FDA’s biosimilar stakeholder submission roundup – Part IV

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In February 2012, the FDA published three biosimilar draft guidance documents for industry. The draft guidance documents provided a 60 day period for stakeholders to provide comments. The FDA opened a docket for the each of the three draft guidance documents, FDA-2011-D-0602 (Quality Considerations), FDA-2011-D-0605 (Scientific Considerations) and FDA-2011-D-0611 (Questions and Answers).

The FDA received 44 public submissions on the Q&A draft guidance document from a wide array of stakeholders.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 fourth 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 Part III, we summarized the submissions of  Biogen Idec, Boehringer Ingelheim, Allergan, Apotex and Pfizer.  In this post, we summarize the submissions of Momenta, Novo Nordisk, Bayer, Elan, Johnson & Johnson, Bristol-Myers Squibb, Teva and Bicon.

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

Momenta

Generally

• agrees with the FDA’s stepwise, flexible, product-specific approach
• agrees with the FDA’s “totality of the evidence” approach
• purpose of the exercise is to demonstrate biosimilarity not to independently establish safety and efficacy

“Highly Similar”

• strongly supports the FDA’s recognition that specific scientific methods for demonstrating biosimilarity and interchangeability may be waived
• demonstrating biosimilarity will require something more complex than assessing comparability (ICH Q5E)
• the FDA should not mandate specific methodologies, including PK/PD studies “as a scientific matter”
  • prospectively mandating certain types of requirements, in the absence of data, may undermine the 351(k) pathway
• extensive analytical “fingerprinting” can serve as a foundation for biosimilar and/or interchangeable biologic development programs
  • depending on the biosimilar applicant’s analytical data, clinical trials may be redundant, unnecessary, and arguably unethical to conduct

Foreign Reference Product

• the relevant scientific question is whether the foreign-licensed reference product is sufficiently similar to the US-licensed reference product
• supports the FDA’s requirement for bridging studies

Indication Carve-Outs

• carve-outs are essential because specific routes of administration, presentation or conditions of use may be patent protected
• carve-outs reflect the statutory intent that the FDA separate intellectual property clearance issues from regulatory approval

Interchangeability

• is concerned that the draft guidance may be interpreted to suggest that interchangeability can never be demonstrated in an initial 351(k) application

Novo Nordisk

Generally

• scientific principles should also apply to applications for follow-on versions of proteins approved under the Food, Drug and Cosmetic Act (FDCA)
• refers to PhRMA submissions for many topics

“Highly Similar”

• every biosimilar applicant should show that its product has the identical amino acid sequence as the reference product
  • should not allow N-terminal or C-terminal truncations or any product differences that were introduced by design
  • any difference in amino acid sequence should disqualify the proposed product from the 351(k) pathway
• FDA should not allow biosimilar applications where the biosimilar applicant cannot adequately characterize the properties of either the proposed biosimilar product or the reference product
• any change in delivery device or a container closure system should be supported by a robust data package
• Brand lot-to-lot variability should not impose a limitation on biosimilar variability

Non-Clinical Studies

• FDA should state that it expects comparative animal toxicity studies
• other nonclinical studies may be waived only if:
  • the impurity profile of the biosimilar is highly similar to that of the reference product; and
  • the same excipients are used in the biosimilar and reference product

Clinical Trials

• comparative PK and PD testing will always be necessary

Immunogenicity

• all applicants should investigate immunogenicity through at least one premarket clinical study
• FDA should exercise caution where the biosimilar has a lower immunogenicity than the reference product

Interchangeability

• is a higher standard than biosimilarity
• should be determined sequentially in relation to biosimilarity determination
• FDA should confirm that certain changes in delivery device or container closure system will preclude a finding of interchangeability

Indication Carve-Outs

• biosimilar’s package insert should prominently disclose the approved indications where only a subset of the reference product’s strengths, routes of administration, dosage forms, or conditions of use are sought

Naming

• FDA should require biosimilars to have unique non-proprietary names

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

• limiting the definition of protein to polypeptides having greater than 40 amino acids is not supported by the statute or any specific scientific literature
• protein should be defined by reference to its method of manufacture

Bayer

Interchangeability / Biosimilarity

• essential to the implementation of the new law that the FDA provide its current views on interchangeability
  • it is critical that the FDA fully reflect the high standard that Congress articulated for interchangeability
• FDA should act cautiously when approving a biosimilar product that has a different delivery device, container closure system or formulation
  • different presentation for the biosimilar product would result in new conditions of use

Indication Carve-Outs

• urges the FDA to act cautiously when approving a biosimilar for less than all of the reference product conditions
• FDA should not allow for the omission of a route of administration that is safer than the remaining routes of administration for a particular patient population

Biosimilar Development

• FDA should allow for input from other stakeholders, including patient groups regarding the requirements for biosimilar and interchangeable products

Reference Product Exclusivity

• no basis to require 351(a) applicant to request exclusivity

“Product Class”

• “product class” should be narrowly defined.

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

• “protein” should be defined to mean an alpha amino acid polymer with a specific defined sequence derived from source material, biological in nature and that relies on higher order structure for functionality
• “chemically synthesized polypeptide” should be defined to mean a linear chain of alpha amino acids that is made entirely by chemical synthesis and does not rely on higher order structure for functionality

Elan

Interchangeability / Biosimilarity

• data and information required by biosimilar applicant should always be greater than required in a comparability exercise for reference product manufacturing changes
• does not believe there are any cases where biosimilarity, particularly for a monoclonal antibody, can be established by analytical comparability alone
• interchangeability should be determined on a indication by indication basis
  • each interchangeable indication should be clinically tested
• lot-to-lot variability of the reference product should not be able to establish biosimilar specifications on the extremities of the ranges observed
• 351(k) pathway is not appropriate where the quality and characterization data of the reference product is not available in the public domain
• biosimilar products should have the same excipients, delivery device, container closure as the reference product
• interchangeability should not be allowed for monoclonal antibodies
  • monoclonal antibodies should be considered a separate group to less complex protein products

Extrapolation of Indications

• each interchangeable indication should be clinically tested

Johnson & Johnson

Generally

• patient welfare is the paramount consideration
• supports the stepwise and totality-of-the-evidence approaches proposed by the FDA
• current analytical methods may not be able to detect all relevant structural and functional differences between two proteins

“Highly Similar”

• more data and information will be needed to establish biosimilarity than is currently required in the comparability exercise for reference product manufacturing changes
• intentional differences between the biosimilar product and the reference product should be allowed only if they are minor, cannot be reasonably avoided, and a robust scientific justification is provided

Foreign Reference Product

• allowing biosimilarity to be determined based on a foreign reference product will add uncertainty
  • any comparative data involving a foreign reference product should generally be used only in a supportive role unless the biosimilar applicant can demonstrate that the US-licensed and foreign-licensed reference products were manufactured in the same facilities and using the same proprietary manufacturing processes and internal specifications

Extrapolation of Indications

• extrapolation of indications will often be risky and inappropriate
• guidance should identify indication-specific and patient-specific factors that could lead to the emergence of clinical differences in an indication not studied clinically
• uncertainty in the mechanisms of action should preclude extrapolation between indications

Immunogenicity

• final guidance document should state that at least one clinical study must directly compare the immunogenicity of the proposed biosimilar with that of the US-licensed reference product

Interchangeability

• at this stage it would be inappropriate or premature for the FDA to designate a biosimilar as interchangeable with its reference product
• a designation of interchangeability should only be available where the biosimilar meets the interchangeability standard in respect of every approved indication of the reference product
  • extrapolation of patient switching data between indications should not be permitted
• FDA should periodically reassess interchangeability to account for the impact of product drift

Naming

• distinct non-proprietary names for biosimilars are necessary

Reference Product Exclusivity

• requests clarification of what information the FDA would like innovators to include when requesting reference product exclusivity
• requests clarification of whether a supplemental application for a nonstructural change will benefit from the original BLA’s exclusivity under an “umbrella provision”
• requests clarification of “related entity” for the purposes of determining whether a supplement is entitled to a 12 year exclusivity period

351(a) v. 351(k)

• asks the FDA to inform stakeholders that they will not accept an application under 351(a) that is in reality a 351(k) application

Bristol-Myers Squibb

 Generally

• supports the comments made by BIO and PhRMA
• paramount concern should be patient welfare
• BPCIA should be interpreted in a way that is consistent with the law’s focus on maintaining incentives for biological innovation
• if a new biological product would need to be submitted as a full BLA it is inherently eligible for its own 12 year period of exclusivity

Teva

Generally

• scientific principles should follow the totality-of-evidence approach and should be based on case-by-case considerations
• all biologics should be approved to the same standards of quality, safety, purity and potency

Interchangeability / Biosimilarity

• interchangeability designation may be available upon first approval provided the requirements of interchangeability have been fulfilled
• suggests that the FDA avoid talking about higher standards for interchangeability

Immunogenicity

• Comparative clinical immunogenicity assessment should be used to confirm there are no major differences between the reference product and the biosimilar product
• differences in immune response may not be clinically relevant and may warrant a risk-based immunogenicity assessment strategy
  • other assessments of rare immunogenicity should be accomplished by a post approval commitment rather than a prior approval, comparative clinical study

Pediatric Studies

• requiring pediatric trials for a biosimilar product is unethical

Naming

• biosimilar products should share the same INN name as the reference product
  • traceability can be insured through unique NDC codes for every drug product in every batch

Biocon

Foreign Reference Product

• biosimilar application should be accepted with data from a foreign-licensed reference product manufactured in a facility inspected by regulatory authorities that has similar scientific and regulatory standards as the FDA

Interchangeability

• demonstrating biosimilarity with a foreign-licensed reference product should be adequate for claiming interchangeability

Pediatric Studies

• no additional pediatric studies should be mandated for interchangeable products

Labeling

• no different labeling requirements should be mandated for interchangeable products

Naming

• all approved biosimilars should have the same INN name as the reference product