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Sub-standard generic medicines killing children globally

Global attention has recently been drawn to the toxic consequences of sub-standard medications, emanating from inferior manufacturing plants and countries with sloppy regulatory processes that permit unchecked, contaminated products to be dispensed to patients worldwide, notes MedicalBrief.

In the latest cases, toxic cough syrups from India have been linked to the deaths of some 300 children in The Gambia, Uzbekistan and Indonesia.

But, reports STAT, an in-depth collaborative investigation has discovered the cough syrup cases were just the tip of the iceberg: in fact, the practice of exporting cheap and often deadly generic medication, and not just cough mixture, has been going on for years, and is widespread. It has killed, and is still killing, children around the globe.

In 2017, when Emily was combing her baby daughter Isadora’s hair, she felt odd lumps. The child had been feverish and listless, unwilling to play or take a bottle. The lumps were clustered on the back of her neck, the size of small beans. Something was very wrong.

At the clinic, in southern Brazil, the doctor found more lumps under Isadora’s arms and in her groin. Emily was urged to take her daughter to hospital, where she watched as doctors hurried her daughter through medical tests. Later, a doctor told her Isadora had an aggressive form of leukaemia, the most common kind of childhood cancer.

Her treatment would be gruelling: a cocktail of chemotherapy drugs that would leave her skeletal, vomiting and lethargic

Isadora began to suffer side effects. Emily believed that, although the drugs were making her daughter sick, they were also curing her.

But one of the most important chemotherapy drugs in Isadora’s concoction was asparaginase, which was then at the heart of an emerging national scandal. Later that year, Brazilian doctors – including some looking after Isadora – would confirm that the brand of asparaginase she received was nowhere near as effective as it should have been. What’s more, it was contaminated, and could make sick patients sicker.

Eventually, a court ordered the Brazilian Government to remove this particular brand, Leuginase, from hospital shelves.

It should have been the end of the scandal, says STAT. Instead, it was just the beginning of a global one.

Reporting by the Bureau of Investigative Journalism, in partnership with STAT, reveals that at least a dozen brands of asparaginase have been proven to be poor quality, with 10 still on the market globally. The drug stops cancer cells from dividing and growing. Without it, patients face a dramatically reduced chance of survival.

But in some cases brands fell well below the standard needed to treat cancer. Many have also been found to contain contaminants such as bacteria that could be harmful to patients.

A spokesperson for Leuginase’s manufacturer, Beijing SL Pharmaceutical, said the drug was tested by Chinese regulators and assessed in-house, where, he claimed, quality results have stayed within statutory limits over the past decade.

In the past five years, these poor-quality brands have been shipped to more than 90 countries, overwhelmingly from companies in India. Many receiving the drugs are low- and middle-income nations without strict regulatory authorities, but in several instances sub-standard drugs have been imported into Western Europe and given to patients in Italy.

At least seven manufacturers continue to sell their products despite being warned they do not meet minimum manufacturing quality standards. Experts estimate 70 000 children worldwide with acute lymphoblastic leukemia (ALL) are at risk, as contaminated and ineffective asparaginase slips through global safety nets.

“What’s happening is a disaster,” said Vaskar Saha, director of the Tata Translational Cancer Research Centre in Kolkata. The majority of children with ALL are in low-income countries.”

Fight for survival

In 2018, shortly after Brazilian courts banned Leuginase, the sub-standard brand of asparaginase, Silvia Brandalise received a package from Haiti. Brandalise, a children’s oncologist in Brazil, had long been suspicious of Leuginase. She had tested the drug in mice, and been slammed for speaking up when she found it was dangerously defective.

The package was sent by the head of Haiti’s only paediatric cancer department. It contained a single vial of asparaginase.

Since asparaginase was introduced in the 1960s, survival rates for children with ALL, Isadora’s cancer, have risen to about 90% in wealthy countries.

In Haiti, physician Pascale Gassant saw only 15 or so patients a year in her department, a fraction of the children with the disease in her country. Her ward did not have a 90% survival rate.

Nonetheless, she had had good success with her patients – until her hospital switched its brand of asparaginase, when she watched her patients’ chances of recovery plummet. Children she would once have been optimistic about – who were otherwise healthy, and who had arrived early enough that treatment could save them – were dying. The hospital’s survival rate for that cancer was just 3.5%.

In Brazil, Brandalise’s colleagues tested the samples. Her worst fears were confirmed. Like the Brazilian Leuginase, the Haitian drug was contaminated with by-products that could cause side effects and even impede treatment. The patients did not stand a chance.

Something else caught Brandalise’s attention. The Haitian product was made by Beijing SL Pharmaceutical, the same Chinese company that manufactured Brazil’s Leuginase. If poor-quality asparaginase had spread to Haiti, how many more countries had it reached?

In fact, bad asparaginase had already begun to flood the world. In 2018 alone, analysis by the Bureau of Investigative Journalism shows that poor-quality brands reached more than 40 countries across Europe, South America, Asia, Africa and the Middle East.

Worse, in the past five years, sub-standard asparaginase has spread to almost 100 countries, from Armenia to Zimbabwe. Shipping data suggest that countries including Nepal, Ecuador, and the United Arab Emirates, have received the most shipments of these brands.

Nearly half of the countries in Africa have received sub-standard drugs.

A representative from Beijing SL Pharmaceutical said the company has produced asparaginase for a dozen countries over the past decade. He disputed the Brazilian doctors’ findings, calling them “absurd”.

He said the company had never sold its asparaginase in Haiti, and offered several theories on how it could have ended up there. It could have been counterfeit, expired, or sold on by South American distributors. He said Beijing SL Pharmaceutical would conduct a thorough investigation of all its asparaginase sold abroad in light of the Bureau’s findings.

Market failure

It wasn’t always like this. For years, cheaper, good-quality asparaginase was available to low- and middle-income countries, where 80% of children with cancer live. But in the past decade, major manufacturers have increased their prices or stopped making asparaginase altogether. The result is a terrifying global shortage of one of the world’s key cancer medicines, and a crisis disproportionately affecting the countries needing it the most.

There are several different types of asparaginase. “Native” asparaginase is made from Escherichia coli (E. coli), a bacterium more commonly associated with nasty sickness than saving lives. Turning the bacterium into medicine is complicated and costly, and even good-quality asparaginase can cause side effects, including severe allergic reactions.

For this reason, doctors prefer to use modified versions of asparaginase. These are less likely to cause allergic reactions, but are much more expensive upfront. In Europe and North America, two brands, Oncaspar and Spectrila, are widely used. (Both have consistently passed quality tests.)

For patients experiencing serious reactions to these forms, there is another type: Erwinia asparaginase. However, only two companies make trusted brands and supplies have frequently been short since 2011.

Manufacturers are increasingly focused on their higher-priced modified products. The cost of these “gold-standard” products has ballooned well beyond what lower-income countries can afford.

Unable to access these products, hospitals in low- and middle-income countries often use cheaper, native asparaginase. Until recently there were at least two good, affordable brands. But the first was discontinued in 2012 due, the company said, to “ongoing manufacturing challenges”. The second was discontinued in 2020, after the sole manufacturer in Japan had its certification of quality revoked.

As these products disappeared, so too did many doctors’ hopes of prescribing asparaginase to their patients. None of the leading manufacturers of asparaginase have stepped in to produce an affordable native form. A market analysis from 2021 found that global demand for the drug was too small to motivate companies to improve their quality, or to encourage other manufacturers to begin producing it.

Bad batches

Contamination of asparaginase with harmful bacteria is potentially deadly. Cancer treatment leaves children with significantly weakened immune systems, making them more prone to infections and other serious complications.

In August and October 2020, the Chilean Health Ministry issued two alerts in quick succession about Onconase, made by United Biotech in India. Both batches were found to contain bacteria after patients suffered fevers.

In spring 2021, the manufacturer of a gold-standard brand put out a letter warning that Onconase had “failed to meet almost all purity specification parameters” and that “striking quality defects” were presumably leading to ineffective treatment and severe side effects.

Even so, shipping data analysis shows Onconase has been imported into Chile at least nine times since its Health Ministry alerts. Government records show the brand has been distributed more than 70 times to more than a dozen different hospitals since late 2020.

Some were still receiving Onconase as recently as October.

The world’s pharmacy

India and its pharmaceutical industry plays a vital role in ensuring people worldwide can access affordable medicine. It is the world’s largest provider of generic drugs, and globally, is known as “the world’s pharmacy”.

Most of its products are safe and work well. But for decades, its industry has been dogged by quality scandals.

Most generics produced by India are “small molecule” drugs, chemicals that are copied exactly but sold for less. Asparaginase, though, is a biologic: made from a living organism. Biologics and their generic versions (known as biosimilars) have much more complex and expensive manufacturing processes than most small molecule drugs.

Recently, a complex network of Indian suppliers has sought to capitalise on chronic shortages of gold-standard asparaginase and the increasing desperation for affordable products.

Some of these new brands fell under the scrutiny of Vasker Saha at the Tata Centre in Kolkata, when he started examine the quality of brands on the Indian market. He tested seven products. None met minimum manufacturing quality standards.

In five brands, drug strength was lower than expected. All seven had purity problems. Nearly 20% of patients given a widely used brand developed allergic reactions and had to be taken off the drug completely.

Saha was concerned. Low drug activity levels of the kind he had observed in his research were “likely to compromise” patients’ ultimate survival, he wrote in a paper published in Paediatric Blood & Cancer in 2021. He was also keenly aware of the inequalities between his patients in India and those in his second home, the UK. In the paper’s conclusion, he noted that drug quality was potentially a “significant determinant” in the differing patient outcomes in high- and low-income nations.

Saha alerted all of the manufacturers to what he had found. Just three replied, saying they wanted to do better. All seven products remain on the global market and were sent to countries around the world in 2022.

“Only a handful of Indian companies actually have capacity and capability to manufacture biologics,” said Dinesh Thakur, a drug safety advocate and former generics industry whistleblower. “It’s a completely different ballgame.”

Nonetheless, according to a national database, the 11 Indian asparaginase manufacturers investigated by the Bureau have received important, WHO-backed quality-assurance certifications. While the WHO sets the framework for these schemes, responsibility for assessing facilities and issuing the certification lies with national governments: in this case, the Indian Health Ministry.

At least one company producing poor-quality asparaginase claims to be “approved” by or “compliant” with western regulatory authorities such as those in the US and UK.

United Biotech, which makes Onconase, is not listed on the FDA’s database of registered drug manufacturers. The FDA refused an import from the company in 2013, and has not inspected their manufacturing plants or authorised their products.

The UK’s Medicines and Healthcare Products Regulatory Agency said it has not granted United Biotech any good manufacturing practices certification.

The Indian-made asparaginase investigated by the Bureau sells for just a fraction of the price of gold-standard brands. One oncologist from Latin America said Onconase was marketed at one-tenth the price of Oncaspar. A Bureau reporter posing as a buyer was offered Indian-made asparaginase for $7 per vial.

Wholesalers also provided documentation from the manufacturers purporting to verify their products’ quality. But right now, Thakur said, the quality certification provided by manufacturers to purchasing countries is “a piece of paper from Indian regulators saying the product is manufactured under good manufacturing practice conditions. How they establish that is not known to anyone.”

He thinks the Indian Government should review and strengthen its drug approval process, particularly for biologics, to ensure strict standards are met. “The regulator has no clue what it’s doing, because how we should approve biosimilars is very different from how we should approve regular small molecule generic drugs,” he said.

The high price of gold-standard products puts them out of reach for much of the the world. “In my dream I’d be giving all children pegylated (modified) asparaginase,” said Simon Bailey, a children’s oncologist who has advised on treating patients in East Africa. In one instance, the East Africa team was alerted to potential defects in their asparaginase.

After weighing the risks, they stopped giving their patients the drug and replaced it with another chemotherapy. “That’s not ideal,” Bailey said. But gold-standard asparaginase was not an option. “It’s just not affordable.”

Given the global nature of the crisis, and that asparaginase is listed as essential by the WHO, some have suggested the organisation do more to boost access to good-quality asparaginase.

The WHO hosts a global monitoring system for fake and sub-standard drugs, and provides technical support in emergencies. However, while it can issue medical product alerts, it does not have the power to reprimand countries for exporting poor-quality medicine, or close down manufacturers.

It relies on countries to report incidents to its monitoring system, and some are more willing to do that than others.

Rutendo Kuwana, head of the WHO’s substandard and falsified medicines team, told the Bureau they do not have any record of sub-standard or fake asparaginase products. While the team was aware of “anecdotal reports” and scientific publications raising concerns about some products, “no definitive product information is available for follow up with competent authorities.”

Kuwana said it was the responsibility of country regulators to initially investigate reports of sub-standard drugs, while the WHO would offer support “on request.”

Roughly 10% of medicines sold in low- and middle-income countries are thought to be fake or sub-standard, with tragic consequences. In October, the deaths of nearly 70 children in The Gambia were linked to an Indian-made cough syrup. Last month, 18 children died in Uzbekistan after taking another Indian-made cough syrup. Fixing the systemic issues that have allowed poor-quality asparaginase to spread could help patients far beyond child cancer wards.

Facing the future

Stemming the tide of poor-quality asparaginase will take global co-operation, money and willpower. While long-term solutions may feel out of reach, a handful of measures to help children who need the drug now are taking shape.

In December 2021, the WHO and St Jude Children’s Research Hospital announced plans to improve the global supply of quality childhood cancer medicines, with asparaginase a priority. A new platform will act as a purchaser on behalf of low- and middle-income countries, giving quality manufacturers a reliable source of demand. In turn, they may be more willing to offer competitive prices for bulk orders. The result should benefit everyone.

The platform has secured $200m over the next five years, and expects to send medicines to the first 12 countries this spring. St Jude predicts 120 000 children could benefit by the end of 2027.

In India, Vaskar Saha is working with the three manufacturers who responded to his research to help improve their asparaginase products. He hopes a collaborative approach will spur Indian manufacturers to create an affordable asparaginase on par with gold-standard brands.

The fastest solution to the crisis could be to convince quality manufacturers to lower their prices, at least for countries who cannot afford them. While this may seem like a non-starter, one leading oncologist said he had argued with both Servier and Medac that selling their products at a price only rich countries could pay limited their profits.

 

STAT News article – The drug was meant to save children’s lives. Instead, they’re dying (Open access)

 

See more from MedicalBrief archives:

 

WHO probes raw materials link in lethal cough syrups

 

Indonesia families launch lawsuit over contaminated cough syrup

 

Probe into Indian cough syrup link to Gambian children’s deaths

 

 

 

 

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