At least 16 hospitals in Italy were treating cancer patients with low-quality imported drugs not approved for use in the EU, an investigation by the Bureau of Investigative Journalism (TBIJ) and POLITICO found. .
Due to gaps between national and EU drug regulations, Italian hospitals are using Serginase (a low-cost cancer treatment that has been found to be substandard) despite the availability of better alternatives. drugs) could be legally requested to be shipped.
Neither the Italian drug regulatory authority nor the Italian Ministry of Health are responsible for checking the quality, efficacy and safety of this drug before allowing its administration in Italian hospitals. It is also not under the jurisdiction of the European Medicines Agency (EMA).
But over the past seven years hundreds of vials of this drug have arrived from India. As a result, it is unknown how many cancer patients may have experienced side effects or a reduced chance of remission. Many vials are still on hospital shelves.
Serginase is a brand of asparaginase, a drug used to treat acute lymphoblastic leukemia, the most common form of childhood cancer. Serginase is manufactured and approved in India and is priced at a fraction of the price of the ‘gold standard’ brand, only €13 versus approximately €2,500 per vial. Published academic studies have found that it does not meet minimum manufacturing standards or consistently reach clinical activity thresholds for treating cancer.
TBIJ and US health news site STAT revealed in January. Low-quality brands of asparaginase, including serginase, have been shipped to more than 90 countries since 2016, putting an estimated 70,000 children at risk worldwide.
In 2018, a nationwide shortage of the ‘gold standard’ asparaginase, Oncaspar, was revealed, and children in Italy were to receive another brand, Aspatello, which later met the criteria. It turned out not. Affiliated hospitals said the request to import Aspartero had been cleared by Italy’s drug regulator and without it “the children’s chances of recovery will be reduced.” The drug regulator confirmed that it had allowed the import.
However, TBIJ and POLITICO confirmed that serginase was being purchased by Italian hospitals even after the gold standard product became available, and in some cases even this year. Further records suggest that serginase is also imported into seven Italian regional health departments, suggesting that the actual number of hospitals using the drug may be much higher.
The informed consent document does not detail the brand of drug administered to the patient or the country in which it is approved. Patients are left in the dark.
take medicine
There are several different types of asparaginase. “Native” asparaginase is made from E. coli. Transforming this bacterium into a drug is complicated, and even good asparaginase can cause side effects, including severe allergic reactions.
For this reason, doctors prefer to use modified asparaginase. These are less likely to cause allergic reactions, but are much more expensive up front.
Both Celginase and Oncaspar are asparaginases, but they are different. Celginase is native and Oncaspar is modified. Oncaspar is a brand of asparaginase approved for use in Europe in 2016 and recommended as first-line treatment for acute lymphoblastic leukemia.
In Italy, if a drug is in short supply, doctors and pharmacists can ask the Italian drug regulator to grant permission to import the same drug from other countries.
Another law stipulates that drugs such as serginase, which are not approved in the EU but are marketed in other parts of the world, can be given to designated individuals if they determine that “there are no effective alternative therapies available”. patients are allowed to import. Since Serginase and Oncaspar are not completely equivalent, doctors could request importation of Serginase even when Oncaspar was available.
Importantly, the process circumvents national drug regulators. In Italy, the Ministry of Health’s customs office instead grants permits, but the permits are only required for hospitals to fill out forms correctly and to ensure that the medicines arriving are as requested.
The agency is not required by law to check the quality of imported medicines or to request data from foreign regulators that have approved them.
Instead, responsibility for the use of these drugs rests with the individual physician who requested them. The Italian pharmaceuticals regulator states that physicians should use qualified and credible import brokers who can guarantee the quality and safety of their medicines, especially to suppliers from non-EU countries, and that physicians should be fully and fully informed of their patients. He said that informed consent should be obtained by providing highly transparent information. Comprehensive information about drugs.
Through a Freedom of Information Request to the Italian Ministry of Health Customs, TBIJ and POLITICO found that at least 16 hospitals, including the National Oncology Institute in Milan and San Camillo Forlanini in Rome, have imported hundreds of Serginase vials into the country. I discovered that A period of 7 years. The National Cancer Institute said it needed to procure serginase because of shortages. He added that patients receiving the drug were either responding or in remission, and that the Italian drug regulator had never provided any information indicating that serginase could be harmful. rice field. San Camilo-Forlanini did not respond to a request for comment.
Attilio Guarini, a doctor who treats patients with acute lymphoblastic leukemia at the Polyclinico di Bari hospital, recommends that doctors use natural asparaginases such as serginase when Oncaspar is available. Said there was no guidance.
Italy’s drug regulator told TBIJ it denied any responsibility for the “efficacy and safety” of drugs imported from non-EU countries that were not licensed according to EU regulations.
The European Medicines Agency (EMA) also does not have the authority to regulate the import of unapproved medicines from non-EU countries, according to Guido Laci, former Director General of the European Medicines Agency (EMA).
Most of the serginase imported to Italy from India was via Switzerland. Swiss Customs told TBIJ and POLITICO that it did not have specific data on the products we inquired about. It is unclear whether Indian asparaginase imported via Switzerland has made its way to EU member states other than Italy, but said serginase is not used in Switzerland.
EU loophole
In certain situations, such as drug shortages, it is important for European countries to be able to import drugs that are not approved in the EU.
In 2001, the EU promulgated a new bloc-wide law allowing the exclusion of medicines “meeting special needs” from European standard regulations on quality, safety, efficacy and manufacturing. But only under severe conditions.
Such medicines (including medicines not approved in the EU) are prescribed according to the specifications of an accredited health care professional such as a doctor or pharmacist and must be administered individually under the “direct personal responsibility” of that practitioner. should be administered to patients with ”.
Countries have incorporated this into their national legislation, with mixed results.
In Italy, the prescribing doctor has to justify the exceptional use, which is then checked by the Ministry of Health customs. In Spain, hospitals or health authorities must request access to unapproved drugs from regulatory authorities. In Ireland a doctor must issue a prescription and the wholesaler or manufacturer must notify the regulatory authority of the importation.
EU legislation was intended to apply only to individual patients, but in practice this is not always the case. In Germany and Italy, for example, there are provisions for ordering large enough quantities to temporarily stock hospital pharmacies. The law has been widely applied in Ireland, and in 2020 more than 1.5 million boxes of the 50 most popular drugs were brought into the country under the regulation.
Grant Castle, Partner at Covington Law Firm, said: “If products for commercial sale routinely flow into the EU as unlicensed medicines and they are supplied under the patient designation system, That’s a problem,” he says.
He said those regulations are meant to give patients access to medicines when there is a genuine medical need and are “not a good basis” for importing medicines for other reasons. . “If that’s what’s happening, it’s a loophole.”
Although it is the responsibility of Member States to establish rules for the supply of unlicensed medicinal products designated to patients,, Castle added that national regulations “usually do not provide the same safeguards.”
Control measures
Gilles Vassal, a pediatric oncologist and director of the European Society of Pediatric Oncology, agreed. As countries deal with shortages by importing medicines not approved in the EU, he asks: [the national] Is there a level to control the quality of imported pharmaceuticals? ”
The Italian drug regulator exchanged information with the World Health Organization in February 2023 about data on the possible lack of efficacy of the Indian drug Aspartero provided in the study featured in TBIJ’s first article, it said. Stated. He added that there appears to be no evidence from WHO or national regulatory authorities of low-quality, dangerous or ineffective asparaginase imported from India.
However, a European Commission spokesperson said the Italian medicines regulator and other Italian authorities were investigating the matter involving some of certain Italian hospitals. A WHO spokesperson said the agency had contacted countries reported in the TBIJ’s initial investigation of asparaginase, but had received no “actionable information”.
Changes to EU law are also underway to address some of these concerns.a Planned revision Regional pharmaceutical laws will include a provision stating that countries “shall encourage” physicians and patients to report safety data on the use of unapproved medicines to their national regulatory authorities. Become.
It could also require drug companies to report potential shortages two to six months in advance, and could require companies and wholesalers to hold more inventory. There is also sex.
In Italy, the customs authorities responded to TBIJ’s inquiry and are working on amending the form to require doctors to explain in more detail the clinical reasons for importation. “We’ve noticed a loophole in the system and we’re working on fixing it,” said Ulrico Angeloni, one of the agency’s coordinators.
Physicians spoken to by TBIJ and POLITICO urged national steps to verify the quality of unlicensed medicines accessed through such loopholes and to increase transparency about their use, efficacy and safety. hopes for
While European medicines are currently among the most regulated in the world, a contradiction remains that medicines shipped from abroad may not meet even the lowest standards.
The manufacturer of Serginase did not respond to a request for comment.
Maria Cristina Fraddosio contributed to the report.
