After years of debate, the FDA is poised to approve its first biosimilar. What comes next?

Most people associate passage of the US Patient Protection and Affordable Care Act (otherwise known as Obamacare) with extending health benefits to the under- and uninsured. But the legislation, signed into law in 2010, also includes the Biologics Price Competition and Innovation (BPCI) Act, which created an abbreviated licensure pathway for biological products demonstrated to be “biosimilar” to or “interchangeable” with a biological product licensed by the Food and Drug Administration (FDA).

Could we finally be seeing our first test case after five years? In a unanimous ruling issued last month, an FDA advisory panel found no “clinically meaningful differences” between an experimental compound made by generics leader Sandoz and Amgen’s immune-boosting drug filgrastim. The FDA, which rarely rejects a panel’s recommendations, is expected to issue a final ruling soon, paving the way for cheaper versions of complex, high-priced, follow-on biological drugs.

How this reshapes the world’s largest biologics market remains an open question. Analysts differ on the long-term growth potential of biosimilars. Europe issued draft framework guidelines in 2005, and authorized the sale of biosimilars the following year. There are now 20 biosimilar products available in Europe, with more on the way. Earlier this month, the European Medicines Agency (EMA) said it would review a biosimilar candidate for the rheumatoid arthritis drug Enbrel® (etanercept).

Here in the US, the trade magazine Chemistry World recently reported that, as of October, the FDA had received nearly 80 requests from companies for initial meetings to discuss biosimilar development programs for 14 different reference products, and had received 28 Investigational New Drug Applications (INDs) for biosimilar development programs.

Analysts estimate the advent of biologics could produce anywhere from US$44 billion to US$250 billion in US health-care savings over the next decade. This wide range in estimates goes to the heart of just how many unknowns are circling this nascent industry. There are a lot of different factors that are impacting whether the biosimilar industry will be successful, and what constitutes success.

The BPCI Act contains two different layers of approval: biosimilarity and interchangeability. It grants 12 years of data exclusivity to the branded biologic before approval of the biosimilar, which the biotech industry pushed for strenuously, and exclusive rights of 12-14 months to the first biosimilar of a branded biologic found to be interchangeable.

But there are still significant questions to be sorted out regarding the development, licensing and regulation of biosimilars. The FDA is the only regulatory agency that makes a distinction between biosimilarity and interchangeability and the lack of specific guidance from the FDA has, in the opinion of many, slowed the development and approval process.

Eureka asked two of our resident experts on biosimilars, Christina Satterwhite, Director of Lab Sciences at the Preclinical Services site in Reno, Nevada and Niall Dinwoodie, Global Coordinator for Analytical Testing within our Biologics Group at Tranent, U.K., to weigh in on the significance of the FDA ruling, and what it means to contract research organizations (CROs). For nearly a decade, Christina has been supporting biosimilar development clients at small virtual biotechnology, mid-tier biotechnology and large pharmaceutical companies. She has worked with many types of biosimilar and biobetters including monoclonal antibodies, antibody drug conjugates, bispecific antibodies, growth factors, enzymes and peptides. Niall has been working with biosimilar characterization, quality control and stability testing programs for a similar period.

The FDA decision on biosimilars has been such a long time in coming that one wonders: How much impact will it have on the biologics market right now?

ND: [THE BPCI Act] allowed the FDA to create an abbreviated licensure pathway for the approval of biosimilars. This recent ruling by the FDA panel validates that. What’s perhaps more interesting is whether the product will also be found to meet the higher standard of interchangeability with the originator product, in other words setting it up to be exactly the same as the originator. I think that’s unlikely. For interchangeability to happen, the FDA will expect the biosimilar to produce the same clinical result as the originator product in any given patient, that the risk of alternating between the biosimilar and the originator product is no greater than keeping the patient on the reference product.

CS: But having interchangeability means the biosimilar can be substituted by the pharmacist for the originator product without the involvement of the health care provider who wrote the initial prescription, which is the case now for generic drugs. If you get interchangeability, sales of biosimilars will be greater and more beneficial to the Sponsor. Another reason the FDA panel’s ruling is really important is that, hopefully, with the approval of this first biosimilar, people who have been in this field for a long time can finally go and look at the reference documents to see what was done for that particular biosimilar program. It’s a complex process taking a biosimilar and comparing it to the originator. It’s a challenge for all companies to obtain enough lots of the originator product, in different regions in the US and Europe, to do the studies. The European Union had the first, and many guidance documents, and has been much more active in allowing a pathway for sponsors to move forward. The FDA took longer and their guidance was not as clear and concise.

ND: Christina is right. There are a lot of regulatory documents out there but they don’t go into any fine detail in terms of how to design these studies. What we have now, though, is a package [of documents] that people will be able to look at that shows what this particular Sponsor did in order to prove biosimilarity. And unlike Europe, the US Freedom of Information Act provides an avenue to obtain the documents.

Why do you think the FDA is unlikely to grant interchangeability, and why have the agency, and the industry, taken so long to move on biosimilars in the US?

ND: Caution. Even in Europe, where biosimilars are on the market, each nation or state is allowed to make a decision on interchangeability. The FDA has been very cautious because even minor changes in the production process can have a significant impact on the efficacy and safety of the end product. This happened when a change in the formulation of the anemia drug epoetin-α after it was marketed outside the United States caused pure red cell aplasia. And this change was made by the originator. So I think the FDA has concluded that if one manufacturer can’t control their own product, what are the chances a biosimilar can do the same thing? The other reason why the biosimilar market has moved so slowly in the US is lobbying by the originator companies, though many originators are now developing their own biosimilars businesses.

CS: Plus, the litigation associated with any of these compounds is going to impede approval processes. Companies are also facing obstacles on how to first determine biosimilarity and how to design trials so you are really looking at comparability. It’s a complex process as each program is defined on a case-by-case basis based on the total evidence.

Why are biosimilars so difficult to create and to evaluate?

ND: It’s simply the complexity of the molecule. With traditional small molecule drugs, and the generics that follow, the chemicals are straightforward, and you can synthesize the same molecule and be confident in the results. You have lots of tools to demonstrate that this is the case. With biologics, the work increases by orders of magnitude. It’s not just the chemical makeup of the drug that you are concerned with, but the structural influences and the fact that the drugs aren’t being made in a factory, they are being made in cells. So how do you show the new version is the same as the previous? That is where the issue lies.

How do CROs, such as Charles River, fit into the biosimilar picture?

ND: Many biosimilar companies have an in-depth knowledge of the product they are developing but where there are gaps in their knowledge, for example with study design or regulatory expectations, CROs can help. This is especially true of CROs that have wide experience of the development of biological products, such as Charles River.

CS: At Charles River, different parts of our labs can do all the different required testing with the exception of the actual clinical trial. So we work on scientific teams to optimize the different assays so they can easily be used throughout the biosimilar development program. We have done a lot of work helping clients develop one immunogenicity assay to evaluate the originator and biosimilar molecules. We will develop, validate and do sample analysis, if required, for a particular program.

What’s the long-term forecast for biosimilars, both here and abroad?

ND: There is quite a lot in the pipeline. The question is what will happen in two to three years time, when more sales data becomes available. What we are seeing is that a lot of companies are developing the same product. In Europe, for instance, there are four different biosimilars for the cancer drug Avastin that are all competing against each other. They estimate that they will come in 20% to 30% cheaper than the originator but if the biosimilar market is then fragmented, lower sales may not support this pricing. It is not like a generic small-molecule drug. There are less cost-savings because you still have production costs—which are high—and on top of that the whole application process for a biosimilar can be hundreds of millions of dollars.