FDA’s biosimilar stakeholder submission roundup – Part III

In March 2010, the Biologics Price Competition and Innovation Act of 2009 (BPCIA) became law and established a legal pathway for the approval of biosimilar protein products in the U.S. While the BPCIA provided the overall framework, many of the details of the pathway were not particularized and the FDA was provided with wide discretion in administering the new approval pathway.

In February 2012, the FDA published three biosimilar draft guidance documents for industry. The draft guidance documents provided a 60 day period for stakeholders to provide comments. The FDA opened a docket for the each of the three draft guidance documents, FDA-2011-D-0602 (Quality Considerations), FDA-2011-D-0605 (Scientific Considerations) and FDA-2011-D-0611 (Questions and Answers).

The FDA received 44 public submissions on the Q&A draft guidance document from a wide array of stakeholders. This is the third in a series of posts that briefly summarizes the public submissions received by the FDA.

In Part I of the roundup, we previously summarized the submissions of BIO, Mylan, Amgen and Novartis. In Part II, we summarized the submissions of PhRMA, Watson, Genentech, Abbott and Merck.  In this post, we summarize the submissions of Biogen Idec, Boehringer Ingelheim, Allergan, Apotex and Pfizer.

Copies of the relevant submissions may be found by clicking on the submitter’s name, below.

Biogen Idec

Foreign Reference Product

  • comparison to a foreign-licensed reference product should only be used to corroborate data generated with the U.S.-licensed reference product

Trade Secrets / Confidential Information

  • concerned about the disclosure of the originator’s trade secrets and confidential information
  • FDA should clarify what information beyond that currently disclosed in an “action package” might be disclosed

Reference Product Exclusivity

  • 12 year exclusivity is presumptive and 351(a) applicants should not be required to provide a justification unless originator or a related entity is filing a supplement for a previously licensed product

Biosimilarity / Interchangeability

  • differences in formulation may put patients at unnecessary risk


  • biosimilar applicants should be required to conduct immunogenicity trials for each indication

Extrapolation of Indications

  • should only be allowed where the reference product’s pharmacology and mechanism of action is fully understood
  • a product that is biosimilar for one indication may not be biosimilar for a different indication

Definition of “protein (except any chemically synthesized polypeptide)”

  • 40 amino acid cut off is unnecessary

Boehringer Ingelheim


  • FDA’s approach should be guided by protecting patient safety
  • recommends that the FDA continue to use a public process to resolve important scientific and legal issues
  • class guidances would give the FDA more information relevant to ensuring safety and efficacy

“Highly Similar”

  • FDA should recommend that applicants minimize controllable differences to the extent possible
  • applicants should provide a scientific justification for changes in any controllable element
    • intentionally introducing changes in the biosimilar potentially increases the risk of clinically meaningful differences and could place patients at risk

Foreign Reference Product

  • comparative analytical, preclinical and clinical studies must use the FDA-licensed reference product
  • foreign reference product cannot, as a matter of law, serve as the reference product
  • in limited circumstances, data comparing the proposed biosimilar product to a foreign-licensed reference product may be used to corroborate biosimilarity

Trade Secrets / Confidential Information

  • maintaining the confidentiality of the originator’s trade secrets is critical to provide incentives for medical innovation
  • release of information beyond summary of clinical trial data could cause grave competitive harm to the reference product sponsor
  • FDA’s regulations regarding the confidentiality of information in BLAs should be updated to protect innovator data
    •  safety and efficacy data may not be released by the FDA until the statutory 12 year exclusivity (plus any pediatric exclusivity) expires
  • allowing abbreviated applications to be approved under 351(a) would constitute an impermissible taking under the fifth amendment of the U.S. Constitution and may conflict with U.S. treaty obligations

Reference Product Exclusivity

  • 351(a) applicants should not be required to provide a justification for the statutory 12 year exclusivity
  • FDA should define “other related entity” as soon as is possible
    • definition of “related” should focus on common ownership and control
  • any modification to the structure of the biological product that results in a change in safety, purity, or potency would result in a new 12 year exclusivity, including:
    • changes in amino acid sequence
    • differences due to post-translational processing
    • infidelity of transcription or translation
    • differences in glycosylation patterns
    • differences in tertiary structure
  • FDA should adopt an umbrella policy wherein supplements to a BLA are entitled to any remaining exclusivity of the initial 351(a) application
  • eligibility for exclusivity should be communicated to the 351(a) applicant as early as possible during the biologic product development process

Patent Certifications

  • biosimilar applicants should be required to certify compliance with the notice requirements of section 351(l)(2) of the PHSA


  • distinct non-proprietary names will be critical for preventing inappropriate substitution of non-interchangeable products
  • FDA should ensure that each biosimilar’s labeling and packaging uses a distinct non-proprietary name



  • largely directed to botulinum toxin serotype A (BOTOX)

Foreign Reference Product

  • comparative data employing a foreign-licensed reference product for the purpose of establishing biosimilarity should not be permitted

Indication Carve-Outs / Interchangeability

  • carve-out should only be available where the biosimilar is seeking approval for an indication that represents a substantial majority of the use of the reference product
  • biosimilar’s labeling should clearly state the indications for which the product is approved and the indications for which the product is not approved

Extrapolation of Indications

  • FDA should require the sponsor to demonstrate biosimilarity for every indication for which licensure is sought
    • particularly important for biologics that act locally

Units of Activity

  • supports FDA’s position that the total content of the biosimilar product must be expressed in the same units as that of the reference product



  • all biologics should be approved to the same standards of quality, safety, purity and potency

Clinical Trials

  • should only be required when necessary to show the outcome is as expected from analytical characterizations

Foreign Reference Product

  • FDA should not require clinical studies to be repeated with the US reference product if no clinically meaningful differences have been shown relative to the European reference product

Pediatric Studies

  • mandating pediatric testing across the board is inappropriate
    • once a product has been shown to be “highly similar” it is scientifically and often ethically inappropriate to mandate pediatric testing

Biosimilar Development

  • it is important to streamline the process of interactions between the FDA and the biosimilar applicant


  • it is not clear why statements that the product is approved as a biosimilar and that the product has/has not been determined to be interchangeable are required

351(a) vs. 351(k)

  •  the appropriate pathway for products that are not deemed suitable for the 351(k) pathway should be clarified


Biosimilarity / Interchangeability

  • FDA should take a position on interchangeability
  • seeks FDA’s comments on development plan seeking to establish biosimilarity and interchangeability in order to provide clarity on whether pediatric studies are required
  • can a biosimilar applicant submit a suitability petition for a change in strength, route of administration, or dosage form from the reference product?



  • supports, in large part, the positions of PhRMA and BIO

Pediatric Studies

  • requirement for pediatric studies should generally be waived for all biosimilars
  • if a high level of similarity in one or more adult populations was demonstrated there would generally be no reason for concern that biosimilarity would not also exist in pediatric populations