‘The response defies belief’: year of inaction leaves children at risk from bad cancer drugs

The World Health Organization (WHO) and national drug regulators around the world have come under fire for failing to protect children from dangerous chemotherapy drugs.

One year on, neither national governments nor the WHO have taken meaningful action, with both sides claiming communication breakdown and a lack of evidence. No alert has been issued by the WHO. And doctors remain frustrated that these brands are still for sale.

“This issue is something that needs to be addressed urgently,” Dr Gregory Reaman, a scientific director at the US National Cancer Institute, said. “These are children who are already sick, and have the potential for being cured. And yet they are given substandard drugs.”

The WHO said it first received information about potentially substandard asparaginase in February 2022. That report was made by Ronald Barr, professor emeritus in paediatrics at McMaster University, Canada, and a veteran child cancer specialist. “I told them there was an obvious problem,” Barr said. Researchers in Brazil and India had published studies that showed several brands of asparaginase to be substandard.

He expected the WHO to investigate immediately and to publish the same kind of alert that warned the world about fatally contaminated cough syrup in 2022 and 2023. But after an initial conversation with a WHO official, he saw no obvious progress.

The WHO said it did follow up Barr’s concerns: it searched a monitoring database for entries about asparaginase, conducted a literature review for relevant studies, contacted other WHO teams and got in touch with officials in the countries Barr had named. But, a WHO spokesperson said, the officials said there was no cause for concern.

At the same time, TBIJ’s reporting sought government data from around the world on any official warnings or recalls they had issued about asparaginase. We found only one country to have taken action. And as well as finding studies that showed major problems with asparaginase brands, our reporting also turned up evidence – such as an internal hospital memo and testimony from doctors – that the WHO’s inquiry appeared to have missed.

Empty efforts

Almost a year after Barr raised his concerns, TBIJ published its investigation, revealing that substandard brands of asparaginase had been shipped to more than 90 countries around the world. The WHO said it then reconvened its team to discuss the matter and contacted the countries we named.

Last October, a WHO official was invited to speak at a conference for childhood cancer specialists in a session dedicated to concerns about substandard chemotherapies.

The official said that only one country had confirmed that it had experienced problems with asparaginase. The others said they had never issued any official warnings about the brands named in our article, or else denied that the drugs had ever been found there. Some countries did not respond at all. (Online attendees were required to agree not to publish or share information from conference speakers, but TBIJ believes it is in the public interest to do so.)

“All investigations rely on impacted [countries] and other stakeholders sharing information with WHO in a timely manner,” a WHO spokesperson told TBIJ. “We carry out extensive desktop research and reach out to our large group of collaborating organisations [...] with whom we work on a regular basis.”

The WHO says its investigation is ongoing. But since its initial enquiries, it appears to have resulted in little meaningful action.

“It was, and remains, difficult to establish whether there are any significant issues of concern,” a WHO spokesperson said.

“It doesn’t seem to matter that there’s published evidence,” said Barr. He gave the WHO the contact details of researchers involved in studies conducted in India, in which multiple brands of asparaginase failed drug strength and purity tests. It appears the WHO never got in touch with them.

TBIJ recently approached researchers involved in seven studies included in our investigation; none had been contacted by the WHO to discuss their results.

A WHO spokesperson said the organisation had reviewed nine published articles related to substandard asparaginase, but found there was “no substantive regulatory-relevant scientific evidence provided to demonstrate the quality issues alleged”. They said the WHO shared these studies with the relevant countries, which bear "primary responsibility" for investigating the products.

The spokesperson said the organisation takes the issue of substandard medicines “very seriously”, but would not make documents relating to its asparaginase investigation available to TBIJ.

“In light of WHO’s ongoing discussions with its member states on this matter, WHO is unfortunately not in a position to provide [further] information,” a spokesperson said. Asked when the inquiries into substandard asparaginase would be concluded, they replied: “I can’t really say.”

The organisation said it handles more than 300 reports of substandard medicines every year. While the WHO says that “all reports are investigated”, it also says it requires detailed information on the drugs from government officials before it is able to take its investigations further.

“WHO relies on countries to share that information,” a spokesperson said. “The WHO mandate does not go beyond that.”

Government action?

The WHO says it has not received any “actionable information” from the governments of countries that appeared in our reporting. This would include, for example, drug samples, “credible test results”, or “clarity on why such a product is classified as substandard or falsified”.

“[This] is why a global medical product alert has not been issued,” a spokesperson said.

The regulatory agency for Italy – where further TBIJ reporting revealed at least 16 hospitals to have been using a poor-quality brand of asparaginase not approved for use in the EU – disputes the WHO’s claim, saying it is “unable to clarify” why the organisation believes no useful information has been received. It said it told the WHO what it knew when requested.

For their part, many national governments seem reluctant to take responsibility for the use of dangerous asparaginase in their countries. In July 2022, the Indian regulatory agency, the CDSCO, sent a letter to its regional drug controllers instructing them to look into the issue of poor-quality asparaginase and take “appropriate action”. But little appears to have been done.

“All the CDSCO does is write letters,” said Dinesh Thakur, a drug safety advocate and former generics industry whistleblower. “Most state drug regulators just ignore [them].”

The CDSCO did not respond to a request for comment.

In Italy, 21 senators raised the issue with the country’s health minister last summer, and demanded to know how the government would take action to protect children from bad drugs. But as of last week there had been no reply, said Sandra Zampa, one of the senators in question.

“The minister, indeed the government, has an obligation to answer,” she said. “This particular case is of great importance, because it has a very significant impact on people’s lives. I am particularly sorry and concerned about this lack of transparency.”

And while the country’s regulators said they replied to the WHO’s request for information, they have said they are unable to investigate the issue further. “The agency has no investigative powers, nor is it vested with regulatory functions that would allow it to conduct a ‘national investigation’ or launch fact-finding initiatives” into Italy’s use of poor-quality asparaginase, a spokesperson said.

“This is a way to shirk [their responsibilities],” Zampa responded. “They should do what they can in the meantime. If not them, who will?”

While the senators have not received a reply for the past six months, the Italian health ministry responded to TBIJ’s questions last week. It confirmed it is considering the problem of substandard asparaginase, and will decide whether to change national regulations on the import of unauthorised drugs and evaluate “possible quality and safety aspects” of those medicines.

At the European Commission, too, questions were raised early last year by MEPs about the presence of substandard asparaginase on the European market. The response from Stella Kyriakides, European commissioner for health and food safety, said that “safety features” in existing European directives “guarantee medicine authenticity” for patients. It did not address the use of substandard asparaginase we found in Italy.

While TBIJ’s investigation has made an impact – researchers in the US and Africa have begun developing cheap, simple tests allowing doctors to check the quality of asparaginase – effective action by national regulators to protect children from these drugs remains elusive. And the WHO insists there are no proven “significant issues of concern”.

“The response from WHO defies belief,” Barr said. “Dismissal of evidence published in highly reputable journals following peer review indicates a combination of incompetence and refuge in bureaucracy which should require investigation of the [WHO substandard medicines] team by higher authority within the organisation.”

“They are not at all transparent about what it is they're actually doing, or what the timeline is,” said Reaman at the National Cancer Institute. “I think patients and families have the right to know.”

This article was updated on 29 January 2024 to include the fact that the WHO shared studies relating to substandard asparaginase with national governments.