Market Access: Biosimilars

Expert Profile

Section 1: The Present

1.1. How would you describe the current market access landscape for biosimilars globally?

In the UK and much of the EU, biosimilars have made tremendous strides and advances in market access and are now becoming part of a routine; they are accepted by clinicians and patients. They are a fundamental part of the therapeutic landscape, which is a total change from the way they were sometimes perceived a few years ago.

The key messages about how biosimilars are developed and, in particular, why whilst not being identical, they are essentially similar to the reference branded products with the same safety and efficacy profiles in use. Of course, they offer significant cost savings – in the UK and EU, everything is positive for biosimilars. I have recently assisted a company with its UK launch of a new biosimilar monoclonal antibody. They had also launched the same product in the majority of the countries in the EU and were getting excellent pickup and penetration rates without any issues. The same cannot be said of the US market, however.

1.2. Which geographies have seen the greatest uptake of biosimilars? Why?

Contrasting the situation in the US with that of Europe, we see that the landscape for biosimilars is fundamentally different. In the US, this primarily goes back to original biosimilars legislation, which came into effect in 2010 as part of Obamacare. I think this was a very strange way of doing it. Why bring in biosimilars legislation as part of the main legislation dealing with health insurance reform?

What happened in the US in 2009 was that the legislation was fundamentally designed to handicap and prevent the wide-scale adoption of biosimilars right from the outset. By contrast, it was the complete opposite when the European Commission drafted the relevant EU legislation which came into effect in 2005. The European legislation was designed to encourage the use of biosimilars and to boost the biosimilar industry. The effect of the US legislation was ultimately the opposite of this, largely due to the lobbying of the big pharma players.

There are many examples of why the US legislation hinders biosimilars; primarily, there is the fundamental split saying, “Well, you can be a “biosimilar product” and you can alternatively be an “interchangeable biosimilar product” and there are different approval standards for each category. In the 10 years since the US passed this legislation, no interchangeable biosimilars have been approved.

This split in approval types simply does not exist in Europe. The concept in Europe is that you get approval, or you do not. Although the approval does not say anywhere that the product is “interchangeable”, in practical use once a biosimilar of this type is approved if the physician wishes to use it that way, they can. This is the same approach that is taken in the EU following the approval of generics. The SmPCs of these products do not use the words “interchangeable”, but if the EU regulators are concerned about interchangeability, then the SmPC will include a warning about “non-interchangeability” (if relevant). Otherwise, all products are potentially interchangeable if they contain the same active(s). In the US, this dichotomy of biosimilar approval types has meant that nobody has ever managed to get an interchangeable approval in the US because the criteria are either too high, too unclear, or both. As a result, all US approvals have been in the standard biosimilar category rather than the interchangeable.

There are other problems with US legislation such as the requirement to submit the entirety of your biosimilar dossier to your competitor at the same time as to the FDA. Normally a pharmaceutical dossier is completely confidential between the company and the regulators. This is the case in Europe, for example. Interestingly, in the US this is the case for all classes of products except biosimilars. This makes the legislation anti-biosimilar and results in frequent patent disputes that hold up regulatory approval hinder, ultimately hindering market access of US biosimilars. These issues were written into the US legislation and have never been changed.

Now, I do not think these problems reflect the views of the FDA and its regulators. From what I’ve seen, the FDA has an approach to the science and most of the guidelines that back up the regulation of biosimilars that is very similar to the approach used by the European regulators. The same approach is seen globally across a wide range of legislation; the Canadians, the Swiss, to some extent the Japanese, the WHO, and other international guidelines on biosimilars follow Europe much more closely than the US. The FDA regulators are relatively aligned with the European regulators, but it is the US lawmakers who passed the US law under the influence of the mainstream pharma lobbyists.

Moreover, there are other factors in the US, which sit outside of legislation that has an impact on biosimilars. Firstly, there are differences in INN rules for the naming of compounds. Whereas in Europe biosimilars are allowed to have the same INN as the originator, in the US they are required to have a different INN with a meaningless four-letter suffix code to distinguish them from each other. This is another aspect that hinders market access for biosimilars in the US. Furthermore, often biosimilars may have to contend with additional state-level legislation in the US on pharmaceutical substitution, which can further impact access.

When you take this all into consideration, it is clear that the US environment for biosimilars is much worse than that in Europe.

1.3. Which companies have experienced the biggest challenges as a result of the loss of exclusivity (LOE) and biosimilars?

One thing to say is that some of the biosimilar companies that are on board now and marketing biosimilar products are mainstream, innovative branded pharmaceutical companies. If you were to go back 10 years or so, you would see that they were against this and were lobbying hard against biosimilars.

However, many of these companies have jumped on the biosimilar bandwagon with biosimilar products of their own. I’m thinking along with the likes of Pfizer or Amgen, who I would have numbered in the ranks of the anti-biosimilar camp, but now have their own biosimilar portfolios and they don’t have a problem with operating on both sides of the divide between branded and biosimilar products. The company that has always been the archetypal anti-biosimilar company – and remains so – is Roche. I believe Roche has never had its own biosimilar products and probably never will.

1.4. How successful have these biosimilar market penetration attempts been?

In terms of the measures that companies can offer to counter biosimilar competition, the first thing to say that biosimilar competition takes a while to develop.

If you look at the example of Humira produced by AbbVie and branded as adalimumab in the EU and UK, you will note that there are also 4-6 biosimilar brands from multiple suppliers available. When adalimumab went off-patent, the very first biosimilars were approved in 2017, and first entered the market in 2018.

Now, Humira had global sales of about USD 20 billion before the entrance of biosimilars onto the market. What is interesting, however, is that AbbVie sales in 2019 – after biosimilars had entered the market – were still maintained at around USD 20 billion. Despite not seeing an increase in global sales revenue, which they had previously seen year on year before the advent of biosimilars, they have managed to hold on to that revenue even when being forced to introduce price cuts in some markets where biosimilar competition is more present.

Section 2: The Future

2.1. Which therapeutic areas could benefit most from biosimilars in the future?

Oncology is the primary area. There’s a huge array of biological monoclonals that have revolutionized the treatment of so many diseases and cancers since they were introduced. There are now either biosimilar versions already available, like trastuzumab, or others on the way, such as bevacizumab and many other oncology actives.

The second key area is for anti-inflammatory conditions, such as rheumatoid arthritis and other arthritis-associated conditions, or conditions such as psoriasis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, ankylosing, spondylitis, and other forms of spondylarthritis. These are the main areas, but monoclonals have the potential to be used in so many different therapeutic areas.

You can see this with the biosimilar version of Avastin. There is controversy over the response to the use of Avastin for macular degeneration or as an anticancer. And of course, there’s an existing branded product, Lucentis, which doesn’t have biosimilar competition.

The question you have to ponder is whether to use branded or biosimilar Avastin and whether it works in the same way? If so, we can see biosimilar products being used in important eye diseases. I would, therefore, suggest that apart from antibiotics and antivirals, which tend not to be biological products, nearly every therapeutic area will be impacted by the advent of market access for biosimilars.

2.2. Which geographies are key battlegrounds for biosimilar manufacturing?

I don’t think any geographies currently dominate and I think that nobody should underestimate the complexity, difficulty, and experience required to develop and manufacture biosimilars to the high standards required by regulatory agencies like the EMA or FDA. That is not to say that manufacturers outside the EU and the US can’t do it, but it is certainly not easy or straightforward. Consequently, the traditional US and European centers will remain very influential and remain the primary manufacturing sites.

That being said, there seems little doubt that there is a potential glut of manufacturing capacity for biologics in general and biosimilars across the board. It is quite possible to arrange a contract for the manufacture of your product, even if you don’t have any in-house manufacturing capabilities.

It is important to remember the early days of biosimilars when there was controversy about the potential for monoclonal antibody biosimilars. From the introduction of the European law in 2005 and for nearly a decade after, no biosimilar monoclonals or related products were approved; they all came later in a wave of approvals. The first one is a biosimilar of infliximab, Remicade, which was developed in Korea, by Celltrion Healthcare who is an expert company and did a great job on the development of their biosimilar infliximab.

Although I mentioned there was an approximate decade-long period when there were no biosimilar monoclonals in Europe, in actuality, there were so-called biosimilars for monoclonal antibodies made in places like India, which sold throughout the local market. None of these products ever tried to get approved in Europe or the US because they knew they did not have the quality of data necessary regarding physicochemical characteristics, as well as broader necessary clinical data. In India, the Indian equivalent of the FDA approved a version of rituximab, many years before there were any similar products on Western markets, because, at that time, there was a mismatch in the standards required by European and US regulators to approve a true biosimilar product. This was also happening in some Southeast Asian countries where you could get approval more easily than you could in Europe or the US. In summary, some products were called “biosimilars” in those local markets, but they weren’t very similar to the originators; rather, they were just copy products that vaguely approximated the originator but could not be assured in terms of their quality and performance. I think this can pose questions about using certain manufacturing sites. That being said, if you consider someone like Celltrion in Korea as an example, there is absolutely no reason why manufacturing sites outside of Europe and the US cannot match and the required standards present in Europe or the US.

2.3. How are pharma companies looking to facilitate greater market access to biosimilars in emerging healthcare markets?

Most of my work has been focused on the EU and the US, but I think that emerging markets do represent an opportunity. The prices depend on local competition, and I think that if biosimilar companies see an opportunity to bring their product into a specific local market, perhaps by dual branding to avoid risks of parallel imports or re-exports, I think that they would look to do so.

2.4. What strategies and initiatives could originator pharma companies adopt to combat the threat of biosimilars? And what will work?

The example of Humira gives us a good case of the sort of things that companies can do to try and protect against biosimilar competition. One thing that AbbVie did was they reformulated their original biosimilar to change it so that all the biosimilars were biosimilar to the original formulation that they had had on the market up till then. AbbVie changed the formulation of both qualitatively and quantitatively. The concentration of activity in the product was doubled, which allowed the option of injecting a smaller volume. This had the potential for less pain and discomfort from the injection and increased patient convenience. They also changed the formulation in terms of its composition, switching it from a citrate buffer formulation to an acetate buffer formulation.

Once this switch had been carried out, they started putting out a story, without any definitive scientific data to support it, that citrate in the biosimilar formulations was responsible for increasing injection site pain. This was the same citrate that had been in their product from 2003 until the reformulation of Humira in about 2017. This was then presented as a reason not to switch from Humira to citrate containing biosimilars. They also reformulated to a new syringe and put a new needle on it. This highlights the importance of the device presentation and the packaging that these products are presented in.

As well as competing on price, these companies will compete in terms of ease of use and even the overall appearance. They will also compete on factors such as shelf life or storage life. For example, I think the reformulated AbbVie product may have a long out of fridge shelf life. The biosimilar manufacturers had targeted an equivalent shelf life to the older version of Humira and shown with data that their product was stable with a two-week shelf life. The new AbbVie product had a four-week shelf life out of the fridge. This allowed them to say, “If you’re going on holiday, camping, or anywhere really where you will not have access to a fridge, with our reformulated product, you can go on a longer trip and you’ve got less hassle with our product rather than with the competing products.”

There is also a whole area of added services that can be bundled in with the sales contract for these sorts of products, with which biosimilar companies need to compete. These include nursing care, home visits to teach the patients how to inject, sometimes associated lab tests, or pharmacokinetic level tests. There may be an added cost for these if they are necessary, which, in some markets, the patient would need to cover themselves. In other markets, these additional costs may be covered by the healthcare services, who are themselves responsible for the contract for the purchase. Therefore, the originator companies can compete by bundling in and saying, “We’ll give you these for free if you buy it from us instead of going to the biosimilar companies.” Of course, the biosimilar companies can then come up with the same sort of deals, packages, and services. This is the nature of a competitive marketplace.

2.5. Which geographies will represent the greatest opportunities for biosimilars?

In the US, we are seeing a greater appreciation for the importance and utility of biosimilars and the advantages, not just to patients and physicians, but also to payers for bringing in these products. I believe that market penetration will continue to grow, albeit at a slower rate than we have seen in Europe. This is because people will say, “Well, you know what? We don’t need to wait for these hypothetical biosimilars that are supposedly interchangeable. We can use the ordinary biosimilars that have been approved so far in an interchangeable fashion.” That’s exactly what payers are approving, and physicians are doing in the US.

It’s always important to remember that the US pharma market is fundamentally different from every other market globally. I don’t know of any other market where there are such easy and accepted incentives for doctors to prescribe the costliest treatment to gain a financial advantage from their patients. This is something that is rarely spoken about but does happen in the US. I’ve witnessed it with some products – not biosimilar products – that have been used at outrageously high prices in the US, which would simply have never been used in Europe. The only reason I can see for these products being used even in niche markets in the US is that they can ensure a financial incentive for physicians to prescribe a more high-priced treatment that has no advantages over equivalent cheaper ones.

This is something that is, as far as I can tell, not illegal in the US but a legitimate part of the American system that doctors can claim a percentage of the cost of the treatment they’ve prescribed. Thus, US physicians may be incentivized to prescribe a more expensive treatment, even where it doesn’t work so well. Such an environment is negative for biosimilars.

2.6. What could be the impact of COVID-19 on biosimilars?

It’s hard to see COVID-19 having any kind of positive impact on biosimilars. Biosimilars are of greatest importance in treating cancers and autoimmune inflammatory conditions. The COVID-19 pandemic has been a tremendous distraction to the provision of normal healthcare. In the UK, and probably also across all of Europe, the result has been that doctors, pharma companies, and hospitals, have not been able to focus on anything other than the current pandemic. I think that we are going to get a backlash, and we may see statistics for measures, such as cancer diagnosis and death rates, have increased significantly in the aftermath of the COVID-19 period all because doctors and healthcare systems have taken their eye off everything except COVID-19. It’s not been positive, and I think that the best thing from the perspective of biosimilars would be to hope that we move back towards normal functioning and normal patterns of use in healthcare in developed countries as soon as possible.