Introduction
Widespread use of biological medicines has transformed outcomes for many patients with inflammatory conditions such as diabetes, autoimmune diseases, and cancers.[1] These therapies come at a price, however, and as their patents expire, biosimilars are entering the market that are more affordable for healthcare organisations and enable greater patient access to treatment.[1]
Biosimilars should be subject to a robust regulatory framework to gain approval, and show that they demonstrate biosimilarity in terms of structure, biological activity and efficacy, safety, and immunogenicity profile.[1] National regulatory bodies can follow World Health Organization (WHO) recommendations to ensure the quality of biosimilars; while some countries adopt similar practices outlined by the European Medicines Agency (EMA) or the US Food and Drug Administration.[2–4] The aims of this Clinical Forum are to explore the experience of switching patients from biologics to biosimilars in different countries and to provide healthcare professionals with the confidence to help their patients make an informed decision regarding their therapy.
What are the main reasons for switching from a reference biologic to a biosimilar medicine?
Valderílio Azevedo (VA): As a rheumatologist, I have seen biologics revolutionise the management of many chronic inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). The main drawback of biologics is their cost, which can limit patients’ access to much needed treatment. In South America, cost is the main reason to switch patients from a reference product to a biosimilar but switching also enables more patients to access these therapies.
Caron Underhill (CU): I work in a large teaching hospital in the south of England that is a tertiary referral centre for autoimmune diseases and we are a huge user of biologics. As a pharmacist, I have led biosimilar switches for our trust since the first biosimilar for infliximab was introduced. In the UK, most patients get their treatment with biologics and biosimilars on the NHS, which is free to all. There is a huge incentive to implement biosimilar switches because of the overspend on drugs.
When we planned the first biosimilar switch from the infliximab originator to an infliximab biosimilar it was on the agreement that 50% of the savings would be reinvested back into the clinical area that made the savings. For us, the use of biosimilars has been successful and we have saved hundreds of thousands of pounds.
Gülen Hatemi (GH): The reception of biosimilars has been good in Turkey as biologics are a big load on the healthcare system. In the rheumatology department at Istanbul University-Cerrahpasa we have a lot of patients with RA and spondyloarthritis (SpA), as well as with Behçet’s syndrome who are treated with biological agents. We have been using biological agents for our patients for more than 22 years.
Most of the patients who are using biologics for rheumatologic conditions are covered by the state’s healthcare insurance system. The state does not mandate us to prescribe biosimilars. The hospital buys the biological agents, rituximab and infliximab, that are administered as infusions in large quantities, so they choose which therapies to buy.
When biosimilars were first made available, a lot of our patients had to switch from one biosimilar to another, from the originator to a biosimilar, and we were worried initially. But we did not see any increase in adverse events or immunogenicity, or loss of efficacy over time, so doctors and patients have become more confident. Savings made by using biosimilars benefit other parts of the healthcare system. Cost-effectiveness is the main reason for switching.
How does the safety and clinical efficacy of biosimilars compare to biologics?
CU: We cannot be complacent with any new medicine but the biosimilars we use have been trialled in at least one disease so it is assumed that we can extrapolate the data to other disease areas. We have collected the data of our patients on biological therapies for more than 15 years. To support pharmacovigilance, we use an electronic prescribing system, record the batches, and add data to national and international registries. Patients are monitored continuously, whether they are on the originator or the biosimilar and patients can access support at any time after switching – this gives patients reassurance. Our data shows that switching to a biosimilar does not alter disease control, the incidence of side effects, or persistence.
GH: The WHO guidelines are followed in Turkey.[3] Overall, we can say that biosimilars are effective in terms of clinical efficacy, patient-reported outcomes, clinical outcomes, laboratory outcomes, composite measures that are a composite of clinical patient and lab reports, as well as data showing radiological outcomes.[5–8] The effect on joint structural damage is also similar for biosimilars to originator products.[9]
I think some caution is still needed. I do not think that showing biosimilars are structurally, chemically, pharmacokinetically similar to the original product always shows that they would be effective. I would like to see clinical data of phase III trials showing efficacy in at least one indication, in at least RA or showing that I could use it in psoriatic arthritis (PsA) or SpA. Pharmacovigilance data alone is not enough to show that the safety and efficacy of a biosimilar is comparable to the original product.
Rheumatologists in Turkey are comfortable with starting a biosimilar first line but some of them have concerns about switching, especially with the monoclonal antibodies. They are afraid that there may be immunogenicity issues, even though the data have not shown that.[5] I think we need more data for multiple switches. We need evidence for individual products rather than talking about the safety and effectiveness of biosimilars as a class.
VA: There is robust evidence showing that single switches from a reference product to a biosimilar or reverse switches from a biosimilar back to a reference product have been successful.[5] Recently, there have also been a couple of papers covering biosimilar to biosimilar switching.[10,11]
What is the financial impact of switching to a biosimilar?
VA: In Brazil biologics account for approximately 50% of the budget for the public health system each year.[12] Using biosimilars, we would expect to have a 30–40% discount and could then increase access with the same budget for more patients, especially in chronic inflammatory diseases.[13,14]
CU: In the UK, the discounts with biosimilars vary. The NHS generally gets the drugs significantly cheaper than list prices. When the first biosimilars for adalimumab became available, there was huge pressure from NHS England for rapid switching of patients because the reference product, Humira (adalimumab), represented the top drug by spend for NHS hospitals. It was estimated that by doing this, the NHS would save at least £150 million per year.[15]
NICE governs which therapies we can use in the UK. It establishes whether a treatment is cost-effective and a good use of NHS resources. Patient scores are used to determine whether patients are eligible to attain biologics. Since biosimilars have been adopted in the UK and drug costs of these therapies for the NHS have reduced, some of the savings have been reinvested into the services. In addition, access to these medicines has been eased. For example, patients with moderate RA can now be started on a biologic, whereas previously the treatment was only available to those with severe RA.[16,17]
GH: Turkey pays less for biological agents than many other countries. Here the difference between biologics and biosimilars is not that drastic. For biosimilars, there is a reduction of around 10% in price in Turkey.[18] These prices are for buying the medicines from a pharmacy but the prices may be less for the Social Security Institution.
VA: In Brazil we have a regionalised system for the public health system. The government negotiates with the pharmaceutical industry. For example, we have six adalimumab biosimilars and a reference product available – so, seven options for adalimumab. The government buys two or three biosimilars but not for the same region, so the northeast of Brazil will have one biosimilar available and the south of Brazil a different one.
CU: Similarly, in the UK several adalimumab biosimilars are available. In our region, one adalimumab biosimilar was made available first line, in addition to the reference product. However, other biosimilars of adalimumab were available to other regions in England. The aim was to ensure that several biosimilars were kept in the market and that all areas of England switched without delay. Normally negotiation determines which biosimilar is going to be used in the region. In addition to cost, the negotiation takes into account factors such as whether the company can provide a good homecare service, whether the device will be amenable to patients, and the presence of excipients that may irritate or trigger allergies.
GH: Over the years the presence of biosimilars has helped the negotiation capacity of the government with the pharmaceutical industry to lower the prices of biologics and biosimilars overall and that has improved the availability of these drugs in Turkey.
Physicians are free to prescribe the original product or any of the biosimilars available. The only exception is for infusion products because the hospital administration decides which IV infusions will be available in the hospital. Every time they buy a new batch of products and depending on the pricing and their negotiation with companies, which biosimilar or originator product they buy may change. I am not particularly happy with that system but nothing bad has happened so far regarding loss of efficacy or safety.
I am worried that the loss of value of our currency compared to the Euro and US$ means that the prices are becoming too low for some of the pharmaceutical companies and some biological products may be retracted from Turkey. I think having biosimilars means it is guaranteed that we will have these agents even if it is decided that the original products are no longer profitable to sell to Turkey.
Another important issue is that caution is required regarding the quality of the product and the production process. If companies are forced to manufacture biosimilars for a very low price, I would be worried about the quality of the product.
CU: My concern about cost is that the price the NHS pays is significantly lower than the rest of Europe. For some of the biosimilars that are low in price, it means the company has to make cutbacks somewhere such as the homecare services. The company that provides the reference product will deliver the drug to patients’ homes regularly and provide a nursing service to patients. Some biosimilar companies will struggle to match the homecare service.
We have not seen the cost of many originator biological agents coming down significantly in the UK. We still have many biologics that cost in excess of £8,000 a year. We use biosimilars first line when available.
When should a patient be switched to a biosimilar?
VA: To be switched to a biosimilar patients should be stable, which may vary from disease to disease, so it depends on the matrix on the disease activity indexes for different diseases. Patients who are failing on a biologic will continue to fail if they are switched to a biosimilar. Similarly, biosimilars are not the best option for patients who are not stable. In terms of rheumatology, we will generally see whether or not patients will respond to a biologic therapy after 12 weeks. But in gastroenterology a patient with Crohn’s disease may take longer to respond/become stable.
GH: We are trying to adopt treat-to-target strategies in these patients. We see patients every 3 months and try to make sure they are in remission or at least in a low disease activity state. When they come for their prescription and we evaluate their clinical state, if they are not at least in low disease activity or in remission, then we would try and switch to an agent with another mechanism of action. If the patient is not doing well with the original product, there is no reason to expect them to do well with a biosimilar.
We see a lot of serious infections in patients treated with biologics. In Turkey, tuberculosis (TB) is a huge problem and if a patient is experiencing infections with an original biologic agent, there would be no point in switching to the biosimilar of that agent as the patient will continue to have serious infections that may even be fatal. So, when switching to a biosimilar, it is important to make sure that the patient is doing well regarding both efficacy and safety for that agent, otherwise we should switch to something else.
CU: Our patients are seen at 3 months initially then every 6 months. However, patients can access support sooner if needed. If a patient was not doing well on a biological agent then we would switch class, we would not switch to the biosimilar of the current biologic. We would only switch stable patients who are doing well to a biosimilar.
VA: We have to define the best profile. What are the indexes or metrics we would use to be reassured that the patient is stable?
GH: I think stability should be more patient dependent. The Patient Acceptable Symptom State tool has a useful question that asks the patient ‘Think about all the ways your condition has affected you during the last 48 hours. If you were to remain in the next few months as you were during the last 48 hours, would this be acceptable to you?’.[19] Low disease activity for RA and PsA has many components and it does not always follow that the patient is happy with their condition. One patient who does not have low disease activity may be happy with their condition because they need fewer drugs and are ok with that situation. Whereas another patient who works as a pianist, for example, may not be happy with low disease activity of RA because there is still some small remaining activity.
VA: It appears that patients with psoriasis are not happy with their treatment in general.[20] They have some concerns about the relationship with their physicians, they do not talk about everything when they are consulting their assistant physician. So perhaps this condition may impair the patient’s perception of the switching process.
CU: What one patient thinks is acceptable disease control may be completely different to what another patient considers acceptable. Peoples’ perception of their pain is very subjective. One person could have high inflammatory markers, lots of inflammation on ultrasound but say they are managing. While another patient may have low disease activity, low inflammatory markers, and no inflammation on ultrasound but consider their disease to not be as well controlled as it should be.
What are the important points to cover when discussing switching to a biosimilar with a patient?
VA: Information needs to be very clear for patients. Patients have the right to know which product they are being treated with and physicians have the right to know what products are being provided to their patients.[21] In Brazil, we prescribe by the international non-proprietary name (INN) in the public health system but in the private health system we prescribe by brand name.
Some physicians may have doubts about the data for biosimilars or for a specific biosimilar. So, before we start the switching process we talk to physicians and discuss the importance of changing reference products to a biosimilar, and explain the pharmacoeconomic process, the benefits for the system, that these products are equivalent, they have good data, and so on.
We do the same for patients. Not all patients understand the biosimilar concept so we explain in a very simple way what a biosimilar is. If a patient switched to a biosimilar encounters a negative attitude from the pharmacist dispensing the biosimilar or from their physician, this can cause problems. Some patients will follow their physician’s opinion because of a lack of understanding about biosimilars.
CU: In our hospital, when we know a biosimilar is on the horizon, the clinician will discuss the concept of the biosimilar with the patient at their next routine clinical review. This may be up to a year beforehand. The clinician involves the patient in the decision and reaches an agreement with the patient, so this is shared decision making.[21] The patient is also given written information about what a biosimilar is, why we are switching, and what the benefits will be to the service. They are reassured that they will continue to be reviewed and if in the unlikely event there was any change to their disease control or the development of side effects, they would be switched back to the originator. They have ample opportunity before the switch to contact their doctor or pharmacist with any concerns.
Nearer the time of the switch, all patients are sent a letter informing them when the switch is going to happen.
GH: I agree that it is important to communicate this well with the patient beforehand. The worst thing would be if the patient goes to the pharmacy and sees a different drug. It is important that they are told in advance and because these are serious drugs patients must be involved in the shared decision-making process.[21]
How we communicate to the patient depends on the patient’s level of understanding, so it differs from patient to patient. But it is important to emphasise that the benefits that would be gained from switching to this product would be added to the healthcare system, which in turn will be beneficial to them overall. It is important for them to understand that the biosimilar has demonstrated similarity with the originator in terms of efficacy and safety, and that the reduced price will be used in ways that will benefit them.
In Turkey, when we prescribe subcutaneous drugs, patients go with their prescription and get their drug from the pharmacy. There are no interchangeable biosimilars; the pharmacy cannot change to a biosimilar, they will give what is prescribed. At that point if the pharmacist is in any way negative about the prescription, or if the patient sees their GP and hears anything negative from their GP this can have a negative impact on the patient.[22,23]
Some of the subjectivity about the treatment response depends on how much the patient believes their medication is effective or how much they will benefit from it. As well as educating and communicating well with the patient, it is important that we also educate GPs and pharmacists who give the drugs to the patients so that there is not a negative impact on how the patient perceives their biosimilar agent.[11,22,23]
CU: In the UK, the hospital may be allocated the biosimilar that has been agreed for the region. When we did our first biosimilar switch, we spent a lot of time explaining to patients what a biosimilar was, along with the pharmacokinetic and pharmacodynamics data. Afterwards, we asked patient groups for their feedback. They told us that patients did not want the clinical data – they just wanted reassurance from their clinician that the biosimilar would be as effective as their original medicine. As a result, we have simplified the letter we give to patients.
VA: In Brazil, the pharmacist dispenses to the patient what is available on the system. We consider all biosimilars in our jurisdiction to be interchangeable – we do not have an interchangeable regulation like the US. We leave the decision sometimes for the patient and the physician, but in general we do not need an agreement with the physician to start a biosimilar because in terms of our regulation these products are equivalent – they have the same efficacy and safety profile as the drug the patient was using before.
There are some triggers for the nocebo effect: patient perception, negative information they receive from a physician or elsewhere, a lack of knowledge of biosimilars, and a lack of coherence in communication with the patient.[11,22,23] The nocebo effect is induced by any negative expectations or attitudes associated with an intervention, and may increase adverse effects or the perception of worsening of symptoms.[22] We have strategies to decrease the possible nocebo effect when we change patients to a biosimilar by better education and having a well-managed switching process. We are just starting this process in Brazil as we have learnt a lot in the last 5 years.
CU: As we prescribe by brand, everyone in the multidisciplinary team (MDT) knows which medicine the patient will get. We do not substitute. The MDT meets regularly, and we try to ensure that everybody is supportive of biosimilars. If a new biosimilar is being considered it is discussed within the MDT. We do not want patients getting conflicting messages about a medicine. We want everyone in the MDT to be in agreement before implementing a switch. We also have representatives from local and national patient groups who have an opportunity to feed in.
GH: We are able to prescribe any originator or biosimilar so we explain this to patients to make them aware we are able to use all of them. It is important to make sure that the patient agrees with using the biosimilar that we would like to switch to and to explain the reasons and make the patient feel confident to combat the nocebo effect. I think that the nocebo effect is actually an important part of the lack of efficacy of many drugs that we use.
I also think patient support groups are a factor – with the increased use of social media, patients will discuss their brands. It is important that patient groups understand the concept of biosimilars correctly so that there are no misinterpretations that might affect patients who are starting a biosimilar.
Are there any other considerations to bear in mind when switching to a biosimilar?
VA: I think that frequency of switching is an important concept. In Brazil, if a patient switches products annually, we would not consider that to be multiple switching. In some cases, a patient has switched every year to another product, from the reference product, to the first biosimilar, and then the second in 3 years. We have had time to report any adverse events so we do not consider that to be multiple switches. But if a patient switched twice in a year, we would consider that as multiple switches. With a product like rituximab, if a patient developed multifocal leukoencephalopathy, we would not know which product to attribute this adverse event to if we had changed more than once in a year.
I think we have to consider the timing of the switching process because it is important in terms of pharmacovigilance and what might be reasonable in terms of the knowledge we have and in terms of the safety of these products. What do you consider as the definition of multiple switches in your countries?
GH: I would view anything more than a single switch as a multiple switch. And that would be ever, not just per year. We do not have so many biosimilars in Turkey. The only time that I have had to use several products was for infusions because of the hospital policies. Some patients had to switch between three IV products (the original and two biosimilars) in total and in some situations they would switch back to the originator because the price was then lower than the biosimilar. I see that as a multiple switch independent of the timeframe.
In the beginning I was worried, particularly regarding immunogenicity. If a patient with uveitis using adalimumab, for example, has a severe attack it could result in a loss of vision that cannot be recovered. But, over time, I saw that patients were doing well and for infliximab and rituximab the multiple switches did not cause any problems.
CU: We would not switch products annually. Patients are switched from the originator to a biosimilar and we do not generally switch them again. We would not consider biosimilar to biosimilar switching routinely – there would have to be a very good reason to do it. For the amount of work it involves and for the upset to patients there would have to be a huge benefit identified in order for us to entertain a switch from one biosimilar to another.
GH: One more thing, which may be exclusive to Turkey, is that every 3 months when we are re-prescribing biologics, our pulmonologist or infectious medical disease specialist has to see the patient to evaluate for potential TB infection. It is important to indicate that this is not a different drug but a biosimilar, so that the patient is not retested for TB.
Summary
Cost is the main reason to switch patients from a biologic to a biosimilar medicine. The financial impact of switching to a biosimilar has been positive in most countries and has given many more patients access to these therapies. The evidence is reassuring about the safety and clinical efficacy of biosimilars. When considering switching from a reference product to a biosimilar, patients should be stable (not worsening), comfortable with the therapy, and preferentially with inactive or very low disease activity. It is important to minimise the nocebo effect when switching to a biosimilar by having a robust switching management system, with education and clear information for patients and physicians, as well as robust pharmacovigilance. We need more pharmacoeconomic studies with biosimilars to understand more about the introduction of these products into different markets worldwide.
Acknowledgement: Sonia Davies, an independent medical writer, helped draft this article.
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Cite this: Switching Patients to Biosimilars—Why, When, and How - Medscape - Dec 14, 2023.
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