Clinicians reminded to tick box to avoid unapproved biosimilar switching

The arrival of a new self-injectable biosimilar used to treat rheumatoid arthritis has prompted a leading Australian gastroenterologist to remind clinicians of the importance of checking the ‘brand substitution not permitted’ box on prescriptions.

The move will prevent switching between biosimilars and biologic without the clinician’s involvement.

This process known as ‘a flagging’ has attracted significant controversy since the government decided to allow patients and pharmacists to choose between the two at dispensing level – unless the prescribing physician ticks the ‘brand substitution not permitted’ box on the prescription.

Clinicians are concerned about the lack of evidence showing whether multiple switching between biosimilars and biologics is safe or effective.

It is almost a year since biosimilar infliximab (Inflectra) has been listed on the PBS for the same indications as Remicade, for the management of inflammatory bowel disease.

In July, Australia’s Pharmaceutical Benefits Scheme Committee recommended the listing of Brenzys as a biosimilar of originator brand etanercept (Enbrel) on a cost minimization basis with Enbrel for all adult indications – rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and chronic plaque psoriasis.

Dr Gregory Moore, head of Inflammatory Bowel Disease at Monash Health, said more evidence was needed to understand the implications of switching between the two drug therapies.

He said the fact that infliximab was hospital-prescribed and given intravenously allowed some control at a clinical level. However some of the next biologic agents to come off patent that will result in biosimilars entering the market, like Brenzys, that will be self-injectable.

Dr Moore said it was vital clinicians understood that biosimilars were not direct copies of the biologic they are designed to replace.

“They’re not generics and should not be treated as such,” he told the limbic. “We tend rarely to tick the box (brand substation permitted) but this is the only way to control which treatment the patient stays on.”

Writing a Perspective in the Medical Journal of Australia, he conceded that the arrival of biosimilar drugs has created much-needed cost savings to the health system, while still maintaining treatment standards.

However, he said there were still concerns that switching between these and the originator products could eradicate clinical efficacy,

Dr Moore said more evidence was needed to understand the implications of switching between the two drug therapies.

Biological therapies are markedly different from chemically synthesised drugs, typically being large protein-containing agents produced from recombinant DNA and cell culture techniques, with complex post-translational modification. To create a biosimilar version, it must have “demonstrable similarity in physicochemical, biological and immunological characteristics, efficacy and safety”.

Dr Moore said these drugs often don’t have demonstrated bioequivalence given that the approval process requires that biosimilar versions demonstrate just one indication of an originator drug. Biologics are immunogenic and can result in antibody formation, reactions and loss of efficacy with time.

Given that biosimilar drugs are not identical, there is a theoretical risk that switching between agents may result in development of neutralising anti-drug bodies (ADAs) and a subsequent loss of efficacy.

While previous studies have investigated a single switch between the originator and the biosimilar agents, multiple switch or switch-back treatments have not been assessed.

“The Australian government has stated that biosimilar and originator anti-TNF-α agents can be considered interchangeable at the point of dispensing from the pharmacy,” he said.

“This practice, known as a-flagging, requires patient consent and may result in patients electing to receive a different agent at each visit to the pharmacy.”

And it is this possibility that raises significant concerns for prescribing clinicians and representative bodies.

“The absence of data about whether there are adverse reactions or the development of ADA from multiple switching does not imply safety,” Dr Moore wrote in his Perspective.

“Ongoing education of prescribers, pharmacists and patients is required, and the minimisation of unnecessary switches until more safety data are available is recommended.”

Dr Moore is also concerned about the absence of any additional pharmacovigilance programs to monitor the outcomes of a-flagging, with only the drug sponsor required to develop a risk management plan and a reliance on voluntary reporting by prescribers of adverse outcomes to the TGA.

“This could be considered equivalent to conducting a clinical trial on the Australian public without the means to accurately capture data such as loss of response, requirement for corticosteroid therapy, or milder adverse reactions that may not result in reporting,” he said.

“However, a consultation process by the government on this with relevant stakeholders is ongoing. Infliximab is only given intravenously, but the next biologic agents to come off patent that will result in biosimilars entering the market will be self-injectable (for example, etanercept and adalimumab for rheumatoid arthritis). The parenteral administration of these agents is far more complex than the taking of an oral agent and requires familiarity and ability to use the delivery devices.”

In the meantime, Dr Moore said clinicians still had some control, but they needed to be vigilant.

“We have a-flagging and it’s here to stay,” he said. “There’s nothing we can do about that but we can tick the brand substitution box.”

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