With some of the world's biggest biologics teetering on the edge of the patent cliff, biosimilars are big business. Yet, with the market still in its infancy, it's not as easy as you might think to get these cheap biologics to the patients that need them

2015 was a landmark year for biosimilars, not least with the first biosimilar launch in the US and the 10th anniversary of the EMA's Guideline on similar biological medicinal products. However, the market is still in its infancy and, if the past few years are anything to go by, faces a lot of uncertainty.

"There are many things we simply don't know right now, so we make assumptions and of course correct as we go but, for me, that is part of the fun of working in such a nascent market," says Carol Lynch, global head of biopharmaceuticals at Sandoz, a division of Novartis and the world's second largest producer of biosimilars. "Moving forwards, there will be many things that we collectively as an industry cannot anticipate, but if this was easy and you could predict the way everything will go then half the fun would be gone. The biosimilars market is not for the faint of heart."

If you spend time with biosimilar manufacturers, you get their message pretty quickly – biosimilars are not generics. "With an innovator product, development costs are at least $1 billion – whatever the latest number is – and at the other end, generics cost $5-10 million," says Lynch. "A biosimilar costs around $250 million, much closer to the originator end. Then there's the timelines; with generics it's 3-5 years, with innovator 8-10 years, but we're talking 6-8 years for a biosimilar, so again closer to the innovator end.

"In terms of risk, where generics are low-risk and innovative high, we're somewhere towards the generic end. While you have longer timelines and higher cost, you have more certainty from a clinical and product perspective, although there is extra uncertainty around processes and what's going to be asked of you. If you like to do business with a recipe book and a well-trodden path then this is not the place for you. With biosimilars you are making that path every time."

Biological patent cliff
Any discussion of biosimilars always involves some very big numbers indeed. "In the last 20 years, we have seen an unprecedented wave of innovation with more than 700 new medicinal products brought to market, not including reformulation or line extensions – that's 700 new molecular entities," says Donal Cumiskey, senior consultant at IMS Health. "By 2020, we estimate another 125 medicines will make their way to the market; a very full pipeline of innovative technologies such as stem cell therapies, gene therapies, gene editing, gene silencing, as well as small molecules and the new wave of oncologics.

"But, as everyone knows, innovation comes with a price tag, and we estimate that the global drugs bill by 2020 will top $1.4 trillion. The question everyone is grappling with is how to make this sustainable, with many people looking to biosimilars," he says. "The global biologics market is expected to exceed $390 billion by 2020 but many of the top ten best-selling drugs are nearing loss of exclusivity. By 2020, biosimilars are predicted to account for 28 percent of the total market. In fact, the use of biosimilars in the five major EU markets and the US alone could see cumulative savings to health systems of $50 billion over the next five years, even reaching $100 billion."

Dr Paul Cornes, consultant oncologist and member of the European School of Oncology's Task Force on Innovation in Cancer, is in no doubt of the value of cheaper biologics. "We are on the threshold of something great and the 100 or so new drugs arriving by 2020 will transform cancer care. Cancer may be 200 or more different diseases, but we have recently discovered that all the complexity can be explained by the deregulation of just a few key pathways. We can bring cancer back under control and, as we've already seen at ASCO this year, when you target people with gene-directed therapy you improve response six-fold.

"However, just at the time when these breakthrough drugs will transform cancer, the money isn't there. After all, the drug only works if we can afford to give it. Cost is limiting access to life-saving drugs right now; people die every day because they can't get the drugs they need, so if we can halve their price and double use, it would solve a serious problem," says Cornes. "I simply cannot see the transformation of the world of cancer, let alone rheumatology and other disease, without the use of biosimilars."

Widening access to life-saving medicines is a key driver for many companies, including Biogen, one of a handful of companies with both originator and biosimilar products. "[We] determined several years ago that biosimilars would be important to help expand access to biologic therapies so that even more patients would be able to benefit from the treatments they need. Real challenges in treatment access exist in many countries across Europe due to health budget constraints. Increasing the availability of high-quality, lower-cost biosimilars can deliver meaningful and sustained cost savings. In the long term, we believe biosimilars can help reduce the burden on healthcare systems which can in turn help support future innovation," says Alpna Seth. head of biosimilars at Biogen.

Education, education, education
While many see biosimilars as the saviours of healthcare, cutting costs and increasing access, actually getting the drugs to the patient is not always easy.

"One of the limitations that could slow the realisation of this benefit is establishing the proper understanding on the clinician side," says Dr Maroud Farouk, global head of medical affairs for biosimilars at Biogen. "It takes time to educate clinicians that our biosimilars are highly similar copies of originator biologics with some minor differences within an acceptable scope."

It can take two to three years to convince physicians of the concept of biosimilarity, he says. "We are starting to see now that, as we do more educational activities, clinicians are realising that biosimilars should be treated completely differently to generics. However, we also know they want to see additional evidence on key questions, especially where physicians are saying that they see the value of biosimilars with naïve patients but have concerns about switching or transitioning stable patients from a reference biologic to a biosimilar. Clinicians want to see real-life data."

However, real-life market data paints another picture, says Sandoz's Lynch. "In Europe, we have seen with the biosimilar monoclonal antibodies, with infliximab and Benepali, that market penetration has been much steeper than anticipated. Uptake is not uniform – there are pockets of rapid penetration and areas where uptake it is slower – but we are seeing a changing pattern in terms of physician acceptance.

"Prior to the launch of infliximab, we heard loud and clear from many physicians, especially gastroenterologists, that they would not prescribe our biosimilar because they didn't see data in their indication. Yet if you look at the post-launch data, they are using them as much as the rheumatologists, so what you see in market research prior to launch doesn't always pan out when a product is introduced. These are really positive signals from a European perspective," she says.

While this level of acceptance may be understandable in the European market, Lynch reports a similar situation in the US, where Sandoz's Zarxio made history last year as the first approved biosimilar. "We anticipated we would have to go on a journey with the physicians, educating them about the concept of biosimilarity, but the reality was that very quickly after launch the conversation with physicians moved on to how they could get the product for their patients."

For biosimilar pioneer Celltrion, physician acceptance comes down to sharing data. The company quoted a survey of ECCO (European Crohn's and Colitis Organisation) members that showed the percentage of respondents that felt little or no confidence in biosimilar monoclonal antibodies dropping from 61 percent in 2013 to 19.5 percent in 2015.

"As physician experience with the biosimilar infliximab has grown, so has confidence in monoclonal antibody biosimilars," Celltrion Healthcare told PharmaTimes. "We're delighted to see a corresponding growth in physician confidence and in willingness to switch to a biosimilar. However, this confidence has been built through the data accumulated for Remsima and the developers of other biosimilars will need to develop their own data package to support physician confidence in, and switching of, their treatments."

The 2015 study also showed that 71.8 percent believed biosimilars to be interchangeable or can be switched with the reference product, up from 27.8 percent in 2013.

What about patients?
Patients have to be part of the process, says IMS' Cumiskey. "Physicians and patients have got lost in the debate recently, yet as more products come to the market we are hearing about patients and physicians not being comfortable with biosimilars. Patients need to be involved more; they can't be taken out of the decision process because ultimately they are the end user of the product."

To help patients accept these drugs, companies such as Sandoz are offering a range of support services. "With an innovative product, if you think about patient involvement, you want them to have the information they need to understand the product and it's no different in some ways with biosimilars," says Lynch. "We have to make sure they have high-quality information so they know what they are taking and what they can expect from the product."

Companies may also offer patient support services, she says. "Patients may be offered a helpline manned by nurses who talk to them about treatment or who could even come to their homes to help with their injections. This approach to patient support services is very similar to the branded side, but what you might call 'branded-lite'."

This slimline approach means doing away with the "bells and whistles" offered by innovative products.
"We seek to really understand the aspects of support and care that are truly valuable to our patients, things that they would be really upset about if you took them away. That way, we can say the patient is not disadvantaged in any way when taking a biosimilar."

A competitive and sustainable market?
While physician education is clearly an essential part of the mix, it is payers that are at the frontline of the biosimilars battle. "Biosimilars offer huge benefit in terms of cost savings but the industry needs to understand that budget holders are under immense pressure," says Cumiskey. "It is really tempting as a budget holder to simply enforce price cuts to save money. It's easy to say you want a 20 percent discount or set the price of a biosimilar at 20 percent lower than the original."

Yet, payers who want to reap long-term benefits should resist the urge, he says. "Some payers might think they can manage biosimilars like generics, but there are multiple examples where imposing a fixed discount between the originator and a generic stifled competition. That's what they did in Canada and now they have some of the highest generic prices in the world."

Everyone must work together to create a sustainable market, says Lynch. "All stakeholders need to understand the investment that companies have made to bring biosimilars to market. It cannot be a generic-like market, with 90 percent discounts on day one; we need to strike a balance between competition and sustainability, and many payer systems struggle with this."

Cost is not the only important factor, says Lynch. "If payers drive the market too hard they will have fewer new biosimilars and so will shoot themselves in the foot. In Germany, for example, they have seen the need to invest in educating physicians and have given them quotas, so it is a balanced approach, while in Norway, the price discount has actually reduced over time."

While agreeing that balance is essential, Cornes cautions against asking payers to wait. "I have huge sympathy for payers; on the one hand, they have the clear and present danger of people dying from lack of access to biologics and, on the other, they're told to wait a couple of years while companies educate physicians. As a payer, I know that even after 30 years of bioequivalent generics KOL doctors like me – white, male, grey haired – are still against them. If I were a payer, why would I wait 30 years? Every success story for generics has come with a stick not a carrot."

While companies will continue to push for a competitive, sustainable market for biosimilars, the reality is that healthcare costs and politics may scupper their plans. Perhaps the most interesting conversation I heard while researching this article was one that took place during a visit to Sandoz's manufacturing plant in Austria. During a break, an eager member of the communications team asked a German payer: "What can we do to impress you? What do you want from a biosimilars company?" His answer was simple – nothing. "If we want a nurse service, we will use our own nurses, paid for by the savings from biosimilars," he said. "What we want are low prices."