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February 27, 2012

FDA Clarifies the Three Biosimilars Draft Guidance’s

Bio Similars
The Food and Drug Administration (FDA) presented an educational webinar on biosimilars, and provided an overview of the law, the FDA's progress in implementation, and updates on next steps. This webinar was recorded, and is now available on the FDA Biosimilars webpage.  The presentation was given by Dr. Rachel Sherman, Associate Director for Medical Policy at the Center for Drug Evaluation and Research (CDER).  

Biologics products are generally produced using a living system or organism.  Biologic products may be manufactured through biotechnology, derived from naturals sources, or produced synthetically. 

Here, you will find a link to the recorded webinar and the slides used in the presentation.  The presentation comes as FDA recently released three draft guidance documents regarding biosimilars. 


The Biologics Price Competition and Innovation Act (BPCI Act) was passed as part of the Affordable Care Act that President Obama signed into law on March 23, 2010. BPCI Act creates an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product [section 351(k) of the Public Health Service Act]. 

The Abbreviated New Drug Application (ANDA) process in section 505(j) was established through the 1984 Hatch-Waxman Amendments to the FFDCA thus creating the generic drug program for “small molecule” drugs.          

“Biological Product” in the Public Health Service Act (PHS Act) now includes “protein”:. . . a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product …applicable to the prevention, treatment, or cure of a disease or condition of human beings… 

Historically, some proteins have been approved as drugs under section 505 of the FD&C Act and other proteins have been licensed as biologics under section 351 of the PHS Act.  Under the BPCI Act, a protein, except any chemically synthesized polypeptide, will be regulated as a biological product. 

A 351(k) application must include information demonstrating that the biological product: 

  • Is biosimilar to a reference product;
  • Utilizes the same mechanism(s) of action for the proposed condition(s) of use -- only to the extent known for the reference product;
  • Condition(s) of use proposed in labeling have been previously approved for the reference product; and
  • Has the same route of administration, dosage form, and strength as the reference product.
  • that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and
  • there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. 

A 351(k) application must include information demonstrating biosimilarity based on data derived from: 

  • Analytical studies demonstrating that the biological product is “highly similar” to the reference product notwithstanding minor differences in clinically inactive components;
  • Animal studies (including the assessment of toxicity); and
  • A clinical study or studies (including the assessment of immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD)) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed.


FDA may determine, in its discretion, that an element described above is unnecessary in a 351(k) application. 

How close do the proposed biosimilar products compare to the reference product?  Advances in current state- of-the art analytical methods enhance the likelihood that a product will be highly similar to another product by better targeting the original product's physicochemical and functional properties. 

FDA said there is no “one size fits all approach” and that it will consider the “totality of the evidence,” which includes clinical, animal studies, clinical immunogenicity, clinical knowledge (i.e. post-market experience), human pharmacokinetics and pharmacodynamics (PK/PD) and structural and functional characterization.  

FDA scientists will evaluate the applicants integration of these various types of information to provide advice on scope and extent of development plan, and ultimately, an overall assessment that a biological product is (or is not) biosimilar to an approved reference product.  FDA stated that “interchangeable or interchangability means: 

  • the biological product is biosimilar to the reference product;
  • it can be expected to produce the same clinical result as the reference product in any given patient; and
  • for a product administered more than once, the safety and reduced efficacy risks of alternating or switching are not greater than with repeated use of the reference product without alternating or switching.

The presentation noted that the interchangeable product may be substituted for the reference product without the authorization of the health care provider.  FDA noted the current status of biosimilar sponsor proposals at the agency is: 

  • 35 Pre-IND meeting requests for proposed biosimilar products to 11 reference products
  • 21 Pre-IND sponsor meetings held to date
  • Development programs include:
    • Prospective development programs
      • “Global” programs
      • “Retrospective” development programs
        • Programs seeking licensure in US for similar biological products licensed outside the US
        • 9 INDs received 

FDA noted that the EU has approved 14 biosimilar products, with reference products being: Filgrastim, Epoetin, Somatropin. 

FDA Biosimilar Guidance 

The guidance reflects public input and questions received by FDA at regulatory meetings. The initial draft guidance is targeted to the highest priority issues and directed to clarifying expectations and providing predictability to sponsors initiating biosimilar development programs.  The initial scope scope of the guidance is 

  • Characterization of the proposed biosimilar product and the reference product (Scientific Considerations; Quality Considerations)
  • Data needed, such as PK/PD, preclinical, clinical (Scientific Considerations; Q&A)
  • Common questions regarding FDA’s initial interpretation of certain statutory terms and requirements (Q&A) 

Scientific Considerations Draft Guidance 

This guidance outlines FDA’s totality-of-the-evidence approach.  It describes the stepwise approach to evidence development, ensuring that development include only those elements necessary to address residual uncertainty.  The guidance document also introduces the concept that only after a thorough review of data from structural and functional analyses can FDA provide meaningful advice on scope and extent of necessary animal and human testing

It also explains general expectations for human clinical trials: 

  • At least one study will be expected (immunogenicity/PK-PD)
  • Comparative safety and effectiveness data may be necessary if residual uncertainty exists              

The Review Paradigm was also described in the presentation.  FDA traditionally relies on integrating various kinds of evidence in making regulatory decisions; a “totality of the evidence” approach can be applied to assessing biosimilars.  It is possible to exceed a current state-of-the-art analysis by evaluating more attributes and combination of attributes at greater sensitivities with multiple complementary methods; such fingerprint-like characterization may reduce further the scope and extent of additional animal and clinical studies.  

To provide the best advice on the scope of any required animal and human studies, FDA should already have completed a thorough review of data from structural and functional analyses. 

Quality Considerations Draft Guidance 

This guidance focuses on analytical studies that may be relevant to assessing the similarity between a proposed biosimilar protein product and a reference product.  General principles include: 

  • Importance of extensive analytical, physico- chemical and biological characterization
  • Advances in manufacturing science and Quality by Design approaches may facilitate “fingerprint”-like analysis
  • Identification of lots used in the various analyses for biosimilarity determination                 

Expanded Scope of a Biological Product 

The presentation defined “protein” as “any alpha amino polymer with a  specific defined sequence that is greater than 40 amino acids in size.  It also defined “chemically synthesized polypeptide” as  “any alpha amino acid polymer that (1) is made entirely by chemical synthesis; and (2) is less than 100 amino acids in size.”          

Transition Provisions

An application for a “biological product” must be submitted under section 351 of the PHS Act. There is an exception however: An application for a biological product may be submitted under the FD&C Act through March 23, 2020, if the product is in a product class for which there is already an approved application under the FD&C Act, unless there is another biological product licensed under section 351(a) of the PHS Act that could serve as its reference product.          

As of March 23, 2020, an application for a biological product approved under section 505 of the FD&C Act will be deemed a biologics license application (“BLA”) licensed under section 351 of the PHS Act. 

Non-U.S.-Licensed Comparator Products 

The PHS Act defines the “reference product” for a 351(k) application as the “single biological product licensed under section 351(a) against which a biological product is evaluated.” FDA evaluated public comments to FDA on: 1) whether comparative animal or clinical data with a non- U.S.-licensed product may support a demonstration of biosimilarity to a U.S.-licensed reference product; and 2) if so, what type of bridging data may be required.          

“Publicly-Available Information” 

Clarify statutory requirement for submission of “publicly-available information” regarding FDA’s previous determination of safety, purity, and potency.  “Action packages” for approved products available on FDA’s Web site. 


The 1st biological product to be licensed as interchangeable is granted a period of exclusivity. During the exclusivity period, a subsequent biological product relying on the same reference product cannot be licensed as interchangeable.  Exclusivity calculus is based on date of approval, date of first commercial marketing, and patent litigation milestones.          

Reference Product: A 351(k) application may not be submitted until 4 years after the date of first licensure of the reference product.  A 351(k) application may not be approved until 12 years after the date of first licensure of reference product.        

Pediatric Study Requirements 

Under the Pediatric Research Equity Act (PREA), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain a pediatric assessment to support dosing, safety, and effectiveness of the product for the claimed indication unless this requirement is waived, deferred, or inapplicable (see section 505B of FD&C Act). 

For purposes of PREA, a biological product determined to be: biosimilar is considered to have a “new active ingredient”;  interchangeable is not considered to have a “new active ingredient.”  FDA however, encourages applicants to submit plans for pediatric studies during the IND stage of product development.

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