Vital chemotherapy drugs used world wide have failed quality checks, leaving most cancers sufferers in additional than 100 international locations vulnerable to ineffective remedies and probably deadly unintended effects, the Bureau of Investigative Journalism (TBIJ) can reveal.
The drugs in query kind the spine of remedy plans for quite a few frequent cancers – together with breast, ovarian and leukaemia. Some drugs contained so little of their key ingredient that pharmacists mentioned giving them to sufferers can be pretty much as good as doing nothing. Other drugs, containing an excessive amount of lively ingredient, put sufferers vulnerable to extreme organ harm and even demise. “Both scenarios are horrendous,” mentioned one pharmacist. “It’s heartbreaking.”
Doctors from a number of international locations informed TBIJ of the drugs in query not working as anticipated, leaving sufferers all of a sudden unresponsive to remedy. Other sufferers suffered unintended effects so poisonous that they may now not tolerate the medication.
The variance discovered within the ranges of lively ingredient was alarming. In some circumstances, drugs from the identical blister pack contained completely different quantities.
These findings expose large holes within the international security nets supposed to forestall profit-seeking producers from slicing corners, and to guard sufferers from unhealthy drugs. All the whereas, sufferers and governments with stretched assets are paying the value for drugs that don’t work.
A world killer
Cancer is likely one of the greatest killers worldwide, linked to round 10 million deaths yearly – roughly one in six. The burden of most cancers is rising, notably in low- and middle-income areas. In sub-Saharan Africa, for instance, cases of most cancers have doubled within the final 30 years.
Much of the worldwide demand for remedy is met by so-called generic drugs. These are variations of a drug that may be made as soon as the unique maker’s exclusivity rights have expired, and are usually made much more cheaply. The unhealthy drugs described on this investigation had been all generics.
Generics are extensively utilized in all international locations however are most important in these with fewer assets, the place costlier remedies is perhaps past attain. If generics weren’t accessible in sub-Saharan Africa, as an example, “any cancer treatment would be likely inaccessible to most of the population”, mentioned Claudia Martinez of the Access to Medicine Foundation*, an NGO.
In chemotherapy drugs, the lively ingredient – which fights most cancers cells – can also be extremely poisonous. Patients must obtain sufficient of it to deal with the most cancers however not a lot that they overdose and undergo damaging unintended effects. As such, hospital pharmacists calculate doses rigorously – and in doing so, depend on the quantity of lively ingredient being precisely what’s said on the label.
Research from a landmark study printed at the moment examined the quantity of lively ingredient in seven frequent forms of most cancers drug: cisplatin, cyclophosphamide, doxorubicin, ifosfamide, leucovorin, methotrexate and oxaliplatin. All of them are classed as important medicines by the World Health Organisation (WHO).
Working with collaborators in Cameroon, Ethiopia, Kenya and Malawi, researchers on the University of Notre Dame, Indiana, analysed drug samples from the 4 international locations.
Of 189 samples that had not expired on the time of testing, about one fifth failed. This consisted of 20 completely different manufacturers of generic drug made by 17 producers (see a full checklist of the manufacturers that failed right here).
“We were all taken aback when we saw the results,” mentioned Marya Lieberman, the professor who led the analysis.
More than 30 producers made merchandise to a great commonplace. But for sufferers receiving the poor-quality drugs, the consequences could possibly be devastating. “Once a person has been diagnosed with cancer, there’s a limited window of opportunity for treatment to work,” mentioned Lieberman. “And if someone is treated with an ineffective product, they can lose that precious window.”
The majority of failed drugs had too little lively ingredient (for many this meant lower than 88% of the quantity said on the label) whereas some contained an excessive amount of (greater than 112%). Both thresholds had been determined by researchers based mostly on worldwide requirements.
“Both scenarios are horrendous in my eyes,” mentioned Shereen Nabhani-Gebara, vice chair of the British Oncology Pharmacists Association. “It takes a lot of courage for someone with cancer to accept a diagnosis, but then to be short-changed like this when they are trying their best is heartbreaking – because this is someone’s life.”
Tracking the risk
Over the previous six years, these manufacturers of drugs have been shipped to greater than 100 international locations in each populated continent on the planet. They vary from low- and middle-income nations like Nepal, Ethiopia and North Korea, to rich international locations such because the US, UK and Saudi Arabia.
The worst-performing drug within the study is made by Indian producer Venus Remedies. It is a drug referred to as cyclophosphamide, which is usually used to deal with cancers together with lymphoma and breast most cancers.
All eight samples of this Venus Remedies drug failed, with six containing lower than half the quantity of lively ingredient claimed by the producer. One contained simply over 1 / 4 of the said dose, which based on a number of most cancers pharmacists can be as efficient as no remedy in any respect.
The drug has been shipped to 6 international locations, with its largest importer being Ethiopia.
Wondemagegnhu Tigeneh, a scientific oncologist within the Ethiopian capital Addis Ababa, informed TBIJ that he has handled sufferers with chemotherapy drugs he believes didn’t work.
“I have a suspicion that the active ingredient was lower than expected,” he mentioned, remembering a drug he gave to a latest affected person who had responded nicely to the primary three rounds of remedy. But on the subsequent spherical, their progress all of a sudden stopped.
Because he has no means to check them, Tigeneh can by no means be certain of the quality of a given drug. But in his 20 years treating most cancers, he has realized to note tell-tale indicators. Sometimes, as an example, there’s a full absence of side-effects corresponding to nausea or hair loss. “That makes it difficult to trust that particular drug,” he mentioned.
Then there are the sufferers whose illness he struggles to get underneath management, corresponding to a affected person whose response to remedy halted with out warning. Rather than decreasing the dimensions of the tumour sufficient to allow surgical procedure, his crew has been compelled to maneuver onto a second-line remedy. If that fails, the subsequent stage is palliative care. “It’s very sad,” mentioned Tigeneh. “We didn’t used to see things like this.”
Cancer sufferers in Ethiopia have much better entry to remedy amenities now than they did 20 years in the past. It doesn’t appear, nevertheless, that the usual of medicines has stored tempo. A 2020 study of most cancers drugs in Ethiopia included 20 samples of cisplatin which had been all discovered to be substandard, averaging simply over half of the said content material. One researcher who checks the quality of drugs within the nation informed TBIJ that they discover unhealthy medicines wherever they go.
Venus Remedies informed TBIJ that the study outcomes had been “not scientifically plausible” given the corporate’s “validated manufacturing systems and quality controls.” It mentioned it has acquired no complaints or issues concerning the batches in query and shared the outcomes of its personal testing that indicated they had been of a great commonplace.
It mentioned storage situations within the provide chain, which might have an effect on drug quality, might need affected the researchers’ take a look at outcomes. However, the absence of comparable quality points throughout your complete knowledge set suggests this isn’t the case.
Venus Remedies is one in every of three corporations or regulators that queried the methodology used by the lab, saying it deviated from worldwide requirements or may give inaccurate outcomes. However, Lieberman mentioned that, though her outcomes are usually not supposed for regulatory functions, her researchers’ strategies are based mostly on these used by regulatory labs and had been verified for suitability, accuracy, and precision. Both the findings and strategies have been scrutinised by impartial lecturers.
Toxic results
Some 3,200 km south of Addis Ababa, in Malawi, specialist most cancers care has solely been accessible for round 15 years. In one of many poorest international locations on this planet, sufferers rely upon healthcare being free on the level of want. That means clinics must depend on generic drugs.
A pharmacist specialising in most cancers care in central Malawi informed TBIJ of seeing sufferers at his hospital overdose on methotrexate, a drug used to deal with leukaemia and lymphoma.
Malawi has additionally imported two of the manufacturers of methotrexate the researchers on this investigation discovered to include an excessive amount of lively ingredient: Zuvitrex, made by Zuvius Lifesciences, and Unitrexate, made by United Biotech. Neither firm responded to a number of requests for remark.
This type of extra could be simply as dangerous as a deficit. A foul overdose can depart a affected person with lifelong unintended effects and even kill them. As Nabhani-Gebara mentioned: “More is not better.”
The Malawian pharmacist mentioned sufferers at his hospital have suffered extreme vomiting and nausea after overdosing on methotrexate, whereas others needed to be moved onto a second-line remedy, which might not be as efficient. For some sufferers, the unintended effects had been so extreme that they needed to pause remedy completely – giving the most cancers an opportunity to develop.
When a pattern of the methotrexate in query was examined as a part of a analysis challenge happening on the time, it was discovered to be too excessive in lively ingredient. “It’s very worrying,” the pharmacist mentioned.
He informed TBIJ that he and his colleagues have from time to time needed to cease utilizing a complete batch of chemotherapy medication and ship samples to the nationwide drug regulator after the medication modified color – an indication one thing is mistaken with it.
“We had patients scheduled for clinic,” he mentioned, “and then we had to break the news to them that we don’t have medicines.”
Failing security nets
Countries all around the world have programs in place to cease unhealthy drugs reaching sufferers. However, there are large disparities of their effectiveness. According to Chaitanya Kumar Koduri of the US Pharmacopeia, an organisation that units requirements for medicines within the US and internationally, “70% of countries cannot take care of their own medicine quality”.
Most governments have a nationwide regulator – however their remit and assets differ massively. And even the better-funded regulators are removed from foolproof. The US Food and Drug Administration (FDA), as an example, is struggling to maintain up with inspections of producing vegetation domestically and in India and China, and has admitted that its inspections haven’t been a dependable indicator of drug quality.
The FDA just lately introduced it might broaden unannounced inspections at overseas manufacturing amenities, saying it will assist expose those that falsify information or conceal violations.
It informed TBIJ “that inspections and reviews will continue to ensure [drug] safety and efficacy”.
One of the international locations the place medication regulation ranks the bottom, based on the WHO, is Nepal. It can also be one of many greatest importers of the failed chemotherapy manufacturers on this investigation.
Despite there being greater than 20,000 manufacturers of medication in the marketplace there, the nation’s drugs regulator has set a goal of testing simply 22 drugs within the subsequent 12 months – and none of them chemotherapy drugs.
Narayan Prasad Dhakal, the regulator’s director basic, informed TBIJ that its lab can’t presently take a look at most cancers drugs and admitted that the state of affairs round quality-testing is “a concern”. He additionally mentioned that whereas his division has the ability to recall most cancers drugs based mostly on exterior proof, it has by no means finished so.
The subject is particularly fraught for sufferers who might have travelled from distant, rural areas to get remedy that then might not even work.
Laxmi Kumari, whose two-year-old son is being handled for most cancers in Kathmandu, Nepal’s capital, has needed to procure chemotherapy drugs from personal pharmacies. The remedy has value the household almost two lakh rupees, equal to a number of months’ common wage in Nepal, and but they don’t have any reassurance that it is going to be efficient.
“We have no way of knowing the quality of the medications being used in his treatment,” mentioned Kumari. “We rely entirely on what the doctors recommend.”
“Neither patients nor their families have any way of knowing the quality of these drugs,” mentioned Smriti Pokharel of the Wish Nepal Foundation, which helps kids from low-income households entry most cancers remedy.
“Even doctors face challenges in verifying their quality. No one seems willing to take responsibility for ensuring proper treatment for cancer patients.”
Race to the underside
Generic drug producers are working in a world market that healthcare professionals and specialists agree is pushed by one factor: worth. It’s a market during which these working underneath a much less watchful eye can discover methods to undercut their rivals.
This may imply scrimping on the quantity or quality of the lively ingredient – the most costly element – or utilizing low-cost or outdated equipment. Research shows that almost all of substandard drugs happen as a result of issues with manufacturing, quality management, packaging or storage.
The outcomes could be deadly. Four kids died in Colombia after being given contaminated most cancers drugs in 2019. Three years later, one other batch of unhealthy medication prompted the deaths of at the very least 10 kids in Yemen who had been being handled for leukaemia.
The price-driven market creates a harmful dynamic during which the variety of corporations making a selected drug shrinks and shrinks till international provide is precariously depending on only a handful of producers. Should one firm slip up, 1000’s of sufferers could be left with out the drugs they rely upon.
It’s a state of affairs that performed out within the US just lately. Between 2018 and 2022, Intas Pharmaceuticals – the guardian firm of Accord Healthcare, which made the worst-performing cisplatin examined on this investigation – grew its market share of cisplatin from 24% to 62%. It additionally elevated its share in methotrexate fivefold in the identical time interval. All the whereas, costs of each these chemotherapy drugs dropped.
Then on the finish of 2022, a shock inspection by the US drug regulator revealed a “cascade of failure” at an Intas manufacturing unit in India, the place employees had been seen shredding and pouring acid on quality information. The shutdown that ensued despatched shockwaves throughout the US, with almost each main most cancers centre reporting shortfalls in chemotherapy drugs in the course of the spring or summer time of 2023, based on the New York Times.
Accord Healthcare mentioned the batch of cisplatin that failed our testing had met all established quality requirements, and shared knowledge from inside and exterior research indicating its quality. It mentioned it has not acquired any market issues associated to this batch.
In India, the world’s largest producer of generic drugs, questions have been raised over whether or not producers are correctly punished for producing drugs that aren’t match for goal – and whether or not overseas regulators have correct oversight.
“The Indian government’s interest is in trying to protect the industry,” mentioned public well being activist and former Big Pharma whistleblower Dinesh Thakur.
Sixteen of the 17 producers recognized on this investigation are based mostly in India, and 5 have been beforehand flagged by a regulator for producing substandard batches of drugs. One of them, Zee Laboratories, has been flagged 46 instances since 2018.
India’s drug regulator informed TBIJ that Zee Laboratories has been audited and given a “stop production order”, which was lifted after the corporate resolved the issues in query. It didn’t give particulars about when this was, which points it pertained to or whether or not the corporate confronted any penalties.
It’s additionally unclear whether or not the producers uncovered in TBIJ’s earlier investigation into substandard asparaginase have confronted any repercussions, regardless of 70,000 kids with leukaemia being in danger.
Three of these corporations – Getwell Pharmaceuticals, United Biotech and VHB Medi Sciences – additionally made a few of the substandard drugs revealed by this investigation.
Thakur mentioned there’s just one solution to clarify the manufacturing of weak drugs by massive corporations: “Somebody’s cutting corners.”
Meanwhile, these medicines proceed to fill pharmacy cabinets. Zuvius Lifesciences and GLS Pharma have equipped their failed manufacturers to over 40 international locations. And prior to now two years, Venus Remedies – which made the drug that pharmacists mentioned wasn’t price prescribing – has been awarded a collection of contracts and licences, together with from the Pan American Health Organization to produce a number of important most cancers drugs to Latin American international locations.
India’s drug regulator defended the oversight system, saying that failing drugs are recalled and producers face “either administrative penalties or legal prosecution in court”.
Getwell Pharmaceuticals, GLS Pharma, VHB Medi Sciences, and Zee Laboratories didn’t reply to a number of requests for remark.
Shortage of assets
In order to make sure that individuals internationally have entry to protected, efficient drugs, the World Health Organization (WHO) has put in place a collection of steps. It has compiled an inventory of “essential medicines”, to assist international locations with restricted assets know what to prioritise. It checks sure drugs, lively substances and their producers to create a pre-approved checklist that international locations can belief.
The WHO additionally oversees a set of requirements for producers and drugs that many international locations confer with when importing medicines.
However, these measures have their very own limitations.
The checklist of advisable medicines, for instance, solely expanded to incorporate most cancers drugs in 2019 and specialists say WHO ought to embrace extra of them on the checklist. Shalini Jayasekar-Zürn of the Union for International Cancer Control, a world membership organisation devoted to taking motion on most cancers, says it presently solely encompasses two most cancers drugs, rituximab and trastuzumab. “It would be great if the list was expanded to include more essential medicines, especially for cancer,” she mentioned.
While the WHO oversees requirements for producers and drugs, it’s as much as the international locations shopping for medicines to verify these requirements are met – which isn’t any simple activity given the assets of nationwide regulators.
Meanwhile, Thakur mentioned that one WHO scheme – a certificates system that claims a given drug meets varied requirements – has been undermined by corporations which have discovered “workarounds” to pay money for the paperwork with out bettering quality. “It’s not worth the paper it’s written on,” he mentioned.
The upshot, specialists say, is that with out the great oversight seen in international locations just like the UK, the WHO’s processes don’t cease substandard medicines making their means onto cabinets.
Reflecting on TBIJ’s findings alongside his personal expertise, Thakur mentioned that the WHO was “clearly not” delivering on its said goal: to advertise well being, preserve the world protected and serve the susceptible.
The WHO didn’t reply to a number of requests for remark made by TBIJ.
A excessive worth
The merciless irony is that on this race to the underside, it’s the most cancers sufferers who are sometimes left to foot the invoice. And those that have the least pay essentially the most: in low earnings international locations, the price of 58% of important most cancers medicines is paid by sufferers, in contrast with 1.8% in upper-middle-income international locations.
One most cancers pharmacist in Ethiopia estimated that it may take over a 12 months for a affected person to save lots of for most cancers remedy. If that medication then seems to be defective, they merely may not be capable of afford to pay for one more.
“Most people believe cancer is incurable,” they mentioned. “When they end up with a medicine that won’t cure them, that’s another tragedy.”
“For me, it’s a question of fairness,” mentioned Lieberman, the lead researcher. “[Patients] have the right to be treated with a medicine that actually is what it says it is. One that has the correct ingredients in it, that hasn’t degraded, and that doesn’t have things in it that will hurt them. It’s too important.”
* The Access to Medicine Foundation is part-funded by the Bill & Melinda Gates Foundation, one in every of TBIJ’s funders.
This article is collectively printed by The Hindu and TBIJ.
