Tropical Health Matters

BBC’s Focus on Africa has identified Africa as the dumping ground for counterfeit goods. Some are cheap knock-offs of branded luxury goods that consumers know are not the real deal. Electronics are another area where the customer should beware. Others camouflage as the original product with packaging that is indistinguishable from the authentic item.

Toothpaste is a good example where the fake, which retailers call ‘Chinese’ contains a poison known as diethylene glycol which is used in anti-freeze.  The retailers sell both products for about the same price, but the incentive for pushing the fakes is profit.

On the genuine product he has made a 13% mark-up, on the counterfeit an impressive 50%. Fair play to him, some might say – after all it is only toothpaste.

But one cannot say ‘it is only medicine’ when drugs are fake. BBC notes that, “According to the World Health Organization (WHO), 30% of medicines sold in developing countries are fakes, and a major problem is that high numbers of government-owned drugs are being illegally obtained and then sold on for profit in the private sector.” BBC worries that …

… with the rising number of direct trade routes between Africa and China, together with porous border controls, outdated legislation and weak enforcement mechanisms, the continent has become fair game for counterfeiters – and the recession has made it worse.

Furthermore, “A UN report published in July 2009 reveals that revenues gained from 45 million counterfeit anti-malarial medicines were worth $438m – more than the annual gross domestic product of Guinea-Bissau.”

SafeMedicines.org keeps an update of fake medicine reports. For example in Ghana, “A citizen brought suspect antimalarial medication to a sentinel site set up by the U.S. Agency for International Development (USAID)’s Drug Quality Information Program (DQI).” This was reported July 22, 2009, and involved a fake of Novartis Pharmaceuticals’ malaria product Coartem.

Researchers at Georgia Tech University shared information on the magnitude of the problem. “The percentage of over-the-counter counterfeit artesunate tablets containing no artesunate apparently increased from 38 to 53 percent in southeast Asia between 1999 and 2004.”

Fake drugs kill directly with dangerous ingredients or indirectly when inadequate or no active ingredients are present. They also may drive legitimate manufacturers out of business.  The threat is real and widespread in its impact.

The new funding program, Affordable Medicines Facility malaria (AMFm) aims to enable countries to place quality low-cost antimalarials into the private sector at prices that will supposedly compete favorably with inappropriate and fake medicines. Careful monitoring will be needed to see if this really happens.

Considering the profit margins mentioned above, the fake drugs may still out-compete the subsidized ones.  In short, nothing can replace a vigorous drug regulatory system and donors need to strengthen technical assistance to countries to regulatory capabilities actually work.

Malaria drug supplies provided by or purchased through major donor programs like the Global Fund, World Bank Booster, and the US President’s Malaria Initiative are safe and of high quality, at least upon arrival at ports in endemic countries. We still need to monitor storage conditions and shelf life. While these sources of malaria medicine are substantial, especially in providing for the public sector, there are huge variations of drug type, formulation and quality available to the average consumer in endemic countries.

Major donors rely on efforts to screen the mass of medicines available for malaria by the World Health Organization that has a medicine ‘prequalification’ program with the following mission:

In close cooperation with national regulatory agencies and partner organizations, the Prequalification Programme aims to make quality priority medicines available for the benefit of those in need. This is achieved through its evaluation and inspection activities, and by building national capacity for sustainable manufacturing and monitoring of quality medicines.

At present there are three prequalified providers of the popular artemether-lumafantrine (AL) combination: Novartis Pharma  of Beijing, China and Suffern, USA, Ajanta Pharma Ltd of Paithan, Aurangabad, Maharashtra, India, Cipla Ltd of Patalganga, India.  The National Agency for Food and Drug Administration in Nigeria has approved AL from twelve pharmaceutical companies, only two of which is prequalified.

One can see that the market for anti-malarial drugs is huge, and not even government approval can always solve the quality problem. Recently Gatonye Gathura and Mike Mwaniki of the Daily Nation reported that in Kenya , “A number of children’s malaria medicines on the Kenyan local market contain organisms that cause disease. Seven of about a dozen anti-malaria  suspensions on sale in Nairobi and registered with the Pharmacy and Poisons Board also dissolve poorly in water. A study published in Malaria Journal says that although dry powder suspensions are few because the active ingredient artemisinin is not stable in solution form, those available are of poor quality.”

Suspensions are easier to administer to children. Unfortunately the Kenyan researchers also found that, “paediatric antimalarial dry powder formulations on the market may contain ineffective or incorrect amounts of preservatives. This is a potential risk to the patient.”

News reports from Cambodia show that the malaria drug problem is a world-wide concern. “Many of the drugs are cheaply made and don’t contain the right chemistry, or are stored at incorrect temperatures, while others are deliberate fakes that have authentic-looking pills and packaging but contain only a small percentage of the active ingredient in each pill,” according to Talea Miller of Online NewsHour.

We cannot allow the caveat “Let the buyer beware” serve the global malaria control effort.  Maybe as donor contributions of quality drugs flood the market, the unsafe and ineffective formulations will be driven out. But unless national food and drug boards take their role more seriously and collaborate with the malaria community, the threat of fake and substandard drugs will continue to threaten lives now and stimulate drug resistance that threatens future generations.

The ‘F’ word has appeared in peer reviewed malaria literature. “Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia,” reads the title of a new article in Malaria Journal. The authors concluded that, “It is unclear whether the treatment failures are due solely to mefloquine resistance or to artesunate resistance as well. The findings of delayed clearance times and elevated artesunate IC50 suggest that artesunate resistance may be emerging on a background of mefloquine resistance.”

In narrowing down an explanation for treatment failure, the authors considered the following:

• Adulterated and counterfeit drugs are on the market, but it was unlikely that these entered into their study
• Mefloquine dosage ideally varies by weight, and some could have been underdosed, but again analysis shows this was not a factor

The authors also surmised that if resistance to mefloquine is at play, this may expose the patient to only a three-day dose of the artesunate, which then would effectively make artesunate a monotherapy and open to provoking resistance at that dose.

Lim and colleagues consider how resistance to artemisinin drugs could develop in artemether-lumefantrine (AL).  Challenges to absorption of lumefantrine exist and may be related to diet. Here again, the artemisin drug would effectively become 3-day dose of monotherapy, if the partner in the combination was compromised.

Fortunately Premji et al. reported in Africa that “food consumption is adequate post-weaning (and) it appears that only a very small amount of dietary fat is necessary to ensure optimal efficacy with AL and that the fat content of standard meals or breast milk in sub-Saharan Africa is adequate.”

Could home management be a tipping point for ACT resistance.  Data from Ajayi et al. “provides encouraging data on parasitological outcomes of children treated with ACT in the context of HMM and adds to the evidence base for HMM as a public health strategy as well as for scaling-up implementation of HMM with ACTs.” A strong health education component to home management is still necessary.

After modeling the scenarios for ACT resistance, Pongtavornpinyo and co-researchers offer a prescription for action.  They conclude that, “The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with mismatched half-lives, together with reducing malaria transmission through vector control measures.”

Pongtavornpinyo also noted that resistance is more likely to develop in low transmission areas such as found in studies from Southeast Asia mentioned above. Even in high transmission areas, “high ACT coverage alone cannot reduce malaria transmission unless it is used together with vector-control measures.”

Unfortunately at present unavailability of ACTs may be a bigger problem in these high transmission areas, such as the frequent stock-outs in Uganda reported by Start News. This is despite several years of Global Fund support for malaria control in Uganda. Purchasing the new ACTs in commercial pharmacies is too expensive for most, and so people resort to buying the older and cheaper drugs for which there is resistance.

Either way – whether resistance to artemisinin develops tomorrow or people are forced to take cheaper but less effective drugs today – the patient suffers.

Since November 2008, Nigeria has experienced another round of child deaths due to fake and adulterated drugs for children. Four months later after 84 deaths “Nigerian drug regulators have announced they have arrested 12 people in connection with the poisoning of 111 babies with a tainted medicine” according to the BBC.

BBC explained the problem with the commercial teething mixture: “The paracetamol-based syrup, used for treating sore gums, was found to have been contaminated with diethylene glycol, used as an engine coolant. It caused the babies’ kidneys to fail.”

The Blog “Nigeria Health Watch” pointed out back on December 12th that, “We had the “normal” responses from the concerned parties in our beloved country as we have come to expect…. “  In short, there was lack of preventive detection for the tainted mixture, but a lot of vocal indignation by authorities in the press after children started to die.

While there have not been reports of deaths from malaria drugs, Onwujekwe and colleagues report on a disturbing situation with quality of drugs in southeastern Nigeria. After collecting and testing products from 225 public and private providers (including medicine shops) in six sites, both rural and urban, they found first and foremost that only around 10% stocked the nationally recommended first line malaria treatment, artemisinin-based combination therapy (ACTs).

Fortunately none of the medicines had passed their expiry dates. Chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) were still being stocked and dispensed although the former has been found to have seriously reduced efficacy and the latter is supposed to be reserved for intermittent preventive treatment (IPT) in antenatal clinics. Around 40% of CQ and SP failed quality testing. The monotherapy artemisinin drugs and the ACTs performed better with only one failure.

While these poor quality malaria drugs will not kill children directly as in the case of the adulterated teething mixture, they contribute to child mortality.  If children can’t get the recommended medicines for malaria and those they get have little or no active ingredient, they may still be receiving a death sentence.

National malaria control efforts involving the Global Fund and DfID are recognizing and responding to the need to involve all sectors in providing appropriate malaria medicines to Nigerian children.  While the drugs provided through such programs are likely of high quality, these donors would also help the country by providing technical assistance and capacity in pharmaceutical surveillance and vigilance so that the total malaria drug supply is safe.

Fake anti-malarial drugs have long been a problem and are of even more concern now that the prices of first-line drugs are so much higher than the standard ones of 10 years ago.  Tanzania is one of the countries trying to confront this problem.

Today IRIN News quotes the president of Tanzania’s Medical Association as saying, “People are interested in getting a profit, but this is a human rights issue. The consequences of this business are really immense. Take, for example, a person with severe malaria: if he or she cannot access the genuine drug, then it means they may die.”

IRIN found that, “fake drugs will generate US$75 billion in revenues by 2010, nearly double that of 2005. Global counterfeit syndicates use evolving consumer technologies that make it ever easier to imitate legitimate drugs.” In addition “The CTI (Confederation of Tanzania Industries) estimates between 15 and 20 percent of all merchandise circulating in the country is counterfeit, earning Tanzania a reputation as a dumping ground for imitation goods, including fake drugs. Officials say suppliers from China, India, Europe and the USA have used the country as a gateway into Africa.”

The challenge arises because, “It is difficult to punish the vendors of fake drugs in Tanzania, because fakes are so hard to identify. In Dar es Salaam, one pharmacist pointed to receipts showing where he sourced the medicines in his shop, and insisted he only purchased drugs from wholesalers that worked with the Tanzania Pharmacy Board,” according to IRIN.

IPP Media traces that this has been a long standing problem –

• In August 1999, fake Metakelfin labeled as a genuine product from the original manufacturer, Pharmacia and Upjohn, was found in circulation in some pharmacies in the country
• Laboratory analysis confirmed that the counterfeit Metakelfin actually contained paracetamol and the public was
  alerted. In May 2000, counterfeit Ampicillin capsules (250mg) were found circulating in some retail pharmacies
• Laboratory analysis confirmed the capsules contained potato starch. In June 2001, expired Chloroquine Injection (from an unregistered Indian company) was relabeled as Quinine Dihydrochloride Injection 600mg/2ml from a company in Cyprus
• In January 2005, fake Gentrisone Cream (a product of Shin Poong, South Korea) was reported. In this case, the active ingredient was replaced with hand and body lotion
• (November 2007) Jacob Hassan was diagnosed with malaria. The medic prescribed three tablets of Metakelfin to be taken at once and three others after a week – as the medical facility had ran out of the tablets then, the patient decided to purchase the dose from a pharmacy in the vicinity – little did he know that the purported medicine he had bought was actually paracetamol

The in October 2008 Interpol reported that, “In Tanzania 191 locations, including pharmacies, warehouses and illicit markets, were inspected resulting in the seizure of some 100 types of products. Among the confiscated drugs were anti-malarial, cardiac, anti-fungal, multivitamin, hormonal and skin medicines. Police closed four pharmacies and 18 drug shops (known as Duka la Dawa Baridis) found to be in breach of the law. A total of 44 police cases were opened.”

With special effort to involve the private sector in achieving malaria treatment coverage targets, there is need also to involve then – industry, private medical clinics, medicine shops and all – in the process of ensuring drug quality, safety and surveillance.

A World AIDS Day approaches people in the field are giving a critical look at efforts to scale up ART. Jeremiah Norris in the Daily Times of Malawi raises the question of drug quality in the push for achieving widespread HIV/AIDS treatment goals. Could these same problems surface in the desire to scale up for impact (SUFI) that Roll Back Malaria partners are promoting? Some excerpts highlight the problem:

While activists have applauded the speed of this “scale-up,” it creates dangers. Many of the copies recommended by WHO are untested so patients cannot be certain that they act on the body in exactly the same way as the original (called bioequivalence). If the level of active ingredient is not absolutely correct, it can accelerate drug resistance and the mutation of the Aids virus. Under Indian law, drugs manufactured for export do not have to prove bioequivalence with the patented original.

Brazil is often held up as the model for universal Aids treatment. It too has based this largely on cheap, untested copy drugs. In July, the government acknowledged that one third of the 190,000 Aids patients under treatment were in what it called “a more advanced stage”–but medical studies had already shown even higher levels of drug-resistance.

 Norris worries that, “WHO, the Global Fund and the Clinton Foundation therefore sanctioned a drug that was not only unapproved and potentially sub-standard but also more expensive.” Most donors depend on WHO’s ‘prequalification’ program for ensuring drug quality, but maybe it is possible in the rush to achieve coverage some governments are buying drugs not on the prequalified list.

The pressure is on to scale up malaria treatment. The Global Fund Board has recently approved taking on management of the Affordable Medicine Facility – malaria (AMFm), which will among other things enhance the role of private sector in increasing access to malaria medicines. The Clinton Foundation has been negotiating with pharmaceutical manufacturers about making more lower coast malaria drugs available.

Norris’ concern that, “many poor countries … cannot carry out drug evaluation themselves” applies for malaria drugs as well as ARVs.  Even if a drug appears on a WHO or FDA list, one cannot guarantee that the medicine that found in a district hospital pharmacy or a local medicine shop in a malaria endemic country is actually of the quality required. Quick wins in scaled up medicine distribution can ultimately result in quick loss of life if capacity is not built to monitor drug quality at the front line.

The Daily Monitor today warns Ugandans about the potential of fake antimalarial drugs in their midst. “According to the Chairman of the National Drug Authority (NDA) Board, Dr Frank Mwesigye, the drugs that are on high demand are the most counterfeited.” Specifically, “Officials at the National Drug Authority, the body charged with ensuring that all drugs coming into the country are of good quality, have now admitted that individuals dealing in counterfeit drugs are maneuvering through the country’s porous borders and selling fake drugs on the local market.”

On the positive side the NDA Chairman “explained that all drugs imports that go through NDA and those manufactured in Uganda are genuine. About 15 per cent of the drugs used in Uganda are manufactured locally.”  Apparently a recent study published in PLoS One stimulated testing by the NDA of 237 different types of drugs, and all were found to be genuine.

NDA staff, speaking to reporters anonymously were not as certain of the effectiveness of the agency and “called for more resources given the additional duties assigned to them. They said they are now required to inspect food stuffs and cosmetics that are imported into and exported out of the country,” in addition to monitoring over 400 pharmacies in the country.

Apparently the NDA believes that most fake drugs would wind up in the private sector. Fortunately patients can make use of quality drugs provided in the public sector through donor efforts like the Global Fund and the US President’s Malaria Initiative, but another story in the Monitor questions whether the country is doing enough:

According to the report released by the UN’s World Health Organisation, expenditure on medicines ranges from $0.04 to $16.30 across least developed countries. Currently, Uganda’s per capita expenditure on drugs is $1.7 (Shs 2771) yet the ideal spending -within in the country’s limits would be $3.7.

Finally, the ability to perform laboratory diagnosis at the Arua Referral Hospital laboratory was curtailed by theft of two microscopes.  “Daily Monitor has learnt that the machines at the hospital are not labelled making it hard for the police to trace them. According to the police, one microscope has been recovered from a casual labourer.”

The lessons from Uganda show that constant vigilance is needed if patients who suffer from malaria expect to receive efficacious and appropriate life saving treatment. It is not enough for donors to provide supplies, commodities and equipment. Each endemic country must have strong infrastructure – both management and regulatory – to protect and deliver these malaria investments.

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Although we have been advocating for continued research into new antimalarial drugs, David Smith of the University of Florida’s Emerging Pathogens Institute says that, “We don’t have anything in the pipeline after ACTs, and it’s basically just a matter of time until drug resistance evolves and artemisinin also fails. So the question becomes how do we keep ACTs in our arsenal for as long as effectively possible?”

Smith, a co-author on a study that is scheduled to publish online this week in the Proceedings of the National Academy of Sciences pointed out that, “The models indicate that we can slow the evolution of resistance to current artemisinin-based therapies if nations use them in combination with two or more partner drugs. Currently, most nations don’t do this. They use one therapy at a time, wait for it to fail, and then switch to a different therapy.”

Issues of cost, logistics and policy implementation are at the root of the problem. In Nigeria, for example, monotherapy artemesinin-based drugs are still available in shops, although the National Agency for Food and Drug Administration is no longer granting new licenses for monotherapies. Some of the old licenses have a few years left, unfortunately.  ACTs brought in through donor programs like the Global Fund have been targeted free for children, which leaves the door open for ‘leakage’ to the adult population who may take lower than effective doses and promote drug resistance.

The upcoming article in PNAS will explain that, “The researchers’ models also show that cycling through single drugs accelerated the rate at which malaria parasites evolved drug resistance. Smith said this occurred because cycling a single drug degraded the parasite’s average fitness, which made it easier for drug-resistant genes to spread throughout the parasite population.”

The contrast still persists with free or subsidized ACTs in the public sector, often aimed only at children and expensive ACTs in the private sector for adults. Unless a comprehensive national malaria drug policy can be implemented throughout all elements of the health sector, the threat of developing resistance to aretesinim-based medicines will persist.

The 6-country study on fake and substandard malaria drugs published earlier this year was a definite warning and wake up call for strengthened and continued pharmaco-vigilance in Africa. Among 210 samples, 35% tested failed dissolution testing or measurement active pharmaceutical ingredient content against internationally acceptable standards.

Kenya is not relying on the results of such studies alone. “Officials from the Pharmacy and Poisons Board, a government regulatory body under the Medical Services Ministry, recently confiscated thousands of counterfeit Artemisinin-based malaria drugs in a shop in Nairobi. The company that manufactured the drugs was ordered to recall the entire batch,” according to IRIN News. Kenya has done its own research, and an officer from the Board told IRIN News that, “Our [government] study was much wider, we went to all eight provinces in Kenya, and took samples from all public, mission [religious] and private hospitals.” They found 16% of drugs to be substandard and feel that their study is more representative of the country.

That said, Board officials were aware that any level of substandard malaria drugs can undermine the confidence of the public. Ineffective customs control, lax enforcement of pharmaceutical regulations and light sentences for those caught help perpetuate the problem.

Hopefully with donor programs including GFATM, PMI and the World Bank Booster Program, antimalarial drugs in the public sector are of high quality. As the Global Fund says, “For any pharmaceutical products to be eligible for purchase with the Global Fund resources, its compliance with quality standards must be assured.”  But in countries where a large portion of the population relies on the informal and private sector for health care, donors must rethink their methods for getting safe and effective medicines to the people.

Whether through formal or informal channels, many people in Africa get their malaria drugs from the commercial sector comprised of private clinics, retail pharmacies, the ubiquitous drug shops or even hawkers in the market. A few years ago, The Lancet reported that drug quality is often compromised simply by the conditions under which these medicines are kept. Now a study in PLoS One revisits the quality issue from two points of view – the actual content of the tablets and the appropriateness of medicines in stock.

The Lancet article (Taylor et al., 2001) reported that in Nigeria shops, “279 (48%) samples did not comply with set pharmacopoeial limits, and this proportion was uniform for the various types of drugs tested. Although some preparations contained no active ingredient, most had amounts just outside the pharmacopoeial limits. We identified samples with both too much and too little active drug content.”

The new study by Bate and colleagues tested “195 different packs of malaria drugs sold in six African cities (and) showed 35 per cent of them either did not contain high enough levels of active ingredient or did not dissolve properly.” World News Australia quoted Dr Bate who explained that, “”Our study shows that efforts to increase access to quality antimalarial drugs in Africa are increasingly important. Substandard drugs not only endanger lives today, but also jeopardise future malaria treatment strategies by accelerating parasite resistance.”

Concerning the specific medicines located and tested, Bate and colleagues found that, “38% of SP, 48% of amodiaquine, 24% of mefloquine, 31% of artesunate, 27% of artemether, 55% of dihydroartemisinin and 19% of artemether- lumefantrine fixed-dose combinations” failed testing by thin-layer chromatography (TLC), dissolution or both.

The actual availability for sale of certain drugs was also cause for concern. WHO has actively recommended against use of monotherapy artemisinin-based drugs to avoid the dangers of promoting resistance to this lifeline of malaria treatment. Specifically, WHO observes that 10 endemic countries never registered monotherapies, 13 have taken regulatory measures against artemisinin montherapy, while another 13 have stated their intentions to do so. Nigeria, one of the largest markets for malaria drugs, is not on this list.

Nigeria appears to be taking a passive approach to artemisinin monotherapies – letting the registration of those already approved lapse. Visits to medicine shops from Abuja to Uyo confirm that this policy does not result in the quick removal of the medicines. Since artemisinin drugs have a shelf life of less than two years, another passive approach would have been to simply disallow further import and let existing stocks run out, but the approach based on lapsing registration allows continued imports.

Another concern about the drugs found in Bate’s study and in visits to Nigerian shops is the continued presence of sulfadoxine- pyrimethamine (SP) for sale as a treatment drug. Since SP is currently the only drug approved for IPTp and since SP continues to experience growing resistance in children, the wise decision in theory has been to withdraw SP from the market and from treatment generally and reserve it only for IPTp in antenatal care clinics.

Promulgations and policies either by global organizations or national bodies do little to help control malaria if there is no functional regulatory enforcement in place. We will quickly lose more malaria control tools – pushing the hope for eradication even farther into the future.