Tropical Health Matters

Reuters has reported on a unique collaboration between police and scientists to stem the tide of fake antimalarial drugs, particularly artemisinin based medicines in southeast Asia. Details of the investigative process form the basis of an article in PLoS Medicine.

The problem has been know for ten years. Reuters commented that, “An investigation coordinated by Interpol, with input from international researchers, found as many as half of the malaria tablets sampled in Vietnam, Cambodia, Laos, Myanmar and on the Thai/Myanmar border were counterfeit.” This is a huge concern, in part because some tablets contained no active ingredients, older antimalarials, or inappropriate drugs and would therefore not provide a cure and also because some contained less than the required amount of active ingredients and would therefore contribute toward aretemisinin resistance, threatening the main drug used around the world to save lives.

Sophisticated scientific techniques for tracing the culprits even ranged to analysis of pollen found in the blister packs. A variety of holographic logos were also found. Specialists were able to spot many fakes simply by examining the packets, the one doubts that the average consumer would be so skilled.

The WHO prequalification process and bulk ordering through GFATM may help some countries avoid fakes, but this does not guarantee safety in the private sector. It also points out the need for speedier efforts to add more antimalarial drugs to the prequalification list. Finally, capacity building is also needed for Food and Drug Agencies in malaria endemic countries to enable timely detection of fakes before they reach clinics and stores.

In August Dodoo et al., reported in The Lancet about community backlash to a deworming program in Ghana. What may have been a few side effects, other diseases or preexisting conditions led to rumors that propelled citizens into ‘mass hysteria and civil unrest,’ and ultimately threatened confidence in the public health system (www.thelancet.com, vol. 370, August 11, 2007, pp. 445-6).

This is not Ghana’s first major public relations disaster with medicines. In 2004 Ghana adopted artesunate-amodiaquine as its first line antimalarial drug, which appeared fortuitous since the drug could be manufactured locally. When the amodiaquine component was wrongly formulated in some products and reactions occurred, the public almost rejected the need for ACTs to treat malaria. fortunately pharmacovigilence capacity did exist at the University of Ghana.

Other incidents in vary from ‘exaggerated’ response to side effects as has occurred in the ivermectin distribution programs for controlling onchocerciasis (Semiyaga et al.) to real life threatening reactions during a Pfizer drug trial debacle in Nigeria. Regardless of the ‘real’ pharmacological outcome of public health drug research and distribution programs, community perceptions, responses and rumors must also be monitored and addressed.

Thus, in addition to pharmacological aspects of pharmacovigilence, we also need a social, emotional and cultural barometer in communities where programs are based. According to Dodoo et al., this social vigilance requires, “excellent communication, and crisis management planning to accompany public-health programmes that involve mass administration of a drug.”

Social vigilance can perform two functions. First it can respond quickly to real threats to health and life, whether from drug reactions or use of drugs that are no longer effective. Secondly it can dispel rumors where these threaten the life saving ability of truly safe community drug distribution programs.

In its most recent newsletter “Malaria Bytes” Care Net Nigeria raises an important health and development question – can Local African pharmaceutical manufacturers play a bigger role in production of needed drugs to treat malaria. Although this issue is not yet posted to the website, the two previous offerings are available for download. In West Africa several drug exporters (e.g. IPCA) and manufacturers (e.g. SWIPHA) have stepped in with branded artesunate-amodiaquine (AS-AQ) products in both adult and child packets. There are many other AS-AQ producers and suppliers. As we know, Coartem, the artemether- lumefantrine (AS-AL) ACT is only produced by Novartis to date. This ‘monopoly’ is supported by WHO’s prequalification processes, although one AS-AQ manufacturer has been added. Mepha also markets its artesunate + mefloquine product in Africa.

Even with these pharmaceutical participants, there are still challenges. For example, when Ghana introduced AS-AQ as a first line ACT, there were problems with formulation and strong side effects. Quality control is needed. In 2005 Ghanaian health authorities had to withdraw the drug for more safety testing.

Recent discussions with representatives of the private sector in Kenya aired concerns that technical assistance is needed to help the African based pharmaceutical manufacturers improve their quality and capacity. In parallel there was also a call for technical assistance to help national Food and Drug Agencies/Authorities improve their capacity for testing and monitoring. Care Net Nigeria echoes this view: “Rather than continue with the monopoly already created by the Global Fund and WHO, manufacturers in developing countries should be assisted to catch up with the quality standards through this financial boom.” Such assistance is needed if the growing gap in malaria treatment needs is to be closed.

The Future Health Systems (FHS) Research Programme Consortium aims to find ways to translate political and financial commitments to meet the health needs of the poor. The consortium addresses fundamental questions about the design of future health systems, and work closely with actors who are leading the transformation of health systems in their new realities. This consortium addresses fundamental questions about the design of future health systems, and works closely with people who are leading the transformation of health systems in their own countries. FHS research themes are:

• Protecting the poor against the impact of health-related shocks
• Developing innovations in health provision
• Understanding health policy processes and the role of research

Eight partners in eight different countries are exploring various ways to make health systems work for the poor. The team based at the University of Ibadan, Nigeria, has been exploring the role of Patent Medicine Vendors (PMVs) in providing quality, appropriate malaria treatment in the poor communities where they are based. A recent workshop analyzed and wrote a working paper based on the first-year scoping study.

Several key aspects of PMV behavior and knowledge were identified. “This study has documented the problems that people have in getting access to appropriate treatment for malaria. They have little knowledge of the changing patterns of drug resistance and the consequent changes in the drugs that are effective. They must rely either on traditional practices or on the advice of the people who provide the drugs. Since patent medicine vendors provide anti-malarial treatment in a substantial proportion of cases, their knowledge and practice strongly influence people’s wellbeing. This study made two major findings about this knowledge and practice. First, patent medicine vendors have little knowledge about new guidelines for drug use and they still recommend that people use drugs whose efficacy is doubtful. Second, there is a lot of concern about the quality of the drugs they supply. Action is needed to address these problems.”

Watch here as well as the FHS website for further updates on this important research that documents the challenges of a major informal provider, the patent medicine vendor, who has been ignored in formulating malaria access policy. In fact the 2003 Nigeria Demographic and Health Survey found that only about 25% of parents sought malaria treatment for their children in the formal sector. The few efforts to train and upgrade PMVs has been documented by BASICS, but more needs to be done if malaria drugs are going to reach all.

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As a note of interest, the previous entry here on Kenya’s looming drug shortage was filed from one of only two cyber cafes in the town of Igbo-Ora in southwest Nigeria pictured here. The town has 60,000 residents, but electricity is erratic to rare. It took several visits to find that the cafe’s generator was working strongly enough to access this site and make a posting. That is life on the edge of the digital divide. This current posting is being made at the airport lounge in Lagos on wireless connection – shows how the average person in Africa has little access to the internet to gather malaria information and engage in malaria advocacy.

Despite a call for pharmacovigilence by the Kenya Pharmacy Board, fake duo-cotexin and cotexin were found in Kenya recently. The producers of duo-cotexin [40mg of dihydroartemisinin (DHA) and 320mg of piperaquine (PPQ)] have promised to introduce counterfeit-proof packaging with features such as a hologram, but in the meantime in Kenya, let the buyer beware. As a Daily Nation editorial opines, at present, “The average person is hardly in a position to differentiate between the counterfeit and the genuine drug. This would mean that there are people who are unnecessarily losing their lives.”

The Daily Nation pinpoints the problem within the Pharmacy Board. “Although the Pharmacy and Poisons Board has drug inspectors who are tasked to not only combat counterfeit drugs but also to ensure that drugs in the market are duly registered, it would appear that they are ill-equipped to police the drug market,” even though the Board claims that, “We ensure that all drugs, locally manufactured, imported and/or exported and registered to ensure their safety quality and efficacy” (sic).

With the presence of major donor programs such as the Global Fund and the President’s Malaria Initiative, Kenya may feel that much of its malaria drug need is being met with provisions of the only WHO prequalified arteseminin-based combination therapy antimalarial, Coartem, but that does not account for the private sector where the fake duo-cotexin appeared. Donor support is needed, not only to import more Coartem, but also to improve the capacity of the National Pharmacy Board and National Quality Control Laboratory to ensure that all Kenyans have access to safe and effective malaria medicines, whether they use the public or private sectors. This same need holds true for other countries in the region.

Yesterday Reuters reported a story of fake drugs produced in China that was subsequently carried by the Independent. Although three types of drugs were mentioned, it was the fake Viagra that captured the headline. Not surprisingly fake bird flu and malaria medicines did not attract as much attention in a story geared to the western press. This falls on the heels of other discoveries of fake or adulterated products from China ranging from pet food to toothpaste, again products of greater interest in the western world.

Still, more people are likely to die or be harmed by fake malaria drugs than fake Viagra. Other fake drugs from China have over the past years killed children in Nigeria and Panama. There is real concern because China is one of the world’s major suppliers of malaria drugs, especially the newer artemisinin-based drugs developed from a Chinese herb that are being adopted as first line treatment in endemic countries.

Three steps by the World Health Organization may help. WHO recommends artemisinin-based combination therapy (ACT) as first line treatment. These combinations include artemisinin and another drug for which there is no parasite resistance. The second step is coming out clearly and stating that monotherapy artemisinin drugs should be withdrawn from use to prevent the spread drug resistance and increase the useful life of the new artemisinin-based medicines. Finally, WHO has a program for pre-qualification of drugs that focuses on quality issues. The main ACT recommended on that list is artemisinin-lumefantrin (AL), which is produced by one company and has tight quality controls. AL is the drug favored by major donor and NGO programs.

Where dangers may arise is within the commercial pharmaceutical sector where monotherapy artemisinin drugs (see picture) are still available and where ACTs that have not received pre-qualification status are sold. Each malaria endemic country has some form of a food and drug authority that should license and regulate drugs. If these agencies are empowered to do their job, the public will also be protected from fake or inappropriate malaria drugs on sale in shops and private clinics.

The American Enterprise Institute has raised concerns about the quality of drugs that might be purchased for large scale donor efforts. Roger Bate explained that for malaria, “only 7% of malarial drugs on the Global Fund’s list have undergone bioequivalence testing yet malaria kills more than a million people a year.” He goes further to note that, “Some of the drugs are “monotherapies,” single drugs which have been actively discouraged by WHO because they encourage drug resistance. The list contains further drugs which go against good medical practice, the specific advice of the WHO and even, according to insiders, against the technical advice of competent people at the Global Fund.” The head of Kenya’s malaria control program quotes as saying that their ministry “plans to buy untested Indian copies of Coartem.” Mr Bate is therefore concerned that, “Uganda and Nigeria are likely to do the same. And this is probably just the tip of the iceberg.”

As we have reported before, there are definite concerns about cost and availability of malaria drugs expressed by African countries. What can be said about quality? The Global Fund, one of the largest sources of money for malaria drug purchases, addressed the quality issue through its Board, which has issued guidelines for countries. These guidelines distinguish four categories od medicines: A, B, Ci and Cii. Of note, “The Global Fund does not endorse or warrant the fitness of any product on the Compliance List for a particular purpose,” These categories are defined as follows:

A – Products acceptable under the WHO Prequalification Program

B – Products authorized for use by a stringent regulatory authority

Ci – The manufacturer has submitted an application for approval of such product to the WHO Prequalification Program or a stringent regulatory authority

Cii – If the manufacturer of such product has not submitted an application for approval of such product to the WHO Prequalification Program or a stringent regulatory authority, such product is manufactured at a GMP compliant manufacturing site, as certified (after inspection) by the WHO or a stringent regulatory authority

Only one drug in the list is found in category A: Artemether-Lumefantrine by Novartis. Only one is ranked in category B: Artesunate-Mefloquine by Mepha. This list is available in the internet for all countries to review and use for planning. The so-called monotherapy drugs are in large part artemether rectal capsules for use in severe malaria only. Sulphadoxine-pyrimethamine is listed since it is the drug used for Intermittent Preventive Treatment/Therapy in Pregnancy.

For the past three months the international Roll Back Malaria Partners have been providing technical guidance to African countries as they develop their next proposal for the Global Fund, and these partners are using such guidance from WHO and GFATM to ensure that countries order quality medicines. Contrary to fears that Nigeria may be ready to buy cheap, poor quality alternatives, the Nigerian proposal development team is at this very moment basing all its procurement and costing estimates on Artemether-Lumefantrine (Coartem). A positive and synergistic aspect of the planning is that if high coverage of long lasting insecticide treated nets is achieved, demand for ACTs will actually decrease, which addresses in part the cost issue.

Finally, although major RBM partners are trying to address quality issues, there are still many areas of concern – what malaria drugs are being imported and sold through the private sector? – what malaria drugs are governments in endemic countries buying with their own funds? The RBM partnership has made a start to ensure malaria drug quality, but must continue advocacy until all organizations and agencies that purchase malaria drugs adhere to quality standards and more drugs are added to the prequalification list.

Last week Dora Akunyili, Director General of Nigeria’s National Agency for Food and Drug Administration (NAFDAC) called on faith based organizations to join the fight against counterfeit malaria drugs in Nigeria. She explained that with the faded efficacy of chloroquine and sulfadoxine-pyrimethamine (SP) Nigeria must be vigilant in protecting the efficacy of ACTs.

NAFDAC does take action as seen in a recent newspaper notice seen in part here that warns the public about unregistered and potentially dangerous drugs. NAFDAC has taken other recent helpful actions. For example, the Agency has asked producers of SP to remove the warning that this drug is contraindicated in pregnancy so that SP can be used for IPTp during the second and third trimesters (but still not the first).

Some challenges remain. Many monotherapy artesunate drugs had been registered over the past 5 years, and although NAFDAC agrees with WHO that such drugs can lead to resistance and should not be sold, NAFDAC has taken a more conservative approach and is simply allowing the licenses on those products to expire. The monotherapy drugs are still in abundance in the medicine and pharmacy shops, particularly in urban areas, and some state pharmacy stores do stock them. While it would mean financial loss to companies, businesses and clinics if monotherapy artemisinin drugs were abruptly withdrawn, the longer term costs of developing resistance to artemisinin-based drugs would be enormous both in terms of lives and finance.

Nigeria is not the only country that should pay attention to its malaria drug supply. Recently I purchased an artesunate-SP combination in a registered pharmacy shop in Entebbe, Uganda as seen in the photo. Again, combinations of artesunate and drugs like chloroquine and SP that have reduced efficacy is dangerous in terms of speeding up development of parasite resistance to the artesunates. WHO expects that this combination “will fail rapidly.”

The time to act to protect ACTs in Africa in now.

[Note that photos of pharmaceutical products do NOT constitute an endorsement.]