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Biosimilars: Not So Similar to FDA Generic Drug Approvals

By Stephen Amato

January 4, 2013 |
Guest Commentary | If you’re a generic drug manufacturer looking to commercialize a generic biologic product, or biosimilar, in the U.S. market, you’re in a tough spot.  As the pharmaceutical and biotechnology industries prepare for a range of key biologics U.S. patents to expire (including Amgen’s Neupogen in 2013, Biogen Idec’s Avonex in 2013 and Genentech’s Herceptin in 2014), the jury is still out on how the FDA will regulate the commercialization of biosimilars.  

While the generic drug regulatory review pathway by the FDA has been well-defined since 1984, and rarely requires clinical trials to show bioequivalence, the process for commercializing generic biologic products is likely to be much more complex.  There are several key reasons for this, many of which are related to the nature of the biologics products themselves.  For example: 

  • Many products defined as biologics by the FDA are large molecules that are megabytes in size, compared with pharmaceutical products which tend to be a thousand-fold smaller. This means that biologic products are often significantly more temperature sensitive and have shorter shelf lives than pharmaceutical products. 
  • Many biologic products are proteins, which are comprised of amino acids that have four disparate and increasingly intricate layers of organization. As a result, biologic products that are identical in one or even two layers of organization can differ substantially in their higher order structures. 
  • Proteins can fold and be modified in myriad different ways, and it is very difficult to show that seemingly generic versions of biologic products are actually identical in terms of their safety and efficacy profiles. 

But it’s important for generics companies to be prepared as the FDA works through the development of its process for biologic generic products approval.  We do know that FDA will use the concepts of high similarity and interchangeability to evaluate whether generic versions of biologic products are truly identical to innovator versions from a clinical standpoint. The FDA issued three biosimilar product commercialization draft guidance documents in February of 2012 (FR Volume 77, Number 31).  Public comments on these documents will likely be published in the early months of 2013, with final versions of the guidance documents released thereafter.  In the meantime, here’s what drug developers need to think about as they enter the world of biosimilars:  

  1. Interact with FDA. While this may seem like a simple step, it’s not often fully leveraged.  Generics manufacturers should open dialog with the FDA by calling reviewers and asking for a meeting, ensuring a smoother process by equipping teams with more information along the way.  
  2. Conduct preclinical safety assessments as required by FDA for innovator biologics. This will put you a step ahead regardless of the regulatory mandates.  
  3. Decide on labeling considerations. For example, what will be the generic biologic product’s specific indication(s) for use?  Are there clinical considerations specific to that class of generic product that may require further clinical study?  Proper labeling can help health care professionals to identify and implement the similarity and interchangeability parameters that FDA will ultimately use in making marketing approval decisions for generic biologic products. 
  4. Develop a long-term manufacturing strategy. Due to the highly technical aspects of producing proteins with consistent quality, purity and potency, it’s critical to consider manufacturing strategy early in order to see whether the desired ROI is feasible. Will the generic biologic product require specific excipients in its formulation in order to reduce the product’s temperature sensitivity and/or increase its shelf life? 

Generic biologic manufacturers must also develop market access strategies that incorporate reimbursement and pricing variables.  Many manufacturers assume that because they launch a generic version of a clinical product that third party payers including Medicare and for-profit insurers will be eager to provide coverage for their utilization. Yet, it is very likely that profit margins for generic biologic products will be substantially less than similar margins for generic pharmaceutical products.  In fact, according to a PricewaterhouseCoopers survey conducted among generic biologic product manufacturers in Europe, biosimilars generally offered only a 10% increase in profit margin as compared to the innovator version of the identical product. Therefore, generic biologic product manufacturers must set relatively higher list prices for their versions in order to achieve an acceptable return on investment. 

In summary, while the regulatory pathways for the commercialization of biosimilar products in the U.S. lag behind the establishment of such pathways in the European Union (EU) and Japan, generics manufacturers should already be taking action to prepare. We already know that high similarity and interchangeability will be the key parameters FDA will use in its evaluation of new biosimiilar products.  Given that biologic products are fundamentally different from pharmaceutical products, additional work by the bio-generics manufacturer on the pre-clinical side of product development, on product labeling and on manufacturing strategy, is warranted.  Just as importantly, a sound market access strategy that incorporates reimbursement and pricing considerations will be a significant driver in determining generic biologic product use by health care providers.      

Stephen Amato, PhD, MBA, RAC, is Managing Director, tJun17Life Sciences. He can be reached at 

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