Opinion

Tricky Road Ahead For Safe Approval of Biosimilars

On February 9th, the FDA’s Arthritis Advisory Committee will discuss biologics license application (BLA) 125544, for CT-P13, a proposed biosimilar to Janssen Biotech Inc.’s REMICADE (infliximab), submitted by Celltrion, Inc.

If the committee gives a thumbs up and the agency approves the product, this will be the second biosimilar approved in the U.S., but the very first monoclonal antibody, a much more complex molecule than filgrastim.

Apart from the product issues, there are many important policy issues that should be discussed. For example: Labeling, naming, coding, substitution, non-medical switching and interchangeability are all-important policy issues that FDA has the authority to impact, and are appropriate to raise at a high level advisory committee.

While extrapolation was allowed for filgrastim, the questions of extrapolation for this product are not as simple or straightforward.

Filgrastim is generally not used as a long-term product for a life-long, chronic disease like infliximab, and is much less complex than infliximab, which is nearly eight times larger.  Monoclonal antibodies are used in patients with moderate to severe diseases like Crohn’s, or ulcerative colitis and disease stability is critical.  With biosimilar entry, the risk of switching the patient to a new, similar product must be carefully considered, due to the complexity of the product and disease state.

Because biosimilars are not identical copies of their reference products – even slight differences in structure can affect the biosimilar’s mechanism of action.  Without clinical data in each therapeutic area, it may be challenging to understand the impact of these differences on clinical outcomes.

Infliximab is particularly relevant to the overall conversation regarding indication extrapolation because structural differences have been identified which are thought to be potentially related to the treatment of inflammatory bowel diseases.  The EMA has granted the product full extrapolation including inflammatory bowel diseases, while Health Canada did not, citing uncertainty regarding the clinical impact of observed structural differences.

Biosimilar sponsors compare the structure and function of their products to the reference product using a range of laboratory (i.e., analytical tests) tests.  Because of the complexity and uncertainty with regard to monoclonal antibodies, we can’t always tell which product attributes (or parts of the structure) will be relevant to ultimate clinical outcome and which won’t be.

This is why it’s critical that FDA take a conservative approach and ensure that the biosimilar and reference product are as highly similar as possible, across a wide variety of structural and functional attributes.

An American College of Rheumatology abstract of infliximab biosimilar data shows difference between adverse events in patients with rheumatoid arthritis (RA) and those with Ankylosing Spondylitis (AS) depending on whether or not they were switched with a 22.5% difference in AS patients that were switched:

  • Ankylosing Spondylitis (AS) TEAEs – 48.9% on biosimilar; 71.4% switched from innovator to biosimilar
  • Rheumatoid Arthritis (RA) TEAEs – 53.5% on biosimilar; 53.8% switched from innovator to biosimilar.

Regulatory authorities recognize the importance of robust post-marketing safety monitoring for all drugs including biosimilars.  What make biosimilars different from other drugs however is that unlike generic small molecule medicines where safety can be assumed to be identical as its branded counterpart, a biosimilar is not identical to its reference drug.

Another defining difference with biosimilars is that all biologic medicines may trigger the human immune system to react in undesirable ways such as rendering the medicine ineffective.  Small difference between products may result in different effects on the body’s immune system.

Post-marketing safety monitoring is heavily dependent upon voluntary reporting of adverse events by health care professionals and patients.  Unfortunately, this system does not have the capability to effectively monitor and accurately identify adverse events as a result of triggering the body’s immune system.  It is unclear how regulators can or will implement robust ways to compare the safety of a biosimilar to its reference product once approved.

It may be February in Maryland – but the heat is on the FDA. 

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