FDA’s biosimilar stakeholder submission roundup – Part II

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In February 2012, the FDA published three biosimilar draft guidance documents for industry. The draft guidance documents provided a 60 day period for stakeholders to provide comments. The FDA opened a docket for the each of the three draft guidance documents, FDA-2011-D-0602 (Quality Considerations), FDA-2011-D-0605 (Scientific Considerations) and FDA-2011-D-0611 (Questions and Answers).

The FDA received 44 public submissions on the Q&A draft guidance document from a wide array of stakeholders.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 second in a series of posts that will briefly summarize the public submissions received by the FDA.

In Part I of the roundup, we previously summarized the submissions of BIO, Mylan, Amgen and Novartis. Today’s post summarizes the submissions of PhRMA, Watson, Genentech, Abbott and Merck.  Copies of the relevant  submissions may be found by clicking on the submitter’s name, below.

Pharmaceutical Research and Manufacturers of America (PhRMA)


  • 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, and that they provide a scientific justification for changes in controllable elements of the proposed biosimilar product
  • 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 a biosimilar applicants comparative studies
  • 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 by providing that 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, and adopt a definition of “related” focusing 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



  • supports a flexible approach

Foreign Reference Product

  • data generated with a foreign licensed reference product may be used to reduce the scope of clinical trials
  • sponsor must scientifically justify the use of  data derived from a foreign-licensed reference product and perform appropriate bridging studies
  • foreign-licensed reference products should be licensed from a highly regulated market with requirement comparable to those of the FDA

Clinical Trials

  • in all situations, unnecessary testing in animals is unwarranted
  • agrees that clinical studies will usually be required as part of the biosimilarity assessment
    • scope of clinical trial should be determined on a case-by-case basis
  • studies performed to evaluate clinical safety and effectiveness must be designed to reduce unwarranted and unethical human exposure wherever possible


  • demonstrating biosimilarity will require more information than the comparability exercise under ICH Q5E
    • biosimilar developer will have less experience predicting how changes to its process could affect its product


  • clinical evaluation of immunogenicity is a key element in the demonstration of biosimilarity
  • scope of biosimilar immunogenicity studies should not go beyond that which was required for the licensure of the reference product
  • in many cases, it may be more appropriate to perform post-market surveillance to monitor rare immune responses rather than to conduct a post-approval trial

Extrapolation of Indications

  • extrapolation provides an opportunity to reduce the requirement for duplicative and unethical clinical studies
  • biosimilar applicant must provide appropriate scientific justification for the extrapolation


  • biosimilars should be distinguished by unique non-proprietary names


  • has concerns that the “meet early and often” approach may increase development timelines unless meetings happen without undue delay

Reference Product Exclusivity

  • FDA should apply scientific discretion in determining if a second-generation biologic is entitled to a new statutory exclusivity period
  • statutory exclusivity for second generation products should only be available if
    • the second generation product is sufficiently differentiated from the previously approved product in terms of safety or potency; and
    • the second generation product is licensed under section 351(a) on the basis of a complete nonclinical and clinical development program


Foreign Reference Product

  • as a scientific matter, biosimilar applicants would generally be expected to provide adequate data or justification for the use of a foreign-licensed reference product to establish biosimilarity

Trade Secrets / Confidential Information

  • FDA should take all appropriate and required actions to ensure that originator’s confidential information is not disclosed to biosimilar applicants
  • FDA should take this opportunity to revise the existing regulations relating to the confidentiality of data and information in a BLA
  • releasable information should only provide a summary of the safety and efficacy data

Indication Carve-Outs / Interchangeability

  • FDA should include a new question and answer guidance document that addresses biosimilar promotion and advertising
  • it is essential that the FDA make clear that the misbranding prohibitions are appropriate to biosimilar products
  • agency should develop specific guidance on biosimilar labeling that addresses differences in presentation, routes of administration, conditions of use
  • FDA needs to focus on guidance development for the types of studies required to show interchangeability

Extrapolation of Indications

  • differences in immunogenicity in different patient populations should be addressed



  • supports comments made by BIO and PhRMA

Foreign Reference Product

  • even the most rigorous sought bridging study will not be able to show that the foreign reference product and the U. S.-licensed reference product are the same
  • statute does not allow for a comparison to a foreign-licensed reference product to establish biosimilarity
  • any data essential to the approval of the biosimilar applicant must use the U. S.-licensed reference product
  • in rare cases, the biosimilar applicant may be able to establish that the foreign-licensed product is the same as the U.S.-licensed product

Trade Secrets / Confidential Information

  • FDA cannot rely on non-public information about the U. S.-licensed reference product to reach any conclusion regarding sameness
  • FDA cannot use any non-public information from a 351(a) application when reviewing a biosimilar 351(k) application
    • FDA is free to consult the originators application to ensure patient safety
  • approval of any 351(a) application that makes reference to a previously-approved reference product would violate the fifth amendment of the U.S. Constitution
  • concerned about accidental disclosure of originator’s trade secrets and confidential information to the biosimilar applicant
    • employees who were significantly involved in the review of the reference product should not be involved in any biosimilar application review activities or any communication with the biosimilar applicant

Reference Product Exclusivity

  • FDA should take an approach to exclusivity that is objective, easy to apply, and consistent with the policy goals of exclusivity
  • “other related entity” should focus on whether the relevant applicants are under common ownership or control
  • exclusivity provisions does not allow the FDA to consider whether any change in the structure of a biological product is significant or whether the clinical profile is significantly different or superior
    •  any structural difference coupled with any clinical difference is sufficient to provide a 12 year exclusivity period
  • structural changes include heavy chain terminal sequences, glycan structure profiles, changes and glycosylation patterns
  • FDA should provide an initial answer on exclusivity early in the development process, immediately following the pre-IND meeting

Patent Certifications

  • biosimilar applicants should be required to certify compliance with the notice provisions of section 351(l)(2) of the PHSA.
  • FDA should refuse to file any biosimilar application that fails to include this certification

351(a) vs. 351(k)

  • FDA should refuse to file any 351(a) application that explicitly or implicitly relies on the FDA’s finding that another sponsors previously approved product is safe, pure and potent
  • application should to be filed under 351(k) if any of the following occurs:
    • it contains comparative analytical data
    • the proposed product has been approved as a biosimilar in another country
    • the analytical section of the application relies on a compendial or similar standard; or
    • most of the preclinical and clinical data are comparative


Off-Label Routes of Administration

  • a separate study should not be required to assess a route of administration that will not be registered

Foreign Reference Product

  • when scientifically justified, the acceptance of foreign data would reduce the unnecessary use of patients, minimize conduct of replicative trials and prevent the delay of bio similar products from reaching patients

Sample Retention

  • reserve samples should only be retained for pivotal bioequivalence PK/PD studies conducted with the US-licensed reference product
  • request flexibility in the 5X amount of product needed for release testing, noting that the availability of lots from wholesalers may be limited

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

  • should be defined as an amino acid polymer with a specific defined confirmation essential for its function
  • “Chemically synthesized polypeptide” should be any linear chain entirely made by chemical synthesis