New biosimilars are set to flood into the Australian market over the next several years as patents on biologics expire… but significant concerns remain about switching
A steep learning curve is likely for community pharmacists, who to date have had comparatively little involvement in the substitution of biosimilars, as since they began to enter the market in 2010, most biosimilars have been dispensed in the hospital setting.
At this stage, many community pharmacists don’t feel comfortable with their involvement with them.
For instance, the 2017 UTS Pharmacy Barometer, which surveyed 360 community pharmacists from around Australia, found that only 37% of pharmacists surveyed felt comfortable providing information to patients on the use of biosimilars.
And only 29% said they were currently confident in substituting them.
What’s the difference?
A key point is that biosimilars are not simply a generic version of the originator biologic medicine – a major driver behind stakeholder concerns about switching.
In 2015, the Pharmaceutical Benefits Advisory Committee made the decision to consider the marking as equivalent – or “a” flagging – of biosimilars and their reference products.
In August of that year, the PBAC “a” flagged Inflectra (infiiximab), a biosimilar of Janssen’s Remicade, used to treat a number of inflammatory conditions including rheumatoid arthritis and psoriatic arthritis.
The move was welcomed by groups including the Generics and Biosimilar Medicines Association, but other groups expressed concern and the PBAC moves towards “a” flagging sparked a debate about whether it was appropriate for pharmacists to substitute biosimilars for originator drugs.
For example Dr Mona Marabani, then President of the Australian Rheumatology Association, said she was worried that patients could potentially “get a different drug every time they go to the chemist”.
A consultant rheumatologist, Dr Marabani presented to the Australian Pharmacy Professional Conference this month about how rheumatologists and pharmacists can work together to maximise patient outcomes, and what pharmacists need to know about biologics and biosimilars.
“Biologics are complex proteins manufactured in living cells,” she told the AJP.
“As these drugs are now starting to come off patent, copies are being made. Those biosimilar copies are made in different cell systems to the originator and will differ slightly as a result of manufacturing differences including post-translational changes.
“So they are biosimilars and not generics,” she says.
Associate Professor Veysel Kayser from the University of Sydney’s Faculty of Pharmacy, also highlighted the fact that the concept of biosimilars is “completely different” to that of generic medicines, as the latter is a term for small molecules.
“Biologics are generally complex large molecules and they are produced in a living system such as a mammalian cell culture,” he explains.
“One can manufacture a highly ‘similar’ product if they follow the same manufacturing conditions and starting raw material to the originator drug. However, this product will still be a ‘similar’ product rather than ‘identical’ to the originator drug.
“That’s one of the reasons why regulatory agencies require high similarity and no clinical differences between a biosimilar and the originator drug.
“This indicates that intrinsically there might be differences between the two products, even though differences might be small, still these differences may cause significant side effects. One of the main reasons that prevents substitution and interchangeability arises from this point.”
The big switch
Australian regulators are quite broadminded about the concept of “a” flagging, stakeholders say.
“My conversation with TGA scientists indicated that the TGA is quite open minded about biosimilars, albeit each application is dealt one-by-one,” A/Prof Kayser says.
“Also, Australia will be likely to follow the USA and EU trend and there are a lot of biosimilar applications to both FDA and EMA.”
Dr Marabani says that “the PBAC’s default position is to recommend ‘a’-flagging, so we will need to deal with the safety and efficacy concerns around repeated switches and the issues around nomenclature and traceability”.
“All brands will have the same INN (International Non-proprietary Name), so working out which drug is to blame for any adverse effect may be difficult.”
Significant concerns remain about switching in pharmacy.
“However, this may change in the future,” says A/Prof Kayser, though these concerns about switching at the pharmacy level are likely to remain for a long time, he warns.
“Switching or interchangeability are still not possible and not commonly observed, neither by GPs nor pharmacists,” he says.
Most authorities do not recommend switching of biologics and biosimilars without the consent of the prescriber, so pharmacists should contact the prescriber if they are unsure or have any other questions, Dr Marabani advises.
“And be aware that the syringes or auto-injectors will differ between brands and the patient may not know how to use them.”
The Pharmacy Guild’s position is that where a biological medicine has been “a” flagged, “the patient should be informed of the availability of an alternative. Being able to offer an ‘a’ flagged biosimilar medicine to the patient at the pharmacy level is consistent with the Brand Premium policy that has been in place for many years for generic medicines”.
Dr Marabani explained the concerns about switching: “Because biologics are large and complex drugs with a three-dimensional structure, they can be immunogenic,” she says.
“And because the biosimilar is slightly different in configuration and structure, it may provoke an immune response too. There is a potential for repeated switching to result in a heightened immune response with the potential to bring about a loss of response or an adverse event.
“There is an increasing evidence base around transition from originators to biosimilars, for example NOR-switch suggesting this is safe and there is no loss of efficacy. But there is much less evidence around multiple switches.”
The NOR-switch study, published in The Lancet in 2017, aimed to examine switching between originator infliximab to a biosimilar with respect to efficacy, safety and immunogenicity; it found that switching was not inferior according to a prespecified non-inferiority margin of 15%.
“A few studies have addressed multiple switches, for example EGALITY, which looked at three switches between Enbrel and GP2015 (etanercept) in psoriasis,” Dr Marabani says.
“It showed no difference in efficacy or safety.”
But it was a small study with a short duration, she says.
She was one of the authors of Biosimilarity and Interchangeability: Principles and Evidence: A Systematic Review, published in BioDrugs in 2018. This study aimed to conduct a systematic literature review of the outcomes of switching between biologics and their biosimilars, and identify any evidence gaps.
A key finding of the study was that “We believe sufficiently powered and appropriately statistically analysed trials and pharmacovigilance studies, with long-term follow-ups and multiple switching sequences, are still needed to support decision-making around biosimilar interchangeability”.
“In the interim, switching should remain a clinical decision made by the treating physician and the patient based on available evidence and individual patient circumstances”.
“At this stage the ARA is recommending choosing a drug- originator or biosimilar—tick the box—and keep the patient on a single agent,” Dr Marabani says.
“This position may change as the evidence base grows. At present no clinician groups world-wide advocate random repeated switching.”
A fast pace of change
Globally, biosimilar approval had a record-breaking year in 2017, according to the data and analytics provider GlobalData.
It says the United States’ Food and Drug Administration alone approved five new biosimilar products, bringing the number of approved biosimilars in the US from four to nine.
This included two products for oncology use: Mylan and Biocon’s Ogivri, is a biosimilar to Genentech’s Herceptin and Amgen and Allergan’s Mvasi, which is a biosimilar to Genentech’s Avastin.
Meanwhile the European Medicines Agency (EMA) approved eight new biosimilars, including biosimilars of AbbVie’s Humira, Genentech’s Rituxan, Herceptin, Eli Lilly’s Humalog (insulin lispro injection), and Eli Lilly’s Forsteo.
GlobalData says it believes that it is likely that this trend of biosimilar approvals will continue in 2018.
GlobalData also reported in March 2018 that emerging markets, such as Brazil and South Korea, have been involved in a growing number of deals for the development or commercialisation of biosimilars.
Deals such as the partnership between Epirus and Orygen Biotecnologia in 2013, which allowed Epirus to market Orygen Biotecnologia’s infliximab, rituximab, and trastuzumab biosimilars in Brazil, have been instrumental in assisting these biosimilars to gain a foothold in emerging markets, GlobalData says.
Locally, Veysel Kayser told the AJP that he expects the biosimilars market globally and in Australia to grow “exponentially”.
“In addition, new ‘biobetter’ biologics such as antibody-drug-conjugates, bispecifics etc. will likely to appear slowly but steadily.
“I feel that the effect of ‘biosimilars’ is still in the wind and that we are still in the early stages and haven’t felt the real impact yet,” he says.
“I expect lots of products are going to come onto the market, both as biological medicines as new drugs, and also as biosimilars; and in the next few years we will see more and more patents being lost, so there will be opportunities to make biosimilars for those products we cannot make biosimilars for at the moment.”
In 2016, six of the top 10 drugs by cost to the Australian Government were biologic medicines.
As well as existing large pharmaceutical suppliers, the market is also likely to be entered by biotech companies from developing countries such as India and China, A/Prof Kayser says.
Startup-like companies may also enter the market, supported by government policy and other funding arrangements – an area where Australia may not be quite up to date.
“In terms of getting guidelines and so on out there, we were before many other countries; but we’re lacking a bit at the moment from the industrial perspective,” he says.
“We don’t really see biotech companies coming into the market trying to produce biosimilars and other biological products. One reason might be lack of funding. In Europe and the US, they put a lot of money into it.”
He cited US state and federal funding available to stakeholders interested in going into business in the sector, as well as funding from top universities such as the UK’s Oxford, where “they do have support for the researchers if they have some ideas that might make some money”.
“They support their researchers and faculty members to establish a biotech company. These initiatives are a little slow in Australia, and I’m hoping it will change in the near future.
“Because we can’t be lagging behind the rest of the world. It’s the kind of field where if we don’t invest now, heavily, we will lag behind considerably.”
Mona Marabani says that at this stage, community pharmacists have not generally had a significant involvement with switching.
“Biosimilars have had limited uptake so far: about 2% for biosimilar etancercept, which has led the government to introduce a streamlined authority for Brenzys for subsequent continuing scripts,” she says.
“This means that for those patients prescribed Brenzys, no application paperwork has to be submitted to Medicare- just a code like any other streamlined authority script.”
As more biosimilars enter the Australian market, awareness is growing among pharmacists.
“But it is still a very new area,” she says. “Most community pharmacists will be dealing with a relatively small number of biologic scripts per month. There is a definite need for evidence-based education on what the introduction of biosimilars means on a practical basis.”
A/Prof Kayser says that pharmacists need to understand that biosimilars will be coming in at a fast pace, so if they are not already familiar with the concept they should brush up on the subject.
“From an education perspective, we teach our students about biosimilars, and I am sure other pharmacy schools in the country also cover the topic,” he says.
“In addition, organisations such as NPS MedicineWise and AusBiotech (and various other professional societies and associations, e.g. rheumatology) have been instrumental in providing educational resources for those interested parties and hence awareness has grown substantially.
“I think more education/information is needed for doctors and pharmacists. Currently, doctors might suggest a biosimilar but very likely they will play safe and continue with the originator drug if the patient has been on it for a while.
“However, a new patient might be offered biosimilar. Nevertheless, pharmacists cannot do this at this stage and offer a cheaper biosimilar version, similar to that of small molecule generics.”