Dutch take the lead on biosimilar switching - others to follow?

As evidence accumulates on the use of biosimilars in the real-world setting, it looks as if regulatory agencies in Europe may be softening their stance on interchangeability after the Dutch regulator the MEB came out in favour of allowing patients taking one biotherapeutic product to be switched to another, including a biosimilar.

Although the EU has had a biosimilar approval pathway in place since 2005, the European Medicines Agency has not issued any guidance on biosimilar interchangeability or substitution, because decisions on prescribing and dispensing are the province of the member states. National regulators, though, have appeared reluctant to take up a firm position either way.

Now things appear to be changing after the MEB published an updated position on biosimilars in which it said that switching a patient from, say, an innovator biological to a biosimilar was permissible provided that it was done with the involvement of health professionals and that the patient was informed of the switch.

This appears to be the first move of its kind in the EU. "As far as we know, the MEB is indeed the first European medicines agency that has updated its position on biosimilars", a spokesperson for the agency told Scrip, adding that the main objective of the move was "fostering the quality of biosimilar products' usage in clinical practice".

But it's likely that other countries will follow suit. The Finnish regulator, for example, says it has already performed an analysis of the interchangeability of biosimilars and plans to formulate its own official position on the matter soon.

Updated position

The MEB last took a position on biosimilars in 2010, when it said it believed that patients must be kept on the same biological medicine as far as possible if they respond well to it clinically.

"Based on a careful study of the most recent literature and experiences in the evaluation of biosimilars, the MEB deems that this strict condition is no longer valid," it said in a 31 March statement. "There is enough evidence to support the use of biosimilars in clinical practice, provided this occurs with caution and under certain conditions. However, these conditions are essential."

Patients could be switched between biological medicines, it said, "regardless of whether they are innovator products or biosimilar medicinal products", provided adequate clinical monitoring was performed and the patient was properly informed.

The MEB's position is now as follows:

• New patients can be treated with a biosimilar right away.
• Uncontrolled exchange between biological medicinal products (regardless of whether they are innovator products or biosimilar medicinal products) must be avoided. In other words, a patient must receive adequate clinical monitoring and clear instructions.
• If a patient is treated with a biological medicinal product, detailed product and batch information must be recorded in the patient file to guarantee the traceability of the product in the event of problems.

The treating physician and the (hospital) pharmacist must be involved in the switch decision, so that an informed decision can be taken, and co-operation in the area of pharmacovigilance is essential, the MEB said. It added that the use of certain products, such as the new generation of biosimilar antibodies, should be subject to intensive monitoring and practice-based research as advocated by the FMS and NVZA (the associations representing specialist doctors and hospital pharmacists).

The agency said it was confident that the Dutch healthcare system could handle the "safe and sustainable" use of biosimilars in patients, although it stressed that switching should be done carefully and not be based solely on financial considerations. "The products are evaluated and approved within the European regulatory system; it's now up to prescribers and pharmacists to make it happen and to align with payers in order to avoid uncontrolled and solely money-driven switching," the spokesman said.

EGA welcomes Dutch move

The MEB's move, which is clearly motivated by the growing evidence base on the use of biosimilars in clinical practice as shown in various studies in recent years, was welcomed by the European Generic and Biosimilar medicines Association (EGA).

The EGA's senior director of scientific affairs, Suzette Kox, said that the majority of biosimilar usage in the EU to date had been through physician-initiated use in new patients or via a physician-initiated switch from another biopharmaceutical. "Real-world evidence of biosimilars is consequently increasing steadily and hence the move of the MEB is a logical and very thoughtful decision," she commented.

Ms Kox agreed that it seemed the MEB was the first EU regulatory authority to formalize its position clearly in this way, and suggested that it would not be the only one. She said the EGA believed that there was more real-world evidence on switching "out there", and that "others are likely to follow suit".

Finland?

Indeed, cost-constrained agencies elsewhere in Europe may well be tempted to follow suit and look at firming up their own policies on interchangeability. Finland, it seems, has already begun the process and may well take a similar stance.

Pekka Kurki, research professor at the Finnish medicines agency Fimea, told Scrip that while Fimea does not currently have an official opinion on the matter, "our agency has performed an analysis of the interchangeability of biosimilars that led to similar conclusions as the Dutch recommendation". He said the next step was to formulate an official position of the agency. "I expect this to happen before June."

Dr Kurki outlined his own views on interchangeability in a recent article in the GABI Journal, in which he wrote that while the main concern regarding switching from a reference product to a biosimilar was the potential for immunogenicity, there was "no theoretical basis or clinical evidence suggesting that a switch itself would cause immunogenicity". He said it was not impossible that a biosimilar might have an inferior immunogenicity profile, but it was "unlikely".

Looking at the reasons for switching, Dr Kurki (who is also the alternate Finnish member on the EMA management board) said that while it seemed to offer no particular benefit for the individual patient, it had to be looked at from the perspective of a "wider understanding of the role of biosimilars to support sustainable pharmacotherapy".

Many prescribers, he said, were already facing rationing of biological therapies because of their high costs, and in view of the growing role of biologicals in pharmacotherapy, this problem was set to escalate rapidly. "Thus, a prescriber must weigh the inconvenience and potential risk of switching, on one hand, and patient access to biologicals, on the other. Prescribers could be given an easier access to new medicines provided that they use biosimilars," Dr Kurki declared. "Available data suggest that the current EU biosimilars are interchangeable with their reference products," he concluded.

Other countries?

Other countries have already taken some sort of action, or are considering doing so, to boost the use of biosimilars, although none seems to have taken a particular stance on switching.

In France the 2014 social security financing law included a provision allowing pharmacists to substitute a biosimilar for a prescribed innovator medicine under strict conditions. However, this provision – which has yet to be implemented by decree – is quite different from switching because it would only apply at the start of treatment, when the pharmacist would dispense a biosimilar rather than the prescribed drug, and the patient would have to stay on the same medicine for the duration of treatment.

Indeed, in a 2013 position paper, ANSM said it was not recommended to switch a patient from one biological drug to another, and that "multiple or frequent changes between medicines declared to be similar (including the reference drug) could expose [the patient] to a higher risk of immunological response against the protein of therapeutic interest and make it difficult to monitor undesirable effects, in particular of immune origin". ANSM said it therefore recommended that, as far as possible, the patient should be treated with the same product "without making changes treatments within a biosimilar family".

Ireland

More recently, the Irish Health Products Regulatory Authority (HPRA) has put out for consultation a guide to biosimilars for healthcare professionals and patients addressing all aspects relating to biosimilars, including interchangeability, which the draft guide says "has been an area of much debate". As biosimilar medicines cannot be treated in the same way as generic medicines, "prescribing practices and interchangeability between medicines needs to be carefully considered", it says.

While noting that prescribing practices are at the discretion of healthcare professionals, the guide does not recommend that patients are switched "back and forth" between a biosimilar and the reference medicinal product, although it does acknowledge that switches may happen. "It is recommended that there is consultation between prescribers, pharmacists and procurement staff in relation to deciding on treatment preferences for using a reference or a biosimilar medicine."

In the hospital setting, it is important that for biological medicines including biosimilars, there is on-going engagement between prescribers, dispensers, and those with responsibility for procurement. "This will ensure that as a greater number of biosimilar medicines continue to be brought onto the marketplace, prescribing and procurement practices remain aligned in terms of ensuring the best patient outcomes."

To facilitate traceability, any biological medicine prescribed, dispensed or sold should be clearly identifiable (brand name or INN accompanied by the name of the marketing authorisation holder) and the batch number supplied documented, the guide recommends. "This will also ensure that substitution of biosimilar medicines does not inadvertently occur when the medicine is prescribed and dispensed by the pharmacist." The draft guide was released for consultation on 10 April, with comments to be in by 22 May.

Norswitch study

In Norway (which is a non-EU country but tends to follow EU legislation and guidance), the government-funded Norswitch study is assessing the safety and efficacy of switching from Janssen's Remicade (infliximab) to the biosimilar version, Celltrion's Remsima, in patients with any of the approved indications (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn's disease and chronic plaque psoriasis). The randomized, double-blind, parallel-group study, involving some 500 patients, began in October last year, with an expected primary completion date of April 2016.

The EGA's Ms Kox also noted that a number of studies had already been carried out on switching, including a 2013 study on the growth hormone somatropin that showed patients were successfully switched with no negative impact on growth and no serious or unexpected adverse drug reactions. A 2012 article by Ebbers et al, she said, had concluded that data on switching was scarce but that it seemed to happen most often with EPOs, and the authors found no evidence from clinical trial or post-marketing data to show that switching among biological medicines caused any safety concerns. She also cited Dr Kurki's article in the GABI journal.