Ireland’s wide use of unlicensed medicines raises safety concerns

Ireland is increasingly plugging holes in pharmacy shelves with unlicensed medicines in a process that has become so ingrained it risks undermining the EU’s rules for ensuring safe medicines, warns a top pharmaceutical lawyer.

The country has been turning to a loophole in EU rules that allows countries to use unlicensed medicines for individual patients in certain, clearly defined cases. And the practice has become so systemic that in many cases unlicensed drugs are used as standard.

But this could put patients at risk, according to lawyer Vincenzo Salvatore, of BonelliErede in Milan, who formerly led the European Medicines Agency’s legal team.

Countries should "avoid the abuse of this power" to allow the general use of unlicensed medicines, he said, "because that could put patients at risk of adverse events or lower safety and quality monitoring of the medicinal products that they are administered.”

Normally, the Irish health system would not reimburse patients for medicines that are unlicensed. But the practice has become so normal that the medicines regulator has issued a list of 166 unlicensed drugs that pharmacists can dispense and still be reimbursed by the national health system.

“In the past, you might have had a couple of different lines [of unlicensed medicines stocked in the pharmacy]; now you could have whole bays and numbers of shelves,” said Susan O’Dwyer, head of professional services at the Irish Pharmacy Union, which represents community pharmacists.

In 2020, more than 1.5 million packs of unlicensed medicines were imported into Ireland — and that’s just counting the top 50 unlicensed drugs by volume. While rates of use of unlicensed medicines in other EU countries are difficult to establish, a pharmaceutical representative with years of experience in medicines trade and granted anonymity to speak freely said Ireland was an extreme outlier.

“There’s no other country in Europe that has such high use of unlicensed medicines,” the pharmaceutical representative said.

A combination of tough generic drug pricing controls and the country’s relatively small size — which combine to deter pharmaceutical companies from going through the licensing process — are largely to blame, according to a pharmacist who has worked in the sector for many years and was granted anonymity to speak candidly. This began more than a decade ago, they said.

“As manufacturers were rationalizing their portfolios, they were often removing products or not renewing licenses [in Ireland],” the pharmacist said. And over the years, other events — such as Brexit and acute drug shortages — have added to the pressure to use more unlicensed medicines.

Most of the unlicensed medicines imported into Ireland will be licensed in other European countries, including the U.K., meaning they have the same high quality standards. But there are risks that lower-quality medicines from third countries could also enter the supply chain.

Raising the stakes

Europe prides itself on its high-quality medicines. Not only must medicines in the EU/EEA’s 30 countries meet stringent standards for their quality, safety and efficacy, but the bloc also has strict scannable packaging rules, designed to make it extremely difficult for counterfeit drugs to enter the supply chain.

If an unlicensed medicine is used, however, none of these rules apply.

"In Ireland, unfortunately, what’s happening is that the [EU] rules are essentially being ignored, so as to provide medicines more expeditiously to patients," the pharmacist said.

The risks from unlicensed medicines are not just theoretical. An investigation by POLITICO and the Bureau of Investigative Journalism last year found at least 16 hospitals in Italy treated cancer patients with a poor-quality leukemia drug imported from India that is not approved in the EU. Hundreds of vials of the product were purchased to treat acute lymphoblastic leukemia, the most common form of childhood cancer, using the legal loophole.

In Ireland, only authorized wholesalers or manufacturers can import unlicensed medicines from countries outside of Europe, and they must inform the country’s medicines regulator, the Health Protection Regulatory Agency (HPRA).

HPRA told POLITICO that it monitors side effects from the use of unlicensed medicines — going further than some EU countries. And it takes action to protect patients where necessary.

For example, from January through September 2023, the regulator recalled batches of 16 unlicensed medicines, which it calls exempt medicinal products (EMPs). “On each occasion, the recall action was swiftly implemented and efficiently managed with a primary focus on the safety of patients,” HPRA said in a statement.

Its rules also seek to prevent fake drugs entering the market. “[Unlicensed medicines] are sourced by authorized pharmaceutical companies from the open market,” HPRA said, and these “must comply with European Good Distribution and Good Manufacturing Practices, including falsified medicine checks before supplying EMPs.”

Liability

Meanwhile, for pharmacists, the practice in Ireland adds a heavy burden to already-stretched staff. They spend increasingly more time each day trying to source medicines for their patients due to chronic shortages. Today, there are 303 medicines in short supply in the country.

When a drug is out of stock, they try to source an alternative through wholesalers. And when there’s no alternative, they look for unlicensed medicines that the health system will reimburse, the Irish Pharmacy Union’s O’Dwyer said.

When this isn’t available, often the only option is an unlicensed medicine that isn’t covered by the state. “That essentially means at the end of the day that the patient is having to foot the bill,” O’Dwyer said.

The pharmacist must get approval from the patient’s doctor, which means a new prescription, and inform patients that their medicine is unlicensed. They also need to provide advice, especially when the leaflet is written in another language.

“A lot of the liability rests then with the prescriber and with the pharmacist,” O’Dwyer said.

Meanwhile, there is little sign that this practice will abate. And in fact, the use of unlicensed medicines throughout Europe looks likely to rise.

In a legally binding text from October setting out ways in which countries can mitigate the scourge of chronic drug shortages, the European Commission states it will launch a high-level response in 2024 to promote “regulatory flexibilities.” A Commission spokesperson confirmed this included the legal exemptions loophole that allows the use of unlicensed medicines.

To O’Dwyer, there is a far simpler solution. Issue EU-wide licenses, instead of national licenses, to all generic medicines in Europe. This would mean commonly used generic drugs in Germany, for example, would also be authorized in Ireland. And a shift to digital labels would do away with foreign language issues.

The good news is that digital labels are proposed in the Commission’s overhaul of medicines legislation currently being scrutinized by MEPs.

The bad news: There’s no mention of a move to European licenses for generics. The legislation does seek to alleviate drug shortages, but it seems this idea hasn’t made the cut. Perhaps the final version of the text will be different.