final economic cost will be. The technological investment that will be required if these new artemisinin-based antimalarials become ineffective, and yet another antimalarial has to be developed, is unthinkable."
The project aims to improve collaboration between the pharmaceutical sectors and law enforcement agencies, and raise public awareness of counterfeit medicines. WHO has worked with the countries to not only develop national, cross-sectoral plans to tackle counterfeits, but also to encourage collaboration, exchange of expertise and information-sharing between them.
A meeting in Hanoi between the Mekong countries and a variety of agencies (Interpol, Management Sciences for Health, Aus AID, JICWELS (Japan International Cooperation for Welfare Services), United States Pharmacopeia, Wellcome Trust, Australia's Therapeutic Goods Administration and USAID) was held in November. Dr Santoso says that, "It's becoming increasingly obvious that countries cannot fight counterfeit medicines in isolation but must work together to track incidence of counterfeits and the counterfeiters themselves, as well as encourage each other to enforce legislation against counterfeit medicines."
Counterfeit medicines are increasingly headline news in both the international and national press
COURTESY OF: International Herald Tribune
Dr Krisantha Weerasuriya, regional adviser in WHO's South-East Asia Regional Office, further commented that almost all health ministry officials of the Mekong Delta countries are now aware of the counterfeit medicines problem and that the next phase included, "making others, such as law enforcement, legal and trade officials equally aware of it".
The Mekong Project continues in 2004, focusing on developing a rapid regional alert system, post marketing surveillance, deterrent legislation and further advocacy.
Eshetu Wondemagegnehu - firstname.lastname@example.org;
Budiono Santoso - email@example.com;
Krisantha Weerasuriya - firstname.lastname@example.org
Poster used in Lao PDR to warn against the dangers of counterfeit medicines
Quality and safety achievements: 2003
In 2003, many long-term activities aimed at ensuring the quality and safety of medicines - carried out in parallel to efforts to increase access to essential medicines - were completed. Some of them are described briefly below.
• Creation of WHO Advisory Committee on the Safety of Medicinal Products, to respond to the growing number of country requests for guidance on medicines safety issues.
• First training course on pharmacovigilance for new antimalarials, which will serve as a model for similar training for HIV/AIDS treatment programme managers to initiate pharmacovigilance for antiretrovirals (ARVs).
• Volume 5 of the 3rd edition of The International Pharmacopoeia published, including 75 new monographs and test procedures. The specifications for all known artemisinin-based antimalarials are especially important. They mean that vital information for improving manufacturing quality control and helping new manufacturers to start producing good-quality antimalarials, is now publicly available. This will contribute to increased competition and lowering of prices.
• Development of internationally validated specifications for ARVs used to treat HIV/AIDS initiated, as a move towards making information on quality standards publicly available. This will help national quality control laboratories to test the quality of products and generic manufacturers to produce ARVs of assured quality.
• Finalization of second series of tests for WHO External Assessment for National Quality Control Laboratories, providing independent, international standards for quality-control testing so that national qualitycontrol laboratories can evaluate their level of performance of quality-control testing of medicines.
• Development and adoption of five new and two revised Good manufacturing practice (GMP) texts to take account of country requests for more GMP guidance and of recent advances in pharmaceutical manufacturing.
• Introduction to Drug Utilization Research published, to guide countries on how they can use and benefit from medicines utilization research.
• ASEAN countries agree on single set of technical requirements for medicines evaluation, enabling better technical collaboration among ASEAN member states, facilitating access to medicines in the ASEAN region, and improvement of the regulatory capacity of less well resourced ASEAN member states.
• Tunisia starts publishing prescribing information for all medicines approved by the national medicines regulatory authority and granted a marketing authorization, indicating that developing countries can make correct medicines information available, thus limiting the negative impacts of unethical medicines promotion.
Lembit Rägo - email@example.com
Working in partnership with the Global Fund to Fight AIDS, Tuberculosis and Malaria
"The Global Fund is already the world's largest single financier of drugs to fight AIDS, tuberculosis (TB) and malaria. To ensure that these drugs are of good quality and safe, we rely heavily on the expertise of WHO. We greatly appreciate the close collaboration between the Global Fund and WHO's Essential Drugs and Medicines Policy Department," comments Professor Richard Feachem, Executive Director of the Global Fund to Fight AIDS, Tuberculosis and Malaria.
On World AIDS Day 2003, WHO announced that three new generic products for first-line AIDS treatment had been prequalified. The products were fixed-dose triple therapy antiretroviral (ARV) combinations containing lamivudine, stavudine and nevirapine. Effective, simple to take as a treatment regimen and easily administered, they are also cost-efficient. By the end of 2003, the list of prequalified products contained more than 50 ARV medicines - in single-drug, two-drug and three-drug combinations. It also contained first- and second-line treatments for TB and one medicine for malaria. By clearly indicating what medicines can safely be procured where, the list is both reducing the time and effort needed for procurement, and helping to ensure that funds for treating the three major diseases of poverty are used optimally.
WHO is also collaborating with the Global Fund to develop policies and procedures for medicines procurement and supply management, providing technical advice, analysis and data. Global Fund procurement and supply management guidelines now incorporate a number of WHO pharmaceutical norms and standards.
Hans Hogerzeil - firstname.lastname@example.org
Easy electronic access to WHO Model Formulary
The WHO Model Formulary was first launched in 2002 and then made available in electronic format on the WHO medicines web site (http://mednet3.who.int/eml/emlintro.asp) in 2003. This practical tool to assist national drug selection committees has also been released on CD ROM, and translation into Arabic, Russian and Spanish is now under way. In 2004, plans will be made for making the Model Formulary available on a palm computer.
The electronic versions (in both pdf and Word formats) of the Model Formulary are especially useful for countries that would like to develop their own formulary. Rather than starting from scratch, they can now start with a full text and adapt that to their specific needs by omitting or adding other information.
Presenting independent information on all 316 medicines on the WHO Model List of Essential Medicines, the 2004 edition of the Model Formulary will also incorporate updates and changes made during the relevant Expert Committee meeting of 2003. A manual describing how countries can best adapt the Model Formulary to national requirements will be made available in electronic format in early 2005.
Lalit Dwivedi - email@example.com
The WHO Model Formulary was first launched in 2002, before being made available on CD ROM in 2003