Chapter 3 - The Brave New World of Biosimilars



    The FDA has been debating for many years over whether to approve biosimilars, cheaper versions of expensive and complex biological drugs used to treat a multitude of diseases.  Biological products are large protein molecules generally derived from living organisms and have chemical modifications that are very different depending on what cells are used to make them.  Biosimilar products are biologicals that are approved based on high similarity to the brand reference product, with very little differences in terms of safety, efficacy and clinical impact. 

    In 2010, Congress passed the Biologics Price Competition and Innovation Act (BPCI Act) which created a new pathway for the reference drugs of biologics, biosimilars, to be approved.  This act was intended to pave the way for cheaper biologics rather like the Hatch-Waxman Act established a way for cheaper small molecule generic drugs to be approved once they show the same effectiveness as brand drugs.  This year, the FDA published the first Biosimilars Action Plan detailing the agency’s vision on how to innovate new cheap biosimilars, while keeping the industry competitive in the market.

    A pretty interesting read for those interested in product development in this area:


    In 2015 when I first wrote this blog series, the FDA had just approved its first biosimilar drug Zarxio by Sandoz, a generic biological drug version of Neupogen by Amgen prescribed for leukemia patients.  By that time, the EMEA in Europe had already approved 21 biosimilars.  Today the FDA has approved 12 biosimilars, following a worldwide explosion in this area of the drug industry.  The biosimilars market is now expected to reach $61.47 million by 2025, an increase from the prediction three years ago.  Major biologics like Rituximab and Trastuzumab from Roche (approved in 1997 and 1998 respectively) have now come off patent and multitude of pharma companies are vying to develop the next biosimilar.

    List of approved biosimilars in the US as of today:


    In coordination with the industry, the FDA has written a list of guidance documents for biosimilar manufacturers to adhere to as well an education program to teach all parties about how biosimilars are developed, marketed and prescribed to patients.

    As developed markets see their patents expire in the next few years, there will be a rapid shift in consumer spending toward new generic medicines such as biosimilars.  A 2015 report from the IMS Institute for Healthcare Informatics estimated that up to 2% or $6 billion of global healthcare expenditure will be accounted for by biosimilars (part of the $200 billion global spending on biologics market).  In the US, biosimilars are estimated to impact between $27 and $58 billion by 2021.  

    The following is based on what I wrote about the Zarxio approval in 2015 and about  a Citizen’s Petition from Abbvie for one of the Biosmilar guidance documents demanding clearer labels to differentiate between brand biologics and biosimilars:


    In March 2015, the FDA released news for the approval of Zarxio, a biosimilar produced by Sandoz Inc (the generic arm of Novartis).  It is similar to the reference drug Neupogen (Filgrastim) licenced to Amgen Inc in 1991.  Neupogen has been prescribed to leukemia cancer patients undergoing harsh chemotherapy regimes who suffer from weakened immune systems.  Neupogen is used to boost the immune system of patients by producing recombinant human granulocyte colony stimulating factor to induce neutrophil production.  Sandoz Inc. filed the biosimilar application under the new Biologics Price Competition and Innovation Act (BPCI Act, 2009) and also under the Public Health Service Act’s section 351(k) provision (PHS Act § 351(k)).  The current regulations require biosimilars to show equivalence to a “reference product” without having to go through the full set of preclinical and clinical study necessary for traditional BLAs. 

    According to the FDA’s guidance:

    “A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.”

    Sandoz Inc managed showed that in a clinical trial involving 388 people with breast cancer, 174 people using Zarxio were able to break it down in the body in a similar way to the Neupogen drug without provoking an adverse immune response.  Zarxio is predicted to cost 40-50% less than Neupogen.  The approval of Zarxio opens the door for companies to start applying for more biosimilars in the United States and allows consumers to buy cheaper biologics in the coming future.

    Despite the green light from the FDA, Sandoz will be fighting Amgen over patent laws with regard to its new drug.  US law requires Sandoz to reveal their manufacturing protocols to Amgen in order to ensure licenses for manufacturing methods have not been violated.  Unfortunately Sandoz wants to keep its manufacturing techniques confidential so that they can file their own patents.  Such licensing laws do not exist in Europe hence the approval of biosimilars has been so rapid and convenient in that region.  Furthermore, Advisory Committees and groups like the Generic Pharmaceutical Association (GPhA) have voiced concerns over whether generic names for new biosimilars will be used to replace brand names that originally existed, causing confusion for patients shopping for cheaper drugs in future.

    Another issue has recently come to surface over the biosimilars guidance document.  AbbVie sent a Citizen Petition to the FDA demanding a change to the guidance entitled “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product”.  The guidance removed the requirement in the 351(k) provision for sponsors to show labeling of bioequivalence to a reference product (as described above) and also removed the need to indicate whether it is “interchangeable with the reference product”.  AbbVie challenged this guidance demanding that the FDA require all biosimilars to differentiate themselves from a reference product. 

    Abbvie wants to see new language in the guidance containing:

    - A clear statement that the product is a biosimilar and that the biosimilar is licensed for fewer than the reference product’s conditions of use.

    - A clear statement that FDA has not determined that the biosimilar product is interchangeable with the reference product

    - A concise description of the data that supports license of the biosimilar and a comparison with data from studies of the reference biological product.

    Abbvie contends that biosimilars, unlike generic drugs, are complex products and substitution of established biological drugs could be much riskier, result in very different clinical outcomes and are less interchangeable compared to generic drug substitutions of branded chemical drugs.  They argue that employing a “Same Labeling” approach for biosimilars as for generics in the ANDA requirements is unsound law.  Interestingly, Abbvie alleges that FDA is violating the Administrative Procedure Act (APA) by removing the provision § 351(k) that was originally in the 2012 draft version of the guidance for biosimilar products.  This could premise future litigations.
    Is your company affected by the new regulations for biosimilars?

    Since biosimilars are likely to become an increasingly prominent product in the industry, changes in legislation concerning these products are likely to affect your company.  The murky area of patent rights for licensing biosimilars, rights to naming the products and rights to manufacturing techniques is likely to affect your company’s future decisions.

    For more information, please carefully read FDA’s latest version of Scientific Considerations in Demonstrating Biosimilarity to a Reference Product and Abbvie’s latest Citizen Petition to FDA


    Ledford H, First biosimilar drug set to enter US market. Nature, In Focus News; 517:253-254 (2015).

    IMS Institute for Healthcare Informatics, The Global Use of Medicines Outlook Through 2016 (July 2012)

    FDA Law Blog, Hyman, Phelps and McNamara June 03 2015

    FDA Press Release March 2015

    Patent Docs blog

    List of Biosimilar Guidances

    Biosimilars market today: