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Are biosimilars key to solving NHS access concerns?

Published on 01/10/18 at 12:15pm

In light of continued austerity gripping the NHS, it was uplifting to hear in July that the health service had generated millions in savings by switching to off-brand medications. Biosimilars formed a key part of this strategy, as Matt Fellows discovers.

The issue of drug pricing is an impassioned topic that, by its very nature, is impossible to divorce from issues of accessibility, whether that is concerned with payment through a nationalised health service, an insurer, or out of the patient’s own pocket. As a result, cost-savings are a constant theme in healthcare and rarely fade from ongoing conversations involving the pharmaceutical and life sciences industries, particularly in the case of the UK’s NHS. 

Besieged by cuts and increasingly buckling under the weight of an ageing population, the beloved service is constantly the victim of scrutiny and unrealistic expectations, and as such conversations around operational efficiency and how to trim expenses are never out of earshot.

That’s why it was such good news when, at the end of July this year, the NHS announced that it had made annual savings of £324 million by switching from expensive brand name drugs to their generic and biosimilar equivalents – medicines which it stressed in the same report are “equally safe and effective.”

Dr Jeremy Marlow, Executive Director of Operational Productivity at NHS Improvement, was quoted in the report as saying: “As more people are diagnosed with long term conditions, such as arthritis and cancer, we must ensure the NHS uses its resources as efficiently as possible to treat and care for them.

“By delivering £324 million in savings in a single year from switching to better value but equally effective and safe medicines, the NHS has been able to help more patients manage their conditions.

“There is more still to do, with £200 million of additional savings to be achieved this year. We will also continue to find further opportunities to use medicines more effectively and make every penny of the NHS’s budget count.”

To better understand how these savings have been generated, [Pharmafocus] turned to Celltrion Healthcare, a company with its own biosimilar versions of rheumatoid arthritis drugs infliximab and rituximab – known by their branded names as Janssen’s Remicade and Genentech’s MabThera, respectively – which recently called for the NHS to increase the use of biosimilar medicines in treatment of the condition, and earlier in the disease pathway.

HoUng Kim, Head of Strategy and Operations Division at Celltrion, explained that there are two principle factors to the equation, which together feed into one another.

“The saving that NHS reported is actually caused by the combination of price reduction and high uptake, and the price reduction has influence on the uptake itself,” he explained. “Uptake also in turn provides price flexibility for the company, which can drive additional product price reductions, so it’s kind of a combined effect.”

…and treatment for some

However, while generics and biosimilars may be being lauded in the UK for their cost-cutting potential – and rightfully so – the latter in particular still face significant hurdles before we see levels of adoption reach their deserved heights, especially in the treatment of rheumatoid arthritis.

NICE, the gatekeeper that judges whether an EU-approved therapy ticks all the boxes for use on the NHS in England and Wales, has strict guidelines on the initialisation of treatment with biologics. In the case of rheumatoid arthritis, it has two conditions: first, a patient’s severity of the disease must be above a threshold of 5.1 on the Disease Activity Score (DAS-28), while the second condition is the number of failures of chemical disease-modifying antirheumatic drugs (DMARDs) in a patient before initiating treatment with a biosimilar; the institute itself recommends at least two prior failures.

When the tight budget of the NHS is taken into account, this can lead to some quite divisive and frustrating decisions, particularly when said drugs prove themselves to be clinically effective, as Kim points out:

“The Technical Appraisal 375 noted that [NICE’s guidance] is not solely because of the medical considerations but also because of cost-effectiveness analysis based on the price before the launch of the biosimilar. But considering the medical data, they reported that, even for moderate cases which have much lower DAS-28 scores – from 3.2 to 5.1 – they have a similar clinical outcome compared to the data for severe patients,” he noted. “In the case of in inflammatory bowel disease as well, they limit the access only for severely active patients, but the rheumatoid arthritis patients could have a similar clinical outcome for the moderate cases once they’re treated with biologics.”

Celltrion itself pointed out in September that access to biologics in the UK has fallen behind the rest of Europe, citing recent findings published in the [Annals of Rheumatic Diseases] which gives a number of factors responsible for the discrepancy, including per capita gross domestic product (GDP), affordability of the medicines, and reimbursement policies.

Kim continued: “The reimbursement guidelines vary country by country, and because of the prerequisite conditions to initiate biologic treatment amongst the 36 European countries, around 40% of patients lose the opportunity to get proper treatment. Focusing on rheumatoid arthritis, usually the conditions are disease duration, severity and the number of failures of DMARDS before initiating biologic treatment; because of those stringent conditions, the patient who could achieve a better clinical outcome loses their opportunity.

“The technical appraisal 375 noted that their current decision was based on cost-effectiveness. NICE acknowledges there would be clinical benefit in the moderate cases, but because of their cost-effectiveness calculation, they do not support the use of biologics in these cases.

“According to a paper by Paul Emery of the University of Leeds, if a patient was allowed access to biologics, they would have much better opportunity to reach remission with rapid response and long-term benefit. Similar findings were reported for inflammatory bowel disease as well. Medical knowledge supports the clinical benefit for the patients who are currently not eligible according to NICE’s guidelines, and NICE itself acknowledges that it’s not down to medical reasons but cost-effectiveness. Taking this into account, we believe that the threshold should be lowered to maximise the clinical benefit, and this could be covered by the savings that biologics generate.”

Generics were also a key component of the NHS’ cost-saving strategy; compared to these therapy versions, biologics actually come in as much more resource-intensive to produce in spite of their clear benefits, so this is another area where challenges remain.

Compared to chemical generics, for biosimilars it could be said that there are some limits to the price reduction because of the nature of relatively high production cost, investment in production facilities, clinical trials, pharmacovigilance, supply chain, cold chain – all of these add additional costs compared to the case of chemical generics,” Kim remarked. “So we need to admit that there are some limits, but because the price itself for the biologics is enormously high, some flexibility to reduce cost could lead to massive savings if combined with a high uptake ratio. To maximise these kinds of budget savings, companies need to find the most efficient methods for production, research and development, regulatory affairs, clinical trials, [etcetera].”

The importance of education

According to the guidelines of the EMA or other agencies around the world, in order to have a biosimilar therapy approved for use, like any treatment you must first provide appropriate data. But that’s not the only key element of the equation.

“We have conducted clinical trials with the most sensitive indications, and those had been the basis for the product approval, but that was after providing additional data to help physicians, patients or other stakeholders to comfortably use biosimilars,” Kim said. “Another factor which drives that would be the price. The price has been reduced, and accordingly it is the basis of the new pharmacoeconomic analysis, which triggered the increased uptake in many countries. So it’s not just the price reduction, but the data and communication.”

This is a key point, and Kim expanded on just how important education and communication of the nature and surrounding issues of biosimilars can be to encourage greater uptake, and in turn drive down prices and improve accessibility.

“You can compare our first biosimilar and second biosimilar to provide a kind of insight into the speed of the uptake,” he explained. “In the first case of the monoclonal antibody biosimilar infliximab, University College London reported that it took around 18 months to replace 90% of the originator product, and in the second biosimilar, rituximab, it took only two to three months to completely replace the originator. The difference can be explained because in the first case it was new to them and they needed some time to acquire the additional data that they required before they decided to use it; it also takes some time to reach a consensus between the different stakeholders.

“In the second case, because of our experience with the first one, we defined which type of data or materials need to be delivered to the different stakeholders, so that at the time of launching they became comfortable and have ascertained a certain level of confidence in the product. So there was active communications even before product approval, and the accumulated experience from the previous biosimilar definitely helped to accelerate product uptake.”

Communication breakdown

Speaking of these issues, while communication and education are absolutely crucial in encouraging greater adoption of biosimilars and all the benefits that come with it, as Dr Kim says, not everyone has been playing ball. In August, Pfizer launched a citizen petition with the FDA, leveraging accusations against a number of big-name pharma firms, including Janssen, Amgen and Genentech, for their conduct when communicating issues surrounding the use of biosimilars.

The document read: “The introduction of biosimilars in the US was intended to increase competition by providing additional safe and effective biologic treatment options, thereby reducing healthcare costs. This intent will be thwarted if reference product sponsors provide patients and healthcare professionals with incomplete or misleading information in promotional materials.

“Unfortunately, Pfizer has observed some reference product sponsor-created physician- and patient-directed materials that mischaracterise important elements of the biosimilar criteria and create doubt and confusion about the safety and efficacy of biosimilars.”

The pharma giant requested in the petition that the US regulator “issue guidance to ensure truthful and non-misleading communications by sponsors concerning the safety and effectiveness of biosimilars, including interchangeable biologics, relative to reference product(s).”

According to the Public Health Service Act, a biosimilar is “highly similar to and has no clinically meaningful differences” from the reference product from which it is replicated, but according to Pfizer, this definition has not been heeded by some of its rivals, and the company was not afraid of pointing out some examples.

“The textual summary comparing biosimilars and generics on Genentech’s “Examine Biosimilars” website explains that “FDA requires a biosimilar to be highly similar, but not identical to the [reference product]”, but fails to state that an approved biosimilar must have no clinically meaningful differences from the reference product,” it noted.

But it didn’t stop there. “A recent tweet by Amgen Biosimilars also contravenes the statutory standard that a biosimilar is highly similar to and has no clinically meaningful differences from the reference product: “Biologics or biosimilars? It’s not just apples to apples. While #biosimilars may be highly similar to their #biologic reference products, there’s still a chance that patients may react differently. See what you’re missing without the suffix:

“Janssen’s materials also caution, “you may be asked to switch to a biosimilar that works in a similar way to Remicade.” The BPCIA explicitly states that a biosimilar is highly similar to the reference product but has the same mechanism of action, meaning that a biosimilar works in the same way as the reference product. Janssen’s materials confuse this distinction by stating that infliximab biosimilars work in a “similar” way to Remicade.

“Misleading statements like these, and the net impression conveyed by such materials,” Pfizer said, “create undue confusion […] and cast doubt on the safety and efficacy of biosimilars generally, contrary to the basic intent of the biosimilar regulatory framework and FDA’s efforts, as highlighted by Commissioner Gottlieb, to correct such misconceptions. Guidance that advises on how to properly characterise the relationship between reference products and biosimilars, including interchangeable biologics, is essential to addressing this problem.”

These are weighty accusations, but of course it is in the interests of a major industry player to discredit its contemporaries in the interest of driving uptake of its own products. But what has been Celltrion’s experience in this regard? As it turns out, Kim notes, it’s had similar experiences, so it’s not a rare occurrence in the industry.

“Regarding those kind of scare tactics, when we launched the Infliximab biosimilar we were told that we only had anti-drug antibody data with the rheumatoid arthritis population which need to use methotrexate, and methotrexate is known to reduce the incidence of anti-drug antibodies,” he remarked. “So it was claimed that our data was not sufficient considering the risk factors related with anti-drug antibodies throughout the indications, but the fact is that we conducted the anti-drug antibody test with monotherapy in the ankylosing spondylitis population, so these distortions or claims not based on fact cause some concerns among patients and physicians.

“Another approach is the misleading labelling of reverse-switched cases as non-responders. Originator users could switch to biosimilars and then for some reason they could reverse-switch to the originator again, and they are then considered as non-responders when they calculate retention rates, which leads to worse rates being reported in the switched group. But the fact is that they consistently use infliximab and they enjoy the clinical benefit throughout treatment; in other words, they are not non-responders but this distorted approach is intentionally applied to exaggerate the difference between the maintenance group and the switched group in terms of retention rates.

“These kinds of attempts actually happen, so Pfizer’s claims do have some grounds.”  

Widening the lens

As previously mentioned, biosimilar uptake in the UK is failing to live up to the expectations set by the rest of Europe, but this is also true in the US. Pfizer argues that this is the direct result of such attempts to beguile and mislead on key issues of the topic, as noted in its petition:

“Biosimilars are a key component of the current and future treatment of patients in the US, but the uptake of biosimilars has lagged expectations. This is due, in significant part, to the false or misleading statements reference product sponsors are making with respect to the safety and effectiveness of biosimilars, including interchangeable biologics, relative to the reference product(s).” 

It’s clearly a troubling issue, particularly when taking into consideration the patients who would be denied access and better outcomes as a result of what Pfizer portrays as underhanded marketing tactics. As such, the US firm called on the US regulator to take action:

“Issuing guidance on communications about these products would be an important contribution toward eliminating unnecessary barriers to successful market success for biosimilars, including, in the future, interchangeable biologics. Additionally, such guidance is critical to ensuring a fair and level playing field for competition in the interests of patients and our healthcare system. Truthful and non-misleading communications about the safety and efficacy of biosimilars are important to increasing uptake of biosimilars, and securing patient and healthcare provider acceptance.”

The US is clearly a very different beast compared to its neighbours across the Atlantic, but it is interesting to note how the challenges it faces are not too dissimilar to those seen in Europe and in the UK in particular. But, according to Kim, the wheels are in motion and things are looking promising with regard to reaching a solution for patients in the near future.

“For the US, it’s a more complicated system which involves a lot of stakeholders like Medicare, Medicaid, private payers, speciality pharmacies, wholesalers, [etcetera], so there are multiple players and consequently the process takes a much longer time than the countries that use a centralised system; the uptake ratio is somewhat slower than places like Europe and especially Nordic countries,” Kim said. “But there are favourable policies driven by the FDA and the Centers for Medicare and Medicaid Services (CMS), encouraging interactive communications to increase the level of biosimilar adoption. With the favourable policies driven by these agencies combined with continued approaches to increase awareness of data relating to biosimilars, we believe that the situation in the US could become similar to those in other countries.”

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