Biosimilars Landscape and FDA Regulatory Expectations

James Harris

The Congressional Budget Office (CBO) has estimated that the United States could save $25 billion from the use of biosimilars over 10 years. In a general sense the term biosimilars refers to follow on biologics or follow on proteins that meet and or satisfy the very high standards often associated with comparability, i.e. safety, efficacy, purity, and potency already established by the approved originator biologic product.

The CBO assertion is further substantiated by Datamonitor, a well respected marketing analysis firm and according to their analysis the worldwide market for biosimilars will grow to $3.7 billion by 2015, from just $243 million in 2010, as more than 30 branded biologics with sales of $51 billion lose patent exclusivity.  These findings hasten biosimilar development and uptake due to the fiscal pressures being placed upon providers of healthcare to issue adequate healthcare at a reasonable cost.

By way of background President Obama on 23 March 2010 signed into law the Patient Protection and Affordable Care Act.  This Act amended the Public Health Service Act (PHS Act) creating an abbreviated approval pathway under section 351(k) for biological products that are demonstrated to be highly similar, i.e. biosimilar to or interchangeable with an FDA-licensed biological product, i.e. reference product.1

Within the Patient Protection and Affordable Care Act resides the Biologics Price Competition and Innovation Act of 2009 commonly known as the BPCI Act (351(k)) which is similar in nature to the Hatch-Waxman Act enabling abbreviated licensure of comparator products to the originator approved products.  In the case of Hatch-Waxman the target products are typically small molecular structures that are manufactured through chemical synthesis whereas under 351(K) large molecular structures will be evaluated. 

The abbreviated pathway for biological products presents a set of unique challenges because these substances are highly complex due to their scientific, technical and manufacturing development.  Specifically, these biological products are produced in living animal or plant cells or in a specified microorganism living system.

To be perfectly clear under section 351 (k) of the PHS Act (42 U.S.C. 262 (k)) added by the BPCI Act lays down the application requirements for a proposed biosimilar product and an application or a supplement for a proposed interchangeable product. 

According to the FDA the definition of a biosimilar as reported within Section 351 (i) is “that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinical meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product.”2

In order for a comparator to submit a 351 (k) application the submission must contain among other things:

  • Information demonstrating that the biological product is “biosimilar” to a reference product
  • This biosimilarity must be based upon data derived from analytical studies, animal studies, and a clinical study or studies unless the FDA determines in its discretion that certain studies are unnecessary

The FDA has also granted the provision of interchangeability.  This differs from the European Medicines Agency (EMA) whereby the EMA does not allow for the reference product being substituted and or interchanged without the intervention of the prescribing healthcare provider.

 In order to meet the higher standard of interchangeability the applicant must:

  • Meet the threshold of biosimilarity and
  • Demonstrate that the biological product, can be expected to produce  the same clinical result as the reference product in any given patient and
  • If the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy or alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.3

 The BPCI Act also includes:

  • A twelve (12) year exclusivity period from the date of first licensure of the reference product
  • A four (4) year exclusivity period from the date of first licensure of the reference product during which a product application may not be submitted.
  • An exclusivity period for the first interchangeable biological product during which a second or subsequent biological product may not be determined interchangeable with that of the reference product
  • An exclusivity period for certain biological products for which pediatric studies are conducted via a written request
  • A transition provision for biological products that have been or will be approved under section 505 of the FD&C Act prior to 23 March 2020 of the Affordable Care Act
  • A provision stating that an application (351 (k)) for a biosimilar contains a “new active ingredient” for purposes of the Pediatric Research Equity Act (PREA) of the FD&C Act4

Finally on 9 February 2012 the FDA issued three draft guidance documents on biosimilar product development to assist industry in developing such products in the United States.  After the sixty (60) day commentary period the FDA will issue its permanent biosimilar guidelines.  Upon issuance the USA will be on par with Europe and others that have put into place a framework for biosimilar adoption.


1.  FDA Biosimilars, 

2.  Scientific Considerations in Demonstrating Biosimilarity to a Reference Product,

3.  Quality Considerations in Demonstrating Biosimilarity to a Reference Product,

4.  Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009,

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