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Bad medicine

In their effort to eradicate malaria, scientists must counter not only mosquitoes, poverty and war—but a vast, criminal industry of fake or substandard drugs
December 6, 2023

It’s a “wicked problem”, says Paul Newton. The Oxford professor of tropical medicine is talking about the faking of drug treatments, a counterfeiting business that has none of the naughty charm of a rip-off Gucci handbag. By wicked, he means that it is difficult: “it’s really hard to know quite how to prioritise what should be done.” But it is wicked in the other sense too. One struggles to imagine how anyone could knowingly be involved in such a trade without evil intent. Fake drugs kill. They most often kill children.

People who are aware of faked medicines may associate the term with Viagra, which has been illicitly copied and sold online to shy or unwary punters around the world. But while linking drug counterfeiting with pills for sexual performance can make for grabby or grubby headlines, it devalues the true problem. Erectile dysfunction is a distressing condition, but it’s not a killer. Malaria is.

Around 600,000 people die of malaria every year—the majority of them small children—despite the existence of very effective drug treatments called ACTs, or artemisinin-based combination therapies. Tu Youyou, a Chinese scientist, won the Nobel prize for physiology or medicine for her discovery of artemisinin, derived from the plant Artemisia annua, in 1972. In her Nobel lecture in 2015, she called it a gift from traditional Chinese medicine to the world. 

If children who have contracted malaria are given artemisinin compounds—some form of artesunate combined with a second antimalarial to thwart resistance in the malaria parasite—they should survive. If they get falsified drugs, containing little or none of the original active ingredients, these children, often already underweight and malnourished, may die. And the malaria parasite, treated with a minimal amount of the drugs in a fake or substandard pill, can develop resistance to the treatment, so that the real thing will no longer work. In this way, the deadly trade in fake drugs is undermining the world’s efforts to eradicate malaria. Ironically, many of the falsified antimalarials are made covertly in China. A gift given with one hand, taken away by the other.

There are two sorts of drugs that don’t work: those that are deliberately faked or falsified, packaged in boxes with convincing batch numbers and labels; and those that are substandard, most likely because of poor manufacture.

For some years, there was dissension and confusion at the World Health Organisation (WHO) over what to call faked medicines—a hangover from the battles over drug patents for the antiretrovirals used to treat HIV and Aids. In the early 2000s, Aids campaigners backed the use of generic HIV drugs. These were cheap but identical copies of patented medicines made by Indian companies who defied Big Pharma and exploited legal loopholes in intellectual property (IP) rules to manufacture affordable drugs for low-income countries. 

For patients around the world, the chances of getting a drug that doesn’t work are high

The multinationals, wanting to protect their patents and the profits they made in affluent western countries, lobbied against generics companies, depicting the low-cost firms as denizens of a new Wild West—rule-breakers making counterfeit pills that were potentially below par. This angered campaigners for access to medicines, who saw generic drugs as lifesavers for people in low-income countries. The row over terminology spilled into malaria control. “There were lots of accusations that the innovative industry was using the word ‘counterfeit’ as a way of countering increasing use of generics. That caused an enormous kerfuffle, in Geneva especially,” says Newton, who heads the Medicine Quality Research Group at Oxford. 

In 2017, the WHO settled the question by labelling dodgy drugs as “falsified” when they have been manufactured with a criminal intent to deceive, or “substandard” when they contain unintentional errors (sometimes “terrible examples of gross negligence,” says Newton).

For patients around the world, the chances of getting a drug that doesn’t work are high. According to the campaigning organisation Fight the Fakes, one in 10 medicines in low- and middle-income countries is thought to be either substandard or falsified. In a report in February 2023, the UN Office on Drugs and Crime (UNODC) estimated that as many as 267,000 deaths a year in sub-Saharan Africa are linked to falsified or substandard antimalarials and nearly 170,000 additional deaths are down to falsified and substandard antibiotics. That’s almost 450,000 needless deaths, mostly in children, every year. The cost to the struggling health systems trying to treat those people whose drugs are not working is said by the WHO to be between $12m and $45m.

 These are wide estimates, perhaps because there’s no exact way to count the number of fake or substandard drugs on the global market, just as it is impossible to enumerate the fake Rolex watches sold worldwide. But every now and then, a successful effort by the authorities gives us a glimpse of the way the trade works. 

In June 2012, a ship from China arrived in Luanda docks in Angola. On board was a container of loudspeakers, in which were hidden 1.4m packets of two important drugs. Some appeared to be the gold-standard antimalarial combination treatment, artemether-lumefantrine. The label said they had been manufactured by the Swiss-based Novartis Pharmaceutical Corporation, and they also bore the logo of the Affordable Medicines Facility, which funds antimalarials for low-income countries. The other packets were of a de-worming treatment for children, labelled as mebendazole, manufactured by Janssen-Cilag.

There were no active pharmaceutical ingredients in the antimalarial tablets. The de-worming tablets contained no mebendazole. They did, however, contain levamisole, a drug that had been withdrawn from human use because of side-effects and was at the time being used to “cut” cocaine. In a 2014 letter to the Lancet on lessons from the Angola haul, Newton notes that the presence of this drug “suggests links between criminals who produce narcotics and those who produce falsified medicines.”

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 But the story of dodgy drugs goes beyond organised crime. The UNODC says, in its report, that “investigations have uncovered a variety of actors involved in the illicit medical product trade. Traffickers include pharmaceutical company employees, public officials, law enforcement officers, health agency workers and street vendors.”

Who are these people and how can they bring themselves to make money from children’s suffering? Dr Bahijja Raimi-Abraham, lecturer in pharmaceutics at King’s College London and founder of the university’s chapter of Fight the Fakes, says she struggles to understand their motivation. “Some of the counterfeited products are high-grade pharmaceutical level. [The producers] have thought about the tablet, the formulation and all this stuff, but they’re putting talcum powder in there. Then there’s the effort to make the label look right, to make the bottle look right, to make sure, if it’s a solution, that there are no particles. I guess this is me being very idealistic, but I can’t believe that anybody can be so evil.”

The powers of one drug after another have waned, as parasites evolved to overcome their effects

It’s hard to get to the dark core of the business. Those who are arrested tend to be the foot soldiers, the guys storing packets in a garage or delivering the goods. But Ian Lancaster, a holograms expert who has been heavily involved in challenging the faking of medicines with the WHO and others, and who now runs a consultancy, says that brand counterfeiting, including medicines, makes big money for criminals. “It’s much more lucrative for them than illegal drugs, and not nearly as heavily policed,” he says. “A counterfeiter is a counterfeiter is a counterfeiter… They don’t care what they are counterfeiting, if they can make money at it.” The 1993 attack on the World Trade Center was partly funded by counterfeiting, he says, as in part was the IRA.

To make a fake medicine, though, you need the know-how and the equipment and chemical components. This is not an enterprise undertaken in somebody’s kitchen. There are stories about pharmaceutical factories in China that manufacture legitimate pills in the day and switch to lucrative fakes once the night shift takes over. Lancaster, who rails against “the lack of policing by brand owners of their contract or subcontract producers,” says this third shift is “notorious”. On a trip to Mumbai, he was invited out one evening to the local market by somebody from one of the major pharmaceutical companies, who showed him all the high-end branded clothing on sale. It was the same as the genuine article but had been produced on the night shift, out of quota. “While these people were simply doing a third shift for something they were legitimately producing, it was an easy step to work for Mr Big and go from trafficking those clothes to saying, well, I think I’m gonna do medicines as well.”

Alice Sherwood, in her recent book Authenticity: Reclaiming Reality in a Counterfeit Culture, accuses governments of moral culpability. China is “allowing—even encouraging—[artemisinin drugs] to be counterfeited,” she writes. “A nation that can land a mission on the moon, that can lock up a city and throw a cordon sanitaire around 60 million people, can surely track down the diluters and counterfeiters in its midst.” But western governments are also to blame, for increasing their own quality checks on Chinese medicines but looking the other way as they are shipped to malaria-endemic countries.

Drug falsification is as old as medicine itself. Quinine, the earliest malaria drug, started to be falsified in the 1800s. The cinchona bark, from which it comes, was faked as early as the 1600s. In Carol Reid’s film The Third Man, based on Graham Greene’s story, the character Harry Lime smuggles fake penicillin in post-war Vienna. His best friend Holly Martins is persuaded to entrap him after police take Martins around wards of sick and dying children, harmed by the drugs. Greene’s fiction was based on fact: the arrest of seven men and three women for manufacturing fake penicillin in Berlin in 1946. The vials and bottles they sold were filled with other drugs (including antimalarials) and with face powder and were probably also contaminated.

As much or more damage to the malaria effort may be done by substandard drugs as by fake ones.  Substandard pills are those that contain the right active ingredients, but perhaps too little of them to kill all the parasites. Artemisinin monotherapy—artesunate on its own without extra antimalarials—is still sold and used, in spite of warnings from the WHO that this can accelerate the malaria parasite’s resistance to treatment. That building of resistance has long been a problem: the curative powers of one malaria drug after another has waned, as parasites have evolved to overcome their effects. Worrying signs began to be detected in the artemisinin compounds in western Cambodia in the early 2000s, when increasing numbers of parasite infections were slow to clear. 

Nick White is one of the world’s leading malaria experts and a professor of tropical medicine at Oxford, though based at Mahidol University in Thailand. He says that falsified and substandard drugs are not the only problems for malaria control. “I think [malaria control] is going well in places where you deliver healthcare well, and it’s going badly in places where you deliver healthcare badly, because of a combination of war, corruption, inefficiency, the usual things that affect low-resource settings.”

He has advocated for mass dosing of populations while the drugs are still effective: giving ACTs to the communities at highest risk, to prevent them getting malaria. The fewer people there are with malaria, the lower the chances that a biting mosquito will pick up a malaria parasite from their blood and pass it on to its next victim. “We did it in the Greater Mekong sub region. We did it in Vietnam, Cambodia and Laos. It worked,” says White. Malaria is now stable there. 

Success was down to more than mass treatment, he says. In villages where mass dosing did not take place, farmers, shopkeepers and others with standing in the community were designated as health workers who could do a rapid diagnostic test for a feverish child and give out drugs when necessary. “They’re identified in that community. And that’s the key intervention that has been incredibly successful in controlling malaria across Southeast Asia, but it has not been adequately implemented in Africa where [prescribing medication] is still the old-fashioned district hospital type thing,” says White.

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The mass treatment programme also worked in the most malarious region of Myanmar, but war has since compromised healthcare and allowed a resurgence of the disease. “You have completely disrupted infrastructure. You can’t even go to the next valley without being shot, so you can’t deliver the product,” says White. “Malaria always prospers under those circumstances. You look where malaria is bad. It’s where there’s war.” He lists the countries where cases are mounting: northern Nigeria, which now has a diphtheria outbreak too. Then there’s the eastern DRC, South Sudan and across the Sahel. Healthcare weakens or collapses under the strain of conflict, and malaria returns.

White and colleagues aim for a treatment cure rate of 90 per cent—and ideally 100 per cent. “The more failures you have, the more quickly resistance spreads... There’s a little bit, you don’t see it… and then suddenly it takes off,” he says. He is now advocating for triple antimalarial combination drugs—an artemisinin compound with two others—instead of the current double. He also thinks there’s a need to better identify the people most likely to fail on treatment. Those are the people with the most parasites in their blood. Old-fashioned microscopy showed that up but the new tests, better in many ways, do not.

It’s not just the tablets they have to worry about, either. The parasites have also developed resistance to the impregnated bednets—and the mosquitoes have become sneaky, White says. “They bite you before you go near a bed, and they’ve got a better chance of surviving than if they bite you when you’re in the bed. So you get these behavioural changes in mosquitoes.”

Excitement around the recent approval of a second malaria vaccine may have caused some people to assume that the long struggle against the killer disease is nearly over. The Oxford vaccine will reach far more children than the Mosquirix vaccine we already have, because it will be manufactured in millions of doses by the Serum Institute of India. But both vaccines require three or four shots, a hard ask for African families living far from a clinic, and will work best when given just before the malaria season starts. Only time will tell how well the vaccines protect children in practice.

Fighting malaria is hard, there’s no doubt about it. The problem is a complex combination of human behaviour, poverty, war and displacement, climate change and the evolution of mosquitoes and their parasites. Fake drugs make the fight so much harder.

Newton and his team are using their ingenuity to beat the criminals at their deadly game, employing forensic techniques that include DNA and stable isotope analysis to find those responsible. Fake drugs contain traces of the environment in which they were made. They may even contain human DNA—although identifying whether it’s the DNA of the drug-maker, or an innocent passer-by, is harder.

Another tool of detection is social network analysis, tracing the origins of fake drugs using the same techniques that are employed to track the poaching and smuggling of African ivory. “Quite surprisingly, there hasn’t been much innovation in trying to work out where fake medicines come from,” Newton says. “The social network analysis… is inspired by work on the illegal wildlife trade, where colleagues use publicly accessible reports about where (for instance) elephant ivory went to try and work out which were the places where enforcement may wish to do more interventions.”

The pharmaceutical companies don’t always make public what they know for fear of damaging confidence in their products. The Angola haul of 1.4m packs of fake drugs was revealed finally only on Facebook, five months after it happened. 

Medicines regulatory authorities need to be able to take tougher action, says Newton. In 2011, he and colleagues called for the WHO to use the International Health Regulations (IHR) to designate bad medicines as a global health threat—a categorisation more normally applied to pandemics—to try to stop the spread of resistance from Asia into Africa by making more resources available, and alerting all countries to the issue. “We are woefully ignorant as to how best to tackle poor medicine quality in different situations and there has been a damaging lack of public health, civil society and political will to tackle the problem, which those combating the fake cinchona bark and quinine scandals in the 17th-19th centuries would have found puzzling,” they wrote in the Malaria Journal. 

While the WHO did not invoke the regulations, it has charted a clear path now that the thorny issue of IP has been put to bed. In 2013, it launched its Global Surveillance and Monitoring System (GSMS) which collects reports of falsified and substandard medicines. Two landmark reports from 2017 spell out the dangers and the progress that has been made, citing major incidents such as the toxic cough syrup containing levomethorphan, a drug five times stronger than morphine, that killed 60 adults in Pakistan in 2012. When 44 children were admitted to hospital in Paraguay the following year with breathing problems, a WHO team identified that they had been given an identical toxic cough syrup and were able to sound the alert and stop its production.

The WHO reports set out what must be done to strengthen those countries’ drug regulatory bodies, which struggle to keep up with globalised medicines supply, while educating professionals and the public on the dangers of fake or inferior drugs and how to spot them. Yet experts say there is still a long way to go. In 2018, delegates to the first-ever international Medicine Quality and Public Health conference, held at Oxford University, called in a statement for more investment, effort and transparency. “Substandard and falsified medical products… represent a significant and growing threat to human health,” wrote the signatories in a letter to the Lancet in November 2019. “In the face of mounting harm, regulatory bodies are alarmingly underequipped”. They called for political commitment. “With significant human health and economic consequences at stake, urgent action is needed now,” the writers concluded. 

Within a month, the first case of Covid would be identified in Wuhan, China, and new batches of fake medicines would soon arrive in global pharmacies. Interpol’s Operation Pangea, which works on pharmaceutical crime, made 121 arrests across 90 countries in the week that the WHO declared Covid-19 a pandemic. “The illicit trade in such counterfeit medical items during a public health crisis, shows a total disregard for people’s lives,” said Interpol’s secretary general Jürgen Stock.

The malaria experts may agree—and perhaps add that the disregard has been going on far too long. There is a roadmap now, as a result of the WHO and the Oxford statement, for dealing with faked and inadequate drugs. The question is how many of the players in this dark trade—from politicians, to medicines regulators to pharma bosses—will follow it, inspired by the possibility of ending many thousands of unnecessary deaths, and how many will sit back and allow the toll to keep on rising.