Biosimilars: From Concept to Reality

A BIOSIMILAR IS defined as a medicine similar to another, already-authorized biologic medicine (including vaccines, blood components, allergenics, somatic cells, gene therapies, tissues and recombinant therapeutic proteins). Biologics are different from conventional medications that are generally made from chemicals or are chemically synthesized. And, because biologics come from living organisms, they are variable in nature and their structures are generally more complex and not as easy to define and characterize. This complexity explains why developing biologics is a far more difficult process than manufacturing conventional drugs.

The United States market for biosimilars, sometimes dubbed “copycat” biologics, has been expanding at a rapid pace in recent years. In 2017 alone, the European Medicines Agency (EMA) approved 16 biosimilars for seven different originator products, and at least five of those — AbbVie’s Humira (adalimumab), Genentech’s Herceptin (trastuzumab), Biogen/Genentech’s Rituxan (rituximab) and Eli Lilly’s Humalog (insulin lispro) and Forteo (teriparatide) — previously had no biosimilars approval in Europe.¹ In a market long led by European innovation, the accomplishment was a significant one.

One of the catalysts for growth was attributed to the U.S. Food and Drug Administration’s (FDA) withdrawal of its draft guidance on statistical methods used to evaluate the analytical similarity between branded drugs and biosimilars. The guidance, titled “Statistical Approaches to Evaluate Analytical Similarity,” was initially issued in September 2017 and was intended to provide advice for biosimilar developers. 2 FDA withdrew its guidance following public input that expressed some concerns. One of the filers was Sarfaraz K. Niazi, an adjunct professor specializing in biosimilar development at the University of Illinois and the founder of Pharmaceutical Scientist Inc., a consulting company. In his petition, Niazi recommended FDA waive bridging studies for qualified non-U.S. comparators and encourage payers to reimburse only for biosimilars when prescribed for new patients.²

Regarding the decision, FDA Commissioner Scott Gottlieb noted, “One of the central aspects of biosimilar development and approval is the analytical studies performed to demonstrate that a biosimilar is highly similar to the reference product. We’re taking a fresh look at our draft recommendations for evaluating analytical studies in order to ensure our guidance takes into consideration the most current and relevant science. … I believe that the FDA can do more to support the development of biosimilars, as well as promote the market acceptance of these products. As the cost to develop a single biosimilar product can reach hundreds of millions of dollars, it’s important that we advance policies that help make the development of biosimilar products more efficient, and patient and provider acceptance more certain.”³

Lessons from the European Landscape

While notable advances in biosimilars are a recent development in the U.S., the products have been widely available in Europe for more than a decade. In 2003, the European Union created a legal pathway to the creation, approval and marketability of biosimilars. EMA, the European equivalent of FDA, was charged with the approval of biosimilars for use in European nations, while approval within specific countries could only be determined at the national level in each country. Following that decision, Omnitrope was the first biosimilar to be approved by EMA, and 19 additional biosimilars earned subsequent EMA approval. 4 Today, the European biosimilars market is the most mature in the world and continues to gather momentum. Overall, there are now more than 40 European Commission-approved biosimilar products across 15 different biologic classes (as of March 31, 2018).⁴

The advancement of biosimilars in the EU does not suggest the approval process is anything less than rigorous. Gaining approval for biosimilars under EMA guidelines requires a demonstration of how two products maintain a similar nature, and comparability studies are required for each biosimilar. To conduct this demonstration, at least eight key points must be addressed by both manufacturers and researchers:

1) The standard generic approach to defining a chemically derived medicine is not applicable to the production’s means and capacity of biosimilars.

2) Demonstration must evaluate whether any significant changes are made within the manufacturing process.

3) Biosimilars must be similar in molecular structure and biological functionality.

4) The potency of the biosimilar and route of administration must remain the same as the originating biologic.

5) Deviations from the referenced product require justification and examination of how such deviations affect treatment with the biosimilar.

6) Biosimilars must be highly purified to remove any possible contaminated data from collection.

7) If any intended changes exist for the purpose of providing an added benefit and advantage to the patient, they are allowed. However, they must adhere to all other guidelines for biosimilars.

8) If a biosimilar is shown to be effective and safe in one setting, the data may be applied to other settings.

It is important to note that although biosimilars must undergo a two-stage approval process at the central level by EMA and the national level for each country, many healthcare entities have continued to express concern over issues like efficacy and patient safety. Healthcare providers, pharmacies and insurance companies all want to ensure postmarketing of a biosimilar does not place marketability above patient satisfaction and safety. These types of concerns are mirrored by stakeholders in the U.S.⁴

When it comes to cost, by nature, biosimilar production may be more expensive than traditional drugs. Yet, biosimilar producers in Europe routinely apply discounts to biosimilar production by as much as 45 percent, with some discounts going as high as 69 percent. According to Roche Chief Executive Severin Schwan, who faced biosimilar competition for two of the company’s top cancer drugs from late 2017, competition is impacting discounts. “Analyst expectations now vary widely, with some saying 30 percent and others 60 percent,” he said in an interview. “Personally, I think we will see material price effects because I believe in the power of markets and competition.”⁵ With that in mind, the global market for biosimilars is expected to bring in sales in excess of $25 billion within the next five years.⁴

Obstacles and Opportunities

A number of significant challenges exist for manufacturers of biosimilars in the U.S. For example, FDA has not outlined what is required for a biosimilar to demonstrate interchangeability. Current guidance states an interchangeable product can be expected to produce the same clinical result as the reference. Unfortunately, to date, FDA has not granted a designation of interchangeability to any of the approved biosimilars.

Another challenge is extrapolating indications. For example, the biologic Remicade is approved in Europe for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease, psoriasis and ulcerative colitis. The hope is that any biosimilar to Remicade, once it proves biosimilarity in one indication, would gain approval for all approved indications. According to FDA, this is potentially possible provided there is comparable evidence and adequate clinical and scientific justification. But, without the ability to extrapolate indications for existing biosimilars, development costs will be higher and the target market will be smaller. Analysts argue, however, that secondary indications typically add only 15 percent to 25 percent to sales revenue, making additional extrapolation testing less advantageous. In contrast, manufacturers maintain that not having all the indications could be perceived as a weakness in the final product.⁶

Using acceptable statistical models for equivalence studies and tailoring Phase III clinical studies has also been part of ongoing discussions surrounding biosimilars and their development. Getting investigators to agree on the appropriate evaluation models would allow an increased focus on addressing any remaining uncertainties surrounding efficacy, potentially reducing the size of large Phase III trials and, ultimately, saving time and costs.⁶

The Payer’s Perspective

Without question, payers play a significant role in encouraging the adoption of biosimilars. According to a survey published by Amgen, payers in the U.S. do not expect the biosimilars market to mimic the generics market, and they also do not expect the U.S. biosimilars market to be comparable to the one in Europe.⁷

The survey of 40 different payers found payer perceptions of biosimilars include the following:

• Payers anticipate biosimilars will be a strategy to reduce specialty drug prices and most (88 percent) believe the category represents a compelling business opportunity.
• Eighty percent do not expect biosimilars to emulate the generics market. Instead, payers expect to consider them as lowercost branded options.
• While there are analogues from the European commercial experience, at this time, few U.S. payers are relying on Europe’s experience for U.S. forecasting.

The survey also showed that although U.S. payers are eager for biosimilars to reduce specialty drug prices, Europe’s experience shows the level of savings may vary. European experience suggests the most important conditions for market uptake of biosimilars are driven by factors such as physician perception, patient acceptance, local pricing and reimbursement regulations, and procurement policies and terms. Amgen’s research also indicates the U.S. path may share few characteristics with the global experience to date.⁷

A Learning Curve in the U.S.

Without question, the U.S. is still on a learning curve in the development of biosimilars. Regulators want more evidence regarding the quality of biosimilar products and their clinical impact on patients. On the other hand, investigators hope in the near future prescribers will develop increasing levels of comfort and experience using these newer therapeutic options in the U.S.